Evidence Report/Technology Assessment 

Number 153 

Breastfeeding and Maternal and Infant Health 

Outcomes in Developed Countries 

Prepared for: 

Agency for Healthcare Research and Quality 

U.S. Department of Health and Human Services 

540 Gaither Road 

Rockville, MD 20850 

www.ahrq.gov

Contract No. 290-02-0022 

Prepared by: 

Tufts-New England Medical Center Evidence-Based Practice Center 

Boston, Massachusetts 

Investigators 

Stanley Ip, M.D., Project Leader 

Mei Chung, M.P.H. 

Gowri Raman, M.D. 

Priscilla Chew, M.P.H. 

Nombulelo Magula, M.D. 

Deirdre DeVine, M.Litt., Project Manager 

Thomas Trikalinos, M.D., Ph.D. 

Joseph Lau, M.D., Principal Investigator 

AHRQ Publication No. 07-E007 

April 2007 
This report is based on research conducted by the Tufts-New England Medical Center 

Evidence-based Practice Center (EPC) under contract to the Agency for Healthcare Research 

and Quality (AHRQ), Rockville, MD (Contract No. 290-02-0022). The findings and 

conclusions in this document are those of the author(s), who are responsible for its content, 

and do not necessarily represent the views of AHRQ. No statement in this report should be 

construed as an official position of AHRQ or of the U.S. Department of Health and Human 

Services. 

The information in this report is intended to help clinicians, employers, policymakers, and 

others make informed decisions about the provision of health care services. This report is

intended as a reference and not as a substitute for clinical judgment. 

This report may be used, in whole or in part, as the basis for the development of clinical 

practice guidelines and other quality enhancement tools, or as a basis for reimbursement and 

coverage policies. AHRQ or U.S. Department of Health and Human Services endorsement of 

such derivative products may not be stated or implied. 
ii

This document is in the public domain and may be used and reprinted without permission except 

those copyrighted materials noted for which further reproduction is prohibited without the 

specific permission of copyright holders. 

Suggested Citation: 

Ip S, Chung M, Raman G, Chew P, Magula N, DeVine D, Trikalinos T, Lau J. Breastfeeding and 

Maternal and Infant Health Outcomes in Developed Countries. Evidence Report/Technology 

Assessment No. 153 (Prepared by Tufts-New England Medical Center Evidence-based Practice 

Center, under Contract No. 290-02-0022). AHRQ Publication No. 07-E007. Rockville, MD: 

Agency for Healthcare Research and Quality. April 2007. 

No investigators have any affiliations or financial involvement (e.g., employment, consultancies, 

honoraria, or stock options, expert testimony, grants, or patents received or pending, or royalties) 

that conflict with material presented in this report. 
iii 

Preface 

The Agency for Healthcare Research and Quality (AHRQ), through its Evidence-Based 

Practice Centers (EPCs), sponsors the development of evidence reports and technology 

assessments to assist public- and private-sector organizations in their efforts to improve the 

quality of health care in the United States. The Office on Women’s Health, Department of Health 

and Human Services, requested and provided funding for this report. The reports and 

assessments provide organizations with comprehensive, science-based information on common, 

costly medical conditions and new health care technologies. The EPCs systematically review the 

relevant scientific literature on topics assigned to them by AHRQ and conduct additional 

analyses when appropriate prior to developing their reports and assessments. 

To bring the broadest range of experts into the development of evidence reports and health 

technology assessments, AHRQ encourages the EPCs to form partnerships and enter into 

collaborations with other medical and research organizations. The EPCs work with these partner 

organizations to ensure that the evidence reports and technology assessments they produce will 

become building blocks for health care quality improvement projects throughout the Nation. The 

reports undergo peer review prior to their release. 

AHRQ expects that the EPC evidence reports and technology assessments will inform 

individual health plans, providers, and purchasers as well as the health care system as a whole by 

providing important information to help improve health care quality. 

We welcome comments on this evidence report. They may be sent by mail to the Task Order 

Officer named below at: Agency for Healthcare Research and Quality, 540 Gaither Road, 

Rockville, MD 20850, or by e-mail to epc@ahrq.hhs.gov.

Carolyn M. Clancy, M.D. 

Director 

Agency for Healthcare Research and Quality 

Jean Slutsky, P.A., M.S.P.H. 

Director, Center for Outcomes and Evidence 

Agency for Healthcare Research and Quality 

Suzanne Haynes, Ph.D. 

Office on Women’s Health 

Department of Health and Human Services 

Beth Collins Sharp, Ph.D., R.N. 

Director, EPC Program 

Agency for Healthcare Research and Quality 

 Ernestine Murray, M.A.S., R.N. 

EPC Program Task Order Officer 

Agency for Healthcare Research and Quality 
iv

Acknowledgments 

 

 We acknowledge with appreciation the members of the Technical Expert Panel for their 

advice and consultation to the Evidence-based Practice Center (EPC) during preparation of this 

report. In designing the study questions and methodology at the outset of this report, the EPC 

consulted these technical and content experts. Broad expertise and perspectives are 

sought. Divergent and conflicted opinions are common and perceived as healthy scientific 

discourse that results in a thoughtful, relevant systematic review. Therefore, in the end, study 

questions, design and/or methodologic approaches do not necessarily represent the views of 

individual technical and content experts. 

Technical Expert Panel 

David Chelmow, M.D. 

Obstetrician-Gynecologist 

Tufts-New England Medical Center 

Tufts University School of Medicine 

Ronald E. Kleinman, M.D. 

Pediatric Gastroenterology and Nutrition 

Department of Pediatrics 

MassGeneral Hospital for Children 

Kathryn G. Dewey, Ph.D. 

Department of Nutrition 

University of California, Davis 

Michael Kramer, M.D. 

McGill University Faculty of Medicine 

Institute of Human Development, Child and Youth Health 

The Montreal Children's Hospital 

Gillman Grave, M.D. 

Endocrinology, Nutrition & Growth 

National Institute of Child Health and Human 

 Development 

Katy Lebbing, B.S., IBCLC, RLC 

Center for Breastfeeding Information 

La Leche League International 

Larry Grummer-Strawn, Ph.D. 

National Center for Chronic Disease Prevention 

 and Health Promotion 

Centers for Disease Control and Prevention 

Ardythe L. Morrow, Ph.D., M.Sc. 

Cincinnati Children's Hospital Medical Center 

Katherine E. Hartmann, M.D., Ph.D. 

Obstetrician-Gynecologist 

Vanderbilt University 

Representative, American College of 

 Obstetricians and Gynecologists

David Meyers, M.D. 

Center for Primary Care, Prevention, and Clinical 

 Partnerships, (CPPO) 

Agency for Healthcare Research and Quality 

Suzanne Haynes, Ph.D. 

Senior Science Advisor 

Office on Women’s Health 

U.S. Department of Health and Human Services 

Barbara L. Philipp, M.D. 

The Breastfeeding Center 

Boston Medical Center 

Jill Janke, RNC, D.NSc. 

University of Alaska 

Representative, Association of Women’s Health, 

 Obstetrical and Neonatal Nurses 

Lori Feldman-Winter, M.D., M.P.H., IBCLC, FAAP, 

FABM 

Robert Wood Johnson Medical School 

University of Medicine and Dentistry of New Jersey 

Representative, AAP and the Section on Breastfeeding 
v

Structured Abstract 

Objectives: We reviewed the evidence on the effects of breastfeeding on short- and long-term 

infant and maternal health outcomes in developed countries. 

Data Sources: We searched MEDLINE®, CINAHL, and the Cochrane Library in November of 

2005. Supplemental searches on selected outcomes were conducted through May of 2006. We 

also identified additional studies in bibliographies of selected reviews and by suggestions from 

technical experts. 

Review Methods: We included systematic reviews/meta-analyses, randomized and nonrandomized comparative trials, prospective cohort, and case-control studies on the effects of 

breastfeeding and relevant outcomes published in the English language. Included studies must 

have a comparative arm of formula feeding or different durations of breastfeeding. Only studies 

conducted in developed countries were included in the updates of previous systematic reviews. 

The studies were graded for methodological quality. 

Results: We screened over 9,000 abstracts. Forty-three primary studies on infant health 

outcomes, 43 primary studies on maternal health outcomes, and 29 systematic reviews or metaanalyses that covered approximately 400 individual studies were included in this review. We 

found that a history of breastfeeding was associated with a reduction in the risk of acute otitis 

media, non-specific gastroenteritis, severe lower respiratory tract infections, atopic dermatitis, 

asthma (young children), obesity, type 1 and 2 diabetes, childhood leukemia, sudden infant death 

syndrome (SIDS), and necrotizing enterocolitis. There was no relationship between breastfeeding 

in term infants and cognitive performance. The relationship between breastfeeding and 

cardiovascular diseases was unclear. Similarly, it was also unclear concerning the relationship 

between breastfeeding and infant mortality in developed countries. For maternal outcomes, a 

history of lactation was associated with a reduced risk of type 2 diabetes, breast, and ovarian 

cancer. Early cessation of breastfeeding or not breastfeeding was associated with an increased 

risk of maternal postpartum depression. There was no relationship between a history of lactation 

and the risk of osteoporosis. The effect of breastfeeding in mothers on return-to-pre-pregnancy 

weight was negligible, and the effect of breastfeeding on postpartum weight loss was unclear. 

Conclusions: A history of breastfeeding is associated with a reduced risk of many diseases in 

infants and mothers from developed countries. Because almost all the data in this review were 

gathered from observational studies, one should not infer causality based on these findings. Also, 

there is a wide range of quality of the body of evidence across different health outcomes. For 

future studies, clear subject selection criteria and definition of “exclusive breastfeeding”, reliable 

collection of feeding data, controlling for important confounders including child-specific factors, 

and blinded assessment of the outcome measures will help. Sibling analysis provides a method to 

control for hereditary and household factors that are important in certain outcomes. In addition, 

cluster randomized controlled studies on the effectiveness of various breastfeeding promotion 

interventions will provide further opportunity to investigate any disparity in health outcomes as a 

result of the intervention.
vi
vii 

Contents 

 

Executive Summary.....................................................................................................................1 

 

Evidence Report.........................................................................................................................11

 

Chapter 1. Introduction ................................................................................................................11 

 

Chapter 2. Methods......................................................................................................................13 

 Overview...............................................................................................................................13 

 Key Questions Addressed in This Report.............................................................................13 

 Definitions of Breastfeeding in This Report.........................................................................14 

 Literature Search Strategy.....................................................................................................14 

 Study Selection .....................................................................................................................15 

 Meta-Analysis.......................................................................................................................16 

 Grading of Studies Analyzed in This Report........................................................................17 

 Grading of Systematic Reviews/Meta-Analyses. .................................................................17 

 Grading of Individual Primary Studies in Updates and New Reviews.................................18 

 Reporting of the Evidence ....................................................................................................20 

 

Chapter 3. Results ........................................................................................................................21 

 Overview...............................................................................................................................21 

 Literature Search Results ......................................................................................................23 

 Organization of Results.........................................................................................................24 

 Part I. Term Infant Outcomes – Relationship of Breastfeeding to Outcomes .....................27 

 Acute Otitis Media........................................................................................................27 

 Atopic Dermatitis..........................................................................................................35 

 Gastrointestinal Infections ............................................................................................37 

 Lower Respiratory Tract Diseases................................................................................40 

 Asthma.................................................................................................. ....42 

 Cognitive Development in Terms Infants.....................................................................50 

 Obesity ..........................................................................................................................62 

 Cardiovascular Diseases ...............................................................................................68 

 Type 1 Diabetes ............................................................................................................75 

 Type 2 Diabetes ............................................................................................................81 

 Childhood Leukemia.....................................................................................................84 

 Infant Mortality.............................................................................................................90 

 Sudden Infant Death Syndrome (SIDS)........................................................................93 

 Part II. Preterm Infant Outcomes – Relationship with Human milk feeding........................98 

 Necrotizing Enterocolitis ............................................................................................98 

 Cognitive Development ..............................................................................................103 

 Part III. Maternal Outcomes – Relationship of Breastfeeding to Outcomes .........................111 

 Return to Pre-pregnancy Weight or Postpartum Weight Change...............................111 

 Type 2 Diabetes ..........................................................................................................119 
viii 

 Osteoporosis................................................................................................................124 

 Postpartum Depression ...............................................................................................130 

 Breast Cancer..............................................................................................................136 

 Ovarian Cancer ...........................................................................................................141 

 Other Research......................................................................................................................155 

 

Chapter 4. Discussion ..................................................................................................................157 

 Future Research ....................................................................................................................162 

 

References and Included Studies .................................................................................................165 

 

Acronyms and Abbreviations ......................................................................................................185 

Figures 

Figure 1. The relationship between breastfeeding and health outcomes in term infants – 

 meta-analysis results ..............................................................................................................21 

Figure 2. The relationship between exclusive breastfeeding and health outcomes in term 

 infants - meta-analysis results................................................................................................22 

Figure 3. The relationship between breastfeeding and maternal outcomes - meta-analysis 

 results .....................................................................................................................................23 

Figure 4. Primary studies available to assess the relationship between breastfeeding and 

 infant health outcomes ...........................................................................................................25 

Figure 5. Primary studies available to assess the relationship between breastfeeding and 

 maternal health outcomes ......................................................................................................26 

Figure 6. Meta-analysis of the association between breastfeeding and the risk of AOM 

 compared to exclusive bottle-feeding in cohort studies.........................................................30 

Figure 7. Meta-Analysis of prospective cohort studies of the association between asthma risk 

 and breastfeeding ≥ 3 months for children with positive family history of asthma or atopy 

 (excluding Wright 2001)........................................................................................................44 

Figure 8. Meta-Analysis of prospective cohort studies of the association between asthma risk 

 and breastfeeding ≥ 3 months for children with positive family history of asthma or atopy 

 (including Wright 2001) ........................................................................................................45 

Figure 9. Meta-Analysis of prospective cohort studies of the association between asthma 

 risk and breastfeeding ≥ 3 months for children without family history of asthma or 

 atopy.......................................................................................................................................45 

Figure 10. Random effects model of summary estimate evaluating the association of 

 breastfeeding and SIDS..........................................................................................................95 

Figure 11. Meta-Analysis of four RCTs on the effects of breast milk feeding and NEC 

 in preterm infants ...................................................................................................................100 

Figure 12. Meta-Analysis of case-control studies on the relationship between breastfeeding 

 and maternal ovarian cancer risk: ever breastfed versus never breastfed.............................143 

Figure 13. Meta-Analysis of case-control studies on the relationship between breastfeeding 

 and maternal ovarian cancer risk: breastfed less than 12 months (cumulative duration) 

 versus never breastfed............................................................................................................144 
ix 

Figure 14. Meta-Analysis of case-control studies on the relationship between breastfeeding 

 and maternal ovarian cancer risk: breastfed at least 12 months (cumulative duration) 

 versus never breastfed...............................................................................................145 

Tables 

 

Table 1. Summary of systematic review/meta-analysis on the relationship between 

 breastfeeding and acute otitis media (AOM).........................................................................31 

Table 2. Summary table for cohort studies on the relationship between breastfeeding and 

 acute otitis media ...................................................................................................................32 

Table 3. Summary of systematic review/meta-analysis on the relationship between 

 breastfeeding and the risk of developing atopic dermatitis ...................................................36 

Table 4. Summary of systematic review/meta-analysis on the relationship between 

 breastfeeding and gastrointestinal (GI) infection...................................................................39 

Table 5. Summary of systematic review/meta-analysis on the relationship between 

 breastfeeding and lower respiratory tract disease ..................................................................41 

Table 6. Summary of systematic review/meta-analysis on the relationship between 

 breastfeeding and asthma.......................................................................................................47 

Table 7. Summary of prospective cohort studies on the relationship between 

 breastfeeding and asthma.......................................................................................................48 

Table 8. Summary of systematic reviews/meta-analyses on the relationship of breastfeeding 

 and cognitive development ....................................................................................................54 

Table 9. Summary of studies on the relationship of breast milk feeding and cognitive 

 development...........................................................................................................................56 

Table 10. Summary of systematic reviews/meta-analyses on the relationship between 

 breastfeeding and overweight or obesity ...............................................................................66 

Table 11. Summary of systematic reviews/meta-analyses on the relationship between 

 breastfeeding and total cholesterol and low-density lipoprotein cholesterol.........................69 

Table 12. Summary table for systematic reviews/meta-analyses on the relationship between 

 breastfeeding in infancy and blood pressure levels later in life.............................................71 

Table 13. Summary of systematic review/meta-analysis on the relationship between 

 breastfeeding and long-term cardiovascular disease mortality..............................................74 

Table 14. Summary of systematic reviews/meta-analyses on the relationship between 

 breastfeeding and type 1 diabetes ..........................................................................................79 

Table 15. Summary of case-control studies on the relationship between breastfeeding and 

 type 1 diabetes........................................................................................................................80 

Table 16. Summary of systematic reviews/meta-analyses on the relationship between 

 breastfeeding and type 2 diabetes ..........................................................................................83 

Table 17. Combined SES-adjusted ORs of ALL for the three case-control studies rated as 

 good and fair methodological quality in the systematic review by Guise et al. (2005).........87 

Table 18. Summary of systematic reviews/meta-analyses on the relationship between 

 breastfeeding and childhood leukemia...................................................................................88 

Table 19. Summary of case-control study on the relationship between breastfeeding and 

 infant mortality.......................................................................................................................92 

Table 20. Summary of systematic review/meta-analysis on the relationship between 

 breastfeeding and Sudden Infant Death Syndrome (SIDS) ...................................................96 
x 

Table 21. Summary of case-control studies on the relationship between breastfeeding and 

 sudden infant death syndrome (SIDS) included in the meta-analysis ...................................97 

Table 22. Meta-Analysis of four RCTs on the effects of breast milk feeding and NEC in 

 preterm infants: Random Effects Model (D&L)....................................................................99 

Table 23. Summary of systematic review/meta-analyse on the relationship between breast 

 milk feeding and necrotizing enterocolitis (NEC) in preterm infants....................................101 

Table 24. Summary of studies on the relationship between breast milk feeding and 

 necrotizing enterocolitis (NEC) in preterm infants................................................................102 

Table 25. Summary of primary studies on the relationship of breast milk feeding and 

 cognitive development in preterm infants..............................................................................106 

Table 26. Summary of prospective cohort studies on the relationship between breastfeeding 

 and returning to pre-pregnancy weights ................................................................................114 

Table 27. Summary of prospective cohort studies on the relationship between breastfeeding 

 and postpartum weight/BMI changes ....................................................................................116 

Table 28. Summary of systematic review/meta-analyse on the relationship between 

 breastfeeding and maternal type 2 diabetes ...........................................................................122 

Table 29. Summary of studies on the relationship between breastfeeding and maternal 

 type 2 diabetes (NIDDM) ......................................................................................................123 

Table 30. Summary of case-control studies on the relationship between breastfeeding and 

 risk of fracture in post-menopausal women...........................................................................127 

Table 31. Summary of prospective cohort studies on the relationship between duration of 

 breastfeeding and the long-term changes of bone mineral density (BMD) or bone 

 mineral content (BMC)..........................................................................................................129 

Table 32. Summary of the studies on the relationship between breastfeeding and 

 postpartum depression ...........................................................................................................132 

Table 33. Summary of systematic reviews/meta-analyses on the relationship between 

 breastfeeding and the risk of breast cancer............................................................................139 

Table 34. Summary of case-control studies on the relationship between breastfeeding and 

 breast cancer...........................................................................................................................140 

Table 35. Summary of case-control studies on the relationship between breastfeeding and 

 maternal ovarian cancer .........................................................................................................147 

Table 36. Summary of case-control studies on the relationship between breastfeeding and 

 maternal ovarian cancer by menopausal status......................................................................151 

Table 37. Summary of case-control studies on the relationship between breastfeeding and 

 maternal ovarian cancer by histologic type ...........................................................................152 

Table 38. Summary of pooled-analysis of case-control studies on the relationship between 

 breastfeeding and ovarian cancer by population subgroups ..................................................154 
xi 

Appendixes 

Appendix A. MEDLINE® Search Strategy 

Appendix B. Sample data abstraction forms 

Appendix C. Evidence Tables 

Appendix D. List of Excluded Studies 

Appendix E. Peer Reviewers 

Appendixes and Evidence Tables are provided electronically at 

http://www.ahrq.gov/downloads/pub/evidence/pdf/brfout/brfout.pdf

1 

Executive Summary 

Introduction 

 The purpose of this report is to summarize the literature concerning the relationship of 

breastfeeding and various infant and maternal health outcomes. This report was requested by the 

Department of Health and Human Services (DHHS) Office on Women’s Health and was 

conducted through the Evidence-based Practice Center (EPC) program at the Agency for 

Healthcare Research and Quality (AHRQ). 

Methods 

Two key questions are addressed: 

1. What are the benefits and harms for infants and children in terms of short-term outcomes, 

such as infectious diseases (including otitis media, diarrhea, and lower respiratory tract 

infections), sudden infant death syndrome (SIDS) and infant mortality, and longerterm outcomes such as cognitive development, childhood cancer (including leukemia), 

type I and II diabetes, asthma, atopic dermatitis, cardiovascular disease (including 

hypertension), hyperlipidemia, and obesity, compared among those who mostly 

breastfeed, mostly formula feed, and mixed feed; and how are these outcomes associated 

with duration of the type of feeding? Do the harms and benefits differ for any specific 

subpopulations based on socio-demographic factors? 

2. What are the benefits and harms on maternal health short-term outcomes, such as postpartum depression and return to pre-pregnancy weight, and long-term outcomes, such as 

breast cancer, ovarian cancer, diabetes and osteoporosis, compared among breastfeeding, 

formula feeding, and mixed feeding, and how are these associated with duration of the 

type of feeding? Do the harms and benefits differ for any specific subpopulations based 

on socio-demographic factors? 

Approach to Evaluating the Literature 

 

 Inclusion Criteria. As it was not feasible to review the large number of primary studies that 

are relevant to all the outcomes of interest, we consulted the Office on Women’s Health and the 

technical expert panel (TEP) and developed an approach that capitalized on the existing large 

number of systematic reviews/meta-analyses. For outcomes of interest that have previously been 

reviewed systematically, we have summarized the findings from those reviews. For acute otitis 

media, childhood asthma, cognitive development, SIDS, infant mortality, NEC, maternal breast 

cancer, return to pre-pregnancy weight, and maternal type 2 diabetes, we have also updated those 

systematic reviews with data from primary studies published subsequent to those reviews. For 

outcomes that have not been previously evaluated systematically (osteoporosis, ovarian cancer, 

postpartum depression, infant mortality), we have reviewed those primary studies that met our 

inclusion criteria. Studies that examined only formula-fed infants were excluded. 
2 

Definitions of Breastfeeding. The majority of the studies did not distinguish between 

exclusive and partially breastfed infants, or explain the difference between “breastfeeding” and 

“feeding of expressed breast milk.” We elected to use the term “breastfeeding” for studies in fullterm infants and the term “human milk feeding” for studies in preterm infants. We elected to 

accept all definitions of “exclusive breastfeeding” as provided by the different study authors but 

qualified our conclusions with respect to those specific definitions. 

 Literature Search Strategy. Comprehensive literature searches of MEDLINE®, CINAHL, 

and the Cochrane Database of Systemic Reviews took place in November of 2005. Search terms 

included subject headings and text words relevant to breastfeeding and the different outcomes. 

Supplemental searches on selected outcomes were conducted through May of 2006. Other 

relevant studies were identified by technical experts or in bibliographies of selected reviews. 

 Specific Inclusion Criteria for Health Conditions Evaluated. We included systematic 

reviews, meta-analyses, observational studies, randomized controlled trials, and comparative 

studies that evaluated the effects or associations of breastfeeding on outcomes of interest. All 

studies must have either a comparator arm that evaluated formula feeding or a comparator arm 

that evaluated different durations of breastfeeding. Only studies conducted in developed 

countries were used in updates of systematic reviews/meta-analyses and de novo reviews of 

primary studies. 

Reporting of Evidence 

 Methodological Quality Grade of Individual Studies. We used a three category grading 

system (A, B, C) to denote methodological quality of each primary study. We did not evaluate 

the methodological quality of the individual studies in the systematic reviews/meta-analyses. 

A (good): Least bias and results are valid; a primary study that adheres mostly to the 

commonly held concepts of high quality 

B (fair/moderate): Susceptible to some bias, but not sufficient to invalidate the results; a 

primary study that does not meet all the criteria in category A 

C (poor): Significant biases that may invalidate the results; a primary study with serious 

errors in design, analysis or reporting 

 Methodological Quality Grade of Systematic reviews/Meta-analyses. We used a similar 

scheme as above for grading systematic reviews/meta-analyses. But we supplemented the 

scheme with the MOOSE guideline (standards for reporting for meta-analysis in observational 

studies in epidemiology) and an additional checklist of items that we devised to evaluate the 

quality of the systematic review of observational studies. Items in this checklist included 

questions on the following: appropriate search strategy; justification for inclusion/exclusion 

criteria for studies; description of well-defined population, intervention/exposure, comparator, 

outcomes and study designs; effort to minimize errors in data extraction; assessment of quality of 

individual studies; consideration on the effect of confounders; combinability of the data for 

meta-analysis; assessment of statistical and clinical heterogeneity; reporting accuracies; and 

appropriateness of the conclusions based on the reported data. 
3 

Results 

We screened over 9,000 abstracts. Forty-three primary studies on infant health outcomes, 43 

primary studies on maternal health outcomes, and 29 systematic reviews or meta-analyses that 

covered approximately 400 individual studies were included in this review. 

 The association studies of breastfeeding and health outcomes mostly presented results as odds 

ratios. To facilitate interpretation of the odds ratio, we chose to present these data as a reduction in 

relative risk, estimated as “(1 – odds ratio) x 100%,” along with the corresponding 95% confidence 

interval (CI).

Full term Infant Outcomes 

Acute Otitis Media. Our meta-analysis of five cohort studies of good and moderate 

methodological quality showed that breastfeeding was associated with a significant reduction in the 

risk of acute otitis media. Comparing ever breastfeeding with exclusive formula feeding, the risk 

reduction of acute otitis media was 23 percent (95% CI 9% to 36%). When comparing exclusive 

breastfeeding with exclusive formula feeding, either for more than 3 or 6 months duration, the 

reduction was 50 percent (95% CI 30% to 64%). These results were adjusted for potential 

confounders.

 Atopic Dermatitis. One good quality meta-analysis of 18 prospective cohort studies on full term 

infants reported a reduction in the risk of atopic dermatitis by 42 percent (95% CI 8% to 59%) in 

children with a family history of atopy and exclusively breastfed for at least 3 months compared with 

those who were breastfed for less than 3 months. The meta-analysis did not distinguish between 

atopic dermatitis of infancy (under 2 years of age) and persistent or new atopic dermatitis at older 

ages. It has been postulated that the diagnosis of atopic dermatitis in patients younger than 2 years of 

age could be attributed to infectious etiologies, which may be prevented by breastfeeding. However, 

a stratified analysis by duration of followup found the risk reduction from breastfeeding was similar 

in subjects with less than 2 years compared with more than 2 years of followup. 

 Gastrointestinal Infections. For non-specific gastroenteritis, one systematic review identified

three primary studies that controlled for potential confounders. These studies reported that there was 

a reduction in the risk of non-specific gastrointestinal infections during the first year of life in 

breastfed infants from developed countries. But a summary adjusted estimate taking into account 

potential confounders could not be determined because the studies did not provide usable quantitative 

data. However, a recent case-control study from England that took into account the role of potential 

confounders reported that infants who were breastfeeding had a 64 percent (95% CI 26% to 82%) 

reduction in the risk of non-specific gastroenteritis compared with infants who were not 

breastfeeding. 

 Lower Respiratory Tract Diseases. The summary estimate from a good quality meta-analysis 

of seven studies reported an overall 72 percent (95% CI 46% to 86%) reduction in the risk of 

hospitalization due to lower respiratory tract diseases in infants less than 1 year of age who were 

exclusively breastfed for 4 months or more. The results remained consistent after adjustment for 

potential confounders. 

 Asthma. The studies on asthma were equivocal. A previously published good quality metaanalysis reported a moderate protective effect and four recent primary studies reaching mixed 

conclusions, including two studies finding an increased risk of asthma associated with breastfeeding. 

We updated the meta-analysis with the new studies. Our analysis showed that breastfeeding for at 

least 3 months was associated with a 27 percent (95% CI 8% to 41%) reduction in the risk of asthma 
4 

in those subjects without a family history of asthma compared with those who were not breastfed. 

For those with a family history of asthma, there was a 40 percent (95% CI 18% to 57%) reduction in 

the risk of asthma in children less than 10 years of age who were breastfed for at least 3 months 

compared with those who were not breastfed. However, the relationship between breastfeeding and 

the risk of asthma in older children and adolescents remains unclear and will need further 

investigation. 

 Cognitive Development. One well-performed sibling analysis and three prospective cohort 

studies of full-term infants, all conducted in developed countries, adjusted their analyses specifically 

for maternal intelligence. The studies found little or no evidence for an association between 

breastfeeding in infancy and cognitive performance in childhood. Most of the published studies 

adjusted their analyses for socioeconomic status and maternal education but not specifically for 

maternal intelligence. For those studies that reported a significant effect after specific adjustment for 

maternal intelligence, residual confounding from other factors such as different home environments 

cannot be ruled out. 

 Obesity. Three meta-analyses of good and moderate methodological quality reported an 

association of breastfeeding and a reduction in the risk of obesity in adolescence and adult life 

compared with those who were not breastfed. One study reported the reduction in the risk of 

overweight/obesity in breastfeeders compared with non-breastfeeders was 24 percent (95% CI 14% 

to 33%); another study reported 7 percent (95% CI 1% to 12%). Both of these estimates took into 

account the role of potential confounders. Furthermore, they also showed that the magnitude of 

association decreased when more confounders were entered into the analyses. The third study used 

meta-regression and found a 4 percent reduction in the risk of being overweight in adult life for each 

additional month of breastfeeding in infancy. Overall, there is an association between a history of 

breastfeeding and a reduction in the risk of being overweight or obese in adolescence and adult life. 

One should be cautious in interpreting all these associations because of the possibility of residual 

confounding. 

 Risk of Cardiovascular Diseases. Results from two moderate quality meta-analyses concluded 

that there was a small reduction of less than 1.5 mm Hg in systolic blood pressures and no more than 

0.5 mm Hg in diastolic blood pressures among adults who were breastfed in their infancy compared 

with those who were formula-fed. The association weakened after stratification by study size, 

suggesting the possibility of bias in the smaller studies. 

 One meta-analysis of cohort and case-control studies reported that there was a reduction in total 

and LDL cholesterol levels by 7.0 mg/dL and 7.7 mg/dL, respectively, in adults who were breastfed 

during infancy compared with those who were not. However, these findings were based on data from 

adults with a wide age range. The analysis did not segregate the data according to gender and 

potential confounders were not explicitly analyzed. Detailed information (e.g., fasting or non-fasting) 

on the collection of specimen for cholesterol testing was not included. Because of these deficiencies, 

the correct characterization of a relationship between breastfeeding and adult cholesterol levels 

cannot be determined at this time. 

 One meta-analysis found little or no difference in all-cause and cardiovascular mortality between 

adults who were breastfed during infancy and those who were not. There were possible biases and 

limitations in the studies reviewed, however. Presence of statistical heterogeneity across studies 

suggests that it may not have been appropriate to combine estimates from individual studies into one 

summary estimate. Because of these reasons, no definitive conclusion could be drawn regarding the 

relationship between a history of breastfeeding and cardiovascular mortality. 

 In summary, the relationship between breastfeeding in infancy and the risk of cardiovascular 

diseases cannot be confidently characterized at this time and will need further investigation. 
5 

 Type 1 Diabetes. Two moderate quality meta-analyses suggest that breastfeeding for at least 3 

months reduced the risk of childhood type 1 diabetes compared with breastfeeding for less than 3 

months. One reported a 19 percent (95% CI 11% to 26%) reduction; the other reported a 27 percent 

(95% CI 18% to 35%) reduction. In addition, findings from five of six studies published since the 

meta-analyses reported similar results. However, these results must be interpreted with caution 

because of the possibility of recall biases and suboptimal adjustments for potential confounders in the 

studies. 

 Type 2 Diabetes. In one well-performed meta-analysis of seven studies of various designs, 

breastfeeding in infancy was associated with a 39 percent (95% CI 15% to 56%) reduced risk of type 

2 diabetes in later life compared with those who were not. However, only three of seven studies 

adjusted for all the important confounders such as birth weight, parental diabetes, socioeconomic 

status, and individual or maternal body size. Though the crude and adjusted estimates did not differ 

in these three studies, the lack of adjustments for potential confounders such as birth weight and 

maternal factors by all studies could exaggerate the magnitude of an association. 

 Childhood Leukemia. The published studies on childhood acute lymphocytic leukemia (ALL) 

were equivocal; a good quality meta-analysis reported a moderate protective effect from 

breastfeeding and the other good quality systematic review reached the opposite conclusion. We 

conducted a meta-analysis including only good and fair quality case-control studies identified in the 

systematic review, since the meta-analysis did not provide methodological quality grading of primary 

studies. We found breastfeeding of at least 6 months duration was associated with a 19 percent (95% 

CI 9% to 29%) reduction in the risk of childhood ALL. The previous meta-analysis also reported an 

association between breastfeeding of at least 6 months duration and a 15 percent reduction (95% CI 

2% to 27%) in the risk of acute myelogenous leukemia (AML). Overall there is an association 

between a history of breastfeeding for at least 6 months duration and a reduction in the risk of both 

leukemias (ALL and AML). 

 Infant Mortality. One study of moderate methodological quality evaluated the relationship 

between breastfeeding and infant mortality. The study reported a protective effect of breastfeeding in 

reducing infant mortality after controlling for some of the potential confounders. However, in 

subgroup analyses of the study, the only statistically significant association reported was between 

“never breastfed” and Sudden Infant Death Syndrome (SIDS) or the risk of injury-related deaths. 

Because of the limited data in this area, the relationship between breastfeeding and infant mortality in 

developed countries remains unclear. Further investigation is needed. 

 Sudden Infant Death Syndrome (SIDS). We conducted a meta-analysis by including only 

studies that reported clear definitions of exposure, outcomes, and results adjusted for well-known 

confounders or risk factors for SIDS. Our meta-analysis of seven case-control studies found that a 

history of breastfeeding was associated with a 36 percent (95% CI 19% to 49%) reduction in the risk 

of SIDS compared to those without a history of breastfeeding. 

Preterm Infant Outcomes 

Cognitive Development. No definitive conclusion can be made regarding the relationship 

between breast milk feeding and cognitive development in preterm infants. One meta-analysis 

reported a five points advantage in standardized mean score and one systematic review identified one 

primary study that reported an eight points advantage in IQ in preterm or low birth weight infants 

who received breast milk feeding. In three of four primary studies of moderate quality that controlled 

for either maternal education or maternal intelligence, the advantage from breastfeeding was reduced 

to a statistically non-significant level after adjustment. The roles of maternal intelligence and home 
6 

environment should be accounted for in future studies on breastfeeding and cognitive development. 

Keeping in mind that cognitive function measured at an early age is not necessarily predictive of later 

cognitive ability, one should also consider carefully the timing and the selection of appropriate 

testing instrument in future studies. 

 Necrotizing Enterocolitis (NEC). Our meta-analysis of four randomized controlled trials of 

breast milk versus formula in comparing the outcome of NEC demonstrated that there was a 

marginally statistically significant association between a history of breast milk feeding and a 

reduction in the risk of NEC (P = 0.04). The estimate of the reduction in relative risk ranged from 4 

percent to 82 percent. The absolute risk difference between the two groups was 5 percent. Because of 

the high case-fatality rate of NEC, this difference is a meaningful clinical outcome. The wide range 

of the estimate reflects the relatively small number of total subjects in the studies and the small 

number of events. One must also be cognizant of the heterogeneity underlying these trials in 

interpreting the findings of the meta-analysis. Examples of which included gestational age that 

ranged from 23 to more than 33 weeks; birth weight ranged from less than 1,000 g to more than 

1,600 g; and some trials included only “healthy” infants, while others included both “healthy” and 

“ill” infants. 

Maternal Outcomes 

Return to Pre-pregnancy Weight. Three moderate quality prospective cohort studies reported 

less than 1 kg weight change from pre-pregnancy or first trimester to 1 to 2 year postpartum period in 

mothers who breastfed. Results from four moderate quality prospective cohort studies showed that 

the effects of breastfeeding on postpartum weight loss were unclear. Results from all seven studies 

consistently showed that many factors other than breastfeeding had larger effects on weight retention 

or postpartum weight loss. Methodological challenges in these studies included the accurate 

measurement of weight change, adequate control for numerous covariables including the amount of 

pregnancy weight gain, and quantifying accurately the exclusivity and the duration of breastfeeding. 

 Maternal Type 2 Diabetes. Two large cohorts from a high quality longitudinal study of 150,000 

parous women in the United States examined the relationship between breastfeeding and the risk of 

maternal type 2 diabetes. In parous women without a history of gestational diabetes, each additional 

year of breastfeeding was associated with a 4 percent (95% CI 1% to 9%) reduced risk of developing 

type 2 diabetes in the first cohort and a 12 percent (95% CI 6% to 18%) reduced risk in the second 

cohort. In women with a history of gestational diabetes, breastfeeding had no significant effect on the 

already increased risk of diabetes. Because only nurses were included in the cohorts, generalization 

of findings to the rest of the population must be done with care. 

 Osteoporosis. There is little or no evidence from six moderate quality case-control studies for an 

association between lifetime breastfeeding duration and the risk of fractures due to osteoporosis. In 

two of three moderate or good quality prospective cohort studies using bone mineral density as a 

surrogate for osteoporosis, lactation does not appear to have an effect on long-term changes in bone 

mineral densities. The third study found a small decrease in the bone mineral contents in the distal 

radius with increased duration of breastfeeding, but no significant changes in bone mineral contents 

in the femoral neck or the trochanter. 

 Postpartum Depression. Four prospective cohort studies of moderate methodological quality 

reported on the relationship between a history of breastfeeding and postpartum depression. None of 

the studies explicitly screened for depression at baseline before the initiation of breastfeeding and 

none of them provided detailed data on breastfeeding. Three of the four studies found an association 

between a history of short duration of breastfeeding or not breastfeeding with postpartum depression. 
7 

The results were adjusted for socio-demographic and obstetric variables. More investigation will be 

needed to determine the nature of this association. It is plausible that postpartum depression led to 

early cessation of breastfeeding, as opposed to breastfeeding altering the risk of depression. Both 

effects might occur concurrently. 

 Breast Cancer. Two meta-analyses of moderate methodological quality concluded that there was 

a reduction of breast cancer risk in women who breastfed their infants. The reduction in breast cancer 

risk was 4.3 percent for each year of breastfeeding in one meta-analysis and 28 percent for 12 or 

more months of breastfeeding in the other. In addition, one of the two meta-analyses and another 

systematic review reported decreased risk of breast cancer primarily in premenopausal women. 

Findings from primary studies published after the meta-analyses concurred with the findings 

from the earlier meta-analyses. In summary, consistent evidence from these studies suggests that 

there is an association between breastfeeding and a reduced risk of breast cancer. 

 Ovarian Cancer. We reviewed 15 case-control studies that examined the relationship 

between breastfeeding and the risk of ovarian cancer, and performed meta-analyses in nine 

studies that adjusted for potential confounders. The overall result from the nine studies showed 

an association between breastfeeding and a 21 percent (95% CI 9% to 32%) reduction in the risk 

of ovarian cancer, compared to never breastfeeding. Because not all the studies reported similar 

comparisons of breastfeeding durations, we had to estimate the comparable risks in five studies. 

Excluding these five studies from the meta-analysis results in loss of statistical significance for 

this association. 

 There was indirect evidence for a dose-response relationship between breastfeeding and a 

reduced risk of ovarian cancer. Breastfeeding of more than 12 months (cumulative duration) was 

associated with a reduced risk of ovarian cancer, compared to never breastfeeding. The 12-month 

cutoff was arbitrary, and the odds ratios were estimated in half of these studies. 

 Overall, there is evidence to suggest an association between breastfeeding and a reduction in 

the risk of maternal ovarian cancer. Because of the aforementioned limitations, one must be 

cautious in interpreting this association. 

Discussion 

Limitations 

 With the availability of many published systematic reviews on breastfeeding, we used this 

literature as the evidence for a large number of outcomes, supplemented by updates of these 

systematic reviews with new primary studies. Even though we have assessed the reporting 

quality of these systematic reviews (using standards of reporting of systematic reviews of 

observational studies (MOOSE statement), and additional parameters that we devised), we 

cannot reliably know the validity of the reported summary data without knowing the details of 

the primary studies. It should also be stressed that a well-performed systematic review does not 

necessarily imply that the body of evidence for a particular outcome of interest is of high quality. 

Any systematic review is limited by the quality of the primary studies included in the review. 

Unless the method used to assess the quality of the primary studies is transparent and the details 

made available for examination, it would be difficult to reliably determine the validity of the 

conclusions. 
8 

 The breastfeeding literature is primarily comprised of observational studies, either cohort or 

case-control studies. There are a number of potential deficiencies related to the observational 

study designs that could limit the internal validity and the generalizability of the findings. Some 

of these potential deficiencies include (1) misclassification of exposure; (2) confounding from 

the process of self-selection; and (3) residual confounding. 

 We have summarized the effects of breastfeeding (or breast milk feeding) on a large number 

of infant and maternal outcomes. Some of the outcomes are well defined and specific (e.g., 

childhood acute lymphocytic leukemia, breast cancer); and some are not so well defined and 

non-specific (e.g., asthma, non-specific gastrointestinal infections). When the reported outcome 

is well defined and specific, it lends confidence that the effect reported is valid for that outcome. 

When the reported outcome is not well defined, one might have some reservation regarding the 

validity of the measured effect for that outcome. For all the above reasons, we find that there is a 

wide range of quality of evidence for the different outcomes examined in this review. 

 An important area of research that is not systematically reviewed in this report is the use of 

breastfeeding promotion intervention trial to measure health effects (this topic is not part of the 

scope of this report and it will be covered in a separate report). The best known of these types of 

studies is the Promotion of Breastfeeding Intervention Trial (PROBIT) conducted in the 

Republic of Belarus. Data from this study provided good evidence that breastfeeding is 

associated with a reduction in the risk of gastrointestinal infection and atopic dermatitis. 

 Lastly, the outcomes analyzed in this review represent only a portion of all possible health 

outcomes related to breastfeeding reported by investigators worldwide. To work within the 

constraints of resources, we relied on the advice from our panel of technical experts in finalizing 

the list of outcomes included in this review. Thus, some important outcomes (e.g., growth and 

nutrition) have, by necessity, not been included in this review. 

Future Research 

 Observational studies will remain the major source of information in this field. Clear subject 

selection criteria, adopting a common definition of “exclusive breastfeeding”, reliable collection 

of feeding data, specific and properly quantifiable outcomes of interest, controlling for important 

potential confounders including child-specific factors, and blinded assessment of the outcome 

measures will help immeasurably to improve the quality of these studies. 

 Sibling analysis provides a method to control for hereditary and household factors that are 

important in certain outcomes, provided that those factors are similar for the siblings of interest. 

Although such analysis may be less susceptible to confounders and effect modifiers that are 

shared by siblings, one must remember that it is not immune to biases. This method should be 

used when the appropriate data are available. 

 Cluster randomized controlled studies similar to the Belarus trial will provide understanding 

of the effectiveness of various breastfeeding promotion interventions. Any substantial 

differences in the degree of breastfeeding between the two groups as a result of the intervention 

will provide further opportunity to investigate any disparity in health outcomes between the two 

groups. 
Evidence Report 
11

Chapter 1. Introduction 

 

 The Department of Health and Human Services (DHHS) Office on Women’s Health has 

requested an evidence report from the Agency for Healthcare Research and Quality (AHRQ) 

through the Evidence-based Practice Center program (EPC) that would critically examine the 

literature concerning the relationship of breastfeeding and various infant and maternal health 

outcomes. EPC evidence reports summarize evidence addressing specific key questions; these 

reports do not make clinical practice or health policy recommendations. 

 Breast milk is the natural nutrition for all infants. According to the American Academy of 

Pediatrics (AAP), it is the preferred choice of feeding for all infants.1

 The goals of Healthy 

People 2010 for breastfeeding are an initiation rate of 75 percent and continuation of 

breastfeeding of 50 percent at 6 months and 25 percent at 12 months postpartum.2

 National 

Immunization Survey of U.S. children in 2005 (NIS 2005) indicated that 73 percent had ever 

been breastfed. The percentage of infants who continued to breastfeed to some extent is 39 

percent at 6 months and 20 percent at 12 months (www.cdc.gov/breastfeeding/data/NIS_data/ 

data_2005.htm). 

 In addition to providing essential nutrients to infants, benefits of breastfeeding for both 

children and their mothers have been reported. Reports of the benefits for children include 

decreases in incidence of otitis media and gastroenteritis,3 lower risk of obesity,4,5 and lower risk 

of asthma.6 Other benefits reported include decreased rates of sudden infant death syndrome, 

reduction in the incidence of type 1 and type 2 diabetes mellitus, certain types of cancer, and 

improved performance on certain tests of cognitive development.7

 Reported benefits for mothers who breastfed their infants include increased postpartum 

uterine activity (inferentially this would lead to reduced postpartum blood loss),8 greater weight 

loss postpartum compared with mothers who bottle-fed their infants,9 decreased incidence of premenopausal breast cancer10 and decreased incidence of ovarian cancer.11 

In 2000, the DHHS Office on Women’s Health, in cooperation with the Surgeon General of 

the United States and several governmental and non-governmental agencies, published the first 

departmental policy on breastfeeding, the HHS Blueprint for Action on Breastfeeding 

(www.womenshealth.gov). The DHHS Office on Women’s Health endorses the recommendation 

from the American Academy of Pediatrics (AAP), American Academy of Family Physicians 

(AAFP), American College of Obstetricians and Gynecologists (ACOG), Association of 

Women’s Health, Obstetrical, and Neonatal Nurses (AWHONN), Le Leche League 

International, National Medical Association (NMA), and many other health organizations, that 

mothers exclusively breastfeed for 6 months. The DHHS Office on Women’s Health has 

commissioned a review to systematically examine the evidence for the effects of breastfeeding. 

The DHHS Office on Women’s Health has also requested that the focus of the review be on 

studies from developed countries (i.e., “high income” classification by World Bank)∗ as the 

findings from those studies are deemed more directly applicable to population in this country. 

 As it is unethical to randomize subjects into breastfeeding versus non-breastfeeding groups 

(although there were some randomized controlled trials (RCTs) in the 1980s on preterm infants 

whose mothers desired not to breastfeed, their infants were randomized into those who received 

 

∗ http://web.worldbank.org/WBSITE/EXTERNAL/DATASTATISTICS/0,,contentMDK:20421402~pagePK:64133150~piPK:64133175~ 

theSitePK:239419,00.html#High_income
12

donor breast milk versus those who received preterm formula12,13), much of the evidence on the 

benefits of breastfeeding came from observational studies. Observational studies are subject to 

confounding. One of the well-known confounders in breastfeeding research is demographic 

difference between mothers who breastfeed and those who chose not to breastfeed due to selfselection. Consistent with previously reported data,14 NIS 2005 showed that mothers who 

breastfeed tend to be white (versus non-Hispanic black or African American), older, more 

educated, and in a higher socioeconomic stratum (cdc.gov/breastfeeding/data/NIS_data/ 

data_2005.htm). While it is possible to control for some of these demographic factors, it is not 

possible to control for behavioral or attitudinal factors intrinsic in the desire to breastfeed. Some 

authors have proposed strict standards in evaluating the quality of observational studies. These 

standards should include the quality of the feeding data, a clear definition of the outcome, the 

elimination of systematic differences in outcome assessment between comparison groups 

(detection bias), and the control of potential and well-known confounders. The feeding data 

should clearly define whether it was prospectively or retrospectively collected, whether there 

was a precise definition of exclusive breastfeeding, and whether the duration of breastfeeding 

was reported.15,16

 Large number of infant and maternal outcomes has been examined in relation to a history of 

breastfeeding. It was not feasible to review all possible outcomes in mothers and children for this 

report; we sought guidance from our panel of technical experts in the field of breastfeeding 

research in deciding on the specific outcomes to review. After taking into consideration the 

following factors: relevance and importance of outcome in a developed country, date (recent or 

old) of the last systematic review on the outcome, availability or non-availability of data from a 

developed country, consistency or inconsistency of outcomes in previously reported studies, and 

consideration of the possibility that breastfeeding may have potential harms as well as benefits, 

the following outcomes from developed countries have been designated for review: for term 

infants, infectious diseases (including otitis media, diarrhea, and lower respiratory tract 

infections), sudden infant death syndrome, infant mortality, cognitive development, childhood 

cancer (including leukemia), type 1 and 2 diabetes, asthma, atopic dermatitis, cardiovascular 

disease (including hypertension), hyperlipidemia, and obesity; for preterm infants, necrotizing 

enterocolitis (NEC) and cognitive development; for mothers, post-partum depression, return to 

pre-pregnancy weight, breast cancer, ovarian cancer, diabetes and osteoporosis. 

 It is also outside the scope of this report to examine the biological mechanisms underpinning 

the effects of breast milk and therefore, studies on individual components of breast milk will not 

be part of this report. Lastly, studies on the effectiveness of interventions to promote and support 

breastfeeding are not systematically covered in this review, as this topic will be reviewed for a 

subsequent report. However, there is good quality evidence to support that some of these 

interventions do lead to an increase in breastfeeding rates and also an improvement of certain 

health outcomes in the study populations. Details of one landmark study17 and its implications 

for future research in the study of the effects of breastfeeding will be discussed in some details in 

this report. 

 
13 

Chapter 2. Methods 

Overview 

 This evidence report on breastfeeding and health outcomes in infants and mothers is based on 

a systematic review of the literature. To identify the specific issues central to this report, the 

Tufts-New England Medical Center (Tufts-NEMC) Evidence-based Practice Center (EPC) held 

teleconferences with a panel of technical experts (TEP) and various stakeholders. A 

comprehensive search of the medical literature was conducted to identify studies addressing the 

key questions. Evidence tables of study characteristics and results were compiled, and the 

methodological quality of the studies was appraised. Study results were summarized with 

qualitative reviews of the evidence, summary tables, and quantitative summary data, when 

appropriate. 

 A number of individuals and groups supported the Tufts-NEMC EPC in preparing this report. 

The TEP served as our science partner. Technical experts and representatives from the Agency 

for Healthcare Research and Quality (AHRQ), DHHS Office on Women’s Health, The National 

Institute of Child Health and Human Development (NICHD), Centers for Disease Control and 

Prevention (CDC), American Academy of Pediatrics (AAP), American College of Obstetrics and 

Gynecology (ACOG), Association of Women’s Health, Obstetrics and Neonatal Nurses 

(AWHONN), and La Leche League worked with the EPC staff to refine key questions, identify 

important issues, and define parameters for literature review in this report. 

 In the early phase of exploring the literature available for this report, it was soon discovered 

that there was a large number of primary studies and systematic reviews/meta-analyses on the 

various outcomes of interest. As it was not feasible to review all the primary studies addressing 

the outcomes of interest, therefore, in consultation with the Office on Women’s Health and the 

TEP, we developed an approach that capitalized on the existing systematic reviews/metaanalyses. For outcomes of interest that had previously been reviewed systematically, we assessed 

the quality of those reviews and summarized their findings. For selected infant (necrotizing 

enterocolitis, cognitive development, acute otitis media, asthma, type 1 and 2 diabetes, SIDS) 

and maternal (weight changes, type 2 diabetes, breast cancer) outcomes, in addition to reporting 

on the existing systematic reviews, we also updated them by summarizing the relevant primary 

studies that were published after those reviews. For outcomes of interest (osteoporosis, ovarian 

cancer, postpartum depression, infant mortality) that had not been reviewed systematically, we 

reviewed all the relevant primary studies that met our inclusion criteria. 

Key Questions Addressed in This Report 

 Two key questions are addressed in this report. Question 1 pertains to infant outcomes and 

question 2 pertains to maternal outcomes. The key questions are: 

1. What are the benefits and harms for infants and children in terms of short-term outcomes, 

such as infectious diseases (including otitis media, diarrhea, and lower respiratory tract 

infections), sudden infant death syndrome and infant mortality, and longer-term outcomes 

such as cognitive development, childhood cancer (including leukemia), type 1 and 2 

diabetes, asthma, atopic dermatitis, cardiovascular disease (including hypertension), 

hyperlipidemia, and obesity, compared among those who mostly breastfeed, mostly 
14 

formula feed, and mixed feed; and how are these outcomes associated with duration of 

the type of feeding? Do the harms and benefits differ for any specific subpopulations 

based on socio-demographic factors? 

2. What are the benefits and harms on maternal health short-term outcomes, such as postpartum depression and return to pre-pregnancy weight, and long-term outcomes, such as 

breast cancer, ovarian cancer, type 2 diabetes mellitus and osteoporosis, compared among 

breastfeeding, formula feeding, and mixed feeding, and how are these associated with 

duration of the type of feeding? Do the harms and benefits differ for any specific 

subpopulations based on socio-demographic factors? 

It should be emphasized that the focus of this review is on the effects of breast milk feeding, 

not formula feeding. However, many studies did not distinguish between exclusive and partially 

breastfed infants; presumably, some of the effects reported from observational studies were from 

infants who received both breast milk and formula milk feedings. Studies that examined only 

formula fed infants were not included in this report. Lastly, studies on infant and maternal health 

outcomes of interventions to promote and support breastfeeding were not systematically covered 

in this review as that subject will be covered in a separate report. However, our panel of 

technical experts felt that the study of breastfeeding promotion in infants from Belarus17 was a 

landmark study and offered new directions into research on effects from breast milk that it 

warrants discussion in this report. The details of that study are described in the section Other 

Research in the results chapter. 

Definitions of Breastfeeding in This Report 

 None of the studies in this review explicitly examined the difference between “breastfeeding” 

an infant (infant suckling at her/his mother’s nipple) and “feeding of expressed breast milk” to an 

infant. To distinguish between the two forms of feedings, we elected to use the term 

“breastfeeding” when the studies concerned primarily full-term infants (presumably they were, 

indeed, breastfed) and the term “breast milk feeding” when the studies concerned primarily 

preterm infants (as most of them received breast milk initially either by gavage- or by bottlefeeding). For term infants, “bottle-feeding” is used synonymously with “formula feeding.” 

 Definitions of “exclusive breastfeeding” varied widely in the literature. They ranged from 

“no supplement of any kind including water while breastfeeding” to “occasional formula is 

permissible while breastfeeding.” We elected to accept all definitions of “exclusive 

breastfeeding” as provided by the different study authors, but we qualified our findings by the 

details regarding those definitions. 

Literature Search Strategy 

 We conducted a comprehensive literature search to address the two key questions. The EPC 

used the Ovid search engine to conduct searches on the MEDLINE® database, CINAHL 

database, and the Cochrane Database of Systemic Reviews. A wide variety of search terms were 

used to capture the many potential sources of information related to the myriad of different 

outcomes (see Appendix A).*

 But the different outcomes were always searched in conjunction 

 

* Appendixes and Evidence Tables cited in this report are provided electronically at http://www.ahrq.gov/clinic/tp/ brfouttp.htm 
15 

with the following: “breastfeeding,” “breast milk feeding,” “breast milk,” “human milk,” 

“nursing”, and “lactation”. Literature search of the outcomes alone without references to breast 

milk feeding was not conducted. The search included citations from 1966 to November of 2005. 

Updated searches on selected outcomes took place in April and May of 2006. We also 

supplemented our computer search by examining the bibliographies of the review articles. We 

also included articles suggested by reviewers, provided that the articles met the inclusion criteria 

for this review. For outcomes that were not slated for updates, additional articles suggested by 

reviewers were also included as an addendum if they provided useful information. We did not 

make efforts to identify unpublished studies. 

Study Selection 

Selection of Outcomes for This Review 

 The TEP offered advice on selection of outcomes for review. Final selection of the list of 

outcomes for review took into account the following factors: the importance of the outcome, 

whether a systematic review of the outcome has previously been reported from a developed 

country, whether the existing systematic review of the outcome is outdated, whether the 

relationship between breastfeeding and the outcome is thought to be equivocal, whether a large 

number of primary studies has been published recently on the outcome, and the total number of 

outcomes that could be adequately reviewed for this report given the time constraint. 

 We included the following outcomes in this report: 

Term infant outcomes: acute otitis media, hospitalization for lower respiratory tract infection, 

gastrointestinal infection, hypertension, cardiovascular diseases, hyperlipidemia, asthma, atopic 

dermatitis, type 1 and 2 diabetes, obesity, sudden infant death syndrome (SIDS), infant mortality, 

cognitive development, and childhood cancer (including leukemia) 

Preterm infant outcomes: necrotizing enterocolitis (NEC) and cognitive development 

Maternal outcomes: maternal weight changes, breast cancer, ovarian cancer, post-partum 

depression, osteoporosis, and type 2 diabetes 

Abstract Screening 

 All abstracts identified through the literature search were screened. At this stage, eligible 

studies included all English language primary experimental or observational studies that reported 

any health outcomes in human subjects in relation to a history of breast milk feeding. As the 

inclusion criteria were broad at this stage, the abstracts rejected at this stage did not undergo a 

second rescreening process. Abstracts that were accepted at this stage were examined a second 

time by different reviewers and categorized into the different outcomes of interest. 

Full Article Inclusion/Exclusion Criteria 

 Articles that passed the abstract screening process were retrieved and the full articles were 

reviewed for eligibility. Full articles were examined only once unless the articles were equivocal 

for inclusion or exclusion. In that event, the article in question was screened again by a different 

reviewer and a consensus was reached after discussion with the first reviewer. 
16 

 Because the outcomes selected ranged from very broad topic with common occurrence (e.g., 

non-specific gastrointestinal infection) to a narrowly focused topic with relatively few 

occurrences (e.g., SIDS), the types of studies available for each outcome varied widely in the 

distribution of study designs, sample sizes, and quality of breastfeeding data, it was not possible 

(nor desirable) to design a strict set of inclusion and exclusion criteria that would be applicable to 

all outcomes. Therefore, additional inclusion/exclusion criteria germane to the specific outcome 

were also described in the Results section under each outcome. 

 

General inclusion criteria for the studies are as follow: 

Study Design. Systematic reviews, experimental (randomized controlled trials) and observational 

studies (prospective cohort and case-control studies only) 

Population. Healthy term infants in developed countries; preterm infants in developed countries 

(for NEC and cognitive development); healthy mothers in developed countries 

Intervention/Exposure. Breastfeeding, breast milk feeding (maternal term and preterm milk, 

banked term and preterm milk, fortified or unfortified), exclusive or mixed feeding 

Comparator. Formula feeding (preterm or term formula, fortified or unfortified) 

Data Extraction and Analysis 

 For those outcomes that have been subjected to a systematic review/meta-analysis, we 

summarized their results into our report. In addition to the results from the systematic reviews, 

we have also extracted and summarized the relevant data from primary studies that were 

published after the latest search dates of the reports for the following infant and maternal 

outcomes: acute otitis media, childhood asthma, cognitive development, SIDS, infant mortality, 

NEC, and maternal breast cancer. 

 For systematic reviews/meta-analyses that reported data from both developed and developing 

countries, we reported only those results pertaining to developed countries, if the reported data 

permitted us to do so. In those instances where that were not possible, we noted that fact as a 

limitation of our findings. 

 For outcomes that have multiple systematic reviews, we noted the overlapping studies and 

examined whether their findings were interpreted similarly or differently across reviews and 

reported our analyses. 

 For NEC, maternal weight changes, and acute otitis media, in order to better clarify the 

overall findings, we also extracted relevant data from the primary studies cited in the systematic 

reviews and combined them with data from the primary studies that were published after the 

latest search dates of the reports and reanalyzed the data. 

 For the remaining included outcomes, we extracted and summarized the relevant data from 

the primary studies. 

 Data forms were developed separately for extraction of systematic reviews/meta-analysis and 

primary studies. For systematic reviews/meta-analysis, items extracted were: databases searched, 

study design, population characteristics, descriptions of intervention/exposure, models used for 

meta-analysis, results, and authors’ conclusions. We reported the estimates in the meta-analyses. 

We also reported any attempt by the authors of the meta-analyses to explore heterogeneity using 

sub-group analyses or meta-regression. For primary studies, items extracted were: study design, 

population characteristics, eligibility criteria, descriptions of intervention/exposure, any 

adjustments for confounders, and results. 
17 

Meta-Analysis 

 We used meta-analysis to expand on the individual studies’ findings, if it was appropriate 

and feasible to do so. Minimal criteria for meta-analysis are comparable groupings, similar study 

designs, and quantifiable outcome data. Secondary criteria for consideration of meta-analysis are 

similar study quality, similar statistical adjustment of outcomes, and other factors. Before 

combining the reported odds ratios or risk ratios reported in the individual studies from the 

previous meta-analysis with the estimates from the updated primary studies into a new summary 

odds ratio or risk ratio, we verified the previous reported odds ratios or risk ratios by examining 

the data from the original studies. 

 We used the DerSimonian and Laird’s random effects model for all meta-analyses.18 The 

random effects model assigns a weight to each study based both on the individual study variance 

and the between-study heterogeneity. Compared with the fixed effect model, the random effects 

model is more conservative in that it generally results in broader confidence intervals when 

between-study heterogeneity is present. We tested for heterogeneity using Cochran’s Q and 

assessed its extent with I2, which evaluates the proportion of between study variability that is 

attributed to heterogeneity rather than chance.19,20 Intercooled Stata 8.2 was used for the 

calculations and graphics. 

Grading of Studies Analyzed in This Evidence Report 

 Studies accepted in evidence reports have been designed, conducted, analyzed, and reported 

with various degrees of methodological rigor and completeness. Deficiencies in any of these 

processes may lead to biased reporting or interpretation of the results. While it is desirable to 

have a simple evidence grading system using a single quantity, the quality of evidence is multidimensional. A single metric cannot adequately capture information needed to interpret a clinical 

study. However, grading of information can help the reader to interpret the studies properly. 

Grading of Systematic Reviews/Meta-Analyses 

 We assessed the methodological quality of studies based on predefined criteria. For the 

assessment of systematic reviews, the criteria for methodological quality was based on the 

QUOROM guidelines for meta-analyses and systematic reviews of RCTs (a checklist organized 

into 21 headings and subheadings for the preferred way to present the abstract, introduction, 

methods, results, and discussion sections of a report of a meta-analysis),21 and reporting 

guidelines for meta-analysis in observational studies in epidemiology (MOOSE) (a checklist for 

the specifications for presenting background, search strategy, methods, results, discussion, 

conclusion, and assessment of quality of individual studies and bias (e.g., publication bias)a).22

As the QUOROM and the MOOSE statements were primarily concerned with the reporting 

standards of the reviews, we have also supplemented those criteria with our own checklist of 

items designed to evaluate the quality of the systematic review of observational studies (see 

Appendix Bb

 for details). Items in this checklist consisted of questions on appropriate search strategy; 

 

a

 Publication bias refers to selective publication of studies according to results. When studies with non-significant or negative 

results are not published, the available studies may overestimate the effect. 

b

 Appendixes and Evidence Tables cited in this report are provided electronically at http://www.ahrq.gov/clinic/tp/ brfouttp.htm. 
18 

justification for inclusion/exclusion criteria; how well-defined were the population, intervention, 

comparator, outcomes and study design; effort to minimize errors in data extraction; assessment of 

individual study quality; consideration on the effect of confounders; combinability of the data for 

meta-analysis; assessment of statistical and clinical heterogeneity; reporting accuracies; and 

appropriateness of the conclusions based on the reported data. 

 We applied a three category summary grading system (A, B, C) to each systematic review/metaanalysis: 

A (good) 

 Category A studies have the least bias and results are considered valid. A study that adheres 

mostly to the commonly held concepts of high quality including the following: a rigorously 

conducted systematic review or meta-analysis; clear description of the population, setting, 

interventions and comparison groups; clear description of the content of the comparison 

groups; appropriate measurement of outcomes; appropriate statistical assumptions and 

analytic methods and reporting; appropriate consideration and adjustment for potential 

confounders; rigorous assessment of individual study quality; no reporting errors; and wellreasoned conclusions based on the data reported. 

B (fair/moderate) 

Category B studies are susceptible to some bias, but not sufficient to invalidate the results. 

They do not meet all the criteria in category A because they have some deficiencies, but none 

of which are likely to cause major biases. The study may have suboptimal adjustment for 

potential confounders. The study may also be missing information, making it difficult to 

assess limitations and potential problems. 

C (poor) 

Category C studies have significant biases that may invalidate the results. The study either 

did not consider potential confounders or did not adjust for them appropriately. These studies 

have serious errors in design, analysis or reporting; have large amounts of missing 

information, or discrepancies in reporting. 

It should be noted that while we assessed the methodological quality of the systematic reviews or 

meta-analyses, it was not possible to evaluate the quality of the primary studies included in those 

reviews/analyses, as we did not examine those studies first hand. For systematic reviews/metaanalyses that had equivocal grading between moderate and poor, the results and the reasons for the 

initial grade assignments were presented to the entire group of project investigators and the final 

grades were adjudicated. 

Grading of Individual Primary Studies in Updates and 

New Reviews 

A well-performed RCT with proper randomization, allocation concealment, clear definitions of 

breastfeeding exposure compared with non-breastfeeding, and blinded assessment of outcomes will 

yield the best evidence in supporting the causality of breast milk in affecting health outcomes. 

But with the recognized benefits of breast milk, this approach is ethically not feasible. Other 

types of studies involve following the health outcomes from randomization of intervention to 

promote and support breastfeeding (e.g., Belarus study17), this type of study will yield indirect 

evidence for the relationship between breastfeeding and health 
19 

outcomes provided that there is a differential effect from the intervention on breastfeeding rates 

between the comparison groups. Prospective observational cohort studies with proper adjustment 

of potential confounders provide the bulk of data in this field. However, the possibility of 

residual confounding that could explain the observed association between breastfeeding and the 

specific health outcomes can never be completely ruled out. Case-controlled design is an even 

less attractive option because of the concern for case selection bias and suboptimal matching to 

control subjects. 

 For the assessment of RCTs, the criteria were based on the CONSORT statement for 

reporting RCTs (a checklist with specifications for reporting all aspects of a trial).23,24 We mainly 

considered the methods used for randomization, allocation concealment, and blinding as well as 

the use of intention-to-treat analysis, the report of well-described valid primary outcomes, and 

the dropout rate. For non-randomized trials, we used the report of eligibility criteria and assessed 

the adequacy of controlling for differences between comparative groups in terms of baseline 

characteristics and prognostic factors. We also considered the report of intention-to-treat 

analysis, and the crossovers when so designed, as well as important differential loss to followup 

between the comparative groups or overall high loss to followup. The validity and the adequate 

description of outcomes and results were also assessed. For the assessment of prospective 

cohorts and case-control studies (cross-over design and retrospective cohort studies were 

excluded from this review), we used a rating checklist largely based on the Newcastle-Ottawa 

Quality Assessment scales for cohort and case-control studies 

(www.ohri.ca/programs/clinical_epidemiology/oxford.htm). Items assessed included selection of 

cases and controls or cohorts, comparability, information concerning exposure/intervention, 

consideration for potential confounders, and percentage of withdrawals or dropouts. In particular, 

we paid close attention to the quality of the breastfeeding data, whether they were obtained 

prospectively or by retrospective recall, whether a distinction was made between exclusive and 

partial breastfeeding, and whether the duration of breastfeeding was reported. We also paid close 

attention to consideration of and appropriate adjustment for potential confounders. 

 We applied a three category summary grading system (A, B, C) to each study. This system 

defines a generic grading system that is applicable to each type of study design including 

randomized controlled trials, cohort, and case-control studies: 

A (good) 

 Category A studies have the least bias and results are considered valid. A study that adheres 

mostly to the commonly held concepts of high quality including the following: clear 

description of the population, setting, interventions and comparison groups; clear description 

of the comparison groups; appropriate measurement of outcomes; appropriate statistical and 

analytic methods and reporting; no reporting errors; less than 20 percent dropout; clear 

reporting of dropouts; and appropriate consideration and adjustment for potential 

confounders. 

B (fair/moderate) 

 Category B studies are susceptible to some bias, but not sufficient to invalidate the results. 

They do not meet all the criteria in category A because they have some deficiencies, but none 

of which are likely to cause major biases. The study may have suboptimal adjustment for 

potential confounders. The study may also be missing information, making it difficult to 

assess limitations and potential problems. 

 
20 

C (poor) 

 Category C studies have significant biases that may invalidate the results. The study either 

did not consider potential confounders or did not adjust for them appropriately. These studies 

have serious errors in design, analysis or reporting; have large amounts of missing 

information, or discrepancies in reporting. 

 For primary studies that had equivocal grading between moderate and poor, those studies 

were reviewed and graded again by different reviewers and consensus was reached after 

discussion among the reviewers. Lastly, it should be noted that the summary quality grading 

system evaluates and grades the studies within their own design strata. It does not attempt to 

assess the comparative validity of studies across different design strata. Thus, one should be 

cognizant of the study design when interpreting the methodological quality grade of a study. 

Reporting of the Evidence 

We reported each outcome separately in its own section in the results chapter. A brief 

explanation of the importance of the outcome is followed by a description of inclusion/exclusion 

criteria of studies examined that are specific to that outcome. A description of the relevant 

systematic review is followed by a description of the primary studies that were published after 

the latest search date of the systematic review. A summary table highlighted important findings. 

A summary conclusion regarding breast milk and that particular outcome is made in the last 

section. Conclusions were drawn only from studies of high or moderate (grade A or B) 

methodological quality. For dichotomous outcome, either the summary risk ratio or odds ratio is 

reported. For continuous outcome, the comparative difference in the actual measurement for that 

outcome is reported (e.g., IQ points, mm Hg of blood pressure). When only studies of C quality 

are available, we summarize the findings from those studies and explain the reasons for the “C’ 

rating, but we do not draw conclusions from them. 

 Extracted data are compiled in evidence tables. The tables offer a detailed description of the 

studies that addressed each of the key questions. The tables (see Appendix C)a provide detailed 

information about the study design, the sample size, the patient characteristics, the intervention 

and comparison group feeding methods, the followup, the major outcomes, and the 

methodological quality. In addition, for systematic reviews and meta-analyses, we reported the 

databases searched and for which time period, the number and the type of primary studies 

included, and the type of comparison addressed. 

 Summary tables succinctly report summary measures of the main outcomes evaluated. They 

include information regarding study design, intervention and comparison group, feeding 

methods, study duration or followup, sample size (subjects enrolled and analyzed in each arm), 

potential confounders, results of major outcomes, and methodological quality. These tables were 

developed by condensing information from the evidence tables. They are designed to facilitate 

comparisons and synthesis across studies. A methodological quality was assigned to each study 

as described previously. 

 

a Appendixes and Evidence Tables cited in this report are provided electronically at http://www.ahrq.gov/clinic/tp/ brfouttp.htm. 
21

Chapter 3. Results 

Overview 

 Twenty-three outcomes were analyzed in this report. We present three overall summary 

figures below to give the reader a quick overview of the results from the meta-analyses included 

in this report on the association of breastfeeding with health outcomes. We use the following 

rules to choose the results: (1) results from good or moderate quality meta-analyses, (2) the latest 

and/or highest quality meta-analysis is preferred if there are multiple meta-analyses addressing 

the same question, and (3) pooled adjusted estimate is preferred. Outcomes that did not have 

meta-analyses are not listed in these figures. 

 Three overall summary figures were created for term infant outcomes: Figure 1 for outcomes 

expressed as odds ratios or risk ratios comparing the different feeding groups; Figure 2 for the 

association between exclusive breastfeeding and infant outcomes; and Figure 3 for maternal 

outcomes expressed as odds ratios or risk ratios comparing the different feeding groups. 

Figure 1. The relationship between breastfeeding and health outcomes in term infants - meta-analysis results 

MA, meta-analysis; AOM, acute otitis media; GI, gastrointestinal; CC, case-control studies; FH, family history; CVD, 

cardiovascular disease; IHD, ischemic heart disease; DM, diabetes; adj, adjusted 

*17 studies in total were included in Norris 1996 meta-analyses. The number of studies per comparison was not 

reported. 
22

†Four historical cohort studies reported data on the relationship between breastfeeding and both CVD and IHD 

mortality. 

Figure 2. The relationship between exclusive breastfeeding and health outcomes in term infants - metaanalysis results 

MA, meta-analysis; AOM, acute otitis media; FH, family history; Hosp, hospitalization; exclu, exclusive; LRTI, lower 

respiratory track infection 

*18 studies in total were included in Gdalevich 2001 meta-analyses. The number of studies per comparison was not 

reported.
23

Figure 3. The relationship between breastfeeding and maternal outcomes - meta-analysis results 

MA, meta-analysis; BC, breast cancer; RR, relative risk; OC, ovarian cancer; adj, adjusted 

Literature Search Results 

 In the early phase of exploring the literature available for this report, a large number of 

published systematic reviews or meta-analyses were identified for various outcomes of interest. 

We screened over 300 abstracts for published systematic reviews and meta-analysis. We 

included all relevant systematic reviews and meta-analyses, although some of them included 

primary studies that were conducted in developing countries. A total of 29 systematic reviews or 

meta-analyses met our inclusion criteria. These systematic reviews or meta-analyses included a 

total minimum of 343 to a maximum of 494 unique primary studies (as some of the same studies 

were covered in multiple reviews). In this chapter, we summarized the findings and authors’ 

conclusions from these systematic reviews and meta-analyses. If multiple systematic reviews and 

meta-analyses were available on the same outcome of interest, we also compared the differences 

and similarities between them. 

 We screened over 9,000 abstracts for potential relevant articles on the relationship between 

breastfeeding or breast milk feeding and various infant and maternal outcomes. After the initial 

screening, we categorized the abstracts according to the populations and outcomes of interest. 

For outcomes of interest that had previously been reviewed systematically, we excluded abstracts 

that were published before the search dates of previous systematic reviews or meta-analyses. For 

the remaining abstracts, we retrieved the corresponding full articles and applied additional 

inclusion or exclusion criteria tailored for the specific outcomes. For outcomes of interest that 

had not been reviewed systematically, we performed a new systematic review on all relevant 

primary studies that were conducted in developed countries. 
24

 Finally, a total of 43 unique primary studies on the relationship between breastfeeding and 

infant health outcomes, and a total of 43 unique primary studies on the relationship between 

breastfeeding and maternal health outcomes were included. Details of the inclusion and 

exclusion of abstracts and full article screenings were summarized in Figures 1 and 2. The full 

article inclusion or exclusion criteria were described in Chapter 2, and the additional inclusion or 

exclusion criteria tailored for the specific outcomes were described under each outcome section 

in this chapter. 

Organization of Results 

 In this chapter, we grouped studies into one of the three parts of this report according to the 

target population – Part I: term infant outcomes, Part II: preterm infant outcomes, Part III: 

maternal outcomes. 

 In Part I, we summarized the results for health outcomes in term infants, including acute 

otitis media, atopic dermatitis, gastrointestinal infections, lower respiratory infection, asthma, 

cognitive development, obesity, cardiovascular diseases, cholesterols, blood pressure, 

cardiovascular mortality, type 1 and 2 diabetes, childhood leukemia, infant mortality, and sudden 

infant death syndrome. 

 In Part II, we summarized the results for necrotizing enterocolitis (NEC) and cognitive 

development in relationship to breast milk feeding in preterm infants, respectively. 

 In Part III, we summarized the results for maternal health outcomes, including returning to 

pre-pregnancy weight, postpartum weight changes, maternal type 2 diabetes, osteoporosis, 

postpartum depression, breast cancer, and ovarian cancer. 
25

Figure 4. Primary studies available to assess the relationship between breastfeeding and infant health outcomes. 

Asthma

27

Cognitive

function

39

Diabetes

18

Infant

mortality

2

NEC

10

AOM

12

Preterm

9

Term

30

Term

8

Preterm

8

AOM

6

NEC

3

Asthma

4

Type 1

15

Type 2

3

Meeting specific inclusion criteria

for the outcome?

Type 1

DM

6

Type 2

DM

0

Excluded

Infant

mortality

2

A total of 43 unique studies were included for updates of infant outcomes

Infant outcomes

See 

Maternal outcomes 9318 abstracts were identified in the search ~400 abstracts were Abstract screening screened-in

Cognitive function

Yes

No

*Exclusion criteria:

1. Conducted in developingcountries2. Published before thesearch dates of the latestsystematic review or metaanalysis3. Non-human studies4. Non-English publications5. No outcome of interest6. Outcomes that are notdesignated for update

Full-text

screening

~8,800

Excluded* Articles from hand search,

bibliography, or

identified by field

experts

~240 Excluded*

for both infant

and maternal

outcomes
26

Figure 5. Primary studies available to assess the relationship between breastfeeding and maternal health outcomes. 

Postpartum

depression

35

Breast

cancer

35

Breast

cancer

3

Postpartum

depression

6

A total of 43 unique studies were included for updates of maternal outcomes

~400 abstracts were

screened-in

Maternal outcomes

See previous page Infant outcomes

Is there a published sytematic

reviews or meta-analyses?

Diabetes

4

Yes

Type 2

DM

1

No

Perform de novo systematic reviews

Osteoporosis

44

Excluded** BMD/BMC

38

Fractures

6

Meet specific inclusion criteria?

BMD/

BMC

4

Fracture

6

Excluded

Return to prepregnancy weight /

postpartum weight

changes

54

Weight

8

Ovaria

Ov

ca

Excluded*

Yes

Full-text

screening

*Exclusion crite

1. Conducted countries3. Non-human 4. Non-Englis5. No outcom

Full-text

screening

**Exclusion criteria:

1. Conducted indeveloping countries2. Published beforethe search dates ofthe latest systematicreview or metaanalysis3. Non-human studies4. Non-Englishpublication
27 

Part I. Term Infant Outcomes 

Relationship between Acute Otitis Media and Breastfeeding 

Background 

 Acute otitis media (AOM) is a common childhood infection. It often begins with an upper 

respiratory tract infection. The viral infection predisposes the child to the development of AOM 

by causing eustachian tube dysfunction. The eustachian tube dysfunction enhances 

nasopharyngeal colonization with middle ear pathogens. The prevalence of a first attack of AOM 

in children under l year of age was estimated to be 44 percent.25 Almost 70 percent of children 

under 6 years of age have had an episode of AOM.25 Several risk factors have been identified for 

increasing the occurrence and recurrence of AOM.26 There is a general consensus that 

breastfeeding protects against many infections, including AOM. Breast milk contains 

immunoglobulins with antibody activity against common bacteria such as Haemophilus 

influenzae and Streptococcus pneumoniae. It also contains components that interfere with the 

attachment of Haemophilus influenzae and Streptococcus pneumoniae to nasopharyngeal 

epithelial cells. The intermittent administration of milk with anti-adhesive substances into the 

nasopharynx of the nursing child may reduce the extent of colonization and protect against 

infection.27

 Commonly considered confounders in the studies of the relationship between breastfeeding 

and AOM were parental history of allergy, number of siblings, use of day care, maternal 

smoking, gender, ethnicity, and socioeconomic status. 

 We identified one meta-analysis of risk factors for AOM that aimed to further clarify 

possible means of preventing AOM in childhood.28 Duration of breastfeeding was one of the 

factors examined. Since this meta-analysis, we identified six studies in seven publications that 

examined the relationship between breastfeeding and AOM. 

Additional Methodological Comments 

 Uhari 1996 compared the risk of AOM among children who were breastfed for various 

durations – breastfeeding for 3 or more months versus less than 3 months, 6 or more months 

versus less than 6 months, and ever breastfeeding versus never breastfeeding. 28 The clinical and 

statistical heterogeneity of the studies included were not reported. The methodological quality of 

the meta-analysis was rated grade C, because there was no consideration for potential 

confounding and poor reporting of study characteristics (Table 1). 

 Since the meta-analysis was of poor quality, we decided to conduct a new meta-analysis 

combining adjusted odds ratios or risk ratios of AOM comparing breastfed infants with nonbreastfed infants from the studies identified in Uhari 1996 and from the update search. We only 

included studies that reported the relationship between breastfeeding and the occurrence of AOM 

in infants without co-morbidities (e.g., cleft palate). Of the 10 studies included in Uhari 1996 

meta-analysis, only three reported adjusted odds ratios or risk ratios of AOM comparing 

breastfed infants with non-breastfed infants.29-31 Those studies are summarized in Table 2. 

 
28 

Studies Identified after the Systematic Review/Meta-analysis (Table 2) 

 A total of five cohort studies (in 6 publications)3,32-36 and one case-control study37 that 

evaluated the relationship of breastfeeding and AOM published after the search dates of Uhari’s 

meta-analysis met our inclusion criteria. We included only studies conducted in developed 

countries among children without co-morbidity. In cohort studies, subjects in the studies were 

followed from birth to a mean of 6 to 24 months. The number of subjects evaluated ranged from 

289 to 15,113 at baseline. Four of the five cohort studies were of methodological quality grade 

B, while the other one was of grade C. In the case-control study, the children were between the 

ages of 3 and 7 years at the time of examination. A total of 179 AOM cases and 305 controls 

were analyzed. The methodological quality of the case-control study was rated C because the 

analysis did not control for potential confounding. 

 Studies varied in the definitions of breastfeeding and comparison groups. All studies were 

designed to evaluate a broad range of potential risk factors in AOM, except for Scariati 1997 in 

which the study specifically aimed to examine the relationship between breastfeeding and 

infections. We focused only on the relationship between breastfeeding and AOM. The studies 

also varied in their definitions of the disease conditions. In most studies, definitions of AOM 

were based on clinical features combined with otoscopic findings. The data were collected from 

medical records and confirmed by a physician in all studies except for Vernacchio 2004 and 

Scariati 1997 where a mother was asked to report ear infection in a list of diagnoses or 

symptoms. 

 All cohort studies adjusted for potential confounders and the case-control study did not. 

Confounding factors considered in the studies included gender, number of siblings, family day 

care, nursery day care, number of children in the home, maternal age, parental race or ethnicity, 

parity, maternal marital status, and parental smoking. 

 Breastfeeding was associated with a reduced risk of AOM compared to bottle-feeding after 

controlling for potential confounders across the five cohort studies, although some studies did 

not report a statistically significant result. 

 When exclusive breastfeeding for more than 3 or 6 months was compared with exclusive 

bottle- or formula- feeding, one study reported 28 percent33 and another study reported 45 

percent3

 relative risk reduction in AOM. The case-control study did not show a significant 

difference in the risk of AOM between the children who were ever breastfed and those who did 

not. However, the analysis did not control for any potential confounding factors. 

 Meta-analysis. In addition to the five cohort studies in the update search, three additional 

cohort studies that reported adjusted odds ratios or risk ratios of AOM from Uhari 1996 were 

reviewed for possible inclusion into our meta-analyses. Studies were heterogeneous in the 

definitions of breastfeeding and comparison groups. In order to minimize the heterogeneity, we 

restricted our analyses to studies that reported an adjusted odds ratio or risk ratio of AOM 

comparing any definition of breastfeeding duration to exclusive bottle-feeding. Five studies that 

reported data from a total of six comparisons met the inclusion criteria for our metaanalyses.3,29,31,33,35 Using a random effects model, pooled data from five cohort studies of good 

and moderate methodological quality showed an adjusted odds ratio of AOM of 0.60 (95%CI 

0.46-0.78) comparing breastfeeding to exclusive bottle-feeding. There is a significant difference 

in the risk reduction of AOM between the studies comparing exclusive breastfeeding with 

exclusive bottle-feeding and the studies comparing ever breastfeeding with exclusive bottlefeeding (P<0.01). Specifically, the pooled adjusted odds ratio of AOM was 0.77 (95%CI 0.64-
29 

0.91), when comparing children who were ever breastfed with children who were exclusively 

bottle-fed in two studies. The pooled adjusted odds ratio was 0.50 (95%CI 0.36-0.70), when 

comparing children who were exclusively breastfed for at least 3 or 6 months with those who 

were exclusively bottle-fed for at least 3 or 6 months in three studies (providing 4 estimates). 

 The three studies that were excluded from our meta-analyses compared breastfeeding for 

more than 13 weeks, 4 months, and 6 months with breastfeeding for less than 13 weeks, 4 

months, and less than 6 months, respectively.29,30,32 There was no significant association between 

the risk of AOM and breastfeeding for more than 13 weeks, while a significant risk reduction in 

AOM was found when comparing children who were breastfed for more than 4 months or 6 

months with those who were breastfed for less than 4 months or 6 months, respectively. 

 
30 

Figure 6. Meta-analysis of the association between breastfeeding and the risk of AOM compared to exclusive 

bottle-feeding in cohort studies 

* Exclusive breastfeeding ≥ 6 months vs. exclusive bottle-feeding and breastfeeding < 4 mo 

Conclusion 

 The results from our meta-analyses of cohort studies of good and moderate methodological 

quality showed that breastfeeding was associated with a significant reduction in the risk of 

AOM. Comparing ever breastfeeding with exclusive bottle-feeding, the pooled adjusted odds 

ratio of AOM was 0.77 (95%CI 0.64 - 0.91). When comparing exclusive breastfeeding with 

exclusive bottle-feeding, either for more than 3 or 6 months duration, the pooled odds ratio was 

0.50 (95%CI 0.36 - 0.70). 
31

Table 1. Summary of systematic review/meta-analysis on the relationship between breastfeeding and acute otitis media (AOM) Author Year Population 

Study 

description 

Intervention 

/Comparator 

Confounders 

considered Results 

Uhari 1996 AOM in children. Specific age groups not specified in the cohorts Case- control: 671 Cohort: 4,455 

MA of 2 casecontrol and 8 cohort studies in developed countries 

Any measures of breastfeeding and comparators 

ND 10 studies evaluated the risk of AOM and recurrence of AOM 

associated with breastfeeding. The diagnosis of AOM varied, but pneumatic otoscopy was used in the diagnosis. There was no restriction on study inclusion according to the diagnostic criteria used. 22 studies evaluating an array of risk factors for development and recurrence of AOM were included in the meta-analysis. Seven of the twenty-two studies specifically evaluated the association between breastfeeding and AOM, while another 3 studies included breastfeeding among other risk factors that were evaluated. 

Breastfeeding for at least 3 months reduced the risk of AOM 

(RR=0.87; 95%CI: 0.79-0.95) 

Children who were breastfed for 3 or more months had a nonstatistically significant reduced risk of recurrent AOM 

compared with those who were breastfed less than 3 months (RR 0.69, 95%CI 0.46 - 1.03). 

When children who were breastfed for 6 months or more were 

compared to those who were breastfed for less than 6 months, a statistically significant reduced risk of recurrent AOM was found (RR=0.69; 95%CI: 0.49-0.97). 

N

c

AOM, Acute Otitis Media; SR, systematic review; MA, meta-analysis 
32

Table 2. Summary table for cohort studies on the relationship between breastfeeding and acute otitis media Author Year OR (95% CI) Country Design

Number of 

subjects 

(Baseline 

/Followup) 

Definition of 

AOM 

Mean 

duration 

Followup 

Breastfeeding 

group (n) 

Comparator 

group (n) Crude Adjusted Con

fac

Studies in update search Vernacchio 2004 USA Prospective cohort 

15,113 

/11,349 

Mother selects 

ear infection from 

a list of diagnoses 

by physician in 

the past month 

6 mo BF at 6 mo (2,771) No BF at 6 mo (8,558) 0.66 (0.59-0.74) 0.69 (0.61-0.78) 

Race/

dayc

ciga

incom

Exclusive 

formula at 6 

mo (891) 

0.45 0.56, p<0.01 

1-57% mixed 

feeding (81) 0.56 0.63, p=0.03 

58-88% 

mixed 

feeding (80) 

0.67 0.71, p<0.05 

Scariati 1997 US Prospective cohort 

1,743 / 

1410 

Mother reported 

symptoms 7 mo Exclusive BF at 6 mo (299) 

89-99% 

mixed 

feeding (59) 

0.83 0.83, p=NS 

Ge

educa

smok

size 

Sassen 1994 Netherlands Prospective cohort 

289 /232 

Clinical diagnosis 

by physician. 

Tympanometry 

results not used. 

23.6 mo 

Overall effect 

before stopping 

BF (OR per 

month) 

Up to 4 mo 

after 

stopping BF 

0.92 

(0.76-1.07) Numbe
33

Table 2. Continued Author Year OR (95% CI) Country Design

Number of 

subjects 

(Baseline 

/Followup) 

Definition of 

AOM 

Mean 

duration 

Followup 

Breastfeeding 

group (n) 

Comparator 

group (n) Crude Adjusted Con

fac

Exclusive RR (95% CI) 

breast: 178 

/ 53 @ 3 

mo / 28 @ 

6 mo 

Exclusive 3-mo 

BF 

Exclusive 3-

mo formula 

0.72 

(0.52-1.00) 

0.72 

(0.52-1.00) 

Combined 

BF and 

formula: 18 @ baseline 

Exclusive 6-mo 

BF 

Exclusive 6-

mo formula 

0.55 

0.34-0.87) 

0.55 

0.34-0.87) 

Duffy 1997 Finlandc Prospective cohort 

Exclusive 

formula: 

110 @ 

baseline 

Exclusive formula: 

110 @ baseline

Exclusive 

formula: 

110 @ 

baseline

6-mo mixed 

feeding 

Exclusive 6-

mo formula 

0.71 

(0.53-0.96) 

0.30 

(0.19-0.48) 

Age at 

care, m

Ever BF (nd) Never BF (nd) 0.8 (0.7-0.9) e Alho 1996 (2 papers) Finland 

Retrospective cohort 

2,512 / 825 

>1 acute 

symptoms and 

one 

pneumatoscopic 

finding up to age 

2 yrs 

22 mo 

BF > 3 mo (735) BF < 3 mo (90) 0.9 (0.8-1.0) 

Gen

siblin

seas

care, 

Stenstrom, 1997 Sweden Case-control study 

AOM 

cases: 179 

Control d: 

305 

> 5 episodes of 

AOM (Otoscopic 

diagnosis) before 

age of 30 mo 

N/A Ever BF Never BF NS 

Studies in MA that reported adjusted OR / RR 

Exclusive BF 

≥ 6 

mo (154) 

0.61 

(0.40-0.92) 

BF 

≥ 4 mo, suppl 

4-6 mo (199) 

0.72 

(0.54-0.95) 

Duncan 1993 US Prospective cohort 

1220 / 

1013 

Diagnosed by 

experienced 

clinicians with an 

average of > 9 yrs 

in pediatric 

practice 

12 mo 

BF 

≥ 4 mo, suppl 

<4 mo (200) 

No BF and 

BF < 4 mo 

(465) 

0.85 

(0.74-0.97) 

Par

alle

siblings

mat

gend

mat
34

Table 2. Continued Author Year OR (95% CI) Country Design

Number of 

subjects 

(Baseline 

/Followup) 

Definition of 

AOM 

Mean 

duration 

Followup 

Breastfeeding 

group (n) 

Comparator 

group (n) Crude Adjusted Con

fac

Teele 1989 US Prospective cohort 

1067 / 877 

 Effusion in one or 

both middle ears 

accompanied by 

≥ 1 signs of acute 

illnessb

12 mo Ever BF (292) Never BF (585) 

≥ 1 episode of 

AOM: 0.83 

≥ 1 episode of 

AOM: 0.64 

(0.44-0.91) 

≥ 3 episode of 

AOM: 0.51 

(0.30-0.89) 

Site 

seas

weig

num

sibling 

of in

Howie 1990 Scotland Prospective cohort 

750 / 617 

Mother reported 

that infant 

experienced 

painful or 

discharging ear 

lasting for 48 hrs 

or more 

12 mo 

Exclusive BF 

≥ 13 

wk (89) or partial 

BF 

≥ 13 wk (121) 

Bottle 

feeders (246) 

and BF < 13 

wk(161) 

0.7 (0.5–1.0) 

NS in the % 

infants 

experienced ear infection 

Fath

ma

par

BF, breastfeeding; excl, exclusive; ROM, recurrent otitis media; SES, socioeconomic status a Mean duration of exclusive BF (95% CI) b Signs of acute illness including earache, otorrhea, ear tugging, fever, irritability, lethargy, anorexia, vomiting or diarrhea c Proportion of infants in the individual categories of feeding method at different time cut-offs is not available d Matched to the case by age and gender e Values were estimated from figure. Statistically modeled to fit the whole sample. 
35

Relationship between Atopic Dermatitis and Breastfeeding 

Background 

 Atopic dermatitis is a common problem with an estimated lifetime prevalence in children of 

10-20 percent.38 Many studies have investigated the possible protective effect of breastfeeding 

on the development of atopic dermatitis. The results have been conflicting.16,38,39 Potential 

confounders considered in the studies included gender, socioeconomic status, family history of 

atopy, parental smoking, and presence of furry animals in the home.40

Published Systematic Review/Meta-Analysis (Table 3) 

 We identified one systematic review/meta-analysis that examined the relationship between 

breastfeeding and the development of atopic dermatitis.40 The methodological quality of this 

systematic review/meta-analysis was rated grade A. 

 Using the MEDLINE database from 1966 to 2000, Gdalevich 2001 identified 18 prospective 

studies from developed countries that qualified for inclusion in the review. Sample size of the 

studies ranged from 17 to 991. A total of 4,158 participants were included. Mean followup 

duration was 4.5 years. Study selection criteria included term infant, restriction of maternal recall 

of the child’s feeding history limited to the first 12 months of the infants’ life, the breastfeeding 

group in the study were exclusively breastfed for at least 3 months, blinding of the feeding 

history during outcome assessment, strict diagnostic criteria of atopic dermatitis provided by the 

authors, and control for confounding variables like socioeconomic status and family history of 

atopy. 

 Using a fixed effect model, the overall summary odds ratio for the development of atopic 

dermatitis was 0.68 (95% CI 0.52 - 0.88) in those subjects with at least 3 months of exclusive 

breastfeeding versus subjects without 3 months of exclusive breastfeeding. When the analysis 

was restricted to those studies with positive family history of atopy, the odds ratio was 0.58 

(95%CI 0.41 - 0.92). When the analysis was restricted to those studies without a family history 

of atopy, the odds ratio was 0.84 (95%CI 0.59 - 1.19). 

 The systematic review did not make a distinction between atopic dermatitis of infancy (under 

2 years of age) and persistent or new atopic dermatitis at older ages. However, in a primary 

analysis, the data were stratified according to different durations of followup (because the 

diagnosis of atopic dermatitis in patients younger than 2 years of age are sometimes attributed to 

symptoms of infectious origin and breastfeeding may have a protective effect against infections). 

The summary odds ratio in the group with less than 2 years of followup was 0.74 (95%CI 0.61 – 

0.90), whereas the summary odds ratio in the group with 2 or more years of followup was 0.78 

(95%CI 0.62 – 0.99). 

 The authors of the review concluded that there was a substantial protective effect of 

breastfeeding against atopic dermatitis in children with a family history of atopy. 

Conclusion 

 Available evidence from one well-performed systematic review/meta-analysis on full term 

infants in developed countries suggests that exclusive breastfeeding for at least 3 months was 
36

associated with a reduction in the risk of atopic dermatitis in those subjects with a family history 

of atopy. 

Table 3. Summary of systematic review/meta-analysis on the relationship between breastfeeding and the risk 

of developing atopic dermatitis 

Author 

Year 

Studies 

description 

Intervention 

/Comparator 

Confounders 

considered Results 

Quality 

of 

SR/MA 

Gdalevich 

2001 

Term 

infants 

4,158 

(17-991) 

18 prospective 

cohort studies 

in developed 

countries 

≥ 3 mo of 

exclusive 

breastfeeding vs. 

without ≥ 3 mo of 

exclusive 

breastfeeding 

SES, gender, family 

history of atopy, parental 

smoking, and presence of 

furry animals at home; 

also considered disease 

in < 2 yr of age vs. ≥ 2 yr 

(to sort out the possible 

confounding protective 

effect of breastfeeding for 

skin rash that is infectious 

in etiology which might be 

confused with the 

diagnosis of atopic 

dermatitis) 

Overall OR 0.68 (95% CI 0.52 - 

0.88, fixed effect model); 

When restricted to those with 

positive family history, OR 0.58 

(95%CI 0.41 - 0.92) 

When restricted to those without 

family history, OR 0.84 (95%CI 

0.59 - 1.19) 

Authors’ conclusion: “There is a 

substantial protective effect of 

breastfeeding against atopic 

dermatitis in children with a 

family history of atopy.” 

A 

SR, systematic review; MA, meta-analysis; SES, socioeconomic status 
37

Relationship between Gastrointestinal Infections and 

Breastfeeding 

Background 

 Gastrointestinal infections are common in infants and children. Rate of diarrheal disease in 

US was estimated to be 1.1 episodes per person-year in children less than 5 years old.41 Many 

studies have investigated the possible protective effect of breastfeeding on the development of 

gastrointestinal infections. A previous review of diarrhea morbidity in both developed and 

developing countries reported that the risk of diarrhea in infants who did not receive breast milk 

were 3.5 to 4.9 times higher than infants who had exclusive breastfeeding in the first 6 months of 

life.42 Factors like secretory IgA, oligosaccharides, lactoferrin and others available in breast milk 

may protect the infant from various infections through passive immunity.1 In vitro and in vivo 

binding studies have demonstrated that fucosylated glycans in breast milk inhibit binding by 

campylobacter jejuni, stable toxin of enterotoxigenic Escherichia coli, and major strains of 

calciviruses (e.g., noroviruses (also known as Norwalk-like viruses)) to their target host cell 

receptors.43 One report suggests that glycoprotein lactadherin found in breast milk protects 

against rotavirus infection.44 Socioeconomic status and child care variables (e.g., home versus 

day care, degree of crowding at home) are thought to be important confounding factors in 

observational studies on gastrointestinal infection and breastfeeding. As the aforementioned 

review also included studies before 1950, it would be instructive to review the more recent 

literature and assess the relationship between breastfeeding and gastrointestinal infections in 

infants from developed countries. 

Published Systematic Review/Meta-Analysis (Table 4) 

 We identified one systematic review/meta-analysis that examined the relationship between 

breastfeeding and the development of gastrointestinal infections in children less than 1 year of 

age from developed countries.45 The methodological quality of this systematic review/metaanalysis was rated grade B. 

 Using the MEDLINE database from 1966 to 1998, and supplementing the results with 

searches of the bibliographies of the primary and review articles, Chien 2001 identified 16 

studies from developed countries that qualified for inclusion in the review. There were 12 

prospective cohort studies totaling 5,473 subjects, 2 retrospective cohort studies totaling 504 

subjects, and 2 case-control studies with 331 pairs of subjects. For the review, gastrointestinal 

infection was defined to be “any illness associated with vomiting, change in consistency or 

frequency of stools, or isolation of a known enteropathogenic bacterial or viral agent.” For the 

final data analysis, infant feeding practices were dichotomized into two groups: exclusive 

breastfeeding and partial/mixed feeding, or exclusive artificial feeding. 

 Results were conflicting. Nine of 16 studies (56 percent) yielded a statistically significant 

protective effect of breastfeeding on gastrointestinal infections. Majority of the studies suffered 

from methodological deficiencies. Four studies fulfilled criteria of controlling for detection bias, 

analyses of confounders, having a clear definition of infant feeding practices and infectious 

outcomes. Three of the studies reported breastfeeding was protective against non-specific 

gastrointestinal infection. The fourth study reported that differences in feeding practice did not 
38

affect the attack rates of rotavirus gastroenteritis. The potential confounders examined in these 

studies included infant sex, race, maternal education, family living standards, marital status, 

paternal social class, and/or parental smoking. Even though these studies adjusted for potential 

confounders, the actual quantitative adjusted odds ratio or risk ratio were not reported. 

 The authors of the systematic review stated that “it was not possible to pool the adjusted 

relative measures of association” in the cohort studies reviewed. Using a fixed effect model, the 

summary crude odds ratio of the 14 cohort studies for the development of gastrointestinal 

infection was 0.36 (95% CI 0.32, 0.41; heterogeneity P<0.01); the summary odds ratio of the two 

case-control studies was 0.54 (95% CI 0.36 - 0.80; heterogeneity, P=0.35). 

Conclusion 

 Available evidence from three primary studies that controlled for potential confounders 

suggests that breastfeeding is associated with a reduction in the risk of non-specific 

gastrointestinal infection during the first year of life in infants from developed countries. 

However, a summary adjusted effect estimate taking into account potential confounders could 

not be determined because not all the studies that adjusted for potential confounders provided 

usable quantitative data for meta-analysis. 

Addendum 

 During the final phase for the preparation of this report, we were alerted to a recent primary 

study on diarrheal disease in infants in 1990s England that provided relevant quantitative data. 

This case-control study of 304 infants (167 cases and 137 controls) showed that the infants who 

were breastfeeding had a reduced risk of diarrhea compared to infants who were not 

breastfeeding (OR 0.36, 95% CI 0.18 to 0.74, P=0.005). The result was adjusted for age, sex, 

social class, contact with person in and outside household, and other factors. This study also 

reported that the protective effect of breastfeeding did not persist beyond 2 months after 

cessation of breastfeeding.46 
39

Table 4. Summary of systematic review/meta-analysis on the relationship between breastfeeding and 

gastrointestinal (GI) infection 

Author Year 

Population 

Studies 

description 

Intervention 

/Comparator Confounders 

considered Results 

Quality 

of 

SR/MA 

Chien 2001 

Prospective 

cohorts: 

5,473 

Retrospective 

cohorts: 504 

Case-control: 

331 pairs 

12 

prospective 

cohort 

studies, 2 

retrospective 

cohort 

studies; 2 

case-control 

studies 

Either 

exclusive 

breastfeeding 

and 

partial/mixed 

feeding or 

exclusive 

artificial 

feeding 

Maternal education, 

single or dual 

parenting, family 

living standards, 

infant sex, race, 

maternal parity, 

marital status, 

paternal social 

class, maternal age, 

parental smoking 

Conflicting results on the effect of 

breastfeeding on GI infection: 9/16 studies 

(56%) yielded a statistically significant 

protective effect of breastfeeding on GI 

infections;

Majority of studies suffered from 

methodological deficiencies; 

 4 studies fulfilled criteria of controlling for 

detection bias, analyses of confounders, 

having a clear definition of infant feeding 

practices and infectious outcomes; 3 of 

these studies reported breastfeeding was 

protective against non-specific GI 

infection; 

Unadjusted pooled estimate of the cohort 

studies: OR 0.36 (95% CI 0.32, 0.41; 

heterogeneity P<0.01) 

Unadjusted pooled estimate of 2 casecontrol studies: OR 0.54 (95% CI 0.36, 

0.80; heterogeneity P=0.35) 

B 

SR, systematic review; MA, meta-analysis 
40

Relationship of Hospitalization Secondary to Lower 

Respiratory Tract Diseases in Infancy and Breastfeeding 

Background 

 Respiratory infection is the most common medical problem among infants and children. Each 

year in the United States, three percent of all infants are hospitalized with moderate to severe 

respiratory infection.47 Severe lower respiratory tract diseases may increase the risk of childhood 

asthma. Viral infections, especially respiratory syncytial virus (RSV) infection, are the most 

common cause of lower respiratory tract disease in developed countries. RSV infection occurs 

most frequently between 2 and 8 months of age. The risk factors associated with rates of 

respiratory illness include age, smoke exposure, day care, race/ethnicity, family size, education, 

and socioeconomic status. We identified one meta-analysis published in 2003 that compared the 

risk of hospitalization for respiratory diseases in healthy full term infants who were breastfed 

with those who were not.48 

Published Systematic Review/Meta-Analysis (Table 5) 

 Bachrach 2003’s meta-analysis included seven cohort (five prospective and two 

retrospective) studies that evaluated the relationship between breastfeeding and hospitalization 

risk secondary to respiratory diseases.48 Primary studies published before April 2002 and 

evaluated healthy full-term infants less than 1 year of age from developed countries were 

included. Only data from exclusive breastfeeding of at least 2 months or any breastfeeding 

totaling 9 months or more were included. Exclusive breastfeeding was defined as little or no 

formula feeding. Studies on cystic fibrosis and allergic conditions were excluded. Unpublished 

data were also examined. The primary outcome variable was hospitalization for lower respiratory 

tract disease secondary to bronchiolitis, asthma, pneumonia, empyema, and infections due to 

specific agents (e.g., RSV). The meta-analysis was restricted to first hospitalization. The analysis 

evaluated the risk of hospitalization in 3,201 breastfed subjects and 1,324 non-breastfed subjects. 

 The meta-analysis used a random effects model. There was an overall 72 percent reduction in 

the risk of hospitalization in infants who were exclusively breastfed for 4 or more months 

compared with those who were formula-fed (summary relative risk 0.28, 95% CI 0.14 - 0.54). 

There was no change in summary relative risk in the subgroup analyses of studies that also 

reported relative risk adjusted for the effects of smoking or socioeconomic status. There was no 

statistical heterogeneity across the studies. The authors performed sensitivity analyses to assess 

the appropriateness of combining studies and found no changes in summary risk. In addition, the 

number needed to treat (NNT) was calculated to be 26. This implies that at least 26 infants will 

have to breastfeed exclusively for 4 or more months to prevent one infant from hospitalization 

secondary to respiratory diseases. The methodological quality of the meta-analysis was rated 

grade A. 

Conclusion 

 The meta-analysis showed an overall 72 percent reduction in the risk of hospitalization 

secondary to respiratory diseases in infants who were exclusively breastfed for 4 or more months 
41

compared with those who were formula-fed. This finding remained statistically significant after 

adjustment for potential confounders. There could be differences across studies with regard to 

duration of followup, diagnosis of respiratory disease, and other factors. However, there was no 

statistically significant heterogeneity detected across the studies. Taking into account the 

methodological quality of the meta-analysis and the consistent findings reported, we conclude 

that breastfeeding for 4 or more months is associated with a reduction in the risk of 

hospitalization secondary to lower respiratory tract diseases. 

Table 5. Summary of systematic review/meta-analysis on the relationship between breastfeeding and lower 

respiratory tract disease 

Author year 

Population 

Study 

description 

Intervention 

/Comparator 

Confounders 

considered Outcomes 

Quality 

of 

SR/MA 

Bachrach 2003 

Infants <1 yr of 

age 

Exposed: 3,201 

Unexposed: 

1,324 

MA of 7 

observational 

studies 

Breastfeeding 

exclusively ≥ 2 mo or ≥ 9 

mo total of any (including 

mixed feed) 

Smoking or 

socioeconomic 

status 

Summary RR of 0.28, 95% CI 0.14-

0.54 

There was an overall 72% reduction of 

hospitalization among infants who were 

exclusively breastfed for ≥ 4 mo 

compared with those who were 

formula-fed. 

A 

SR, systematic review; MA, meta-analysis
42

Relationship between Asthma and Breastfeeding 

Background 

 Asthma is a bronchial disorder accompanied by breathing difficulties, wheezing, coughing, 

and production of thick mucus. Triggering factors have been attributed to foreign substances, 

tobacco smoke or pollutants, exercise, infection, and emotional stress. An increase in the 

prevalence of asthma has been reported in some countries during the second half of the 20th

century.49 In 2002-2003, about six percent of the children in the United States had an asthma 

attack (www.cdc.gov/nchs/data/hus/hus05.pdf). In addition, the hygiene hypothesis (a lack of 

early childhood exposure to infectious agents increases susceptibility to allergic diseases50,51) has 

been proffered as a possible explanation for some of the increase in incidence and prevalence of 

asthma, but that hypothesis remains a matter of debate.49 Potential confounders considered in the 

studies of breastfeeding and asthma include age, socioeconomic status, family history of atopy, 

and parental smoking. 

 Findings from primary studies on the relationship between breastfeeding and the 

development of asthma have been conflicting. One meta-analysis published in 2001 aimed to 

examine this relationship.52 We identified three relevant prospective longitudinal cohort studies 

and one followup study (to one of the primary studies in the meta-analysis) published subsequent 

to the meta-analysis.53-56 Three of the four studies met the inclusion criteria of the original metaanalysis and an updated meta-analysis stratified by family history of asthma was conducted. 

Published Systematic Review/Meta-Analysis (Table 6) 

 Gdalevich 2001 conducted a meta-analysis that included 12 prospective observational studies 

with 8,183 term infants followed for a mean of 4.1 years. Study inclusion criteria included 

subjects from developed countries, exclusive of breastfeeding for at least 3 months, blinding of 

diagnosing physician to feeding status, and maternal recall of child’s feeding history of not more 

than 12 months. Exclusive breastfeeding was defined as having no substitutes or additions. 

Critical appraisal of the studies was conducted based on the standards suggested by Kramer.16

Potential confounders including age, socioeconomic status, family history of atopy, and parental 

smoking were controlled for by means of multivariate analysis. The outcome of asthma was 

diagnosis by a physician. 

 Meta-analysis of the 12 studies with followup of 2 or more years reported a summary odds 

ratio of 0.70 (95% CI 0.60 - 0.81), suggesting an association of breastfeeding and a reduction in 

the risk of the development of asthma. Subgroup analysis reported that children with a family 

history of asthma or atopy benefited more from breastfeeding (OR 0.52, 95% CI 0.35 - 0.79) in 

the risk reduction of the development of asthma, compared with children who did not have a 

family history of asthma or atopy. There was no statistical heterogeneity in the studies. 

Sensitivity analysis indicated the exclusion of any one study did not change the overall results. 

Methodological quality for the meta-analysis was rated grade A. 
43

Studies Identified after the Published Systematic Review/MetaAnalysis (Table 7) 

 We identified three prospective cohort studies, including one that had both prospective and 

retrospective analyses, and one followup publication examining the relationship between 

breastfeeding and risk of the development of asthma.53-55 Methodological quality of these four 

studies ranged from grade C to grade A. 

 Subjects selected in these studies ranged from healthy full-term infants to any live births 

from mainly population-based samples. Sample sizes at followup ranged from 1,037 to 4,964 

with zero to 31 percent dropouts or withdrawals. Verification of asthma varied from parental 

confirmation through questionnaires to clinic assessment and physician diagnosis. Although all 

four studies adjusted for confounding, the only variable common to all studies was maternal 

smoking, either during pregnancy or after birth. 

 Two of the studies were population-based, one was hospital-based, and one study was done 

in a large health maintenance organization (HMO). Wright 2001 and Kull 2004 looked at 

exclusive breastfeeding whereas Burgess 2006 did not define breastfeeding but acknowledged 

that exclusive breastfeeding was in practice difficult to verify. Another issue is that there were no 

gold standards for the diagnosis of asthma in population studies. To confirm the diagnosis of 

asthma, Kull 2004 relied on clinical examinations as well as blood sampling and pulmonary 

function tests. Burgess 2006 used data from a questionnaire that asked about medications, 

symptoms, hospitalization, and family history to formulate the diagnosis. Sears 2002 based the 

diagnosis on pulmonary function tests with the addition of maternal description of symptoms. 

Wright 2001 and Kull 2004 appeared to have the most rigorous criteria for diagnosis of asthma 

by considering recent symptoms, results from testings, and confirmation by a physician. Two 

studies gathered feeding data post-delivery by recall, first study at 6 months,53 and the second 

study at 2 months with another followup at 12 months.54 Two studies relied on objective data for 

feeding history; Sears 2002 relied on data from nursing program records,55 and Wright 2001 

relied on breastfeeding data from clinic visits.56 The methodological quality of the studies by 

Kull, Wright, and Sears were rated grade B, and Burgess was rated grade C. 

Study findings. Kull 2004 followed 3,384 newborns for the first 4 years of life and reported 

that there was a statistically significant association of exclusive breastfeeding for 4 months or 

more and a reduction in the risk of the development of asthma (OR 0.72, 95%CI 0.53 - 0.97).54

Furthermore, subgroup analysis showed that the association was stronger for children whose 

parents did not have a history of allergic diseases. 

 Sears 2002 enrolled 1,037 subjects at age 3 years and a retrospective record review found 

that approximately half were breastfed and half were not (533 breastfed, 504 not breastfed).55

The subjects were followed prospectively until 21 or 26 years of age. The study found an 

increased risk of asthma in those subjects who were breastfed compared with those who were not 

for all time points assessed. Length of breastfeeding duration had no protective effect against 

asthma. Family history of asthma did not significantly affect these results. Even though 

“exclusive breastfeeding” rate was reported in the study, the authors acknowledged that it was 

common practice for the hospital staff to feed the newborns with formula for the first few nights 

post-delivery to allow the mothers to sleep. 

 Wright 2001 is a followup publication to one of the primary studies from the Gdalevich 2001 

meta-analysis. This study reported that there was no association between duration of exclusive 

breastfeeding and asthma for 926 children by age 13 years followed since birth, except in those 
44

children who were atopic and whose mothers had a history of asthma.56 This was the only study 

to report that a family history of asthma is an effect modifier of breastfeeding in the increased 

risk of the development of asthma in children. 

 Burgess 2006 investigated 4,964 children at 14 years of age concerning their history of 

asthma (“yes” or “no”) as reported by their mothers. This study found that there was no 

significant relationship between the duration of breastfeeding and the prevalence of asthma. The 

rates of asthma were the same for any given rates of breastfeeding regardless of the maternal 

history concerning asthma.53 Data on feeding were collected at 6 months after birth. 

Updating the Previous Meta-Analysis 

 We performed an update meta-analysis stratified by family history of asthma using the 

random effects model including three of the four recent publications.53,54,56 The fourth study did 

not qualify for inclusion because it did not have a comparison group of at least 3 months duration 

of breastfeeding. In the subgroup analysis of those children with a positive family history of 

asthma, two studies (Wright56 and Kull54) met the inclusion criteria set by Gdalevich. One of the 

studies reported a very large adjusted odds ratio (OR 8.7, 95%CI 3.4 – 22.2) in a followup of 13 

year olds, compared with the other studies.56 Sensitivity analyses were conducted to examine the 

source of heterogeneity by including or excluding this study. Excluding Wright, a history of 

exclusive breastfeeding for more than 3 months was associated with a reduction in the risk of 

asthma (ORadj 0.60; 95%CI 0.43 - 0.82), compared with no breastfeeding. Including Wright, 

there was no longer a statistically significant association between a history of breastfeeding and 

the risk of asthma (ORadj 0.81, 95%CI 0.41 – 1.60). This result suggests that the heterogeneity 

can be explained by a single study. Compared with the other studies in the analyses, the age of 

followup was 13 years in Wright 2001, while it ranged from 2 to 9 years in the other studies. 

 In the analysis of those children without a family history of asthma, the addition of the two 

subsequent studies (Kull54 and Burgess53) did not alter the statistically significant association of 

breastfeeding and the reduction in the risk of asthma (OR 0.73, 95%CI 0.59 – 0.92) compared 

with the original results reported by Gdalevich. It should be noted that Burgess reported only the 

unadjusted odds ratio, stating that the adjusted was “minimally altered”. 
45

Figure 7. Meta-Analysis of prospective cohort studies of the association between asthma risk and 

breastfeeding ≥ 3 months for children with positive family history of asthma or atopy (excluding Wright 2001) 

 

Figure 8. Meta-Analysis of prospective cohort studies of the association between asthma risk and 

breastfeeding ≥ 3 months for children with positive family history of asthma or atopy (including Wright 2001) 
46

Figure 9. Meta-Analysis of prospective cohort studies of the association between asthma risk and 

breastfeeding ≥ 3 months for children without family history of asthma or atopy 

Conclusion 

 A well-performed meta-analysis from 2001 concluded that breastfeeding was associated with 

a reduction in the risk of developing asthma. This association was stronger in those subjects with 

a positive family history. However, three new primary studies and one followup study reported 

conflicting results. With our new meta-analyses including three of these studies, it is clear that 

there remained an association between breastfeeding and a reduction in the risk of asthma in 

those subjects without a family history of asthma. This association was also found in subjects 

under 10 years of age with a positive family history of asthma. It is unclear whether this 

association changes for older children. It should also be noted that the fourth study, which did 

not qualify for inclusion in our new meta-analyses, reported an increase in asthma risk with 

increased duration of breastfeeding in those subjects with a maternal history of asthma. Further 

studies concerning the effect of a family history of asthma on long-term outcome of asthma is 

warranted.
47

Table 6. Summary of systematic review/meta-analysis on the relationship between breastfeeding and asthma Author Year Population Studies description Intervention /Comparator Confounders considered Results Gdalevich 2001 Term infants 

MA of 12 prospective studies in developed countries 

≥ 3 mo exclusive breastfeeding vs. without ≥ 3 mo of exclusive breastfeeding 

SES, gender, family history of atopy, parental smoking, and presence of furry animals at home 

≥ 2 years followup, breast feeding had protective 

effect against asthma, summary OR 0.72 (95% 0.62 – 0.84) 

Subgroup analysis of children from family with 

asthma or atopy showed higher protective effbreast feeding OR 0.52 (95% CI, 0.35 - 0.79) 

Subgroup analysis of children from family withou

asthma or atopy, OR 0.73 (95% CI, 0.62 - 0.8

SR, systematic review; MA, meta-analysis 
48

Table 7. Summary of prospective cohort studies on the relationship between breastfeeding and asthma Author Year Country Population 

Study Description Breast milk feeding exposure Assessment of asthma Confounders adjusted for Outcomes 

Kull 2004 Sweden Enrolled: 4,089 Follow-up: 3,384 All newborns from catchments area of Stockholm 

Prospective, longitudinal cohort with questionnaires at child’s age of 2 months, 1, 2, and 4 years. Clinic assessment at 4 years. 

Exclusive breastfeeding was dichotomized with the 25th percentile as the 

cutoff point (<4 months and 

≥4 

months) and as a 3-level categorical variable (0-2, 3-4, and 

≥5 months) 

At age 4 years, 4 episodes of wheezing during the last 12 months or at least 1 episode of wheezing during the same period if the child was receiving inhaled steroids 

Maternal age, maternal smoking during pregnancy or at 2 months of age, and heredity of allergic diseases 

• Overall exclusive 

breastfeeding for 

≥ 4 

month associated with lower risk than those who breastfed <4 months, adjOR 0.72 (0.53-0.97) 

• Children with no heredity 

allergic diseases was associated with lower asthma risk, adjOR 0.58 (0.38-0.88) 

• Children with heredity of 

allergic diseases had adjOR 0.73 (0.43-1.20) 

Sears 2002 New Zealand Enrolled: 1,037 Followup:1,037 Populationbased cohort from single hospital center 

Both prospective and retrospective cohort study design enrolled at age 3 and data collected retrospective and prospective, followed prospectively up to 21 years 

Breastfeeding categorized by duration:  Not breastfed 

Breastfed > 4 weeks 

Asthma as reported by child or parent 

SES, birth order, sheepskin use in infancy, maternal smoking 

• Breastfeeding at least 4 

weeks compared with no tless than 4 weeks associated with higher adjusted OR of asthma, 2.40 (1.36-4.26) 

Wright 2001 USA Enrolled: 1,246 Followup: 1,043 Healthy newborns from large HMO 

Prospective, longitudinal newborn cohort with questionnaires at 2, 3, 6, 9, 11, 13 years; Additional data collection by MD health surveillance 

Exclusive 

breastfeeding categorized by duration: never breastfed 

 breastfed <4 

months 

 breastfed >4 

months 

Physician diagnosed asthma, wheezing or asthma symptoms reported 

≥ 2 

questionnaires from ages 6 to 13 years 

Maternal education, smoking status in 1st

year, sex, ethnicity, 2 or more siblings at home or day care use versus neither first 6 months, paternal asthma 

• Nonsignificant relationship 

between asthma and exclusive breastfeeding duration at 13 years 

• Children with maternal 

history of asthma: exclusivbreastfeeding associated with asthma, adjusted OR 8.7 (3.4-22.2) 
49

Table 7. Continued Author Year Country Population 

Study Description 

Breast milk 

feeding 

exposure 

Assessment of asthma Confounders adjusted for Outcomes 

Burgess 2006 Australia Enrolled: 7,223 Followup: 4,964 Singleton term deliveries from public clinic of University Hospital 

Prospective, longitudinal cohort with questionnaires at birth, 6 months, 5 and 14 years. 

Breastfeeding categorized by duration:  Never 

breastfed 

 < 3 weeks  3 – 6 weeks  7 weeks – 3 

months ≥ 4 months 

From questionnaire: episodes of asthma in past 6 months, frequency of asthma meds, asthmarelated sick days from school, asthma-related hospital admissions 

Maternal asthma, paternal asthma, smoking early and late pregnancy, frequency of coughs and cold first 6 months, annual family income 

• Breastfeeding at least 4 

months not associated wasthma compared to no breastfeeding, unadjusted OR 1.03 (0.9-1.2) 

SES, socioeconomic status
50 

Relationship between Cognitive Development and 

Breastfeeding in Term Infants 

Background 

 Many studies have examined the relationship between breastfeeding and cognitive 

development. Results have been conflicting. Many of them did not have a clear definition of 

breastfeeding or breast milk exposure. Different cognitive assessment tools were used. Outcomes 

were measured anywhere from less than 2 years of age to adulthoods. Confounders commonly 

considered in these studies were socioeconomic status, maternal education, birthweight, 

gestational age, birth order and gender.57 Jain et al. considered SES and quality and quantity of 

stimulation of the child (including social interactions) to be crucial confounders. 58 These authors 

did not consider maternal or paternal intelligence, marital status, number of children, and 

maternal age to be crucial because to “some degree, they are markers of socioeconomic status, 

and are not clearly related to both feeding method and intelligence independent of 

socioeconomic status”. Three systematic reviews from 1999 to 2002 have tried to either establish 

methodological standards to assess the observational studies or adjust for covariates in pooled 

analysis. Since the last systematic review by Jain et al. in 2002,58 there have been eight 

prospective cohort studies on healthy term infants that examined the relationship of breastfeeding 

to some aspects of cognitive development. 

Additional Methodological Comments 

 We searched for systematic reviews on breastfeeding and cognitive development using terms 

like “cognitive”, “neurodevelopment”, “intelligence”...etc. Using similar terms, we searched 

MEDLINE and CINAHL in January and April of 2006, respectively, for additional primary 

studies published after 2000. We also identified additional articles based on reviews of the 

bibliographies cited in the relevant retrieved studies from the search and from suggestions by the 

reviewers for this report. For primary studies, qualifying study designs included prospective 

cohort and case-control studies; only studies from developed countries were included. For the 

healthy term infants, subgroups like infants of diabetic mothers and small-for-gestational age 

infants were not included. For preterm infants, no subgroups were excluded. Studies concerned 

exclusively with individual breast milk factor supplements (e.g., long chain polyunsaturated fatty 

acids, nucleotides) were not included. There was no restriction on timing of and the tools used 

for cognitive assessment. Only data on cognitive outcomes were extracted, data from motor, 

psychomotor, or visual development were not extracted. 

Published Meta-Analyses/Systematic Reviews (Table 8) 

 Jain 2002 identified 40 relevant publications (30 birth cohorts, five RCTs, five school 

registry cohorts, and three case-control studies) from 1929 to 2001. Most of them studied term 

infants. A few studies included only preterm infants in their analyses. Each study was assessed 

according to a set of eight clinical epidemiological standards: study design, target population, 

sample size, quality of feeding data (suitable definition and duration of breastfeeding, and 

appropriate timing and source of feeding data), whether studies controlled for socioeconomic 
51 

status and stimulation of the child, whether observers of the outcome were blind to feeding 

status, whether a standardized individual test of general intelligence at older than 2 years of age 

was used, and whether studies reported an effect size. Two studies on term infants met all the 

proposed methodological standards. One concluded that the effect of breastfeeding on intellect 

was significant (4.6 points in IQ at age 3 years in children who breastfed compared with those 

who bottle-fed),59 and the other concluded that the effect on cognitive performance was 

statistically non-significant.60

 Drane 2000 examined 24 studies from 1966 to 1998.57 Twenty-one included term infants, 

two included low birthweight infants, and one involved small-for-gestational age infants. Each 

study was assessed according to a set of three methodological standards: definition of outcome, 

correct classification of type of infant feeding, and control of potential confounding variables 

(socioeconomic status, maternal education, birthweight, gestational age, birth order, gender). 

Five of the 24 studies met all three methodological standards. These studies indicated an 

advantage in IQ to breastfed infants in the range of two to five points for term infants and eight 

points for low birth weight infants. 

 Interestingly, of the two studies that were identified by Jain 2002 to have met all the 

proposed methodological reporting standards, the feeding data from one did not meet the feeding 

data reporting standard put forth in the review by Drane 2000. The study at issue was Wigg 

1998, in which the following statement could be found: “Feeding methods (i.e., breast, bottle-fed 

or mixed) and duration of breastfeeding in infancy were recorded at age 6 months by the trained 

research nurse”.60 Jain 2002 interpreted that study to have met their requirement of adequate 

reporting of feeding data (“whether infants received breast milk exclusively or with supplemental 

formula or other foods”), while Drane 2000 interpreted that study not to have adequately 

distinguished between partial and exclusive breastfeeding. The other study that met all the 

methodological standards according to Jain 2002 was published in 1996,59 but it was not 

included in Drane 2000’s review; reason of which was not readily apparent. 

 Anderson 1999 examined 11 studies from 1978 to 1995 that controlled for at least five 

covariates (breastfeeding duration, sex, maternal smoking history, maternal age, maternal 

intelligence, maternal education, maternal training, paternal education, race or ethnicity, 

socioeconomic status, family size, birth order, birth weight, gestational age, and childhood 

experiences) and presented unadjusted and adjusted results.61 Eight studies included term infants; 

three studies included only preterm infants. The results were combined in a meta-analysis. The 

adjusted (fixed effects) pooled mean difference was 3.16 points (standardized effect estimate of 

cognitive developmental mean score, 95% CI 2.35 - 3.98) in favor of the breastfeeding group. 

Low birthweight infants showed larger differences (5.18 points in cognitive developmental 

score; 95%CI 3.59 - 6.77) than did normal birth weight infants (2.66 points; 95%CI 2.15 - 3.17). 

Other methodological quality of the studies was not assessed. 

Studies Identified after the Published Meta-Analysis/Systematic 

Review in Term Infants (Table 9) 

 Prospective cohort. One secondary analysis of a prospectively collected data set62 and seven 

prospective cohort studies ranging from 44 to 3880 term subjects reported on the relationship 

between breast milk feeding and some aspects of cognitive development since 2002. 63-71

 None of the cohort studies made a clear distinction between partial and exclusive 

breastfeeding. Two studies stated to have a prospective design, but the breastfeeding information 
52 

was collected retrospectively. Subjects were breastfed from less than 3 weeks to 12 months. 

Three studies reported the proportion of subjects who breastfed for more than 6 to 7 months, they 

ranged from 9 percent to 62 percent. 

 Bayley Mental Development Index Scale (MDI) was the cognitive assessment tool for 

subjects under 2 years of age. Peabody Picture Vocabulary Test (PPVT-R) and Wechsler 

Preschool and Primary Scale of Intelligence (WPPSI-R) were used in subjects under 7 years of 

age. Wechsler Adult Intelligence Scale (WAIS), Raven’s standard progressive matrices, standard 

reading, verbal, and mathematical reasoning tests were used in adults up to 27 years of age. Time 

of assessment ranged from 1 to 27 years. 

 Der 2006 analyzed the database from the US National Longitudinal Survey of Youth 1979 

(NLSY79).62 This database has information on the participants and their offsprings. The study 

reported that the adjusted effect of breastfeeding on Peabody individual achievement test 

(standardized mean of 100 and SD of 15) at 14 years was reduced to +0.52 from +4.7 after 

adjustment for maternal IQ, education, age, family poverty, home stimulation, and birth order. 

Further analysis of 332 pairs of siblings discordant for breastfeeding status found non-significant 

difference between groups in both status and duration of breastfeeding. Meta-regression of nine 

unique studies (including the data from NLSY79) reported an advantage of breastfeeding of 0.16 

cognitive points after controlling for maternal IQ and other confounders. This study was rated 

good methodological quality (grade A). 

 Der 2006 also combined its estimate with the estimate from the only other sibling analysis in 

the literature to date (Evenhouse 2005,72 this study did not qualify for inclusion in this review 

because it was an analysis of data obtained from a cross-sectional design study). Evenhouse 2005 

analyzed the database from the National Longitudinal Study of Adolescent Health (Add Health) 

1994 (This database oversamples low-income, African-American, and Hispanic children and 

provided information on an abbreviated Peabody Picture Vocabulary Test results. There were 

523 pairs of siblings with different breastfeeding history in this data set). The combined estimate 

from NLSY79 and Add Health was 0.025 (P=0.54) for breastfeeding status and 0.04 (P=0.271) 

for duration of breastfeeding. 

 Of the six prospective cohort studies of moderate (grade B) methodological quality, five 

reported an advantage in cognitive development in subjects who breastfed. Specifically, Lawlor 

2006 reported that the adjusted score (for sex, parental characteristics, birthweight, and perinatal 

characteristics) in Raven’s standard progressive matrices at age 14 years showed a mean 

difference of 6.79 (95%CI, 5.33-8.26) in less than 4 months of breastfeeding versus never 

breastfeeding (compared to an unadjusted mean of 8.20).71 Quinn 2001 reported that the mean 

PPVT-R at 5 years for those breastfed for at least 6 months was 8.2 points (95%CI, 6.5-9.9) 

higher for females and 5.8 points (95%CI, 4.1-7.5) higher for males when compared to those 

never breastfed. PPVT-R was adjusted for birthweight, poverty, maternal education, maternal 

age, time in daycare or preschool, the number of children in the household at 5 years, English 

speaking background in parents, and infant stimulation.70 Similarly, Oddy 2003 and 2004, 

reported that the PPVT-R score at 6 years was 3.56 point higher for children breastfed more than 

6 months compared with children never breastfed (F=8.59, P=0.003).68,69 The result was adjusted 

for gender, gestational age, maternal age and education, parental smoking, and the presence of 

older siblings. Mortensen 2002 reported that the duration of breastfeeding was associated with 

significantly higher scores on the verbal, performance, and full scale WAIS at 27 years.67 With 

regression adjustment for parental social status and education, single mother status, mother’s 

height, age, and weight gain during pregnancy, cigarette smoking during 3rd trimester, number of 
53 

pregnancies, estimated gestational age, birth weight, birth length, and indices of pregnancy and 

delivery complications, the mean full scale WAIS were 99.4, 101.7, 102.3, 106.0, and 104.0 for 

breastfeeding durations of < 1 month, 2 to 3 months, 4 to 6 months, 7 to 9 months, and > 9 

months, respectively (P=0.003). GomezSanchiz 2004 reported that the Bayley MDI at 24 months 

was 4.3 points higher in those breastfed more than 4 months compared with those breastfed less 

than 4 months after multiple linear regression adjusting for parental IQ.66 Angelsen 2001 

reported that adjustment for differences in maternal intelligence reduced the odds ratio of having 

a low IQ score among children who were breastfed for <3 months compared to ≥ 6 months from 

2.8 (95%CI 1.4-5.3) to 1.5 (95%CI 1.0-2.1).64

Conclusion 

 One well-performed sibling analysis and prospective studies that controlled specifically for 

maternal intelligence demonstrated that there is either little or no evidence for an association 

between breastfeeding and cognitive performance in children. It is clear that maternal 

intelligence is a major confounder in the studies on relationship between breastfeeding and 

cognitive development. For those studies that still reported a significant effect after adjustment 

for maternal intelligence, residual confounding from other factors like different home 

environments cannot be ruled out. Many studies controlled for socioeconomic status and 

maternal education but not specifically for maternal intelligence. It is clear that maternal 

intelligence should be controlled for separately from socioeconomic status and maternal 

education in any studies of breastfeeding and cognitive development. As cautioned by Der et al., 

“The generalizability of the results presented here must be considered carefully. This study and 

the others included in the meta-analysis are all based on samples from developed countries. 

Generalization of the findings beyond these and similar societies would be unwise. We have also 

excluded premature and low birthweight infants for whom the effect may be different.”62
54

Table 8. Summary of systematic reviews/meta-analyses on the relationship of breastfeeding and cognitive development Author Year Population Studies description Intervention /Comparator Confounders considered Results Jain 2002 50 to >11,000 Term and preterm 

30 birth cohorts; 2 RCTs; 5 school registry cohorts; 3 case-control studies 

Breastfeeding, breast milk, or choice to breastfeed 

SES (parental education, occupation, income or any combination), quality and quantity of stimulation of the child (including social interactions) 

Quality of feeding data evaluated by 4 criteria (exc

breastfeeding or not, timing of feeding data collesource of feeding data, duration of breastfeedinmet all 4 criteria (8 full-term cohorts). 

22 studies used an appropriate measure of cognitiOnly 2 studies met all the methodological standard

study concluded that “any beneficial effect of bron cognitive development is quite small in magnanother study found that children who were bremean IQ scores 4.6 points higher than those nebreastfed after controlling for socioeconomic staother factors. Among the studies that controlled socioeconomic status and stimulation/interactiochild, three concluded that breastfeeding promodevelopment, and four did not. 

Drane 2000 N in individual studies not provided in the review Term and preterm 

24 studies (1 RCT and 23 cohorts) met inclusion criteria: birth 1960-98, English language, examined cognitive development 

Actual breastfeeding intervention in individual studies not described in the review 

SES, maternal education, birthweight, gestational age, birth order, gender 

5 studies met the 3 methodological standards (ope

definition of cognitive outcome and outcome mestandardized tests; correct classification of type measure breastfeeding as a continuous variable as a 3-level categorical variable (exclusive breaformula-fed; partial breastfed) and control for poconfounding variables. 

The only RCT did not find statistical significant diffe

Bayley MDI in infants fed solely on a diet of donmilk compared with infants fed solely on a diet oformula. 

Advantages in IQ as measured by the WISC-R, Ba

McCarthy were observed in 4 cohort studies. 

In term infants, effects on IQ in the range of 2-5 po

SD) were found. 
55

Table 8. Continued Author Year Population 

Studies 

description 

Intervention 

/Comparator Confounders considered Results 

Anderson, 1999 7,081 Term and low birthweight 

11 cohort studies with results adjusted for covariates 

Breastfeeding vs. formula feeding (no detailed information) 

breastfeeding duration, sex, maternal smoking, age, intelligence, education, training, paternal education, race or ethnicity, SES, family size, birth order, birth weight, gestational age, and childhood experiences 

Adjusted (fixed effects) pooled mea

difference of standardized effect estimate of cognitive developmescore was 3.16 (95% CI 2.35, 3.favor of breastfeeding;

An average adjusted benefit from 

breastfeeding of 5.18 points in cognitive developmental score wobtained for low-birth weight chiacross 6 available observations. 

MDI, Bayley Mental Development Index; SR, systematic review; MA, meta-analysis; SES, socioeconomic status 
56

Table 9. Summary of studies on the relationship of breast milk feeding and cognitive development Author Year Country Population 

Study 

Description 

Breast milk 

feeding 

exposure 

Assessment 

tools for 

cognitive 

development 

Confounders 

adjusted for Outcomes 

Database analysis of a prospective cohort study Der 2006 US Database from the US national longitudinal survey of youth 1979 (NLSY79) and children of the women in the survey, Full term infants 

Database analysis of a prospective study; sibling pairs analysis, and metaanalysis; Cognitive test administered to children between 5 yr and 14 yr biennially from 1986 to 2002; For metaanalysis, only included studies that quantified the effect of breastfeeding on cognitive ability after controlling for parental intelligence 

Breastfeeding 

history 

obtained 

within a year 

of birth in 

most cases 

Peabody individual achievement test (PIAT) was administered to children 

Adjustment for variables associated with breastfeeding in the survey, home environment (HOMESF), child demographics, maternal characteristics 

PIAT (all outcomes standardized to a mean of 100 an15) 

Unadjusted effect of breastfeeding +4.7 compared to 

breastfeeding (3,161 mothers, 5,475 children, 16,74assessments); after adjustment for maternal Armed Qualification Test (AFQT) score, education, age, fampoverty, HOME stimulation score, and birth order, thdifference became +0.52 (P=0.149) 

332 pairs of sibling discordant for breastfeeding statu

545 discordant for duration of breastfeeding, differebetween groups (status) = -0.63 (P=0.506); (duratio-0.13 (P=0.866) 

Meta-regression of 9 unique studies (including the da

NLSY79): an advantage of breastfeeding of 0.16 aftcontrolling for IQ and 8 additional confounders. 

Combined data from NLSY79 and sibling analysis stu

Evenhouse 2005 (see separate extraction): estimate (P=0.54) for breastfeeding status and 0.04 (P=0.271duration of breastfeeding 
57

Table 9. Continued Author Year Country Population 

Study 

Description 

Breast milk 

feeding 

exposure 

Assessment 

tools for 

cognitive 

development 

Confounders 

adjusted for Outcomes 

Prospective cohort Lawlor 2006 Australia Enrolled 7,223 Followup 3,794 (>98% term) 

Enrolled subjects at birth and did Peabody Picture Vocabulary test at 5 yr and Raven’s standard progressive matrices (nonverbal reasoning or general intelligence) at 14 yr, most of the data reported were from age 14 (see Quinn 2001 for 5-yr data) 

Classified by 

never, < 4 

mo, 

≥ 4 mo 

(obtained 

from mothers 

at the 6-mo 

followup) 

Raven’s standard progressive matrices at 14 years 

Sex, parental characteristics (maternal age, ethnicity, education, paternal education, family income, gravidity, maternal smoking), labor, Apgar scores, birthweight, height, BMI 

At age 14 yr, Never breastfed = 694, <4 mo = 1372, 

≥ 

1,606 

 All parental characteristics were related to offspring I

score. 

Unadjusted scores at age 14 showed a mean differen

4.43 (95%CI 3.09 to 5.77) in <4 mos breastfeeding never breastfeeding; 8.20 (95%C I6.89 to 9.49) in 

≥ 

breastfeeding vs. never breastfeeding (P<0.001) 

Adjusted scores at age 14 yr (N=3,099) showed a me

difference of 4.07 (95%CI 2.61 to 5.53) in <4 mo breastfeeding vs. never breastfeeding; 6.79 (95%CI 8.26) in 

≥ 4 mo breastfeeding vs. never breastfeedi

(P<0.001) 

Family income, parental education and breastfeeding 

explained 7.5% of the variation in intelligence at age 

Loss to followup was selective, those subjects were m

likely to have mothers who were from poorer social backgrounds, lower education, and younger; regresanalysis repeated using Heckman’s sample selectioadjustment with maternal age, parental education, afamily income as the selection variables; results of tregression models did not differ from those who had followup. 
58

Table 9. Continued Author Year Country Population 

Study 

Description 

Breast milk 

feeding 

exposure 

Assessment 

tools for 

cognitive 

development 

Confounders 

adjusted for Outcomes 

Quinn 2001 Australia Enrolled 7,357 Followup 3,880 Singleton; children with major neurological abnormalities and those for whom the data were incomplete were excluded 

Enrolled women attending antenatal clinic; data collected at baseline, after birth, 6 mo and 5 yr 

No distinction was made between partial or complete breastfeeding; classified by never, 

< 3 wk, 3 to < 

7 wk, 7 wk to 

< 4 mo, 4 mo 

to < 6 mo, or 

≥ 6 mo 

Peabody Picture Vocabulary Test (PPVTR) was administered at 5 years. 

Birth weight, poverty, maternal education, maternal age, time in daycare or preschool, number of children in the household at 5 years 

Breastfeeding 

≥ 6 mo 103.6 (SD 13.1) 

No breastfeeding 94.2 (SD 14.1) There was a significant trend towards increasing PPV

with increased duration of breastfeeding (P=0.0000) 

Before adjustment, the mean for those breastfed 

≥6 m

10.9 points (95%,CI 9.3, 12.5) higher for females anpoints (95% CI 5.9, 9.1) higher for males when comto those never breastfed.

After adjustment, the mean for those breastfed 

≥6 mo

8.2 points (95%,CI 6.5, 9.9) higher for females and points (95%,CI 4.1, 7.5) higher for males when comto those never breastfed. 
59

Table 9. Continued Author Year Country Population 

Study 

Description 

Breast milk 

feeding 

exposure 

Assessment 

tools for 

cognitive 

development 

Confounders 

adjusted for Outcomes 

Oddy, 2003, 2004 (same data) Australia 2,393 at birth, 1,444 at 6 yr, 1,371 at 8 yr 

37-39 wk 

gestation 

Comparing no breastfeeding, <4 mo, 4-6 mo, and >6 mo of breastfeeding 

90% of 

children were 

breastfed at 

some point, 

28% were 

breastfed for 

>6 mo, solid 

foods were 

introduced at 

≤6 mo in 88% 

of infants. 

Peabody Picture Vocabulary Test (PPVTR) was administered at 6 y/o and a Performance subtest (Perceptual organization WISC- Block Design) at 8 y/o 

Gender, gestational age, maternal age and education, parental smoking, and the presence of older siblings. 

Both verbal IQ and performance scores increase with 

increasing maternal education combined with a longduration of breastfeeding, with the most profound efbreastfeeding occurring in the highest education gro(P<0.005). In the lower education groups, these trenwere less consistent. 

Before adjustments for covariates, children breastfed 

mo had mean verbal IQ scores 6.44 points higher aBlock Design scores that were 1.13 points higher thchildren never breastfed. 

After adjustment for covariates, there was an associa

between duration of breastfeeding and verbal IQ wi3.56 point advantage for children breastfed >6 mo compared with children never breastfed (P=0.003). adjusted association of full breastfeeding with the Performance subtest was not significant (P=0.223). 

There was an association of low PPVT-R and non-En

maternal language; children of non-English speakinparents (n=100) were excluded from further analyse
60

Table 9. Continued Author Year Country Population 

Study Description 

Breast milk 

feeding 

exposure 

Assessment 

tools for 

cognitive 

development 

Confounders 

adjusted for Outcomes 

Mortensen 2002 Denmark Enrolled 9,125 (4668 males) 973 had WAIS; 2,280 had BPP & BF data 

Prospective cohort; but breastfeeding information collected retrospectively at 1-year exam 

Divided into 5 BF groups: ≤ 1 mo 32%; 2-3 mo 32%; 4-6 mo 24%; 7-9 mo 9%; 

> 9 mo 3% 

2 sub-cohorts; one (50% male) took the WAIS at 27 yr; the other (100% male) took the draft board intelligence test: Borge Priens Prove (BPP) at 18.7 yr 

Parental social status and education, single mother status, mother’s height, age, and weight gain during pregnancy, cigarette during 3rd

trimester, number of pregnancies, estimated gestational age, birthweight, birth length, and indices of pregnancy and delivery complications 

 Breastfeeding duration (mo)  <1 2-3 4-6 7-9 > 9 Unadjusted 98.1 101.3 103.3 108.2 102.8 Adjusted 99 102 102 106 104 WAIS P=0.003 for overall F Unadjusted 36.9 39 40.8 43.1 40.2 Adjusted 38 39 40 40 40 BPP P=0.01 for overall F 

GomezSanchiz, 2003, 2004 Spain 296 at birth; 249 at 18 mo; 238 at 24 mo 

37-42 wk 

gestation 

1 rural and 1 urban sites, comparing breastfed > 4 mo, <4 mo, and formula-fed; breastfeeding information was from medical records; (reported as a prospective cohort by authors, but parents were informed of the project and gave consent for the study at 15 months check up) 

≤ 4 mo 49% > 4 mo 28% (no distinction between exclusive or partial breastfeeding) 

Formula-fed 

23% 

Bayley was administered at 18 and 24 mo 

Parental IQ, social class, parental education, number of siblings 

Parental IQ was obtained only for 164 couples; their c

had MDI 2.3 points higher than the children whose pdid not take part in IQ testing (P<0.05). Infants were breastfed for a mean of 85.7 days 

± SD 76.4 days. 

Duration of breastfeeding had a correlation with MDmo (r=0.42; P<0.001) and at 24 mo (r=0.37; P<0.00

At 24 mo, after multiple linear regression adjusting for 

parental IQ, difference between formula and breastf≤ 4 mo no longer significant; difference of 4.3 points remained significant when comparing breastfeeding with 

≤ 4 mo. 
61

Table 9. Continued Author Year Country Population 

Study Description 

Breast milk 

feeding 

exposure 

Assessment 

tools for 

cognitive 

development

Confounders 

adjusted for Outcomes 

Angelsen, 2001 Norway and Sweden Enrolled 521 Followup 291 (5 yr) Term Excluded congenital malformations 

Prospective cohort; but duration of breastfeeding retrospectively recorded at 13 mo 

< 3 mo 17%; 3-6 mo 21%; ≥ 6 mo 62% 

Bayley MDI at 13 mo Wechsler Preschool and Primary Scales of Intelligence (WPPSI-R) at 5 y/o 

Maternal IQ, age, education, smoking 

Bayley MDI at 13 mo: 117.7 (SD11.7) in ≥ 6 mo 

breastfeeding compared to 109.9 (SD13.1) in < 3 m(P<0.001). 

There was a linear increase in MDI plotted against 

breastfeeding duration (P<0.001). Maternal intellige(Raven test score) was also related to duration of breastfeeding. Adjustment for differences in maternintelligence reduced the OR of having a low MDI amchildren who were breast fed for <3 mo to 1.6 (95%2.3) from 3.2 (95%CI 1.7-5.9). 

Total IQ at 5 y/o: 111 (SD14.3) in ≥ 6 mo breastfeedin

compared to 103.6 (SD14.6) in < 3 mo (P<0.001). Adjustment for differences in maternal intelligence rthe OR of having a low IQ score among children whbreastfed for <3 mo to 1.5 (95%CI 1.0-2.1) from 2.8 1.4-5.3). 

Agostoni, 2001 Italy Enrolled 95 Followup 44 Term infants 

Bayley results at 1 yr were compared in breastfeeding ≥6 mo with 3-6 mo 

≥ 3 mo 46% 6 mo 31% 9 mo 18% 

12 mo 11% 

Bayley MDI at 1 y/o 

Parity, maternal education, age, and smoking habits 

Unadjusted Bayley MDI in 29 subjects breastfed > 6 m

in 15 subjects breastfed 3-6 mo = 92.1; 

 After adjustment, Bayley MDI in 29 subjects breastfe

compared to 15 subjects breastfed 3-6 mo showed point advantage (95% CI –3.2, 7.3). 

BMI, body mass index; MDI, Mental Development Index; NLSY79, national longitudinal survey of youth 1979; PIAT, Peabody individual a

Peabody Picture Vocabulary Test; SR, systematic review; MA, meta-analysis; SES, socioeconomic status; WPPSI-R, Wechsler Prescho

Intelligence 
62

Relationship between Obesity and Breastfeeding 

Background 

The prevalence of overweight or obesity among children and adolescents has rapidly 

increased in the past two decades. Results from the 1999-2002 National Health and Nutrition 

Examination Survey (NHANES) showed that an estimated 16 percent of children and 

adolescents ages 6-19 years were overweight. This represents a 45 percent increase from the 

overweight estimate of 11 percent obtained from NHANES III (1988-94). 

(www.cdc.gov/nchs/products/pubs/pubd/hestats/overwght99.htm) It is increasingly recognized 

that nutrition in early life may have long-term physiologic effects. Relationships between the 

types of postnatal feeding and the subsequent development of fat and fat-free mass are quite 

complex and are dependent on multiple factors including differences in food composition 

(human milk versus formula), food delivery (breast versus bottle), food “lifestyle” (breastfeeding 

versus formula feeding) and food behavior (self-regulation and feeding on demand versus set 

schedules of feeding of predetermined amounts).73 It is known that infants fed breast milk differ 

in their growth kinetics from formula-fed infants. Formula-fed infants demonstrate higher weight 

and length gains compared with breastfed infants. A systematic review of 19 studies in 

developed countries concluded that by the age of 12 months, the cumulative difference in body 

weight amounted to approximately 400 g less in infants breastfed for 9 months compared with 

formula-infants, and as much as 600-650 g less in infants breastfed for 12 months compared with 

formula-fed infants.74 Differences in feeding behavior and mother-child interaction between 

breast- and formula-fed infants may account for some of the differences reported. For instance, 

breastfed infants showed a different suckling pattern, and appeared to have greater degree of 

control on meal sizes and feeding intervals than infants who were formula-fed.75 Diet-related 

differences in the circulating levels of biochemical markers (such as leptin, ghrelin, insulin-like 

growth factors, and other compounds) implicated in energy metabolism during infancy might 

explain some of the anthropometric and behavioral differences between breastfed and formulafed infants. These observed differences may have potential long-term consequences.73

Commonly considered confounders in the studies of relationship between obesity or 

overweight and breastfeeding were birth weight, parental overweight, parental smoking, dietary 

factors, physical activity, socioeconomic status (SES), age, sex, birth order, and number of 

siblings. 

Additional Methodological Comments 

We identified three systematic reviews and meta-analyses that examined the relationship 

between breastfeeding and childhood obesity or obesity across all ages.76-78 Although the 

outcomes of interest were similar among these systematic reviews and meta-analyses, they 

answered slightly different research questions because of the differences in their study eligibility 

criteria and analyses. Thus, we have summarized and discussed these systematic reviews and 

meta-analyses separately. 
63

Published Systematic Reviews/Meta-Analyses (Table 10) 

 Arenz 2004 was a meta-analysis of studies from 1966 to December 2003 that examined the 

relationship between breastfeeding and childhood obesity in children at least one year of age. 

Inclusion criteria for the meta-analysis were: obesity defined by a body mass index (BMI) 

greater than 90th, 95th or 97th percentile; adjustment for at least three potential confounding or 

interacting factors; reported either odds ratio or relative risk; and last followup between 5 and 18 

years of age. Nine of 28 studies reviewed met the eligibility criteria for meta-analysis. There 

were two prospective cohort and seven cross-sectional studies totaling more than 69,000 children 

from developed countries. The meta-analysis used both fixed- and random-effects models and 

pooled crude and adjusted odds ratios from the individual studies. Definitions of breastfeeding 

and comparative feedings were heterogeneous across studies. Sensitivity analyses were 

performed to assess for heterogeneity. The factors analyzed were cohort study or cross-sectional 

study, different definitions of breastfeeding, different definitions of obesity, different age groups 

and number of potential confounders considered for adjustment. The methodological quality of 

this meta-analysis was grade A. 

 The pooled crude odds ratio for breastfeeding and obesity defined as a BMI > 90th, 95th or 

97th percentile could be calculated for six of the nine studies included. The odds ratio was 0.67 

(95% CI 0.62 - 0.73). The adjusted odds ratio for the nine studies was 0.78 (95% CI 0.71 - 0.85) 

for both the fixed and random-effects models, suggesting that there was no heterogeneity 

between the studies. Sensitivity analyses showed that the protective effect of breastfeeding was 

more pronounced in studies with adjustment for less than seven potential confounding factors 

compared with adjustment for seven or more potential confounding factors (adjusted OR 0.69 vs. 

0.78, respectively). Other criteria (e.g., cohort study or cross-sectional study, different definitions 

of breastfeeding, different definitions of obesity, different age-groups) did not affect the 

summary estimates significantly. For example, the pooled adjusted odds ratio of obesity was 0.76 

(95%CI 0.67-0.86) in studies comparing ever breastfeeding to never breastfeeding, versus 0.74 

(95%CI 0.64-0.85) in studies that used other definitions of breastfeeding and comparative 

feedings. 

 Eight studies analyzed the relationship between breastfeeding duration and the risk of 

overweight or obesity in later childhood. Exclusivity of breastfeeding was not reported. Four 

studies reported an inverse association of breastfeeding duration and the prevalence of obesity 

both in the crude and the adjusted estimates. One of the studies lost statistical significance after 

adjustment. Three studies found no significant effect of duration of breastfeeding on obesity. 

 Harder 2005 was a meta-analysis of 17 qualifying studies published from 1966 to December 

2003. A total of 120,831 subjects (66 to 32,200 subjects per study) from developed countries 

were included. Eligibility criteria included any original report comparing breastfed subjects with 

exclusively formula-fed subjects at any age, the reports must have either reported odds ratio or 

contained data for the calculation of odds ratio for the risk of overweight or obesity in 

relationship to the feeding history, and the duration of breastfeeding must have been reported. 

All definitions of overweight or obesity were included. Three different meta-analytic techniques 

that specifically required the use of crude odds ratios and 95% confidence intervals were 

employed. Because of suboptimal consideration for potential confounding, we rated the 

methodological quality of this meta-analyses grade B. 

Fourteen studies provided data for more than one category of duration of breastfeeding, 

leading to 52 estimates included in the meta-regression analysis. In the analysis, duration of 
64

breastfeeding was significantly negatively related to the risk of overweight (regression 

coefficient: 0.94, 95%CI 0.89 - 0.98). Categorical analysis showed that from 1 month of 

breastfeeding onward (the reference group), the risk of subsequent overweight continued to 

decrease, reaching a plateau of more than 30 percent risk reduction at 9 months of breastfeeding. 

Using the “pool-first method” (that is to calculate a study-specific regression coefficient and 

corresponding 95 percent confidence interval for each study using a log-linear model and then 

pooled all studies with a random effects model) to quantify the dose-response relationship, the 

results showed that each month of breastfeeding was associated with a four percent decrease in 

risk of overweight per month of breastfeeding exposure (OR 0.96/month of breastfeeding, 

95%CI 0.94 - 0.98). A fixed effect model reported a similar pooled odds ratio (OR 0.96/month of 

breastfeeding, 95%CI 0.95 - 0.98). The age at examination had little influence on the magnitude 

of the effect of duration of breastfeeding on the risk of overweight. The pooled odds ratio from 

five studies investigating subjects up to 5 years of age was 0.97 (95%CI 0.94 - 0.99); while for 

six studies on subjects 6 or more years of age, it was 0.96 (95%CI 0.93 - 0.99). 

The effect of the duration of exclusive breastfeeding was analyzed in two studies. The pooled 

odds ratio for the risk of overweight per month of exclusive breastfeeding was 0.94 (95%CI 0.89 

- 0.99, random effects model). 

Subgroup analyses showed that the different definitions of overweight influenced the 

estimate of odds ratio only slightly. In eight studies that used BMI to define overweight, the 

pooled odds ratio was 0.96 (95%CI 0.94 - 0.98); while in three studies that used another 

measures (e.g., percentile of weight for length, or weight for age) to define overweight or 

obesity, the odds ratio was 0.93 (95%CI 0.87 - 0.99).

Lastly, Owen 2005 was a systematic review of 61 observational studies from 1966 to 

September 2003 that examined the effects of infant feeding on a measure of adiposity 

(quantitatively or narratively) in later life. Twenty-eight studies (totaling 298,900 subjects) that 

provided 29 unadjusted odds ratios relating the initial infant feeding method and obesity were 

included in a meta-analysis. A fixed effect model was used. Meta-regression and sensitivity 

analyses were used to examine the influence of various factors defined a priori, including the 

effects of adjustment for factors such as parental body size (mostly BMI), SES, and maternal 

smoking. Because of suboptimal consideration for potential confounding, we rated the 

methodological quality of this systematic review and meta-analyses grade B. 

Twenty-eight of 29 estimates related breastfeeding to a lower risk of obesity in later life. 

Four estimates were for infants, 23 for children, and two for adults. There was evidence of 

marked heterogeneity among studies (P < 0.001). In a fixed-effect meta-analysis, breastfed 

subjects were less likely to be defined as obese than were formula-fed subjects (OR 0.87, 95% CI 

0.85 - 0.89). In six studies, it was possible to examine the effect of adjustment for the following 

potential confounders: SES (based on parental education in two studies), parental BMI, and 

current maternal smoking or maternal smoking in early life. The pooled odds ratio in these 

studies changed from 0.86 (95% CI 0.81 - 0.91) before adjustment to 0.93 (95% CI 0.88 - 0.99) 

after combined adjustment. The effect of adjustment for birth weight (based on either actual birth 

weight or prevalence of low birth weight) was examined in 10 studies; this had no appreciable 

effect on the odds ratios. 

There was no clear evidence that the protective effect of breastfeeding altered with increasing 

age of outcome assessment. Odds ratios of 0.50 (95% CI 0.26 - 0.94) for infants, 0.90 (95% CI 

0.87 - 0.92) for young children, 0.66 (95% CI 0.60 - 0.72) for older children, and 0.80 (95% CI 

0.71 - 0.91) for adults were observed (test for trend, P = .85, adjusted for study size; P = .99 with 
65

the exclusion of infants). The protective effect of breastfeeding on obesity was stronger and more 

homogeneous among four studies in which initial feeding groups were exclusive (OR 0.76; 95% 

CI 0.70 - 0.83; test for heterogeneity between estimates, P= .143), compared with all other 

studies. In 14 studies that provided data on breastfeeding duration, the protective effect of 

breastfeeding over formula feeding was greater among subjects breastfed for at least 2 months 

(OR 0.81, 95% CI 0.77 - 0.84), compared with those breastfed for any duration (OR 0.89, 95% 

CI 0.86 - 0.91). In six studies, it was possible to examine the effect of adjustment for the 

following potentially important confounders: socioeconomic status, parental BMI, and current 

maternal smoking or maternal smoking in early life. The pooled odds ratio in these studies was 

reduced from 0.86 (95% CI: 0.81– 0.91) before adjustment to 0.93 (95% CI: 0.88–0.99) after 

adjustment. 

Thirty-three studies totaling 12,505 subjects explored the relationship between breastfeeding 

and obesity even though they did not provide odds ratio. However, they provided 35 reports of 

directions of association; of these, breastfeeding was unrelated to the risk of obesity in 33, 

related to a reduced risk in one, and related to an increased risk in another. Studies that did not 

provide odds ratios were much less likely to report that breastfeeding was associated with a 

reduced risk of obesity, compared with studies that did provide odds ratios (1 of 35 studies and 

18 of 29 studies, respectively; P < .001).

Conclusion 

Findings from three systematic reviews and meta-analyses of good and moderate 

methodological quality suggest that a history of breastfeeding is associated with a reduction in 

the risk of obesity in later life. The pooled adjusted odds ratio of overweight/obesity comparing 

ever breastfeeders to never breastfeeders was 0.76 (95%CI 0.67-0.86) and 0.93 (95%CI: 0.88–

0.99) in Arenz 2004 and Owen 2006 meta-analysis, respectively. In Harder 2005 meta-analysis, 

duration of breastfeeding was significantly negatively related to the unadjusted risk of 

overweight (regression coefficient: 0.94, 95%CI 0.89 - 0.98), and each month of breastfeeding 

was found to be associated with a four percent decrease in risk (unadjusted OR 0.96/month of 

breastfeeding, 95%CI 0.94 - 0.98). However, the results from Harder 2005 meta-analysis 

employed techniques that required the use of crude odds ratios from the primary studies for its 

summary estimates. Therefore, those estimates may not be accurate because potential 

confounders could not be accounted for in the analysis. As demonstrated in the sensitivity 

analyses in both Arenz 2004 and Owen 2005, the magnitude of effects was reduced when more 

confounders were adjusted for in the analyses. The observed association between breastfeeding 

and a reduced risk of obesity could also reflect selective reporting and/or publication bias. The 

exclusivity of breastfeeding was not described in the majority of the studies. 
66

Table 10. Summary of systematic reviews/meta-analyses on the relationship between breastfeeding and overweight or obesity Author year Population Study description Intervention /Comparator Confounders considered Results Arenz 2004 Children and adolescents. One study included some adult subjects. N=69,000 

MA of 7 crosssectional and 2 prospective cohort studies in developed countries 

Never BF or partly BF < 3 months vs. BF 

≥ 3 

month; mostly or only BF vs. mostly or only formula feeding in the first 6 months; BF never vs. ever; BF never vs. > 6 months, BF groups: <1 week, 1 week-1 months, 2-3 months, 4-6 months, 7-9 month, > 9 months (exclusivity of BF not reported) 

Studies with > 3 the following relevant confounding factors birth weight, parental overweight, parental smoking, dietary factors, physical activity and SES were included. Other confounders in the included studies: age, sex, diet and weight concerns, Tanner stadium, birth order, race, introduction of solid foods, number of siblings 

• The pooled adjusted OR for breastfeed

and obesity defined as BMI >90th, 95th or 97tpercentile calculated for nine studies was 0.78 (95%CI 0.71-0.85) for both fixed and randomeffects model. 

• Protective effect of breastfeeding was 

more pronounced in studies with adjustment fless than 7 (but more than 3) potential confounding factors compared to adjustment seven or more potential confounding factors (0.69 vs. 0.78 respectively). 

• Pooled adjusted OR of obesity was 0.7

(95%CI 0.67-0.86) compared ever breastfeedto never breastfeeding, while it was 0.74 (95%0.64-0.85) in studies using other definitions of breastfeeding. 

Harder 2005 Children and adolescents. Two studies included adult subjects. N=120,831 (ranged from 66 to 32,200) 

MA of 16 cohort or cross-sectional studies and 1 casecontrol study in developed countries 

Median duration of breastfeeding categories: < 1 month (reference), 1-3 month, 4-6 months, 7-9 months, > 9month. To studies that provided data for more than two categories of duration of breastfeeding, “pool-first method” was used to quantify the doseresponse relation (per month of breastfeeding). 

Age, sex, birth weight, SES, Tanner stage, physical activity, eating habits, concerns to gain weight, birth order, dietary intakes, maternal BMI, maternal smoking 

• In the weighted meta-regression (52 

estimates from 14 gave data for more than oncategory of duration of breastfeeding), duratiobreastfeeding was significantly negatively relato risk of overweight (regression coefficient: 095%CI 0.89-0.98). 

• From 1 month of breastfeeding onward

the risk of subsequent overweight continuousdecreased up to a reduction of more than 30%reaching a plateau at 9 months of breastfeedi

• Each month of breastfeeding was found 

be associated with a 4% decrease in risk (OR0.96/month of breastfeeding, 95%CI 0.94-0.98
67

Table 10. Continued Author year Population Study description Intervention /Comparator Confounders considered Results Owen 2005 28 studies provided 29 unadjusted odds ratios relating the initial infant feeding method and obesity. Four observations were for infants, 23 for children, and 2 for adults. N=298,900 in metaanalyses N=12,505 in the studies that did not provide an estimate of relative risk 

SR of 61 studies that compared a measure of obesity (quantitatively or narratively) among breastfed and formula-fed subjects; with metaanalyses of 28 studies reported sufficient data 

Breastfed vs. formula-fed 

Parental body size (mostly BMI), socioeconomic status, maternal smoking, physical activity, weight gain during pregnancy, introduction of solid foods, birth order, dietary intakes, maternal BMI, maternal smoking, and parental obesity/overweight 

• In a fixed-effects model including all 28 

studies, breastfed subjects were less likely to defined as obese than were formula-fed subje(OR: 0.87; 95% CI: 0.85–0.89). There was eviof marked heterogeneity among studies (p<0.0

• Data from 6 studies, the pooled odds ra

was reduced from 0.86 (95% CI: 0.81– 0.91) badjustment for confounders to 0.93 (95% CI: 00.99) after adjustment. 

• In 14 studies with information on 

breastfeeding duration, the protective effect of breastfeeding over formula feeding was greateamong subjects breastfed for 

≥2 months (odd

ratio: 0.81; 95% CI: 0.77– 0.84), compared witthose breastfed for any duration (odds ratio: 095% CI: 0.86–0.91) in the same studies. 

• 35 studies (12,505 participants), reporte

only directions of association; of these, breastfeeding was unrelated to risk of obesity related to a reduced risk in 1, and related to an increased risk in 1. 

BF, Breastfed; BMI, Body Mass Index; SR, systematic review; MA, meta-analysis; MAs, meta-analyses; SES, socioeconomic status a Results from overall MA was inappropriate due to heterogeneous definitions of breastfeeding and comparators across studies. Howeve

different breastfeeding definitions were performed. 
68

Relationship between the Risk of Cardiovascular Diseases 

and Breastfeeding 

Background 

 Abnormal levels of total cholesterol, low-density lipoprotein (LDL) cholesterol, and blood 

pressure in adults are major risk factors for cardiovascular disease (CVD). Observational studies 

of large cohorts of men and women have consistently reported that serum cholesterol level >200 

mg/dL was associated with an increased risk of all-cause and CVD mortality.79,80 Each increment 

of 20 mm Hg of systolic blood pressure and 10 mm Hg of diastolic blood pressure doubles the 

risk for CVD.81 Diet modification, weight reduction, and pharmacotherapy can reduce the risk of 

CVD. We identified one meta-analysis that evaluated the relationship of breastfeeding during 

infancy with cholesterol levels in adolescents and adults,82 two meta-analyses that evaluated the 

relationship of breastfeeding with adult blood pressure,83,84 and one systematic review and metaanalysis that examined the relationship between breastfeeding and cardiovascular disease 

mortality in later life.85

Cholesterols 

Published Systematic Reviews/Meta-Analyses (Table 11) 

 One meta-analysis of 37 cohort and cross-sectional studies evaluated the effect of 

breastfeeding on total and LDL cholesterol levels among infants, adolescents, and adults.82 All 

primary studies published in English language from both developed and developing countries 

that reported estimates of a mean difference and standard error in cholesterol levels between 

breastfed and formula-fed infants were included in the meta-analysis. The meta-analysis utilized 

a random effects model. A total of 5,829 breastfed and 4,852 formula-fed subjects were 

evaluated. Data from the included primary studies were categorized into three age strata: infancy 

(< 1 year of age), children and adolescents (1 to 16 years), and adults (17 years to 65 years). 

Outcomes included total and LDL cholesterol levels. No information was provided on the timing 

of the sample collection in relation to fasting or not fasting. Of the 37 studies, there were 26 

outcomes (total or LDL cholesterol levels) in infants, 17 in children and adolescents, and nine in 

adults. The analysis combined data from a broad age category for the adult participants. It was 

unclear if there were adjustments for potential confounders such as body mass index, height, and 

socioeconomic status for the data on cholesterol. The methodological quality of the metaanalysis was rated grade C. 

 In 25 of 26 observations, infants who were breastfed reported higher mean total cholesterol 

levels compared with infants who were formula-fed. The overall mean difference was +24.75 

mg/dL (95% CI 18.95 to 30.55). There was a statistically significant heterogeneity across the 

studies. The meta-analysis did not find an association between total cholesterol level and age or 

gender. There were only seven reported observations on LDL cholesterol levels in infants, six of 

which reported higher mean levels of LDL cholesterol in breastfed infants compared with 

formula-fed infants. The mean difference was +22 mg/dL (95% CI 15.47 to 29.0 mg/dL). There 

was no statistical heterogeneity. 
69

 In 16 of 17 observations, the mean total cholesterol levels in children or adolescents who 

were breastfed in their infancy were similar to those who were formula-fed. The overall mean 

difference was 0.0 mg/dL (95% CI −2.7 to 2.7 mg/dL). A statistically significant heterogeneity 

was observed across studies. There was no association between total cholesterol level and age or 

gender. There were only four observations of LDL cholesterol levels in children or adolescents. 

The mean levels of LDL cholesterol in children or adolescents who were breastfed in their 

infancy were similar to those who were formula-fed. The mean difference was +0.39 mg/dL 

(95% CI −2.7 to 3.09 mg/dL). There was no statistical heterogeneity between the studies. 

 The mean age of adults evaluated in the primary studies ranged from 17 to 64 years. Lower 

mean total cholesterol levels in adults who were breastfed in their infancy compared with those 

who were formula-fed in their infancy were reported in seven of nine observations. The overall 

mean difference was −6.96 mg/dL (95% CI −2.32 to −11.6 mg/dL). There was no statistically 

significant heterogeneity between the studies. There were only four observations of LDL 

cholesterol reported in adults. Adults who were breastfed in their infancy had lower mean LDL 

cholesterol levels compared with those who were formula-fed. The mean difference was −7.7 

mg/dL (95% CI −3.09 to −12.37 mg/dL). There was no statistical heterogeneity between the 

studies. 

Conclusion 

 Results from the meta-analysis of cohort and case-control studies reported that there was a 

reduction in total and LDL cholesterol levels in adults who were breastfed during infancy 

compared with those who were formula-fed. While higher serum lipid levels were observed in 

infancy, the meta-analysis found that breastfeeding was associated with a reduction in serum 

lipid level in adult life. The significance of higher serum lipid levels observed in infancy is 

unclear and studies have neither shown benefit nor harm from such high levels.86 These findings 

were based on data from adults with a wide age range. The analysis did not segregate the data 

according to gender. Potential confounders were not explicitly analyzed. Detailed information 

(e.g., fasting or non-fasting) on the collection of specimen for cholesterol testing was not 

included. The methodological quality of the meta-analysis was rated grade C. Because of the 

poor methodological quality of the meta-analysis, we find that the conclusions drawn by the 

authors were suspect. We conclude that the relationship between breastfeeding and adult 

cholesterol levels cannot be correctly characterized at this time. 
70

Table 11. Summary of systematic reviews/meta-analyses on the relationship between breastfeeding and total 

cholesterol and low-density lipoprotein cholesterol 

Author 

year 

Number 

of 

subjects 

Population 

Confounders 

considered Study 

description 

Intervention 

/ 

Comparator 

Results 

Quality 

of 

SR/MA 

Combined mean difference (95%CI)

3 age 

strata: Total cholesterol 

(mg/dL) 

LDL 

cholesterol 

(mg/dL) 

Age <1 yr +24.75 (18.95 to 30.55) 

+22.0 

(15.47 to 

29.0) 

1 to 16 yr 0.0 (– 2.7 to 2.7) 

+0.39 

(−2.7 to 

3.09) 

Owen 

2002 

5,829 vs. 

4,852 

≥17 to 65 

yr 

None 

MA of 37 

cohort and 

crosssectional 

studies 

Breastfeeding 

vs. formula 

feeding in 

infancy 

–6.96 (2.32 to 11.6) –7.7 (3.09 

to 12.37) 

C 

LDL, low-density lipoprotein;SR, systematic review; MA, meta-analysis 

Blood Pressure 

Published Systematic Reviews/Meta-Analyses (Table 12) 

 Two meta-analyses evaluated a total of 26 studies of various designs for the effect of 

breastfeeding and formula feeding in infancy on systolic and diastolic blood pressure levels in 

adult life. The primary studies included in these meta-analyses were conducted in developed and 

developing countries. Outcomes assessed were differences in systolic and diastolic blood 

pressures in adulthood. Both meta-analyses examined potential confounders in the studies and 

also explored the possibility of publication bias. Potential confounders considered in the studies 

were age, gender, race, height, and body mass index. Among the 26 primary studies evaluated, 

13 studies were common to both meta-analyses. Both meta-analyses included at least one study 

that included preterm infants. Duration and exclusivity of breastfeeding or formula feeding were 

heterogeneous in the studies. The methodological quality of both meta-analyses were rated grade 

B. 

 The meta-analysis by Martin 2005 included 15 studies with 17 observations published until 

2004 that evaluated a total of 17,503 eligible subjects.83 In these studies, blood pressure was 

measured in subjects whose age ranged from 1 to 60 years. The meta-analysis utilized a random 

effects model. Meta-regression was performed to evaluate the effect of heterogeneity in study 

size, age at measurement of blood pressure (<10 years, 11-45 years, >45 years), maternal recall, 

exclusivity of the feeds, methods of blood pressure measurement, and other variables on the 

summary estimates. Mean systolic blood pressures were reduced by 1.4 mm Hg (95% CI 0.6 to 

2.2) in adulthood among subjects who were breastfed in infancy compared with those who were 

formula-fed. There was a statistically significant heterogeneity across studies for this outcome. 

Mean diastolic blood pressures were reduced by 0.5 mm Hg (95% CI 0.04 to 0.9) in adulthood 

among subjects who were breastfed in infancy compared with those who were formula-fed, with 

no heterogeneity for this outcome. 

 Owen 2003 included 24 studies published until 2003 with 26 observations for systolic blood 

pressure and 23 observations for diastolic blood pressure.84 The meta-analysis evaluated 8,471 

subjects who were breastfed in infancy and 11,292 who were formula-fed. In these studies, blood 

pressure was measured in subjects whose age ranged from 1 to 71 years. The meta-analyses 
71

utilized a random effects model. Subgroup analyses evaluated the effect of heterogeneity in study 

size, age of assessment of outcomes, and year of birth. Mean systolic blood pressures were 

reduced by 1.10 mm Hg (95% CI 0.42 to 1.78) in adulthood among subjects who were breastfed 

in infancy compared with those who were formula-fed. When stratified by age groups (≤1 year, 

>1 to 16 years, ≥17 years), a similar association was observed among age groups that ranged 

from more than 1 year to 16 years. There was a statistically significant heterogeneity for this 

outcome. Mean diastolic blood pressures were reduced by 0.36 mm Hg (95% CI – 0.08 to 0.79) 

among subjects who were breastfed compared with subjects who were formula-fed. There was 

no statistical heterogeneity for this outcome. 

 Both meta-analyses observed smaller association of breastfeeding on systolic blood pressure 

in large studies (>300 and/or >1000 participants) compared with smaller studies. Both metaanalyses attributed this observation to publication bias. Similar effect size reduction of 

breastfeeding on diastolic blood pressure was not observed. In studies that adjusted for potential 

confounders, results remained similar before and after adjustment for potential confounders. 

Conclusion 

 Results from both meta-analyses concluded that there was a small reduction in systolic blood 

pressures among adults who were breastfed in their infancy compared with those who were 

formula-fed. The association weakened after stratification by study size, suggesting the 

possibility of bias. Although both analyses had moderate methodological quality and reported 

similar findings, the authors had different appraisals of the public health importance of the small 

reduction in systolic blood pressure. In conclusion, there is an association between a history of 

breastfeeding during infancy and a small reduction in adult blood pressure, but the clinical or 

public health implication of this finding is unclear. 

Table 12. Summary table for systematic reviews/meta-analyses on the relationship between breastfeeding in 

infancy and blood pressure levels later in life 

Author 

year 

Population 

Confounders 

considered 

Study 

description 

Intervention / 

Comparator Results 

Quality of 

SR/MA 

Limitations 

Combined mean difference (95%CI)

SBP mmHg DBP mmHg 

Martin 

2005 

N=17,503 

Age > 1to 

60 yr 

Meta-analysis of 

15 studies 

(Observations 

within 2RCTs, 8 

prospective 

cohorts, 1 

retrospective 

cohort, and 4 

cross-sectional 

studies) 

Breastfeeding vs. 

formula feeding 

in infancy 

–1.4 

(–2.2, –0.6) 

p=0.001 

–0.5 

(–0.9, –0.04) 

p=0.03 

B 

No pooled 

adjusted 

estimate 

Combined mean difference (95%CI)

Owen 2003 SBP mmHg DBP mmHg 

N=8471 vs. 

11,292 

Age > 1to 

71 yr 

Considered but 

not pooled: age, 

gender, race, 

height, and 

body mass 

index Meta-analysis of 

24 studies 

(Observations 

within 1RCT, 12 

cross-sectional, 

and 11 cohort 

studies) 

Breastfeeding vs. 

formula feeding 

in infancy –1.10 

(–1.8, –0.4) 

– 0.36 

(–0.79, 0.08)

B 

No pooled 

adjusted 

estimate 

SBP, systolic blood pressure; DBP, diastolic blood pressure; SR, systematic review; MA,meta-analysis 
72

Cardiovascular Disease Mortality 

Published Systematic Review/Meta-Analysis (Table 13) 

 We identified one systematic review and meta-analysis that examined the relationship 

between breastfeeding and cardiovascular disease (CVD) mortality in later life.85 Articles were 

included in the systematic review if breastfed infants were compared with bottle-fed infants, if 

the outcome was cardiovascular disease or ischemic heart disease mortality, and if estimates of 

the association between having been breastfed and cardiovascular disease or ischemic heart 

disease mortality could be obtained from the paper or after correspondence with the authors. A 

total of four historical cohort studies from developed countries were identified, involving 25,166 

subjects at baseline and 10,785 subjects at followup. The studies were not graded for their 

methodological quality. The meta-analysis used a random-effects model. Heterogeneity across 

studies was assessed. The methodological quality of this systematic review and meta-analysis 

was rated grade B due to incomplete consideration of the heterogeneity across studies in the 

meta-analyses. 

 The four historical cohorts included in the systematic review and meta-analysis were 

Wingard cohort, 1,373 birth children in California (85 percent in followup); Hertfordshire 

cohort, 5,908 women and 10,374 men born in Hertfordshire (43 percent in followup); Boyd Orr 

cohort, 4,999 men and women from a survey of diet and health in pre-war Britain (71 percent in 

followup); and Caerphilly cohort, 2,512 middle-aged men living in Caerphilly, South Wales (63 

percent in followup). Subjects from these four cohorts were born between 1904 and 1939. 

Potential confounders considered in the association between the risk of CVD mortality and 

breastfeeding in the four studies were age, birth weight, infant health, socioeconomic status, 

and/or birth order. 

 Random-effects model showed little difference in all cause mortality between breast- and 

bottle-fed subjects (pooled rate ratio = 1.01; 95% CI: 0.91 - 1.13, P=0.8), and there was little 

evidence of heterogeneity. Five observations from three studies suggested little or no association 

between breastfeeding and cardiovascular disease mortality in both males and females, and one 

suggested a possible adverse effect (Caerphilly cohort). In random effects meta-analysis, CVD 

mortality was similar in breastfed versus bottle-fed subjects (pooled rate ratio = 1.06; 95% CI: 

0.94 – 1.20), and there was no statistical evidence of between-study heterogeneity. 

 Ischemic heart disease mortality was 6 percent lower among males who had been breastfed in 

the Hertfordshire cohort, but 56 percent higher among breastfed females. This result was in 

agreement with point estimates from the Boyd Orr cohort, suggesting that ischemic heart disease 

mortality was 10 percent lower among males who had been breastfed, but 40 percent higher 

among breastfed females (although there was little statistical evidence of interaction: P = 0.2). In 

Caerphilly, however, ischemic heart disease mortality was 73 percent higher among breastfed 

males. In a random effects meta-analysis (pooled rate ratio = 1.19; 95% CI 0.89 - 1.58, P = 0.3), 

and there was evidence of heterogeneity.

Similar analyses were also performed to examine the association between prolonged 

breastfeeding (> 1 year duration) and the risk of all-cause, CVD, and ischemic heart disease 

mortality in later life. There was little evidence that prolonged breastfeeding was associated with 

all-cause mortality (pooled rate ratio: 0.94; 95% CI 0.71 – 1.24), although there was moderate 

statistical evidence of heterogeneity. There was some evidence that prolonged breastfeeding was 

associated with a 16 percent increase (95% CI 0.99 – 1.36; P = 0.06) in CVD mortality, and no 
73

evidence of inconsistency in estimates. There was little evidence that prolonged breastfeeding 

was associated with ischemic heart disease mortality (rate ratio: 1.08; 95% CI 0.88 – 1.31; P = 

0.5) and there was no heterogeneity. 

Conclusion 

 The authors concluded that the data reviewed did not provide evidence that breastfeeding 

was related to all-cause or CVD mortality. The confidence limits around the point estimates and 

the observed between-study heterogeneity for associations between breastfeeding and ischemic 

heart disease, however, do not rule out important beneficial or adverse cardiovascular effects of 

breastfeeding. 

 There were some possible sources of bias and limitations in the studies reviewed. Two of the 

four studies had followup rate of less than 70 percent of the original population; therefore, 

selection bias cannot be ruled out. Recall bias was possible in the three studies where 

breastfeeding data were collect retrospectively. As confounding and biases may have distorted 

results from individual studies, the statistical combination of estimates into a single rate ratio 

needs to be interpreted with caution. All four studies in the meta-analyses were historical cohorts 

(born between 1904 and 1939). Given the statistical heterogeneity across studies, combining 

study results might not be appropriate. For the outcome of ischemic heart disease mortality, it 

may not be appropriate to combine results for men and women into a single analysis because of 

apparent effect modification by gender. 

 Because of the above limitations, no definitive conclusions can be drawn regarding the 

relationship between breastfeeding and CVD mortality. Further investigation is warranted. 
74

Table 13. Summary of systematic review/meta-analysis on the relationship between breastfeeding and long-term cardiovasculaAuthor year Population 

Study 

description 

Intervention 

/Comparator 

Confounders 

considered Results 

Martin 2004 

Wingard (1994) cohort: 

1373 birth children in California (85% in follow-up) 

Hertfordshire cohort 

(update to 1999): 5908 women and 10374 men born in 11 of 12 districts in Hertfordshire (43% in followup) 

Boyd Orr (2003): 4999 

men and women from a survey of diet and health in pre-war Britain (71% in followup) 

Caerphilly (2003): 2512 

middle-aged men living in Caerphilly, South Wales (63% in followup) 

Total N=25,166 at baseline; 13,302 at followup 

MA of 4 historical cohort studies in developed countries 

Any or exclusively breastfed vs. bottlefed; prolonged (>1 yr) breastfed vs. bottle-fed 

Age, birth weight, 

infant health, 

socioeconomic status, 

number of siblings, 

and/or birth order 

All four studies were historical cohorts born between 

1904 and 1939. 

Five observations from three studies suggested little 

no association between breastfeeding and CVD mortality in both males and females (pooled rate ra1.06; 95% CI: 0.94–1.20), and one suggested a possible adverse effect (Caerphilly cohort). There wno statistical evidence of between-study heterogen

IHD mortality was 6% lower amongst males who had 

been breastfed in the Hertfordshire cohort, but 56% higher amongst breastfed females. This result is in with point estimates from the Boyd Orr cohort suggesting that IHD mortality was 10% lower amonmales who had been breastfed, but 40% higher amongst breastfed females (although there was littstatistical evidence of interaction: p=0.2). In Caerphowever, IHD mortality was 73% higher amongst breastfed males. In a random effects meta-analysis (pooled rate ratio: 1.19; 95% CI 0.89-1.58, p=0.3), was evidence of heterogeneity. 

There was weak evidence that prolonged breastfeed

was associated with a 16% increase (95% CI: 0.991.36; p=0.06) in CVD mortality, and no evidence of inconsistency in estimates. 

There was little evidence that prolonged breastfeedin

was associated with IHD mortality (rate ratio: 1.08; CI: 0.88–1.31; p=0.5) and there was no heterogene

IHD, Ischemic heart disease; CVD, cardiovascular disease; SR, systematic review; MA, meta-analysis 
75

Relationship between Type 1 Diabetes and Breastfeeding 

Background 

 Type 1 diabetes results from destruction of the insulin-producing β cells of the pancreatic islets. 

Various exogenous triggers, such as certain dietary factors and viruses, are thought to induce the 

immune-mediated process leading to extensive β cell destruction.87 Putative mechanisms of 

protection against type 1 diabetes afforded by breast milk include passive immunity provided by 

secretory immunoglobulin A antibodies, increased β cell proliferation observed in breastfed 

compared with formula-fed infants, or delayed exposure to foreign food antigens in exclusively 

breastfed infants.87 In addition, hypotheses have been proposed to explain the putative 

diabetogenicity of cow milk.87 For example, β-lactoglobulin, a cow milk-specific protein, has been 

implicated as a possible trigger of the immune defect, leading to type 1 diabetes. Therefore, 

concerns regarding the safety and advisability of feeding cow milk-based products to infants have 

been raised.88 Gersterin 1994 conducted a systematic review of the epidemiological and clinical 

literature that explored a possible link between cow milk and type 1 diabetes.89 Subsequently, 

Norris and Scott 1996 performed meta-analyses on all published case-control studies from 1966 to 

1994 that examined infant diet exposures and type 1 diabetes.90 Since this meta-analysis, we 

identified six case-control studies that reported outcome of type 1 diabetes in relation to 

breastfeeding during infancy. 

 Commonly considered confounders in the relationship between type 1 diabetes and 

breastfeeding were maternal/parental education, maternal age at birth, birth order, household 

income, race/ethnicity, social class, family history of type 1 diabetes, neonatal illness, and type of 

delivery. 

Published Systematic Reviews/Meta-Analyses (Table 14) 

 Gersterin 1994 conducted a systematic review on literature that explored a possible link between 

cow milk and type 1 diabetes. Articles were excluded if they exclusively used surrogate markers for 

either type 1 diabetes or cow milk exposure. A total of three ecological and time-series studies, 13 

case-control studies, one cohort study, and one case series were included. Meta-analysis of all 

included case-control studies was performed, using a fixed effect model. Both adjusted and 

unadjusted odds ratios were used, but there was no further analysis or discussion on potential 

impacts of confounding by combining unadjusted odds ratios. The methodological quality of the 

systematic review and meta-analysis was rated grade B, due to insufficient consideration for the 

potential confounding in the primary studies. 

 In the included time-series and ecological studies, the results showed an inverse association 

(geographical and temporal) between the rate/prevalence of breastfeeding and the rate/prevalence of 

type 1 diabetes. 

 The cohort study was an analysis of two groups of children born in the UK in 1958 and 1970, 

who were followed for 16 and 10 years, respectively. This study did not find any association 

between breastfeeding for less than 1 month and the risk of development of type 1 diabetes. 

 In the 13 case-control studies in which the neonatal feeding history of patients with type 1 

diabetes and individually matched non-diabetic control subjects were compared, the results were 

mixed. A total of 3,708 type 1 diabetes cases and 20,340 non-diabetic controls were included. None 

of these studies satisfied all six methodological criteria defined by the author. Four of the 13 case-
76

control studies fulfilled five of six methodological criteria (e.g., inclusion of ≥75 percent of eligible 

diabetic patients, unbiased selection of unrelated nondiabetic control subjects, control subjects 

derived from the same population as diabetic subjects, an identical means of determination of infant 

feeding practices in both diabetic and nondiabetic groups, blind determination of early feeding 

history, and identification of diabetic patients from incident cases). When these four studies were 

combined, the overall odds ratio (adjusted odds ratios were used) for type 1 diabetes in patients 

exposed to less than 3 months of breastfeeding was 1.43 (95%CI 1.15 - 1.77; P=0.3 for 

homogeneity). When all 13 included case-control studies were combined, the overall odds ratio 

(mixed crude and adjusted odds ratios were used) for type 1 diabetes in patients exposed to less than 

3 months of breastfeeding was 1.37 (95%CI 1.22-1.53; P=0.11 for homogeneity). 

 In 1996, Norris and Scott performed a meta-analysis of infant diet and type 1 diabetes to 

examine further the inconsistent results reported in the literature. A total of 17 case-control studies 

with appropriate data for meta-analysis were included. The analysis included 4,656 type 1 diabetes 

cases and 16,383 non-diabetic controls. The authors abstracted case and control data for four 

separate exposures: breastfeeding status (ever/never), total breastfeeding duration, exposure to 

breast-milk substitutes, and exposure to cow milk-based substitutes. Due to the limitation of the 

meta-analytic technique, only unadjusted odds ratios were calculated and combined, although some 

primary studies had adjustments for maternal education, maternal age at birth, birth order, 

household income, race/ethnicity, and/or social class. Authors performed sensitivity analyses on 

various characteristics of study methodological quality to explore the impacts of potential biases on 

the summary odds ratios. The methodological quality of this meta-analysis was rated grade B, due 

to insufficient consideration for the potential confounding in the primary studies. 

 The overall odds ratio of all included case-control studies that examined the association between 

never breastfed and type 1 diabetes was 1.13 (95%CI 1.04 - 1.23). Among these studies, fourteen 

also examined type 1 diabetes risk by months of breastfeeding duration. The duration categories in 

the analysis were cumulative, rather than mutually exclusive (i.e., some studies provided data on 

both 3-month and 6 month breastfeeding data in the same subjects). The summary odds ratios 

showed consistently elevated risks of type 1 diabetes associated with age at first exposure to any 

breast milk substitutes before 6 months of age. Since the majority of the studies reported odds ratios 

using a cutoff of 3 months when examining continuous exposures, this cutoff was used for the metaanalysis. The summary odds ratio for type 1 diabetes in subjects who were breastfed for less than 3 

months compared with those who were breastfed for at least 3 months was 1.23 (95%CI 1.12 - 

1.35). 

 Stratified analyses of studies by methodological and study population characteristics were 

performed to see whether differences in these characteristics might explain the heterogeneity. The 

characteristics were prevalent versus incident case-control study design, adequate versus inadequate 

response rates of the cases and controls, the breastfeeding prevalence in the background population, 

the type 1 diabetes risk in the background population, and retrospective versus concurrent infant 

diet assessment. All of these factors had differential impacts on the summary odds ratios for the risk 

of type 1 diabetes associated with infant diet exposures. 

 Norris and Scott concluded that their meta-analysis showed that the increased risk of type 1 

diabetes associated with any of the infant diet exposures was small. According to these authors, 

interpretation of weak associations (i.e., an odds ratio of less than 2.0) can be problematic, since 

weak associations can more readily be explained by biases. 
77

Studies Identified after the Published Systematic Reviews/MetaAnalyses/Systematic Review (Table 15) 

 We only included all studies that examined the outcome of type 1 diabetes in relation to 

breastfeeding in developed countries. To be consistent with previous meta-analyses, articles were 

excluded if they only used surrogate markers for type 1 diabetes (e.g., the presence of islet cell 

antibodies). A total of six case-control studies were identified,91-96 The studies included 1,293 

patients with type 1 diabetes and 3,262 control subjects. Five studies were conducted in Europe, and 

one in Taiwan. Four studies were rated grade B in methodological quality; two studies were rated 

grade C. Commonly considered confounders in these studies were family history of type 1 diabetes, 

neonatal illness, maternal age at birth, birth order, maternal/parental education, and type of delivery. 

 In four studies, the definition of type 1 diabetes cases was children with juvenile-onset diabetes 

(or developing diabetes before 17 years of age). In the other two studies, the cases were registered 

type 1 diabetes patients who were younger than 30 years of age and children with diabetes who 

were identified through hospital records. Matched controls were those without type 1 diabetes 

selected from various sources in the same population as the cases. 

 Three studies reported odds ratio of type 1 diabetes comparing subjects who were ever breastfed 

with those who were never breastfed. Two studies found a reduced risk of type 1 diabetes in 

subjects who were ever breastfed (ORs 0.5695 and 0.7591), while the third study reported an 

increased risk (OR 2.4494). 

 Three studies compared subjects who were breastfed for more than 3 months or 6 months with 

those who were never breastfed. Two studies reported a reduced risk of type 1 diabetes in subjects 

who were breastfed for more than 3 or 6 months (adjusted OR 0.5796 and 0.2595, respectively). The 

third study94 reported an opposite finding (this was the same study that reported an increased risk 

with ever breastfed). A reduced risk of type 1 diabetes was found when comparing subjects who 

were never breastfed with those who were breastfed for more than 6 months (adjusted OR 0.36, 

95%CI 0.14 - 0.94). The data also showed a slight increase in the risk of type 1 diabetes with longer 

duration of breastfeeding (1 month increment). The control subjects in this study were selected from 

children admitted to the same hospital as the cases, whether this explained the finding was unclear. 

 One study reported a reduced risk of type 1 diabetes comparing subjects who were initially 

exclusively breastfed with those who were not (adjusted OR 0.6, 95%CI 0.41 - 0.89).93 Another 

study found a small, but non-significant increased risk of type 1 diabetes with not breastfeeding at 

discharge (RR 1.33, 95%CI 0.76 - 2.31).92 This study was rated to have poor methodological quality 

because only univariate analysis was performed and potential confounders were not considered. 

Conclusion 

 Our findings from the six additional case-control studies are similar to the findings from the two 

meta-analyses. However, the exclusivity of breastfeeding was not addressed in all studies, and the 

assessment of infant diet was based on long-term recall in five of six studies. We elected not to 

perform a meta-analysis, because it is unlikely to change the pooled estimates from the previous 

meta-analyses by adding additional three studies from the updates that compared subjects who were 

breastfed for more than 3 or 6 months with those who were never breastfed. 

 Two meta-analyses of moderate methodological quality reported statistically significant odds 

ratios of 1.23 and 1.43, respectively, for the risk of type 1 diabetes in subjects exposed to less 

than 3 months compared with more than 3 months of breastfeeding. Since case-control studies are 

prone to recall biases, Norris and Scott compared the odds ratios in studies relied on long-
78

term recall to assess infant diet with studies that did not. The results showed that studies using 

existing infant records to determine breastfeeding initiation and duration failed to show the 

associations reported in the studies relying on long-term recall for their exposure data. This 

suggests that subjects with type 1 diabetes were more likely to report shorter duration of 

breastfeeding than control subjects. 

 In conclusion, even though there is some evidence to suggest that breastfeeding for more 

than 3 months is associated with a reduced risk of type 1 diabetes, this evidence must be 

interpreted with caution because of the possibility of recall biases and suboptimal adjustments 

for potential confounders in the primary studies. 
79

Table 14. Summary of systematic reviews/meta-analyses on the relationship between breastfeeding and type 1 diabetes Author Year Population Study description Intervention /Comparator Confounders considered Results Norris 1996 Case-control studies in which the neonatal feeding histories of patients with type 1 DM and individually matched non-DM control subjects were compared Cases: 4,656 Controls: 16,383 

MA of 17 casecontrol studies published from 1966 to 1994. 

A=breastfeeding status (ever/never) B=total breastfeeding duration C=exposure to breastmilk substitutes D=exposure to cow’s milk-based substitutes 

Maternal education, maternal age at birth, birth order, household income, race/ethnicity, social class 

The summary OR for type 1 DM in patients w

were never being breast-fed was 1.13 (95% 1.04-123). 

The summary OR for type 1 DM in subjects w

were breast-fed for < 3 mo compared with twho were breast-fed for at least 3 mo was (95%CI 1.12-1.35). 

Stratified analyses of studies were performed 

prevalent vs. incident case-control study deadequate vs. inadequate response rates of cases and controls, the breastfeeding prevalence in the background population, ttype 1 DM risk in the background populatioand retrospective vs. concurrent infant diet assessment. All of these factors had impacthe summary ORs for the risk of type 1 DM associated with infant diet exposures. 

Gerstein 1994 Case-control studies in which the neonatal feeding histories of patients with type 1 DM and individually matched non-DM control subjects were compared Cases: 3,708 Controls: 20,340 

A SR review of 3 ecological and timeseries studies, 13 case-control studies, one cohort study, and one case series. MA was performed for the case-control studies. 

Cow’s milk exposure (and therefore nonexclusive breastfeeding) vs. Cow’s milk avoidance (and therefore breastfeeding) 

ND Results from the 13 case-control studies were 

mixed. The combined OR for type 1 DM in patients exposed to < 3 mo of breastfeedinwas 1.38 (95% CI 1.22-1.53; p=0.11 for homogeneity). 

An analysis of 2 cohorts of children born in the 

in 1958 and 1970 followed for 16 and 10 yrrespectively, failed to show any association between breastfeeding for < 1 mo and type DM.

None of the 13 case-control studies fulfilled a

methodological criteria. Four case-control studies (31%) fulfilled five out of the six crit(considered high quality) 

MA, meta-analyses; SR, systematic review 
80

Table 15. Summary of case-control studies on the relationship between breastfeeding and type 1 diabetes Author OR* (95% CI) year Country 

Cases 

(N) 

Control 

(N) 

Definition 

of type 1 

DM 

Mean 

Age at 

Dx (year) 

Breastfeeding 

group 

Comparator 

group Crude Adjust 

Potential confound

adjusted 

EURODIAS 2002 Europe 

610 1616 

Onset < 15 

yr in 1989-

1995 

ND Ever BF Never BF 0.75 (0.58-0.96) 0.59 (0.35-0.97) Ht SDS, Wt SDS

maternal age, jaund

RTI, Vit D suppl, asth

McKinney 1999 UK 

196 325 

Onset < 16 

yr in 1993-

1994 

0-15 Initial exclusive BF Initial not exclusive BF 0.68 p=0.04 0.60 (0.41-0.89) 

[Sex, age]a, maternal 

maternal type 1 DM

preeclampsia, C-sec

neonatal illnesses 

Ever BF Never BF 0.56 (0.40-1.2) 

BF < 6 mo 0.82 (0.47-1.42) 0.84 (0.45-1.59) Tai 1998 Taiwan 177 193 

Registered type 1 DM, 

age < 30 yr, 

born in 

1984-1993 

8.3 

BF 

≥ 6 mo 

Never BF 0.39 

(0.16-0.94) 

0.25 

(0.09-0.69) 

[Age, sex, parenta

education]a, birth ord

paternal age, GA, typ

delivery, BW, month

family income 

Ever BF Never BF 2.44 (1.10-7.14) 

 BF 3-5 mo 0.85 (0.37-1.92) 

BF > 6 mo BF 1-2 mo 2.08 (0.18-5.26) 

 BF 0 mo 2.78 (1.06-7.14) 

Meloni 1997 Italy 

100 100 

Onset < 17 

yr in 1983-

1994 

6 (1-15) 

BF as continuous coefficient (1 

mo increment) 

1.10 

(0.99-1.22) 

[Age, sex]a, mother

education, number 

siblings 

Visalli 2003 Italy 150 750 

Onset < 15 

yr, born 

in1977-

1989 

ND BF 

≥ 3 mo BF < 3 mo 0.47 (0.31-0.72) 0.57 (041-0.74) 

[Age]a, family history 

type 1 DM, infectio

disease during pregna

eczema 

Jones, 1998 UK 

60 458 

Dx at 

discharge, 

born in 

1976-1986 

ND BF at discharge Not BF at discharge 0.75 (0.43-1.32) [Age, sex]a 

Dx, diagnosis; BF, breastfeeding; SR, systematic review; MA, meta-analysis; SDS, standard deviation score; Ht, height; Wt, weight; RTI

D suppl, Vitamin D supplementation; C-section, delivery by cesarean section; GA, gestational age; BW, birth weight; LTC, long-term SES, socioeconomic status

*Odds ratio of type 1 DM, compared the breastfeeding group to the comparator group (or the reference group), unless noted a Matching factors for controls
81

Relationship between Type 2 Diabetes and Breastfeeding 

Background 

 In 2002, it was estimated that a total of 18.2 million people, or 6.3 percent of the US 

population carried a diagnosis of diabetes (cdc.gov/diabetes/pubs/estimates.htm#prev). No data 

are currently available on the prevalence of type 2 diabetes in children and adolescents. The 

Centers for Disease Control and Prevention (CDC) estimated that among new cases of childhood 

diabetes, the proportion of those with type 2 diabetes ranges between eight percent and 43 

percent (www.cdc.gov/diabetes/pubs/factsheets/search.htm). Type 2 diabetes begins when the 

body develops a resistance to insulin and no longer uses insulin properly. Adults and children 

who develop type 2 diabetes are typically overweight or obese and have a family history of the 

disease. Furthermore, offsprings of mothers who had diabetes during pregnancy had higher rates 

of type 2 diabetes and obesity.97 It is increasingly recognized that nutrition in early postnatal life 

may have long-term physiologic effects. Studies have suggested that breastfeeding may be 

protective against later obesity.77,78 Therefore, it seems biologically plausible that there may be a 

relationship between breastfeeding and long-term glucose and insulin metabolism. 

 We identified one systematic review by Taylor et al.98 in our initial literature search and we 

also identified one additional systematic review by Owen et al.99 during final phase for the 

preparation of this report. We did not identify any additional systematic reviews. 

 Commonly considered confounders in the studies of relationship between type 2 diabetes and 

breastfeeding were age, sex, BMI, birth weight, socioeconomic status, history of parental 

diabetes, maternal diabetes during pregnancy, maternal diet and smoking, and prepregnancy 

BMI. 

Additional Methodological Comments 

 We have elected to describe in details only the Owen 2006 systematic review because it 

superseded the Taylor 2005 systematic review. Owen 2006 included two of the three primary 

studies that were covered in Taylor 2005. In addition, Taylor 2005 was of poor methodological 

quality because there was no synthesis of results and it was unclear how conclusions were drawn. 

Published Systematic Reviews/Meta-Analyses (Table 16) 

 Owen 2006 conducted a systematic review and meta-analyses to examine the influence of 

breastfeeding on type 2 diabetes and blood glucose and insulin concentrations.99 Studies that did 

not provide the odds ratios of type 2 diabetes comparing breastfed to formula-fed subjects were 

excluded. In addition to two of the three studies included in the Taylor 2005 review (the third 

study was excluded from Owen 2006 because it did not provide odds ratio of the disease), five 

additional studies were identified in the Owen 2006 review. Seven studies (six in adults and one 

in adolescents) totaling 76,744 subjects provided odds ratios that related initial infant feeding 

methods and type 2 diabetes were included in the meta-analyses. There were three historical 

cohort, two cross-sectional, one prospective cohort, and one case-control studies. All seven 

studies were conducted in developed countries. The effects of study size, year of birth, the 

method of ascertainment of infant feeding status (whether contemporary or recalled up to 71 
82

years after birth), type of formula feeding, study response rate, study design, and whether infants 

were born pre- or full-term were examined by using meta-regression and sensitivity analyses. 

Sensitivity analyses were also used to examine the effect of adjustment for important 

confounders and of fasting status. The methodological quality of this systematic review and 

meta-analyses was rated grade A.

 Six of seven studies related breastfeeding to a lower risk of type 2 diabetes, and there was no 

evidence of heterogeneity across studies. Overall, the subjects who were breastfed showed a 

lower risk of type 2 diabetes than those who were formula-fed (pooled adjusted OR 0.61; 95%CI 

0.44-0.85, P=0.003). Three studies considered the effects of potential confounding by birth 

weight, parental diabetes, socioeconomic status, and individual or maternal body size, while the 

other four studies only considered the effects of confounding by age, sex and/or birth weight. 

However, the odds ratio relating breastfeeding and diabetes risk was similar before (OR 0.55; 

95% CI: 0.35-0.86; P=0.009) and after adjustment for all the important confounders (OR 0.55, 

95% CI 0.34-0.90; P=0.017) in the three studies. The method of ascertaining feeding exposure 

was unrelated to the odds ratios, although there was insufficient power to detect appreciable 

differences in examining the effect of potential biases (such as study size, year of birth, the 

method of ascertaining infant feeding status, type of formula feeding, study response rate, study 

design, and whether infants were born pre- or full-term) by using meta-regression and sensitivity 

analyses. 

Studies Identified after the Published Meta-Analysis/Systematic 

Review 

 None was found. 

Conclusion 

 Results from a high-quality systematic review and meta-analyses of seven studies suggest 

that breastfeeding is associated with a lower risk of type 2 diabetes in later life, compared with 

formula feeding. Comparing subjects who were ever breastfed to those who were formula fed, 

the pooled adjusted odds ratio of type 2 diabetes in later life was 0.61 (95%CI 0.44-0.85). 

However, only three studies appropriately adjusted for all the important confounders, including 

birth weight, parental diabetes, socioeconomic status, and individual or maternal body size. Even 

though these three studies found that adjustment did not alter the crude estimate, we cannot be 

completely confident that potential confounding by birth weight and maternal factors has been 

ruled out for the overall pooled estimate. This could lead to an overestimate of the association. 

Publication bias is also a possible explanation for the consistent associations observed in these 

studies. 
83

Table 16. Summary of systematic reviews/meta-analyses on the relationship between breastfeeding and type 2 diabetes Author Year Population Study description Intervention /Comparator Confounders considered Results Owen 2006 N=76,744 6 studies conducted in adults and 1 study conducted in adolescents 

MA of 7 studies (3 historical cohort, 2 cross-sectional, 1 prospective cohort and 1 case-control studies) 

Ever breastfed vs. formula fed in all 7 studies. Feeding status was reported as being exclusive in one of these studies. 

Age, sex, BMI, birth weight, socioeconomic status, parental diabetes, maternal diabetes in pregnancy, hospital duration in infancy, maternal diet and smoking, and prepregnancy BMI 

• Overall, the subjects who were brea

showed a lower risk of type 2 diabetes did those who were formula fed (poole0.61; 95%CI 0.44-0.85; p=0.003). 

• OR relating breastfeeding and diab

risk was similar before (0.55; 95% CI: 00.86; p=0.009) and after (0.55, 95% C0.90; p=0.017) adjustment in 3 studies had information on relevant confounde

Taylor 2005 N=1,430

Age, sex, birth date, parental diabetes, and birth weight 

• In a retrospective cohort study of 720 

age 10-39 years old, type 2 diabetes (dby OGTT testing) was 59% less commexclusively breastfed people compared those who were exclusively bottle-fed (adjusted OR: 0.41; 95%CI 0.18-0.93) 

GDM, use of traditional diet, smoking, and alcohol during pregnancy, mother’s prepregnancy BMI, and birth weight 

• In a case-control study of native Ca

Some breastfeeding for one year or lonwas a significant independent predictofuture diabetes (adjusted OR: 0.24; 950.07-0.84) as was some breastfeeding months of longer (adjusted OR: 0.36; 90.13-0.99). 

People of all ages 

Systematic review of 2 cohort studies and 1 case-control study 

Variable 

None • Type 2 diabetes (defined by OGTT 

in the next generation was less commoamong children who were breastfed exclusively for > 2 months (6.9% vs. 30among offspring of women without diaand women with diabetes, respectivelyamong bottle-fed children (11.9% vs. 4respectively). 

GDM, gestational diabetes; OGTT, oral glucose tolerance test; BMI, body mass index (kg/m2); SR, systematic review; MA, meta-analysis 
84

Relationship between Childhood Leukemia and 

Breastfeeding 

Background 

 Leukemia, the most common cancer in children, encompasses multiple diseases including 

three types: acute lymphocytic leukemia (ALL), acute myelogenous leukemia (AML), and 

chronic myelogenous leukemia. In the United States, approximately 3,250 children are diagnosed 

with leukemia each year and 2,400 (74 percent) of them have ALL. With the exception of 

prenatal exposure to x-rays and specific genetic syndromes, little is known about the causes of 

childhood ALL (National Cancer Institute: seer.cancer.gov/publications/childhood/ 

leukemia.pdf). Although the majority of human leukemias or lymphomas have no readily 

identifiable infectious etiologies, viral causes have been identified for Burkitt’s lymphoma and a 

rare form of adult leukemia/lymphoma.100,101 Because breast milk is noted for providing passive 

immunity and protection of newborns from some early infections, investigators have 

hypothesized that breastfeeding may reduce the risk of childhood leukemia.102

 Some of the confounders that had been considered in the studies of the relationship between 

childhood leukemia and breastfeeding were age, sex, race, socioeconomic status (such as 

mother’s education, region of residence at the time of diagnosis, parental occupation, deprivation 

index, and/or annual household income), parental alcohol consumption, parental smoking, birth 

order, birth weight, parity, and age of mother at birth of index child. 

Additional Methodological Comments 

 We identified four systematic reviews or meta-analyses that examined the relationship 

between breastfeeding and childhood leukemia103-106 We have elected to describe in details only 

the Guise 2005104 systematic review and Kwan 2004106 meta-analysis because they superseded 

the Beral 2001103 meta-analysis and Davis 1998105 systematic review. All studies included in 

Beral 2001 and Davis 10998 were also included in Kwan 2004 or Guise 2005, except that Guise 

2005 review excluded studies published before 1990, unpublished data, and studies conducted in 

developing countries. Kwan 2004 also included three additional studies published after 2001. In 

addition, the reporting and analysis in Beral 2001 and Davis 1998 were poor due to deficiency in 

reporting of the meta-analysis methods, search strategy and/or study eligibility criteria, and there 

was a lack of consideration of potential confounding in the included studies. 

 Guise 2005’s systematic review was the only study that reported methodological grading for 

individual studies. Guise 2005 did not perform a meta-analysis. Kwan 2004 combined all casecontrol studies regardless of their study quality into a meta-analyses. To understand further how 

study quality can affect the effect estimate, we decided to perform meta-analyses on the effect 

estimates from the four studies graded as good or fair quality in Guise 2005’s systematic review. 

Published Systematic Reviews/Meta-Analyses (Table 18) 

 Guise 2005 conducted a systematic review of case-control studies related to breastfeeding 

and the risk of childhood leukemia. Ten case-control studies totaling 9,653 subjects with 

leukemia were included. All the studies were conducted in developed countries. Study quality 
85

was rated by the authors in a three-levels scale: good, fair, or poor. The following aspects of the 

study quality were assessed: reliability of the diagnoses of leukemia, comparability of the case 

and control groups, differences in nonrespondents in cases versus controls, and the conduct of 

controlling for confounding. There were two good, two fair, and six poor quality studies. All 

studies but one focused solely on childhood leukemia. There was no meta-analysis or statistical 

analysis performed. The methodological quality of this systematic review was rated grade A. 

Many of the studies in Guise 2005 systematic review did not provide data on exclusivity of 

breastfeeding and did not consider potential confounders such as infectious exposures from 

household or school contacts. Six of the ten studies explicitly sought to characterize the 

relationship between breastfeeding and leukemia. 

Guise 2005 concluded that the few high-quality studies disagreed in regards to the 

association between breastfeeding and the risk of ALL. Specifically, the two good-quality 

studies, or UKCCS and CCG study,103,107 presented “conflicting results” (Table 17). Similarly, 

the two fair-quality studies disagreed on the protective effect of breastfeeding. 

 Kwan 2004 conducted a meta-analysis of 14 case-control studies on breastfeeding and the 

risk of childhood leukemia. A total of 8,051 subjects with leukemia were included in the 

analysis. The meta-analysis examined the relationship between short-term breastfeeding (defined 

as breastfeeding for 6 months or less) or long-term breastfeeding (defined as breastfeeding for 

more than 6 months) and the risk of childhood leukemias. Twelve studies from developed 

countries and two studies from developing countries, including any type of leukemia in children 

15 years or younger that reported odds ratio and duration of breastfeeding, were included in the 

meta-analysis. Kwan 2004 did not formally assess the individual study quality. However, the 

potential for confounding in each study was considered in the meta-analysis. The methodological 

quality of this meta-analysis was rated grade A. 

For each of the 14 primary studies in the meta-analysis, Kwan 2004 selected odds ratio 

adjusted for SES when available. The meta-analysis showed a statistically significant reduced 

risk of ALL with short- and long-term breastfeeding (OR 0.88, 95%CI 0.80 - 0.96; OR 0.76, 

95%CI 0.68 - 0.84, respectively). The analysis reported a statistically significant reduction in 

AML for long-term breastfeeding (OR 0.85, 95%CI 0.73 - 0.98) but not for short-term 

breastfeeding (OR 0.90, 95%CI 0.80 - 1.02). The unadjusted and adjusted odds ratios for 

reduction of the risk of ALL in short-term breastfeeding were both statistically significant. For 

reduction of the risk of ALL in long-term breastfeeding, only the adjusted odds ratio was 

statistically significant. The same sensitivity analyses were performed for the reduction of the 

risk of AML in short- and long-term breastfeeding, and similar results were found. 

Studies included in the additional analysis. Guise 2005 identified two good and two fair 

methodological quality studies. We have analyzed these studies further as detailed below. 

 The two good studies were the UKCCS and the CCG studies. The UKCCS included 1,401 

(87 percent) ALL and 214 (13 percent) AML case patients recruited from health programs that 

enrolled 98 percent of the total childhood cancers throughout England, Scotland and Wales over 

the period 1991-1998; control subjects were selected from population-based health rosters. In 

contrast, the CCG study included 1,744 (79 percent) ALL and 456 (21 percent) AML case 

patients enrolled from specific CCG centers, and control subjects were selected via randomdigit-dialing. Both studies excluded leukemia diagnoses less than 1 year of age because most 

leukemias occurring during infancy are thought to have different etiologies from childhood 

leukemias. Both studies found that long-term breastfeeding (> 6 months duration) was protective 

for ALL, but the confidence interval for the risk estimate from the UKCCS did not exclude unity 
86

(1.00), whereas the confidence interval for the risk estimate reported by the CCG study clearly 

excluded unity (1.00), indicating statistical significance. The UKCCS, however, found no 

association between short- or long-term breastfeeding and the risk of AML, while the CCG study 

found a significant protective effect of long-term breastfeeding for AML. 

 The two fair quality studies were Dockerty 1999 and Rosenbaum 2000. They were graded 

fair quality due to potential selection biases.108,109 Dockerty 1999 included 121 newly diagnosed 

leukemia cases (ages 0-14 years) and 121 age- and sex-matched control subjects selected 

randomly from the New Zealand national birth records. The primary purpose of the study was to 

examine the relationship between infections, vaccinations, and the risk of childhood leukemia. 

Breastfeeding was one of the secondary factors examined in the study. Compared with children 

who never breastfed, those who breastfed for more than 6 months to 1 year had about a 20 

percent reduced risk of ALL; those who were breastfed for more than 1 year had the lowest risk 

(OR 0.47; 95%CI 0.15 – 1.43). Even though these estimates were not statistically significant 

(Table 22), a trend analysis indicated a statistically significant effect in reducing the risk of ALL 

with increasing duration of breastfeeding (P = 0.04). Rosenbaum 2000 included 255 ALL cases 

from hospital registries and 760 matched control randomly selected from birth certificates in US. 

This study aimed to examine the relationship between early child-care (including breastfeeding) 

and the risk of childhood ALL. Like Dockerty 1999, children under 1 year of age were included 

in Rosenbaum 2000. The analysis of the relationship between breastfeeding and the risk of 

childhood ALL did not adjust for any other potential confounders, except for the factors used to 

identify matched controls (gender, race, and birth year). They found that 47 percent of cases of 

ALL and 51 percent of control were breastfed at birth (OR 1.20, 95%CI was not reported). This 

association was not statistically significant. 

 Meta-analysis. We used a random-effects model to combine SES-adjusted odds ratios of 

ALL in relation to short-term (≤ 6 months) and long-term (> 6 months) breastfeeding from 

UKCCS103, CCG107study, and Dockerty 1999 (Table 17). Rosenbaum 2000 was excluded from 

the analysis because the duration of breastfeeding was not reported. The results from our metaanalysis suggest that long-term breastfeeding is associated with a reduction in the risk of ALL 

(OR 0.80; 95%CI 0.71 - 0.91). 
87

Table 17. Combined SES-adjusted ORs of ALL for the three case-control studies rated as good and fair 

methodological quality in the systematic review by Guise et al. (2005) 

Study OR (≤ 6 mo vs. never BF) Lower CI Upper CI 

UKCCS 2001 

 <1 mo 0.90 0.77 1.04 

 1-6 mo 0.98 0.82 1.17 

CCG study 1999 0.86 0.73 1.01 

Dockerty 1999 1.24 0.47 3.23 

Pooled 0.91 0.83 1.00 

Kwan 2004 meta-analysis results 0.88 0.80 0.96 

 

Study OR (> 6 mo vs. never BF) Lower CI Upper CI 

UKCCS 2001 0.89 0.75 1.05 

CCG study 1999 0.72 0.60 0.87 

Dockerty 1999 

 >6 mo to 1 yr 0.82 0.29 2.27 

 >1 yr 0.47 0.15 1.43 

Pooled 0.80 0.71 0.91 

Kwan 2004meta-analysis results 0.76 0.68 0.84 

 

Conclusion 

Our meta-analyses of the three case-control studies concerning breastfeeding and the risk of 

ALL were consistent with the results from Kwan 2004’s meta-analysis, but with smaller effect 

size and smaller statistical significance (Table 17). Kwan 2004 also found an association 

between a history of breastfeeding and a reduced risk of AML. We conclude that there is 

association between a history of breastfeeding of at least 6 months duration and a reduction in 

the risk of both ALL and AML. 

Further evaluation of the biological mechanisms underlying this relationship while taking 

into consideration potential biases can be achieved with more large-scale case-control studies 

utilizing population-based and socioeconomic status-matched controls. 
88

Table 18. Summary of systematic reviews/meta-analyses on the relationship between breastfeeding and childhood leukemia Author Year Population 

Study 

description 

Intervention 

/Comparator Confounders considered Results 

Guise 2005 Childhood ALL or all childhood leukemias: 9,653 

SR of 10 casecontrol studies in developed countries 

Any measures of breastfeeding and comparators 

Gender, year of birth, race, SES (region of residence, maternal education, family income), gestational age, birthweight, maternal age, and smoking 

• Six studies were conducted in European countr

Six of the studies explicitly sought to characterizthe relationship between breastfeeding and leukemia as the primary objective, whereas the others included breastfeeding measures from thperspective measuring broader characteristics othe immune system and early infections in the etiology. Of the 10 studies, 2 were of good qual2 were of fair quality, and 6 were of poor quality

• The 2 good-quality studies (UKCCS and CCG 

studies) present “conflicting results” regarding tassociation between breastfeeding and leukem

• Similarly, the 2 fair-quality studies disagreed on 

the protective effect of breastfeeding. 

Kwan 2004 Children with ALL, AML or ANLL: 6,835 (Note: 8 of the 14 studies excluded cases of leukemia in infants) 

MA of 14 casecontrol studies in both developed and developing countries 

Compared short-term breastfeeding (≤6 

months) or long-term breastfeeding (>6 months) to no breastfeeding or never been breastfed 

Age, sex, race, SES (mother’s education, region of residence at the time of diagnosis, parental occupation, deprivation index, and/or annual household income), parental alcohol consumption, parental smoking, birth order, birthweight, parity, age of mother at birth of index child. 

• A significant negative association was observed 

between short-term breastfeeding and ALL (OR=0.88, 95% CI 0.80-0.96), but the AML res(OR=0.90, 95% CI 0.80-1.02) were not significa

• A significant negative association was observed 

between long-term breastfeeding and ALL (OR=0.76, 95% CI 0.68-0.84), and AML (OR=0.85, 95% CI 0.73-0.98). 

Beral 2001 Children with all leukemia, including ALL: 7,401 

MA of 15 casecontrol studies in both developed and developing countries 

Compared ever breastfeeding, breastfeeding duration ≤ 6 months, or breastfeeding duration > 6 months to never been breastfed 

ND • There is evidence of a statistically significant 

reduction in the OR associated with ever having been breastfed (OR=0.86, 95%CI 0.81-0.92) anhaving been breastfed for more than 6 months (OR=0.78, 95% CI 0.71-0.85). 
89

Table 18. Continued Author Year Population 

Study 

description 

Intervention 

/Comparator Confounders considered Results 

Davis 1998 Children with all leukemia, ALL or ANLL: 1,656 

SR of 5 casecontrol studies in developed countries 

Compared any breastfeeding, or longterm breastfeeding (6-8 months) to artificial infant feeding (or never been breastfed) 

None • None of the included studies reported a signific

association between all leukemia, ALL or ANLL and infant feeding. 

ALL, acute lymphocytic leukemia; ANLL, Acute non-lymphocytic leukemia; AML, acute myeloid leukemia; SES, socioeconomic status; Smeta-analysis 
90

Relationship between Infant Mortality and Breastfeeding 

Background 

 Infant mortality (both neonatal and post-neonatal mortality) is on the decline in both 

developing and developed countries during the past four decades. In the United States, the 

national average of infant mortality was 7.0 deaths per 1000 live births in 2002.110 Leading 

causes of infant death in a developed country include congenital abnormalities, pre-term births, 

low birth weight, Sudden Infant Death Syndrome (SIDS), problems related to complications of 

pregnancy, and respiratory distress syndrome.110 The common risk factors that are associated 

with infant mortality include infant and maternal age, gender, race, socioeconomic status, birth 

order, birth weight, congenital malformation at birth, and maternal smoking during pregnancy. 

Breastfeeding protects against infectious diarrhea and respiratory diseases, which are the leading 

causes of infant mortality in developing countries.111 However, the role of breastfeeding in 

preventing infant deaths in developed countries is less clear. We elect to review the relationship 

between breastfeeding and post-neonatal mortality. 

Additional Methodological Comments 

 For this section, infant mortality is defined as any death that occurred more than 1 month but 

less than 12 months after birth. Neonatal mortality (death < 1 month of age) is not considered in 

this review. No published meta-analysis was identified that evaluated the relationship between 

breastfeeding and infant mortality. We included only studies conducted in developed countries 

that evaluated the relationship between breastfeeding and infant mortality (excluding SIDS). 

Results (Table 19) 

 We identified two studies conducted in the United States that evaluated the role of 

breastfeeding in infant deaths other than SIDS.112,113; one study did not qualify for inclusion in 

this review because it was an analysis based on data collected from cross-sectional surveys.113

The study that qualified for inclusion was a case-control study that selected subjects from 

nationally representative samples.112 The study excluded infants who died at less than one month 

of age. The methodological quality of the study was rated grade B. 

 Chen 2004 analyzed the 1988 US National Maternal and Infant Health Survey (NMIHS) data 

using a case-control study design. Their sample included 1,204 infants who died between 28 

days and 1 year of age. The authors excluded infants who died from congenital anomalies or 

malignant tumors. In an attempt to address the issue of reverse causality, only infants who 

survived beyond the neonatal period were included and feeding status was categorized based on 

the assessments undertaken some time before death occurred. The controls included 7,740 live 

births who were alive and older than 1 year of age at the time of survey. Mothers were surveyed 

using a mailed questionnaire. Breastfeeding was assessed as “ever breastfed” or “never 

breastfed.” The study did not report the mean or the range of duration of maternal recall for 

breastfeeding. Overall and cause-specific odds ratios were calculated to evaluate “ever” versus 

“never” breastfeeding. Since there was an oversampling of black and low birth weight infants in 

the original sample, in order for the study population to be more representative of the US 
91

population, additional analyses were performed with SUDAAN software adjusted samples. This 

adjusted sample included a total of 9,145 cases and 3,186,497 controls. The analyses were 

adjusted for sampling strategy and potential confounders such as maternal age, education, 

smoking, infant gender, race, birth weight, congenital malformation, live birth order, plurality, 

and status of enrollment in the Special Supplemental Nutrition Program for Women, Infant, and 

Children program (WIC). The study reported that the odds of death in the postneonatal period 

were 21 percent lower for “ever breastfed” compared with “never breastfed” infants. However, 

in subgroup analyses of cause-specific death, the only statistically significant association was 

reported between SIDS (in the original sample) or injury-related death (in the SUDAANadjusted sample) and “never breastfed” status. 

Conclusion 

 One study of moderate methodological quality using a large sample of infants reported a 

protective effect of breastfeeding in reducing infant mortality after controlling for some of the 

potential confounders. However, in subgroup analyses of the study, the only statistically 

significant association reported was between “never breastfeeding” and SIDS or the risk of 

injury-related deaths. Because of the limited data in this area, the relationship between 

breastfeeding and post-neonatal infant mortality remains unclear. Further research is warranted. 
92

Table 19. Summary of case-control study on the relationship between breastfeeding and infant mortality 

OR* (95% CI) 

Author year Country 

Cases 

(N) 

Control 

(N) 

Definition 

of infant 

mortality 

Mean 

Age at 

Dx 

(year) 

Breastfeeding 

group 

Comparator 

group Crude Adjust 

Poten

confoun

adjus

Postneonatal 

death a

(9145) 

Live birth a

(3 186 497) nd 0.79 (0.67-0.93) Chen 2004 

USA National Maternal and Infant Health Survey 1998 (NMIHS) 

Postneonatal 

death b 

(1204) 

Live birth b 

(7740) 

Death > 28d of age % Ever % Never 

nd 0.76 (0.65-0.88) 

Maternal: aeducation, smoking Infant: genrace, birth wcongenital malformatiobirth order, plurality, anstatus 

a SUDAAN software adjusted sample b Original sample 
93

Relationship between Sudden Infant Death Syndrome (SIDS) 

and Breastfeeding 

Background 

 Sudden infant death syndrome (SIDS) is the leading cause of mortality among infants aged 

1 to 12 months in the United States.114 SIDS accounted for a death rate of 0.55 per 1000 live 

births for the year 2004 according to the National Center for Health Statistics (NCHS) at CDC 

(www.cdc.gov/nchs/deaths.htm.). Several modifiable risk factors for SIDS are sleeping 

positions, maternal smoking, and bed sharing. Other potential risk factors include birth weight, 

gender, and socioeconomic status. The relationship of breastfeeding and SIDS has been 

evaluated among a broad range of potential risk factors. However, the role of breastfeeding as a 

protective factor in SIDS is unclear. One meta-analysis published in 2000 assessed the 

relationship of breastfeeding and SIDS. 

Additional Methodological Comments 

 We identified four eligible studies conducted in developed countries that evaluated the role 

of breastfeeding in SIDS, and published since 1997, the cutoff date for the literature search of the 

published meta-analysis. . 

Published Systematic Review/Meta-Analysis (Table 20) 

 One meta-analysis115 of 23 studies (18 case-control; four nested case-control; and one 

observational cohort) evaluated the relationship of breastfeeding and SIDS. All studies were 

conducted in developed countries from 1965 to 1997. Studies that reported a minimal definition 

of SIDS – sudden unexplained death of an infant or young child – met the eligibility criteria. The 

meta-analysis analyzed a total of 4,251 cases of SIDS and 58,055 controls. Seventeen studies 

included subjects from birth to 2 years old when SIDS occurred; eight studies did not provide 

age data. The studies differed in their definition of breastfeeding exposure. Also, the studies 

varied in their description of SIDS. Of these, only 14 studies reported autopsy-confirmed 

diagnoses of SIDS. Three studies were specifically designed to examine the relationship of 

breastfeeding and SIDS. The rest of the studies examined multiple risk factors and their 

association with SIDS, of which feeding history would be one. 

 The meta-analysis utilized a random effects model. It reported an overall risk of SIDS twice 

as great for formula-fed infants compared with breastfed infants (crude odds ratio (OR) of 2.11; 

95% CI 1.66 to 2.68). The methodological quality of individual studies was appraised. The 

authors conducted a separate meta-analysis for those studies published since 1988 when more 

advanced epidemiological and autopsy procedures were available. A separate analysis was also 

performed for those studies with “high” quality scores. The results from these meta-analyses 

concurred with the overall result. Heterogeneity was not explored, i.e., no subgroup analyses 

were performed to account for the different definitions of interventions or outcomes. The authors 

reported “no publication bias”. Differences in case matching precluded them from combining 

adjusted odds ratios in the meta-analysis. Four of the 16 studies showed a dose response trend 
94

with the risk of SIDS increasing with increasing formula feeding. The overall methodological 

quality of the meta-analysis was rated grade C. 

Studies Identified after the Published Meta-Analysis (Table 21) 

 We identified four eligible studies from five publications conducted in developed countries 

and published since 1997 that evaluated the relationship of breastfeeding and SIDS.116-120 Three 

were case-control studies and the fourth, a case-cohort study (a cohort study analyzed as a casecontrol study). The methodological quality ranged from grades B to C. There were a total of 769 

cases of SIDS and 2,681 controls. 

 All studies were designed to evaluate a broad range of potential risk factors for SIDS. The 

studies differed in their description of the duration of breastfeeding. Similarly, the studies varied 

in their definition of the time interval when SIDS occurs in infants, but all studies reported 

autopsy-confirmed diagnoses. The mean age of the infants with SIDS ranged from 2 to 19 

weeks. All studies provided adjusted odds ratios for the association of breastfeeding and SIDS. 

Three of the four studies identified statistically significant increased risk of SIDS in bottle-fed 

infants.117,119,120 Two studies reported that the risk of SIDS was twice or more for non-breastfed 

infants compared with some or ever breastfed infants.117,119 One study reported an approximately 

two times increased risk of SIDS among those breastfed less than 2 weeks compared with those 

breastfed more than 2 weeks.120 One case-cohort study (a cohort study analyzed as case-control 

study) did not find a statistically significant increased risk of SIDS in bottle fed infants.118

Meta-analysis results. Because of the limitations of the previous meta-analysis, we elected 

to conduct our own meta-analysis using only studies that provided an objective definition of 

SIDS (autopsy confirmed SIDS among infants 1 week to 1 year of age), clear reporting of 

breastfeeding data, and outcomes adjusted for important confounders or risk factors (e.g., 

sleeping positions, maternal smoking, and socioeconomic status). Four studies included in the 

previously published meta-analysis121-124 and two studies published since 1997 met the eligibility 

criteria.118,120 The majority of the studies provided data on ever versus never breastfeeding and 

this was combined using a random effects model. The results from our meta-analysis found that 

ever breastfeeding was associated with a reduction in both crude and adjusted risk of SIDS 

(crude OR 0.41; 95%CI (0.28, 0.58), and adjusted OR 0.64; 95%CI (0.51, 0.81), respectively); 

both estimates were statistically significant with a reduction in SIDS for the ever breastfed 

infants. 
95

Figure 10. Random effects model of summary estimate evaluating the association of breastfeeding and SIDS 

Conclusion 

 Results from the previously published meta-analysis of case-control studies concluded that 

an overall crude risk of SIDS was twice as great for formula-fed infants compared with breastfed 

infants. The conclusion may be biased because the reported association was not adjusted for 

potential confounders. Misclassification biases may occur because of differences among studies 

with regard to definitions of breastfeeding exposure, definitions of SIDS, and the wide age range 

of population included in the studies. 

 Findings from the four studies published subsequent to the meta-analysis in developed 

countries concurred with the findings from the meta-analysis. All studies reported autopsyconfirmed diagnoses of SIDS and adjusted for potential confounders. However, the definitions of 

breastfeeding exposure and the time intervals accepted for defining SIDS varied across studies. 

Three of four studies reported statistically significant increased risk of SIDS associated with nonbreastfeeding or reduced duration of breastfeeding and the fourth study reported a statistically 

non-significant increased risk. 

 Our meta-analysis included only studies that reported clear definitions of exposure, 

outcomes, and results adjusted for well-known confounders or risk factors for SIDS. The 

summary estimate found a statistically significant adjusted odds ratio for an association between 

breastfeeding and a reduced risk of SIDS (adjusted OR 0.64, 95%CI 0.51 - 0.81). We conclude 

that there is a relationship between breastfeeding and a reduced risk of SIDS. 

Reduction in risk with breastfeeding Adjusted O R of SIDS Increase in risk with breastfeeding

.1 .5 .8 1 1.5 2 5

Study

Adjusted O R of SIDS

(95% CI) % W eight Q uality

Brooke 1997 0.99 ( 0.37, 2.56) 5.1 A

W ennergren 1997 0.50 ( 0.45, 0.77) 28.6 A

Flem ing 1996 1.06 ( 0.57, 1.98) 10.6 A

M itchell 1993 0.53 ( 0.38, 0.74) 23.6 B

Vennemann 2005 0.59 ( 0.36, 0.94) 15.5 B

M itchell 1997 0.76 ( 0.40, 1.47) 9.9 B

M itchell2 1997 1.07 ( 0.47, 2.43) 6.7 B

Overall 0.64 ( 0.51, 0.81) 100.0 
96

Table 20. Summary of systematic review/meta-analysis on the relationship between breastfeeding and Sudden Infant Death SyAuthor year 

Study 

description 

Number of 

subjects Population Intervention /Comparator Results 

McVea 2000 

MA of 23 observational studies 

Cases 4,251 Controls 58,055 

Children who were diagnosed of SIDS 

Breastfeeding (any) 

The pooled OR for the 23 studies using random effects m

in an OR = 2.11 (95% CI 1.66-2.68) i.e., the overall ristwice as great for bottle-fed infants compared to breas

The pooled OR from the higher quality studies also dem

fold increase in risk among bottle fed infants OR = 2.2

The pooled OR from studies after 1988 OR = 2.32 Confounders: Individual studies adjusted for potential co

studies reported adjusted OR; 4 studies reported no pof breastfeeding, while 2 reported adjusted OR that resignificant. 

Dose-response relationship: 4 out of 9 studies showed a 

trend with the risk of SIDS increasing with increasing fNone of the studies had sufficient power to demonstrasignificant difference between partial vs. no breastfeed

SR, systematic review; MA, meta-analysis 
97 

Table 21. Summary of case-control studies on the relationship between breastfeeding and sudden infant death syndrome (SIDS

analysis 

OR* (95% CI) 

Author year Country 

Cases 

(N) 

Control 

(N) 

Definition 

of SIDS 

Mean 

Age at 

Dx 

(week) 

Breastfeeding 

group 

Comparator 

group Crude Adjust Potential confounders 

Wennegran, 1997 Alm 2002 Scandinavia 

244 869 Validated definition 16 Ever (At the time of death) Never 0.59 (0.4, 0.83) 0.5 (0.45, 0.77) Sleep position, maternal sm

feeding at the time of death time of death 

Fleming, 1996 UK 

195 780 7d-1y nd Ever Never 

0.5 (0.35, 0.71) 

1.06 (0.57, 1.98) 

Maternal age, gestation, birexposure to tobacco, sleepienvironment 

Brooke, 1992 UK (Scotland) 

147 275 7d-1y 15-18 

Ever (At the time of death) 

Never 

0.22 

(0.11, 

0.47) 

0.99 (0.37, 2.56) 

Exposure to Parental smokiposition, old mattress use, m<27, deprivation score of 7, in previous wk, marital statumother, SE status, gender obirth weight etc 

Mitchell, 1993 New Zealand Population 1987-1990

460 1757 >28d-1yr nd 

Ever (At the time of discharge from obstetric dept) 

Never 0.42(0.33, 0.53) 0.53(0.38, 0.74) 

Region, time of day, baby’s class, school leaving age of marital status of mother, sex admission to neonatal unit, previous pregnancies, sociostatus, birthweight, gestatiobaby, season, mothers age pregnancy, mothers age at position, bed sharing with amaternal smoking and brea

Vennemann 2005 Germany 

333 998 8d-1 yr 19 >2 wk <2 wk 

0.19 

(0.14, 

0.25) 

0.59 

(0.36, 

0.94) 

Maternal age, family status, pregnancy. Previous live birsocioeconomic status 

79 679 Any at initial contact None at initial contact 0.60 (0.35, 1.03) 0.76 (0.40,1.47) Mitchell 1997a 

New Zealand 38 588 

29d-1 yr 2.6-9 

Any at 2 mo None at 2 mo 0.76 (0.41, 1.39) 1.07 (0.47, 2.43) 

Maternal age, marital statusleft school, previous numbepregnancies, infant’s sex, einfant, birthweight, sleep posharing/maternal smoking c

a A case-cohort study 
98

Part II. Preterm Infant Outcomes 

Relationship between Necrotizing Enterocolitis and Breast 

Milk Feeding in Preterm Infants 

Background 

Necrotizing enterocolitis (NEC) is a serious gastrointestinal disease in the preterm infants. 

No definitive causes have been identified. A population-based epidemiological study published 

in 2002 reported that the highest incidence occurred in infants with birth weights 750 to 1000 g 

and decreased with increasing birth weights.125 Observational studies have suggested that breast 

milk might be protective. There have been very few randomized controlled trials (RCTs) that 

examined this issue. McGuire 2001 performed a meta-analysis of RCTs of breast milk 

comparing with formula milk in preterm infants to reduce the risk of NEC.126 Since that metaanalysis, we identified one RCT127 and two prospective cohort studies128,129 that reported 

outcome of NEC in preterm infants in relation to a history of breast milk feeding. Some of the 

potential confounders that may affect the results of neonatal morbidity and mortality include 

birth weight, ethnicity, and sex.128 

Published Systematic Review/Meta-Analysis (Table 23) 

McGuire 2001’s meta-analysis compared formula feeding with term breast milk feeding in 

low birth weight or preterm infants. Three RCTs published in 1983 and 1984 totaling 308 

preterm infants were included: Gross 1983 compared formula with unfortified term donor breast 

milk;12 Tyson 1983 compared preterm formula with pooled banked term breast milk;13 and Lucas 

1984130 (results for NEC reported in 1990131) compared preterm formula with banked term breast 

milk as the sole diet. In the meta-analysis comparing formula with breast milk, the risk ratio for 

developing NEC was 2.5 (95% CI 0.9 - 7.3); risk difference was 0.05 (95% CI 0.00 - 0.1). The 

authors concluded that there was no statistically significant difference in the risk of NEC with 

either form of milk feeding. 

Studies Identified after the Published Systematic Review/MetaAnalysis (Table 24) 

Randomized controlled trial. Schanler 2005 enrolled 243 infants ≤ 29-week gestation 

whose mothers were expected to breastfeed.127 If these infants’ own mothers’ milk were 

unavailable, the infants were then randomly assigned to receive either pasteurized donor milk or 

preterm formula. However, both groups continued to receive mother’s milk partially if they were 

available during the study. The infants who were fed mother’s milk exclusively were not 

randomized and served as a reference group. The incidence of NEC in Donor milk versus 

Preterm formula was 5/78 versus 10/88 (P = 0.27). The non-randomized group “mother’s milk” 

had fewer repeated episodes of late-onset sepsis and/or NEC (OR 0.18, 95% CI 0.04 - 0.79) 

compared with combined groups “donor milk” and “preterm formula”. The methodological 

quality of this study was rated B. 
99

Prospective cohort. Furman 2003 was a prospective cohort study on 119 infants with 

gestational age < 33 weeks and birth weight 600-1499 g.128 Enteral feeding was begun by day 2 

or 3 of life, parenteral nutrition was continued until a daily enteral intake of 120 mL/kg of body 

weight was reached. Infants received their mother’s milk in the sequence it was expressed, 

except that fresh rather than frozen milk was given if available. Maternal milk was fortified, and 

preterm infant formula was offered when the infant reached a daily oral intake of at least 110 

mL/kg. Limited availability of maternal milk was the sole reason infants were fed preterm 

formula in addition to maternal milk. Four subgroups were analyzed: no maternal milk, daily 

maternal milk of 1-24 mL/kg, 25-49 mL/kg, and ≥ 50 mL/kg. Rates of NEC did not differ 

according to the amounts of maternal milk received. The results of the regression analysis were 

adjusted for birth weight, ethnicity, and sex. The methodological quality of this study was rated 

B. 

Ronnestad 2005 was a prospective cohort study of late-onset sepsis on 462 infants with 

gestational age <28 weeks or birth weight < 1000 g in Norway.129 NEC was not the primary 

outcome of interest; it was studied as a potential confounder in the analysis of late-onset sepsis. 

Four hundred five survived until day 7. Participating centers had a common policy of achieving 

full enteral feeding with the mother’s milk or banked donor milk as early as possible, although 

there was no uniformity in a detailed protocol for feeding strategies. Enteral feeding with breast 

milk was commenced within 1, 2, or 3 days for 61 percent, 92 percent, and 96 percent of the 

infants, respectively. Nine of 405 (2.2 percent) patients had confirmed NEC. There was no 

concurrent comparison reported in this study. The methodological quality of this study was rate 

C with respect to the outcome of NEC. 

Updating the previous meta-analysis. We performed a new meta-analysis using a random 

effects model by combining the data from the Schanler 2005 RCT with the three RCTs in 

McGuire 2001. We combined all breast milk into one group because the proportion of the 

preterm versus term banked breast milk in the four studies cannot be determined. For outcome, 

we only counted confirmed cases of NEC as provided by the authors (either pneumatosis 

intestinalis or confirmed at surgery). We reported the results as risk ratios of developing NEC. 

The meta-analysis of four RCTs with a total of 476 infants provided a risk ratio of 0.42 (95% CI 

0.18, 0.96) for the development of NEC, in favor of breast milk (Table 22; Figure 11). 

Table 22. Meta-Analysis of four RCTs on the effects of breast milk feeding and NEC in preterm infants: 

Random Effects Model (D&L) 

Breast milk 

feeding Control 95% CI Study, year 

Event Total Event Total 

Risk Ratio 

Low High 

Gross, 1983 1 41 3 26 0.21 0.02 1.93 

Tyson, 1983 0 37 1 44 0.39 0.02 9.41 

Lucas. 1984 1 86 4 76 0.22 0.03 1.93 

Schanler, 2005 5 78 10 88 0.56 0.20 1.58 

Total patients = 476 7 242 18 234 0.42 0.18 0.96 

 z = -2.0629 2P = 0.039 

 Overall Heterogeneity: Q = 1.02 Tau^2 = 0.0000
100

Figure 11. Meta-Analysis of four RCTs on the effects of breast milk feeding and NEC in preterm infants 

Conclusion 

 Even though the observational study by Furman et al. did not find a difference in the rates of 

NEC according to the amount of maternal milk received by the infants, our meta-analysis of four 

RCTs demonstrated that there was a marginally statistically significant association between 

breast milk feeding and the reduction in the risk of NEC. The confidence interval for the estimate 

in the relative risk reduction ranged from four percent to 82 percent. The absolute risk difference 

was five percent. The wide confidence of the estimate reflects the relatively small number of 

total subjects in the studies and the small number of events. One must be cognizant of the clinical 

heterogeneity underlying these RCTs in interpreting the findings of the meta-analysis. Some of 

them were: different time periods when the studies were conducted; different preterm formulas 

as comparators; wide range of gestational ages and birth weights in the subjects; different degree 

of illnesses in the subjects; and others. How the heterogeneity in the studies affected the findings 

is unclear. Lastly, one may question the importance of an absolute risk difference of five percent 

between groups. Taking into account the high case-fatality rate of NEC, we consider this 

estimate is of meaningful clinical difference. In conclusion, there is evidence to support an 

association between breast milk feeding and a reduction in the risk of NEC in preterm infants. 
101

Table 23. Summary of systematic review/meta-analysis on the relationship between breast milk feeding and necrotizing enterocinfants Author year 

Study 

description N Population Intervention/Comparator Resu

Gross 1983 27-33 wk, < 1600 g N=67 US 

Unfortified term donor breast milk, fed until 1800 g or until withdrawal secondary to feed intolerance or NEC; compared to 

standard calorie, protein enriched formula 

Tyson 1983 “very low birth weight infants” N=81 US 

Pooled banked term breast milk, allocation at 10th day of life, fed 

until 2000 g or until withdrawal secondary to illness requiring parenteral fat or protein; compared to enriched calorie and protein formula 

McGuire 2001 

MA of 3 RCTs 310 

Lucas 1984 preterm infants < 1850 g N=162 UK 

Banked term breast milk 200 mL/kg/d, fed until 2000 g or until d/c; compared to enriched calorie and protein formula

formula vs. breaRR: 2.5 (95% CRD: 0.05 (95% C

SR, systematic review; MA, meta-analysis
102

Table 24. Summary of studies on the relationship between breast milk feeding and necrotizing enterocolitis (NEC) in preterm inAuthor year N Population Intervention/Comparator Outcomes Randomized Controlled Trial Schanler 2005 

243 <29 wk 

infants, mothers expected to breastfeed US 

Donor milk (DM) (+ mother’s milk partially) Small quantities of mother’s milk (~20 mL/kg/day) was initiated in the first week and continued for ~3 to 5 days before the volume was advanced. Milk intake was increased by ~20 mL/kg daily to 100 mL/kg, at which time milk fortifier was added, this was advanced by ~20 mL/kg daily until 160 mL/kg per day was achieved. Comparator: Preterm formula (PF) (+ mother’s milk partially) Reference group: non-randomized, exclusive mother’s milk (MM) 

Incidence of NEC: DM vs. PF: 5/78 vs. 10/88 (P=0.27) Non-randomized group MM had fewer repepisodes of late-onset-sepsis and/or NEC 95% CI 0.04–0.79) compared with combinDM and PF 

Prospective Cohort Studies Furman 2003 

119 <33 wk, 

birth weight 600-1499 g US 

The study compared the effect of varying dosages of maternal milk on neonatal outcomes. Intravenous dextrose during the first 24 hrs; enteral intake was begun by day 2 or 3 of life, parenteral nutrition was continued until a daily enteral intake of 120 mL/kg of body weight was reached. Infants received their mother’s milk in the sequence it was expressed, except that fresh rather than frozen milk was given if available. Maternal milk was fortified, and preterm infant formula was offered when the infant reached a daily oral intake of at least 110 mL/kg. Limited availability of maternal milk was the sole reason infants were fed preterm formula in addition to maternal milk. 

0 maternal milk 3/40 1-24 mL/kg 2/29 (OR 1.15 95% CI 25-49 mL/kg 2/18 (OR 1.99 95% CI ≥ 50 mL/kg 0/32 (OR 0 95% CI Results were adjusted for birth weight, ethsex 

Ronnestad 2005 

462 <28 wk or 

birth weight < 1000g Norway 

Tube feeding with breast milk was usually started within a few hours after delivery, with 1 to 2 mL of milk every 2 or 3 hrs, increasing by 0.5 to 1 mL every 6 to 8 hrs as tolerated. Enteral nutrition was supplemented with parenteral glucose from day 1, amino acids and lipids from day 2 and day 3, respectively. 

Enteral feeding with breast milk was commwithin 1, 2, or 3 days for 61%, 92%, and 9infants. 9/405 (2.2%) patients had confirm

DM, donor milk; MM, exclusive mother’s milk; NEC, necrotizing enterocolitis; PF, preterm formula 
103

Relationship between Cognitive Development and Breast 

Milk Feeding in Preterm Infants 

Background 

 Many studies have examined the relationship between breastfeeding and cognitive 

development. Results have been conflicting. Most of the studies were observational in design. 

Many of them did not have a clear definition of breastfeeding or breast milk exposure. Different 

cognitive assessment tools were used. Outcomes were measured anywhere from less than 2 years 

of age to adulthood. 

 Three systematic reviews from 1999 to 2002 have tried to either establish methodological 

standards to assess the observational studies or adjust for covariates in pooled analysis (see 

discussion of confounders in section on cognitive outcomes in term infants). Since the last 

systematic review by Jain et al. in 2002,58 there have been eight cohort studies on preterm infants 

that examined the relationship of breast milk feeding to some aspects of cognitive development. 

 A note of caution is in order here. The Mental Developmental Index of the Bayley Scales of 

Infant Development is widely used to assess the cognitive ability of young children in the studies 

reviewed in this report. One must keep in mind that the primary purpose of the Bayley Scales is 

to identify children who may be at risk from developmental delay; it was not the primary purpose 

to use the results of the Bayley Scales to predict IQ at a later age. Even though some recent 

studies on preterm infants have shown some predictive ability of the Bayley Scales, the ability to 

do so is imperfect.132,133 Comorbidities (e.g., neurological impairment, extremely low birth 

weight, other neonatal illnesses), early intervention, environmental, and socioeconomic factors 

are some of the additional important variables that could affect the prediction of future cognitive 

function. 

Published Systematic Review/Meta-Analysis (Please Refer To Table 8 

In Part I) 

Studies Identified after the Published Systematic Review/MetaAnalysis (Table 25) 

 Since 2002, five prospective cohort studies,134-139 two nested case control studies,140,141 and 

one secondary data analysis of a previous randomized controlled trial on supplemental 

arachidonic and docosahexaenoic acid142 reported on the relationship between breast milk 

feeding and some aspects of cognitive development in preterm infants. Sample size of the studies 

ranged from 39 to 1,035. Five of the studies were of moderate methodological quality,135,137,140-

142 and three studies were of poor methodological quality.134,136,138,139 Each study was graded 

within its own study design stratum and only with respect to the data on the relationship of breast 

milk feeding and cognitive development. 

 Gestational age of the infants ranged from 26 to 33 weeks. Except for one study that 

specifically enrolled children who had cerebral ultrasound abnormalities, including echodensity, 

echolucency, and/or ventriculomegaly,140 the rest of the studies excluded infants with severe 

congenital abnormalities. Some also excluded infants with perinatal asphyxia and sensorineural 

abnormalities. 
104

 One study reported that half of the subjects had received breast milk exclusively.137 Most 

studies provided information on the amount of breast milk intake and whether the milk had 

added cow-milk based fortifiers or not while the subjects were in the neonatal wards, but the 

information on breast milk intake was less informative after discharge to home. Three studies 

reported the proportion of subjects who breastfed for more than 6 to 7 months; they were 20 

percent,140 27 percent,137 and 29 percent,141 respectively. 

 Bayley Mental Development Index Scale (MDI) was the cognitive assessment tool for 

subjects up to 2 years of age. Wechsler Preschool and Primary Scale of Intelligence (WPPSI-R) 

was used in subjects under 7 years of age. Weschler Intelligence Scale for Children (WISC-R) 

was used in 7 years and 11 years old. Kaufman Assessment Battery for children (test for overall 

intellectual function) and Peabody Picture Vocabulary Test (PPVT-R) were administered to 6 to 

8 year old children in one study.140

Prospective cohort. Elgen 2003 prospectively studied 130 low birth weight children at 5 

years and 11 years of age using the Wechsler Preschool and Primary Scale of Intelligence 

(WPPSI-R) and the Weschler Intelligence Scale for Children (WISC-R), respectively.135 Twentyseven percent of them received less than 30 percent breast milk in the neonatal ward. After 

adjustment for parental confounding (paternal and maternal education), breast milk was no 

longer a statistically significant predictor of IQ. 

 Pinelli 2003 prospectively studied 128 infants with birth weight <1,500 g at 6 months and 12 

months corrected age using Bayley Mental Development Index Scale (MDI).137 Fifty percent of 

them received breast milk exclusively in the neonatal ward. Twenty-seven percent of infants 

were breastfeeding at 6 months. After adjustment for sex, SES, birth weight and maternal age, no 

statistically significant difference in MDI at 12 months was found between the predominantly 

breastfed group and the predominantly formula-fed group. 

 The other three lesser quality studies suffered from selection biases (e.g., convenience 

sample), lack of adjustment for potential confounders (e.g., lack of adjustment for maternal 

intelligence), small sample sizes, or had issues with incomplete reporting. 

 One prospective study (in two publications) with post hoc comparisons reported significant 

differences (P < 0.05) in Bayley MDI at 6 months between substantial breast milk feeding group 

(> 75 percent of nutrition as breast milk) and intermediate (25-75 percent) or minimal feeding 

groups (< 25 percent) (94.2±8.8 vs. 91.7±7.2 vs. 90.5±8.5, respectively).134,136 Maternal 

education or SES were not adjusted for in these results. 

 In a cohort study of subjects from a convenience sample (29 in breast milk group; 10 in 

formula group), a regression analysis showed an association between the amount of milk infants 

received in the special care nursery and the Bayley MDI at 7 months (r=0.4, R2

=0.1, P < 0.05) 

and 12 months (r= 0.4, R2

=0.2, P < 0.025).139

 In a prospective study of 775 preterm infants who were fed breast milk and 260 preterm 

infants who were not fed breast milk, the adjusted Bayley MDI at 18 to 22 months of age was 

79.9 ± 18 (SD) in the breast milk group versus 75.8 ± 16 (SD) in the no breast milk group (P = 

0.07).138 The result was adjusted for maternal (education, age, marital status) and perinatal (sex, 

gestational age, oxygen need, birth weight, and illnesses) factors. Mothers in the breast milk 

group were more likely to have private health insurance, be white and married, and have a 

college degree. Mothers who had low household income, higher parity, or were black were less 

likely to provide breast milk feeds. It was unclear if the results were actually adjusted for 

household income or not. Further analysis of breast milk intake by quintile relative to the no 
105

breast milk group showed that there was a 13.1 point difference in MDI between ≤ 20th quintile 

and >80th quintile (P<0.0044). 

 Re-analysis of a previous RCT on supplemental arachidonic and docosahexaenoic acid. 

O’Connor 2003 re-analyzed data on 463 subjects from a randomized controlled trial on 

supplemental formulas in infants less than 33 weeks gestation.142 Bayley MDI was evaluated at 

12 months corrected age. There were no differences in the Bayley MDI among feeding groups. 

After controlling for home environment and maternal intelligence, there was a significant 

positive association between duration of breastfeeding and the Bayley MDI at 12 months 

corrected age in a “full” statistical model (P = 0.03, adjusted for large number of preplanned 

covariates for developmental outcomes), but not in a “reduced” statistical model (P = 0.07, 

adjusted only for those preplanned covariates with a P value of < 0.15).

142

Nested case-control. Smith 2003 studied 119 preterm subjects with cerebral ultrasound 

abnormalities and 320 subjects (presumably without ultrasound abnormalities) matched for 

gestational age in a nested case-control design.140 The Kaufman Assessment Battery for children 

were administered to these 6 to 8 years old subjects. In the regression model that included 

adjustment for maternal verbal ability, home environment, and composite socioeconomic status, 

the advantage in overall intellectual function associated with direct breastfeeding was 3.6 points 

(95% CI -0.3 to 7.5; outcome measure was standardized with a mean of 100 points and a 

standard deviation of 15 points). 

 Horwood 2001 studied 280 subjects with very low birth weight at 7 years using WISC-R.141

After adjustment for perinatal (sex, gestation, birth weight, multiple birth, Apgar score), sociodemographic (family income, single/two parent family, child ethnicity), and maternal factors 

(age, education, smoking), there remained a significant association between duration of receipt 

of breast milk and verbal IQ, with a 6 point advantage for infants who received breast milk for ≥

8 months compared with no breastfeeding (P<0.001). 

Conclusion 

 No definitive conclusion can be made regarding the relationship between breast milk feeding 

and cognitive development in preterm infants. One meta-analysis reported a five points 

advantage in standardized mean score and one systematic review identified one primary study 

that reported an eight points advantage in IQ in preterm or low birth weight infants who received 

breast milk feeding. In three of four primary studies of moderate quality that controlled for either 

maternal education or maternal intelligence, the advantage from breastfeeding was reduced to a 

statistically non-significant level after adjustment; the fourth study reported a positive 

association between duration of breastfeeding and the Bayley MDI at 12 months after controlling 

for maternal intelligence and home environment. 

 The roles of maternal intelligence and home environment should be accounted for in future 

studies on breastfeeding and cognitive development. Keeping in mind that cognitive function 

measured at an early age is not necessarily predictive of later cognitive ability, one should also 

consider carefully the timing and the selection of appropriate testing instrument in future studies. 

In addition, clear subject selection criteria, controlling for differences in early complications of 

prematurity and its relation to receiving breast milk, accounting for subjects lost to follow up, 

clear distinction between direct breastfeeding and bottle/gavage feeding of breast milk, collect 

data on breast milk fortifiers or supplemental preterm formulas, and better data collection on 

breast milk feeding after discharge from the neonatal units will improve the quality of these 

studies. 
106

Table 25. Summary of primary studies on the relationship of breast milk feeding and cognitive development in preterm infants 

Author Year 

Country 

Population 

Study 

Description 

Breast milk 

feeding exposure Assessment tools Confounders adjusted for Outcomes 

Prospective cohort Elgen 2003 Norway 130 Low birth weight (<2000 g) 

Cohort assessed at 5 yr and 11 yr; excluded cerebral palsy, blindness, deafness, multiple malformations, chromosomal abnormalities 

27% received <30% breast milk in neonatal ward 

Weschler Preschool and Primary Scale of Intelligence- R at 5 yr; Weschler Intelligence Scale for Children-R (WISC-R) at 11 yr 

Breast milk, birth weight, paternal and maternal education, chorioamnionitis, gestational age, length of oxygen treatment, sex, 5 minute Apgar, smoking during pregnancy, intrapartum stress, cerebral hemorrhage in subjects with birth weight <1500 g 

Unadjusted regression: lack of breast milk wassociated with a mean reduction in IQ of 5(95% CI –11 to –1). After adjustment for paconfounding, breast milk was no longer a stsignificant predictor of IQ. 

Pinelli 2003 Canada 148 <1500 g 128 breastfeeding; 20 formulafed infants were recruited as controls 

Cohort from an RCT on conventional breastfeeding support versus supplementary structured breastfeeding counseling; excluded multiple births, severe congenital abnormalities, infants of nonEnglish speaking parents 

50% exclusively; some received fortification per explicit criteria; 27% still breastfeeding at 6 mo 

Bayley MDI at 6 mo and 12 mo 

Sex, SES, birth weight, maternal age 

64/128 infants received breast milk exclusivAdjusted MDI at 6 mo (corrected age) for >breastmilk group: 93 (SD 16); for <80% bregroup: 94 (SD 15); Adjusted MDI at 12 mo (corrected age) for breastmilk group: 92 (SD 15); for <80% bregroup: 91 (SD 12); P>0.05 for all comparisons 
107

Table 25. Continued 

Author Year 

Country 

Population 

Study Description 

Breast milk 

feeding 

exposure 

Assessment tools Confounders adjusted for Outcomes 

Vohr 2006 US 1,035 Preterm with mean gestation of 26.5 wk and birth weight of ~790 g 

Enrolled prospectively in the Glutamine Trial at 15 sites of Neonatal Research Network; survivors who received some breast milk and had cognitive testing 

Breast milk group– received some breast milk during hospitalization; total volume received calculated per day, values were interpolated for days of the week in which the data were not collected 

Bayley Mental Development Index (MDI) at 18 to 22 mos corrected age 

marital status, maternal education, age, race/ethnicity, infant’s gestational age, gender, culture positive sepsis, grade 3 to 4 intraventricular hemorrhage, oxygen at 36 wks gestational age, necrotizing enterocolitis, and weight <10th %tile 

There were 775 infants in the breast milk gr260 in the no breast milk group. 95 subjectscould not be administered successfully; thewere not included. Mothers of infants who wat followup were more likely to have receivecare than mothers of infants who were not swere no differences in infant characteristicsInformation on breast milk feeding was not after discharge from hospital. 30.6% of infabreast milk group were still receiving breast Mothers in the breast milk group were more be white, married, have a college degree anprivate health insurance. Mothers who had household income, higher parity or were blaless likely to provide breast milk feeds. Adjusted Bayley MDI 79.9 ± 18 in BM 75noBM P=0.0709 MDI <85∗ 421 (58.1%) in BM 16in noBM P=0.0355 Multiple regression with adjusted factors=0.P=0.0002 Breast milk intake was analyzed by quintile the no breast milk group; for MDI, there was point difference between ≤ 20th quintile and 

quintile (P<0.0044). 
108

Table 25. Continued 

Author Year 

Country 

Population 

Study Description 

Breast milk 

feeding 

exposure 

Assessment tools Confounders adjusted for Outcomes 

Eidelman, 2004 Feldman, 2003 Israel 86 gestational age 30.5 wk (26-33 wk) 

3 groups stratified by amount of breast milk feeding; cognitive assessment at 6 mo corrected age; excluded infants with IVH grade 3 or 4, perinatal asphyxia, metabolic, genetic disease 

3 groups: >75% of nutrition as breast milk; 25-75%; and <25%; duration of breast milk feeding: no data 

Bayley MDI at 6 mo 

Number of breastfeeding episodes was used as a covariate; MANCOVA performed with human milk and infant gender as the between subject factors 

Univariate analyses showed group differencMDI. Post hoc comparisons reported significant dbetween the substantial milk group and the groups: 94.2±8.8 vs. 91.7±7.2 vs. 90.5±8.5 

Bier 2002 US 39 28.6 wk gestation (range 23-34 wk); 29 in breast milk group; 10 in formula group 

convenience sample; excluded infants with mothers who used illicit drugs, had mental illness, HIV infection, and others; 

17% of mean volume intake in breast milk group was from premature formula, 9/29 (31%) continued breastfeeding between 3 and 7 mo corrected age 

Bayley MDI assessed at 7 mo and 12 mo 

maternal result of Peabody Picture Vocabulary Test (PPVT) and days of oxygen 

Adjusted for maternal Peabody Picture VocTest (PPVT) result; mean Bayley MDI at 7 mo, breast milk grou

in formula group = 90 

± 9 (Difference NS); 

at 12 mo, breast milk group = 101 

± 11, for

= 90 

± 9 (P<0.05); 

regression analysis showed an association the amount of milk infants received in the spnursery by gavage and/or bottle and the Ba7 mo (P<0.05) and 12 mo (P<0.025). 
109

Table 25. Continued 

Author Year 

Country 

Population 

Study Description 

Breast milk 

feeding 

exposure 

Assessment tools Confounders adjusted for Outcomes 

Nested case-control Smith, 2003 US 119 with ultrasound abnormalities; 320 frequency matched (1:4) were included; gestational age 27.4 wk 

Birth subjects from Developmental Epidemiology Network (n=1442); 439 subjects who had undergone neuropsychological testing and for whom parental questionnaires were completed by 9/2002 were included in this study 

153 did not receive breast milk; 142 received expressed milk without progressing to direct breastfeeding; 125 received direct breastfeeding (the majority of them first received expressed breast milk); 20% of infants received breast milk > 6 mo. 

Kaufman; Peabody Picture Vocabulary Test and Clinical Evaluation of Language Fundamentals; California Children’s Verbal Learning Test; at age 6-8 yr 

Maternal verbal ability, Home Observation for Measurement of the Environment Inventory, SES, duration of hospitalization 

Outcome measures were standardized wit100 points and standard deviation of 15 poBreast milk feedings were associated with unadjusted test scores for each domain of function except memory. In the regression model that included sociaand neonatal morbidity, the adjusted score intellectual function associated with direct breastfeeding was reduced to 3.6 points (9to 7.5). 

Horwood, 2001 New Zealand 280 Very low birth weight survivors of a national birth cohort 

retrospective recall of breast milk feeding and duration of feeding; assessed at 7 yr; excluded sensorineural disability and incomplete breastfeeding data 

Breastfed < 4 mo (n=99) (49%) 4-7 mo (n=46) (22%) ≥ 8 mo (n=59) (29%) Not breastfed (n=76) 

WISC-R at 7 yr Perinatal, sociodemographic 

(family income, single/two parent family, child ethnicity), and maternal factors (age, education, smoking); 

Children who were breastfed 

≥ 8 mo had m

IQ 10.2 (SD 0.56) higher and mean perform6.2 (SD 0.35) higher than children who did breast milk. After adjustment for covariates, there remasignificant association between duration of breast milk and verbal IQ, with a 6 point adinfants who received breast milk for 

≥ 8 m

with no breastfeeding (P<0.001). 
110

Table 25. Continued 

Author 

Year 

Country 

Study 

Description 

Breast milk 

feeding exposure Assessment tools Confounders adjusted for Outcomes 

Secondary data analysis of a previous RCT on supplemental arachidonic and docosahexaenoic acidO‘Connor, 2003 Chile, US, UK 463 <33 wk gestation 

Cohort, secondary analysis of a previous RCT on supplemental arachidonic and docosahexaenoic acid; excluded congenital abnormalities that could affect growth and development, major surgery, and others 

divided into 4 mutually exclusive groups: predominantly breast milk or formula groups; 

≥

or < 50% of total energy as breast milk; 43 infants (9%) on predominantly breast milk until term corrected age; 119 (26%) on predominantly formula until term corrected age 

Bayley at 12 mo Maternal intelligence 

and home environment 

No differences in the Bayley MDI were found feeding groups. There was a positive assocbetween duration of breastfeeding and the B12 mo corrected age (P=0.032 in full, and P=reduced statistical models) after controlling fenvironment and maternal intelligence. 

Bayley MDI, Bayley Mental Development Index; MANCOVA , Multivariate analysis of variance; NS, Non-significant; PPVT, Peabody Pict

socioeconomic status; WISC-R, Weschler Intelligence Scale for Children-R; 
111

Part III. Maternal Outcomes 

Relationship between Return to Pre-Pregnancy Weight or 

Postpartum Weight Change and Breastfeeding 

Background 

Return to pre-pregnancy weight is desirable since postpartum weight retention is a possible 

risk factor for obesity and its ensuing medical complications.143 The change in weight results 

from changes in energy metabolism during pregnancy and lactation. This is mediated through the 

complex neuroendocrine and biochemical stimuli that follow from conception. 

Despite the fact that the average weight retention associated with child bearing is modest, 

estimated at approximately 1.51 kg (s.d.=5.95 kg)144-146 for some, there is some risk of major 

weight gain with pregnancy. Ohlin and Rossner 1990 reported changes in body weight that 

ranged from –12.3 to +26.5 kg from preconception to 1 year postpartum.144 In various studies, 

the proportion of women retaining 5 kg or more after 6 months postpartum ranged from 14 to 

20%.146-148 Studies of the impact of physiological and behavioral influences, such as dietary 

intake, physical activity, and lactation on postpartum weight change reported mixed results. 

Studies of postpartum weight changes in lactating and non-lactating women also were equivocal 

within and across populations, with some showing that the length and intensity of breastfeeding 

were associated with less weight retention after pregnancy, while other studies reported that 

women who fed their infants formula lost more weight than women who nursed their infants. 

Commonly considered confounders in the relationship between return to pre-pregnancy 

weight or post-partum weight change and breastfeeding were pre-pregnancy weight or BMI, age, 

educational level, physical activity, parity, smoking status, dieting practice, and ethnicity. 

Additional Methodological Comments 

To assess the relationship between breastfeeding and return to pre-pregnancy weight and 

postpartum weight/BMI changes, we relied on Fraser 2003,149 the only published systematic 

review of the effect of lactation on maternal body weight. Since Fraser 2003 did not provide any 

descriptive or summary tables for further analysis, we contacted the authors to obtain copies of 

their evidence tables. However, the tables made available lacked the appropriate data for 

additional clarification of the authors’ conclusions. Therefore, we decided to perform a primary 

analysis of all the studies cited in Fraser 2003. We also screened the references in the primary 

studies to identify additional studies for inclusion in our systematic review. In addition, we also 

evaluated primary studies that were published after Fraser 2003 and from suggestions by the 

reviewers of this report. These primary studies had been identified by our general literature 

search on the intervention of breastfeeding (see Methods chapter). We did not perform a search 

on maternal weight change by itself without any reference to breastfeeding. 

Because of the known methodological problems in the studies of the relationship between 

breastfeeding and maternal weight,15,150,151 we adopted the following inclusion criteria for our 

review: prospective cohort studies conducted in developed countries which directly compared 
112

weight changes of nonlactating women with that of lactating women and for whom the 

exclusivity or the amount of breastfeeding was clear. The sample size criterion was at least 50 

women per feeding group in the final analyses (e.g., lactating versus nonlactating). 

For studies of the relationship between postpartum weight change and breastfeeding, studies 

need to control for subjects’ gestational weight gain or pre-pregnancy weight and have at least 3-

months postpartum followup to be included. 

Results (Tables 26-27) 

A total of 54 potentially relevant articles were retrieved for full-text screening. Forty-five 

articles were excluded because they were cross-sectional design, non-comparative studies, 

review articles, sample size less than 50 subjects per group, or had unclear breastfeeding data 

(exclusivity or amount of breastfeeding not clearly reported). 

We included a total of three prospective cohort studies that examined the relationship 

between exclusive or full breastfeeding and return to pre-pregnancy weight145,152,153 and five 

prospective cohort studies (in six publications) that examined postpartum weight changes in 

relation to exclusive breastfeeding.144,154-157 One study, Linne 2003, was a 15-year followup of 

the two earlier Ohlin and Rossner studies of 1990 and 1996. 

 The reporting of breastfeeding data varied across studies. Some studies reported explicit and 

quantifiable amount of breastfeeding (e.g., providing at least two-thirds of the needed energy 

intake per kilogram of the infant’s weight in breast milk, or infants received 120 mL/day or less 

of other milk until at least 1 year of age), while others did not quantify the amount of 

breastfeeding the infants received. 

Relationship between breastfeeding and return to pre-pregnancy weight (Table 26) 

 A total of three prospective cohort studies were identified, involving 4,318, 540, and 95 

women, with follow up durations of 3 years, 1 year and 1.5 years postpartum, respectively. All 

studies were conducted in the United States. All studies enrolled nulliparous and primiparous 

women between 24 and 40 years of age with normal and above normal pre-pregnancy weights, 

and all three studies were rated methodological quality grade B. 

 Overall effect of breastfeeding on return to pre-pregnancy weight or weight retention was 

negligible. The average weight retention was only within 1 kg range at 1 to 2 years postpartum. 

The large study of 4,318 nulliparous and primiparous women reported that, compared with 

women who did not breastfeed, exclusive breastfeeding was associated with a weight gain of 

approximately 1 kg from pre-pregnancy to 1 to 2 years postpartum, adjusting for age, physical 

activity and pre-pregnancy BMI.152 This finding is only statistically significant for nulliparous 

women who had normal pre-pregnancy weight (BMI < 25) and for those primiparous women 

who were overweight at baseline (BMI ≥ 25). However, the duration of exclusive breastfeeding 

was not related to the magnitude of weight change from pre-pregnancy to 1 to 2 year postpartum. 

The study of 540 parous women reported that breastfeeding at 1 year was significantly associated 

with less weight retention from first trimester to 1 year postpartum (P = 0.04). The study of 95 

nulliparous and primiparous women found that less weight was retained by lactating women than 

by non-lactating women, and this was statistically significant.153 Exclusive breastfeeding was 

associated with approximately 1 kg weight loss from pre-pregnancy to 1 year postpartum. Bottlefeeding was associated with a weight retention of 2 kg during the same time period. Once 

lactation was discontinued, slower rates of weight loss were observed. Exclusively breastfeeding 
113

women achieved their pre-pregnancy weights about 6 months earlier than women who 

exclusively bottle-fed their infants. 

Relationship between breastfeeding and postpartum weight changes (Table 27) 

 Five prospective cohort studies involving a total of 2,097 parous women were identified. 

Followup durations ranged from 6 months to 15 years. Two studies were conducted in Sweden, 

two in the United States, and one in Canada. This group of studies measured the post-delivery 

weight changes in women. Half of the studies did not report women’s pre-pregnancy weights. 

All studies attempted to control for various confounding factors that could influence the 

relationship between breastfeeding and postpartum weight changes. Five studies were of 

moderate methodological quality (Grade B), and one of poor methodological quality (Grade C). 

 The results from the five studies were inconsistent. Among the studies utilized a lactation 

score to express duration and intensity or exclusivity of breastfeeding, amount of breastfeeding 

was negatively associated with the postpartum weight change.144,157 Among the three studies that 

examined postpartum weight changes and compared women who exclusively breastfed with 

women who partially breastfed or exclusively bottle-fed, none of them found a significant 

relationship between weight loss and breastfeeding among the comparison groups.155,156,158

Conclusion 

 Based on the results from three prospective cohort studies, we concluded that the overall 

effect of breastfeeding on return-to-pre-pregnancy weight (weight change from pre-pregnancy or 

first trimester to 1 to 2 year postpartum) was negligible (less than 1 kg). Results from four 

prospective cohort studies showed that the effects of breastfeeding on postpartum weight loss 

were unclear. All seven studies consistently suggested that many other factors have larger effects 

on weight retention or postpartum weight loss than breastfeeding. Examples of which included 

annual household income, baseline BMI, ethnicity, gestational weight gain, and energy intake. 

Undoubtedly, all these factors need to be carefully considered in any future investigation of the 

relationship between breastfeeding and postpartum weight changes. 
114

Table 26. Summary of prospective cohort studies on the relationship between breastfeeding and returning to pre-pregnancy w

Author Year 

Country 

(N baseline 

/followup) 

Study 

followup 

period(s) 

Breastfeeding 

exposure 

Comparative 

feeding 

groups 

Prepregnancy 

weight (kg) / 

BMI (kg/m2) 

Confounders adjusted 

for Results 

Sichieri 2003 US Nulliparous: 1,538/1,538; Primiparous: 2,810/2,810 

3 yr 

Exclusive breastfeeding:

introduction of daily 

formula/milk was 

assumed to represent the 

end of exclusive 

breastfeeding perioda

Never 

breastfeeding 

62 / 82% <25; 18% ≥25 

Age, physical activity, BMI, gestational weight gain 

After adjusting for confounders

associated with a weight gaprepregnancy to 1-2 yr postapproximately 1 kg (statisticonly for women nulliparous BMI <25 (P=0.02) and for thprimiparous with a baseline 

(P=0.04), comparing women with women who did not. 

Duration of exclusive lactation 

to the magnitude of weight cprepregnancy to 1-2 yr post(P>0.40). 

Effect of breastfeeding on mate

negligible. 

Olson, 2003 US 597/540 

1 yr 

postpartum 

Breastfeeding after 6 mo was considered to 

be non-exclusive; a breastfeeding score 

similar to Ohlin and Rossner’s was 

constructedb

ND / 59% ≤26; 

41% >26 

Age, educational level, 

smoking status at 1 yr 

post-partum, annual 

household income level, 

pre-pregnancy BMI 

category, and parity, 

gestational weight gain 

Women who were breastfeedin

retainedc less weight compa

women who weren’t (P = 0.0

Breastfeeding at all other time 

breastfeeding score were norelated to postpartum weigh

Women at < 185% federal pov(PIR) who gained more in pregInstitute of Medicine (IOM) recowere 3.73 kg heavier that low iwho gained below or within the guidelines for gestational weig(P<0.001). 
115

Table 26. continued 

Author Year 

Country 

 (N baseline 

/followup) 

Study 

followup 

period(s) 

Breastfeeding 

exposure 

Comparative 

feeding groups 

Prepregnancy 

weight (kg) / 

BMI (kg/m2) 

Confounders 

adjusted for Results 

Janney 1997 US 110/95 

0.5, 2, 4, 6, 12, 

and 18 mo 

postpartum 

Fully 

breastfeeding was 

defined as 

providing at least 

2/3 of the needed 

energy intake per 

kilogram of the 

infant’s weight in 

breast milk 

Partial 

breastfeeding; full 

bottle feeding 

59.7 / 22.2 

Weight gained 

during pregnancy, 

amount of 

education, parity, 

type of delivery, 

season of delivery, 

marital status, age, 

smoking status 

before and during 

pregnancy, 

physical activity 

Duration of lactation practice was 

predictor of postpartum weightime (P<0.001). Breastfeeding achieved their pre-pregnancy months earlier than women wtheir infants. 

Time returned to prepregnancy w

postpartum):d

Bottle-feeding only: ~18Partly breast-feeding at 2 mo, 

feeding thereafter: ~12 

Fully breast-feeding for 6 mon

feeding thereafter: ~11 

Fully breastfeeding for 6 mo, p

feeding at 12 mo, and bottlemo: ~ 10 

Martial status is predictor of weig

over time (0.5-18 mo after parP<0.001. Study showed greatretention in unmarried than ma

BMI, Body Mass Index; IOM, Institute of Medicine; ND, not documented; PIR, poverty index ratio a Individual breastfeeding data were collected retrospectively in the followup. Women asked to recall their lifetime breastfeeding history. b 1 point for each week of coverage of exclusive breastfeeding and 0.5 point for each week of mixed feeding. c Weight measured in the first trimester of pregnancy was used to calculate weight retention. d Estimated values from figure
116 

Table 27. Summary of prospective cohort studies on the relationship between breastfeeding and postpartum weight/BMI chang

Author Year 

Country 

 (N baseline 

/followup) 

Study 

followup 

period(s) 

Breastfeed

ing 

exposure 

Comparative 

feeding 

groups 

Prepregnancy 

weight (kg) / 

BMI (kg/m2) 

Confounders 

adjusted for Results 

Ohlin 1990; Ohlin 1996 Sweden 2295/1423 Stockholm Pregnancy and Women’s Nutrition Study (SPAWN) 

1 yr 

postpartum 

Lactation score (scale 0-48): 

Every month with full lactation 

was given 4 points, and every 

month with mixed feeding was 

given 2 points. 

59.6 / 21.5 

Weight gain during pregnancy, lactation score, age, prepregnancy BMI, parity, weight retention after previous pregnancy, dieting, profession, smoking habits, contraceptive practices, physical activity. 

Overall, relationship between the 

∆ weight a

score is statistically significant though weap<0.01). 

The weight loss between 2.5 and 6 months p

significantly higher in groups with lactation than < 20. However, the total weight loss and 12 months postpartum did not differ sbetween groups. 

30% lost weight, 56% gain 0-5 kg, 13% gaine

1.5% gained >=10 kg 1 year after delivery. overweight women (BMI>=23.9) increased before pregnancy to 21% 1 year post-partu

The coefficients between the 

∆ weight and la

age, pre-pregnancy weight and parity were (multiple r=0.38, p<0.001). Lactation and athe total proportion of explained variance beach.

Linne 2003 Stockholm 1423/563e

(SPAWN)

15 yr Ohlin’s lactation score (scale 0- 48) 59.8 / 21.5 As above Those women who became overweight had 

scores than women who remained normal wfollow up (21.7 vs. 24.0, P < 0.05). 
117 

Table 27. continued Author Year Country  (N baseline /followup) 

Study 

followup 

period(s) 

Breastfeeding 

exposure 

Comparative 

feeding groups 

Prepregnancy 

weight (kg) / 

BMI (kg/m2) 

Confounders adjusted 

for Outcom

Walker 2004 US ND/382 

6 wk, and 3, 6, 

and 12 mo 

postpartum 

Full (exclusive) 

breastfeeding 

Partial 

breastfeeding; full 

bottle feeding 

ND 

Ethnicity, maternal education, 

parity, smoking, physical 

activity, time of weight 

measurement, interaction of 

ethnicity and time, prepregnant BMI, gestational 

weight gain, energy intakes, 

fat intake, contraception, 

emotional eating, depressive 

symptoms 

Infant feeding method was 

with postpartum BMI (p

Ethnicity is associated with 

In addition, BMI for the parallel until 3 months pthe African American abegin increasing in BMgroup begins decreasinthe White group continuthe African American gincrease and the Hispato decrease.

Haiek 2001 Canada 242/236 

6 wk, 3-5, 6-8 

mo, and 9 mo 

postpartum 

Predominantly 

breastfeeding (i.e., 

exclusive 

breastfeeding or 

average daily 

intake of formula 

of 4 oz or less) 

Mixed-feeding 

(i.e., average daily 

intake of formula 

and breast milk of 

> 4 oz); 

predominantly 

bottle-feeding (i.e., 

exclusive bottlefeeding or 

average daily 

intake of breast 

milk of 4 oz or 

less) 

22.5 

Gestational weight gain, 

postpartum smoking, infant’s 

solid intake, maternal place 

of birth 

The unadjusted monthly ra

change was similar amfeeding groups for all tinone of the time periodweight loss greater in thbreastfeeding group. 

In the multivariate regress

mixed-feeding nor predfeeding was significantlpostpartum weight changroup was the referenc
118 

Table 27. continued Author Year Country  (N baseline /followup) 

Study 

followup 

period(s) 

Breastfeeding 

exposure 

Comparative 

feeding groups 

Prepregnancy 

weight (kg) / 

BMI (kg/m2) 

Confounders adjusted 

for Outcom

Brewer 1989 US 70/56 

3 and 6 mo 

postpartum 

Exclusive 

breastfeeding 

Exclusive formula 

feeding; mixed 

breast and 

formula feeding 

ND 

Age, parity, pre-pregnancy 

weight, socioeconomic data, 

energy intake, energy 

expenditure exclusive of 

lactation (physical activity) 

Weight loss averaged 1.6, 

for exclusive breastfeedformula feed, and mixeduring the first 3 mo cofluid loss of 2 kg. Excluresulted in an additionaover the second 3 mo (mixed feed averaging a nonlactating women exessentially no change. 

All groups significantly dec

maternal weight over thperiod (p<0.001). No sidifferences in total weigobserved between the lactating groups. 

BMI, body mass index. a This study is the 15-yr followup of Ohlin 1990;1996. Responders were slightly older, had higher educational attainment, and higher inco

 Nonresponse was more common in non-Nordic citizens. 

b Other variables also included the multivariate model: ethnicity, time, pre-pregnant BMI and other variables (such as parity, gestational w

 gain, Cesarean section etc.) 
119

Relationship between Maternal Type 2 Diabetes and 

Breastfeeding 

Background 

 Studies have shown that lactation has a beneficial effect on glucose and lipid metabolism; 

and improved pancreatic beta-cell function in women with gestational diabetes.159,160 Thus, it is 

plausible that lactation could reduce the risk of the development of type 2 diabetes. 

 Commonly considered confounders in the studies of relationship between maternal type 2 

diabetes and breastfeeding were parity, body mass index (BMI), diet, physical activity, family 

history of diabetes, and smoking status. 

Published Systematic Review/Meta-Analysis (Table 28) 

 One systematic review examined the effect of breastfeeding on maternal risk of subsequent 

diabetes.98 The authors identified three studies that evaluated the effects of breastfeeding on 

glucose tolerance and insulin levels; one study that evaluated the risk factors for recurrent 

gestational diabetes (GDM); and one study that examined the relationship between lactation and 

the risk of developing type 2 diabetes in women who had GDM. For this report, we focused only 

on the one study that examined the relationship between breastfeeding and the risk of developing 

type 2 diabetes in women with GDM. 

 Kjos 1998 conducted a retrospective cohort study of 904 Hispanic American women with 

GDM.161 Kjos 1998 found that the use of progestin-only oral contraceptives was associated with 

an almost three-fold risk of developing type 2 diabetes compared with the use of combination 

estrogen-progestin oral contraceptives for breastfeeding Latina women with recent GDM. Since 

progestin-only oral contraceptive use was invariably associated with breastfeeding in this cohort, 

the authors then looked for an independent effect of breastfeeding on the risk of developing 

diabetes among women who initially elected nonhormonal forms of contraception and who were 

breastfeeding at the time of their initial postpartum examination. The results showed that the risk 

of developing diabetes in these women was not significantly different from the risk in women 

who elected nonhormonal contraception but did not breastfeed (unadjusted RR 0.90, 95%CI 0.56 

- 1.46; adjusted RR 1.16, 95%CI 0.70 - 1.92). The authors of the systematic review did not 

assess the quality of this study. 

 The authors of the systematic review concluded that although no study has ever reported an 

increased risk of developing diabetes from breastfeeding, a single study did show a potential 

harm from the use of progestin-only oral contraceptive among breastfeeding Latino women with 

recent GDM. 

Studies Identified after the Published Systematic Review/MetaAnalysis (Table 29) 

 One prospective, longitudinal cohort study on the association between the duration of 

lactation and the incidence of type 2 diabetes was identified.162 The study consisted of two large 

cohorts in the United States, including participants from the Nurses’ Health Study (NHS) and 

Nurses’ Health Study II (NHS II). The Nurses’ Health Study (NHS) was initiated in 1976 and 
120

enrolled 121,700 women from 11 states. Participants were between 30 and 55 years of age at 

baseline, and each woman completed a detailed baseline questionnaire regarding diseases and 

health related topics. The Nurses’ Health Study II (NHS II), begun in 1989, enrolled 116,671 

women from 14 states. Participants were between 25 and 42 years of age and completed a similar 

baseline questionnaire as well as biennial followup questionnaires. This study was graded as high 

methodological quality (grade A). 

 The assessments of lactation history and type 2 diabetes were performed longitudinally. 

Women in the NHS II were also asked to report the diagnosis of GDM on each biennial 

questionnaire. Cox proportional hazards model was used to calculate the hazard ratio (HR) for 

type 2 diabetes by lactation history. All models were age-adjusted. Potential confounders 

including parity, BMI at age 18 years, diet, physical activity, family history of diabetes, and 

smoking status were included in the multivariate model a priori. Lifetime lactation history among 

parous women was stratified into six groups: none (reference group), 0 to 3 months, more than 3 

to 6 months, more than 6 to 11 months, more than 11 to 23 months, and more than 23 months. 

Lifetime duration was updated every 2 years. Linear trend was assessed using midpoints of 

lactation categories. In the analysis of HR per year of lactation, the midpoints of reporting 

categories to calculate total lifetime lactation were used because this was the closest 

approximation of the original reported duration. 

 In the NHS, women who had ever breastfed had a covariate-adjusted HR for type 2 diabetes 

of 0.97 (95%CI 0.91 - 1.02) compared with women who never breastfed. There was a modest but 

statistically significant inverse association between duration of lactation and the risk of type 2 

diabetes. In the multivariate-adjusted model including current BMI, each additional year of 

lactation was associated with an HR of 0.96 (95%CI 0.92 - 0.99) for type 2 diabetes. 

 Among women who had ever breastfed in the NHS II, the covariate-adjusted HR for type 2 

diabetes was 0.90 (95%CI 0.77 - 1.04). Each year of lactation was associated with a covariateadjusted HR of 0.84 (95%CI 0.78 - 0.89). When BMI was added to this model, the HR was 0.88 

(95%CI 0.82 - 0.94) for each additional year of lactation. 

 Women with a history of GDM had a markedly increased risk of type 2 diabetes in the NHS 

II cohort, with 624 cases per 100,000 person years compared with 118 cases per 100,000 personyears among those without such a history. Lactation had no effect on diabetes risk in the GDM 

group, with a covariate-adjusted HR of 0.96 (95% CI 0.84 - 1.09) per additional year of lactation. 

 The effects of exclusive versus total breastfeeding could be compared in the NHS II cohort 

data. In models controlling for age and parity, each year of lifetime exclusive breastfeeding was 

associated with an HR for type 2 diabetes of 0.63 (95%CI 0.54 - 0.73), while each year of total 

breastfeeding was associated with an HR of 0.76 (95%CI 0.71 - 0.81). 

Conclusion 

 Based on the longitudinal study of two large cohorts in the United States with over 150,000 

parous women, we conclude that a longer duration of lifetime breastfeeding is associated with a 

reduced risk of developing type 2 diabetes among parous women who did not have a history of 

GDM. There was a difference in the risk of developing type 2 diabetes between women with and 

without GDM in relation to lactation. Compared with women who did not have a history of 

GDM, women with a history of GDM had a markedly increased risk of type 2 diabetes; and 

lactation showed no significant relationship with diabetes risk among this group of women. One 
121

must be cautious in interpreting these findings, as they are only generalizable to population with 

characteristics similar to that of the Nurses’ Health cohort. 
122 

Table 28. Summary of systematic review/meta-analysis on the relationship between breastfeeding and maternal type 2 diabetes Author year Population Study description Intervention /Comparator Confounders considered Results Taylor 2005 Kjos et al. (1998): A retrospective cohort study of 904 Latinas living in US with GDM (based on National Diabetes Data Group Criteria) who gave birth between January 1987 and March 1994, in whom postpartum diabetes was excluded at 4 to 16 weeks post partum. 

SR of 1 retrospective cohort study on the association between breast milk feeding (or lactation) and maternal type 2 diabetes 

At their baseline postpartum visits, 

461 of the study subjects chose to use an oral contraceptive (OC) and 443 chose a nonhormonal method of contraception. 

Of those electing to use an OC, 78 

were given the progestin-only OC since they were breast-feeding at their baseline postpartum visits and planned to continue breastfeeding. 

Since progestin-only OC use was 

invariably associated with breastfeeding in this cohort, the author then looked for an independent effect of breast-feeding on the risk of developing type 2 diabetes among women who initially elected nonhormonal forms of contraception (n=443). 

Gestational age at diagnosis of GDM, highest fasting glucose level during the index pregnancy, and glucose area under the curve from the diagnostic OGTT 

The risk of developindiabetes was not sigdifferent between breastfeeding womebottle feeding womechose non-hormonacontraception (adjus1.16; 95%CI 0.70-1.

GDM, gestational diabetes; RR, relative risk a We did not grade the methodological quality for Kjos 1998 in the systematic review. Taylor 2005 review is also summarized in infant ou

section. 
123 

Table 29. Summary of studies on the relationship between breastfeeding and maternal type 2 diabetes (NIDDM) Author year Country 

Study design Number of subjects 

Mean 

age at 

followup (year) Definitions of type 2 diabetes 

Breast milk feeding 

duration (months), 

parous women only 

Adju

Hazar

(95%

NHS –  None Refe >0 to 3 0.98 (0. >3 to 6 1.03 (0. >6 to 11 0.96 (0. >11 to 23 0.92 (0. >23 0.88 (0. Per year of lactation 0.96 (0.NHS II –  None Refe >0 to 3 1.04 (0. >3 to 6 0.91 (0. >6 to 11 0.87 (0. >11 to 23 0.88 (0. >23 0.67 (0. Per year of lactation 0.88 (0.NHS II, never had GDM –  None Refe >0 to 3 1.00 (0. >3 to 6 0.80 (0. >6 to 11 0.86 (0. >11 to 23 0.77 (0. >23 0.58 (0. Per year of lactation 0.84 (0.NHS II, ever had GDM –  None Refe >0 to 3 1.18 (0. >3 to 6 1.30 (0. >6 to 11 0.89 (0. >11 to 23 1.19 (0. >23 0.97 (0.

Stuebe 2005 US 

Prospective longitudinal cohorts (NHS and NHS II studies) NHS: prospective analysis using cases from 1986 to 2002 NHS II, retrospective analysis using lactation data from 1997 and 2003, cases from 1989 to 2001, parous women only 

Nurses’ Health Study (NHS): 121,700 (83,585 parous women) NHS II: 116,671 (73,418 parous women) 

NHS: ~52 NHS II: ~35 

(1) 1 or more classic symptoms (i.e., excessive thirst, polyuria, weight loss, or hunger) plus either a fasting glucose level of 140 mg/dL (7.8 mmol/L) or more or random plasma glucose level of 200 mg/dL (11.1 mmol/L) or more; (2) at least 2 instances of elevated plasma glucose concentration (fasting glucose 

≥140 mg/dL, random plasma 

glucose 

≥200 mg/dL, or oral glucose 

tolerance test 

≥200 mg/dL after 2 

hours) on different occasions in the absence of symptoms; or (3) treatment with insulin or an oral hypoglycemic medication. 

The criteria for diagnosis of diabetes 

changed in 1997, when a fasting glucose level of 126 mg/dL (7.0 mmol/L) or higher was made the diagnostic threshold. 

 Per year of lactation 0.96 (0.

GDM, gestational diabetes a Confounders adjusted in the model include parity, BMI, diet, physical activity, family history of diabetes, and smoking status.
124

 Relationship between Osteoporosis and Breastfeeding 

Background 

Osteoporosis is a condition of decreased bone mass. This leads to fragile bones that are at an 

increased risk for fractures. The World Health Organization (WHO) has established criteria for 

making the diagnosis of osteoporosis, and for determining levels that predict higher chances of 

fractures. These criteria are based on comparing bone mineral density (BMD) in a particular 

patient with those of a healthy 25-year-old female (T-scores). BMD values (T-scores) which fall 

well below the average for the 25-year-old female (stated statistically as 2.5 standard deviations 

below the average) are diagnosed as osteoporosis. Although BMD T-scores were based 

originally on assessment of BMD at the hip by dual-energy X-ray absorptiometry (DXA), they 

have been applied to define diagnostic thresholds at other skeletal sites and for other techniques. 

Experts have expressed concern that this approach may not produce comparable data between 

sites and techniques. Of the various sampling sites, measurements of BMD made at the hip 

predict hip fracture better than measurements made at other sites, while BMD measurement at 

the spine predicts spine fracture better than measurements at other sites 

(consensus.nih.gov/2000/2000Osteoporosis111html.htm). 

Calcium and bone metabolismis substantially altered during pregnancy and lactation. The 

typical daily loss of calcium in breast milk has been estimated to range from 280 to 400 mg, 

although daily losses as great as 1000 mg calcium have been reported.163 Physiologically, during 

nursing, the body could theoreticallymeet this demand by increasing the intestinal absorption of

calcium, decreasing renal calcium losses, and increasing the resorption of calcium from the 

maternal skeleton. Bone densities can decrease and increase 3 to 10 percent in the span of a few 

months in healthy mothers.164 Prospective cohort studies have reported that lactation is 

associated with bone mineral loss in the first 6 months to 1 year postpartum, but such loss 

rebounds overtime.165-169

Confounders commonly considered in the studies of relationship between fracture risk and 

breastfeeding were age, hormone replacement therapy, parity and BMI. 

Inclusion and Exclusion Criteria 

To evaluate the relationship between breastfeeding and the development of osteoporosis, we 

included all studies that examined the link between breastfeeding and fracture. We also included 

long-term prospective cohort studies (greater than 1 year of followup duration) that examined the 

relationship between the duration of breastfeeding and changes in bone mineral densities or bone 

mineral contents. Articles were excluded if they only used surrogate measures of fracture (e.g., 

fracture risk score or index) or bone turnover markers. 

Results (Tables 30-31) 

 A total of 44 potential relevant articles were retrieved for full-text screening. Thirty-four 

articles were excluded due to various reasons (e.g., cross-sectional design, relatively short 

duration of follow up (< 2 years), studies done in developing countries). We included a total of 

six case-control studies that examined the risk of fractures in relation to a history of 
125

breastfeeding,170-175 and four long-term prospective cohort studies that examined the changes of 

bone mineral densities or bone mineral contents in relation to the duration of breastfeeding.176-179

 Risk of fractures in relation to a history of breastfeeding (Table 30). A total of six casecontrol studies were identified. There were a total of 1,594 subjects with hip, forearm, or 

vertebral fractures and 3,523 controls. All subjects were post-menopausal women with an age 

that ranged from 45 to 103 years old. Three studies were conducted in the United States; one 

study each was conducted in Australia, Hong Kong, and Sweden. Four studies were rated 

methodological quality grade B; two was rated grade C. 

 Incident cases of hip and forearm fractures were identified from hospital or clinical records 

(with or without radiography confirmations) in five studies. Matched or unmatched general 

population controls living in the same area were used in three studies, while hospital controls 

were used in the other two studies. In the remaining one study, all women who were living in 

three housing blocks were enrolled. Cases of definite vertebral fractures were classified 

according to the radiological diagnoses and the remaining enrolled subjects without fractures 

were classified as control subjects. Assessments of breastfeeding history were based on subjects’ 

long-term recalls in all studies. Only one study reported blinded interviewers. 

 Overall, there was no significant association between a history of breastfeeding and the risk 

of hip, forearm, or vertebral fractures after adjustment for potential confounders. In four of six 

studies, parity was considered a potential effect modifier or confounder. Other confounders 

examined included age, body mass index or weight, hormone replacement therapies, and 

bilateral oophorectomy. None of the studies provided data on the exclusivity of breastfeeding. 

 Long-term changes in bone mineral densities or bone mineral contents in relation to the 

duration of lactation (Table 31). A total of four prospective cohort studies were identified. 

Followup durations ranged from 2.5 to 12 years. Studies were done in different countries: one 

studied 113 pre-menopausal parous women in Japan, one studied 169 pre- and peri-menopausal 

parous women with European heritage living in the United States, one studied 92 premenopausal women in Finland, and one studied 121 post-menopausal women in Denmark. One 

study was of methodological quality grade A, two were of grade B, and one was of grade C, 

respectively. 

 Matsushita 2002 examined the effects of multiple pregnancies on BMD of lumbar spine (L2-

L4) in 110 parous Japanese women. The outcome was the percent change in BMD, calculated by 

subtracting the value at the time of the initial pregnancy from the value at the time of the second 

pregnancy. The results showed that the BMD after the subsequent delivery was significantly 

higher than the BMD after the initial delivery (P = 0.001), with a percent change in BMD of 1.4 

percent. Independent determinants of the percent change in BMD were explored by multiple 

regression analysis. The length of lactation between the deliveries showed no correlation with the 

percent change in BMD (correlation coefficient = -0.06, P = 0.702). Age was the most significant 

predictor for the percent change in BMD in the model. 

 Sowers 1992 examined various risk factors for 5-year radial BMD changes in 169 pre- and 

post-menopausal parous women with European heritage living in the United States. The authors 

reported that “a recalled history of breastfeeding in parous women did not predict significant 

differences in BMD level or amount of BMD change”. 

 Uusi-Rasi 2002 examined the relationship between physical activity, calcium intake, and the 

maintenance of bone mass in 92 non-smoking premenopausal women living in Finland. The 

effects of total breastfeeding duration on changes in bone mineral contents (BMC) were also 
126

analyzed. According to the multiple stepwise regression analyses, the statistically significant 

independent predictors for site-specific bone loss were low calcium intake at the baseline and 

change in body weight both at the proximal femur and at the distal radius sites. In addition, 

breastfeeding was associated with radial bone loss; the longer the duration of breastfeeding the 

greater the bone loss (correlation coefficient = -0.34, P = 0.015).

Hansen 1991 examined the risk factors for the development of postmenopausal osteoporosis 

over a 12-year period in 121 postmenopausal women living in Denmark. One hundred eleven of 

them (92 percent) had one or more pregnancies (mean 2.6) and breastfed their infants for a mean 

total breastfeeding duration of 13 months. Comparing postmenopausal women who never 

breastfed their infants with those who did, there was no significant difference in lumbar spine 

BMD between groups. In addition, there was no significant difference in the annual rate of 

postmenopausal bone loss between these two groups. 

Conclusion 

 There is no evidence of an association between lifetime breastfeeding duration and 

osteoporosis. In six case-control studies, there was no significant relationship between a history 

of lactation and the risk of fractures in postmenopausal women. In two of three moderate or good 

quality prospective cohort studies using bone mineral density as a surrogate for osteoporosis, 

lactation does not appear to have an effect on long-term changes in bone mineral densities. The 

third study found a small decrease in the bone mineral contents in the distal radius with increased 

duration of breastfeeding, but no significant changes in bone mineral contents in the femoral 

neck or the trochanter. However, these findings should be interpreted with caution because the 

feeding history was obtained by maternal recall and data on exclusivity of breastfeeding were not 

provided. Further investigation with accurate breastfeeding data is warranted. 
127

Table 30. Summary of case-control studies on the relationship between breastfeeding and risk of fracture in post-menopausal 

OR (95% CI) Author 

year Country 

Cases 

(N) 

Controls 

(N) 

Definition of 

fracture 

Mean Age 

at Dx of 

fracture 

(year) 

Lactation 

group 

Comparator 

group Age-adjusted Full adjusted* 

c

All post-menopausal women 

BF 1-12 mo 1.60 (0.91-2.96) 

164 BF 13-24 mo 0.40 (0.17-1.10) 

Hip fractures 

based on 

clinical records BF > 24 mo 

Never BF 

0.50 (0.21-1.44) 

BF 1-12 mo 0.80 (0.45-1.58) 

BF 13-24 mo 0.80 (0.40-1.79) 

Alderman 1986 USA 

180 

318 Forearm 

fractures based 

on clinical 

records 

50-74 

BF > 24 mo 

Never BF 

0.80 (0.38-1.87) 

A

lo

est

re

Cumming 1993 Australia 

174 137 

Hip fractures 

presenting to 

the hospitals 

65-100 Ever BF Never BF 0.72 (0.43-1.20) 0.64 (0.30-1.38) 

Ag

of 

pm

cu

s

d

c

sc

sta

an

Ever BF Never BF 0.66 (0.41-1.05) 

BF 

≤ 12 mo 0.67 (0.39-1.13) 

Hoffman 1993 USA 

170 173 

First hip 

fracture 

confirmed by 

radiography 

identified from 

hospital 

records 

50-103 

BF > 12 mo 

Never BF 

0.64 (0.32-1.29) 

 

BF < 24 mo 0.70 (0.40-1.30) 

Chan 1996 Hong Kong 144 163 

Definite 

vertebral 

fractures by 

radiography 

75 

BF 

≥ 24 mo 

Never BF 

0.60 (0.30-1.00) 

 
128

Table 30. Continued 

OR (95% CI) Author 

year Country 

Cases 

(N) 

Controls 

(N) 

Definition of 

fracture 

Mean Age 

at Dx of 

fracture 

(year) 

Lactation 

group 

Comparator 

group Age-adjusted Full adjusted* 

Po

confo

adj

83b 0.50 (0.20-0.90)b Kreiger 

1982 USA 

98 

801c

First hip 

fracture 

confirmed by 

radiography 

identified 

from hospital 

records 

45-74 BF (12-month increase) 

0.60 (0.30, 1.0)c

Age a

bil

ovar

an

Parous post-menopausal women 

BF 6-10 mo 0.83 (0.66-1.05) 0.87 (0.68-1.11) 

BF 11-16 

mo 0.84 (0.65-1.08) 0.86 (0.66-1.12) 

BF > 16 mo 

BF 1-5 mo 

0.76 (0.60-0.98) 0.86 (0.67-1.12) 

Michaelsson 2001 Sweden 

664 1,848 

Hip fractures 

based on 

clinical or 

register records 

71 

BF (3-month increase) 0.96 (0.94-0.99) 0.98 (0.95-1.01) 

Age, H

contr

use, 

BF 1-12 mo 1.20 (0.73-1.95) 

BF 13-24 

mo 

Alderman 0.70 (0.34-1.29) 1986 USA 

268 211 

Hip or 

forearm 

fractures 

based on 

clinical 

records 

50-74 

BF > 24 mo 

Never BF 

0.80 (0.38-1.51) 

Same 

Ever BF Never BF 0.47 (0.22-0.99) 0.55 (0.10-2.90) 

BF 0.5-3 

moa 0.56 (0.19-1.68) 0.64 (0.13-3.06) 

BF 3-6 moa 0.41 (0.15-1.13) 0.79 (0.18-3.51) 

BF 6-9 moa 0.47 (0.19-1.19) 0.41 (0.09-1.82) 

Cumming 1993 Australia 

131 107 

Hip fractures 

presenting to 

the hospitals 

65-100 

BF >9 mo a

Never BF

0.28 (0.07-1.18) 0.24 (0.04-1.53) 

Same 

Ever BF Never BF 0.87 (0.47-1.61) 

BF 

≤ 12 

mo 0.80 (0.42-1.55) 

Hoffman 1993 USA 

103 125 

First hip 

fracture 

confirmed by 

radiography 

identified 

from hospital 

records 

50-103 

BF > 12 mo 

Never BF 

1.08 (0.45-2.60) 

Ag

numb

b

Dx, diagnosis; BF, breastfeeding; HRT, hormone replacement therapy; PA, physical activity

* Adjusted for potential confounders, including age 

a Average breastfeeding duration per child; b trauma controls ; c non-trauma controls
129

Table 31. Summary of prospective cohort studies on the relationship between duration of breastfeeding and the long-term cha

density (BMD) or bone mineral content (BMC) 

Author, Year Country 

Population 

Mean 

baseline age 

(yr) 

Mean duration 

of followup (yr) N Duration of lactation

∆BMD(g/cm2) or 

∆BMC 

p 

Matsushita, 2001 Japan 

Pre-menopausal, 

parous women 

30 2.5 113 

Length of lactation 

between 1st and 2nd

delivery (mo) 

∆BMDspine: 

-0.06% a NS 

Sowers, 1992 USA 

Mixed pre- & perimenopausal, parous 

women 

22-54 5 169 Lactation vs. no lactation “No significant differences in BMD level or change” NS 

%∆BMCfemoral neck c NS 

%∆BMCtrochanter c NS Uusi-Rasi, 2002 

Finland 

Pre-menopausal 

women 

28 

(25-30) 

4.2 

(3.2-5.4) 92 Total duration of breastfeeding b

%∆BMCdistal radius: 

β=-0.34 c 0.01 

Hansen, 

∆BMDspine: 0.04 NS 

1991 Denmark 

Post-menopausal 

women 

51 12 121 

Lactation (87%): mean 

13 mo vs. 

no lactation b

∆BMCarm: 

0.1% per year NS 

NS, not statistically significant; BMDspine, lumbar spine bone mineral density; BMCarm, forearm bone mineral content a Variables in the multiple regression model: interval between the scans (yr), lumbar spine BMD after the initial delivery (g/cm2), bone are

 delivery (cm2), body weight after the initial delivery (kg), age at initial delivery (yr), 

∆BA (cm2), body weight changes between the scans 

 between the scans (mo), interval between the time at which breast-feeding was stopped and the next conception (mo); age at next deliv

 variable, 

∆BMD%, r2=0.174, p=0.037. The percent change in BMD (

∆BMD%) was calculated by subtracting the value at the time of the 

 value at the time of the second pregnancy 

b Not clear whether nulliparous women were included in the analyses c Multivariate stepwise regression for percent bone loss included the following variables: age, body weight, muscle strength, estimated m

 calcium intake, the absolute changes in body weight, muscle strength, estimated maximal oxygen uptake, calcium intake, physical, acti

 breastfeeding and time from weaning. Only statistical significant variables were kept in the final model. 
130

Relation between Postpartum Depression and Breastfeeding 

Background 

 Postpartum depression is a serious health problem. The prevalence has been estimated at 

around 13%.180 It not only affects mother’s health, it also affects her ability to care for her infant. 

Breastfeeding plays a role in affecting an infant’s health and in maternal-infant bonding. It is 

important to understand the nature of the relationship between postpartum depression and the 

decision to initiate and continue breastfeeding. 

 Many studies have examined the relationship between breastfeeding and the development of 

postpartum depression. The results have been quite variable. This may be explained by the lack 

of a uniform standard in arriving at a diagnosis of postpartum depression. Some studies used 

questionnaires and some used clinical interviews and different criteria of depression. Many of the 

studies had relatively small number of subjects. Furthermore, the items commonly used to assess 

clinical depression like fatigue and sleep problems are to be expected in caring for a newborn. 

Some of the potential confounders thought to be important in studies of depressive symptoms 

and feeding practices were marital status, employment status, and whether or not the pregnancy 

was planned.181

Additional Methodological Comments 

 We screened the abstracts identified from the MEDLINE general search on breastfeeding in 

November 2005. Abstracts qualifying for full text retrieval included studies on the relationship 

between breastfeeding and postpartum depression, psychological disorders, psychiatric illnesses, 

or mental health issues. We also identified additional articles based on reviews of the 

bibliographies cited in the relevant retrieved studies from the search. We only included studies 

that had at least 100 nursing mothers. Qualifying study designs included prospective cohort 

studies and case-control studies. All methods of assessment of depression were included. Only 

data pertaining to the relationship of breastfeeding and postpartum depression were extracted 

from the studies. 

Results (Table 32) 

Prospective cohort. A total of six prospective cohort studies qualified for inclusion.181-186

There were no case-control studies. The number of women in each study ranged from 113 to 

2,375. Three of six studies were rated methodological quality grade B within their respective 

study design hierarchy and with respect to only the data on the relationship of breastfeeding and 

postpartum depression. Studies of methodological quality grade C suffered from a combination 

of incomplete reporting of relevant data, inadequate blinding, lack of or suboptimal adjustment 

for confounding factors. 

 Four of six studies did not have specific inclusion criteria based on baseline mental health 

status. Four studies screened for depression using the Edinburgh Postnatal Depression Scale 

(EPDS), but the cut off point ranged from 9 to 13 (lowest severity score was zero, highest 

severity score was 30). Four studies established the diagnosis of depression after clinical 

interviews. None of the studies provided a clear definition of breastfeeding. 
131

 Four prospective cohort studies of moderate methodological quality totaling 4,941 subjects 

reported postpartum depression rates of 6% to 18%.181-183,185 In addition to a history of 

breastfeeding, all of the studies also considered socio-demographic and obstetric variables as 

independent predictors of postpartum depression. Assessment of depression by self-reported 

questionnaires or interviews took place from 1 to 12 months after birth. Except for one study,182

all of them reported that not breastfeeding or early cessation of breastfeeding was associated with 

postpartum depression. One study reported that onset of postpartum depression occurred before 

cessation of breastfeeding in most cases.185 One study reported that depressed mothers were less 

likely to continue breastfeeding beyond 2 to 4 months compared with mothers who were not 

depressed.183 In the one study that reported no significant difference in the development of 

depression in mothers who breastfed versus those who did not breastfeed, women who were 

breastfeeding at 1 month and were worried about breastfeeding were significantly more likely to 

become depressed than those who did not worry (RR 3.0, 95%CI 1.041 - 9.216).182

 Despite the poor methodological quality of the remaining studies, their findings were also 

consistent with those from studies of moderate quality. One study reported that high EPDS 

scorers experienced breastfeeding more negatively than the low EPDS scorers (51% versus 16%, 

P < 0.0001).186 One study reported that mothers who were depressed were less likely to initiate 

breastfeeding.184

Conclusion 

 Studies of moderate quality reported an association between not breastfeeding or short 

duration of breastfeeding and postpartum depression. More investigation will be needed to 

determine the nature of this association. It is plausible that postpartum depression led to early 

cessation of breastfeeding, as opposed to breastfeeding altering the risk of depression. Both 

effects might occur concurrently. Additional factors that may have a bearing on both postpartum 

depression and the decision to initiate or terminate breastfeeding should also be sought. 

Moreover, documentation of baseline mental health status before the initiation of breastfeeding 

and detailed recording of breastfeeding data will improve the quality of the studies and help 

understand the nature of the association. 
132

Table 32.Summary of the studies on the relationship between breastfeeding and postpartum depression Author Year Country Population 

Study description Definition of depression Confounders adjusted for Comparators Results 

Prospective Cohort Warner 1996 UK 2,375 Subjects recruited from postnatal wards prior to discharge 

Home interview 6-8 wk after delivery; Edinburgh Postnatal Depression Scale (EPDS) was completed at the interview 

Screening: high and low scores using an EPDS threshold of 12/13 

Sociodemographic and obstetric variables 

Examined “not breastfeeding” as one of the factors in logistic analysis 

280/2,375 scored >12 on EPDS; not breastfeeding at 6 wk (OR 1.52, 95%CI 1.12-2.06), unplanned pregnancy (OR 1.44), unemployment in mother (OR 1.56) or in head of household (OR 1.50) were associated with an EPDS >12 in a stepwise logistic analysis. 

Henderson 2003 Australia 1,745 Subjects recruited from postnatal wards; not under psychological care at the time of recruitment 

Self-reported questionnaires were completed at 2, 6, and 12 mo after birth; subjects with high EPDS score were offered a diagnostic interview 

Screening: EPDS >12. Diagnosis: DSM IV 

Demographic, perinatal, and postnatal factors 

Examined “early cessation of breastfeeding” in adjusted hazard ratio 

18% developed depression in the 12 mo after birth. Early cessation of breastfeeding was found to be associated with postpartum depression (adjusted hazard ratio 1.25, 95% CI 1.03 to 1.52). Onset of postpartum depression occurred before cessation of breastfeeding in most cases. 
133

Table 32. Continued Author Year Country Population 

Study description Definition of depression Confounders adjusted for Comparators Results 

Chaudron 2001 US 465 Subjects not depressed at 1 month postpartum 

Subjects participated in an interview during the 2nd trimester, and at 1 

and 4 mo after delivery; both the Diagnostic Interview Schedule (DIS) and Center for Epidemiologic Studies Depression Scale (CESD) were administered at each interview 

DSM-III-R criteria; ≥16 on 

the CES-D; and/or receiving antidepressants 

Age, depression during pregnancy, postpartum thoughts of death and dying, difficulty falling asleep 

Breastfeeding vs. not breastfeeding 

6% became depressed between 1 and 4 mo; Women who breastfed their infants were not significantly different in their development of depression from women who did not breastfeed. Of those women who were breastfeeding at 1 mo, women who worried about breastfeeding were significantly more likely to become depressed than those who did not worry (P=0.04) 
134

Table 32. Continued Author Year Country Study description Definition of depression Confounders adjusted for Comparators Results Cooper 1993  UK 243 at Oxford; 113 at Cambridge No restriction on mental health status prior to enrollment noted 

2 separate cohort studies (Oxford and Cambridge) At Cambridge, prospective subjects were screened at 6 wk postpartum using the EPDS. All high scorers (≥13) and other selected participants received full psychiatric assessment between 2 and 3 mo postpartum. 

Research Diagnostic Criteria (RDC) 

Social class, age, and education 

Reported only on “ceased breastfeeding” 

At Oxford, 56% of subjects psychiatric symptoms vers23% of subjects without psychiatric symptoms had ceased breastfeeding by 8 postpartum (P<0.01). In edepression preceded cessof breastfeeding; in two, depression was the subseevent; and in four, the two events arose contemporaneously. At Cambridge, 56% of subwith an episode of depresversus 21% of subjects widepression postpartum haceased breastfeeding by 8 (P<0.001). In all cases, thof depression preceded thcessation of breastfeeding

Seimyr 2004 Sweden 352 All Swedish speaking pregnant women from six antenatal clinics, with their partners or alone 

Administered EPDS at 2 mo before childbirth (I), 2 mo (II) and 12 mo (III) after child birth 

Cut-off point of 9/10 on EPDS is used to set the threshold for vulnerability to depression 

Did not report actual adjustment, but reported that there was no difference with regards to age, education, parity, and length of marital relationship between low and high-scoring women 

Breastfed vs. not breastfed 

Fewer high EPDS (I) scorebreastfed compared to the scorers (82% vs. 94%, P<Fewer high EPDS (II) scorbreastfed compared to the scorers (85% vs. 93%, P<High EPDS scorers experbreastfeeding more negatthan the women scoring loEPDS. High EPDS (II) scorers brefor a shorter time comparethe low-scoring women (4vs. 5.3 mo, P<0.04) 
135

Table 32. Continued Author Year Country Study description Definition of depression Confounders adjusted for Comparators Results Hannah 1992 UK 231 Women who had delivered a live baby 

Questionnaires (general questionnaire and EPDS) on 5th day 

postpartum and repeat EPDS at 6 weeks postpartum 

Postpartum depression defined by EPDS ≥ 13 at 6 weeks 

Did not report adjustment for breastfeeding, but did report that low mood after a previous delivery was a predictor of post-natal depression 

Ever breastfed vs. never breastfed 

At 6 wk, 18/26 (69%) womwith EPDS ≥ 13 vs. 175/20

(88%) women with EPDS had ever breastfed. 

CES-D, Center for Epidemiological Studies Depression Scale; DIS, Diagnostic Interview Schedule; DSM IV, Diagnostic Statistical Manual

Postnatal Depression Scale; RDC, Research Diagnostic Criteria
136

Relationship between Maternal Breast Cancer and Ovarian 

Cancer and Breastfeeding 

Background 

 Breast cancer is the second most frequently diagnosed and second most deadly cancer among 

women.187 Risk factors associated with increased risk of breast cancer include: family history, 

nulliparity, early menarche, hormone replacement therapy, obesity, and advanced age. Ovarian 

cancer ranks seventh in the most frequently diagnosed and fourth in the most deadly cancer 

among women.187 Risk factors for ovarian cancers are similar to those of breast cancer. While 

breast and ovarian cancers are closely associated with parity, women with increased parity also 

have increased lifetime duration of breastfeeding. Therefore, it would be instructive to examine 

the relationship of breastfeeding and the risk of developing breast or ovarian cancer. 

Breast Cancer 

Methods 

 We identified two meta-analyses and one systematic review that evaluated the relationship 

between breastfeeding and maternal breast cancer.188-190 We also identified 23 primary studies 

published since 2001, the cut-off date for literature search used in the latest meta-analysis. 

Primary studies were screened based on the same inclusion criteria described in the latest metaanalysis. In addition, we elected to include only primary studies conducted in developed 

countries. Twenty of the 23 primary studies were excluded for the following reasons: studies 

published in developing countries (5); studies that did not meet the eligibility criteria (e.g., 

studies that did not provide data on the following: incident invasive breast cancers, reproductive 

factors, and use of hormonal preparation) (13); duplicate study (1); and review that was not 

systematically conducted (1). A total of three studies from developed countries published 

subsequent to the latest meta-analysis were included in the update.191-193

Published Systematic Reviews and/or Meta-Analyses (Table 33) 

 The most recent meta-analysis published by the Collaborative Group on Hormonal Factors in 

breast cancer combined 45 studies published through 2001 and two unpublished studies.189 The 

meta-analysis evaluated a total of 50,302 parous women with incident invasive breast cancer and 

96,973 controls. Included in the meta-analysis were primary studies that analyzed at least 100 

cases of incident invasive breast cancers per study regardless of the menopausal status with 

additional information on reproductive factors and use of hormonal preparations. Both cohort 

and case-control studies from developed and developing countries were included. Individual 

subject data from the primary studies were analyzed for homogeneity across study definitions. 

The majority of the primary studies did not differentiate between exclusive and partial 

breastfeeding, and some studies varied in the definition of “ever breastfeeding”. The average age 

at diagnosis of breast cancer in the studies was 50 years. There was a higher proportion of 

women with either nulliparity or low parity in the breast cancer group compared with the control 

group. In addition, lower number of the parous women in the breast cancer group had ever 
137

breastfed their infants compared with the control group. There was a statistically significant 

reduction in risk of breast cancer by 4.3% (95% CI 2.9-5.8) for each year of breastfeeding. The 

reduction in the risk of breast cancer with breastfeeding remained unaltered even after 

stratification for potential confounders such as parity, number of children breastfed, menopausal 

status, and lifetime duration of breastfeeding. The results were also adjusted for ethnic origin, 

education, family history of breast cancer, age at menarche, height, weight, body mass index, and 

use of hormonal contraceptives, alcohol, and tobacco. Decrease in the relative risk of breast 

cancer associated with each year of breastfeeding remained homogeneous across the studies with 

regards to developed versus developing countries, age at diagnosis, menopausal status, family 

history of breast cancer, and study designs. In addition, the decrease in relative risk of breast 

cancer in parous women, according to breastfeeding history (ever versus never) and number of 

births, was more pronounced after four or more births. The methodological quality of the metaanalysis was rated grade A. 

 In the meta-analysis by Bernier 2000 evaluated the relationship of breastfeeding with 

histologically diagnosed breast cancer in parous women.188 The meta-analysis combined 25,871 

cases and 44,910 controls from 23 primary case-control studies. Criteria for inclusion are studies 

from developed and developing countries published in English or French languages between 

1980 and 1998 that provided usable data for the calculation of odds ratio of breastfeeding and 

breast cancer risk. The meta-analysis used both fixed and random effects model. There was a 

small, but statistically significant decreased risk of breast cancer in women who had breastfed 

their infants compared with women who had not. The decreased risk was further explored by 

examining the menopausal status at the time of diagnosis of breast cancer and the duration of 

breastfeeding. Women who were pre-menopausal at the time of diagnosis of breast cancer had a 

small but statistically significant decreased risk of breast cancer compared with menopausal 

women. The duration of breastfeeding was divided into categories of 1 to 6 months, 7 to 12 

months, and more than 12 months. When these categories of breastfeeding were compared with 

non-breastfeeding, only those whose lifetime duration of breastfeeding was longer than 12 

months (compared to never) had a small but statistically significant reduction in the risk of breast 

cancer in subgroup analysis. The authors reported that there was no “publication bias”. The 

methodological quality of the meta-analysis was rated grade B. 

 Another systematic review included all English language studies published through 1998 and 

enrolled at least 200 women with breast cancer.190 In addition, only studies that explicitly 

adjusted for the number of full-term pregnancies and age at first birth were included. The data 

included 19,482 cases and 37,627 controls from 24 case-control studies, and 3,857 cases 

identified from three longitudinal followup studies that comprised of 229,574 subjects. The casecontrol studies were conducted in hospital- or population-based settings. Studies conducted in 

developed and developing countries were included. Based on qualitative appraisal, the authors 

concluded that either there was no relationship between breastfeeding and the risk of 

development of breast cancer or there was a weak protective effect of ever breastfeeding against 

the development of breast cancer. The authors did report some reduction in the risk of 

development of breast cancer in premenopausal women who had breastfed their infants for long 

duration. The methodological quality of the systematic review was rated grade B. 
138

Studies Published after the Systematic Reviews/Meta-Analyses 

(Table 34) 

 We identified three eligible studies from developed countries that were published subsequent 

to the latest meta-analysis.191-193 One study was multi-center;192 the remainders were single 

center.191,193 One study was a prospective cohort of Korean women and evaluated only 

premenopausal women.193 The other two were case-control studies; one evaluated the 

relationship between breast cancer and breastfeeding among carriers of deleterious BRCA1 and 

BRCA2 mutations,192 the other evaluated incident invasive breast cancer patients.191 Two studies 

included only women whose mean age at diagnosis of breast cancer was in the premenopausal 

range.192,193 All studies reported a statistically significant reduced risk or odds of breast cancer 

with increased duration of breastfeeding, which varied across the studies. The duration of 

breastfeeding ranged from 12 to 24 or more months. The methodological quality of the studies 

ranged from grade B to C. 

Conclusion 

 Results from both meta-analyses concluded that there was a reduction in the risk of breast 

cancer in women who breastfed their infants. No studies evaluated exclusive breastfeeding. 

Studies also reported decreased risk or odds of breast cancer in women with a lifetime 

breastfeeding of more than 12 months. Neither one of the meta-analyses detected any publication 

bias. In addition, one of the meta-analyses and the systematic review reported decreased odds of 

breast cancer primarily in premenopausal women. Findings from primary studies published 

subsequent to the meta-analyses concurred with the findings from the meta-analyses. In 

conclusion, there is evidence to support the observation that breastfeeding is associated with a 

reduction in the risk of breast cancer. 
139

Table 33. Summary of systematic reviews/meta-analyses on the relationship between breastfeeding and the risk of breast canc

Author Year 

Number 

of 

subjects 

Study 

description Population 

Confounders considered Intervention 

/Comparator R

Per 12 mo of breastfeeding 

RR reduct

cancer 0.8) 

Breastfeeding ever / never 

Adjusted R

0.2, p=

Collaborative Group on Hormonal Factors in Breast Cancer 2002 

50,302 cases 96,973 controls 

MA of cohort and casecontrol studies 

Incident invasive breast cancer 

Ethnic origin, education, family history of breast cancer, age at menarche, height, weight, body mass index, and use of hormonal contraceptives, alcohol, and tobacco Increasing duration of 

breastfeeding 

Adjusted R

0.01, p

Breastfeeding ever / never 

Summary 0.91 

Breastfeeding ever versus never and menopausal at the time of breast cancer diagnosis 

Summary 1.03) 

Breastfeeding ever versus never and non menopausal at the time of breast cancer diagnosis 

Summary 0.91) 

Breast feeding 0+ to 6 mo versus never 

Summary 1.16) 

6+ to 12 mo v never Summary 

1.09) 

Bernier 2000 25,871 

cases 44,910 controls 

MA of casecontrol studies Parous women with histologically 

diagnosed breast cancer 

Age at diagnosis or at full term pregnancy, parity, ethnicity, age at menarche, family history of breast cancer, parity 

12+ mo v never Summary 

0.80) 

Lipworth 2000 19,482

cases 37,627controls 

SR of casecontrol studies Premenopausal women with breast 

cancer 

Yes, descriptive summary Breastfeeding ever / 

never 

Qualitative Author’s co“Evidence protective breastfeedcancer is lbe interpre

MA, meta-analyses; SR, systematic review; RR, relative risk; OR, odds ratio; SE, standard error; NA, not applicable 
140

Table 34. Summary of case-control studies on the relationship between breastfeeding and breast cancer Author, year Country 

Cases 

(N) 

Controls 

(N) 

Definition of 

disease 

Age at diagnosis of 

disease 

(year) 

Breastfeeding 

group 

Comparator 

group 

Confounders 

adjusted 

149 1-12 mo 

32 13-24 mo 

Lee 2003a Korea 

18 

 Incident 33-44 

>24 mo 

Never 

(N=161) 

Age, oral contraceptives, parity, smoking, exercise and obesity 

≤1 yr 

685 685 Invasive BRCA1 39 

>1 yr 

Never 

≤1 yr 

Jernstrom 2004 Multi-center 

280 280 Invasive BRCA2 39 

>1 yr 

Never 

Oral 

contraceptive 

use and parity 

<2 mo 

2-5 mo 

6-13 mo 

Gammon 002 USA 

1,508 1,556 Incident; invasive and in-situ <35 to 85+ 

14+ mo 

Never Age 

a Prospective cohort study; Relative risk 
141

Ovarian Cancer 

Methods 

 No meta-analysis was identified on this topic. Eligible designs included prospective cohorts, 

case-cohort studies or nested case-control studies. Cross-sectional studies were excluded, as 

described in the Methods section. Eligible studies were conducted in developed countries. We 

quantified the association between breastfeeding and any type of histopathologically defined 

maternal ovarian cancer. No specific exclusion criteria were used for the participants in the 

primary studies. 

 We recorded or estimated odds ratios for the association between breastfeeding and ovarian 

cancer for the following comparisons: women who ever breastfed versus never breastfed; women 

who breastfed less than 12 months (cumulative duration) versus those who never breastfed; and 

women who breastfed at least 12 months (cumulative duration) versus never. The 12-months 

cutoff was arbitrary, and was chosen for symmetry with analyses on maternal breast cancer 

outcomes. At a minimum, studies that were included in the meta-analyses must have been 

adjusted for parity (or used matching for parity). Adjustment for the use of oral contraceptives 

(or appropriate matching) was desirable but not mandatory. Studies that reported unadjusted 

effects only were not included in the meta-analyses, but are reported in the tables and text. 

 For each study, we estimated the odds ratios for the comparisons of interest when they were 

not directly reported. This was done for studies that analyzed breastfeeding as an ordinal 

categorical predictor using cutoffs other than 12 months, provided that mothers who never 

breastfed were the reference category. In such studies, the odds ratios for the comparisons of 

interest were estimated by combining odds ratios for different durations of breastfeeding using a 

random effects model. For example, Riman 2002194 did not report the odds ratio of ever versus 

never breastfeeding, but reported odds ratios for specific durations of breastfeeding versus never 

breastfeeding. Compared with women who never breastfed, the adjusted odds ratio in the Riman 

study for 1 to 5 months of cumulative breastfeeding was 0.99 (95%CI 0.64 -1.52); for 6 to 11 

months, it was 0.77 (95%CI 0.50 - 1.19) and for at least 12 months of cumulative breastfeeding, 

it was 0.87 (95%CI 0.56 - 1.35). We can estimate the odds ratio of ever versus never 

breastfeeding in the Riman 2002 study with a random effects meta-analysis of the 

aforementioned duration-specific odds ratios (estimated adjusted odds ratio was 0.87, 95%CI 

0.68 - 1.12). 

Results (Tables 35-38) 

 We did not identify any prospective studies. We found 15 eligible case-control studies that 

examined the relationship between breastfeeding and maternal ovarian cancer.194-210 In addition, 

we identified three studies that conducted secondary analyses on population subgroups including 

white, black, and Jewish women by pooling data from case-control studies.211-213 Populationbased controls were used in nine of the 15 studies and hospital-based controls were used in the 

remaining six. A total of 6,006 subjects with ovarian cancer were studied. The smallest sample 

included 76 subjects with ovarian cancer matched with 76 hospital-based controls,208 and the 

largest included 1,028 subjects matched with 2,390 hospital-based controls.195 
142

 Data were gathered from interviewers using structured questionnaires, and therefore outcome 

assessment was not blinded. Participant’s age ranged from 17 to 79 years. The reporting of 

information on breastfeeding duration generally did not distinguish between exclusive or partial 

breastfeeding. Terms commonly used were breastfeeding, lactation, and in one instance, nursing. 

In 13 out of 15 case-control studies the outcome was histologically confirmed epithelial ovarian 

cancer. All protocols included women regardless of menopausal status, except for one study that 

examined peri- and postmenopausal women, and another restricted to women under age 55 

years.194,198 One primary study included white women only.202 None of the studies verified 

details of the breastfeeding history by objective data such as hospital or clinic records. Finally, 

there was wide variability in how breastfeeding duration was categorized in the various studies 

(Table 35). Because of potential recall bias of breastfeeding history, lack of data verification, and 

lack of blinding, the majority of the case control studies (n=11) was rated methodological grade 

B. The remaining four case-control studies were rated grade C. All studies adjusted for parity, 

and all but one study also adjusted for oral contraceptive use. 

Meta-analyses 

Ever breastfed versus never breastfed. Nine studies with a total of 4,387 cases and 10,574 

controls were included in the comparison of ever versus never breastfeeding (Figure 12). The 

random effects meta-analysis found an association between breastfeeding and reduced ovarian 

cancer risk (ORadj 0.79, 95%CI 0.68 – 0.91).194,195,197,199-201,204-206,210 There was a statistically 

significant between-study heterogeneity (P=0.02), which was mainly due to the outlying study of 

Chiaffarino 2005. Excluding the study yielded very similar estimates without a statistically 

significant heterogeneity. 

 For five of the nine studies we, estimated the odds ratio of ever versus never 

breastfeeding.194,197,199-201,210 If we exclude these five studies from the meta-analysis, a total of 

2,582 cases and 4,138 controls remained; and the association between breastfeeding and reduced 

ovarian cancer risk was no longer statistically significant (ORadj 0.80, 95%CI 0.59 – 1.09)195,204-

206 Again, there was a statistically significant heterogeneity among the four remaining studies 

(p<0.01), but the heterogeneity was not readily explained by the characteristics of the primary 

studies. Excluding the study by Chiaffarino 2005,195, which was an obvious outlier, the summary 

odds ratio suggested a slightly stronger (and formally statistically significant) association (0.70 

[95%CI, 0.59-0.83]). 
143

Figure 12. Meta-Analysis of case-control studies on the relationship between breastfeeding and maternal 

ovarian cancer risk: ever breastfed versus never breastfed. 

 

 Less than 12 months of cumulative breastfeeding versus never breastfed. Cumulative 

breastfeeding for less than 12 months was not statistically significantly associated with a 

decreased risk of ovarian cancer in a meta-analysis of six studies, including 1,911 cases and 

5,007 controls in total (ORadj 0.95; 95%CI: 0.80 – 1.12). (Figure 13) The odds ratios for this 

comparison were estimated for three of the six studies.194,195,200,201 There was no statistically 

significant heterogeneity between the six studies. Two studies (Chiaffarino 2005195 and Hartge 

1989199) were included in this meta-analysis despite the fact that they used as cutoffs shorter 

cumulative duration of breastfeeding (10 and 9 months, respectively). Excluding them, the 

summary of the adjusted odds ratio remained statistically non-significant (0.87, 95%CI 0.74 - 

1.02). 
144

Figure 13. Meta-Analysis of case-control studies on the relationship between breastfeeding and maternal 

ovarian cancer risk: breastfed less than 12 months (cumulative duration) versus never breastfed 

Two studies (Chiaffarino 2005195 and Hartge 1989199) were included in this meta-analysis despite the fact that they 

used as cutoffs shorter cumulative different than 12 months (10 and 9 months, respectively). A sensitivity analysis 

that excluded them yielded similar inferences (summary of adjusted odds ratios 0.87 [95%CI 0.74, 1.02]). 

At least 12 months of cumulative breastfeeding versus never breastfed. Six studies including 

1,650 cases and 4,575 controls provided adjusted odds ratios for this comparison,194,197,210 or 

allowed an approximation.195,199-201 (Figure 14) Breastfeeding of at least 12 months cumulative 

duration was associated with 28% lower odds for ovarian cancer (ORadj 0.72, 95%CI 0.54 – 

0.97). There was a statistically significant heterogeneity across the six studies. Two studies 

(Chiaffarino 2005195 and Hartge 1989199) were included in this meta-analysis despite the fact that 

they used as cutoffs shorter cumulative duration of breastfeeding (10 and 9 months, 

respectively). Excluding them, the summary adjusted odds ratio was even more suggestive of a 

protective association (0.63 [95%CI 0.50, 0.79]). 
145

Figure 14. Meta-Analysis of case-control studies on the relationship between breastfeeding and maternal 

ovarian cancer risk: breastfed at least 12 months (cumulative duration) versus never breastfed. 

Two studies (Chiaffarino 2005195 and Hartge 1989199) were included in this meta-analysis despite the fact that they 

used as cutoffs shorter cumulative different than 12 months (10 and 9 months, respectively). A sensitivity analysis 

that excluded them yielded similar inferences (summary of adjusted odds ratios 0.63 [95%CI 0.50, 0.79]). 

Subgroup analyses and additional results 

Pre- versus post-menopausal women (Table 36). Three studies reported on the risk of ovarian 

cancer stratified by menopausal status. There were sporadic statistically significant associations 

between specific categories of breastfeeding duration and reduced risk for ovarian cancer in 

Sikind 1997204 and Tung 2005.207 Tung 2005 reported a significant dose-response trend between 

increasing breastfeeding duration and reduction in maternal ovarian cancer risk for postmenopausal women (P value for trend = 0.003). No statistically significant dose-response trends 

were found in the postmenopausal stratum of Tung 2005 and in both strata in the other two 

studies. Wynder 1969 reported that in premenopausal women, 10 percent of the cases versus 

seven percent of the controls breastfed for 12 months or more;209 for postmenopausal women, 24 

percent of the cases versus 21 percent of the controls breastfed for 12 months or more. No 

statistical comparison was reported. 

Risk by histologic type (Table 37). Five studies reported the relationship between 

breastfeeding and the risk of ovarian cancer subgrouped by tumor histology.194,195,201,205-207

Comparisons between tumor types included mucinous versus nonmucinous, and invasive versus 

borderline tumors. Data were limited to allow robust conclusions per histologic type. Moreover, 

these analyses were subgroup analyses, and therefore, should be viewed as hypothesis forming 

observations and be interpreted conservatively. 

 Sporadic associations between specific durations or breastfeeding and reduced risk for 

histological subtypes were reported in all studies except for Chiaffarino 2005. Breastfeeding was 

not protective for mucinous or serous cancers consistently across the five studies. Increased 

duration of breastfeeding was associated with reduced risk for non-mucinous cancers in Tung 

2003 (P for trend < 0.001). Titus-Ernstoff 2001 reported an association of breastfeeding with 

reduced risk for combined endometrioid and clear cell carcinomas, and Riman 2002 reported an 
146

association with reduced risk for clear cell ovarian cancer for a specific duration of cumulative 

breastfeeding (5 months). 

Pooled analysis of subgroups (Table 38). Secondary subgroup analyses were conducted on 

different racial groups in three studies. John 1993 studied 53 cases of ovarian cancer in black 

women using data from seven case-control studies,211 whereas Whittemore 1992 examined data 

of white women from the same studies and added the cases from five additional studies for a 

combined population of 1,071 cases. Ever having breastfed was not associated with the risk of 

development of ovarian cancer in black women but was reported to reduce the risk for white 

women. Whittemore 1992 divided the sample into hospital and population subjects, the odds 

ratio for those who breastfed their infants compared with those who did not in the development 

of ovarian cancer were 0.73 (95%CI 0.51-1.0) and 0.81 (95%CI 0.68-0.95), respectively.212

Modugno 2003 analyzed 242 Jewish women from five studies conducted in Israel and the United 

States.213 This was a cohort study comparing carriers and noncarriers of BRCA1 or BRCA2. The 

study did not find a difference between carriers and noncarriers of BRCA1 or BRCA2 mutation 

in the breastfeeding status or breastfeeding duration and the risk of ovarian cancer. 

Conclusion 

 We reviewed 15 case-control studies that examined the relationship between breastfeeding 

and the risk of ovarian cancer, and performed quantitative syntheses using data from nine studies 

that adjusted for potential confounders. The overall result from the nine studies suggests an 

association between breastfeeding and a reduction in the risk of ovarian cancer. Because the 

reporting in these studies was inconsistent, we needed to estimate the odds ratios in five of nine 

studies for the meta-analysis. Excluding these five studies results in loss of statistical 

significance for this association. 

 There was indirect evidence for a dose-response relationship between breastfeeding and a 

reduction in the risk of ovarian cancer. Breastfeeding of less than 12 months (cumulative 

duration) was not statistically significantly associated with a reduction in the risk of ovarian 

cancer in a meta-analysis of six studies. However, breastfeeding of more than 12 months 

(cumulative duration) was associated with a reduction in the risk of ovarian cancer, compared 

with never breastfeeding. We caution that the cutoff of 12 months was arbitrary, and the odds 

ratios were estimated in half of these studies. Therefore, the interpretation of the postulated doseresponse relationship should be done with caution. 

 Finally, several studies assessed subgroups of pre- and post-menopausal women and ovarian 

cancer histology. Overall, few sporadic statistically significant associations were identified in 

some subgroups and for some specific durations of breastfeeding. These findings do not 

constitute robust evidence. 

 We conclude that there is some evidence to suggest an association between breastfeeding and 

a reduction in the risk of maternal ovarian cancer. However, one must be cautious in interpreting 

this association because it was largely based on estimations of the odds ratios from retrospective 

studies. 
147

Table 35. Summary of case-control studies on the relationship between breastfeeding and maternal ovarian cancer Author Year Country 

Cases 

(N) 

Controls 

(N) 

Definition of 

disease 

Mean / median 

age at dx of 

disease 

(year) 

Breastfeeding 

group 

Comparator 

group Confounders adjusted 

A

o

Ever BF Never BF 

(0

BF 1-4 mo 

(0

BF 5-8 mo 

(0

BF 9-16 mo 

(0

Chiaffarino 2005 Italy 

1,028 2,390 

Epithelial ovarian 

cancer based on 

histology 

56a

BF ≥17 mo 

Never BF 

Age, center, education, 

parity, oral contraceptive 

use, family history of 

ovarian/breast cancer in 

first degree relatives 

(0

BF 1-5 mo 

(0

BF 6-11 mo 

(0

Riman 2002 Sweden 655 3899 Epithelial ovarian cancer based on histology Cases 62 Controls 63 

BF ≥12 mo

BF <1 mo 

Age, BMI, parity, age at 

menopause, duration of 

oral contraceptive use, 

HRT use 

(0

Ever BF 

(0

BF 1-6 mo 

(

BF 7-12 mo 

(0

BF 13-24 mo 

(

BF 25-36 mo 

(

> 36 mo 

Never BF 

(

Siskind 1997 Australia 

618 724 

Epithelial ovarian 

cancer based on 

histology 

Cases 57 Controls 56 

Reduction risk per month BF 

Age, parity, age at 1st

birth, education, oral 

contraceptive use, 

smoking history, 

menopausal status 

(
148 

Table 35. Continued Author Year Country 

Cases 

(N) 

Controls 

(N) 

Definition of 

disease 

Mean / median 

age at dx of 

disease 

(year) 

Breastfeeding 

group 

Comparator 

group Confounders adjusted 

A

o

Ever BF 

BF 

≤5 mo 

BF 6-16 mo 

Tung 2003; 2005 USA 

558 607 

Epithelial ovarian 

cancer based on 

histology 

Cases  Mucinous 50 Nonmucinous 55 Controls 56 

BF >16 mo 

Never BF 

Age, ethnicity, study site, 

education, oral 

contraceptive use, tubal 

ligation 

BF 1-5 mo 

BF 6-11 mo 

BF 12-23 mo 

Ness 2000 Modugno 2001 USA 

531 1190 

Epithelial ovarian 

cancer based on 

histology 

Cases  Invasive 53  Borderline 45 Controls 49 

BF 

≥24 mo 

Never BF 

Age, number of 

pregnancies, family 

history of ovarian cancer, 

race, oral contraceptive 

use, tubal ligation, 

hysterectomy, 

breastfeeding 

Total duration 

BF of cases 

(0.51 yr) 

Total 

duration of 

controls 

(0.65 yr) 

Risch (01994 Canada

450 564 

Epithelial ovarian 

cancer based on 

histology 

Cases 57 Controls 58 BF duration/ 

pregnancy of 

cases (2.24 

mo) 

BF duration/ 

pregnancy 

of controls 

(2.72 mo) 

Regression adjusted for 

3 age groups, continuous 

variables age, total 

duration of oral 

contraceptive use 

(0
149 

Table 35. Continued Author Year Country 

Cases 

(N) 

Controls 

(N) 

Definition of 

disease 

Mean or median 

age at dx of 

disease 

(year) 

Breastfeeding 

group 

Comparator 

group 

Confounders 

adjusted 

Ever BF 

BF 1-2 mo BF 3-5 mo 

BF 6-11 mo 

BF 12-23 mo 

Gwinn 1990 USA 

436 3833 

Epithelial ovarian 

cancer based on 

histology 

20-54 

BF ≥24 mo 

Never BF 

Pregnancy, oral 

contraceptive 

use, age, and 

age-pregnancy 

interaction 

Ever BF 

BF <3 mo 

BF 3-6 mo 

BF >6 mo 

Never BF Age, state, parity 

TitusErnstoff 2001 USA 

378 417 

Epithelial ovarian 

cancer based on 

pathology or slides 

Cases 20-74 Controls matched within 4 years 

2.4% Reduction risk per month B

BF ≤12 mo 

Greggi 2000 Italy 

330 721 Ovarian cancer based on histology 54 BF >12 mo Never BF 

Age, education, 

parity, oral 

contraceptive 

use, family 

history of 

ovarian cancer 

BF 1-9 mo 

BF 10-18 mo 

Hartge 1989 USA 

203 257 

Epithelial ovarian 

cancer based on 

histology 

Cases 54 Controls 55 

BF 19-110 mo 

Never BF 

Age, race, 

parity, difficulty 

conceiving, oral 

contraceptives, 

surgical 

menopause, 

HRT, or family 

history of 

ovarian cancer 

as needed 
150 

Table 35. Continued Author Year Country 

Cases 

(N) 

Controls 

(N) 

Definition of 

disease 

Mean or 

median age 

at dx of 

disease 

(year) 

Breastfeeding 

group 

Comparator 

group Confounders adjusted 

BF ≤1 yr 

Yen 2003 Taiwan 

86 369H 

Epithelial ovarian 

cancer based on 

histology 

Cases 47 Controls 44 

BF >1 yr 

Never BF Parity 

Risch 1983 USA 

284 705P 

Malignant & 

borderline 

malignant epithelial 

ovarian cancer 

Cases 20-74 Controls 21-75 

BF ≥3 mo BF <3 mob

Age at diagnosis 20-44, nulliparou

no miscarriages, < 1 year total 

exposure to combined oral 

contraceptives, non-obese 

Cramer 1983 USA 

215 215P Epithelial ovarian 

cancer 

53 Ever BF Never BF None 

Wynder 1969 USA 

158 300H 

Epithelial ovarian 

cancer based on 

histology 

Cases 52 Control ND 

No difference 

between groups for 

never BF 

--- ND 

West 1966 USA 

76 76H 

Malignant ovarian 

cancer based on 

pathology 

Cases 53 Controls 50 

Cases  (6.6 mo) Controls  (5.8 mo) p > 0.3 

--- None 

 Dx, diagnosis; BF, breastfeeding; Mo, month(s); Yr, year(s) a Chiaffarino -dx within past year, Risch –dx within past 18 months b Nulliparous and parous women 
151 

Table 36. Summary of case-control studies on the relationship between breastfeeding and maternal ovarian cancer by menopa

Author 

Year 

Country 

Cases 

(N) 

Controls 

(N) 

Definition of 

disease 

Mean or 

median age 

at dx of 

disease 

(year) 

Breastfeeding 

group 

Comparator 

group 

Confounders 

adjusted ORadj (9

BF 

≤6 mo 0.96 (0.4

BF 6-12 mo 0.81 (0.4

Premenopausal  217 

Premenopausal 256 BF >12 mo 

Never BF 

0.46 (0.2

BF 

≤6 mo 0.64 (0.4

BF 6-12 mo 0.60 (0.3

Tung 2003; 2005 USA 

Postmenopausal  341 

Postmenopausal  351 

Epithelial ovarian 

cancer based on 

histology 

Cases 55 Controls 55 

BF >12 mo 

Never BF 

Age, ethnicity, 

study site, 

education, tubal 

ligation, HRT, 

ovulation 

0.69 (0.4

BF 1-6 mo 0.75 (0.4

BF 7-12 mo 0.53 (0.3

BF 13-24 mo 1.03 (0.5

Premenopausal  215 

Premenopausal 264 

BF >24 mo 

Never BF 

0.29 (0.0

BF 1-6 mo 0.98 (0.6

BF 7-12 mo 0.83 (0.5

BF 13-24 mo 0.88 (0.5BF 25-36 mo 0.93 (0.4

Siskind 1997 Australia Postmenopausal 

 403 

Postmenopausal  460 

Epithelial ovarian 

cancer based on 

histology 

Cases 58 

Controls 57 

BF >36 mo 

Never BF 

Age, parity, age at 

1st birth, education, 

oral contraceptive 

use, smoking 

history, 

menopausal status 

1.27 (0.5

Premenopausal 55 

Premenopausal 95 

BF >12 mo  9% Cases 

Wynder 7% Controls 1969 USA Postmenopausal 

95 

Postmenopausal 205 

Epithelial ovarian 

cancer based on 

histology 

Cases 52 

Control ND BF >12 mo 

 24% Cases  21% Controls 

--- ND --

Dx, diagnosis; BF, breastfeeding; Mo, month(s); Yr, year(s) 
152 

Table 37. Summary of case-control studies on the relationship between breastfeeding and maternal ovarian cancer by histologAuthor Year Country 

Cases 

(N) 

Controls 

(N) 

Mean age at dx 

of disease 

(year) 

Histologic type (n) Breastfeeding group Comparato r group Confounders adjusted Adj

odd

(95

Serous (492) 

(0.8

Chiaffarino 2005 Italy 

1028 2390 Cases 56 Controls 57 Mucinous (81) Ever BF Never BF 

Age, center, 

education, parity, 

oral contraceptive 

use, family hx of 

ovarian/ breast 

cancer in 1o

relatives 

1

(0.8

Serous borderline (86) 0.8 (0Serous invasive (229) 1.0 (0Mucinous (83) 0.6 (0

TitusErnstoff 2001 USA 

528 523 

Cases 20-74 Controls matched within 4 years Endometrioid/clear cell (130) 

Ever BF Never BF Age, state, parity 

0.4 (0

Mucinous (109) 

Ever BF BF 

≤5 mo 

BF 6-16 mo BF >16 mo 

Never BF 

0.8 (00.6 (00.7 (00.9 (0

Tung 2003 USA 

558 607 

Cases  Mucinous 50  Nonmucinous 55 Controls 56 Nonmucinous (449) 

Ever BF BF 

≤5 mo 

BF 6-16 mo BF >16 mo 

Never BF 

Age, ethnicity, study 

site, education, oral 

contraceptive use, 

tubal ligation 

0.8 (00.7 (00.5 (00.4 (0

Borderline  Serous (79)  Mucinous (60) 

Months BF 

0

(0.9

0

(0.9

Ness 2000 Modugno 2001 USA 

531 1,190 

Cases  Invasive 53  Borderline 45 Controls 49 Invasive Serous (278) 

 Mucinous (52)  Endometrioid (136)  Other (150) 

Months BF 

Age, number of live 

births, years of oral 

contraceptive use, 

years of noncontraceptive 

estrogen use and 

months breastfed, 

tubal ligation, 

hysterectomy, 

family history of 

ovarian and breast 

cancer, ethnicity 

1

(0.9

1

(0.9

0

(0.9

0

(0.9
153 

Table 37. Continued Author Year Country 

Cases 

(N) 

Controls 

(N) 

Mean age at dx 

of disease 

(year) 

Histologic type (n) Breastfeeding group Comparato r group Confounders adjusted Adj

odd

(95

Invasive  Serous (240) 

BF 1-5 mo 

BF 6-11 mo 

BF 

≥12 mo 

BF <1 mo 

0

(0.50

0

(0.3

0

(0.4

 Mucinous (44) 

BF 1-5 mo 

BF 6-11 mo 

BF 

≥12 mo 

BF <1 mo 

2

(0.4

1

(0.3

0

(0.1

Endometrioid (126) 

BF 1-5 mo 

BF 6-11 mo 

BF 

≥12 mo 

BF <1 mo 

1

(0.4

1

(0.50

1

(0.4

Riman 2002 Sweden 

655 3,899 Cases 62 Controls 63 

 Clear cell (25) 

BF 1-5 mo 

BF 6-11 mo 

BF 

≥12 mo 

BF <1 mo 

Age, BMI, parity, 

age at menopause, 

duration of oral 

contraceptive use, 

HRT use 

0

(0.1

0

(0.0

0

(0.0

* p<0.05 
154 

Table 38. Summary of pooled-analysis of case-control studies on the relationship between breastfeeding and ovarian cancer bAuthor Year Country 

Population 

characteristic 

Cases 

(N) 

Controls 

(N) 

Definition of 

disease 

Mean age at 

dx of 

disease 

(year) 

Breastfeeding 

group 

Comparator 

group 

Confounders 

adjusted 

Ever BF 

BF 1-5 mo 

BF 6-11 mo 

BF 12-23 mo 

201 1,081 

BF ≥24 mo 

Never BF 

Ever BF 

BF 1-5 mo 

BF 6-11 mo 

BF 12-23 mo 

Whittemorea 1992 USA 

White 

870 4,624 

Epithelial 

ovarian cancer ND 

BF ≥24 mo 

Never BF 

Age, study, 

parity, oral 

contraceptive 

use 

Ever BF 

BF 1-5 mo 

Johnb

1993 USA 

Black 53 259 Epithelial ovarian cancer 

Cases  Invasive 53  Borderline 37 Controls ND ≥6 mo 

Never BF 

Study, birth 

year, reference 

age, parity 

BRCA1  Ever BF  Duration BF 

BRCA

BRCA2  Ever BF  Duration BF 

BRCA

Modugnoc

2003 USA, Israel 

Jewish 95 147 Epithelial ovarian cancer 

Cases  BRCA1 51  BRCA2 61 Controls  BRCA- 58 

BRCA1/2  Ever BF  Duration BF 

BRCAAge at diagnosis, yea

of birth, number of live births, oral contraceptive use, history of tubal ligation 

H-hospital or clinic controls; P, population controls a Sample also included Cramer 1983 and Hartge 1989; b Sample also included Ness 2000. c Cases defined as Jewish women with ovarian cancer and BRCA1 or BRCA2 mutation, controls defined as ovarian cancer cases only. 
155

Other Research 

 An important area of research that is not systematically reviewed in this report is the use of 

breastfeeding promotion intervention trial to measure health effects (this topic will be covered in 

a separate report). The best known of these types of studies is the Promotion of Breastfeeding 

Intervention Trial (PROBIT) conducted in the Republic of Belarus.17 This was a cluster 

randomized controlled trial of 34 maternal hospitals and associated polyclinics with a total of 

17,046 mother-infant pairs consisting of full term infants and their healthy mothers who intended 

to breastfeed. The experimental intervention was modeled on the Baby-Friendly Initiative of the 

World Health Organization and United Nations Children’s Fund, which emphasizes assistance 

with initiating and maintaining breastfeeding and lactation and postnatal breastfeeding support. 

The control intervention was continuation of the usual infant feeding practices. Results from the 

study showed that infants in the intervention arm were more likely to be exclusively breastfed at 

3 months (43.3% vs. 6.4%; P<0.001) and at 6 months (7.9% vs. 0.6%; P=0.01), and had a 

significant reduction in the risk of one or more gastrointestinal infections (9.1% vs. 13.2%; 

adjusted OR 0.60; 95%CI 0.40-0.91) and of atopic dermatitis (3.3% vs. 6.3%; adjusted OR 0.54; 

95%CI 0.31-0.95), but no significant reduction in respiratory tract infection. Secondary 

observational analysis showed that the group of infants who were exclusively breastfed at least 6 

months compared to the group of infants who were breastfed 3 to 6 months had a statistically 

significant reduced risk of one or more episodes of gastrointestinal infection in the first 12 

months of life (RR 0.67; 95%CI 0.46-0.97), which was maintained in a multivariate mixed 

model controlling for geographic origin, urban versus rural location, maternal education, and 

number of siblings in the household (adjusted OR = 0.61; 95%CI 0.41-0.93).214 The same 

analysis also reported that there was a very low absolute risk of atopic dermatitis in both feeding 

groups but no risk reduction in the group that was exclusively breastfed for at least 6 months 

compared with the group that was exclusively breastfed for 3 to 6 months. 

 
157 

Chapter 4. Discussion 

 

 Twenty-three outcomes were analyzed in this report. Approximately 400 articles would 

needed to be reviewed if only articles with primary data were included; this is a much larger 

volume of literature than can be feasibly reviewed within the time period of this report. With the 

availability of many published systematic reviews on breastfeeding, we used this literature as the 

evidence for a large number of outcomes, supplemented by updates of these systematic reviews 

with new primary studies. We performed several new systematic reviews on outcomes not 

previously reported. The existing systematic reviews were conducted over a wide span of time 

and by diverse groups of investigators; there were large variations in the approach and quality of 

these reviews. 

 Even though we have assessed the reporting quality of these systematic reviews (using 

standards of reporting of systematic reviews of observational studies – MOOSE statement22 and 

additional parameters that we devised), we cannot reliably know the validity of the reported 

summary data without knowing the details of the primary studies. A number of systematic 

reviews reported that inclusion and exclusion of some primary studies were reached by 

consensus between at least two investigators. Without knowing the details of how those 

consensuses were reached, it would be difficult to replicate the findings in those reviews as it is 

quite plausible that someone who is not familiar with the details of the consensus might have 

come up with a different set of studies for inclusion in the review. It should also be stressed that 

a well-performed systematic review does not necessarily imply that the body of evidence for a 

particular outcome of interest is of high quality. While some systematic reviews assessed the 

quality of the individual studies, the methods used varied. Any systematic review is limited by 

the quality of the primary studies included in the review. Unless the method used to assess the 

quality of the primary studies is transparent and the details made available for examination, it 

would be difficult to reliably determine the validity of the conclusions. 

 In most circumstances, it would be unethical to randomize mother-infant pair into 

breastfeeding (or breast milk feeding) or not breastfeeding arm in a trial. Therefore, the 

breastfeeding literature is primarily comprised of observational studies, either cohort or casecontrol studies. There are a number of potential deficiencies related to the study designs that 

could limit the internal validity and the generalizability of the findings. Some of these potential 

deficiencies include (1) misclassification of exposure; (2) confounding from the process of selfselection; (3) residual confounding; and (4) insufficient statistical power. 

 Misclassification of exposure (breastfeeding status/duration) is likely in the studies reviewed 

in this report. Most studies relied on mothers’ recall for the data on breastfeeding. Recall is prone 

to error. One study from South Africa reported that at 6 to 9 months post-delivery, 13 percent of 

mothers could not remember the specific timing when they gave something other than breast 

milk to their infant. In those mothers who could remember, 57 percent of them overestimated the 

duration of exclusive breastfeeding by about 8 weeks, and 15 percent underestimated the 

duration by about 3 weeks.215 Misclassification, may bias the effect estimate; particularly if the 

recall error is nonrandom, such as in studies where cases are more likely to underestimate the 

amount of breastfeeding than controls (for an example, see Norris and Scott 199690). 

 In studies where subjects were self-selected, there could be confounding from the process of 

self-selection (e.g., if subjects who perceive their diseases are due to a lack of breastfeeding were 

more likely to participate in the study). 
158 

 Residual confounding is a possibility for all observational studies, because it is difficult (if 

not impossible) to control for all potential confounding variables in these studies. Although it is 

possible to control for differences in demographic factors, it may not be possible to control for 

behavioral factors intrinsic in the desire to breastfeed. 

 Large sample size is often needed to examine the relationship between breastfeeding and 

various diseases and health conditions because of the need to adjust for numerous confounders to 

minimize all the potential biases described earlier. It is impossible to predict how these different 

limitations may interact to increase or decrease the effect estimate. 

 Compounding the issue of less-than-ideal study design are the heterogeneity of the breast 

milk itself and differences in how the feedings of breast milk were defined across different 

studies. The composition of breast milk varies both within and between individuals.216,217 The 

composition could vary depending on preterm versus term delivery, the maternal diet, maternal 

body weight, time of day, beginning versus near the end of feed, first few months of lactation 

versus later lactation, milk volume, and numerous other factors. On the other hand, the 

composition of formulas has also changed significantly over the last twenty years. For example, 

contemporary formulas have added ingredients like nucleotides and long-chain polyunsaturated 

fatty acids that were absent from older formulations. How the heterogeneity both within and 

between comparators would affect the effect estimate is unclear. Also, studies defined 

breastfeeding differently. Many studies did not have a category of “exclusive breastfeeding”. In 

the ones that did have this category, “exclusive” could mean no supplement of any kind 

including water or it could mean occasional formula supplement is permissible. This mixing in 

of formula in the “exclusive” breastfeeding group may potentially dilute the true effect of breast 

milk and bias the results toward the null finding. In addition, no study in this review examined 

the differences between actually breastfeeding an infant and bottle or gavage feeding an infant 

with breast milk. How the act of breastfeeding itself plays a role in the different effects measured 

is unknown. 

 We have summarized the effects of breastfeeding (or breast milk feeding) on a large number 

of infant and maternal outcomes. Some of the outcomes are well defined and specific (e.g., 

childhood acute lymphocytic leukemia, breast cancer); and some are not so well defined and 

non-specific (e.g., asthma, gastrointestinal infections). When the reported outcome is well 

defined and specific, it lends confidence that the effect reported is valid for that outcome. When 

the reported outcome is not well defined, one might have some reservation regarding the validity 

of the measured effect for that outcome. 

 For all the above reasons, we find that there is a wide range of quality of evidence for the 

different outcomes examined in this review. 

 For severe lower respiratory tract diseases, good quality studies did find a relationship 

between breastfeeding and a reduction in the risk of hospitalization secondary to lower 

respiratory tract diseases. 

 For acute otitis media, the results from our meta-analyses of cohort studies of good and 

moderate methodological quality showed that breastfeeding was associated with a significant 

reduction in the risk of acute otitis media. Comparing ever breastfeeding with exclusive bottlefeeding, the pooled adjusted odds ratio of acute otitis media was 0.77 (95%CI 0.64 - 0.91). When 

comparing exclusive breastfeeding with exclusive bottle-feeding, either for more than 3 or 6 

months duration, the pooled odds ratio was 0.50 (95%CI 0.36 - 0.70). 

 For non-specific gastroenteritis, one systematic review identified three primary studies that 

controlled for potential confounders. These studies reported that there was a reduction in the risk 
159 

of non-specific gastrointestinal infections during the first year of life in breastfed infants from 

developed countries, although the observed range of risk reduction was wide. However, one 

recent case-control study of 304 infants (167 cases and 137 controls) from England showed that 

the infants who were breastfeeding had a reduced risk of diarrhea compared to infants who were 

not breastfeeding (adjusted OR 0.36, 95% CI 0.18 to 0.74, P=0.005). The result was adjusted for 

age, sex, social class, contact with person in and outside household, and other factors. Also, 

analysis of nested observational cohorts from the Belarus trial showed that the group of infants 

who were exclusively breastfed for at least 6 months compared to the group of infants who were 

breastfed for 3 to 6 months had a statistically significant reduced risk of one or more episodes of 

gastrointestinal infection in the first 12 months of life (adjusted OR = 0.61; 95%CI 0.41-0.93).214

The result was adjusted for geographic origin, urban versus rural location, maternal education, 

and number of siblings in the household. 

 For necrotizing enterocolitis (NEC) in preterm infants, our meta-analysis of four RCTs found 

a marginally statistically significant reduction (5% risk difference) of the NEC risk with breast 

milk feeding. Taking into account the high case-fatality rate of NEC, we consider this estimate is 

of meaningful clinical difference. However, One must be cognizant of the clinical heterogeneity 

underlying these RCTs in interpreting the findings of the meta-analysis. Three of the four RCTs 

were published in the 1980’s. Whether infants born in the early 1980’s should be combined with 

infants born in the late 1990’s into a meta-analysis is debatable. Neonatal care has made 

tremendous strides in the last 20 years. Present day preterm formula milk is vastly different from 

preterm formula milk 20 years ago. All the studies had patient populations that were quite 

heterogeneous, gestational age ranged from 23 weeks to more than 33 weeks and birth weight 

ranged from less than 1000 g to more than 1,600 g. One study included only “healthy” infants, 

another included both “healthy” and “ill” infants. In addition, the types of breast milk, the 

methods of feedings, and the times of enrollments into the trials were all different. How the 

heterogeneity in the studies affected the findings is not clear. In addition, studies examining the 

issue of NEC were frequently also examining the issue of neonatal sepsis, as it is not possible to 

have NEC without concomitant sepsis. In future studies, it would be worthwhile to examine the 

relationship of breast milk exposure and sepsis in preterm infants. 

 For asthma, our subgroup analysis showed that breastfeeding was associated with a reduced 

risk in children under 10 years of age with a positive family history. However, this association 

does not hold true for older children as one publication reported a very large adjusted odds ratio 

(OR 8.7, 95%CI 3.4 – 22.2) for developing asthma in children 6 to 13 years of age who were 

exclusively breastfed for at least 4 months and had a positive history of maternal asthma.56 The 

relationship of breastfeeding, maternal history, and long-term outcome of asthma bears further 

investigation. 

 For atopic dermatitis, available evidence from one well-performed systematic review on full 

term infants in developed countries suggest that exclusive breastfeeding for at least 3 months 

confer a protective advantage in the development of atopic dermatitis in those subjects with a 

family history of atopy. The systematic review did not make a distinction between atopic 

dermatitis of infancy (under 2 years of age) and persistent or new atopic dermatitis at older ages. 

This is important because the diagnosis of atopic dermatitis in patients younger than 2 years of 

age are sometimes attributed to symptoms of infectious origin and breastfeeding may have a 

protective effect against infections. But a stratified analysis by different durations of followup 

showed that the risk reduction was similar in those with less than 2 years compared with more 

than 2 years of followup. 
160 

 For cognitive outcome in term infants from developed countries, sibling analysis and 

prospective studies that controlled specifically for maternal intelligence found little or no 

evidence to support an association between breastfeeding and cognitive performance in children. 

Most of the published studies adjusted their analyses for socioeconomic status and maternal 

education but not specifically for maternal intelligence. For those studies that still reported a 

significant effect after specific adjustment for maternal intelligence, residual confounding from 

other factors like different home environments cannot be ruled out. 

 No definitive conclusion regarding the relationship of breast milk exposure and cognitive 

development in preterm infants can be drawn at this time. Studies that controlled for maternal 

intelligence reported conflicting results. In addition to maternal intelligence, comorbidities (e.g., 

neurological impairment, extremely low birth weight, other neonatal illnesses), early 

intervention, environmental, and socioeconomic factors should also be controlled for in future 

investigation of this relationship. 

 For adult blood pressure, evidence suggests that there is an association between a history of 

breastfeeding during pregnancy and a small reduction in adult blood pressure, but the clinical or 

public health implication of this finding is unclear. Furthermore, The association weakened after 

stratification by study size, suggesting the possibility of bias. 

 For adult cholesterol, a lack of explicit analysis of potential confounders in the meta-analysis 

hampered the conclusion drawn from the study. Therefore, the relationship between 

breastfeeding and adult cholesterol levels cannot be adequately addressed at this time. 

 For cardiovascular mortality in adults, the meta-analysis was limited by the statistical 

heterogeneity across studies, apparent outcome modification by differences in gender (and 

therefore, calls into question the appropriateness of combining outcomes from men and women 

into a single analysis), and more than 30% of the subjects dropped out in the studies. Because of 

these reasons, no definitive conclusions can be drawn regarding the relationship between 

breastfeeding and cardiovascular mortality. Further investigation is warranted. 

 For Sudden Infant Death Syndrome (SIDS), our meta-analysis included only studies that 

reported clear definitions of exposure, outcomes, and results adjusted for well-known 

confounders or risk factors for SIDS. The summary estimate found a statistically significant 

adjusted odds ratio for an association between breastfeeding and a reduced risk of SIDS 

(adjusted OR 0.64, 95%CI 0.51 - 0.81). We conclude that there is a relationship between 

breastfeeding and a reduced risk of SIDS. One must be cautious in interpreting this relationship, 

however. As this finding stems from analysis of observational studies, this finding cannot prove 

causality. It is plausible that infants who breastfed and breastfed well are less prone to SIDS 

because of some yet unclarified neurophysiological reasons, and not because breastfeeding itself 

directly confers a protective effect. Further investigation is warranted. 

 For post-neonatal mortality (excluding SIDS), there are insufficient data to characterize the 

relationship between breastfeeding and post-neonatal infant mortality adequately. Further 

investigation is warranted. 

For childhood leukemia, available evidence suggests that there is an association between 

breastfeeding and a reduced risk of acute lymphocytic leukemia and acute myelogenous 

leukemia. Our findings from the meta-analyses of the three case-controlled studies that were 

graded good or fair quality by one systematic review were consistent with the results from the 

other meta-analysis, but with smaller effect size and smaller statistical significance. Further 

evaluation of the biological mechanisms underpinning this relationship while taking into 
161 

consideration potential biases can be achieved with more large-scale case-controlled studies 

utilizing population-based and socioeconomic status-matched controls. 

For obesity, evidence from three systematic reviews and meta-analyses suggests that a 

history of breastfeeding is associated with a reduction in the risk of obesity in later life. 

However, one must be aware of the possibility of residual confounding in interpreting this 

association. The pooled adjusted odds ratio of obesity comparing ever breastfed to never 

breastfed was 0.76 (95%CI 0.67-0.86) in one meta-analysis and 0.93 (95%CI: 0.88–0.99) in the 

other. The magnitude of effects was reduced when more confounders were adjusted in these 

analyses. 

 For type 2 diabetes, based on findings from a high-quality systematic review and metaanalyses of seven studies, early breastfeeding was associated with a lower risk of type 2 diabetes 

in later life compared with those initially formula-fed. However, only three studies appropriately 

adjusted for all the important confounders, including birth weight, parental diabetes, 

socioeconomic status, and individual or maternal body size. Even though these three studies 

found that adjustment did not alter the crude estimate, we cannot be completely confident that 

potential confounding by birth weight and maternal factors has been ruled out for the overall 

pooled estimate. This potentially could exaggerate the magnitude of the association. 

 For type 1 diabetes, even though there are some data to support that breastfeeding for more 

than 3 months is associated with a reduced risk of type 1 diabetes, this finding must be 

interpreted with caution because of the likelihood of recall biases and suboptimal adjustments for 

potential confounders in the primary studies. 

 For postpartum depression, studies of moderate quality reported an association between not 

breastfeeding or short duration of breastfeeding and postpartum depression. It is plausible that 

postpartum depression led to early cessation of breastfeeding, as opposed to breastfeeding 

altering the risk of depression. Both effects might occur concurrently. Additional factors that 

may have a bearing on both postpartum depression and the decision to initiate or terminate 

breastfeeding should be sought. Documentation of baseline mental health status before the 

initiation of breastfeeding and detailed recording of breastfeeding data will improve the quality 

of the studies and help understand the nature of the association. 

 There is no evidence of an association between lifetime breastfeeding duration and maternal 

osteoporosis. Lactation does not appear to have an effect on long-term changes in bone mineral 

densities. However, this conclusion is limited by the fact that the feeding history in the studies 

was obtained by maternal recall and no data on exclusivity of breastfeeding were available. 

Further investigation with accurate breastfeeding data is warranted. 

 For breast cancer, there is good evidence to support the observation that breastfeeding is 

associated with a reduction in the risk of breast cancer. This association is more likely in those 

women with increased lifetime months of breastfeeding their infants. 

 For ovarian cancer, there is some evidence to suggest an association between breastfeeding 

and a reduction in the risk of maternal ovarian cancer. However, one must be cautious in 

interpreting this association because it was largely based on estimations of the odds ratios from 

retrospective studies. 

 For postpartum weight change, we found that the overall effect of breastfeeding on return-topre-pregnancy weight (weight change from pre-pregnancy or first trimester to 1 to 2 year 

postpartum) was negligible (less than 1 kg), and the effect of breastfeeding on postpartum weight 

change was unclear. Results from the studies also suggest that many other factors have larger 

effects on weight retention or postpartum weight loss than breastfeeding. Methodological 
162 

challenges in these studies include the accurate measurement of energy balance, adequate control 

for numerous covariables, and quantifying accurately the exclusivity and the duration of 

breastfeeding. None of the included studies tackled all of these challenges. 

 Concerning the risk of maternal type 2 diabetes, a longer duration of lifetime breastfeeding is 

associated with a reduced risk of developing type 2 diabetes among parous women who did not 

have a history of gestational diabetes (GDM). There was a difference in the risk of developing 

type 2 diabetes between women with and without GDM in relation to lactation. Compared with 

women who did not have a history of GDM, women with a history of GDM had a markedly 

increased risk of type 2 diabetes; and lactation showed no significant relationship with diabetes 

risk among this group of women. One must be cautious in interpreting these findings, as they are 

only generalizable to population with characteristics similar to that of the Nurses’ Health cohort. 

 An important area of research that is not systematically reviewed in this report is the use of 

breastfeeding promotion intervention trial to measure health effects (this topic is not part of the 

scope of this report and it will be covered in a separate report). The best known of these types of 

studies is the previously described Promotion of Breastfeeding Intervention Trial (PROBIT) 

conducted in the Republic of Belarus.17 Data from this study provided good evidence that 

breastfeeding is associated with a reduction in the risk of gastrointestinal infection and atopic 

dermatitis. Whether results from studies conducted in other countries are applicable to the United 

States is unclear. In Belarus, mothers often stay in the hospital close to one week post delivery, 

infant formulas can cost as much as 20% of an average salary, and there is an obligatory 

prolonged maternity leave (approximately 3 years in most cases). In contrast, in the United 

States, mothers are often discharged within 48 hours post delivery and formula manufacturers 

provide rebates to the Special Supplemental Nutrition Program for Women, Infants, and Children 

(www.wicprogram.org). The factors in Belarus could work in conjunction with the intervention 

to help promote the increase in the rate of exclusive breastfeeding. On the other hand, one may 

argue that the results reported in the Belarus study could serve as a best-case scenario in terms of 

the potential benefits of breastfeeding when optimal promotion and support of breastfeeding are 

in place. More research in this country along the line of the Belarus study should be considered. 

 Of note, there were a few individual primary studies on asthma, cardiovascular mortality, and 

type 1 diabetes that reported increase in risk of those diseases in subjects who had been 

breastfed. Even though those studies were few in numbers, those findings should not be ignored 

and further investigation should be done. 

 Lastly, the outcomes analyzed in this review represent only a portion of all possible health 

outcomes related to breastfeeding reported by investigators worldwide. To work within the 

constraints of resources, we relied on the advice from our panel of technical experts in finalizing 

the list of outcomes included in this review. Thus, some important outcomes (e.g., growth and 

nutrition) have, by necessity, not been included in this review. Additional systematic reviews 

germane to those important outcomes would be of value. 

Future Research 

Assessment of the association between breastfeeding and health outcomes 

 Observational studies will remain the major source of information in this field. Clear subject 

selection criteria, adopting a common definition of “exclusive breastfeeding”, reliable collection 

of feeding data, specific and properly quantifiable outcomes of interest, controlling for important 

potential confounders including child-specific factors, and blinded assessment of the outcome 

measures will help immeasurably to improve the quality of these studies. Traditional 
163 

retrospective case-control studies, usually used when the disease is rare, are less desirable 

because of the many caveats noted earlier. Prospective nested case-control studies with blinded 

assessment of the outcome measures would provide more reliable results. 

 As have been mentioned previously, it is not possible to eliminate self-selection bias in 

observational studies because of behavioral or attitudinal factors intrinsic in the desire to 

breastfeed. Thus, it is worthwhile to study these factors to further understand the reasons for the 

decision to breastfeed. 

 Sibling analysis provides a method to control for hereditary and household factors that are 

important in certain outcomes, provided that those factors are similar for the siblings of interest. 

Although such analysis may be less susceptible to confounders and effect modifiers that are 

shared by siblings, one must remember that it is not immune to biases. This method should be 

used when the appropriate data are available. 

 There is a large degree of heterogeneity across studies among many of the outcomes. The 

heterogeneity persisted after adjusting for potential confounders. It might be helpful to study 

breast milk composition (e.g., oligosaccharides, nucleotides, and others) with respect to the 

residual heterogeneity. In addition, maternal genetic variations in the production of those factors 

of interest from breast milk can be studied (for an example, see the discussion by Newburg 

2005218 concerning the variability of antidiarrheal effect of breastfeeding according to the 

prevalence of the secretor gene (fucosyltransferase 2) and the Lewis gene (fucosyltransferase 3) 

in the study population). 

Assessment of the efficacy/effectiveness of breastfeeding promotion interventions 

 Cluster randomized controlled studies similar to the Belarus trial will provide understanding 

of the effectiveness of various breastfeeding promotion interventions. Any substantial 

differences in the degree of breastfeeding between the two groups as a result of the intervention 

will provide further opportunity to investigate any disparity in health outcomes between the two 

groups. 
165 

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revisiting the incessant ovulation hypothesis. Am J 

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Washington, DC, U.S. Government Printing Office. 

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Uhari M, Mantysaari K, Niemela M. A meta-analytic 

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185

List of Acronyms and Abbreviations 

Abbreviation Description

Adj Adjusted 

AHRQ Agency for Healthcare Research and Quality 

ALL Acute Lymphocytic Leukemia 

AML Acute myeloid leukemia 

AOM Acute Otitis Media 

Bayley MDI Bayley Mental Development Index 

BF Breastfeeding 

BMCarm Forearm bone mineral content 

BMDspine Lumbar spine bone mineral density 

BMI Body mass index 

BW Birth weight 

CDC Centers for Disease Control and Prevention 

CES-D Center for Epidemiological Studies Depression Scale 

CI Confidence interval 

C-section Delivery by cesarean section 

CVD Cardiovascular disease 

DBP Diastolic blood pressure 

DIS Diagnostic Interview Schedule 

DM Donor milk 

DSM IV Diagnostic Statistical Manual 

Dx Diagnosis 

EPDS Edinburgh Postnatal Depression Scale 

Exclu Exclusive 

FH Family history 

GA Gestational age 

GDM Gestational diabetes 

H Hospital or clinic controls 

Hosp Hospitalization 

HRT Hormone replacement therapy 

Ht Height 

IHD Ischemic heart disease 

IOM Institute of Medicine 

IQ Intelligence quotient 

LDL Low-density lipoprotein 

LRTI Lower respiratory track infection 

LTC Long-term recalls 
186

Abbreviation Description

MA Meta-analysis 

MANCOVA Multivariate analysis of variance 

MDI Bayley Mental Development Index 

MM Exclusive mother’s milk 

Mo Months 

NA Not applicable 

ND No data/not documented 

NEC Necrotizing Entercolitis 

NLSY79 National longitudinal survey of youth 1979 

NS Non-significant 

OC Ovarian cancer 

OGTT Oral glucose tolerance test 

OR Odds Ratio 

P Population controls 

PA Physical activity 

PIAT Peabody individual achievement test 

PIAR Poverty index ratio 

PPVT-R Peabody Picture Vocabulary Test 

ROM Recurrent Otitis Media 

PF Preterm formula 

RDC Research Diagnostic Criteria 

RR Relative risk 

RTI Respiratory infection 

SBP Systolic blood pressure 

SDS Standard deviation score 

SE Standard error 

SES Socioeconomic status 

SR Systematic review 

SUDAAN Software adjusted sample 

TEP Technical Expert Panel 

Vit D suppl Vitamin D supplementation 

WISC-R Weschler Intelligence Scale for Children 

wk Week 

WPPSI-R Wechsler Preschool and Primary Scales of Intelligence 

Wt Weight 

Yr Year 
A-1

Appendix A. MEDLINE® Search Strategy 

MEDLINE 1966-April 2006

# Search History Results

1 exp infant nutrition/ 28620 

2 exp Milk, Human/ 10900 

3 human milk.mp. 5231 

4 (human adj2 milk).tw. 6040 

5 breast milk.mp. 4994 

6 breastmilk.mp. 315 

7 breast feeding.mp. 18905 

8 breastfeed$.mp. 5099 

9 breast fed.mp. 3434 

10 breastfed.mp. 1339 

11 (breast adj2 fed).tw. 3705 

12 exp lactation/ 24059 

13 (lactating or lactation).mp. 33361 

14 or/1-13 68554 

15 exp HIV Infections/ 150356 

16 HIV.mp. 151368 

17 *fatty acids/ 21008 

18 *amino acids/ 32481 

19 or/15-18 243664 

20 14 not 19 66018 

21 limit 20 to animals 32196 

22 20 not 21 33822 

23 limit 22 to english language 27054 

24 follow-up studies/ 308818 

25 (follow-up or followup).tw. 340039 

26 exp Case-Control Studies/ 297283 

27 (case adj20 control).tw. 44954 

28 exp Longitudinal Studies/ 508275 

29 longitudinal.tw. 62652 

30 exp Cohort Studies/ 548011 

31 cohort.tw. 73505 

32 (random$ or rct).tw. 324163 

33 exp Randomized Controlled Trials/ 39966 

34 exp random allocation/ 54141 
A-2

35 exp Double-Blind Method/ 84061 

36 exp Single-Blind Method/ 9446 

37 randomized controlled trial.pt. 208988 

38 clinical trial.pt. 420410 

39 controlled clinical trials/ 3005 

40 (clin$ adj trial$).tw. 90860 

41 ((singl$ or doubl$ or trebl$ or tripl$) adj (blind$ or mask$)).tw. 80586 

42 exp PLACEBOS/ 24212 

43 placebo$.tw. 91878 

44 exp Research Design/ 197961 

45 exp Evaluation Studies/ 539139 

46 exp Prospective Studies/ 195111 

47 exp Comparative Study/ 1233790

48 or/24-47 2803651

49 23 and 48 8238 

50 

limit 49 to (addresses or bibliography or biography or case reports or congresses 

or consensus development conference or consensus development conference, 

nih or dictionary or directory or editorial or festschrift or government 

publications or interview or lectures or legal cases or legislation or letter or 

news or newspaper article or overall or patient education handout or periodical 

index) 

360 

51 49 not 50 7878 
B-1

Appendix B. Sample Data Abstraction Forms 

Evidence table for Systematic Reviews 

Author, 

Year[UI] 

Topic 

Systematic reviews/Meta-analyses/Both 

Databases searched (Dates of literature search) 

Countries where primary studies conducted 

(Developed countries only or mixed) 

Study design [No. of studies] 

No. of subjects 

Study population and sampling 

Intervention/Exposure 

Comparator 

Outcomes 

Methods used for meta-analyses 

Heterogeneity assessments 

Results 

Authors’ conclusions 

Quality of the systematic review 

Comments 
B-2

Author, yr: 

Topic of the systematic review*/MA: 

Reporting yes/no 

Reporting of Background 

1 Description of study outcomes 

2 Types of exposure or intervention used 

3 Types of study designs used 

4 Study population 

Reporting of Search strategy 

5 Search strategy, including time period and key words 

6 Effort to include all available studies (contact with authors) 

7 Databases and registries searched 

8 Method of addressing published articles other than English 

9 Method of handling abstracts and unpublished studies 

Reporting of Methods 

10 Rationale for selection and/or coding of data 

11 Assessment of confounding 

12 Assessment of quality 

13 Assessment of heterogeneity 

14 Description of statistical methods sufficient to replicate 

15 Provision of appropriate tables and graphs 

Reporting of Results 

16 Graphic summarizing of individual study estimates and overall 

17 Tables giving descriptive information of each study included 

18 Results of sensitivity testing (subgroup analysis) 

19 Indication of statistical uncertainty of findings 

20 Quantitative assessment of bias (eg. publication bias) 

Overall quality 

*When grading a systematic review, please skip item #14, 18-20 

Please fill the white areas only 

Evaluation of quality of a systematic review or meta-analysis Yes /No 

/Partially 

1 Is search strategy appropriate/relevant to the key question(s)? 

2 Did authors give justifications for inclusion/exclusion criteria pertaining to the studies of 

interest? 

3 Were Population, Intervention/Exposure, Comparator/Control, Outcomes, and Study 

Designs well-defined? 

4 Did authors attempt to minimize errors in data extraction (such as collecting the 

relevant data, double data extraction, verification of data extraction...etc.)? 

5 Was individual study quality (such as sample size, study design, blinding, various 

biases and confounders, study subject attrition rate...etc.) assessed? 

6 Did authors consider appropriate confounders and justification for adjusting or not 

adjusting for those confounders? 

7 Was the justification for combining or not-combining data for meta-analysis, or the use 

of a particular analytic method or model appropriate? 

8 Was heterogeneity explored (this is in addition to any statistical test of heterogeneity, 

did the authors look at the actual differences in PICOS, for example?)? 

8 Were results reported accurately (eg, no discrepancies between text and tables)? 

9 Were conclusions justified by the reported/collected data and analysis? 
B-3

Author, Year, UI # 

Study characteristics 

Subjects’ 

health 

conditions 

Study design and 

follow-up duration Eligibility criteria 

Breastfeeding 

Exposures or 

Interventions 

Mean age (range): Pre-pregnancy BW (range): Pre-pregnancy BMI (range): Race: Enrolled/Evaluate: Location: Sites: Funding: Outcome Definition Statistical analyses and confounders adjusted Results Bias/confo

C

A: strong, B: moderate, C: weak 

Selection Study design Confounder Blinding Data collection Withdraw and dropout Analyses Intervention integrity 

Overall: 
B-4

Domain/question Place an “X” 

Selection Bias Are individuals selected to participate likely to be representative of target population? Very 

likely 

Somewhat likely 

l

What % of selected individuals agreed to participate? 80-100 60-79 Allocation Bias (RCTs only, for quasi-experimental, case-control/before/after, no control group or other skip to “Confouncders”) Is the method of random allocation stated Yes No If the method of random allocation is stated, is it appropriate Yes No Was the method of random allocation reported as concealed? Yes No Confounders Prior to the intervention, were there between group differences for important confounders reported in the paper? 

Yes No Ca

If there were differences between groups for important confounders, were they adequately managed in the 

analysis? 

Yes No 

Were there important confounders NOT reported in the paper (describe above under quality score)? Yes No Blinding Was (were) the outcome assessor(s) blinded to the intervention or exposure status of the participants? Yes No Data Collection methods Were data collection tools shown or are they known to be valid? Yes No Were data collection tools shown or are they known to be reliable? Yes No Withdrawals and Dropouts Indicate the % of participants completing the study. (If the % differs by groups, record the lowest). 80-100 60-79 Analysis Is there a sample size calculation or power calculation Yes Partially Is there a statistically significant difference between groups? Yes No Are the statistical methods appropriate? Yes No Indicate the unit of allocation Communit

y 

Organization/group Pr

Indicate the unit of analysis Communit

y 

Organization/group Pr

If the unit of allocation and analysis differed, was the cluster analysis done? Yes No Is the analysis performed by intervention allocation status (i.e. intention to treat) rather than the actual intervention received? 

Yes No Ca

Intervention Integrity What % of participants received the allocated intervention or exposure of interest? 80-100 60-79 Was the consistency of the intervention measured (i.e. intervention was provided to all participants in the same way)? 

Yes No 

Is it likely that subjects received an unintended intervention (contamination or cointervention) that may influence the results? 

Yes No Ca
Appendix C. Evidence Tables 

Part I. Term Infant Outcomes 

Acute Otitis Media 

Alho 1996 

Duffy 1997 

Sassen 1994 

Stenstrom 1997 

Uhari 1994 SRMA* 

Vernacchio 2004 

* Systematic Review/Meta-Analysis 

C-1
Alho, 1996[ 8633605] 

Study characteristics Study design and follow-up duration Eligibility criteria Breastfeeding Exposures or Interventions Control Ex

Mean GA (range): ND Mean BW (range): ND % Male: ND Race: ND Enrolled/Evaluate: 2512/ 825 Location: Northern Finland Sites: Single Funding: 

Retrospective Mean follow-up = 22 mo 

All pregnant women in the two northernmost provinces of Finland with estimated dates of delivery between July1, 1985 and June30, 1986 were enrolled. The research program investigated the fetal period and the later development and illnesses of the children. 

Breastfeeding among children older than 3 mo of age 

Bottle feedin3 mo of age 

Alho, 1996[ 8633605] 

Outcome Definition Statistical analyses and confounders adjusted Results Bias

Co

Diagnostic criteria for AOM: At least one acute SymptomEarache, fever, irritability, respiratory symptoms, Restless sleep, etc.  and one pneumo-otoscopic findingdistinct redness and outward bulging or reduced mobility of the eardrum 

Adjusted OR Confounders:  Day care  Parental smoking 

OR=0.9 

CI: 0.8 - 1.0 

A: strong, B: modera

Selection Study design Confounder Blinding Data collection Withdraw and dropoAnalyses Intervention integrity 

Overall: C High dropout rate 

C-2
Duffy, 1997 [9310540] 

Study characteristics Study design and follow-up duration Eligibility criteria Breastfeeding Exposures or Interventions 

Mean GA (range): Mean BW (range): % Male: 52 Race: 99% Caucasian Enrolled/Evaluate: 306/238 Location: USA Sites: Multi Funding: National Institute Of Child Health and Human Development Grant 19679 

Prospective Follow-up duration: 24 mo 

Consecutive infants at well baby visits shortly after birth. Infants with craniofacial abnormalities, genetic disorders, immune deficiencies were excluded 

Changes in feeding modes were assessed at scheduled office visits 

• Exclusive milk breastfeeding • Combined breast- and formulafeeding 

Maternal guardians completed a questionnaire at 24months to determine the reliability of various postnatal parameters. K statistics: r>0.9 for classification and duration of feeding modes (birth, 3, 6, and 12 mo of age) 

Cwo

Duffy, 1997 [9310540] 

Outcome Definition Statistical analyses and confounders adjusted Results Bias/li

Com

AOM defined by presence of one or more of Fever, irritability, ear pain, pulling at the ears, And Tympanic membrane changes including Increased thickness, bulging, loss of landmarks, Decreased mobility 

RR Confounder: age of colonization 

Exclusive BF at 3 mo was associated with RR= 0.62; 95%CI: 0.43-.89; At 6 mo, RR=0.46; 95%CI: 0.29-0.74 

A: strong, B: moderate, C

Selection Study design Confounder Blinding Data collection Withdraw and dropout Analyses Intervention integrity 

Overall: B 

C-3
Sassen, 1994 [7978038] 

Study characteristics Study design and follow-up duration Eligibility criteria Breastfeeding Exposures or Interventions C

Mean GA (range): ND Mean BW (range): ND % Male: 53 Race: 96.6% Dutch Enrolled/Evaluate: 289/232 Location: Netherlands Sites: Multi; 1 urban and 2 rural Funding: ND 

Prospective Mean follow-up = 23.6 mo 

Children born between July 1987 and October 1988 

Before breastfeeding was stopped 

 (or per month) U

Sassen, 1994 [7978038] 

Outcome Definition Statistical analyses and confounders adjusted Results Bias/lim

Comm

AOM diagnosis by physician; 

If purulent otorrhea; or 

 if treatment for AOM given 

Criteria for AOM consisted of: 

Acute symptoms- 

 ear ache, fever, irritability, restless sleep, etc. 

Otoscopic signsdistinct redness and/or 

Outward bulging of the tympanic membrane 

Tympanometry results not used 

Adjusted for 1. Number of siblings  2. Socio-economic status  3. Duration of breastfeeding 

OR= 0.92 95%  CI: 0.76-1.07 

A: strong, B: moderate, C: w

Selection Study design Confounder Blinding Data collection Withdraw and dropout Analyses Intervention integrity 

Overall: B Parents who are not Dutch coEnroll their infants because thQuestionnaire was not transla

C-4
Stenstrom, 1997 [9039487] 

Study 

characteristics 

Study design and followup duration Eligibility criteria Breastfeeding Exposures o

Interventions 

Mean GA (range): Mean BW (range): % Male: 61 Race: Enrolled/Evaluate: Location: Sweden Sites: Single/Multi Funding: 

Case-control At examination children were between 3 and 7 years old Controls were between 4 and 6 years 

All children born in the period 1978-81 registered to have had five or more episodes of AOM before age 30mo were selected and classified as cases (otitis-prone) From the official computerized population register in Malmo, 412 children with less than 5 episodes of AOM Were selected at random as a control group, and matched with otitis-prone children for age and sex so that each otitisprone child had two matched controls 

Ever breastfeeding 

Stenstrom, 1997 [9039487] 

Outcome Definition Statistical analyses and confounders adjusted Results B

AOM diagnosed otoscopically by an ENT physician, Pediatrician or general practitioner 

Estimates not reported No adjustment for confounders 

No differences between the groups found 

A: strong, B: mweak 

Selection Study design Confounder Blinding Data collection Withdraw and Analyses Intervention in

Overall: C No confounders 

C-5
Evidence table for Systematic Reviews of Breastfeeding and Acute otitis media 

Author, 

Year[UI] 

Topic Uhari, 1996 Acute otitis media 

Literature search (Dates) Medline (1966-1994); Other databases searched? (yes); unpublished data used? (no) 

Countries where primary 

studies conducted 

Finland, USA, Scotland 

Study eligibility / inclusion 

criteria 

Search was limited to the English language and to human subjects. Only original studies of 

risk factors with adequate control groups and that reported actual numbers of patients were 

included 

Study design [No. Of 

studies] 

2Case-control [12,17] 8Observational [[13,15,16,20,22,23,25,27] 

No. of subjects Case control: 671 Observational: 4455 

Breastfeeding > 3 months 2,548 

Breastfeeding > 6 months 3,384 

Breastfeeding (yes/no) 2, 193 

Study population 

(definition in included 

studies) 

Studies of association between breastfeeding and acute otitis media and recurrence of AOM 

• Specific age groups of children in the cohorts are not specified 

Intervention/Exposure 

(definition in included 

studies) 

The studies reviewed reported breastfeeding as yes/no or breastfeeding > 3months vs < 3 

months or breastfeeding > 6 months vs < 6 months 

Comparator (definition in 

included studies) 

Duration of breastfeeding 

Outcomes (definition in 

included studies) 

10 studies evaluated the risk of Acute otitis media and recurrence of Acute otitis associated 

with breast milk feeding. The diagnosis of AOM varied, but pneumatic otoscopy was used in 

the diagnosis. There was no restriction on study inclusion according to the diagnostic criteria 

used. Twenty-two studies evaluating an array of risk factors for development and recurrence 

of AOM were included in the Meta-analysis. Seven of the twenty-two studies explicitly 

evaluated the association between breast milk feeding and AOM, while another 3/22 studies 

included breast milk feeding among other risk factors that were evaluated. All the studies 

agreed on the protective effect of breast milk feeding against AOM. 

Heterogeneity 

assessments 

Pooled estimate of the relative risk and the 95% CI were calculated from data from studies 

that were sufficiently homogeneous. Pooled estimates of risks were derived with the random 

effects model. 

Details of clinical and statistical heterogeneity assessment is published elsewhere 

Quality assessments Not done 

Publication bias 

assessments 

Not done 

Statistical Analysis or 

meta-analytic methods 

 Random effects model used for the pooled estimates of risks 

Results • breastfeeding for at least 3 months and AOM ;RR=0.87; 95% CI: 0.79 – 0.95; p = 0.003 

• breastfeeding yes/no and recurrent AOM: RR=0.48; 95% CI: 0.32-0.72; p=0.0004 

• breastfeeding > 3 mo vs < 3 mo and recurrent AOM: RR= 0.69; 95% CI: 0.46-1.03; 

p=0.07 

• breastfeeding > 6 mo vs < 6 mo and recurrent AOM: RR= 0.69; 95% CI: 0.49-0.97; 

p=0.03 

Quality of the systematic 

review 

Not done 

Author’s interpretations of 

the results 

• In the meta-analysis, breastfeeding was beneficial and breastfeeding even for only 3 

months decreased the risk of AOM 

C-6
Author, 

Year[UI] 

Topic Uhari, 1996 Acute otitis media 

• Breastfeeding for 6 months or more decreased the recurrence of AOM 

• Breastfeeding should be promoted to protect against acute otitis media. 

Comments / Limitations There was no restriction on inclusion according to the diagnostic criteria used for AOM. 

There are no details on how breastfeeding data was collected or duration of follow-up. 

Meta-analyses combined both case-control and cohort studies and did not address the 

potential biases in the individual studies. 

Author, yr: Uhari, 1994 

Topic of the systematic review*/MA: Acute otitis media

Reporting yes/no 

Reporting of Background 

1 Description of study outcomes Yes 

2 Types of exposure or intervention used Yes 

3 Types of study designs used Yes 

4 Study population Yes 

Reporting of Search strategy 

5 Search strategy, including time period and key words Yes 

6 Effort to include all available studies (contact with authors) No (Medline only) 

7 Databases and registries searched Yes 

8 Method of addressing published articles other than English No 

9 Method of handling abstracts and unpublished studies No 

Reporting of Methods 

10 Rationale for selection and/or coding of data No 

11 Assessment of confounding No 

12 Assessment of quality No 

13 Assessment of heterogeneity Yes 

14 Description of statistical methods sufficient to replicate Yes 

15 Provision of appropriate tables and graphs Yes 

Reporting of Results 

16 Graphic summarizing of individual study estimates and overall Yes 

17 Tables giving descriptive information of each study included Partially 

18 Results of sensitivity testing (subgroup analysis) No 

19 Indication of statistical uncertainty of findings Yes 

20 Quantitative assessment of bias (eg. publication bias) No 

Overall quality C 

*When grading a systematic review, please skip item #14, 18-20 

Please fill the white areas only 

Evaluation of quality of a systematic review or meta-analysis 

Yes /No 

/Partially 

1 Is search strategy appropriate/relevant to the key question(s)? Partially 

2 Did authors give justifications for inclusion/exclusion criteria pertaining to the studies of 

interest? 

Yes 

3 Were Population, Intervention/Exposure, Comparator/Control, Outcomes, and Study 

Designs well-defined? 

Yes 

4 Did authors attempt to minimize errors in data extraction (such as collecting the 

relevant data, double data extraction, verification of data extraction...etc.)? 

Yes 

5 Was individual study quality (such as sample size, study design, blinding, various No 

C-7
Evaluation of quality of a systematic review or meta-analysis 

Yes /No 

/Partially 

biases and confounders, study subject attrition rate...etc.) assessed? 

6 Did authors consider appropriate confounders and justification for adjusting or not 

adjusting for those confounders? 

No 

7 Was the justification for combining or not-combining data for meta-analysis, or the use 

of a particular analytic method or model appropriate? 

Yes 

8 Was heterogeneity explored (this is in addition to any statistical test of heterogeneity, 

did the authors look at the actual differences in PICOS, for example?)? 

Yes 

8 Were results reported accurately (eg, no discrepancies between text and tables)? N/A 

9 Were conclusions justified by the reported/collected data and analysis? Yes 

C-8
Vernacchio, 2004 [15126021] 

Study characteristics Study design and follow-up duration Eligibility criteria Breastfeeding Exposures or Interventions 

Mean GA (range): Mean BW (range): 3,400,median % Male: 50.8 Race: 68.4% both parents white Enrolled/Evaluate: 15,113/11,349 Location: USA Sites: Multi Funding: Contract no. 1-HD-4-3221 National Institute of Child and Human Development and the National Institute on Deafness and other Communication Disorders 

Prospective Followup- 6 mo 

6 mo old infants who participated in the infant care practices study 

Breastfeeding A child was considered to be breastfed at 6 mo if he or she was breastfeeding at the time of the 6 mo questionnaire, whether or not supplemental formula or solid foods were used 

Vernacchio,2004 [15126021] 

Outcome Definition Statistical analyses and confounders adjusted Results B

As part of the 6 mo questionnaire, each mother was asked health care provider in the month prior to date of completing the questionnaire. I so, they were asked to select a diagnosis from a menu of options that included “ear infection” 

OR Confounders  Gender  Daycare attendance  Mother’s marital status Mother’s age  Mother’s parity  Number of children in the home 

Unadjusted OR=0.66 95%CI: 0.59-0.74 Adjusted OR=0.69 95%CI: 0.61-0.78 

A: strong, B: mweak 

Selection Study design Confounder Blinding Data collection Withdraw and dAnalyses Intervention int

Overall: B 

C-9
Appendix C. Evidence Tables 

Part I. Term Infant Outcomes 

Asthma 

Burgess 2006 

Gdalevich 2001 SRMA* 

Kull 2004 

Sears 2002 

Wright 2001 

* Systematic Review/Meta-Analysis 

C-10
Burgess, 2006 [16585289] 

Study 

characteristics Study design and follow-up duration Eligibility criteria Breastfeeding Exposures or Interventions 

Mean GA (range): 185 Mean BW (range): 3402 % Male: 52 Race: ND Enrolled/Evaluate: 7223/4964 Location: Australia Sites: Single Funding: ND 

Prospective cohort with questionnaires at birth, 6 months, 5 and 14 years. Breastfeeding data collected at 6 months 

Mothers and term singletons 

Categories:  Never breastfed  < 3 weeks  3 – 6 weeks  7 weeks – 3 months 

≥ 4 months 

Burgess, 2006 [16585289] 

Outcome Definition Statistical analyses and confounders adjusted Results Bia

At 14 years, mother reported asthma, qualitative answers to episodes of asthma past in 6 months. Supplemental questionnaire at 14 year follow-up requesting data on frequency of asthma meds, asthma-related sick days from school, asthma-related hospital admissions, parental history of asthma 

Chi-square for categorical variables Logistic regression adjusting for breastfeeding, maternal asthma, paternal asthma, smoking early and late pregnancy, frequency of coughs and cold first 6 months, annual family income 

Outcome Breastfeeding duration 

No BF 3 wk-3 

mo 

≥4 mo 

Asthma ORunadj (95% CI) 

1.0 1.03 

(0.9-

1.2) 

1.03 (0.9-

1.2) 

Of 4,964 subjects with breastfeeding and asthma data, 1408 (28%) mother-reported cases of adolescent asthma 3,720 returned 14 year follow-up questionnaire Nonsignificant relationship between duration of breastfeeding and asthma. Stratification for parental asthma or child’s sex had no effect. No association for breastfeeding duration and asthma meds, asthmarelated sick days from school or hospitalization 

A: strong, B: modweak 

Selection Study design Confounder Blinding Data collection Withdraw and drAnalyses Intervention integ

No reporting of adjmales in table, drosignificant differennoncompleters, no breastfeeding. Overall C 

C-11
Evidence table for Systematic Reviews of Breastfeeding 

Author, Year[UI] Topic Gdalevich, 2001 Asthma 

Literature search (Dates) Medline (1966 to 1999); Other databases searched? (no); unpublished data used? (no) 

Countries where primary 

studies conducted 

Developed only: USA, Canada, UK, Italy, Australia and New Zealand 

Study eligibility / inclusion 

criteria 

Prospective studies; maternal recall of the child’s feeding history of not more than 12 months; 

duration of BF for 3 months or more. 

Study design [No. Of 

studies] 

Prospective study design [12] 

No. of subjects 8,183 

Study population 

(definition in included 

studies) 

Children (with and without family h/o atopy and asthma and combined population) 

Intervention/Exposure 

(definition in included 

studies) 

Exclusive breastfeeding (3 mo or more with no substitutes or supplements to mother’s milk or 

solids) 

Comparator (definition in 

included studies) 

without ≥ 3 mo of exclusive breastfeeding 

Outcomes (definition in 

included studies) 

Asthma (Diagnosed by physician, consecutive reporting of wheezing beyond the age of 1 

year, and treatment for lower respiratory tract allergy were defined as study outcomes) 

Heterogeneity 

assessments 

Yes by graphical presentation and application of heterogeneity test 

Quality assessments Unclear; studies critically appraised on 8 items (maternal recall; blinded to exposure; duration 

of bf; exclusivity of bf; diagnostic criteria; blinded ascertainment of outcome; age; control for 

confounding) 

Publication bias 

assessments 

Yes; calculation of the fail-safe N 

Statistical Analysis or 

meta-analytic methods 

Fixed effect model ; was also compared to random effects model 

Metric used odds ratio 

Results The summary OR was 0.47 (95% CI, 0.34-0.66) in the 5 studies (1788 subjects) with less than 2 years 

of follow-up, and 0.72 (95% CI, 0.62-0.84) in the 12 studies with 2 or more years of follow-up. 

The protective effect estimate of BF was more pronounced in the children with a family history of atopy 

in the subset of studies that assessed this population separately, OR= 0.52 (95% CI, 0.35-0.79), than in 

the studies in which both unstratified population data and children without atopic first-degree relatives 

were included, OR = 0.73 (95% CI, 0.62-0.86). When we further restricted the analysis to studies 

involving only children without a family history of atopy, the OR was 0.99 (95% CI, 0.48-2.03). 

Exclusion from the analysis of the studies with borderline blinding of diagnosing physicians10,15,19 or 

those lacking a statement of BF exclusivity20 yielded respective ORs of 0.71 (95% CI, 0.61-0.84) and 

0.72 (95% CI, 0.61-0.85). 

Quality of the systematic 

review 

A 

Author’s interpretations of 

the results 

The summary analysis of the 12 prospective studies supports the role of exclusive BF in the 

prevention of childhood asthma. The protective effect was higher in the subgroup of children 

with a positive family history of asthma or atopy. 

Comments / Limitations Children age range not mentioned; included studies that did not adjust for confounding; 

C-12
Author, yr: Gdalevich, 2001 

Topic of the systematic review*/MA: Asthma

Reporting yes/no 

Reporting of Background 

1 Description of study outcomes Y 

2 Types of exposure or intervention used Y 

3 Types of study designs used Y 

4 Study population Y 

Reporting of Search strategy 

5 Search strategy, including time period and key words Y 

6 Effort to include all available studies (contact with authors) Y 

7 Databases and registries searched Y 

8 Method of addressing published articles other than English N 

9 Method of handling abstracts and unpublished studies Y 

Reporting of Methods 

10 Rationale for selection and/or coding of data Y 

11 Assessment of confounding Y 

12 Assessment of quality Y 

13 Assessment of heterogeneity Y 

14 Description of statistical methods sufficient to replicate Y 

15 Provision of appropriate tables and graphs Y 

Reporting of Results 

16 Graphic summarizing of individual study estimates and overall Y 

17 Tables giving descriptive information of each study included Y 

18 Results of sensitivity testing (subgroup analysis) Y 

19 Indication of statistical uncertainty of findings Y 

20 Quantitative assessment of bias (eg. publication bias) N 

Overall quality A 

*When grading a systematic review, please skip item #14, 18-20 

Please fill the white areas only 

Evaluation of quality of a systematic review or meta-analysis Yes /No 

/Partially 

1 Is search strategy appropriate/relevant to the key question(s)? Y 

2 Did authors give justifications for inclusion/exclusion criteria pertaining to the studies of 

interest? 

Y 

3 Were Population, Intervention/Exposure, Comparator/Control, Outcomes, and Study 

Designs well-defined? 

Y 

4 Did authors attempt to minimize errors in data extraction (such as collecting the 

relevant data, double data extraction, verification of data extraction...etc.)? 

Y 

5 Was individual study quality (such as sample size, study design, blinding, various 

biases and confounders, study subject attrition rate...etc.) assessed? 

Y 

6 Did authors consider appropriate confounders and justification for adjusting or not 

adjusting for those confounders? 

Y 

7 Was the justification for combining or not-combining data for meta-analysis, or the use 

of a particular analytic method or model appropriate? 

Y 

8 Was heterogeneity explored (this is in addition to any statistical test of heterogeneity, 

did the authors look at the actual differences in PICOS, for example?)? 

Y 

8 Were results reported accurately (eg, no discrepancies between text and tables)? Y 

9 Were conclusions justified by the reported/collected data and analysis? Y 

C-13
Kull, 2004; Kull, 2002 

Wickman 2003 

Study 

characteristics 

Study design and 

follow-up duration Eligibility criteria Breastfeeding Exposures or Interventions 

Mean GA (range): 

ND 

Mean BW (range): 

ND 

% Male: 50.5 Race: ND Enrolled/Evaluate: 

4089/3601 

Location: Sweden Sites: Multiple Funding: Nonprofit; 

government 

Prospective, longitudinal cohort with final data collection at 4 year follow-up 

All newborns from February 1994 

through November 1996 in a predefined area of Stockholm, Sweden were invited to the study. 4089 (75%) of all infants were included. 

Data from all 4 questionnaires (at 2 

months, 1, 2, and 4 years of age) were available for 3619 (88%) children. 

Complete answers on the subjects of 

breast-feeding, potential confounders, and outcome were required to be included in the analyses, leaving 3601 children (88% of the original study base) for analyses. 

The independent variable of breast-feeding was categ

as follows: exclusive breast-feeding was dichotomized w25th percentile as the cutoff point (<4 months and 

≥4 mo

and as a 3-level categorical variable (0-2, 3-4, and 

≥5 m

The variable for exclusive breast-feeding was used in 

combination with a dichotomized variable of partial breasfeeding (0-2 and 

≥3 months) to disentangle the effects o

exclusive breast-feeding and an additional period of partbreast-feeding. The period of additional partial breast-feewas calculated from the point when exclusive breastfeedfinished. 

C-14
Kull, 2004; Kull, 2002 

Outcome Definition Statistical analyses and confounders adjusted Results 

Asthma: At 4 years of age, 

asthma was defined as at least 4 episodes of wheezing during the last 12 months or at least 1 episode of wheezing during the same period if the child was receiving inhaled steroids. 

Early-onset persistent 

asthma implies that the child fulfilled the asthma criteria not only at 4 years but also during the first 2 years of life.

Early-onset transient asthma 

denotes that the child was fulfilling asthma criteria during the first 2 years of life but not at 4 years of age. 

Late onset of asthma implies 

that the child was not classified as having asthma during the first 2 years of life but fulfilled the asthma criteria at 4 years. 

The relationship between 

breast-feeding and health outcomes was analyzed with logistic regression, adjusted for maternal age, maternal smoking during pregnancy or at 2 months of age, and heredity.

Heredity: Heredity for 

allergic diseases was defined as physician diagnosed asthma, hay fever, or both in combination with allergy to a furred pet, pollen, or both in 1 (single heredity) or 2 (double heredity) parents. 

Outcome Exclusive BF 

0-2 mo 3-4 mo 

≥5 mo 

Asthma n/N 48/541 41/701 111/2142 ORadj (95% CI) 1.0 0.67 (0.43-

1.03) 

0.61 (0.42-

0.86) 

Asthma & No heredity 

n/N 30/383 24/502 55/1500 

ORadj (95% CI) 1.0 0.61 (0.36-

1.06) 

0.48 (0.30-

0.77) 

Asthma & Heredity n/N 18/158 17/199 56/642 ORadj (95% CI) 1.0 0.76 (0.37-

1.54) 

0.81 (0.46-

1.44) 

Early-onset & persistent asthma 

n/N 25/532 19/687 36/2118 

ORadj (95% CI) 1.0 0.56 (0.30-

1.04) 

0.35 (0.21-

0.60) 

Early-onset transient asthma 

n/N 36/532 19/687 73/2118 

ORadj (95% CI) 1.0 0.39 (0.22-

0.69) 

0.51 (0.30-

0.77) 

Late onset of asthma 

n/N 22/532 21/687 73/2118 

ORadj (95% CI) 1.0 0.71 (0.38-

1.31) 

0.82 (0.50-

1.35) 

Note: The interaction between asthma and heredity was not statistically significant. 

The prevalence of asthma among children exclusively breastfed for 

less than 4 months was 9.1% compared with 6.4% among children breast-fed for 4 months or more (ORadj, 0.72; 95% CI, 0.53-0.97). The 

ORadj for asthma related to breast-feeding for 4 months or more was 

0.58 (95% CI, 0.38-0.88) in children without heredity for allergic diseases and 0.73 (95% CI, 0.43-1.20) in children with heredity.

Amw

SSCBDWdAIi

Ov

C-15
Sears, 2002 [16585289] 

Study 

characteristics Study design and follow-up duration Eligibility criteria Breastfeeding Exposures or Interventions 

Mean GA (range): ND Mean BW (range):ND % Male: ND Race: ND Enrolled/Evaluate: 1037/1037 Location: New Zealand Sites: Single Funding: Government 

Ambidirectional cohort study - enrolled at age 3 and followed prospectively up to 21 years. Accompanied and unaccompanied assessments at 3, 5, 7, 9, 11, 13, 15, 18, 21, and 26 years. 

Population study of liveborn children 

Categories:  Not breastfed  Breastfed > 4 weeks Breastfed definition includes some formula feeding 

during birthing stay at hospital. Feeding history including duration of breastfeeding from regular, initially weekly, home & clinic visits during first 2years 

C-16
Sears, 2002 [16585289] 

Outcome Definition 

Statistical analyses 

and confounders 

adjusted 

Results 

At age 9 years, ever having asthma from comprehensive questionnaires by interviewers with data on frequency of wheezing, asthma diagnosis, drugs, clinical characteristics, admissions; current asthma defined as positive response as reported by child or parent with accompanied symptoms of last 12 months; some verification by airway hyper-responsiveness 

Chi-square for categorical variables Multivariate regression controlling for SES, birth order, sheepskin use in infancy, maternal smoking 

Outcome BF status 

No BF 

(n=504) 

>4 weeks 

n=(533) 

P value 

Asthma ever at 9 years 

n/N 27/417 

(6%) 

47/398 

(12%) 

ORadj (95% CI) 1.0 1.93 

(1.18-3.17) 

0.0081 

Current asthma at 26 years 

n/N 74/496 

(15%) 

113/484 

(23%) 

ORadj (95% CI) 1.0 1.74 

(1.26-2.40) 

0.0008 

Current asthma with AHR at 9 years 

n/N 11/409 

(3%) 

28/385 

(7%) 

ORadj (95% CI) 1.0 2.83 

(1.39-5.78) 

0.0028 

Asthma ever at 9 years Family history negative 

n/N 23/216 

(11%) 

ORadj (95% CI) 

10/229 

(4%) 

2.61 

(1.21-5.62) 

Asthma ever at 9 years Family history positive 

n/N 23/174 

(13%) 

ORadj (95% CI) 

16/174 

(9%) 

1.50 

(0.77-2.96) 

0.291 

AHR, airway hyper-responsiveness to methacholine or salbutamol Multivariate analysis of current asthma at 9 years with breastfeeding > 4 weeks with adjusted OR 2.40 (1.36-4.26), p = 0.0027 Analysis for different duration of BF showed similar results of greater risk of asthma at 9 years for more 

O

C-17
Wright, 2000 [11065066] 

Wright, 2001 [11182011] 

Study 

characteristics Study design and follow-up duration Eligibility criteria Breastfeeding Exposures or Interventions 

Mean GA (range): ND Mean BW (range): ND % Male: ND Race: ND Enrolled/Evaluate: 1,246/926 Location: USA Sites: Multiple Funding: Government 

Prospective, longitudinal newborn cohort with questionnaires ascertaining respiratory health at 2, 3, 6, 9, 11, 13 years Additional data collection by health surveillance visit to MD 

Healthy newborn infants 

Children classified by duration of exclusive breast feedinever breast fed, breast fed exclusively <4 months, brefed exclusively >4 months 

Wright, 2000 [11065066] Wright, 2001 [11182011] 

Outcome Definition Statistical analyses and confounders adjusted Results 

Physician diagnosed asthma, wheezing or asthma symptoms reported ≥ 2 questionnaires from ages 6 to 13 years 

Bivariate analyses between feeding history and asthma, and stratified by maternal asthma status Logistic regression to assess odds of asthma, recurrent wheeze were related to breast feeding and maternal asthma adjusting for confounders: maternal education, smoking status in 1st year, 

sex, ethnicity, 2 or more siblings at home or day care use versus neither first 6 months, paternal asthma 

Age 6-13: Nonsignificant for breastfeeding duration and asthma Nonsignificant for breastfeeding duration and asthma for children with non-asthmatic mothers ORadj 2.1 (0.9-

5.1) 

Significant for maternal asthmatics ORadj 8.7 (3.4-22.2) 

BF status 

Maternal asthma status 

Never 

BF 

<4 mo ≥4 mo 

Maternal asthma p<0.05 

% n/N 

9.1 

1/11 

23.5 

12/51 

46 

17/37 

No maternal asthma 11.4 

15/132 

12.3 

48/390 

13 

38/294 

A: strmodeSelecStudy ConfBlindData WithdAnalyInterv

OveraNo expdiscrepBF

C-18
Appendix C. Evidence Tables 

Part I. Term Infant Outcomes 

Atopic Dermatitis 

Gdalevich 2001 SRMA*

* Systematic Review/Meta-Analysis 

C-19
Evidence table for Systematic Reviews of Breastfeeding 

Author, Year[UI] Topic Gdalevich 2001 (UI 11568741) Atopic dermatitis 

Literature search (Dates) Medline (1966 to 5/2000); Other databases searched? No; unpublished data used? No 

Countries where primary 

studies conducted 

Not reported; but all studies were performed in developed countries 

Study eligibility / inclusion 

criteria 

Prospective studies of full-term infants in whom the ORs of atopic dermatitis associated 

with breastfeeding were reported or could be calculated. Exclusion: breastfeeding 

duration of <3 months; see paper for additional inclusion/exclusion criteria 

Study design [No. Of studies] 18 prospective studies were included 

No. of subjects 4158 subjects 

Study population (definition in 

included studies) 

Full-term infants 

Intervention/Exposure 

(definition in included studies) 

Exclusive breastfeeding for ≥ 3 months 

Comparator (definition in 

included studies) 

Outcomes (definition in 

included studies) 

Strict diagnostic criteria for atopic dermatitis provided by the authors of the primary 

studies 

Heterogeneity assessments Nonsignificant heterogeneity (P=0.27) 

Quality assessments 

Publication bias assessments 

Statistical Analysis or metaanalytic methods 

Results Fixed effect, overall OR 0.68 (95% CI 0.52, 0.88); 

After exclusion of unblinded studies, OR 0.77 (95% CI 0.60, 0.98) 

Analyses restricted to those with positive family history, OR 0.58 (95%CI 0.41, 0.92) 

Analyses restricted to those without family history, OR 0.84 (95%CI 0.59, 1.19) 

Quality of the systematic 

review 

A 

Author’s interpretations of the 

results 

There is a substantial protective effect of breastfeeding against atopic dermatitis in 

children with a family history of atopy. 

Comments / Limitations 

C-20
Author, yr: Gdalevich 2001 

Topic of the systematic review*/MA: Atopic dermatitis

Reporting yes/no 

Reporting of Background 

1 Description of study outcomes Y 

2 Types of exposure or intervention used Y 

3 Types of study designs used Y 

4 Study population Y 

Reporting of Search strategy 

5 Search strategy, including time period and key words Y 

6 Effort to include all available studies (contact with authors) Y 

7 Databases and registries searched Y 

8 Method of addressing published articles other than English N 

9 Method of handling abstracts and unpublished studies N 

Reporting of Methods 

10 Rationale for selection and/or coding of data Y 

11 Assessment of confounding Y 

12 Assessment of quality Y 

13 Assessment of heterogeneity Y 

14 Description of statistical methods sufficient to replicate Y 

15 Provision of appropriate tables and graphs Y 

Reporting of Results 

16 Graphic summarizing of individual study estimates and overall Y 

17 Tables giving descriptive information of each study included N 

18 Results of sensitivity testing (subgroup analysis) Y 

19 Indication of statistical uncertainty of findings Y 

20 Quantitative assessment of bias (eg. publication bias) N 

Overall quality 

*When grading a systematic review, please skip item #14, 18-20 

Please fill the white areas only 

Evaluation of quality of a systematic review or meta-analysis Yes /No 

/Partially 

1 Is search strategy appropriate/relevant to the key question(s)? Y 

2 Did authors give justifications for inclusion/exclusion criteria pertaining to the studies of 

interest? 

Y 

3 Were Population, Intervention/Exposure, Comparator/Control, Outcomes, and Study 

Designs well-defined? 

Y 

4 Did authors attempt to minimize errors in data extraction (such as collecting the 

relevant data, double data extraction, verification of data extraction...etc.)? 

Y 

5 Was individual study quality (such as sample size, study design, blinding, various 

biases and confounders, study subject attrition rate...etc.) assessed? 

Y 

6 Did authors consider appropriate confounders and justification for adjusting or not 

adjusting for those confounders? 

Y 

7 Was the justification for combining or not-combining data for meta-analysis, or the use 

of a particular analytic method or model appropriate? 

Y 

8 Was heterogeneity explored (this is in addition to any statistical test of heterogeneity, 

did the authors look at the actual differences in PICOS, for example?)? 

Y/N 

8 Were results reported accurately (eg, no discrepancies between text and tables)? Y 

9 Were conclusions justified by the reported/collected data and analysis? Y 

C-21
Appendix C. Evidence Tables 

Part I. Term Infant Outcomes 

CVD Mortality 

Martin 2004 SRMA*

* Systematic Review/Meta-Analysis

C-22
Evidence table for Systematic Reviews of Breastfeeding 

Author,Year[UI] Topic Martin, 2004 Cardiovascular Mortality 

Literature search (Dates) Medline (up to April 2003); Other databases searched? (yes); unpublished data used? (yes) 

Countries where primary 

studies conducted 

Developed countries: US and UK 

Study eligibility / inclusion 

criteria 

Articles were considered eligible for inclusion in the current review if infants who had been 

breastfed were compared with those who had been bottle (artificially) fed, if the outcome 

was cardiovascular disease or ischemic heart disease mortality, and if estimates of the 

association between having been breastfed in infancy and cardiovascular disease or 

ischemic heart disease mortality could be obtained from the paper or after correspondence 

with the authors. 

Study design [No. Of 

studies] 

Historical cohort studies [4] 

No. of subjects 25,166 at baseline; 10,785 at follow-up 

Study population (definition 

in included studies) 

Wingard, 1994: 1373 birth children in California 

Hertfordshire cohort: 5908 women and 10374 men born in 11 of 12 districts in Hertfordshire 

Boyd Orr: 4999 men and women from a survey of diet and health in pre-war Britain 

Caerphilly, 2003: 2512 meddle-aged men living in Caerphilly, South Wales 

Intervention/Exposure 

(definition in included 

studies) 

• Any or exclusive breastfeeding. If results for both any or exclusive breastfeeding were 

presented in the paper, the exclusive breastfeeding association was used in the metaanalysis. 

• Prolonged breastfeeding: any or exclusive breastfeeding >1 year. 

Comparator (definition in 

included studies) 

Exclusive bottle-feeding 

Outcomes (definition in 

included studies) 

Cardiovascular disease or ischemic heart disease mortality 

Heterogeneity assessments Cochran’s Q statistic 

I

2 test 

Quality assessments No quality score was used, although specific aspects of the quality of each study, including 

control of confounding, loss to follow-up, recall bias, definition of breastfeeding, and sample 

size, were discussed 

Publication bias 

assessments 

Not done, although there was a discussion on publication bias as one of the potential 

limitations of the meta-analyses. 

Statistical Analysis or metaanalytic methods 

Random effect model 

Results • All four studies were historical cohorts born between 1904 and 1939. 

• Random-effect models showed little difference in all cause mortality between breast 

and bottle-fed subjects (pooled rate ratio: 1.01; 95% CI: 0.91-1.13, p=0.8), and there 

was little evidence of heterogeneity. 

• Five observations from three studies suggested little or no association between 

breastfeeding and cardiovascular disease mortality in both males and females, and one 

suggested a possible adverse effect (Caerphilly cohort). In random effects metaanalysis, cardiovascular disease mortality was similar in breastfed versus bottlefed 

subjects (pooled rate ratio: 1.06; 95% CI: 0.94–1.20). There was no statistical evidence 

of between-study heterogeneity. 

• Ischemic heart disease mortality was 6% lower amongst males who had been breastfed 

in the Hertfordshire cohort, but 56% higher amongst breastfed females. This result is in 

line with point estimates from the Boyd Orr cohort suggesting that ischemic heart 

disease mortality was 10% lower amongst males who had been breastfed, but 40% 

higher amongst breastfed females (although there was little statistical evidence of 

interaction: p=0.2). In Caerphilly, however, ischemic heart disease mortality was 73% 

higher amongst breastfed males. In a random effects meta-analysis, there was 

evidence of heterogeneity. 

C-23
Author,Year[UI] Topic Martin, 2004 Cardiovascular Mortality 

• There was little evidence that prolonged breastfeeding was associated with all-cause 

mortality (pooled rate ratio: 0.94; 95% CI: 0.71–1.24), although there was moderate 

statistical evidence of heterogeneity. 

• There was weak evidence that prolonged breastfeeding was associated with a 16% 

increase (95% CI: 0.99–1.36; p=0.06) in cardiovascular disease mortality, and no 

evidence of inconsistency in estimates. 

• There was little evidence that prolonged breastfeeding was associated with ischemic 

heart disease mortality (rate ratio: 1.08; 95% CI: 0.88–1.31; p=0.5) and there was no 

heterogeneity. 

Quality of the systematic 

review 

B 

Author’s interpretations of 

the results 

• There are at least three possible sources of bias in the studies reviewed: selection bias, 

information bias or recall bias (except for one study) and publication bias. Only 2 of the 

4 studies had at least 70% of the target population in the follow-up. Recall bias is 

unlikely in only Hertfordshire cohort as breastfeeding was prospectively ascertained. 

Publication bias is possible but the studies were relatively large and unpublished 

estimates were obtained. 

• As confounding and bias may have distorted results from individual studies, the 

statistical combination of estimates into a combined rate ratio needs to be interpreted 

with caution. Our new analysis, together with evidence from published and unpublished 

literature, does not provide strong evidence that breastfeeding is related to all-cause or 

cardiovascular disease mortality. The confidence limits around our point estimates and 

the observed between-study heterogeneity for associations between breastfeeding and 

ischemic heart disease, however, do not rule out important beneficial or adverse 

cardiovascular effects of breastfeeding. 

• Although we found little evidence to support a cardioprotective effect of breastfeeding 

extending into old age, its beneficial influence on infant and child health and cognitive 

development supports the idea that it should be promoted as the infant feeding method 

of choice. 

Comments / Limitations We agree with authors’ conclusion and discussion on the limitations of the meta-analyses. 

However, given large heterogeneity across studies (especially for IHD mortality), metaanalyses might not be appropriate. At least for the outcome of IHD mortality, men and 

women should be combined separately because of apparent effect modification by gender. 

Results from Hertford cohort were only adjusted for age. 

C-24
Author, yr: Martin, 2004 

Topic of the systematic review*/MA: CVD mortality

Reporting yes/no 

Reporting of Background 

1 Description of study outcomes Yes 

2 Types of exposure or intervention used Yes 

3 Types of study designs used Yes 

4 Study population Yes 

Reporting of Search strategy 

5 Search strategy, including time period and key words Yes 

6 Effort to include all available studies (contact with authors) Yes 

7 Databases and registries searched Yes 

8 Method of addressing published articles other than English No 

9 Method of handling abstracts and unpublished studies Yes 

Reporting of Methods 

10 Rationale for selection and/or coding of data No 

11 Assessment of confounding Yes 

12 Assessment of quality Yes 

13 Assessment of heterogeneity Partially 

14 Description of statistical methods sufficient to replicate Yes 

15 Provision of appropriate tables and graphs Yes 

Reporting of Results 

16 Graphic summarizing of individual study estimates and overall Yes 

17 Tables giving descriptive information of each study included Yes 

18 Results of sensitivity testing (subgroup analysis) No 

19 Indication of statistical uncertainty of findings Yes 

20 Quantitative assessment of bias (eg. publication bias) No 

Overall quality B 

*When grading a systematic review, please skip item #14, 18-20 

Please fill the white areas only 

Evaluation of quality of a systematic review or meta-analysis Yes /No 

/Partially 

1 Is search strategy appropriate/relevant to the key question(s)? Yes 

2 Did authors give justifications for inclusion/exclusion criteria pertaining to the studies of 

interest? 

Yes 

3 Were Population, Intervention/Exposure, Comparator/Control, Outcomes, and Study 

Designs well-defined? 

Yes 

4 Did authors attempt to minimize errors in data extraction (such as collecting the 

relevant data, double data extraction, verification of data extraction...etc.)? 

No 

5 Was individual study quality (such as sample size, study design, blinding, various 

biases and confounders, study subject attrition rate...etc.) assessed? 

Yes 

6 Did authors consider appropriate confounders and justification for adjusting or not 

adjusting for those confounders? 

Partially 

7 Was the justification for combining or not-combining data for meta-analysis, or the use 

of a particular analytic method or model appropriate? 

No 

8 Was heterogeneity explored (this is in addition to any statistical test of heterogeneity, 

did the authors look at the actual differences in PICOS, for example?)? 

Partially 

8 Were results reported accurately (eg, no discrepancies between text and tables)? Yes 

9 Were conclusions justified by the reported/collected data and analysis? Yes 

C-25
Appendix C. Evidence Tables 

Part I. Term Infant Outcomes 

Leukemia 

Beral 2001 SRMA* 

Davis 1998 SRMA* 

Guise 2005 SRMA* 

Kwan 2004 SRMA*

* Systematic Review/Meta-Analysis

C-26
Evidence table for Systematic Reviews of Breastfeeding 

Author, Year[UI] Topic Beral (or USCCS Investigators), 2000; 2001 Leukemia 

Literature search (Dates) ND 

Countries where primary 

studies conducted 

Mixed developed and developing countries 

Study eligibility / inclusion 

criteria 

Not described. Meta-analyses were performed for the associations between breastfeeding 

and leukemia, Hodgkin’s disease, non-Hodgkin’s lymphoma, other childhood cancers and all 

childhood cancers combined. For the purpose of our review, we focus on childhood leukemia 

only. 

Study design [No. Of 

studies] 

Case-control studies [15] 

No. of subjects Cases: 7,401 Controls: 14,587 

Study population 

(definition in included 

studies) 

Cases: Children with all leukemia, including ALL 

Controls: ND 

Intervention/Exposure 

(definition in included 

studies) 

Ever breastfeeding 

Breastfeeding duration ≤ 6 months 

Breastfeeding duration > 6 months 

Comparator (definition in 

included studies) 

never breast fed 

Outcomes (definition in 

included studies) 

All leukemia, including ALL 

Heterogeneity 

assessments 

ND 

Quality assessments ND 

Publication bias 

assessments 

ND 

Statistical Analysis or 

meta-analytic methods 

This is a primary study (UKCCS study) plus meta-analyses. 

No methods of meta-analyses were described. 

Results The UKCCS results did not differ significantly from those of previous studies. Results from 

previous studies were combined with UKCCS results. For childhood leukemia, there is 

evidence of a statistically significant reduction in the OR associated with ever having been 

breastfed (OR=0.86, 95%CI 0.81-0.92) and having been breastfed for more than 6 months 

(OR=0.78, 95% CI 0.71-0.85). 

Quality of the systematic 

review 

C 

Author’s interpretations of 

the results 

It is unclear whether the apparent small reduction in the risk of each type of childhood cancer 

reported here is a non-specific effect of breastfeeding on childhood cancer or whether it 

reflects some systematic bias shared by the majority of the case-control studies that have 

investigated etiological factors in childhood cancer. We are unable to decide which of these 

possibilities is the more likely. 

Comments / Limitations This is a primary study (UKCCS study) plus meta-analyses. Authors focused on their results 

regarding the association between breastfeeding and childhood cancer in UKCCS study. No 

methods for the meta-analyses were described. They did not report the standard steps 

required for a systematic review, including explicit search criteria, inclusion and exclusion 

criteria, and quality assessment. 

However, we agree with the author’s interpretations of the results. 

C-27
Author, yr: Beral 2000; 2001 

Topic of the systematic review*/MA: Leukemia

Reporting yes/no 

Reporting of Background 

1 Description of study outcomes Yes 

2 Types of exposure or intervention used Yes 

3 Types of study designs used Yes 

4 Study population No 

Reporting of Search strategy 

5 Search strategy, including time period and key words No 

6 Effort to include all available studies (contact with authors) No 

7 Databases and registries searched No 

8 Method of addressing published articles other than English No 

9 Method of handling abstracts and unpublished studies No 

Reporting of Methods 

10 Rationale for selection and/or coding of data No 

11 Assessment of confounding No 

12 Assessment of quality No 

13 Assessment of heterogeneity Yes 

14 Description of statistical methods sufficient to replicate Yes 

15 Provision of appropriate tables and graphs Yes 

Reporting of Results 

16 Graphic summarizing of individual study estimates and overall Yes 

17 Tables giving descriptive information of each study included No 

18 Results of sensitivity testing (subgroup analysis) No 

19 Indication of statistical uncertainty of findings Yes 

20 Quantitative assessment of bias (eg. publication bias) No 

Overall quality C 

*When grading a systematic review, please skip item #14, 18-20 

Please fill the white areas only 

Evaluation of quality of a systematic review or meta-analysis Yes /No 

/Partially 

1 Is search strategy appropriate/relevant to the key question(s)? Unclear 

2 Did authors give justifications for inclusion/exclusion criteria pertaining to the studies of 

interest? 

No 

3 Were Population, Intervention/Exposure, Comparator/Control, Outcomes, and Study 

Designs well-defined? 

Yes 

4 Did authors attempt to minimize errors in data extraction (such as collecting the 

relevant data, double data extraction, verification of data extraction...etc.)? 

No 

5 Was individual study quality (such as sample size, study design, blinding, various 

biases and confounders, study subject attrition rate...etc.) assessed? 

No 

6 Did authors consider appropriate confounders and justification for adjusting or not 

adjusting for those confounders? 

No 

7 Was the justification for combining or not-combining data for meta-analysis, or the use 

of a particular analytic method or model appropriate? 

No 

8 Was heterogeneity explored (this is in addition to any statistical test of heterogeneity, 

did the authors look at the actual differences in PICOS, for example?)? 

No 

8 Were results reported accurately (eg, no discrepancies between text and tables)? Yes 

9 Were conclusions justified by the reported/collected data and analysis? Yes 

C-28
Evidence table for Systematic Reviews of Breastfeeding 

Author, Year[UI] Topic Davis, 1998 Leukemia 

Literature search (Dates) Medline (“over the past 10 to 15 years”); Other databases searched? (no); unpublished 

data used? (no) 

Countries where primary 

studies conducted 

Primarily developed countries: UK, USA, Italy 

Included one developing country: China 

For the purpose of our review, we excluded the study from China 

Study eligibility / inclusion 

criteria 

Not described, except the author stated that hypothesis of the study was that artificial 

infant feeding (or never breast fed) increases the risk for cancer in childhood. For the 

purpose of our review, we focus on childhood leukemia only. 

Study design [No. Of 

studies] 

Case-control studies [5] 

No. of subjects All leukemia [reported in 1 study]- Cases: 171 Controls: 342 

Acute lymphoblastic leukemia (ALL) [reported in all 5 studies]- Cases:1,356 Controls: 

1,336 

Acute non-lymphoblastic leukemia (ANLL) [reported in 2 studies]- Cases: 129 Controls: 

379 

Study population (definition 

in included studies) 

Cases: Children with all leukemia, ALL or ANLL 

Controls: Children with no cancers, except for one study used children with 

rhabdomyosarcoma as controls 

Intervention/Exposure 

(definition in included 

studies) 

Any breastfeeding 

Long-term breastfeeding: more than 6 to 8 months 

Comparator (definition in 

included studies) 

Artificial infant feeding (or never breast fed) 

Outcomes (definition in 

included studies) 

“All leukemia, ALL, and ANLL” 

Heterogeneity assessments ND 

Quality assessments ND 

Publication bias 

assessments 

ND 

Statistical Analysis or metaanalytic methods 

No meta-analysis was performed. 

The odds ratio and 95% CI or p values for the relationship between infant feeding and 

cancer in childhood were provided in the papers; in other cases where the number of 

exposed and unexposed cases and controls were provided, additional effect estimates 

were calculated in order to compare studies. 

Results None of the included studies reported a significant association between all leukemia, ALL 

or ANLL and infant feeding. 

Quality of the systematic 

review 

C 

Author’s interpretations of 

the results 

No evidence of an association between infant feeding and any childhood cancer except for 

Hodgkin’s disease. 

Comments / Limitations The main purpose of this review was to examine the association between infant feeding 

and childhood cancer. Due to non-significant findings for leukemia, the author did not focus 

on the results on leukemia. Inclusion or exclusion criteria were not described, no 

assessments of study heterogeneity or methodology quality. 

C-29
Author, yr: Davis, 1998 

Topic of the systematic review*/MA: Leukemia

Reporting yes/no 

Reporting of Background 

1 Description of study outcomes Yes 

2 Types of exposure or intervention used Yes 

3 Types of study designs used Yes 

4 Study population Yes 

Reporting of Search strategy 

5 Search strategy, including time period and key words No 

6 Effort to include all available studies (contact with authors) No 

7 Databases and registries searched Yes 

8 Method of addressing published articles other than English No 

9 Method of handling abstracts and unpublished studies No 

Reporting of Methods 

10 Rationale for selection and/or coding of data Yes 

11 Assessment of confounding No 

12 Assessment of quality No 

13 Assessment of heterogeneity No 

14 Description of statistical methods sufficient to replicate N/A 

15 Provision of appropriate tables and graphs Yes 

Reporting of Results 

16 Graphic summarizing of individual study estimates and overall No 

17 Tables giving descriptive information of each study included Yes 

18 Results of sensitivity testing (subgroup analysis) N/A 

19 Indication of statistical uncertainty of findings N/A 

20 Quantitative assessment of bias (eg. publication bias) N/A 

Overall quality C 

*When grading a systematic review, please skip item #14, 18-20 

Please fill the white areas only 

Evaluation of quality of a systematic review or meta-analysis Yes /No 

/Partially 

1 Is search strategy appropriate/relevant to the key question(s)? No 

2 Did authors give justifications for inclusion/exclusion criteria pertaining to the studies of 

interest? 

Yes 

3 Were Population, Intervention/Exposure, Comparator/Control, Outcomes, and Study 

Designs well-defined? 

Yes 

4 Did authors attempt to minimize errors in data extraction (such as collecting the 

relevant data, double data extraction, verification of data extraction...etc.)? 

No 

5 Was individual study quality (such as sample size, study design, blinding, various 

biases and confounders, study subject attrition rate...etc.) assessed? 

No 

6 Did authors consider appropriate confounders and justification for adjusting or not 

adjusting for those confounders? 

No 

7 Was the justification for combining or not-combining data for meta-analysis, or the use 

of a particular analytic method or model appropriate? 

N/A 

8 Was heterogeneity explored (this is in addition to any statistical test of heterogeneity, 

did the authors look at the actual differences in PICOS, for example?)? 

No 

8 Were results reported accurately (eg, no discrepancies between text and tables)? Yes 

9 Were conclusions justified by the reported/collected data and analysis? Partially 

C-30
Evidence table for Systematic Reviews of Breastfeeding

Author,Year[UI] Topic Guise, 2005 Leukemia 

Literature search (Dates) Medline (1990-March 2004); Other databases searched? (no); unpublished data used? (no) 

Countries where primary 

studies conducted 

Developed countries only: Netherlands, Italy, US, Germany, Australia, New Zealand, 

Canada, England, Wales, Scotland, Sweden, France 

Study eligibility / inclusion 

criteria 

Studies providing data regarding the association of breastfeeding and occurrence of 

childhood leukemia. A study must have been in full text, been published after 1990, 

contained more than 100 participants, had concurrent comparison groups, been conducted 

in a developed country, and been published in the English language. 

Study design [No. Of 

studies] 

Case-control studies [10] 

No. of subjects 9,653 leukemia cases 

Study population (definition 

in included studies) 

Cases: Childhood ALL or all childhood leukemias 

Controls: Matched or unmatched population (majority) and hospital controls 

Intervention/Exposure 

(definition in included 

studies) 

Any measures of breastfeeding 

Comparator (definition in 

included studies) 

Any 

Outcomes (definition in 

included studies) 

Childhood ALL or all childhood leukemias defined in the original studies 

Heterogeneity assessments ND 

Quality assessments 2 independent investigators rated study quality by using criteria from the US Preventive 

Services Task Force and the National Health Service Center for Reviews and 

Dissemination. Three levels of grade: good, fair and poor quality. Studies received a poor 

rating if the cases were not assessed reliably, if the groups assembled were not 

comparable, if there was considerable attrition or differences in nonrespondents between 

cases and controls, or if there was not adequate consideration given to confounding. 

Publication bias 

assessments 

ND 

Statistical Analysis or metaanalytic methods 

No meta-analysis or statistical analysis was performed. 

Results Ten studies met all inclusion criteria and were reviewed for study quality to identify 2 

good-quality case-control studies, 2 fair-quality studies, and 6 poor-quality studies. Of the 

10 studies, 6 were conducted in European countries. All studies but 1 focused solely on 

childhood leukemia. The majority included <1000 cases. Notably, 6 of the studies explicitly 

sought to characterize the relationship between breastfeeding and leukemia as the primary 

objective, whereas the others included breastfeeding measures from the perspective 

measuring broader characteristics of the immune system and early infections in the 

etiology. 

The presented results focus on details and findings of the 2 good-quality studies, 

comparisons to the 2 fair quality studies, factors that distinguish them from studies rated as 

“poor” in quality, and implications for future research. 

The 2 good-quality studies (UKCCS and CCG studies) present conflicting results 

regarding the association between breastfeeding and leukemia. Similarly, the 2 fair-quality 

studies disagreed on the protective effect of breastfeeding. 

Quality of the systematic 

review 

A 

Author’s interpretations of 

the results 

Of the 10 studies reviewed, only 4 were sufficient to provide at least fair-quality evidence 

regarding the association between maternal breastfeeding and childhood leukemia. Half of 

these 4 studies associated breastfeeding with a lower risk of ALL. Our review differs in 

methodology from previous meta-analyses performed by Beral et al and Kwan et al. Either 

of these groups examined studies for quality or used quality ratings as a determinate for 

C-31
Author,Year[UI] Topic Guise, 2005 Leukemia 

inclusion in analysis. 

The primary findings of our review indicate that there are few high-quality studies. The 

studies frequently failed to measure important factors such as breastfeeding exclusivity 

(reporting ever breastfed rather than quantifying breastfeeding by exclusivity combined with 

duration) and consideration of other important confounders such as SES and other 

infectious exposures (such as household or school contacts). None of the studies included 

in this systematic review ere without flaw. An optimal study might be conducted within the 

framework of a large population-based registry or cohort with full access to medical records, 

pathology, and demographic data that would be able to accurately identify all cases of ALL 

diagnosed (with pathologic confirmation) at >1 year of age within a defined time period. 

Comments / Limitations A meta-analysis by Beral, 2001 (or UKCCS investigators) seemed to have performed a 

comprehensive search, but they did not report the standard steps required for a systematic 

review, including explicit search criteria, inclusion and exclusion criteria, and quality 

assessment. This meta-analysis included 15 studies. Of these 15 studies, 8 were also 

included in Guise, 2005. Four were excluded because they were published before 1990, 

and 3 were conducted in developing countries. 

Guise, 2005 (10 studies included) and Kwan, 2004 (14 studies included) had same set of 

studies, except that Guise excluded studies published before1990, and in developing 

countries. Guise, 2005 did not include non-peer-reviewed studies. 

Guise et al. discussed the differences between their review and previous meta-analyses by 

UKCCS investigators and Guise, 2005 in details. We thought their comments were fair. 

It would have been preferable if meta-analyses by taking into account study quality grading 

were also performed. 

C-32
Author, yr: Guise, 2005 

Topic of the systematic review*/MA: Leukemia

Reporting yes/no 

Reporting of Background 

1 Description of study outcomes Yes 

2 Types of exposure or intervention used Yes 

3 Types of study designs used Yes 

4 Study population Yes 

Reporting of Search strategy 

5 Search strategy, including time period and key words Yes 

6 Effort to include all available studies (contact with authors) No 

7 Databases and registries searched Yes 

8 Method of addressing published articles other than English No 

9 Method of handling abstracts and unpublished studies No 

Reporting of Methods 

10 Rationale for selection and/or coding of data Yes 

11 Assessment of confounding Yes 

12 Assessment of quality Yes 

13 Assessment of heterogeneity N/A 

14 Description of statistical methods sufficient to replicate N/A 

15 Provision of appropriate tables and graphs Yes 

Reporting of Results 

16 Graphic summarizing of individual study estimates and overall No 

17 Tables giving descriptive information of each study included Yes 

18 Results of sensitivity testing (subgroup analysis) N/A 

19 Indication of statistical uncertainty of findings N/A 

20 Quantitative assessment of bias (eg. publication bias) N/A 

Overall quality A 

*When grading a systematic review, please skip item #14, 18-20 

Please fill the white areas only 

Evaluation of quality of a systematic review or meta-analysis Yes /No 

/Partially 

1 Is search strategy appropriate/relevant to the key question(s)? Yes 

2 Did authors give justifications for inclusion/exclusion criteria pertaining to the studies of 

interest? 

Yes 

3 Were Population, Intervention/Exposure, Comparator/Control, Outcomes, and Study 

Designs well-defined? 

Yes 

4 Did authors attempt to minimize errors in data extraction (such as collecting the 

relevant data, double data extraction, verification of data extraction...etc.)? 

Yes 

5 Was individual study quality (such as sample size, study design, blinding, various 

biases and confounders, study subject attrition rate...etc.) assessed? 

Yes 

6 Did authors consider appropriate confounders and justification for adjusting or not 

adjusting for those confounders? 

Yes 

7 Was the justification for combining or not-combining data for meta-analysis, or the use 

of a particular analytic method or model appropriate? 

No 

8 Was heterogeneity explored (this is in addition to any statistical test of heterogeneity, 

did the authors look at the actual differences in PICOS, for example?)? 

Yes 

8 Were results reported accurately (eg, no discrepancies between text and tables)? Yes 

9 Were conclusions justified by the reported/collected data and analysis? Partially 

C-33
Evidence table for Systematic Reviews of Breastfeeding

Author, 

Year[UI] 

Topic Kwan, 2004 Leukemia 

Literature search (Dates) Medline (up to 2003); Other databases searched? (yes); unpublished data used? (yes) 

Countries where primary 

studies conducted 

Mostly developed countries: Netherlands, Italy, US, Germany, Australia, New Zealand, 

Canada, England, Wales, Scotland, Sweden, France 

2 developing countries: China, Russia, 

Study eligibility / inclusion 

criteria 

Studies that presented data on any type of leukemia on children 15 years or younger in terms 

of an odds ratio and confidence interval and analyzed duration of breastfeeding in months 

were selected for the analysis. 

Study design [No. Of 

studies] 

Case-control studies [n=14] 

*Note 12 studies in developed countries. Since this is a meta-analysis article, we could not 

separate these 12 studies. Three of the 14 studies were not peer-reviewed. 

No. of subjects 6,835 ALL cases and 1,216 acute myeloid leukemia (AML), which included ANLL 

Study population 

(definition in included 

studies) 

Eight of the 14 studies excluded cases of leukemia in infants (usually children younger than 1 

year of age) to avoid possible biases associated with premature cessation of breastfeeding in 

children with cancer and also because most leukemias occurring during infancy are know to 

have different etiologies from childhood leukemias. 

Intervention/Exposure 

(definition in included 

studies) 

Short-term breastfeeding, defined as breastfeeding for six months or less 

Long-term breastfeeding, defined as breastfeeding for more than six months 

Comparator (definition in 

included studies) 

No breastfeeding or never been breast-fed 

Outcomes (definition in 

included studies) 

The ALL classification was generally straightforward, with only one study specifying “leukemia” 

instead of “ALL”. 

Four studies used the classifications “other leukemias” or ANLL instead of AML. Nevertheless, 

they were included in the AML group since the majority of such cases are AML cases. 

Heterogeneity 

assessments 

Chi-square statistic 

Quality assessments ND, although there are comments on the potential biases for each included study in the 

summary tables 

Publication bias 

assessments 

Funnel plot 

Statistical Analysis or 

meta-analytic methods 

Fixed- and random-effect models. 

For each of the 14 articles reviewed, and R and its 95% CI were extracted. When available, 

ORs adjusted for SES were selected since SES was the most widely used potential 

confounder in these studies. 

Results • No evidence of publication bias was apparent for studies reporting results on the 

association between long-term breastfeeding and risk of ALL (p=0.58) or AML (p=0.46). 

• A significant negative association was observed between short-term breastfeeding and 

ALL (OR=0.88, 95%CI 0.80-0.96), but the AML results (OR=0.90, 95%CI 0.80-1.02) were 

not significant. 

• A significant negative association was observed between long-term breastfeeding and 

ALL (OR=0.76, 95%CI 0.68-0.84), and AML (OR=0.85, 95%CI 0.73-0.98). 

• Heterogeneity statistics for leukemia types and duration of breastfeeding were not 

significant except for the ALL analysis addressing short-term breastfeeding (p=0.03). 

However, the results from fixed- and random-effect models were almost exactly the 

same. 

• The following table (modified from table 4 in the original table) shows the ORs for SESadjusted data from the meta-analysis , as well as separately from the United Kingdom 

Childhood Cancer study (UKCCS) and the Children’s Cancer Group (CCG) study. 

Overall, SES as a potential confounder appeared to play no substantial role in the 

findings of either the short-term or long-term breastfeeding studies. 

C-34
Author, 

Year[UI] 

Topic Kwan, 2004 Leukemia 

Duration of breastfeeding OR (95% CI) 

ALL AML 

Meta-analysis N=6470 (85%) N=1179 (15%) 

 ≤6 months 0.90 (0.82, 0.99) 0.91 (0.80, 1.04) 

 >6 months 0.75 (0.67, 0.85) 0.85 (0.73, 0.98) 

UKCCS 2001 N=1401 (87%) N=214 (13%) 

 ≤6 months 0.90 (0.77, 1.04) 0.85 (0.60, 1.20) 

 >6 months 0.89 (0.75, 1.05) 0.65 (0.43, 1.00) 

CCG study 1999 N=1744 (79%) N=456 (21%) 

 ≤6 months 0.86 (0.73, 1.01) 0.95 (0.68, 1.33) 

 >6 months 0.72 (0.60, 0.87) 0.57 (0.39, 0.84) 

Quality of the systematic 

review 

A 

Author’s interpretations of 

the results 

This meta-analysis demonstrated protective association between breastfeeding and risk of 

childhood ALL and possibly AML. However, three alternative explanations must be considered 

First, a systematic bias may be present in case-control studies of childhood leukemia arising 

from differential participation rates for case and control samples that differed in SES. In the 

current meta-analysis, participation rates could be calculated for only six of the 14 included 

studies. For five of these six studies, the participation rates for cases were higher than those 

for controls, and in most of these studies, the controls were higher SES than the cases. 

Therefore the association of breastfeeding with SES in combination with differential 

participation rates by SES could have biased the OR toward a protective effect. Second, the 

effect on ALL risk may be spurious, as suggested by the results of the two cohort studies 

(Ref#22 and 23), unfortunately, these studies provided no information regarding AML. Third, 

the protective effect of breastfeeding may not be limited to ALL. Further evaluation of the 

biological mechanisms while taking into consideration potential biases can be feasibly 

achieved with more large-scale case-control studies utilizing population-based, SES-matched 

controls. 

In conclusion, the potential protective effect of breastfeeding on risk of childhood ALL may be 

more complicated than the current literature suggests. Nevertheless, the available evidence 

suggests that such a protective effect exists for both ALL and AML, with the caveats noted. 

Comments / Limitations We agree with authors’ concerns regarding potential biases in the included studies. Their 

conclusion was appropriately cautious. However, the review still combined all studies 

regardless of these potential biases, and over-emphasized the importance of the results from 

the meta-analysis. We could not determine whether specific study should be included in the 

analyses. Perhaps combining results from only high-quality studies would be preferable, but 

unfortunately the review did not appraise the methodological quality of the primary studies. 

C-35
Author, yr: Kwan, 2004 

Topic of the systematic review*/MA: Leukemia

Reporting yes/no 

Reporting of Background 

1 Description of study outcomes Yes 

2 Types of exposure or intervention used Yes 

3 Types of study designs used Yes 

4 Study population Yes 

Reporting of Search strategy 

5 Search strategy, including time period and key words Yes 

6 Effort to include all available studies (contact with authors) Yes 

7 Databases and registries searched Yes 

8 Method of addressing published articles other than English No 

9 Method of handling abstracts and unpublished studies Yes 

Reporting of Methods 

10 Rationale for selection and/or coding of data Yes 

11 Assessment of confounding Yes 

12 Assessment of quality Yes 

13 Assessment of heterogeneity Yes 

14 Description of statistical methods sufficient to replicate Yes 

15 Provision of appropriate tables and graphs Yes 

Reporting of Results 

16 Graphic summarizing of individual study estimates and overall Yes 

17 Tables giving descriptive information of each study included Yes 

18 Results of sensitivity testing (subgroup analysis) Yes 

19 Indication of statistical uncertainty of findings Yes 

20 Quantitative assessment of bias (eg. publication bias) Yes 

Overall quality A 

*When grading a systematic review, please skip item #14, 18-20 

Please fill the white areas only 

Evaluation of quality of a systematic review or meta-analysis Yes /No 

/Partially 

1 Is search strategy appropriate/relevant to the key question(s)? Yes 

2 Did authors give justifications for inclusion/exclusion criteria pertaining to the studies of 

interest? 

Yes 

3 Were Population, Intervention/Exposure, Comparator/Control, Outcomes, and Study 

Designs well-defined? 

Yes 

4 Did authors attempt to minimize errors in data extraction (such as collecting the 

relevant data, double data extraction, verification of data extraction...etc.)? 

No 

5 Was individual study quality (such as sample size, study design, blinding, various 

biases and confounders, study subject attrition rate...etc.) assessed? 

Yes 

6 Did authors consider appropriate confounders and justification for adjusting or not 

adjusting for those confounders? 

Yes 

7 Was the justification for combining or not-combining data for meta-analysis, or the use 

of a particular analytic method or model appropriate? 

Yes 

8 Was heterogeneity explored (this is in addition to any statistical test of heterogeneity, 

did the authors look at the actual differences in PICOS, for example?)? 

Yes 

8 Were results reported accurately (eg, no discrepancies between text and tables)? Yes 

9 Were conclusions justified by the reported/collected data and analysis? Yes 

C-36
Appendix C. Evidence Tables 

Part I. Term Infant Outcomes 

Cognitive 

Agostoni 2001 

Anderson 1999 SRMA* 

Angelsen 2001 

Der 2006 

Drane 2000 SRMA* 

GomezSanchiz 2003 2004 

Jain 2002 SRMA* 

Lawlor 2006 

Mortensen 2002 

Oddy 2003 2004 

Quinn 2001

* Systematic Review/Meta-Analysis

C-37
Agostoni, 2001 [11787675] 

Study 

characteristics Study design and follow-up duration Eligibility criteria Breastfeeding Exposures or Interventions 

Mean GA (range): term Mean BW (range): % Male: 55% Race: Enrolled/Evaluate: 44/44 Location: Italy Sites: Single/Multi Funding: 

Prospective cohort; Bayley results at 1 y/o were compared in breastfeeding ≥6 mo with 3-6 mo 

Term infants; exclusively breastfed ≥3 mo 

Agostoni, 2001 [11787675] 

Outcome Definition Statistical analyses and confounders adjusted Results 

Cognitive outcome of interest: Bayley Mental Development Index (MDI) 

Adjustment for parity, maternal education, age, and smoking habits 

After adjustment, Bayley MDI in 29 subjects breastfed >6 mo compared to 15 subjects breastfed 3-6 mo showed a 2.0 point advantage (95% CI –3.2, 7.3). 

A: strmode

SelecStudy ConfBlindData WithddropoAnalyIntervinteg

OveraSmall age

C-38
Evidence table for Systematic Reviews 

Author, Year[UI] Topic Anderson, 1999 [UI] Cognitive Development 

Systematic reviews/Metaanalyses/Both 

Meta-analysis 

Databases searched (Dates of 

literature search)

Medline (1966-1996); references identified in bibliographies. 

Countries where primary studies 

conducted (Developed countries 

only or mixed) 

Developed countries only: UK, US, Australia, Germany, New Zealand, and Spain 

Study design [No. of studies] Observational (n=11) 

No. of subjects 7,081 

Study population and sampling • Studies of association between breastfeeding and cognitive development in 

full-term and low-birth weight infants (?premature) 

Intervention/Exposure 

Comparator 

Many of the studies that were reviewed only reported breastfeeding versus bottle 

feeding, without more detailed information on exclusivity, frequency, or duration. 

Information on timing and duration of breastfeeding were included where available. 

Outcomes • 

Methods used for meta-analyses Both fixed effects and random effects were calculated 

Heterogeneity assessments See below 

Results • Unadjusted (fixed effects) pooled mean difference for the 11 observations was 

5.32 (95% CI, 4.51, 6.14); heterogeneous across studies 

• Adjusted (fixed effects) pooled mean difference was 3.16 (95% CI, 2.35, 3.98); 

homogeneous across studies 

• An average adjusted benefit of 5.18 points was obtained for low-birth weight 

children across 6 available observations 

Authors’ conclusions After adjustment for key cofactors, breast-feeding was associated with significantly 

higher scores for cognitive development than was formula feeding 

Quality of the systematic review B 

Comments No appraisals of study quality (other than confounding); effect score is a 

standardized mean difference score of different cognitive measurements 

C-39
Author, yr: Anderson, 1999 

Topic of the systematic review*/MA: Cognitive SR

Reporting yes/no 

Reporting of Background 

1 Description of study outcomes Y 

2 Types of exposure or intervention used Y 

3 Types of study designs used Y 

4 Study population Y 

Reporting of Search strategy 

5 Search strategy, including time period and key words Y/N 

6 Effort to include all available studies (contact with authors) N 

7 Databases and registries searched Y 

8 Method of addressing published articles other than English N 

9 Method of handling abstracts and unpublished studies N 

Reporting of Methods 

10 Rationale for selection and/or coding of data Y 

11 Assessment of confounding Y 

12 Assessment of quality (in addition to confounding) N 

13 Assessment of heterogeneity Y 

14 Description of statistical methods sufficient to replicate Y 

15 Provision of appropriate tables and graphs Y 

Reporting of Results 

16 Graphic summarizing of individual study estimates and overall Y 

17 Tables giving descriptive information of each study included Y 

18 Results of sensitivity testing (subgroup analysis) Y 

19 Indication of statistical uncertainty of findings Y 

20 Quantitative assessment of bias (eg. publication bias) N 

Overall quality 

*When grading a systematic review, please skip item #14, 18-20 

Please fill the white areas only 

Evaluation of quality of a systematic review or meta-analysis Yes /No 

/Partially 

1 Is search strategy appropriate/relevant to the key question(s)? Y 

2 Did authors give justifications for inclusion/exclusion criteria pertaining to the studies of 

interest? 

Y 

3 Were Population, Intervention/Exposure, Comparator/Control, Outcomes, and Study 

Designs well-defined? 

Y/N 

4 Did authors attempt to minimize errors in data extraction (such as collecting the 

relevant data, double data extraction, verification of data extraction...etc.)? 

N 

5 Was individual study quality (such as sample size, study design, blinding, various 

biases and confounders, study subject attrition rate...etc.) assessed? 

N 

6 Did authors consider appropriate confounders and justification for adjusting or not 

adjusting for those confounders? 

Y/N 

7 Was the justification for combining or not-combining data for meta-analysis, or the use 

of a particular analytic method or model appropriate? 

Y 

8 Was heterogeneity explored (this is in addition to any statistical test of heterogeneity, 

did the authors look at the actual differences in PICOS, for example?)? 

Y 

8 Were results reported accurately (eg, no discrepancies between text and tables)? Y 

9 Were conclusions justified by the reported/collected data and analysis? Y 

C-40
Angelsen, 2001 [11517096] 

Study characteristics Study design and follow-up duration Eligibility criteria Breastfeeding Exposures or Interventions 

Mean GA (range): 39.6 wk Mean BW (range): 3656 g % Male: Race: white Enrolled/Evaluate: 521/345/291 (5 yr) Location: Norway & Sweden Sites: Multi Funding: 

Prospective cohort; 10% randomly selected from eligible population; Duration of breastfeeding: retrospectively recorded 

White, parity 1 or 2, singleton, registered prior to 20th wk gestation Excluded: <37 wk gestation, congenital malformation 

<3 mo, 3-6 mo, 

≥ 6 mo 

Angelsen, 2001 [11517096] 

Outcome 

Definition 

Statistical analyses 

and confounders 

adjusted 

Results 

Cognitive outcomes of interest: Bayley mental scores at 13 mo Wechsler Preschool and Primary Scales of Intelligence (WPPSI-R) at 5 y/o 

Maternal IQ, age, education, smoking 

Bayley mental score at 13 mo: 117.7 (SD11.7) in 

≥ 6 mo breastfeeding compared to 109.9 

(SD13.1) in < 3 mo (P<0.001). There was a linear increase in mental development index plotted against breastfeeding duration (P<0.001). Maternal intelligence (Raven test score) was also related to duration of breastfeeding. Adjustment for differences in maternal intelligence reduced the OR of having a low mental developmental index among children who were breast fed for <3 mo to 1.6 (95%CI 1.1-2.3) from 3.2 (95%CI 1.7-5.9). Total IQ at 5 y/o: 111 (SD14.3) in 

≥ 6 mo breastfeeding compared to 103.6 (SD14.6) in < 3 

mo (P<0.001, Sheffe’s test). Adjustment for differences in maternal intelligence reduced the OR of having a low IQ score among children who were breastfed for <3 mo to 1.5 (95%CI 1.0-2.1) from 2.8 (95%CI 1.4-5.3). 

A: strmode

SelecStudy ConfoBlindData WithddropoAnalyIntervintegr

OveralResults not rep

C-41
Der, 2006 UI 17020911 

Study characteristics Study design and follow-up duration Eligibility criteria Breastfeed

Exposures 

Interventio

Mean GA (range): term Mean BW (range): % Male: Race: Enrolled/Evaluate: 3161 mothers and 5475 children Location: US Sites: Multi Funding: 

Database analysis of a prospective study; sibling pairs analysis, and metaanalysis; Database from the US national longitudinal survey of youth 1979 (NLSY79) and children of the women in the survey, Peabody individual achievement test (PIAT) was administered to children between the ages of 5 and 14 biennially from 1986 to 2002, all outcomes standardized to a mean of 100 and SD of 15; maternal cognitive ability was measured with the Armed Forces Qualification Test (AFQT); For meta-analysis, only included studies that quantified the effect of breastfeeding status on cognitive ability after controlling for parental intelligence among full term infants (Medline 1966 to 1/2006 and other sources) 

Excluded <35 wk gestation, <2500 g, born before 1979 

Breastfeeding hobtained within of birth in most c

Der, 2006 

Outcome Definition Statistical analyses and confounders adjusted Results 

Cognitive outcome of interest: Peabody individual achievement test 

Adjustment for variables associated with breastfeeding in the survey, home environment (HOME-SF), child demographics, maternal characteristics 

Unadjusted effect of breastfeeding +4.7 compared to nonbreastfeeding (3161 mothers, 5475 children, 16,744 assessments); after adjustment for maternal AFQT score, education, age, family poverty, HOME stimulation score, and birth order, the difference became +0.52 (P=0.149) 332 pairs of sibling discordant for breastfeeding status and 545 discordant for duration of breastfeeding, difference between groups (status) = -0.63 (P=0.506); (duration) = -0.13 (P=0.866) Meta-regression of 9 unique studies (including the data from NLSY79): an advantage of breastfeeding of 0.16 after controlling for IQ and 8 additional confounders. Combined data from NLSY79 and sibling analysis study by Evenhouse (see separate extraction): estimate 0.025 (P=0.54) for breastfeeding status and 0.04 (P=0.271) for duration of breastfeeding 

Amw

SSCBDWdrAInin

Ov

No bre

C-42
Domain/question Place an “X” 

Selection Bias Are individuals selected to participate likely to be representative of target population? Very 

likely 

Somewhat likely 

l

What % of selected individuals agreed to participate? 80-100 60-79 Allocation Bias (RCTs only, for quasi-experimental, case-control/before/after, no control group or other skip to “Confounders”) Is the method of random allocation stated Yes No If the method of random allocation is stated, is it appropriate Yes No Was the method of random allocation reported as concealed? Yes No Confounders Prior to the intervention, were there between group differences for important confounders reported in the paper? 

Yes No Ca

If there were differences between groups for important confounders, were they adequately managed in the 

analysis? 

Yes No 

Were there important confounders NOT reported in the paper (describe above under quality score)? Yes No Blinding Was (were) the outcome assessor(s) blinded to the intervention or exposure status of the participants? Yes No Data Collection methods Were data collection tools shown or are they known to be valid? Yes No Were data collection tools shown or are they known to be reliable? Yes No Withdrawals and Dropouts Indicate the % of participants completing the study. (If the % differs by groups, record the lowest). 80-100 60-79 Analysis Is there a sample size calculation or power calculation Yes Partially Is there a statistically significant difference between groups? Yes No Are the statistical methods appropriate? Yes No Indicate the unit of allocation Communit

y 

Organization/group Pr

Indicate the unit of analysis Communit

y 

Organization/group Pr

If the unit of allocation and analysis differed, was the cluster analysis done? Yes No Is the analysis performed by intervention allocation status (i.e. intention to treat) rather than the actual intervention received? 

Yes No Ca

Intervention Integrity What % of participants received the allocated intervention or exposure of interest? 80-100 60-79 Was the consistency of the intervention measured (i.e. intervention was provided to all participants in the same way)? 

Yes No 

Is it likely that subjects received an unintended intervention (contamination or cointervention) that may influence the results? 

Yes No Ca

C-43
Evidence table for Systematic Reviews of Breastfeeding 

Author,Year[UI] Topic Drane 2000 Cognitive Development 

Literature search (Dates) Database not specified; literature search from 1966-98 

Countries where primary 

studies conducted 

Study eligibility / inclusion 

criteria 

Subjects born between 1960 and 1998, English language, studies examined some aspect 

of cognitive development 

Study design [No. Of 

studies] 

Studies were assessed to determine if they met 3 methodological standards: definition of 

outcome: operational definition of cognitive outcome and outcome measure using 

standardized tests; correct classification of type of feeding: measure breast feeding as a 

continuous variable (duration of exclusive breast feeding or proportion of diet as breast milk) 

or at least as a 3-level categorical variable (exclusive breast or formula fed; partial breast 

fed); and control for potential confounding variables: socio-economic status, maternal 

education, birth weight, gestational age, birth order, gender in studies measuring verbal 

ability 

No. of subjects 

Study population (definition 

in included studies) 

Term and preterm infants 

Intervention/Exposure 

(definition in included 

studies) 

Comparator (definition in 

included studies) 

Outcomes (definition in 

included studies) 

Heterogeneity assessments 

Quality assessments 

Publication bias 

assessments 

Statistical Analysis or metaanalytic methods 

Results 24/30 studies met entry criteria. 5 studies met the 3 methodological standards. 

Lucas 1992, Lucas 1994, Horwood 1998, Malloy 1998; Rogan 1993 (considered to have 

met 2.5 standards because the duration that a baby was mostly breast fed was measured) 

Lucas 1994 was a RCT, the remaining 5 studies were cohorts. 

Advantages in IQ as measured by the WISC-R, Bayley and McCarthy Scales were 

observed in Lucas 1992, Rogan 1993, Pollock 1994, and Horwood 1998. 

In term infants, effects on IQ in the range of 2-5 points (0.2-0.3 SD) were found. 

In low birth weight infants who received breast milk, Lucas 1992 reported an 8 IQ point 

advantage. 

Lucas 1994 did not find statistical significant difference in Bayley Mental Development Scale 

scores in infants fed solely on a diet of donor breast milk compared with infants fed solely 

on a diet of term formula. Malloy 1998 did not find an effect of infant feeding on WISC-R 

scores at 9-10 years of age in term infants. 

Quality of the systematic 

review 

B 

Author’s interpretations of 

the results 

“The question of whether breast feeding and formula feeding have differential effects on 

cognitive development has not been comprehensively answered. A minority of the studies 

reviewed met acceptable standards for validity and, thus, are likely to provide inaccurate 

estimates of the association between infant feeding and cognitive development.” 

Comments / Limitations The methodological standards proposed may not be universally accepted. Study designs 

were not taken into consideration. Conclusions are also limited by the fact that almost all the 

studies were cohorts. 

C-44
Author, yr: Drane, 2000 

Topic of the systematic review*/MA: cognitive

Reporting yes/no 

Reporting of Background 

1 Description of study outcomes Y 

2 Types of exposure or intervention used Y 

3 Types of study designs used Y 

4 Study population Y 

Reporting of Search strategy 

5 Search strategy, including time period and key words Y 

6 Effort to include all available studies (contact with authors) N 

7 Databases and registries searched N 

8 Method of addressing published articles other than English N 

9 Method of handling abstracts and unpublished studies N 

Reporting of Methods 

10 Rationale for selection and/or coding of data Y 

11 Assessment of confounding Y 

12 Assessment of quality Y 

13 Assessment of heterogeneity Y/N 

14 Description of statistical methods sufficient to replicate N/A 

15 Provision of appropriate tables and graphs Y 

Reporting of Results 

16 Graphic summarizing of individual study estimates and overall Y 

17 Tables giving descriptive information of each study included Y/N 

18 Results of sensitivity testing (subgroup analysis) N/A 

19 Indication of statistical uncertainty of findings N/A 

20 Quantitative assessment of bias (eg. publication bias) N/A 

Overall quality 

*When grading a systematic review, please skip item #14, 18-20 

Please fill the white areas only 

Evaluation of quality of a systematic review or meta-analysis Yes /No 

/Partially 

1 Is search strategy appropriate/relevant to the key question(s)? Y/N 

2 Did authors give justifications for inclusion/exclusion criteria pertaining to the studies of 

interest? 

Y 

3 Were Population, Intervention/Exposure, Comparator/Control, Outcomes, and Study 

Designs well-defined? 

Y 

4 Did authors attempt to minimize errors in data extraction (such as collecting the 

relevant data, double data extraction, verification of data extraction...etc.)? 

N 

5 Was individual study quality (such as sample size, study design, blinding, various 

biases and confounders, study subject attrition rate...etc.) assessed? 

Y/N 

6 Did authors consider appropriate confounders and justification for adjusting or not 

adjusting for those confounders? 

Y 

7 Was the justification for combining or not-combining data for meta-analysis, or the use 

of a particular analytic method or model appropriate? 

Y 

8 Was heterogeneity explored (this is in addition to any statistical test of heterogeneity, 

did the authors look at the actual differences in PICOS, for example?)? 

Y/N 

8 Were results reported accurately (eg, no discrepancies between text and tables)? Y 

9 Were conclusions justified by the reported/collected data and analysis? Y 

C-45
GomezSanchiz, 2003 [12635980] 

GomezSanchiz, 2004 [15494884] 

Study 

characteristics Study design and follow-up duration Eligibility criteria 

Breastfeed

Exposures 

Interventio

Mean GA (range): 39.6 wk Mean BW (range): 3344 g % Male: Race: Enrolled/Evaluate: 296/249 at 18 mo; 238 at 24 mo Location: Spain Sites: 1 rural, 1 urban Funding: 

Prospective cohort from 1 rural (born 10/1995-9/1997) and 1 urban (born 3/1996-2/1998) sites, comparing breastfed > 4 mo, <4 mo, and formula fed; parents were informed of the project at 15 mo, Bayley was administered at 18 mo and 24 mo 

37-42 wk gestation, Apgar at 5 minutes 

≥7, 

birthweight 2500-4500 g; Exclusion: multiple births, adopted babies, mechanical ventilation, hospitalization during the neonatal period, major physical malformation, chromosome disorder, psychosocial risks or any circumstances likely to result in “retarded development”, height or weight <3%tile at 18 mo 

Information abouand duration of fwas taken from records 

GomezSanchiz, 2003 [12635980] GomezSanchiz, 2004 [15494884] 

Outcome 

Definition 

Statistical analyses 

and confounders 

adjusted 

Results 

Cognitive outcome of interest: Bayley Mental Development index 

Adjusted for parental IQ 

249/296 completed the study at 18 mo; 238 completed the study at 24 mo; the only difference between children taking part in the study and those not taking part was that the latter were less frequently first in birth order. Parental IQ was obtained only for 164 couples; their children had Mental Development Index 2.3 points higher than the children whose parents did not take part in IQ testing (P<0.05). Infants were breastfed for a mean of 85.7 days 

± SD 76.4 days. Duration of 

breastfeeding had a correlation with Mental Development Index at 18 mo (r=0.42; P<0.001) and at 24 mo (r=0.37; P<0.001). 

 Mental Development Index at 18 mo Formula 106.0±9.2 Breastfeeding 

≤ 4 mo 111.5±9.6 

Breastfeeding > 4 mo 118.2±8.9 P<0.05 by Bonferroni in all post hoc pair comparisons At both 18 mo and 24 mo, after multiple linear regression adjusting for parental IQ, difference between formula and breastfeeding 

≤ 4 mo no longer significant; difference of 4.3 points remained 

significant when comparing breastfeeding > 4 mo with 

≤ 4 mo. 

Amw

SSCBDWdAInin

Ov

C-46
Domain/question Place an “X” 

Selection Bias Are individuals selected to participate likely to be representative of target population? Very 

likely 

Somewhat likely 

l

What % of selected individuals agreed to participate? 80-100 60-79 Allocation Bias (RCTs only, for quasi-experimental, case-control/before/after, no control group or other skip to “Confounders”) Is the method of random allocation stated Yes No If the method of random allocation is stated, is it appropriate Yes No Was the method of random allocation reported as concealed? Yes No Confounders Prior to the intervention, were there between group differences for important confounders reported in the paper? 

Yes No Ca

If there were differences between groups for important confounders, were they adequately managed in the 

analysis? 

Yes No 

Were there important confounders NOT reported in the paper (describe above under quality score)? Yes No Blinding Was (were) the outcome assessor(s) blinded to the intervention or exposure status of the participants? Yes No Data Collection methods Were data collection tools shown or are they known to be valid? Yes No Were data collection tools shown or are they known to be reliable? Yes No Withdrawals and Dropouts Indicate the % of participants completing the study. (If the % differs by groups, record the lowest). 80-100 60-79 Analysis Is there a sample size calculation or power calculation Yes Partially Is there a statistically significant difference between groups? Yes No Are the statistical methods appropriate? Yes No Indicate the unit of allocation Communit

y 

Organization/group Pr

Indicate the unit of analysis Communit

y 

Organization/group Pr

If the unit of allocation and analysis differed, was the cluster analysis done? Yes No Is the analysis performed by intervention allocation status (i.e. intention to treat) rather than the actual intervention received? 

Yes No Ca

Intervention Integrity What % of participants received the allocated intervention or exposure of interest? 80-100 60-79 Was the consistency of the intervention measured (i.e. intervention was provided to all participants in the same way)? 

Yes No 

Is it likely that subjects received an unintended intervention (contamination or cointervention) that may influence the results? 

Yes No Ca

C-47
Evidence table for Systematic Reviews of Breastfeeding 

Author, 

Year[UI] 

Topic Jain, 2002 Cognitive Development

Literature search (Dates) Medline (1996-2/2001); Other databases searched? (no); unpublished data used? (no) 

Countries where primary 

studies conducted 

Study eligibility / inclusion 

criteria 

English language studies; independently assessed the relationship between breastfeeding 

and a cognitive outcome; tests of motor ability alone were not included 

Study design [No. Of 

studies] 

30 birth cohorts; 2 RCTs; 5 school registry cohorts; 3 case-control studies 

No. of subjects Ranged from 50 to >11,000 

Study population 

(definition in included 

studies) 

Term and pre-term children 

Intervention/Exposure 

(definition in included 

studies) 

Breastfeeding, breast milk, or choice to breast feed 

Comparator (definition in 

included studies) 

Outcomes (definition in 

included studies) 

Appropriate outcome: standardized individual measure of general intelligence and that the 

assessment be done when the child was at least 2 years of age 

Heterogeneity 

assessments 

Quality assessments Following were examined for each article: overall design of the study, sample size, target 

population, quality of feeding data, control of susceptibility bias, blinding, outcome measures, 

and format of results 

Publication bias 

assessments 

Statistical Analysis or 

meta-analytic methods 

Results 40 studies from 1929 to 2/2001 were included in this review 

1. 40 separate papers were published. Because some of these papers investigated 

the same sample, there were only studies of 33 different groups of children. 

2. 30 cohorts (27 with full-term children), 2 RCTs in preterm children, 5 school registry 

cohorts, and 3 case-control studies. 

3. 35 articles either studied mixed full-term and preterm infants, only full-term infants, 

or did not specify the gestational age or birth weight. 5 articles studied exclusively 

low birth weight infants. 

4. Sample size ranged from 50 to >11,000 

5. Quality of feeding data (exclusive breastfeeding or not, timing of feeding data 

collection, source of feeding data, duration of breastfeeding): 9 articles met all 4 

criteria (8 full-term cohorts); 15 articles did not adequately define breastfeeding by 

failing to report whether infants only received breast milk or were supplemented 

with formula or food. 2 preterm observational birth cohorts did not meet standard for 

appropriate definition of breastfeeding, it was defined as the “intent to breastfeed.” 

21 studies did not meet the standard for timing of data collection because the 

information was obtained either too late or too early. 27 included a feeding group for 

whom breastfeeding duration was at least 1 month. 

6. 9 studies controlled adequately for both socioeconomic status and level of 

stimulation of the child; 31 studies controlled for socioeconomic status. 

7. 15 studies stated that observers of the outcome were blind to feeding status. 

8. 22 studies used an appropriate measure of cognition. Of the remaining studies, 8 

measured outcomes in children <2 years of age, 3 used screening measures to 

C-48
Author, 

Year[UI] 

Topic Jain, 2002 Cognitive Development

assess cognition, 1 case control study used the presence of a learning disorder as 

its outcome measure, the other 2 case control studies used the diagnoses of 

pervasive developmental disorder and infantile autism, respectively, as outcome 

measures. 

9. 33 studies reported some way to interpret the clinical significance of results, and 21 

allowed calculation of an effect size. 

10. 7 studies that found that the effects of breastfeeding statistically significant in the 

unadjusted analysis, became insignificant when controlling for socioeconomic 

status, stimulation, or other factors. 

11. Only 2 studies met all the methodological standards. One study concluded that “any 

beneficial effect of breastfeeding on cognitive development is quite small in 

magnitude”, another study found that children who were breastfed had mean IQ 

scores 4.6 points higher than those never breastfed after controlling for 

socioeconomic status and other factors. Among the studies that controlled for 

socioeconomic status and stimulation/interaction of the child (not including the 

previous 2), 3 concluded that breastfeeding promotes cognitive development, and 4 

did not. 

Quality of the systematic 

review 

A 

Author’s interpretations of 

the results 

“No convincing evidence exists regarding he comparative effects of breastfeeding and 

artificial feeding on intelligence.” 

Comments / Limitations Selection of methodological standards may not be acceptable to all investigators. 

Author, yr: Jain, 2002 

Topic of the systematic review*/MA: cognitive

Reporting yes/no 

Reporting of Background 

1 Description of study outcomes Y 

2 Types of exposure or intervention used Y 

3 Types of study designs used Y 

4 Study population Y 

Reporting of Search strategy 

5 Search strategy, including time period and key words Y 

6 Effort to include all available studies (contact with authors) N 

7 Databases and registries searched Y 

8 Method of addressing published articles other than English Y 

9 Method of handling abstracts and unpublished studies N 

Reporting of Methods 

10 Rationale for selection and/or coding of data Y 

11 Assessment of confounding Y 

12 Assessment of quality Y 

13 Assessment of heterogeneity Y/N 

14 Description of statistical methods sufficient to replicate Y 

15 Provision of appropriate tables and graphs Y 

Reporting of Results 

16 Graphic summarizing of individual study estimates and overall N/A 

17 Tables giving descriptive information of each study included Y 

18 Results of sensitivity testing (subgroup analysis) N 

19 Indication of statistical uncertainty of findings Y/N 

C-49
Reporting yes/no 

20 Quantitative assessment of bias (eg. publication bias) N 

Overall quality 

*When grading a systematic review, please skip item #14, 18-20 

Please fill the white areas only 

Evaluation of quality of a systematic review or meta-analysis Yes /No 

/Partially 

1 Is search strategy appropriate/relevant to the key question(s)? Y 

2 Did authors give justifications for inclusion/exclusion criteria pertaining to the studies of 

interest? 

Y 

3 Were Population, Intervention/Exposure, Comparator/Control, Outcomes, and Study 

Designs well-defined? 

Y 

4 Did authors attempt to minimize errors in data extraction (such as collecting the 

relevant data, double data extraction, verification of data extraction...etc.)? 

Y 

5 Was individual study quality (such as sample size, study design, blinding, various 

biases and confounders, study subject attrition rate...etc.) assessed? 

Y 

6 Did authors consider appropriate confounders and justification for adjusting or not 

adjusting for those confounders? 

Y 

7 Was the justification for combining or not-combining data for meta-analysis, or the use 

of a particular analytic method or model appropriate? 

Y 

8 Was heterogeneity explored (this is in addition to any statistical test of heterogeneity, 

did the authors look at the actual differences in PICOS, for example?)? 

Y/N 

8 Were results reported accurately (eg, no discrepancies between text and tables)? Y 

9 Were conclusions justified by the reported/collected data and analysis? Y 

C-50
Lawlor 2006 [16466433] 

Study characteristics Study design and follow-up duration Eligibility criteria Breastfeeding Exposures or Interventions 

Mean GA (range): term and preterm (>98% term in followup N=3794) Mean BW (range): 3794 ( % Male: 52% Race: Enrolled/Evaluate: 7223/3999 (5 yrs)/3794 (14 yrs) Location: Australia Sites: Single Funding: 

Prospective cohort; Peabody Picture Vocabulary test at 5 years and Raven’s standard progressive matrices at 14 years 

Live birth who did not die before discharge from hospital 

Duration of breastfeeding (never, <4 mo4 mos) was obtained from mothers at thmonth followup assessment 

C-51
Lawlor 2006 [16466433] 

Outcome Definition Statistical analyses and confounders adjusted Results 

Cognitive outcome of interest: Raven’s standard progressive matrices at 14 years 

Adjustment for sex, parental characteristics (maternal age, ethnicity, education, paternal education, family income, gravidity, maternal smoking), labor, Apgar scores, birthweight, height, BMI 

At age 14 years, Never breastfed = 694, <4 months = 1372, 

≥ 4 

months = 1606 

All parental characteristics were related to offspring IQ score. Unadjusted scores at age 14 showed a mean difference of 4.43 (95%CI 3.09 to 5.77) in <4 mos breastfeeding vs never breastfeeding; 8.20 (95%CI6.89 to9.49) in 

≥ 4 mos breastfeeding vs never 

breastfeeding (P<0.001) Adjusted scores at age 14 (N=3099) for sex, parental characteristics (maternal age, ethnicity, education, paternal education, family income, gravidity, maternal smoking), labor, Apgar scores, birthweight, height, BMI showed a mean difference of 4.07 (95%CI 2.61 to 5.53) in <4 mos breastfeeding vs never breastfeeding; 6.79 (95%CI 5.33 to 8.26) in 

≥ 4 mos breastfeeding vs never 

breastfeeding (P<0.001) Family income, parental education and breastfeeding explained 7.5% of the variation in intelligence at age 14. Loss to followup was selective, those subjects were more likely to have mothers who were from poorer social backgrounds, lower education, and younger; regression analysis repeated using Heckman’s sample selection bias adjustment with maternal age, parental education, and family income as the selection variables; results of these regression models did not differ from those who had followup. 

A: stronmodera

SelectioStudy dConfounBlinding Data coWithdradropout AnalyseInterven

Overall: B No informbreastfeeevaluatio

C-52
Domain/question Place an “X” 

Selection Bias Are individuals selected to participate likely to be representative of target population? Very 

likely 

Somewhat likely 

l

What % of selected individuals agreed to participate? 80-100 60-79 Allocation Bias (RCTs only, for quasi-experimental, case-control/before/after, no control group or other skip to “Confounders”) Is the method of random allocation stated Yes No If the method of random allocation is stated, is it appropriate Yes No Was the method of random allocation reported as concealed? Yes No Confounders Prior to the intervention, were there between group differences for important confounders reported in the paper? 

Yes No Ca

If there were differences between groups for important confounders, were they adequately managed in the 

analysis? 

Yes No 

Were there important confounders NOT reported in the paper (describe above under quality score)? Yes No Blinding Was (were) the outcome assessor(s) blinded to the intervention or exposure status of the participants? Yes No Data Collection methods Were data collection tools shown or are they known to be valid? Yes No Were data collection tools shown or are they known to be reliable? Yes No Withdrawals and Dropouts Indicate the % of participants completing the study. (If the % differs by groups, record the lowest). 80-100 60-79 Analysis Is there a sample size calculation or power calculation Yes Partially Is there a statistically significant difference between groups? Yes No Are the statistical methods appropriate? Yes No Indicate the unit of allocation Communit

y 

Organization/group Pr

Indicate the unit of analysis Communit

y 

Organization/group Pr

If the unit of allocation and analysis differed, was the cluster analysis done? Yes No Is the analysis performed by intervention allocation status (i.e. intention to treat) rather than the actual intervention received? 

Yes No Ca

Intervention Integrity What % of participants received the allocated intervention or exposure of interest? 80-100 60-79 Was the consistency of the intervention measured (i.e. intervention was provided to all participants in the same way)? 

Yes No 

Is it likely that subjects received an unintended intervention (contamination or cointervention) that may influence the results? 

Yes No Ca

C-53
Mortensen 2002 [11988057] 

Study characteristics Study design and follow-up duration Eligibility criteria Breastfeed

Exposures 

Interventio

Mean GA (range): Mean BW (range): % Male: 490/973 (50% in cohort 1); 2280 (100% in cohort 2) Race: Enrolled/Evaluate: 973 had WAIS, 2280 had BPP test Location: Denmark Sites: Single/Multi Funding: 

Prospective cohort but the breastfeeding information was collected retrospectively at the 1-year examination. There were 2 sub-cohorts; one participated in an ongoing developmental research program between 1982-1994 and took the WAIS at 27.2 years old; the other one took the draft board intelligence test: Borge Priens Prove (BPP) at 18.7 years; the BPP has a correlation of 0.82 with the full scale WAIS IQ. 

Excluded twins 

Mortensen 2002 [11988057] 

Outcome Definition Statistical analyses and confounders adjusted Results Bi

Relationship of WAIS score and BPP score to duration of breastfeeding 

Adjusted for parental social status and education, single mother status, mother’s height, age, and weight gain during pregnancy, cigarette during 3rd

trimester, number of pregnancies, estimated gestational age, birthweight, birth length, and indices of pregnancy and delivery complications 

 Breastfeeding duration  <1mo 2-3 mo 4-6 mo 7-9 mo >9 mo WAIS 99.4 101.7 102.3 106.0 104.0 Adjusted P=0.003 for overall F test BPP 38.0 39.2 39.9 40.1 40.1 Adjusted P=0.01 for overall F test 

A: strong, B: moweak 

Selection Study design Confounder Blinding Data collection Withdrawal and Analyses Intervention inte

Overall: B 

C-54
Domain/question Place an “X” 

Selection Bias Are individuals selected to participate likely to be representative of target population? Very 

likely 

Somewhat likely 

l

What % of selected individuals agreed to participate? 80-100 60-79 Allocation Bias (RCTs only, for quasi-experimental, case-control/before/after, no control group or other skip to “Confounders”) Is the method of random allocation stated Yes No If the method of random allocation is stated, is it appropriate Yes No Was the method of random allocation reported as concealed? Yes No Confounders Prior to the intervention, were there between group differences for important confounders reported in the paper? 

Yes No Ca

If there were differences between groups for important confounders, were they adequately managed in the 

analysis? 

Yes No 

Were there important confounders NOT reported in the paper (describe above under quality score)? Yes No Blinding Was (were) the outcome assessor(s) blinded to the intervention or exposure status of the participants? Yes No Data Collection methods Were data collection tools shown or are they known to be valid? Yes No Were data collection tools shown or are they known to be reliable? Yes No Withdrawals and Dropouts Indicate the % of participants completing the study. (If the % differs by groups, record the lowest). 80-100 60-79 Analysis Is there a sample size calculation or power calculation Yes Partially Is there a statistically significant difference between groups? Yes No Are the statistical methods appropriate? Yes No Indicate the unit of allocation Communit

y 

Organization/group Pr

Indicate the unit of analysis Communit

y 

Organization/group Pr

If the unit of allocation and analysis differed, was the cluster analysis done? Yes No Is the analysis performed by intervention allocation status (i.e. intention to treat) rather than the actual intervention received? 

Yes No Ca

Intervention Integrity What % of participants received the allocated intervention or exposure of interest? 80-100 60-79 Was the consistency of the intervention measured (i.e. intervention was provided to all participants in the same way)? 

Yes No 

Is it likely that subjects received an unintended intervention (contamination or cointervention) that may influence the results? 

Yes No Ca

C-55
Oddy, 2003 [12562475] contains the same data as in Oddy, 2004 [15384602] 

Study characteristics Study design and follow-up duration Eligibility criteria 

Breastfeedin

Exposures o

Interventions 

Mean GA (range): 37-39 wk Mean BW (range): % Male: Race: Enrolled/Evaluate: 2393 term at birth, 1444 at 6 years, 1371 at 8 years Location: Australia Sites: Single/Multi Funding: 

Prospective cohort comparing no breastfeeding, <4 mo, 4-6 mo, and >4 mo of breastfeeding; Peabody Picture Vocabulary Test (PPVT-R) was administered at 6 y/o and a Performance subtest (Perceptual organization WISC- Block Design) at 8 y/o 

Children with non-English speaking parents were excluded; preterm infants were also excluded 

Oddy, 2003 [12562475] contains the same data as in Oddy, 2004 [15384602] 

Outcome 

Definition 

Statistical analyses and confounders 

adjusted Results 

Score of PPV-R at 6 y/o and Block Design score at 8 y/o 

Association between breastfeeding duration and PPVT-R at 6 years and Block Design at 8 years were adjusted for gender, gestational age, maternal age and education, parental smoking, and the presence of older siblings. 

90% of children were breastfed at some point, 28% were breastfed for >6 mo, solid foods were introduced at 

≤6 mo in 88% of infants 

Both verbal IQ and performance scores increase with increasing maternal education combined with a longer duration of breastfeeding, with the most profound effect of breastfeeding occurring in the highest education groups (P<0.005). In the lower education groups, these trends were less consistent. After adjustment for covariates, there was an association between duration of breastfeeding and verbal IQ with a 3.56 point advantage for children breastfed >6 mo compared with children never breastfed (F=8.59, P=0.003). The adjusted association of full breastfeeding with the Performance subtest was not significant (F=1.49, P=0.223). 

Amw

SSCBDWaAIi

Ov

C-56
Domain/question Place an “X” 

Selection Bias Are individuals selected to participate likely to be representative of target population? Very 

likely 

Somewhat likely 

l

What % of selected individuals agreed to participate? 80-100 60-79 Allocation Bias (RCTs only, for quasi-experimental, case-control/before/after, no control group or other skip to “Confounders”) Is the method of random allocation stated Yes No If the method of random allocation is stated, is it appropriate Yes No Was the method of random allocation reported as concealed? Yes No Confounders Prior to the intervention, were there between group differences for important confounders reported in the paper? 

Yes No Ca

If there were differences between groups for important confounders, were they adequately managed in the 

analysis? 

Yes No 

Were there important confounders NOT reported in the paper (describe above under quality score)? Yes No Blinding Was (were) the outcome assessor(s) blinded to the intervention or exposure status of the participants? Yes No Data Collection methods Were data collection tools shown or are they known to be valid? Yes No Were data collection tools shown or are they known to be reliable? Yes No Withdrawals and Dropouts Indicate the % of participants completing the study. (If the % differs by groups, record the lowest). 80-100 60-79 Analysis Is there a sample size calculation or power calculation Yes Partially Is there a statistically significant difference between groups? Yes No Are the statistical methods appropriate? Yes No Indicate the unit of allocation Communit

y 

Organization/group Pr

Indicate the unit of analysis Communit

y 

Organization/group Pr

If the unit of allocation and analysis differed, was the cluster analysis done? Yes No Is the analysis performed by intervention allocation status (i.e. intention to treat) rather than the actual intervention received? 

Yes No Ca

Intervention Integrity What % of participants received the allocated intervention or exposure of interest? 80-100 60-79 Was the consistency of the intervention measured (i.e. intervention was provided to all participants in the same way)? 

Yes No 

Is it likely that subjects received an unintended intervention (contamination or cointervention) that may influence the results? 

Yes No Ca

C-57
Quinn 2001 [11885710] 

Study 

characteristics Study design and follow-up duration Eligibility criteria 

Breastfeeding 

Exposures or 

Interventions 

Mean GA (range): Mean BW (range): % Male: 53% Race: Enrolled/Evaluate: 4049/3880 Location: Australia Sites: Single Funding: 

Prospective cohort; data were collected at enrollment, shortly after birth, at 6 months and at 5 years. Peabody Picture Vocabulary Test (PPVT-R) was administered at 5 years. Results were analyzed in relation to breastfeeding duration. 

Singleton; At 5 years, children with major neurological abnormalities and those for whom the data were incomplete were excluded 

Quinn 2001 [11885710] 

Outcome 

Definition Statistical analyses and confounders adjusted Results 

Score on PPVT-R 

Adjusted for birthweight, poverty, maternal education, maternal age, time in daycare or preschool, number of children in the household at 5 years 

Breastfeeding ≥6 mo 103.6 (SD 13.1) No breastfeeding 94.2 (SD 14.1) There was a significant trend towards increasing PPVT-R with increased duration of breastfeeding (P=0.0000) After adjustment, the mean for those breastfed ≥6 mo was 8.2 points (95%CI 6.5, 9.9) higher for females and 5.8 points (95%CI 4.1, 7.5) higher for males when compared to those never breastfed. 

A: smodwea

SelStuConBlinDatWitdroAnaInteinte

Over

C-58
Domain/question Place an “X” 

Selection Bias Are individuals selected to participate likely to be representative of target population? Very 

likely 

Somewhat likely 

l

What % of selected individuals agreed to participate? 80-100 60-79 Allocation Bias (RCTs only, for quasi-experimental, case-control/before/after, no control group or other skip to “Confounders”) Is the method of random allocation stated Yes No If the method of random allocation is stated, is it appropriate Yes No Was the method of random allocation reported as concealed? Yes No Confounders Prior to the intervention, were there between group differences for important confounders reported in the paper? 

Yes No Ca

If there were differences between groups for important confounders, were they adequately managed in the 

analysis? 

Yes No 

Were there important confounders NOT reported in the paper (describe above under quality score)? Yes No Blinding Was (were) the outcome assessor(s) blinded to the intervention or exposure status of the participants? Yes No Data Collection methods Were data collection tools shown or are they known to be valid? Yes No Were data collection tools shown or are they known to be reliable? Yes No Withdrawals and Dropouts Indicate the % of participants completing the study. (If the % differs by groups, record the lowest). 80-100 60-79 Analysis Is there a sample size calculation or power calculation Yes Partially Is there a statistically significant difference between groups? Yes No Are the statistical methods appropriate? Yes No Indicate the unit of allocation Communit

y 

Organization/group Pr

Indicate the unit of analysis Communit

y 

Organization/group Pr

If the unit of allocation and analysis differed, was the cluster analysis done? Yes No Is the analysis performed by intervention allocation status (i.e. intention to treat) rather than the actual intervention received? 

Yes No Ca

Intervention Integrity What % of participants received the allocated intervention or exposure of interest? 80-100 60-79 Was the consistency of the intervention measured (i.e. intervention was provided to all participants in the same way)? 

Yes No 

Is it likely that subjects received an unintended intervention (contamination or cointervention) that may influence the results? 

Yes No Ca

C-59
Appendix C. Evidence Tables 

Part I. Term Infant Outcomes 

Gastrointestinal Infections 

Chien 2001 SRMA* 

Quigley 2006 

* Systematic Review/Meta-Analysis

C-60
Evidence table for Systematic Reviews of Breastfeeding 

Author, 

Year[UI] 

Topic Chien, 2001 UI 11795054 Gastrointestinal (GI) Infection 

Literature search 

(Dates)

Medline (1996 to 1/1998); Other databases searched? (Yes) Science Citation Index was used to 

identify frequently cited articles in the reference lists of studies from MEDLINE; unpublished data 

used? No 

Countries where 

primary studies 

conducted 

Industrialized countries (UK, New Zealand, US, Australia, Scotland) 

Study eligibility / 

inclusion criteria 

GI infection was defined to be any illness associated with vomiting, change in consistency or 

frequency of stools, or isolation of a known enteropathogenic bacterial or viral agent; GI outcome 

restricted to first year of life; excluded studies in which mortality was employed as a combined 

outcome event; excluded studies in which all the various types of infections were combined as an 

outcome measure 

Study design [No. Of 

studies] 

Prospective (12 studies, 5473 subjects) and retrospective (2 studies, 504 subjects) cohort studies; 

case-control studies (2 studies, 331 pairs); 

No. of subjects See above 

Study population 

(definition in included 

studies) 

Intervention/Exposure 

(definition in included 

studies) 

Comparator 

(definition in included 

studies) 

Infant feeding practices grouped into either exclusive breastfeeding and partial/mixed feeding or 

exclusive artificial feeding 

Outcomes (definition 

in included studies) 

Heterogeneity 

assessments 

Yes 

Quality assessments 

Publication bias 

assessments 

Statistical Analysis or 

meta-analytic 

methods 

Fixed effect model; pooled results weighted according to sample size 

Results Conflicting results on the effect of breastfeeding on GI infection: 9/16 studies (56%) yielded a 

statistically significant protective effect of breastfeeding on GI infections; 

Majority of studies suffered from methodological deficiencies; 4 studies fulfilled criteria of controlling 

for detection bias, analyses of confounders, having a clear definition of infant feeding practices and 

infectious outcomes; 3 of these studies reported breastfeeding was protective against GI infection; 

Pooled estimate of the cohort studies: OR 0.36 (95% CI 0.32, 0.41; heterogeneity P<0.01) 

Pooled estimate of 2 case-control studies: OR 0.54 (95% CI 0.36, 0.80; heterogeneity P=0.35) 

Quality of the 

systematic review 

B 

Author’s 

interpretations of the 

results 

“No firm conclusion can be drawn about the magnitude of a protective effect of breastfeeding 

against infections in industrialized countries, there is no doubt that it is protective in the case of 

many infants. This trend is most obvious in the studies of the highest quality.” 

Comments / 

Limitations 

Random effect model would be more appropriate; weighted according to sample size; not analyzed 

for potential confounding 

C-61
Author, yr: Chien, 2001 

Topic of the systematic review*/MA: 

Reporting yes/no 

Reporting of Background 

1 Description of study outcomes Y 

2 Types of exposure or intervention used Y 

3 Types of study designs used Y 

4 Study population Y 

Reporting of Search strategy 

5 Search strategy, including time period and key words Y/N 

6 Effort to include all available studies (contact with authors) N 

7 Databases and registries searched Y 

8 Method of addressing published articles other than English N 

9 Method of handling abstracts and unpublished studies N 

Reporting of Methods 

10 Rationale for selection and/or coding of data Y 

11 Assessment of confounding Y/N 

12 Assessment of quality Y 

13 Assessment of heterogeneity Y 

14 Description of statistical methods sufficient to replicate Y 

15 Provision of appropriate tables and graphs Y 

Reporting of Results 

16 Graphic summarizing of individual study estimates and overall Y 

17 Tables giving descriptive information of each study included Y 

18 Results of sensitivity testing (subgroup analysis) N 

19 Indication of statistical uncertainty of findings Y 

20 Quantitative assessment of bias (eg. publication bias) N 

Overall quality 

*When grading a systematic review, please skip item #14, 18-20 

Please fill the white areas only 

Evaluation of quality of a systematic review or meta-analysis Yes /No 

/Partially 

1 Is search strategy appropriate/relevant to the key question(s)? Y/N 

2 Did authors give justifications for inclusion/exclusion criteria pertaining to the studies of 

interest? 

Y 

3 Were Population, Intervention/Exposure, Comparator/Control, Outcomes, and Study 

Designs well-defined? 

Y 

4 Did authors attempt to minimize errors in data extraction (such as collecting the 

relevant data, double data extraction, verification of data extraction...etc.)? 

N 

5 Was individual study quality (such as sample size, study design, blinding, various 

biases and confounders, study subject attrition rate...etc.) assessed? 

Y/N 

6 Did authors consider appropriate confounders and justification for adjusting or not 

adjusting for those confounders? 

Y 

7 Was the justification for combining or not-combining data for meta-analysis, or the use 

of a particular analytic method or model appropriate? 

Y/N 

8 Was heterogeneity explored (this is in addition to any statistical test of heterogeneity, 

did the authors look at the actual differences in PICOS, for example?)? 

Y/N 

8 Were results reported accurately (eg, no discrepancies between text and tables)? Y 

9 Were conclusions justified by the reported/collected data and analysis? Y 

C-62
Quigley, 2006 [16308409] 

Study characteristics Study design and follow-up duration Eligibility criteria Breastfeeding Exposures or Interventions Control E

Interv

Mean GA (range): Mean BW (range): % Male: 58 Race: Enrolled/Evaluate: 167 cases/ 137 controls Location: UK Sites: Multi Funding: 

Case-control study; stratified by age group (0-3 mo, 3-5.9 mo, 6-8.9 mo, 

≥ 9 

mo), social deprivation score, location of practice (London, not London); questionnaire on current milk feeding 

< 1 yr old and had data on infant feeding 

Current exclusive breast milk (only milk received was breast milk, but many had been weaned on to solids), mixed feeding 

Current formula 

Quigley, 2006 [16308409] 

Outcome Definition Statistical analyses and confounders adjusted Results Bias/limitati

Comment

A diarrheal case was defined as “someone who presented to the General Practitioner with loose stools or significant vomiting < 2 weeks, in the absence of a known non-infectious cause and preceded by a symptom-free period of 3 weeks.” 

age, sex, weaning, social class, travel, no access to food mixer, contact with person with diarrhea/vomiting in and outside household Multivariate analysis 

Completed questionnaire: 190 cases (60%); 161 controls (90%); excluded 23 cases and 24 controls (no feeding data, no match, “other” feeding) Analyzed: 167 cases/ 137 controls  Adjusted OR of diarrhea Current BF 0.36 (95% CI 0.18, 0.74) Current not BF 1 P=0.005 “Little evidence of the protection of breastfeeding persisting beyond 2 months following breastfeeding cessation.” 

A: strong, B: moderate, C: weak 

A 

Selection x Study design x Confounder x Blinding Data collection x Withdraw and dropout 

x 

Analyses x Intervention integrity 

Cannot rule out recall or respon

C-63
Appendix C. Evidence Tables 

Part I. Term Infant Outcomes 

Infant Mortality 

Chen 2004 

C-64
Chen 2004 [15121986] 

Study characteristics Study design and follow- up duration Eligibility criteria Breastfeeding Exposures or Interventions 

Mean GA (range): ND Mean BW (range):<2500g 26% live birth (controls) and 24% postneonatal death (cases) % Male: 50.3 live birth 59.8% postneonatal death Race: White 44.4 (controls) 50.0 (cases)  Black 52.2 (controls) 46.6 (cases)  Others 3.4 (controls) 3.4 (cases) Enrolled/Evaluate: NA Location: national level data Sites: Multi (population based) Funding: ND 

Case control study design Follow-up NA 

Subjects included in the 1988 US National Maternal and Infant Health Survey data to analyze the association between breastfeeding and postneonatal death. 

Ever vs Never 

Chen 2004 [15121986] 

Outcome 

Definition Statistical analyses and confounders adjusted Results 

Post neonatal death: death after 28 days 

Because of the oversampling of black and low birth weight infants SUDAAN adjusted analysis was performed to re-weight the sample for the overall estimates and to calculate the ORs and 95% confidence intervals in the final models. Logistic regression models Adjusted for mother’s age, education, and smoking during pregnancy and infant’s gender, race (except for race subgroup analyses), birth weight (except for birth weight subgroup analyses), congenital malformation reported at birth, live birth order, plurality, and WIC status. 

Showed an OR of 0.79 (95% CI: 0.67–0.93) for ever breastfed. Race-specific analyses gave similar estimates for the OR, although the proportion ever breastfed was much lower in black infants. For duration of breastfeeding, comparing cases who survived 3 months (n = 691 in original sample and n = 5363 after adjustment 

with SUDAAN) and all controls, 3 months or more of breastfeeding showed an OR of 0.62 (95% CI: 0.46–0.82), less (ie, more protective) than the OR for ever/never breastfed (0.79; 95% CI:0.67–0.93). 

The OR for overall postneonatal death was 0.74 (95% CI: 0.63–0.87). Among cases only, a proportional hazard model showed that the risk of death at any specific time was marginally lower in the ever breastfed infants (hazard ratio: 0.91; 95% CI: 0.79–1.06). 

O

C-65
Appendix C. Evidence Tables 

Part I. Term Infant Outcomes 

Respiratory Tract Diseases 

Bachrach 2003 SRMA* 

* Systematic Review/Meta-Analysis

C-66
Evidence table for Systematic Reviews of Breastfeeding 

Author, Year[UI] Topic Bachrach, 2003 [12622672] Respiratory Illness 

Literature search (Dates) Medline (1966-2002); Other databases searched? (yes); unpublished data used? 

(yes) 

Countries where primary studies 

conducted 

Developed countries (US, Canada, New Zealand, Australia, Scotland, Norway) 

Study eligibility / inclusion criteria Included studies from developed countries; healthy full-term infants; and provided 

data on exclusive breast feeding 

Excluded studies on cystic fibrosis and allergic conditions; sick, premature, and/or 

low birth weight infants 

Study design [No. Of studies] Prospective cohort [5]; retrospective cohort [2]; ecological study [1]; cross-sectional 

[1]. Only cohort studies were combined. 

No. of subjects 3201 exposed / 1324 unexposed 

Study population (definition in 

included studies) 

Healthy full term infants 

Intervention/Exposure (definition 

in included studies) 

Exclusive breastfeeding at least of 2 months or 9 months of total (any) breastfeeding 

Comparator (definition in included 

studies) 

None breastfeeding 

Outcomes (definition in included 

studies) 

Hospitalization due to lower respiratory tract disease (LRTD) in infancy: bronchiolitis, 

asthma, pneumonia, empyema, and infections due to specific agents (eg, RSV) 

Heterogeneity assessments Yes; No statistical heterogeneity. Used sensitivity analysis to test appropriateness of 

combining studies. 

Quality assessments None 

Publication bias assessments None (but the authors examined unpublished data) 

Statistical Analysis or metaanalytic methods 

Random effects model; subgroup analyses for two covariates – smoking and SES 

Results Summary relative risk from 7 cohort studies: 0.28 (0.14 - 0.54) 

Quality of the systematic review A 

Author’s interpretations of the 

results 

Consistent effect was found among all primary studies that indicated a protective 

role of breastfeeding in LRTD 

Comments / Limitations Included studies that had precise definition of breastfeeding 

C-67
Author, yr: Bachrach, 2003 

Topic of the systematic review*/MA: Breastfeeding and LRTI

Reporting yes/no 

Reporting of Background 

1 Description of study outcomes Y 

2 Types of exposure or intervention used Y 

3 Types of study designs used Y 

4 Study population Y 

Reporting of Search strategy 

5 Search strategy, including time period and key words Y 

6 Effort to include all available studies (contact with authors) Y 

7 Databases and registries searched Y 

8 Method of addressing published articles other than English Y 

9 Method of handling abstracts and unpublished studies Y 

Reporting of Methods 

10 Rationale for selection and/or coding of data Y 

11 Assessment of confounding Y 

12 Assessment of quality N 

13 Assessment of heterogeneity Y 

14 Description of statistical methods sufficient to replicate Y 

15 Provision of appropriate tables and graphs Y 

Reporting of Results 

16 Graphic summarizing of individual study estimates and overall Y 

17 Tables giving descriptive information of each study included Y 

18 Results of sensitivity testing (subgroup analysis) Y 

19 Indication of statistical uncertainty of findings N 

20 Quantitative assessment of bias (eg. publication bias) N 

Overall quality A 

*When grading a systematic review, please skip item #14, 18-20 

Please fill the white areas only 

Evaluation of quality of a systematic review or meta-analysis Yes /No 

/Partially 

1 Is search strategy appropriate/relevant to the key question(s)? 

2 Did authors give justifications for inclusion/exclusion criteria pertaining to the studies of 

interest? 

yes 

3 Were Population, Intervention/Exposure, Comparator/Control, Outcomes, and Study 

Designs well-defined? 

yes 

4 Did authors attempt to minimize errors in data extraction (such as collecting the 

relevant data, double data extraction, verification of data extraction...etc.)? 

partially 

5 Was individual study quality (such as sample size, study design, blinding, various 

biases and confounders, study subject attrition rate...etc.) assessed? 

no 

6 Did authors consider appropriate confounders and justification for adjusting or not 

adjusting for those confounders? 

yes 

7 Was the justification for combining or not-combining data for meta-analysis, or the use 

of a particular analytic method or model appropriate? 

yes 

8 Was heterogeneity explored (this is in addition to any statistical test of heterogeneity, 

did the authors look at the actual differences in PICOS, for example?)? 

yes 

8 Were results reported accurately (eg, no discrepancies between text and tables)? yes 

9 Were conclusions justified by the reported/collected data and analysis? yes 

C-68
Appendix C. Evidence Tables 

Part I. Term Infant Outcomes 

Obesity 

Arenz 2004 SRMA* 

Harder 2005 SRMA* 

Owen 2005 SRMA*

* Systematic Review/Meta-Analysis

C-69
Evidence table for Systematic Reviews of Breastfeeding 

Author,Year[UI] Topic Arenz, 2004 [15314625] Obesity 

Literature search (Dates) Medline (1966-Dec 2003); Other databases searched? (yes); unpublished data used? (no) 

Countries where primary 

studies conducted 

Developed countries: Germany, USA, Britain, Australia, New Zealand, Czech Republic 

Study eligibility / inclusion 

criteria 

• Population-based cohort, cross-sectional or case–control studies with children older than 

1 y at the last follow-up stage, published in English, French, Italian, Spanish or German. 

• Only studies with adjustment for at least three of the following relevant confounding or 

interacting factors birth weight, parental overweight, parental smoking, dietary factors, 

physical activity and socioeconomic status were included in this meta-analysis. 

• Odds ratio or relative risk had to be reported and age at the last follow-up had to be 

between 5 and 18 y; feeding-mode had to be assessed and reported and obesity as 

outcome had to be defined by body mass index (BMI) percentiles >90, 95 or 97 kg/m2. If 

risk estimates were calculated for different percentile values in a particular study, the 

estimate for the highest percentile-value was included in the meta-analysis.

Study design [No. Of 

studies] 

Studies did not meet inclusion criteria for meta-analyses: prospective cohort study [11]; 

retrospective cohort [1]; cross-sectional study [4]; case-control study [2] 

Studies met inclusion criteria for meta-analyses: prospective cohort study [2]; crosssectional study [7] 

No. of subjects For studies met inclusion criteria for meta-analyses only: 69,000 

Study population (definition 

in included studies) 

Children and adolescents. One study included some adult subjects but the various odds 

ratios were reported depending on age and not clear which odds ratio was used in the 

meta-analyses. 

Intervention/Exposure 

(definition in included 

studies) 

Comparator (definition in 

included studies) 

Definition of feeding mode varied across studies: 

Never BF or partly BF < 3 months vs. BF ≥ 3 month; mostly or only BF vs. mostly or only 

formula feeding in the first 6 months; BF never vs. ever; BF never vs. > 6 months, BF 

groups: <1 week, 1 week-1 months, 2-3 months, 4-6 months, 7-9 month, > 9 months 

(exclusivity of BF not reported) 

Outcomes (definition in 

included studies) 

Definition of childhood obesity varied across studies: 

BMI ≥97th percentile, >95th percentile, definition according to Cole et al. 

Heterogeneity assessments Sensitivity analyses by testing the stability of the findings across different approaches in 

study design, exposure ascertainment and selection of study participants. 

Quality assessments ND 

Publication bias 

assessments 

Funnel plot 

Statistical Analysis or metaanalytic methods 

Fixed-effect and random-effect model: both crude and adjusted odds ratios (AOR) of the 

studies were used. 

Results • In total, 28 studies met the inclusion criteria for the systematic review, 19 of them were 

not eligible for the meta-analysis. 

• The pooled crude OR for breast-feeding and obesity defined as BMI >90th, 95th or 97th 

percentile could be calculated for six studies. In the fixed-effects model, the OR was 0.67, 

95% CI (0.62, 0.73). In the random effects model an almost identical OR was found (data 

not shown). 

• The AOR calculated for nine studies was 0.78, 95% CI (0.71, 0.85) for both fixed and 

random-effects model. 

• Sensitivity analyses were performed, comparing the studies according to the following 

criteria: cohort study or cross-sectional study, different definitions of breast-feeding, 

different definitions of obesity, different age-groups and number of potential confounders 

considered for adjustment. The protective effect of breast-feeding was more pronounced 

in studies with adjustment for less than seven potential confounding factors compared to 

adjustment for seven or more potential confounding factors.

• The funnel plot showed an asymmetric pattern, which was due to a particular study. The 

funnel plot regression analysis did not reject the null hypothesis of symmetry (df=8, 

C-70
Author,Year[UI] Topic Arenz, 2004 [15314625] Obesity 

P=0.71), suggesting that there was no publication bias. 

Quality of the systematic 

review 

A 

Author’s interpretations of 

the results 

“The results from meta-analysis indicate that breast-feeding is associated with a small but 

consistent protective effect against obesity risk in later childhood.” 

Comments / Limitations Highly heterogeneous definitions of breastfeeding across studies overall meta-analysis was 

inappropriate, but sensitivity analyses were performed to reduce heterogeneity. Sensitivity 

analyses are very important but very few studies in each stratum due to small number of 

studies met the criteria for meta-analyses. 

C-71
Author, yr: Arenz, 2004 

Topic of the systematic review*/MA: 

Reporting yes/no 

Reporting of Background 

1 Description of study outcomes Yes 

2 Types of exposure or intervention used Yes 

3 Types of study designs used Yes 

4 Study population Yes 

Reporting of Search strategy 

5 Search strategy, including time period and key words Yes 

6 Effort to include all available studies (contact with authors) Yes 

7 Databases and registries searched Yes 

8 Method of addressing published articles other than English No 

9 Method of handling abstracts and unpublished studies No 

Reporting of Methods 

10 Rationale for selection and/or coding of data Yes 

11 Assessment of confounding Yes 

12 Assessment of quality Yes 

13 Assessment of heterogeneity Yes 

14 Description of statistical methods sufficient to replicate Yes 

15 Provision of appropriate tables and graphs Yes 

Reporting of Results 

16 Graphic summarizing of individual study estimates and overall Yes 

17 Tables giving descriptive information of each study included Yes 

18 Results of sensitivity testing (subgroup analysis) Yes 

19 Indication of statistical uncertainty of findings Yes 

20 Quantitative assessment of bias (eg. publication bias) Yes 

Overall quality A 

*When grading a systematic review, please skip item #14, 18-20 

Please fill the white areas only 

Evaluation of quality of a systematic review or meta-analysis Yes /No 

/Partially 

1 Is search strategy appropriate/relevant to the key question(s)? Yes 

2 Did authors give justifications for inclusion/exclusion criteria pertaining to the studies of 

interest? 

Yes 

3 Were Population, Intervention/Exposure, Comparator/Control, Outcomes, and Study 

Designs well-defined? 

Yes 

4 Did authors attempt to minimize errors in data extraction (such as collecting the 

relevant data, double data extraction, verification of data extraction...etc.)? 

ND 

5 Was individual study quality (such as sample size, study design, blinding, various 

biases and confounders, study subject attrition rate...etc.) assessed? 

Yes 

6 Did authors consider appropriate confounders and justification for adjusting or not 

adjusting for those confounders? 

Yes 

7 Was the justification for combining or not-combining data for meta-analysis, or the use 

of a particular analytic method or model appropriate? 

Yes 

8 Was heterogeneity explored (this is in addition to any statistical test of heterogeneity, 

did the authors look at the actual differences in PICOS, for example?)? 

Yes 

8 Were results reported accurately (eg, no discrepancies between text and tables)? Partially 

9 Were conclusions justified by the reported/collected data and analysis? Yes 

C-72
Evidence table for Systematic Reviews of Breastfeeding 

Author, 

Year[UI] 

Topic Harder, 2005 [16076830] Obesity 

Literature search (Dates) Medline (1966-December 2003); Other databases searched? (yes); unpublished data used? 

(no) 

Countries where primary 

studies conducted 

Developed countries: UK, US, Canada, Germany, Australia, New Zealand, Czechoslovakia 

Study eligibility / 

inclusion criteria 

1) an original report comparing breastfed subjects with exclusively formula-fed subjects 

(referent group) of any given age, 2) report the odds ratio and 95% CI (or data to calculate 

them) of overweight or obesity associated with breastfeeding, and 3) report the duration of 

breastfeeding for at least one exposure group. 

Study design [No. Of 

studies] 

Cohort (including cross-sectional design) [16]; case-control study [1] 

No. of subjects Ranged 66 to 32,200 total 120,831 

Study population 

(definition in included 

studies) 

Primarily children. Two studies included adults. 

Intervention/Exposure 

(definition in included 

studies) 

Comparator (definition in 

included studies) 

Median duration of breastfeeding categories: < 1 month (reference), 1-3 month, 4-6 months, 7-

9 months, > 9month 

Each month increase in the duration of breastfeeding: We calculated a study specific 

regression coefficient and corresponding 95% CI for each study by use of a log-linear model. 

The resulting odds ratio and 95% CI for change in risk for each month of breastfeeding were 

pooled with a random-effect model 

Outcomes (definition in 

included studies) 

Any definition of overweight or obesity, varied across studies 

Heterogeneity 

assessments 

ND 

Quality assessments ND 

Publication bias 

assessments 

Funnel plot with Begg test and Egger test 

Statistical Analysis or 

meta-analytic methods 

Unadjusted odds ratios and 95% CI were calculated directly from the data given in the articles, 

where possible. Otherwise, the published odds ratio and 95% CI were used. Three approaches 

were taken: First, duration of breastfeeding as the independent variable and the weighted odds 

ratio for overweight in breastfed probands, compared with formula-fed subjects, as the 

dependent variable (for meta-regression). Second, the random-effect model pooled odds ratio 

for overweight in breastfed subjects was calculated separately for five predefined categories of 

duration of breastfeeding. Third, the pool-first method was used to combine the regression 

coefficients obtained from the studies (for trend estimation). 

For meta-regression analysis, all duration-specific odds ratios had to be related to the 

respective duration of breastfeeding. The median of the upper and lower limits of each category 

of duration of breastfeeding was assigned to the particular estimate in each study. Estimates 

were plotted against the respective duration of breastfeeding as independent variable. A 

weighted meta-regression with duration of breastfeeding as the covariate was perform 

(random-effects model). 

For studies that provided data for more than two categories of duration of breastfeeding, we 

applied the “pool-first method” to quantify the dose-response relation. This was possible for 11 

studies. We calculated a study specific regression coefficient and corresponding 95% CI for 

each study by use of a log-linear model. The resulting odds ratio and 95% CI for change in risk 

for each month of breastfeeding were pooled with a random-effect model. 

Results • From the 17 studies that reported duration of breastfeeding, 14 gave data for more than one 

category of duration of breastfeeding, leading to 52 estimates included in the meta-regression 

analysis. In the weighted meta-regression, duration of breastfeeding was significantly 

negatively related to risk of overweight (regression coefficient: 0.94, 95%CI 0.89-0.98). 

C-73
Author, 

Year[UI] 

Topic Harder, 2005 [16076830] Obesity 

• From 1 month of breastfeeding onward, the risk of subsequent overweight continuously 

decreased up to a reduction of more than 30%, reaching a plateau at 9 months of 

breastfeeding. 

Duration of breastfeeding 

<1 mo 1-3 mo 4-6 mo 7-9 mo >9 mo 

No. of durationspecific study 

estimates 

5 14 15 11 7 

OR for overweight 1.0 0.81 0.76 0.67 0.68 

95% CI 0.65, 1.55 0.74, 0.88 0.67, 0.86 0.55, 0.82 0.50, 0.91 

• Each month of breastfeeding was found to be associated with a 4% decrease in risk (OR: 

0.96/month of breastfeeding, 95%CI 0.94-0.98). A fixed-effects model revealed a similar 

pooled OR and a nearly identical 95% CI (OR: 0.96/month of breastfeeding, 95%CI 0.95-

0.98) 

• In only two of these studies was the influence of the duration of exclusive breastfeeding 

analyzed. The pooled OR for risk of overweight per month of exclusive breastfeeding was 

0.94 (95%CI 0.89-0.99, random-effect model) 

• Subgroup analyses revealed that the definition of overweight influenced the estimate only 

slightly. In studies that used BMI to define overweight, the pooled OR was 0.96 (95%CI 0.94-

0.98) for 8 studies, while the OR was 0.93 (95%CI 0.87-0.99) for the 3 studies that used 

another measure to define overweight or obesity. 

• The age at examination had only a marginal influence on the magnitude of the effect of 

duration of breastfeeding on risk of overweight. The pooled OR from all 5 studies 

investigating probands up to or including 5 years of age was 0.97 (95%CI 0.94-0.99), while in 

older subjects aged 6 or more years, it was 0.96 (95%CI 0.93-0.99) for 6 studies. 

• No evidence of publication bias was observed, as indicated by a symmetric funnel plot and a 

nonsignificant Begg test and Egger test. 

Quality of the systematic 

review 

B 

Author’s interpretations 

of the results 

“Using three different techniques, we show that a longer duration of breastfeeding is associated 

with a larger decrease in risk of overweight. Each of the three methods used in our study has its 

own advantages and limitations.” 

“In summary, we found that the duration of breastfeeding is inversely and linearly associated 

with the risk of overweight. The risk of overweight was reduced by 4% for each month of 

breastfeeding. This effect lasted up to a duration of breastfeeding of 9 months and was 

independent of the definition of overweight and age at follow-up. Even if interpreted as being of 

relatively small size, this association, if causal, might be of importance for the general 

population. Since the majority of studies analyzed here used partially breastfed subjects, it 

might be concluded that, beyond exclusive breastfeeding, also longer partial breastfeeding up 

to 9 months leads to a greater decrease in risk of overweight in later life, which might be 

considered in future clinical recommendation.” 

Comments / Limitations The meta-analyses addressing the relationship between duration of breastfeeding and the risk 

of overweight was well-performed. However, the authors’ conclusion implied a causal 

relationship, which is not appropriate because most of the “cohort” studies included in the 

analyses were in fact cross-sectional studies because the breastfeeding exposure was 

ascertained retrospectively at the time of the assessment of obesity. Causality cannot be 

ascertained in cross-sectional design. Most importantly, crude OR was used in the metaanalyses, which is the major limitation. 

C-74
Author, yr: Harder, 2005 

Topic of the systematic review*/MA: Obesity

Reporting yes/no 

Reporting of Background 

1 Description of study outcomes Yes 

2 Types of exposure or intervention used Yes 

3 Types of study designs used Yes 

4 Study population Yes 

Reporting of Search strategy 

5 Search strategy, including time period and key words Yes 

6 Effort to include all available studies (contact with authors) Yes 

7 Databases and registries searched Yes 

8 Method of addressing published articles other than English No 

9 Method of handling abstracts and unpublished studies No 

Reporting of Methods 

10 Rationale for selection and/or coding of data Yes 

11 Assessment of confounding Partially 

12 Assessment of quality Partially 

13 Assessment of heterogeneity No 

14 Description of statistical methods sufficient to replicate Yes 

15 Provision of appropriate tables and graphs Yes 

Reporting of Results 

16 Graphic summarizing of individual study estimates and overall Yes 

17 Tables giving descriptive information of each study included Yes 

18 Results of sensitivity testing (subgroup analysis) Yes 

19 Indication of statistical uncertainty of findings Yes 

20 Quantitative assessment of bias (eg. publication bias) Yes 

Overall quality B 

*When grading a systematic review, please skip item #14, 18-20 

Please fill the white areas only 

Evaluation of quality of a systematic review or meta-analysis Yes /No 

/Partially 

1 Is search strategy appropriate/relevant to the key question(s)? Yes 

2 Did authors give justifications for inclusion/exclusion criteria pertaining to the studies of 

interest? 

Yes 

3 Were Population, Intervention/Exposure, Comparator/Control, Outcomes, and Study 

Designs well-defined? 

Yes 

4 Did authors attempt to minimize errors in data extraction (such as collecting the 

relevant data, double data extraction, verification of data extraction...etc.)? 

ND 

5 Was individual study quality (such as sample size, study design, blinding, various 

biases and confounders, study subject attrition rate...etc.) assessed? 

Partially 

6 Did authors consider appropriate confounders and justification for adjusting or not 

adjusting for those confounders? 

Yes 

7 Was the justification for combining or not-combining data for meta-analysis, or the use 

of a particular analytic method or model appropriate? 

Yes 

8 Was heterogeneity explored (this is in addition to any statistical test of heterogeneity, 

did the authors look at the actual differences in PICOS, for example?)? 

Partially 

8 Were results reported accurately (eg, no discrepancies between text and tables)? Yes 

9 Were conclusions justified by the reported/collected data and analysis? Yes 

C-75
Evidence table for Systematic Reviews of Breastfeeding 

Author, Year[UI] Topic Owen, 2005 Obesity 

Literature search (Dates) Medline (completed in September 2003); Other databases searched? (yes); unpublished 

data used? (no) 

Countries where primary 

studies conducted 

Developed and developing countries: UK, Germany, USA, Canada, Italy, Turkey, Australia, 

New Zealand, Slovak Republic, China, Czech Republic, Sweden 

Study eligibility / inclusion 

criteria 

61 studies that compared a measure of obesity (quantitatively or narratively) among 

breastfed and formula-fed subjects were considered. Studies that defined the odds of obesity 

or being overweight for breastfed and formula-fed subjects were reported more often and 

were included in a meta-analysis; 28 studies with 29 estimates (1 study reported results for 2 

populations) met this inclusion criterion.

Study design [No. Of 

studies] 

Historical cohort, prospective cohort, cross-sectional studies: total 61 studies, and 28 studies 

included in the meta-analyses 

No. of subjects N=298,900 in the overall meta-analysis 

Study population 

(definition in included 

studies) 

28 studies (298,900 subjects) provided 29 unadjusted odds ratios relating the initial infant 

feeding method and obesity. Four observations were for infants, 23 for children, and 2 for 

adults. 

Intervention/Exposure 

(definition in included 

studies) 

Comparator (definition in 

included studies) 

Breastfed vs. formula-fed. 

The exclusiveness of infant feeding was based on the classification given in each article. The 

feeding groups were defined as being mutually exclusive in 4 studies, the breastfed group 

included mixed feeders in 7 studies and the formula-fed group included mixed feeders in 7 

studies. In 2 studies in which infants were breastfed exclusively, the exclusivity of formula 

feeding could not be determined. 

Outcomes (definition in 

included studies) 

Any measures of obesity or adiposity. 

Most studies used a percentile cutoff based on BMI, describing subjects at the tail of the 

distribution. The 95th or 97th percentile was used most often, although some studies used 

cutoff values as low as the 85th percentile. A smaller number of studies used absolute BMI 

values or cutoff values based on standardized weight or weight for height. Studies involving 

infants used definitions based on percentiles of weight for length or percentiles of weight 

only. 

Heterogeneity 

assessments 

Q test with chi-square statistics 

Quality assessments ND 

Publication bias 

assessments 

Begg funnel plot. Reporting bias was also assessed. 

Statistical Analysis or 

meta-analytic methods 

Results from fixed-effects models are reported throughout, because these reflect only the 

random error within each study, are more conservative because they are less affected by 

results of smaller studies that show stronger associations, and make no assumptions about 

the representativeness of the available studies. 

Meta-regression was used to examine the influence of the following factors (defined a priori) 

with a test for trend: study size (<500, 500–2500, or >2500 subjects), age group at outcome 

measurement (infants <=1 year of age, young children >1 to 9 years of age, older children 10 

to <16 years of age, or adults >=16 years of age), year of birth, and response rates 

(analyzed as a continuous variable). The effects of adjustment for factors such as parental 

body size (mostly BMI), socioeconomic status, and maternal smoking were examined in 6 

studies that provided data before and after adjustment for all 3 of these factors. The effects 

of study methods, particularly the method of ascertainment of infant feeding status (whether 

contemporary or recalled over a period of >=3 years), study response rate, and definition of 

obesity (equivalent to <95th percentile, 95th to <97th percentile, or >=97th percentile of BMI), 

were examined with meta-regression and sensitivity analyses. 

Results • Among 61 observational studies that reported on the effects of infant feeding on a measure 

of adiposity in later life, 28 studies (298 900 subjects) provided 29 unadjusted odds ratios 

relating the initial infant feeding method and obesity. Four observations were for infants, 23 

for children, and 2 for adults. 

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Author, Year[UI] Topic Owen, 2005 Obesity 

• In a fixed-effects model including all studies, breastfed subjects were less likely to be 

defined as obese than were formula-fed subjects (OR: 0.87; 95% CI: 0.85–0.89). There 

was evidence of marked heterogeneity among studies (p<0.001). 

• Odds ratios of 0.50 (95% CI: 0.26– 0.94) for infants, 0.90 (95% CI: 0.87– 0.92) for young 

children, 0.66 (95% CI: 0.60–0.72) for older children, and 0.80 (95% CI: 0.71– 0.91) for 

adults were observed (test for trend, P= .85, adjusted for study size; P=.99 with the 

exclusion of infants). 

• In 6 studies, it was possible to examine the effect of adjustment for the following potentially 

important confounders: socioeconomic status, parental BMI, and current maternal smoking 

or maternal smoking in early life. The pooled odds ratio in these studies was reduced from 

0.86 (95% CI: 0.81– 0.91) before adjustment to 0.93 (95% CI: 0.88–0.99) after combined 

adjustment. 

• In 14 studies with information on breastfeeding duration, the effect of breastfeeding over 

formula feeding was greater among subjects breastfed for >=2 months (OR: 0.81; 95% CI: 

0.77– 0.84), compared with those breastfed for any duration (OR: 0.89; 95% CI: 0.86–0.91) 

in the same studies. 

• Studies that did not provide odds ratios were much less likely to report that breastfeeding 

was associated with a reduced risk of obesity, compared with studies that did provide odds 

ratios (1 of 35 studies and 18 of 29 studies, respectively; P<.001). 

Quality of the systematic 

review 

B 

Author’s interpretations of 

the results 

“The association between breastfeeding and obesity could reflect selective reporting and/or 

publication. Our results indicated selective reporting of odds ratios by studies that showed a 

relationship between breastfeeding and reduced risk of obesity. However, because the 

studies that did not present odds ratios were on average much smaller than those that 

presented data, their inclusion had a minimal impact on effect estimates.” 

Comments / Limitations Why not use random-effect model? 

C-77
Author, yr: Owen, 2005 

Topic of the systematic review*/MA: 

Reporting yes/no 

Reporting of Background 

1 Description of study outcomes Yes 

2 Types of exposure or intervention used Yes 

3 Types of study designs used Yes 

4 Study population Yes 

Reporting of Search strategy 

5 Search strategy, including time period and key words Yes 

6 Effort to include all available studies (contact with authors) Yes 

7 Databases and registries searched Yes 

8 Method of addressing published articles other than English No 

9 Method of handling abstracts and unpublished studies No 

Reporting of Methods 

10 Rationale for selection and/or coding of data Yes 

11 Assessment of confounding Partially 

12 Assessment of quality Yes 

13 Assessment of heterogeneity Yes 

14 Description of statistical methods sufficient to replicate Yes 

15 Provision of appropriate tables and graphs Yes 

Reporting of Results 

16 Graphic summarizing of individual study estimates and overall Yes 

17 Tables giving descriptive information of each study included Yes 

18 Results of sensitivity testing (subgroup analysis) Yes 

19 Indication of statistical uncertainty of findings Yes 

20 Quantitative assessment of bias (eg. publication bias) Yes 

Overall quality B 

*When grading a systematic review, please skip item #14, 18-20 

Please fill the white areas only 

Evaluation of quality of a systematic review or meta-analysis Yes /No 

/Partially 

1 Is search strategy appropriate/relevant to the key question(s)? Yes 

2 Did authors give justifications for inclusion/exclusion criteria pertaining to the studies of 

interest? 

Yes 

3 Were Population, Intervention/Exposure, Comparator/Control, Outcomes, and Study 

Designs well-defined? 

Yes 

4 Did authors attempt to minimize errors in data extraction (such as collecting the 

relevant data, double data extraction, verification of data extraction...etc.)? 

Yes 

5 Was individual study quality (such as sample size, study design, blinding, various 

biases and confounders, study subject attrition rate...etc.) assessed? 

Yes 

6 Did authors consider appropriate confounders and justification for adjusting or not 

adjusting for those confounders? 

Partially 

7 Was the justification for combining or not-combining data for meta-analysis, or the use 

of a particular analytic method or model appropriate? 

Yes 

8 Was heterogeneity explored (this is in addition to any statistical test of heterogeneity, 

did the authors look at the actual differences in PICOS, for example?)? 

Yes 

8 Were results reported accurately (eg, no discrepancies between text and tables)? Yes 

9 Were conclusions justified by the reported/collected data and analysis? Yes 

C-78
Appendix C. Evidence Tables 

Part I. Term Infant Outcomes 

Sudden Infant Death Syndrome 

Hauck 2003 

McVea 2000 SRMA* 

Mitchell 1997 

Schellscheidt 1997 

Venneman 2005 

* Systematic Review/Meta-Analysis

C-79
Hauck, 2003 [UI# 12728140] 

Study characteristics 

Study design 

and follow-up 

duration 

Eligibility criteria 

Breastfeedi

Exposures 

Intervention

Mean GA (range): 89 days for cases and 85 days for controls Mean BW (range): 2813 g cases and 2915g for controls % Male: nd Race: 75% black; 13.1% Hispanic white; 11.9% nonHispanic white Enrolled/Evaluate: 260 SIDS and 260 matched controls Location: community Sites: Single/Multi Population based Funding: Gov 

Case-control study Follow-up NA 

Cases: Included Chicago resident infants whose death between Nov 1993 and April 1996 was determined by the office of medical examiner of Cook County, Illinois to be caused by SIDS Two weeks after caregivers were asked 235 questions Controls: One living control infant was matched to each case infant on maternal race/ethnicity, age at death/interview; and birth weight. They were randomly selected in groups of 20 for white infants and in groups of 40 for Hispanic and black infants 

Breastfeeding cuyes and ever yes 

Hauck, 2003 [UI# 12728140] 

Outcome Definition Statistical analyses and confounders adjusted Results 

SIDS: The sudden death of an infant under 1 yr of age, which remains unexplained after a thorough case investigation, including performance of a complete autopsy, examination of the death scene, and review of the clinical history. 

Univariate and multivariate models Adjusted for maternal age, marital status, education, and index of prenatal care 

Breast feeding No was reference Breast feeding ever No (cases v controls)/Yes (cases v controls) N=205 v 130 / 55 v 130 OR=0.2 (0.1-0.3) Adj OR=0.4 (0.2-0.7) Breastfeeding current No (cases v controls)/Yes (cases v controls) N=243 v 199 / 17 v 61 OR=0.2 (0.1-0.4) Adj OR=0.3 (0.2-0.7) 

A: mowe

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C-80
Evidence table for Systematic Reviews of Breastfeeding 

Author, Year[UI] McVea 2000 [11138219] SIDS 

Topic The role of breastfeeding in sudden infant death syndrome (SIDS) 

Key questions addressed Question 1 – Infant mortality 

Dates of literature search – 1966-1997 

Databases searched MEDLINE-all English language literature search 

Dissertation Abstracts Online 

Bibliography of all relevant articles 

Countries where primary studies 

conducted 

(Developed v developing) 

Developed (Regions - North America, Europe, and Australia) 

Study eligibility / inclusion criteria Minimal definition of SIDS was met (sudden unexplained death of an infant or young 

child) 

Original data presented that allowed calculation of an odds ratio for bottle feeding 

Study design [No. Of studies] Total = 23 

Case control [18] 

Nested case control [4] 

Cohort [1] 

No. of subjects Cases (n=99) Controls (n=47 413) 

Study population (definition in 

included studies) 

Children (Age range birth to 2 years when outcome occurred – 17 studies; 8 studies 

nd on age range) 

Intervention (definition in included 

studies) 

Breast feeding (No standard method of measuring breast feeding was used in the 

studies - breastfed at birth, breastfed at the time of death, “breast fed”, “partially 

breast fed”) 

Comparator (definition in included 

studies) 

Bottle fed (nd) 

Outcomes (definition in included 

studies) 

SIDS (autopsy proven in majority – 14 studies, death certificates or coroner’s reports 

– 4 studies, unclear – 6 studies) 

Heterogeneity Not explored although studies were heterogeneous with respect to a variety of 

factors 

Quality of Individual studies Yes. Quality scores of studies ranged from 11 to 36 points (on a 42 point max score) 

Better quality studies reported slightly higher risks of bottle feeding 

Publication bias Yes. “The shape of the funnel graph endorsed the absence of publication bias of 

only positive studies” 

Statistical Analysis Random Effects model 

Used unadjusted odds ratio for the meta-analysis 

Separate meta-analysis was performed using only those studies with “good” quality 

scores and after 1988 

Dose-response relationship explored 

Results The pooled OR for the 23 studies using random effects model resulted in an OR = 

2.11 (95% CI 1.66-2.68) i.e. the overall risk of SIDS was twice as great for bottle-fed 

infants compared to breastfed infants. 

The pooled OR from the higher quality studies also demonstrated a two fold 

increase in risk among bottle fed infants OR = 2.24 

The pooled OR from studies after 1988 OR = 2.32 

Confounders: Individual studies adjusted for potential confounders; 6 studies 

reported adjusted OR; 4 studies reported no protective effect of breastfeeding, while 

2 reported adj OR that remained significant. 

Dose Response relationship: 4 out of 9 studies showed a dose response trend 

with the risk of SIDS increasing with increasing formula feeding. None of the studies 

had sufficient power to demonstrate a statistically significant difference between 

partial v no breastfeeding. 

Quality of the systematic review C (see limitations) 

C-81
Author, Year[UI] McVea 2000 [11138219] SIDS 

Comments / Limitations Misclassification of SIDS and breastfeeding 

Unadjusted odds ratio for pooled analysis 

Heterogeneity not explored 

Unable to combine studies with adjusted OR in the pooled analysis because of 

differences in case matching 

C-82
Author, yr: McVea, 2000 

Topic of the systematic review*/MA: The role of breastfeeding in SIDS

Reporting yes/no 

Reporting of Background 

1 Description of study outcomes Y 

2 Types of exposure or intervention used Y 

3 Types of study designs used Y 

4 Study population Y 

Reporting of Search strategy 

5 Search strategy, including time period and key words Y 

6 Effort to include all available studies (contact with authors) N 

7 Databases and registries searched Y 

8 Method of addressing published articles other than English N 

9 Method of handling abstracts and unpublished studies Y 

Reporting of Methods 

10 Rationale for selection and/or coding of data Y 

11 Assessment of confounding N 

12 Assessment of quality Y 

13 Assessment of heterogeneity N 

14 Description of statistical methods sufficient to replicate Y 

15 Provision of appropriate tables and graphs Y 

Reporting of Results 

16 Graphic summarizing of individual study estimates and overall Y 

17 Tables giving descriptive information of each study included Y 

18 Results of sensitivity testing (subgroup analysis) N 

19 Indication of statistical uncertainty of findings Y 

20 Quantitative assessment of bias (eg. publication bias) N 

Overall Quality C 

*When grading a systematic review, please skip item #14, 18-20 

Please fill the white areas only 

Evaluation of quality of a systematic review or meta-analysis Yes /No 

/Partially 

1 Is search strategy appropriate/relevant to the key question(s)? partially 

2 Did authors give justifications for inclusion/exclusion criteria pertaining to the studies of 

interest? 

partially 

3 Were Population, Intervention/Exposure, Comparator/Control, Outcomes, and Study 

Designs well-defined? 

yes 

4 Did authors attempt to minimize errors in data extraction (such as collecting the 

relevant data, double data extraction, verification of data extraction...etc.)? 

no 

5 Was individual study quality (such as sample size, study design, blinding, various 

biases and confounders, study subject attrition rate...etc.) assessed? 

yes 

6 Did authors consider appropriate confounders and justification for adjusting or not 

adjusting for those confounders? 

yes 

7 Was the justification for combining or not-combining data for meta-analysis, or the use 

of a particular analytic method or model appropriate? 

yes 

8 Was heterogeneity explored (this is in addition to any statistical test of heterogeneity, 

did the authors look at the actual differences in PICOS, for example?)? 

no 

8 Were results reported accurately (eg, no discrepancies between text and tables)? yes 

9 Were conclusions justified by the reported/collected data and analysis? partially 

C-83
Mitchell 1997 [UI# 9346984] 

Study characteristics 

Study 

design and 

follow-up 

duration 

Eligibility criteria Breastfeeding Exposu

Interventions 

Mean GA (range): 2.6-9.1 wk for cases; 2.4-9.2 wk for controls Mean BW (range): <2500 to 3500+ % Male: 60% cases; 52% controls Race: Maori 56% cases and 22% controls Non Maori 44% cases and 78% controls Enrolled/Evaluate: 232 cases and 922 controls Location: community Sites: Single/Multi Population based Funding: Gov 

Case-cohort study design 2 yr cohort; follow-up duration NA 

Cases: All deaths registered by the New Zealand Health Information Service as attributable to SIDS in the postneonatal age group (dying after 28 completed days and within the first year of life) form the cases of this study. 98% of deaths classified as SIDS have had a autopsy. Controls: Randomly selected sample from a prospectively collected cohort on all births in the 2 yr period. The method of sampling was 1) a date of birth was randomly selected from all the days in the study period; 2) an obstetric hospital was randomly chosen in proportion to the number of births; 3) in the obstetric hospital with multiple births on nominated date of birth random numbers were used to select a particular infant from among those born on that day; 4) a direction variable which indicates to either go forward or back in looking for a birth in the situation where the hospital did not have one on the nominated day was also randomly chosen 

Three measures of breastfeeding reference yExclusive breastfeeding adischarge from the obstethospital; any breastfeedininitial contact; and any brefeeding at 2 months 

Mitchell 1997 [UI# 9346984] 

Outcome Definition Statistical analyses and confounders adjusted Results B

SIDS: dying after 28 completed days and within the first year of life 

Univariate and multivariate analysis Controlled for: maternal age, marital status, age mother left school, previous number of pregnancies, infant’s sex, ethnicity of infant, birthweight, sleep position, breastfeeding and bed sharing/maternal smoking combinations. 

The three measures of breastfeeding were not statistically associated with a statistically significant reduction in the risk of SIDS 

A: strong, B: mweak 

Selection Study design Confounder Blinding Data collectioWithdraw and Analyses Intervention in

Comments The controls were randomly selected from a prospective cohort; however the analysis was conducted as a case-control s

C-84
Schellscheidt J 1997 [UI# 9266202] 

Study characteristics Study design and follow-up duration Eligibility criteria Breastfeeding Exposures or Interventions 

Mean GA (range): 8 days to one yr Mean BW (range): nd % Male: nd Race: nd Enrolled/Evaluate: 59 Location: community Sites: Single/Multi Population based study Funding: nd 

Case-control study Follow-up Not applicable Incidence of SIDS during the 2 yrs 

For cases: No positive autopsy findings; minimal findings without any relationship to death; findings possibly related to death (but not explaining it) and autopsy findings explaining death. For controls: Two controls were selected for each case of the same age ±4 weeks and sex randomly by the pediatrician or a general practitioner 

Breastfeeding in week>12 wks (ref) 

Schellscheidt J 1997 [UI# 9266202] 

Outcome Definition Statistical analyses and confounders adjusted Results Bias

Co

Same as eligibility criteria Variables were entered as dichotomous indicators 

Analyses were univariate. No confounders were adjusted 

Breast feeding cases versus controls  None (N=29 vs 27) OR=7.7 (2.7, 22.3) 1-6 wk (N=12 vs 40) OR=2.1 (0.7, 6.7) 7-12 wk (N=10 vs 39) OR=1.8 (0.6, 6.0) >12 wk (N=7 vs 50) REF 

A: strong, B: mode

Selection Study design Confounder Blinding Data collection Withdraw and dropAnalyses Intervention integrit

C-85
Vennemann, 2005 [UI# 16188764] 

Study characteristics Study design and follow-up duration Eligibility criteria Breastfeeding Exposure

or Interventions 

Mean GA (range): nd Mean BW (range): nd % Male: cases 60.4% Controls 60.3% Race: nd Enrolled/Evaluate: SIDS cases 404/333 Location: population based Sites: Single/Multi 18 centers involved Funding: nd 

Case-control study design Duration SIDS during 3 yr period Follow-up duration NA 

Cases: All reported cases of sudden and unexpected deaths in the first year of life after the first 7 d and all cases were autopsied. Controls: Three controls with the best age matching were chosen 

Breastfeeding >2 wk yes 

Vennemann, 2005 [UI# 16188764] 

Outcome Definition Statistical analyses and confounders adjusted Results 

Sudden and unexpected deaths in the first year of life after the first 7 d and all cases were autopsied. 

Univariate and multivariate analysis were done using conditional logistic regression. The multivariate model includes all variables which were found significant at the 5% level in the univariate analysis except gestational age, as this was closely related to birthweight 

Breastfeeding >2wk Yes N=165/827 (cases/controls) No N=168/171 Univariate OR=5.36 (3.97-7.23) Multivariate OR=1.71 (1.06-2.77) 

A: moweSeStuCoBliDaWidroAnIntinte

Ove

C-86
Appendix C. Evidence Tables 

Part I. Term Infant Outcomes 

Type 1 DM 

EURODIAS 2002 

Gerstein 1994 SRMA* 

Jones 1998 

McKinney 1999 

Meloni 1997 

Norris 1996 SRMA* 

Tai 1998 

Visalli 2003 

* Systematic Review/Meta-Analysis

C-87
EURODIAS, 2002 [12351473] 

Study characteristics 

Study 

design and 

follow-up 

duration 

Eligibility criteria Breastfeeding Exposures or Interven

Age at Dx of IDDM: ND Mean GA (range): ND Mean BW (range): ND % Male: ND Race: ND Enrolled/Evaluate: 683/610 for cases; 2167/1616 for controls Location: Europe Sites: Multi Funding: Government 

Case-control study 

Cases: cases were identified from a population-based 

register of childhood-onset diabetes operating in a substudy of EURODIAB (5 participating centers) 

Controls: a population-based sample of control children, 

matched to the patients in age distribution, was obtained in each center using sources that depended on local circumstances as previously described (including schools, population register, polyclinics, and general practitioner register) 

Parents were interviewed or filled in the questionnaire regarding information aboufeeding (duration of breast-feeding, age aintroduction of formula feeding, dairy milkcontaining fruit, vegetable, fish, meat, and Breast-feeding of any duration (or ever brfeeding) 

EURODIAS, 2002 [12351473] 

Outcome 

Definition Statistical analyses and confounders adjusted Results 

Pooled ORs of IDDM for exposures obtained from each center 

Mantel Haenszel approach was used to pool odds ratio 

(ORs) for exposures (e.g. breastfeeding, early introduction of solid food) obtained from each center, to test the significance of the combined OR, and to test for heterogeneity in the ORs between centers. 

To adjust for potential confounders, logistic regression 

analysis was used with terms included in the model to represent centers. Adjustments included height SDS, weight SDS, maternal age at delivery, neonatal jaundice, neonatal respiratory infection, vitamin D supplementation, and asthma. 

Breast-feeding of any duration was associated with a reduction 

in risk, with a pooled OR of 0.75 (95% CI 0.58-0.96) and no evidence of heterogeneity between centers. 

The introduction of cow’s milk before 3 months of age (OR 1.15, 

95%CI 0.74-1.81), cow’s milk or formula (OR 1.01, 95%CI 0.81-1.25), or solid foods (OR 0.74, 95%CI 0.57-0.95) was not associated with any significant elevation in risk. Indeed the finding for solid foods suggested a reduced risk, although there was significant heterogeneity between centers (p<0.001). 

The OR associated with breastfeeding in multivariate analysis 

remained significant (OR=0.59, 95%CI 0.35-0.97) 

AwWA

OLo

C-88
Q1: Insulin-Dependent Diabetes Mellitus 

Author, Year[UI] Gerstein, 1994 [8112184] Type 1 Diabetes Mellitus 

Literature search 

(Dates)

Medline (no data); Other databases searched? (no); unpublished data used? (yes) 

Countries where 

primary studies 

conducted 

Developed countries only: Norway, Denmark, Italy, US, Australia, Canada, Sweden, Finland, UK 

Study eligibility / 

inclusion criteria 

Articles or letters to the editor were eligible for inclusion if they reported original research dealing 

with both type I diabetes and cow’s milk exposure or avoidance and were published in peerreviewed journals. Articles were excluded if they exclusively used surrogate markers for either type 

I diabetes or cow’s milk exposure. 

Study design [No. Of 

studies] 

Ecological and time-series studies [3]; Case-control studies [13]; Cohort study [1]; case series [1] 

No. of subjects Data available for case-control studies only: 

Cases: 3,708 Controls: 20,340 

Study population 

(definition in included 

studies) 

• Ecological and time-series studies in which the prevalence of type I DM was compared 

with the rate of breast-feeding or cow’s milk consumption in different populations or over 

a specified period of time. 

• Case-control studies in which the neonatal feeding histories of patients with type I DM 

and individually matched non-DM control subjects were compared. Studies that used 

population breast-feeding registries as control data also were included, because the low 

prevalence of type I DM in the general population ensures that population data is 

representative of the breast-feeding habits of non-DM individuals. 

• There was a letter to the editor reporting an analysis of two cohort studies and an article 

that described the neonatal feeding history of a series of patients with DM. 

• There were no controlled trials of exposure to cow’s milk. 

Intervention/Exposure 

(definition in included 

studies) 

Cow’s milk exposure (and therefore non-exclusive breastfeeding) 

Comparator 

(definition in included 

studies) 

Cow’s milk avoidance (and therefore breastfeeding) 

Outcomes (definition 

in included studies) 

Type I DM. 

Surrogate markers of type I DM (such as the presence of islet cell antibodies) were excluded. 

Heterogeneity 

assessments 

Q statistics and chi-square distribution 

Quality assessments Six methodological criteria were assessed for case-control studies only. Each criterion was marked 

individually and listed in a summary table of all studies. There was no summary grading. 

Publication bias 

assessments 

Not done 

Statistical Analysis or 

meta-analytic 

methods 

Meta-analyses of ORs were done for case-control studies. Both adjusted (preferred) and 

unadjusted ORs were used. Fixed-effect model. 

C-89
Author, Year[UI] Gerstein, 1994 [8112184] Type 1 Diabetes Mellitus 

Results • Time-series and ecological studies showed an association (geographically and 

temporally) between rate/prevalence of breastfeeding and the incidence of type I DM. 

• Results from the 13 case-control studies were mixed. Some of these studies 

demonstrated that patients with type I DM were more likely to have a history of neonatal 

cow’s milk exposure or a short/negative history of breast-feeding than non-DM control 

subjects; other studies failed to demonstrate such a relationship. When these results 

were meta-analyzed, the OR for type I DM in patients exposed to <3 months of breastfeeding was 1.38 (95% CI 1.22-1.53; p=0.11 for homogeneity). Similarly, the overall OR 

for cow’s milk exposure before 3-4 months of age in patients with type I DM was 1.57 

(95% CI 1.19-2.07; p=0.10 for homogeneity). 

• An analysis of two cohorts of children born in the UK in 1958 and 1970 followed for 16 

and 10 years, respectively, failed to show any association between breastfeeding for <1 

month and type I DM. 

Quality of the 

systematic review 

B 

Author’s 

interpretations of the 

results 

The results of this review are consistent with the hypothesis that avoidance of cow’s milk products 

during the first few months of life may reduce the risk of type I DM. A feeding intervention trial in 

which susceptible newborns would be randomized to receive formula with or without cow’s milk and 

followed for the development of DM would most clearly resolve the issue. 

Comments / 

Limitations 

This systematic review primarily aimed to examine the relationship between early cow’s milk 

exposure and type I DM. However, exclusive breastfeeding is a way of avoidance of cow’s milk 

exposure; then therefore this review also examined the association between breastfeeding and 

type I DM. The exclusivity of breastfeeding was not addressed in the meta-analyses. 

Combining both adjusted and crude OR. 

Author, yr: Gerstein, 1994 

Topic of the systematic review*/MA: Type 1 DM

Reporting yes/no 

Reporting of Background 

1 Description of study outcomes Yes 

2 Types of exposure or intervention used Yes 

3 Types of study designs used Yes 

4 Study population Yes 

Reporting of Search strategy 

5 Search strategy, including time period and key words No 

6 Effort to include all available studies (contact with authors) No 

7 Databases and registries searched Yes 

8 Method of addressing published articles other than English No 

9 Method of handling abstracts and unpublished studies No 

Reporting of Methods 

10 Rationale for selection and/or coding of data Yes 

11 Assessment of confounding No 

12 Assessment of quality Yes 

13 Assessment of heterogeneity Yes 

14 Description of statistical methods sufficient to replicate Yes 

15 Provision of appropriate tables and graphs Yes 

Reporting of Results 

16 Graphic summarizing of individual study estimates and overall Yes 

17 Tables giving descriptive information of each study included Yes 

18 Results of sensitivity testing (subgroup analysis) Yes 

19 Indication of statistical uncertainty of findings Yes 

C-90
Reporting yes/no 

20 Quantitative assessment of bias (eg. publication bias) Yes 

Overall quality B 

*When grading a systematic review, please skip item #14, 18-20 

Please fill the white areas only 

Evaluation of quality of a systematic review or meta-analysis Yes /No 

/Partially 

1 Is search strategy appropriate/relevant to the key question(s)? Partially 

2 Did authors give justifications for inclusion/exclusion criteria pertaining to the studies of 

interest? 

Yes 

3 Were Population, Intervention/Exposure, Comparator/Control, Outcomes, and Study 

Designs well-defined? 

Yes 

4 Did authors attempt to minimize errors in data extraction (such as collecting the 

relevant data, double data extraction, verification of data extraction...etc.)? 

No 

5 Was individual study quality (such as sample size, study design, blinding, various 

biases and confounders, study subject attrition rate...etc.) assessed? 

Yes 

6 Did authors consider appropriate confounders and justification for adjusting or not 

adjusting for those confounders? 

Partially 

7 Was the justification for combining or not-combining data for meta-analysis, or the use 

of a particular analytic method or model appropriate? 

Partially 

8 Was heterogeneity explored (this is in addition to any statistical test of heterogeneity, 

did the authors look at the actual differences in PICOS, for example?)? 

Yes 

8 Were results reported accurately (eg, no discrepancies between text and tables)? Yes 

9 Were conclusions justified by the reported/collected data and analysis? Yes 

C-91
Jones, 1998 [9698133] 

Study characteristics 

Study 

design and 

follow-up 

duration 

Eligibility criteria 

Breastfeed

Exposures 

Interventio

Age at Dx of IDDM: ND Mean GA (range): ND Mean BW (range): ND % Male: 53 Race: ND Enrolled/Evaluate: <76/60 for cases Location: UK Sites: Multi Funding: Government 

Case-control study 

Cases: Oxford Record Linkage Study (ORLS) records of hospital admissions for 

discharge diagnoses coded to diabetes mellitus were searched. Cases were identified as children who were diagnosed with diabetes 1965-1987, and who had been born during 1965-1986 (N=315). 98% of cases born 1970-1986 were matched with 5 or more controls each. 

Controls: for cases born 1970-1986, 8 controls from all livebirths in the ORLS areas 

were randomly selected. Controls were individually matched to cases on sex, year and hospital of delivery, or if domiciliary to another domiciliary delivery. 

Exclusion: children with cystic fibrosis or major congenital anomalies, or who were part 

of twin or higher order deliveries. 

Breastfeeding data were routinely collected only from 1976 so this result is based upon 

60 cases and 458 controls born 1976-1986, of which 7 controls had missing data. 

Breastfeeding discharge 

Jones, 1998 [9698133] 

Outcome 

Definition Statistical analyses and confounders adjusted Results 

Relative risk of IDDM 

Relative risks were calculated by estimating rate ratios using conditional logistic regression for matched casecontrol studies. 

There was a small, but not significant, raised risk of diabetes with not breastfeeding at discharge (RR=1.33, 95% CI: 0.76-2.31). 

A: strong, BC: weak 

Selection Study desigConfoundeBlinding Data collecWithdraw aAnalyses Intervention 

Overall: C Poor adjustmdefinition of B

C-92
McKinney, 1999 [10372244] 

Study characteristics 

Study 

design and 

follow-up 

duration 

Eligibility criteria Breastfeeding Exposur

Interventions 

Age at Dx of IDDM: 0-15 Mean GA (range): 11% 

≤37 wks 

Mean BW (range): 7% <2500g, 58% 2500-3500g; 35% 

≥3500g 

% Male: 55 Race: 95% White, 3.5% India or Pakistan Enrolled/Evaluate: 202/196 for cases354/325 for controls Location: UK Sites: Single Funding: Private 

Case-control study 

Cases: Incident cases included those diagnosed with type 1 DM 

over a 2-year period (1993-1994) and taken from the population-based Yorkshire Childhood Diabetes Register (YCDR). The register ascertained children from 3 independent sources and was estimated to be 97% complete. 

Controls: 2 control subjects per case, matched by sex and age, 

were randomly selected from the primary care registrations of the Family Health Service Authority (FHSA) of the matched case. 

Exclusion: 6 cases and 29 control subjects had no matching 

control subjects or cases and were lost to the matched analysis 

Mothers were interviewed. Participation rates for the interview study were 93.6% 81.9% for case and control mothers, respectively. Initial exclusive breast feed(yes): mothers were asked the infant was first fed 

McKinney, 1999 [10372244] 

Outcome 

Definition Statistical analyses and confounders adjusted Results 

OR of IDDM ORs with95% CI and p values were calculated 

using conditional logistic regression with a single term in the model for univariate estimates. Variables significantly associated with disease obtained from the analysis of individual variables were modeled together in a multivariable analysis. 

Variables significant at the 5% level in a 

univariate analysis in our study were mother's age (<25, 25-35, >35), type 1 diabetes mothers, preeclampsia, delivery by cesarean section, neonatal illnesses, and breast feeding. These potential explanatory variables were modeled together in a multivariable analysis. 

Factors in the model Cases Controls OR (95% CI) 

n 196 325 Mother’s age  25-35 years 123 182 1.69 (1.11-2.60)  >35 years 2.07 (0.97-4.43) Mother with IDDM 4 0 -- Preeclampsia 44 49 1.60 1.01-2.54) Cesarean delivery 34 35 1.45 (0.82-2.55 Neonatal illnesses 

≥1 61 35 1.55 (1.00-2.42) 

Initial exclusive breast feeding 

73 151 0.60 (0.41-0.89) 

Results show all variables retained their significance in the multivariate model. The addition of neonatal illnesses and breast feeding significantly improved the model fit (likelihood ratio test, chi squared 9.96, P = 0.007). Note: Crude OR = (73*174)/(151*123)=0.68, p=0.04 

A: smowea

SelStuConBlinDatWitdroAnaInteinte

OverNo a

C-93
Meloni, 1997 [9051384] 

Study 

characteristics 

Study 

design and 

follow-up 

duration 

Eligibility criteria Breastfeeding Exposures or Interventions 

Age at Dx of IDDM: 6 (1-15) yr Mean GA (range): ND Mean BW (range): ND % Male: 53 Race: ND Enrolled/Evaluate: 115/100 for cases Location: Italy Sites: Single Funding: ND 

Case-control study 

Cases: All diabetic subjects followed up at the university hospital who 

met the inclusion criteria: 1: age < 17 years at diagnosis of IDDM, 2) diagnosis of IDDM was achieved between 1983 and1994, and 3) patient’s mother was currently living, which was considered necessary to obtain accurate infant diet information. According to these criteria, 100 IDDM patients (of the 115 eligible) were included. 

Controls: children admitted at the same university hospital, matched each 

diabetic case for sex and age. None of the control subjects had a family history of IDDM. 

Long-term maternal recall of the duration of complete or partial breast-feeding during infant’s 1st year of life. 

Meloni, 1997 [9051384] 

Outcome Definition Statistical analyses and confounders adjusted Results 

Risk of IDDM, compared children who had been breast-fed to those who had not been breast fed Risk of IDDM, compared children who had been breast-fed for 1-2 months, 3-5 months, or >6 months to those who had not been breast-fed. 

The OR of diabetes according to breast-feeding, the duration of breast-feeding, the age at introduction of dietary products containing cow’s milk, and the age at introduction of solid food were estimated by means of conditional logistic regression, where the strata were defined by single year of age at interview and sex. Also included in the models were terms for mother’s education and number of siblings. 

IDDM 

cases 

Controls OR (95% CI) 

BF  Yes 84 70 1*  No 16 30 0.41 (0.19-0.91) Duration of BF (mo)  >6 25 19 1*  3-5 41 25 1.18 (0.52-2.68)  1-2 18 26 0.48 (0.19-1.24)  0 16 30 0.36 (0.14-0.94)  Continuous coefficient** 

1.10 (0.99-1.22) 

*reference category **continuous per 1 month increase 

A: strmodeweak 

SelecStudy ConfoBlindiData WithddropoAnalyIntervintegr

OveralLimitatrecalls. 

C-94
Q1: Insulin-Dependent Diabetes Mellitus 

Author, Year[UI] Norris, 1996 [8664407] Type 1 Diabetes Mellitus

Literature search 

(Dates)

Medline (1966-1994); Other databases searched? (no); unpublished data used? (yes) 

Countries where 

primary studies 

conducted 

Developed countries only: Norway, Denmark, Italy, US, Australia, Canada, Sweden, Finland, British 

Isles, Ireland, UK 

Study eligibility / 

inclusion criteria 

Inclusion: all epidemiologic studies examining infant diet and IDDM risk 

Exclusion: studies with insufficient data for meta-analyses 

Study design [No. Of 

studies] 

Case-control studies [17] 

No. of subjects Cases: 4,656 Controls: 16,383 

Study population 

(definition in included 

studies) 

Cases: IDDM patients identified from diabetes clinics, school surveys, registries, physician surveys, 

or pediatric departments. 

Controls: non-IDDM controls selected from siblings, national population data, friends, classmates, 

physician referred samples, national population registry, random sample of household, child health 

system, or schools and day care 

Intervention/Exposure 

(definition in included 

studies) 

A=breastfeeding status (ever/never) 

B=total breastfeeding duration 

Comparator 

(definition in included 

studies) 

C=exposure to breast-milk substitutes 

D=exposure to cow’s milk-based substitutes 

Outcomes (definition 

in included studies) 

Odds ratios for the risk of IDDM 

Heterogeneity 

assessments 

“The addition to the model of a variable for each study in the analyses resulted in an improvement 

in the overall fit of the model (as determined by the log-likelihood statistic) compared with the model 

containing only the exposure variable, indicating heterogeneity of effect across studies. We also 

evaluated study heterogeneity by adding to the model product terms obtained by multiplying the 

exposure variable by each study variable.” 

Quality assessments Sensitivity analyses on various study characteristics 

Publication bias 

assessments 

Including unpublished data 

Statistical Analysis or 

meta-analytic 

methods 

Stratified unconditional logistic regression was used to estimate OR and 95%CI. This method 

weights each study by its sample size. Variables for the individual studies and for the exposure of 

interest were included in the model. Both matched and unmatched ORs were used. 

Results • The summary odds ratio (OR) of the 18 studies that examined the association between never 

being breast-fed and IDDM was 1.13 (95% CI = 1.04-123). 

• Meta-analyses of summary ORs were done in the 14 studies that examined IDDM risk by 

months of breastfeeding duration. The duration categories in the analyses were cumulative, 

rather than mutually exclusive. The summary OR for IDDM in subjects who were breast-fed for 

less than 3 months compared with those who were breast-fed for at least 3 months was 1.23 

(95%CI = 1.12-1.35). 

• When comparing the ORs by whether or not the studies relied on long-term recall to assess 

infant diet, studies using existing infant records to determine breastfeeding initiation and 

duration failed to show the associations reported in the studies relying on long-term recall for 

their exposure data. 

Quality of the 

systematic review 

B 

Author’s 

interpretations of the 

results 

Our meta-analysis showed that the increased risk of IDDM associated with any of the infant diet 

exposures is small Interpretation of weak associations (that is, generally an OR<2) can be 

problematic, since weak associations can more readily be explained by bias. 

C-95
Author, Year[UI] Norris, 1996 [8664407] Type 1 Diabetes Mellitus

Comments / 

Limitations 

Very thoughtful analyses but the analysis cannot be replicated due to lack of individual study data. 

Only crude ORs were used in the meta-analyses due to limitation of meta-analytic technique. 

Conclusions were well justified. 

C-96
Author, yr: Norris, 1996 

Topic of the systematic review*/MA: Type 1 DM

Reporting yes/no 

Reporting of Background 

1 Description of study outcomes yes 

2 Types of exposure or intervention used yes 

3 Types of study designs used yes 

4 Study population yes 

Reporting of Search strategy 

5 Search strategy, including time period and key words no 

6 Effort to include all available studies (contact with authors) yes 

7 Databases and registries searched yes 

8 Method of addressing published articles other than English no 

9 Method of handling abstracts and unpublished studies yes 

Reporting of Methods 

10 Rationale for selection and/or coding of data yes 

11 Assessment of confounding yes/no 

12 Assessment of quality yes 

13 Assessment of heterogeneity yes 

14 Description of statistical methods sufficient to replicate yes 

15 Provision of appropriate tables and graphs yes 

Reporting of Results 

16 Graphic summarizing of individual study estimates and overall no 

17 Tables giving descriptive information of each study included yes 

18 Results of sensitivity testing (subgroup analysis) yes 

19 Indication of statistical uncertainty of findings yes 

20 Quantitative assessment of bias (eg. publication bias) yes 

Overall quality B 

*When grading a systematic review, please skip item #14, 18-20 

Please fill the white areas only 

Evaluation of quality of a systematic review or meta-analysis Yes /No 

/Partially 

1 Is search strategy appropriate/relevant to the key question(s)? Partially 

2 Did authors give justifications for inclusion/exclusion criteria pertaining to the studies of 

interest? 

Yes 

3 Were Population, Intervention/Exposure, Comparator/Control, Outcomes, and Study 

Designs well-defined? 

Yes 

4 Did authors attempt to minimize errors in data extraction (such as collecting the 

relevant data, double data extraction, verification of data extraction...etc.)? 

Yes 

5 Was individual study quality (such as sample size, study design, blinding, various 

biases and confounders, study subject attrition rate...etc.) assessed? 

Yes 

6 Did authors consider appropriate confounders and justification for adjusting or not 

adjusting for those confounders? 

Partially 

7 Was the justification for combining or not-combining data for meta-analysis, or the use 

of a particular analytic method or model appropriate? 

Yes 

8 Was heterogeneity explored (this is in addition to any statistical test of heterogeneity, 

did the authors look at the actual differences in PICOS, for example?)? 

Yes 

8 Were results reported accurately (eg, no discrepancies between text and tables)? Yes 

9 Were conclusions justified by the reported/collected data and analysis? Yes 

C-97
Tai, 1998 [9925351] 

Study characteristics 

Study design 

and follow-up 

duration 

Eligibility criteria Breastfeeding Exposures 

Interventions 

Age at Dx of IDDM: 8.3±3.3 SD Mean GA (range): 1% 

≤36 wk; 

99% >36 wk 

Mean BW (range): 21% <3 kg, 69% 3-3.9 kg; 10% 

≥4 kg 

% Male: 37 Race: Asian Enrolled/Evaluate: 117/117 for cases; 193/193 for controls Location: Taipei, R.O.C. Sites: Single Funding: Government 

Case-control study 

Cases: From 1984 to 1993, there were a total of 161 

registered type 1 diabetes patients who were under the age of 30, born in Taipei City and continuously living in the same city. Among these, 119 (73%) subjects agreed to participate in the study. Their overnight fasting serum C-peptide concentration was < 0. 12 nmol/l and/or an increment in C-peptide from basal value after 1mg glucagons intravenous injection. 

Controls: The control group was selected from normal 

classmates or colleagues of the type 1 diabetes subjects. They were frequency-mated for age, sex, and parental and individual educational levels. All controls had a plasma glucose concentration, 2 h after 1.75 g/kg glucose loading, <140 mg/dl, fasting C-peptide value >0.16 nmol/l and were negative for islet cell antibody. 

In the majority of the study subjeccases and 75% controls), their mowere interviewed by 2 trained nuthe remaining study subjects, the questionnaire interviews were ansby the subjects themselves or by fathers with the help of their mothFeeding style during infancy: breafeeding Duration of breast-feeding: <6, 

≥6 

C-98
Tai, 1998 [9925351] 

Outcome 

Definition 

Statistical analyses and confounders 

adjusted Results 

OR of developing IDDM 

Age and sex were adjusted using logistic regression analysis. The age-sexadjusted ORs were estimated from the regression coefficient and its S.E. for the risk factor. Multiple logistic regression analysis was then carried out by including risk factors which were statistically significant in univariate analyses as well as those reported in other studies in the model. 

I. Age-sex-adjusted ORs of developing IDDM (univariate): 

Risk factors Cases N Controls N OR (95% CI) 

Feeding style during infancy  Breast-feeding 46 82 1.00  Cow’s milk 70 109 1.43 (0.83-2.47) Duration of BF (months)  Never 70 109 1.00  <6 32 52 0.82 (0.47-1.42) 

≥6 10 25 0.39 (0.16-0.94) 

II. Multiple logistic regression in which the order of pregnancy, paternal age at the conception of the study subjects, gestational age, type of delivery, birth weight, duration of breast-feeding and monthly family income were included in the model. 

Duration of BF (months) OR (95% CI) 

 Never 1.00  <6 0.84 (0.45-1.59) 

≥6 0.25 (0.09-0.69) 

The dose-response relationship with type 1 DM for pregnancy order and the reverse pattern for duration of breast-feeding remained statistically significant after adjustment for multiple risk factors. 

A: stronmodera

SelectioStudy dConfounBlinding Data coWithdraAnalyseInterven

Overall: B Inconsisteascertain

C-99
Visalli, 2003 [12876166] 

Study characteristics 

Study design 

and follow-up 

duration 

Eligibility criteria 

Breastfeedi

Exposures 

Interventio

Age at Dx of IDDM: ND Mean GA (range): ND Mean BW (range): ND % Male: 50 Race: ND Enrolled/Evaluate: 330/150 for cases; 1200/750 for controls Location: Italy Sites: Multi Funding: 

Case-control 

study 

Cases: type 1 DM patients selected (330 cases) for this study were diagnosed 

within the EURODIAS ACE study, and were born between 1977 and 1989. 

Controls: population based control subjects born in the same period were chosen from primary and secondary school enrolment records in the region, and the selection process was designed in collaboration with EURODIAS Substudy 2 group. Out of 1,100 controls replied to the questionnaires, 750 were randomly selected, matching 1 case with 5 controls by age. 

Questionnaires wdistributed to all pof cases and conDuration of breasfeeding ≥ 3 montEnd of breast fee3 months 

Visalli, 2003 [12876166] 

Outcome 

Definition 

Statistical analyses and 

confounders adjusted Results Bia

C

OR of IDDM Conditional logistic 

regression analysis was performed to adjust the possible confounders (those significant in univariate analyses). 

I. Univariate analysis: 

Risk factors OR 95% CI 

Full term birth 1.44 0.81-2.56 Duration of BF < 3 mo 2.12 1.38-3.26 Beginning of weaning < 3 mo 1.81 1.06-3.07 End of breast feeding < 3 mo 2.03 1.24-3.33 Cow’s milk before 23 mo 1.49 0.72-3.11 

II. Multivariate logistic regression analysis for risk factors which have been found to be significant 

Risk factors OR 95% CI 

Duration of BF < 3 mo 1.74 1.40-2.45 Family history of type 1 DM 1.17 1.05-1.76 Presence of infectious disease during mother’s pregnancy 

1.60 1.32-2.20 

Occurrence of eczema 1.61 1.25-2.66 

A: strong, B: mod

Selection Study design Confounder Blinding Data collection Withdraw and droAnalyses Intervention integr

Overall: C Only 45% of the eligcontacted. 

C-100
Appendix C. Evidence Tables 

Part I. Term Infant Outcomes 

Infant Type 2 DM 

Owen 2006 SRMA* 

Taylor 2005 SRMA* 

* Systematic Review/Meta-Analysis

C-101
Evidence table for Systematic Reviews of Breastfeeding 

Author, Year[UI] Topic Owen, 2006 Type 2 diabetes 

Literature search (Dates) Medline (1966-November 2004); Other databases searched? (yes); unpublished data used? 

(no) 

Countries where primary 

studies conducted 

Developed countries: UK, US, Canada, Dutch 

Study eligibility / inclusion 

criteria 

Exclusion criteria: infant feeding status or measures of diabetes were not recorded. Studies 

did not compare diabetic outcomes among those formula and breastfed. Studies did not 

provide the odds of type 2 diabetes, mean differences in blood glucose, or differences in 

plasma insulin between those breastfed and formula fed. 

Note: For the purpose of this review, we only focus on those studies reported OR of type 2 

diabetes as an outcomes. 

Study design [No. Of 

studies] 

Historical cohort study [3]; Cross-sectional study [2]; Prospective cohort [1]; Case-control 

study [1] 

No. of subjects Total of 76,744 subjects 

Study population (definition 

in included studies) 

6 studies conducted in adults and 1 conducted in adolescents 

Intervention/Exposure 

(definition in included 

studies) 

Comparator (definition in 

included studies) 

Ever breastfed vs. formula fed in all 7 studies. 

Feeding status was reported as being exclusive in one of these studies. 

Outcomes (definition in 

included studies) 

OR (95% CI) of type 2 diabetes 

Heterogeneity assessments Chi-squared test. 

Meta-regression and sensitivity analysis were used to examine potential heterogeneity 

across studies (see Quality assessment) 

Quality assessments The effect of study size, year of birth, the method of ascertainment of infant feeding status 

(whether contemporary or recalled up to 71 y after birth), type of formula fed, study response 

rate (analyzed as a continuous variable), study design (randomized controlled trial, casecontrol, or cohort), and whether infants were born pre- or full-term was examined by using 

meta-regression and sensitivity analysis. 

Sensitivity analyses were used to examine the effect of adjustment for important 

confounders and of fasting status. 

Publication bias 

assessments 

Funnel plots with Begg and Egger tests 

Statistical Analysis or metaanalytic methods 

Fixed-effect model. 

Results • Six of the 7 studies related breastfeeding to a lower risk of type 2 diabetes, and there 

was no evidence of heterogeneity across studies. 

• Overall, the subjects who were breastfed showed a lower risk of type 2 diabetes than did 

those who were formula fed (pooled OR: 0.61; 0.44-0.85; p=0.003). 

• Three studies had information on relevant confounders (birthweight, parental diabetes, 

socioeconomic status, and individual or maternal body size). However the OR relating 

breastfeeding and diabetes risk was similar before (0.55; 95% CI: 0.35-0.86; p=0.009) 

and after (0.55, 95% CI 0.34-0.90; p=0.017) adjustment. 

• The method for ascertaining feeding exposure was unrelated to the ORs. 

Quality of the systematic 

review 

A 

Author’s interpretations of 

the results 

In the present overview of published studies relating infant feeding and risk of diabetes, the 

pooled estimate from 6 studies conducted in adults and 1 study conducted in adolescents 

showed that early breastfeeding was consistently associated with a lower risk of type 2 

diabetes in later life compared with those initially formula fed. 

C-102
Author, Year[UI] Topic Owen, 2006 Type 2 diabetes 

Publication bias is an important potential explanation for the consistent associations 

observed in these published studies. The results provide no evidence of marked publication 

bias, although the statistical power of formal tests was limited by the small number of studies 

available for analysis. 

It is possible that confounding by birthweight and maternal factors could lead to 

overestimation of the association between breastfeeding and diabetes in later life. 

Comments / Limitations Pooled different study designs 

C-103
Author, yr: Owen, 2006 

Topic of the systematic review*/MA: Type 2 DM

Reporting yes/no 

Reporting of Background 

1 Description of study outcomes yes 

2 Types of exposure or intervention used yes 

3 Types of study designs used yes 

4 Study population yes 

Reporting of Search strategy 

5 Search strategy, including time period and key words yes 

6 Effort to include all available studies (contact with authors) no 

7 Databases and registries searched yes 

8 Method of addressing published articles other than English no 

9 Method of handling abstracts and unpublished studies no 

Reporting of Methods 

10 Rationale for selection and/or coding of data yes 

11 Assessment of confounding yes 

12 Assessment of quality yes 

13 Assessment of heterogeneity yes 

14 Description of statistical methods sufficient to replicate yes 

15 Provision of appropriate tables and graphs yes 

Reporting of Results 

16 Graphic summarizing of individual study estimates and overall Yes 

17 Tables giving descriptive information of each study included yes 

18 Results of sensitivity testing (subgroup analysis) yes 

19 Indication of statistical uncertainty of findings yes 

20 Quantitative assessment of bias (eg. publication bias) yes 

Overall quality A 

*When grading a systematic review, please skip item #14, 18-20 

Please fill the white areas only 

Evaluation of quality of a systematic review or meta-analysis Yes /No 

/Partially 

1 Is search strategy appropriate/relevant to the key question(s)? Yes 

2 Did authors give justifications for inclusion/exclusion criteria pertaining to the studies of 

interest? 

Yes 

3 Were Population, Intervention/Exposure, Comparator/Control, Outcomes, and Study 

Designs well-defined? 

Yes 

4 Did authors attempt to minimize errors in data extraction (such as collecting the 

relevant data, double data extraction, verification of data extraction...etc.)? 

Partially 

5 Was individual study quality (such as sample size, study design, blinding, various 

biases and confounders, study subject attrition rate...etc.) assessed? 

Yes 

6 Did authors consider appropriate confounders and justification for adjusting or not 

adjusting for those confounders? 

Yes 

7 Was the justification for combining or not-combining data for meta-analysis, or the use 

of a particular analytic method or model appropriate? 

Yes 

8 Was heterogeneity explored (this is in addition to any statistical test of heterogeneity, 

did the authors look at the actual differences in PICOS, for example?)? 

Yes 

8 Were results reported accurately (eg, no discrepancies between text and tables)? Yes 

9 Were conclusions justified by the reported/collected data and analysis? Yes 

C-104
Evidence table for Systematic Reviews of Breastfeeding 

Author, Year[UI] Topic Taylor, 2005 [UI] Type 2 diabetes 

Literature search (Dates) Medline (1966-2003); Other databases searched? (yes); unpublished data used? (no) 

Countries where primary 

studies conducted 

Developed countries only: US, Canada, Germany 

Study eligibility / inclusion 

criteria 

Search was limited to the English language and to human subjects. All studies involved 

term singleton infants unless otherwise noted. 

Study design [No. Of studies] Cohort studies [2]; case-control study [1] 

No. of subjects 1,514 

Study population (definition in 

included studies) 

• Studies of association between breastfeeding and type 2 diabetes 

• Children of mothers with diabetes 

Intervention/Exposure 

(definition in included studies) 

Comparator (definition in 

included studies) 

Many of the studies that were reviewed only reported breastfeeding versus bottle 

feeding, without more detailed information on exclusivity, frequency, or duration. 

Information on timing and duration of breastfeeding were included where available. 

Outcomes (definition in 

included studies) 

• Impaired glucose tolerance (IGT): fasting glucose < 140 mg/dL and 2-hour glucose 

> 140 mg/dL (after 1.75 g/kg OGTT) 

• Type 2 diabetes (NIDDM): 2-hour glucose ≥ 200 mg/dL (after 75 g OGTT) or fasting 

glucose ≥ 126 mg/dL 

Heterogeneity assessments N/A 

Quality assessments N/A 

Publication bias assessments N/A 

Statistical Analysis or metaanalytic methods 

N/A 

Results Association between breastfeeding and type 2 DM: 

• Consistently in 2 studies (1 retrospective cohort; 1 case-control study), exclusive 

breastfeeding is associated with lower risk of diabetes. 

Children of Mothers with DM: 

• One retrospective cohort study found that DM in the next generation was less 

common among breastfed children than among bottle-fed children, of both mothers 

with DM and without DM. 

Quality of the systematic 

review 

C 

Author’s interpretations of the 

results 

Based on the literature reviewed, breastfeeding should be strongly encouraged for all 

women, with or without diabetes. 

Comments / Limitations No synthesis of results or appraisals of study quality. Unclear how the conclusions were 

reached. 

C-105
Author, yr: Taylor, 2005 

Topic of the systematic review*/MA: Type 2 DM

Reporting yes/no 

Reporting of Background 

1 Description of study outcomes yes 

2 Types of exposure or intervention used yes 

3 Types of study designs used yes 

4 Study population yes 

Reporting of Search strategy 

5 Search strategy, including time period and key words yes 

6 Effort to include all available studies (contact with authors) no 

7 Databases and registries searched yes 

8 Method of addressing published articles other than English no 

9 Method of handling abstracts and unpublished studies no 

Reporting of Methods 

10 Rationale for selection and/or coding of data yes 

11 Assessment of confounding partially 

12 Assessment of quality no 

13 Assessment of heterogeneity N/A 

14 Description of statistical methods sufficient to replicate N/A 

15 Provision of appropriate tables and graphs no 

Reporting of Results 

16 Graphic summarizing of individual study estimates and overall no 

17 Tables giving descriptive information of each study included no 

18 Results of sensitivity testing (subgroup analysis) N/A 

19 Indication of statistical uncertainty of findings yes 

20 Quantitative assessment of bias (eg. publication bias) no 

Overall quality C 

*When grading a systematic review, please skip item #14, 18-20 

Please fill the white areas only 

Evaluation of quality of a systematic review or meta-analysis Yes /No 

/Partially 

1 Is search strategy appropriate/relevant to the key question(s)? Partially 

2 Did authors give justifications for inclusion/exclusion criteria pertaining to the studies of 

interest? 

Yes 

3 Were Population, Intervention/Exposure, Comparator/Control, Outcomes, and Study 

Designs well-defined? 

Yes 

4 Did authors attempt to minimize errors in data extraction (such as collecting the 

relevant data, double data extraction, verification of data extraction...etc.)? 

No 

5 Was individual study quality (such as sample size, study design, blinding, various 

biases and confounders, study subject attrition rate...etc.) assessed? 

No 

6 Did authors consider appropriate confounders and justification for adjusting or not 

adjusting for those confounders? 

Partially 

7 Was the justification for combining or not-combining data for meta-analysis, or the use 

of a particular analytic method or model appropriate? 

No 

8 Was heterogeneity explored (this is in addition to any statistical test of heterogeneity, 

did the authors look at the actual differences in PICOS, for example?)? 

Partially 

8 Were results reported accurately (eg, no discrepancies between text and tables)? Unclear 

(no tables) 

9 Were conclusions justified by the reported/collected data and analysis? No 

C-106
Appendix C. Evidence Tables 

Part II. Preterm Infant Outcomes 

Cognitive Premature Infants 

Bier 2002 

Eidelman 2004 

Elgen 2002 

Feldman 2003 

Horwood 2001 

O’Connor 2003 

Pinelli 2003 

Smith 2003 

Vohr 2006 

C-107
Bier 2002 [2003020034] 

Study characteristics Study design and follow-up duration Eligibility criteria 

Breastfeeding 

Exposures or 

Interventions 

Mean GA (range) breast milk group: 28.6 wk (23-34) Mean BW (range): 1174 g (600-1965) % Male: 45% Race: Enrolled/Evaluate: 29 in human milk group; 10 in formula group Location: US Sites: Multi Funding: 

Non-randomized comparison of breast milk versus formula fed preterm infants (convenience sample) 

Excluded infants with mothers who used illicit drugs, had mental illness, HIV infection, and others. 

Bier 2002 [2003020034] 

Outcome 

Definition 

Statistical analyses and 

confounders adjusted Results Bias/limitation

Comments 

Bayley MDI at 7-month and at 12-month 

Adjusted for maternal result of Peabody Picture Vocabulary Test (PPVT) and days of oxygen 

Mean Bayley MDI at 7 month, human milk group = 94 ± 7, in formula group = 90 ± 9 (Difference NS) 

At 12 months, human milk group = 101 ± 11, formula group = 90 ± 9 (P<0.05) ANOVA, adjusted for days of oxygen and maternal PPVT, Bayley MDI in human milk vs formula, 100 ± 12 vs 91 ± 10 (R2, P<0.025) 

Regression analysis showed an association between the amount of milk infants received in the special care nursery (mL/wk) by gavage and/or bottle and the Bayley MDI at 7 mo (P<0.05) and 12 mo (P<0.025). 

A: strong, B: moderate, C: weak A B 

Selection Study design Confounder/bias x Blinding x Data collection Withdraw and dropout Analyses Intervention integrity 

Actual number of mothers approached for accounted for, small sample size, cognitive investigator was available to all mothers at related questions 

C-108
Eidelman 2004 [15384601] 

Study 

characteristics Study design and follow-up duration Eligibility criteria Breastfeeding Exposures 

Interventions 

Mean GA (range): 30.5 wk (26-33 wk) Mean BW (range): 1298 g (640-1720 g) % Male: 53% Race: Evaluated: 86 Location: Israel Sites: Single Funding: 

Prospective cohort separated into 3 groups based on amount of human milk feeding; Bayley scales assessed at 6 months corrected age 

<33 wk gestation; birth weight < 1750 g; exclusion criteria: intraventricular hemorrhage grade 3 or 4, perinatal asphyxia, metabolic or genetic disease 

Exact amount of human milk aformula an infant received was recorded after each meal. Divided into >75% of nutrition human milk; 25-75%; and <25

Eidelman 2004 [15384601] 

Outcome 

Definition Statistical analyses and confounders adjusted Results Bia

C

MDI at 6 months corrected age 

Number of breastfeeding episodes was used as a covariate; MANCOVA performed with human milk and infant gender as the between subject factors 

The number of breastfeeding episodes was <5%. Univariate analyses showed group differences on the MDI. Post hoc comparisons reported significant differences between the substantial milk group and the other two groups: 94.2±8.8 vs 91.7±7.2 vs 90.5±8.5 (P<0.05) 

A: strong, B: modeSelection Study design Confounder Blinding Data collection Withdraw and dropAnalyses Intervention integri

Not adjusted for SESintelligence; small saat young age 

C-109
Elgen, 2003 [14580653] 

Study 

characteristics 

Study design and 

follow-up duration Eligibility criteria 

Breastfeeding 

Exposures or 

Interventions 

Mean GA (range):  BW (range): <2000 g % Male: Race: Evaluate: 130 Location: Norway Sites: Single/Multi Funding: 

Prospective cohort, followed ‘til 11 yr 

Born in the county of Hordaland, Norway, between 4/1986 and 8/1988; survived to 11 yr; low birth weight; no cerebral palsy, blindness, deafness, multiple malformations, or chromosomal abnormalities 

27% received <30% human milk in neonataward 

Elgen, 2003 [14580653] 

Outcome Definition Statistical analyses and confounders adjusted Results 

Weschler Preschool and Primary Scale of Intelligence- Revised at 5 yr; Weschler Intelligence Scale for Children-Revised at 11 yr 

Breast milk, birth weight, paternal and maternal education, chorioamnionitis, gestational age, length of oxygen treatment, sex, Apgar at 5 minutes, smoking during pregnancy, intrapartum stress, cerebral hemorrhage in subjects with birth weight <1500 g 

Unadjusted regression: lack of breast milk was associated with a mean reduction in IQ of 5.8 points (95% CI –11 to –1). After adjustment for parental confounding, breast milk was no longer a statistically significant predictor of IQ (paternal education was a significant confounder with breast milk). 

A: strmode

SelecStudy ConfBlindData WithddropoAnalyIntervinteg

Lack obreast 

C-110
Feldman, 2003 [12918090] 

Study 

characteristics 

Study design and 

follow-up duration Eligibility criteria Breastfeeding Exposures or Interventio

Mean GA (range): 30 wk (26-33) Mean BW (range): 1298 (640-1720) % Male: Race: Enrolled/Evaluate: 86 Location: Israel Sites: Single/Multi Funding: 

Prospective cohort; consecutive enrollment (6 declined) 

<33 wk gestation; <1750 g Excluded infants with congenital malformation, severe hemorrhage; also excluded poverty, single parenting, teenage mothering, and maternal drug use 

>75%, 25-75%, and <25% nutrition from breamilk; exact amount of breast milk and formula infant received was recorded after each meal nursing staff 

Feldman, 2003 [12918090] 

Outcome 

Definition Statistical analyses and confounders adjusted Results 

Bayley MDI at 6 months corrected age 

Multivariate ANOCOVA with breast milk and infant gender as the between-subject factors and the number of breast-feeding episodes as the covariate was computed for the cognitive indices at 6 months 

An overall main effect for breast milk group was found (F=3.14, P<0.05) Univariate analysis: A (n=34) >75% group MDI 94.16 ± 8.75 B (n=21) 25-75% 91.66 ± 7.20 C (n=31) <25% 90.53 ± 8.54 (F=3.34, P<0.05, A>B, C) 

A: strong, BC: weak 

Selection Study desigConfoundeBlinding Data collecWithdraw aAnalyses Intervention 

Not adjusted or intelligenccognitive tes

C-111
Horwood, 2001 [11124919] 

Study 

characteristics Study design and follow-up duration Eligibility criteria Breastfee

Exposure

Interventi

Mean GA (range): Mean BW (range): % Male: Race: Evaluated: 298/280 analyzed Location: New Zealand Sites: Single/Multi Funding: 

Cross-sectional; all 413 very low birth birthweight infants who were live born in 1986 who were admitted to one neonatal unit; retrospective recall of breast milk feeding and duration of feeding; children were assessed by WISC-R (excluded 17 children who could not reliably be assessed because of sensorineural disability; 1 child was excluded because the data on breastfeeding were missing) at 7 yr 

Live born very low birthweight infants 

Not breastfed Breastfed < 4 months (n=994-7 months (n≥ 8 months (n

Horwood, 2001 [11124919] 

Outcome 

Definition Statistical analyses and confounders adjusted Results 

WISC-R Controlled for perinatal, socio-demographic (family income, single/two 

parent family, child ethnicity), and maternal factors (age, education, smoking); the data were analyzed using multiple linear regression techniques in which the measures of verbal and performance IQ were regressed on the four level measure of breastfeeding treated as a continuous variable and significant covariate factors. 

Children who were breastfed ≥ 8 months had mean verbal IQ 10.2 (SD 0.56) higher and mean performance IQ 6.2 (SD 0.35) higher than children who did not receive breast milk. After adjustment for covariates, there remained a significant association between duration of receipt of breast milk and verbal IQ, with a 6 point advantage for infants who received breast milk for ≥ 8 months compared with no breastfeeding (P<0.001). 

A: stmodweak 

SeleStudConfBlindData WithdropAnalInterinteg

C-112
O’Connor, 2003 [14508214] 

Study 

characteristics 

Study design and followup duration Eligibility criteria Breastfeeding Exposure

Interventions 

GA ): <33 wk BW (range): 750-1805 g % Male: Race: Enrolled/Evaluate: 463 Location: US, UK and Chile Sites: Multi Funding: 

Cohort, re-analysis of a previous RCT on supplemented formulas 

Could be enrolled within 72 hours of first enteral feeding initiated by the 28th day of life; excluded congenital 

abnormalities that could affect growth and development, major surgery, and others 

4 mutually exclusive groups

1. predominantly hum

milk (see details in paper) 

2. predominantly form3. ≥ 50% of total ene

as human milk 

4. < 50% of total ene

as human milk 

O’Connor, 2003 [14508214] 

Outcome Definition 

Statistical analyses 

and confounders 

adjusted 

Results 

Bayley at 12 mo; MacArthur Communicative Development Inventories at 9 mo, 14 mo 

Maternal intelligence and home environment 

No differences in the Bayley MDI were found among feeding groups. There was a positive association between duration of breastfeeding and the Bayley MDI at 12 months corrected age (P=0.032 in full, and P=0.073 in reduced statistical models) after controlling for home environment and maternal intelligence. 

A: stromode

SelecStudy ConfoBlindiData WithddropoAnalyIntervintegr

Cogniti

C-113
Pinelli, 2003 [2003083348] 

Study 

characteristics Study design and follow-up duration Eligibility criteria 

Breastfeedin

Exposures o

Intervention

Mean GA (range): <1500 g Mean BW (range): % Male: Race: Enrolled/Evaluate: 148/137 Location: Canada Sites: Single Funding: 

Prospective cohort (consecutive enrollment); sample from a RCT on conventional breastfeeding support versus supplementary structured breastfeeding counseling; 20 totally formula fed infants were recruited as controls 

Excluded: multiple births, severe congenital abnormalities; infants of non-English speaking parents 

>80% breast milk v<80% breast milk obreast milk 

Pinelli, 2003 [2003083348] 

Outcome 

Definition 

Statistical analyses and 

confounders adjusted Results 

Bayley MDI at 12 mo 

Sex, SES, birth weight, maternal age 

64/128 infants received breastmilk exclusively; Adjusted MDI at 6 mo (corrected age) for >80% breastmilk group: 93 (SD 16); for <80% breastmilk group: 94 (SD 15); Adjusted MDI at 12 mo (corrected age) for >80% breastmilk group: 92 (SD 15); for <80% breastmilk group: 91 (SD 12); P>0.05 for all comparisons 

A: strong, BC: weak 

Selection Study desigConfoundeBlinding Data collecWithdraw aAnalyses Intervention 

Cognitive tes

C-114
Smith, 2003 [14630603] 

Study characteristics Study design and follow-up duration Eligibility criteria Breastfeeding Exp

or Intervention

Median GA (range): 27.4 wk Median BW (range): 1014 g % Male: Race: Enrolled/Evaluate: 439/420 Location: US Sites: Multi Funding: 

Cohort; subjects were from Developmental Epidemiology Network cohort (n=1442), 439 enrolled in follow up studies at 6 to 8 yr 

Surviving children with selected ultrasound abnormalities were included (n=119), and a random sample (1:4 ratio) of infants frequency matched for gestation were included; had undergone neuropsychological assessment and for whom parental questionnaires were complete by 9/2002 

Received expressed without progressing tbreastfeeding, receivdirect breastfeeding 

Smith, 2003 [14630603] 

Outcome Definition Statistical analyses and confounders adjusted Results 

Kaufman Assessment Battery for Children (an estimate for overall intellectual function); Peabody Picture Vocabulary Test and Clinical Evaluation of Language Fundamentals (verbal); California Children’s Verbal Learning Test (memory); Wide Range Assessment of Visual Motor Abilities (visualspatial skill) These measures were standardized with a mean of 100 points and standard deviation of 15 points. 

Maternal verbal ability, Home Observation for Measurement of the Environment Inventory, SES, duration of hospitalization 

Compared with nonparticipating mothers, those who participated were older, more educated, more likely to be married, be non-smokers, and have private medical insurance. 153 subjects did not receive human milk; 142 received expressed milk without progressing to direct breastfeeding; 125 received direct breastfeeding (the majority of them first received expressed breast milk); 20% of infants received breast milk >6 mo. Breast milk feedings were associated with higher unadjusted test scores for each domain of cognitive function except memory. In the regression model that included social advantage and neonatal morbidity, the adjusted score in overall intellectual function associated with direct breastfeeding was reduced to 3.6 points (95% CI, -0.3, 7.5) from 10.7 (95%CI, 7.0, 14.4). Breastfed children had an advantage in visual-motor integration measure (adjusted IQ 5.1, 95% CI, 1.0, 9.2) 

A: strong, C: weak 

Selection Study desConfoundBlinding Data colleWithdraw Analyses Interventio

27% of subabnormalitiebreastfeedi

C-115
Vohr, 2006 [16818526] 

Study characteristics Study design and follow-up duration Eligibility criteria Breastfeeding Exposures or Interventions 

Mean GA (range): 26.5 wk Mean BW (range): 785 g (BM), 794 (no) % Male: 45% Race: Enrolled/Evaluate: 1159/1035 Location: US Sites: Multi Funding: 

Prospective cohort; Bayley results at 18 to 22 mos corrected age; examiner blinded to feeding history, primary caretaker stayed with the child during the Bayley examination 

Enrolled prospectively in the Glutamine Trial at 15 sites of Neonatal Research Network; survivors 

Breast milk – received some breast milk during hospitalization; total volume received calculateper day, values were interpolated for days of thweek in which the data were not collected 

C-116
Vohr, 2006 [16818526] 

Outcome Definition 

Statistical analyses 

and confounders 

adjusted 

Results Bia

C

Cognitive outcome of interest: Bayley Mental Development Index (MDI) 

Adjustment for marital status, maternal education, age, race/ethnicity, infant’s gestational age, gender, culture positive sepsis, grade 3 to 4 intraventricular hemorrhage, oxygen at 36 wks gestational age, necrotizing enterocolitis, and weight <10th %tile 

There were 775 infants in the breast milk group and 260 in the no breast milk group. 95 subjects’ Bayley could not be administered successfully; these data were not included. Mothers of infants who were seen at followup were more likely to have received prenatal care than mothers of infants who were not seen. There were no differences in infant characteristics. Information on breast milk feeding was not collected after discharge from hospital. 30.6% of infants in the breast milk group were still receiving breast milk. Mothers in the breast milk group were more likely to be white, married, have a college degree and have private health insurance. Mothers who had low household income, higher parity or were black were less likely to provide breast milk feeds. Adjusted Bayley MDI 79.9 

± 18 in BM 75.8 

± 16 in noBM P=0.0709 

MDI <85 421 (58.1%) in BM 168 (70.9%) in noBM P=0.0355 Multiple regression with adjusted factors=0.53 for MDI, P=0.0002 Breast milk intake was analyzed by quintile relative to the no breast milk group; for MDI, there was a 13.1 point difference between 

≤ 20th quintile 

and >80th quintile (P<0.0044) 

A: strong, B: mode

Selection Study design Confounder/bias Blinding Data collection Withdraw and dropAnalyses Intervention integri

Residual confoundincannot be ruled out; proportion of subjecthave been adjusted; adjusted or not (Reswas, but the discussBayley was done blistated in Methods, b

C-117
Appendix C. Evidence Tables 

Part II. Preterm Infant Outcomes 

Necrotizing Enterocolitis 

Furman 2003 

Gross 1983 

Lucas 1984 1990 

McGuire 2001 SRMA* 

Ronnestad 2005 

Schanler 2005 

Tyson 1983

* Systematic Review/Meta-Analysis 

C-118
Furman, 2003 [UI# 12517197] 

Study 

characteristics 

Study design and 

follow-up duration Eligibility criteria Breastfeeding Exposures or Interventions 

Mean GA (range): 28 wk Mean BW (range): 1056 g % Male: 57% Race: Enrolled/Evaluate: 119 Location: Cleveland Sites: Single Funding: 

Prospective cohort; The study compared the effect of varying dosages of maternal milk on neonatal outcomes 

Singleton, birth weight 600-1499 g, gestational age < 33 wk, no positive drug screen, major congenital anomaly, intrauterine infection, or insurmountable maternal social factors 

Intravenous dextrose during the first 24 hrs; enteral intake was by day 2 or 3 of life, parenteral nutrition was continued until a enteral intake of 120 mL/kg of body weight was reached. Infanreceived their mother’s milk in the sequence it was expressedthat fresh rather than frozen milk was given if available. Materwas fortified, and preterm infant formula was offered when the reached a daily oral intake of at least 110 mL/kg. Limited avaimaternal milk was the sole reason infants were fed preterm foaddition to maternal milk. 

Furman, 2003 [UI# 12517197] 

Outcome Definition 

Statistical analyses 

and confounders 

adjusted 

Results Bia

C

NEC in the 4 subgroups: No maternal milk Daily 1-24 mL/kg of maternal milk Daily 25-49 mL/kg of maternal milk Daily ≥ 50 mL/kg of maternal milk 

Logistic regression; adjusted for birth weight, ethnicity, and sex 

0 maternal milk 3/40 1-24 mL/kg 2/29 (OR 1.15 95% CI 0.8-12.13) 25-49 mL/kg 2/18 (OR 1.99 95% CI 0.14-21.03) ≥ 50 mL/kg 0/32 (OR 0 95% CI 0 – 3.56) 

A: strong, B: mode

Selection Study design Confounder Blinding Data collection Withdraw and dropAnalyses Intervention integri

C-119
Gross, 1983 [UI# :6848932] 

Study 

characteristics Study design and follow-up duration Eligibility criteria 

Breastfeed

Exposures 

Interventio

Mean GA (range): 31 wk Mean BW (range): 1322 g % Male: Race: Enrolled/Evaluate: Location: US Sites: Single Funding: 

Random number assignment into 3 groups: mature human milk, preterm human milk, whey-based formula; any infant withdrawn from the study was replaced by the next infant enrolled, until there were 20 infants in each group; remained in the study until they reached 1800 g 

27 – 33 wk gestation; ≤ 1600 g; no congenital abnormalities or major diseases; ability to begin enteral feed by 6th day of life; absence of breast milk from 

own mother 

Feedings begabetween the firsixth days of lif

Gross, 1983 [UI#:6848932] 

Outcome Definition Statistical analyses and confounders adjusted Results 

NEC (abdominal distention, gastric aspirates, guaiac-positive stools, and pneumatosis intestinalis) 

NEC was analyzed as infants who withdrew from the study 

67 infants recruited for the study; 1/41 (BM) vs. 3/26 (FM) with NEC 

A: strong, C: weak 

Selection Study desConfoundBlinding Data colleWithdraw Analyses Interventio

C-120
Lucas, 1984 [UI# 6476868]; 1990 [UI# 1979363] 

Study 

characteristics Study design and follow-up duration Eligibility criteria 

Breastfeeding 

Exposures or 

Interventions 

Mean GA (range): 31 wk Mean BW (SD): 1370 g ( 320 g) % Male: Race: Enrolled/Evaluate: Location: UK Sites: /Multi Funding: 

Randomization within 48 h of birth for infants whose mothers decided not to breastfeed, randomized into banked donor human milk vs. preterm formula; only infants fed exclusively on donor milk or formula were compared 

<1850 g, excluded severe congenital abnormalities 

Lucas, 1984, [UI# 6476868]; 1990 [UI# 1979363] 

Outcome Definition Statistical analyses and confounders adjusted Results B

Confirmed NEC – required surgery or who died 

Logistic regression was used to adjust for factors that have been associated with NEC. 

1/86 (BM) vs. 4/76 (FM) OR 4.7 (0.5 – 43) 

A: strong, B: weak 

Selection Study design Confounder Blinding Data collectiWithdraw anAnalyses Intervention 

C-121
Evidence table for Systematic Reviews of Breastfeeding and NEC 

Author,Year[UI] Topic McGuire, 2001 [11687169] NEC 

Literature search (Dates)1966-

10/2003

Medline; Other databases searched? (yes, CENTRAL, EMBASE, CINAHL); 

unpublished data used? (no) 

Countries where primary studies 

conducted 

ND 

Study eligibility / inclusion criteria RCT comparing feeding with formula milk versus term human milk in low birth 

weight or preterm infants 

Study design [No. Of studies] RCT: 3 studies with outcomes re: NEC 

No. of subjects 287 

Study population (definition in 

included studies) 

Gross 1983 27-33 wk, bw < 1600 g 

Tyson 1983 very low birth weight infants 

Lucas 1984 preterm infants < 1850 g 

Intervention/Exposure (definition 

in included studies) 

Gross 1983 unfortified term donor breast milk, fed until 1800 g or until withdrawal 

secondary to feed intolerance or NEC 

Tyson 1983 pooled banked term human milk, allocation at 10th day of life, fed until 

2000 g or until withdrawal secondary to illness requiring parenteral fat or protein 

Lucas 1984 banked term human milk 200 mL/kg/d, fed until 2000 g or until d/c 

Comparator (definition in included 

studies) 

Gross 1983 standard calorie (0.67 kcal/mL, protein enriched (1.9 g/100 mL) 

formula 

Tyson 1983 enriched calorie (0.87 kcal/mL), protein enriched (2.2 g/100 mL) 

formula 

Lucas 1984 enriched calorie (0.80 kcal/mL), protein enriched (2.0 g/100 mL) 

formula at 180 mL/kg/d

Outcomes (definition in included 

studies) 

Necrotizing enterocolitis 

Heterogeneity assessments 

Quality assessments Gross 1983 & Tyson 1983 The studies did not attempt blinding of parents, carers, 

or assessors. Adverse events were not reported as primary end points but rather as 

withdrawal criteria. 

Lucas 1984 The study did not attempt blinding of parents, carers, or assessors. 

Data on NEC on all 159 recruited infants were reported 

Publication bias assessments 

Statistical Analysis or metaanalytic methods 

3 trials were combined in a meta-analysis: formula vs human milk, RR: 2.5 (95% CI 

0.9, 7.3); RD: 0.05 (95% CI 0.00, 0.1) 

Results Gross 1983 incidence of NEC in formula vs human milk: RR 2.4 (95% CI 0.3, 

21.6); RD: 0.07 (95% CI 0.09, 0.22) 

Tyson 1983 incidence of NEC in formula vs human milk: RR 4.2 (95% CI 0.2, 

85.3); RD: 0.05 (95% CI –0.03, 0.12) 

Lucas 1984 incidence of NEC in formula vs human milk: RR 2.2 (95% CI 0.6, 8.4); 

RD: 0.04 (95% CI –0.03, 0.12) 

Quality of the systematic review 

Author’s interpretations of the 

results 

We did not find any statistically significant difference in the risk of NEC with formula 

milk versus term human milk feeding. 

Comments / Limitations Donor milk, not mother specific milk 

C-122
Author, yr: McGuire, 2001 

Topic of the systematic review*/MA: 

Reporting yes/no 

Reporting of Background 

1 Description of study outcomes Y 

2 Types of exposure or intervention used Y 

3 Types of study designs used Y 

4 Study population Y 

Reporting of Search strategy 

5 Search strategy, including time period and key words Y 

6 Effort to include all available studies (contact with authors) Y 

7 Databases and registries searched Y 

8 Method of addressing published articles other than English Y/N 

9 Method of handling abstracts and unpublished studies N 

Reporting of Methods 

10 Rationale for selection and/or coding of data Y 

11 Assessment of confounding Y/N 

12 Assessment of quality Y 

13 Assessment of heterogeneity Y 

14 Description of statistical methods sufficient to replicate Y 

15 Provision of appropriate tables and graphs Y 

Reporting of Results 

16 Graphic summarizing of individual study estimates and overall Y 

17 Tables giving descriptive information of each study included N 

18 Results of sensitivity testing (subgroup analysis) Y 

19 Indication of statistical uncertainty of findings Y 

20 Quantitative assessment of bias (eg. publication bias) N 

Overall quality 

*When grading a systematic review, please skip item #14, 18-20 

Please fill the white areas only 

Evaluation of quality of a systematic review or meta-analysis Yes /No 

/Partially 

1 Is search strategy appropriate/relevant to the key question(s)? Y 

2 Did authors give justifications for inclusion/exclusion criteria pertaining to the studies of 

interest? 

Y 

3 Were Population, Intervention/Exposure, Comparator/Control, Outcomes, and Study 

Designs well-defined? 

Y 

4 Did authors attempt to minimize errors in data extraction (such as collecting the 

relevant data, double data extraction, verification of data extraction...etc.)? 

Y/N 

5 Was individual study quality (such as sample size, study design, blinding, various 

biases and confounders, study subject attrition rate...etc.) assessed? 

Y/N 

6 Did authors consider appropriate confounders and justification for adjusting or not 

adjusting for those confounders? 

Y/N 

7 Was the justification for combining or not-combining data for meta-analysis, or the use 

of a particular analytic method or model appropriate? 

Y 

8 Was heterogeneity explored (this is in addition to any statistical test of heterogeneity, 

did the authors look at the actual differences in PICOS, for example?)? 

Y 

8 Were results reported accurately (eg, no discrepancies between text and tables)? Y/N 

9 Were conclusions justified by the reported/collected data and analysis? Y 

C-123
Ronnestad, 2005 [UI# 15687416] 

Study characteristics 

Study design 

and follow-up 

duration 

Eligibility criteria Breastfeeding Exposures or Interventions 

Mean GA (range): 22-27 wk Mean BW (range): 845 g (est.) % Male: 56% Race: Enrolled/Evaluate: 462 enrolled; 405 survived until day 7 Location: Norway Sites: Multi-center Funding: 

Prospective cohort 

Participating centers had a common policy of achieving full enteral feeding with the mother’s milk or banked donor milk as early as possible, although there was no consensus in terms of a detailed protocol for feeding strategies. All infants born in Norway in 1999 and 2000 with gestational age of <28 wk or birth weight < 1000 g. 

Tube feeding with human milk was usually started witfew hours after delivery, with 1 to 2 mL of milk every hrs, increasing by 0.5 to 1 mL every 6 to 8 hours as toEnteral nutrition was supplemented with parenteral gfrom day, amino acids and lipids from day 2 and day respectively. 

Ronnestad, 2005 [UI# 15687416] 

Outcome Definition Statistical analyses and confounders adjusted Results 

This was a study primarily examining late-onset septicemia (after day 6 of life) that also reported outcome on NEC after day 6 of life. 

No analysis/adjustment specific to NEC was reported. 

Enteral feeding with human milk was commenced within 1, 2, or 3 days for 61%, 92%, and 96% of the infants. 9/405 (2.2%) patients had confirmed NEC. 

A: smodwea

SeleStudConBlinDatWithdropAnaInteinte

C-124
Schanler, 2005 [UI# 16061595] 

Study 

characteristics 

Study design 

and follow-up 

duration 

Eligibility criteria Breastfeeding Exposures or Interventions 

Mean GA (range): 23-26wk & 27-29 wk Mean BW (range): 952 g % Male: 53% Race: ND Enrolled/Evaluate: 243 Location: Texas Children’s Hospital Sites: Multi Funding: government 

RCT 4 days to 90 days of age or discharge from the hospital 

Infants with mother expected to breastfeed; if mother’s own milk was unavailable; then infants were randomized to Donor Milk versus Preterm formula 

Donor milk (DM) (+ mother’s milk partially) Reference group: non-randomized, exclusive mother’s milk (MMSmall quantities of mother’s milk (~20 mL/kg/day) was initiated first week and continued for ~3 to 5 days before the volume was advanced. Milk intake was increased by ~20 mL/kg daily to 100 mL/kg, at which time milk fortifier was added, this was advanced ~20 mL/kg daily until 160 mL/kg per day was achieved. 

Schanler, 2005 [UI# 16061595] 

Outcome Definition Statistical analyses and confounders adjusted Results 

NEC Only cases of NEC that occurred after the infant attained a milk intake of ≥50 mL/kg were analyzed for the primary outcome. 

17 infants (21%) in DM were switched to PF because of poor weight gain. All infants remained in the original assigned group for analysis. 

Incidence of NEC: DM vs PF: 5/78 vs 10/88 (P=0.27) Non-randomized group MM had fewer repeated episodes of late-onset-sepsis and/or NEC (OR 0.18; 95% CI 0.04–0.79) compared with combined groups DM and PF 

A: mowe

SeStuCoBliDaWidroAnIntint

C-125
Tyson, 1983 [UI# - 6864403] 

Study 

characteristics Study design and follow-up duration Eligibility criteria 

Breastfeeding 

Exposures or 

Interventions 

Mean GA (range): 31.5 wk Mean BW (range): 1232 g % Male: Race: Enrolled/Evaluate: Location: US Sites: Single Funding: 

RCT; infants were not enrolled until the 10th

day; enrolled into donor human milk or formula milk groups 

Infants whose mothers continued to provide milk at 10 days were excluded, as infants with any significant illnesses 

Tyson, 1983 [UI# - 6864403] 

Outcome Definition Statistical analyses and confounders adjusted Results B

NEC confirmed at surgery; suspected NEC 

NEC was analyzed as subjects who dropped out of the study. 

0/37 (BM) vs. 1/44 (FM) for confirmed NEC 

A: strong, B: mweak 

Selection Study design Confounder Blinding Data collectioWithdraw and Analyses Intervention in

C-126
Appendix C. Evidence Tables 

Part III. Maternal Outcomes 

Breast Cancer 

Bernier 2000 SRMA* 

CGHFBC 2002 SRMA* 

Gammon 2002 

Jernstrom 2004 

Lee 2003 

Lipworth 2000 SRMA*

* Systematic Review/Meta-Analysis 

C-127
Evidence table for Systematic Reviews of Breastfeeding 

Author, Year[UI] Topic Bernier, 2000 Breast cancer 

Literature search (Dates) Medline (1980-1998); Other databases searched? (yes-Embase); unpublished data used? 

(no) 

Countries where primary 

studies conducted 

Developed and developing countries (Estonia, Canada, USA, Sicilia, Costa Rica, Australia, 

India, China, Greece, Italy, Mexico, New Zealand) 

Study eligibility / inclusion 

criteria 

A study was included in the analysis: 1) it was published between 1980 and 1998 2) it 

presented primary original data; 3) it was published either in English or French; 4) the type of 

study was either a case-control, or a prospective cohort study; 5) data on breastfeeding 

exposure were reported and used in the analysis 6) breast cancer was the event of interest 

7) specific odds ratio measuring the breastfeeding and breast cancer association were given 

or could be derived. 

Excluded were studies in which data from parous women who had not breastfed could not 

be separated from nulliparous women 

Study design [No. Of 

studies] 

23 [Case-control studies] 

No. of subjects 25871 cases/44910 controls 

Study population 

(definition in included 

studies) 

Parous women with breast cancer 

Intervention/Exposure 

(definition in included 

studies) 

Breastfeeding (Ever) 

Comparator (definition in 

included studies) 

Breastfeeding (never) 

Outcomes (definition in 

included studies) 

Breast cancer (histologically diagnosed) 

Heterogeneity 

assessments 

Yes; homogeneity graph and by subgroup analysis (menopausal status; duration of 

breastfeeding) 

Quality assessments Unclear (MA discussed methodologic quality with subheading of origin of the women; breast 

cancer diagnosis; and data collection) 

Publication bias 

assessments 

Yes (funnel plot) 

Statistical Analysis or 

meta-analytic methods 

Both random and fixed effects model 

Results Breast cancer risk ever vs never breastfeeding 

 Pooled OR using the fixed effects model 0.90 (0.86-0.94) 

 Pooled OR using random effects model 0.84 (0.78-0.91 

These results were not modified using adjusted ORs 

Breast cancer risk according to the menopausal status at the time of the diagnosis in 

ever vs never breastfeeding mothers 

Menopausal at the time of breast cancer diagnosis 

 Pooled OR using the fixed effects model 1.01 (0.94-1.09) 

 Pooled OR using random effects model 0.84 (0.69-1.03) 

Non-menopausal at the time of breast cancer diagnosis 

 Pooled OR using the fixed effects model 0.83 (0.76-0.91) 

 Pooled OR using random effects model 0.81 (0.72-0.91) 

Breast cancer risk according to duration of breast feeding 

0+ to 6 mo v never 

Pooled OR using the fixed effects model 1.02 (0.94-1.10) 

 Pooled OR using random effects model 1.00 (0.86-1.16) 

6+ to 12 mo v never 

Pooled OR using the fixed effects model 0.97 (0.88-1.06) 

 Pooled OR using random effects model 0.97 (0.86-1.09) 

12+ mo vs. never 

Pooled OR using the fixed effects model 0.75 (0.70-0.80) 

C-128
Author, Year[UI] Topic Bernier, 2000 Breast cancer 

 Pooled OR using random effects model 0.72 (0.65-0.80) 

Quality of the systematic 

review 

B 

Author’s interpretations of 

the results 

Breastfeeding appeared to be a protective factor but was of small magnitude compared with 

other known risk factors of breast cancer 

Comments / Limitations Quality score for individual studies not assessed 

C-129
Author, yr: Bernier 2000 

Topic of the systematic review*/MA: Breast cancer and breastfeeding

Reporting yes/no 

Reporting of Background 

1 Description of study outcomes Y 

2 Types of exposure or intervention used Y 

3 Types of study designs used Y 

4 Study population Y 

Reporting of Search strategy 

5 Search strategy, including time period and key words Y 

6 Effort to include all available studies (contact with authors) N 

7 Databases and registries searched Y 

8 Method of addressing published articles other than English N 

9 Method of handling abstracts and unpublished studies N 

Reporting of Methods 

10 Rationale for selection and/or coding of data Y 

11 Assessment of confounding Y 

12 Assessment of quality Unclear 

13 Assessment of heterogeneity Y 

14 Description of statistical methods sufficient to replicate Y 

15 Provision of appropriate tables and graphs Y 

Reporting of Results 

16 Graphic summarizing of individual study estimates and overall Y 

17 Tables giving descriptive information of each study included Partially yes 

18 Results of sensitivity testing (subgroup analysis) Y 

19 Indication of statistical uncertainty of findings N 

20 Quantitative assessment of bias (eg. publication bias) Y 

Authors’ Conclusions 

21 Consistent with the presented results Y 

22 Commenting on the validity of the conclusions Y 

23 Presenting alternative explanations Y 

Overall quality B 

*When grading a systematic review, please skip item #14, 18-20 

Please fill the white areas only

Evaluation of quality of a systematic review or meta-analysis 

Yes /No 

/Partially 

1 Is search strategy appropriate/relevant to the key question(s)? Yes 

2 Did authors give justifications for inclusion/exclusion criteria pertaining to studies of 

interest? 

Partially 

3 Were Population, Intervention/Exposure, Comparator/Control, Outcomes, and Study 

Designs well-defined? 

Yes 

4 Did authors attempt to minimize errors in data extraction (such as collecting the relevant 

data, double data extraction, verification of data extraction...etc.)? 

Partially 

5 Was individual study quality (such as sample size, study design, blinding, various biases 

and confounders, study subject attrition rate...etc.) assessed? 

No 

6 Did authors consider appropriate confounders and justification for adjusting or not 

adjusting for those confounders? 

Yes 

7 Was the justification for combining or not-combining data for meta-analysis, or the use of 

a particular analytic method or model appropriate? 

Yes 

8 Was heterogeneity explored (this is in addition to any statistical test of heterogeneity, did 

the authors look at the actual differences in PICOS, for example?)? 

Yes 

8 Were results reported accurately (eg, no discrepancies between text and tables)? No 

9 Were conclusions justified by the reported/collected data and analysis? Yes 

C-130
Evidence table for Systematic Reviews of Breastfeeding 

Author, Year[UI] Topic Collaborative Group on Hormonal Factors in Breast Cancer 

(CGHFBC) 2002 [12133652]

Breast Cancer 

Literature search (Dates) ND Available in prior publications 

Medline (nd); Other databases searched? (nd); unpublished data used? (yes) 

Countries where primary 

studies conducted 

International studies including developed and developing nations 

Study eligibility / inclusion 

criteria 

Studies that had data on at least 100 women with incident invasive breast cancer and had 

recorded information on each women with respect to reproductive factors and use of 

hormonal preparations. For the cohort studies, a nested case-control study design was 

used, in which four randomly selected controls per case were matched for age at 

diagnosis and where appropriate, broad geographical region 

Study design [No. Of 

studies] 

case-control and cohort studies [47] 

No. of subjects 50,302/96,973

Study population 

(definition in included 

studies) 

Women with breast cancer and controls 

Intervention/Exposure 

(definition in included 

studies) 

Breastfeeding (Ever and lifetime months of breastfeeding (median)) 

Comparator (definition in 

included studies) 

Breastfeeding Never 

Outcomes (definition in 

included studies) 

Breast cancer (ND) 

Heterogeneity 

assessments 

Subgroup analyses including women from developed and developing countries, women of 

different ages, ethnic origins, familial patterns of disease, and 11 other possible relevant 

factors 

Quality assessments None 

Publication bias 

assessments 

ND 

Statistical Analysis or 

meta-analytic methods 

Analyses were routinely stratified by study, by center within study, by fine divisions of age, by 

age at first birth and by menopausal status. Where appropriate, parous women are further 

stratified by fine divisions of parity. 

Data combined by means of the Mantel-Haenszel stratification technique, the stratum 

specific quantities calculated being the standard observed minus expected numbers of 

women with breast cancer, together with their variances and covariates. 

Results % reduction in relative risk of breast cancer per 12 months of breastfeeding and 99% (SE)= 

4.3 (0.8) 

Data also available for floating absolute risk and floated SE for subgroups 

 Parous women who never breastfed v ever breastfed 

 Life time months of breastfeeding 

Quality of the systematic 

review 

A 

Author’s interpretations of 

the results 

The longer women breastfeed the more they are protected against breast cancer. The lack 

of or short lifetime duration of breastfeeding typical of women in developed countries makes 

a major contribution to the high incidence of breast cancer in these countries. 

Comments / Limitations Individual patient level data 

C-131
Author, yr: Collaborative group on Hormonal factors in breast cancer, 2002 

Topic of the systematic review*/MA: Breast cancer and breastfeeding

Reporting yes/no 

Reporting of Background 

1 Description of study outcomes Y 

2 Types of exposure or intervention used Y 

3 Types of study designs used Y 

4 Study population Y 

Reporting of Search strategy 

5 Search strategy, including time period and key words N 

6 Effort to include all available studies (contact with authors) N 

7 Databases and registries searched N 

8 Method of addressing published articles other than English N 

9 Method of handling abstracts and unpublished studies N 

Reporting of Methods 

10 Rationale for selection and/or coding of data Y 

11 Assessment of confounding Y 

12 Assessment of quality N 

13 Assessment of heterogeneity Y 

14 Description of statistical methods sufficient to replicate Y 

15 Provision of appropriate tables and graphs Y 

Reporting of Results 

16 Graphic summarizing of individual study estimates and overall Y 

17 Tables giving descriptive information of each study included Y 

18 Results of sensitivity testing (subgroup analysis) Y 

19 Indication of statistical uncertainty of findings N 

20 Quantitative assessment of bias (eg. publication bias) N 

Authors’ Conclusions 

21 Consistent with the presented results Y 

22 Commenting on the validity of the conclusions Y 

23 Presenting alternative explanations Y 

Overall quality A 

*When grading a systematic review, please skip item #14, 18-20 

Please fill the white areas only 

Evaluation of quality of a systematic review or meta-analysis Yes /No 

/Partially 

1 Is search strategy appropriate/relevant to the key question(s)? No 

2 Did authors give justifications for inclusion/exclusion criteria pertaining to the studies of 

interest? 

yes 

3 Were Population, Intervention/Exposure, Comparator/Control, Outcomes, and Study 

Designs well-defined? 

yes 

4 Did authors attempt to minimize errors in data extraction (such as collecting the 

relevant data, double data extraction, verification of data extraction...etc.)? 

partially 

5 Was individual study quality (such as sample size, study design, blinding, various 

biases and confounders, study subject attrition rate...etc.) assessed? 

Individual 

patient 

level data 

6 Did authors consider appropriate confounders and justification for adjusting or not 

adjusting for those confounders? 

yes 

7 Was the justification for combining or not-combining data for meta-analysis, or the use 

of a particular analytic method or model appropriate? 

yes 

C-132
Evaluation of quality of a systematic review or meta-analysis Yes /No 

/Partially 

8 Was heterogeneity explored (this is in addition to any statistical test of heterogeneity, 

did the authors look at the actual differences in PICOS, for example?)? 

yes 

8 Were results reported accurately (eg, no discrepancies between text and tables)? yes 

9 Were conclusions justified by the reported/collected data and analysis? yes 

C-133
Gammon 2002 [12206514] 

Study characteristics Subjects’ health conditions 

Study 

design and 

follow-up 

duration 

Eligibility criteria 

Breastfe

Exposur

Interven

Mean age (range): <35 to 85+ yrs Menopause: mix Race: white 92-93%; Black 5%; and other 2-3% Enrolled/Evaluate: 1508 cases/1556 controls Location: population based Sites: Multi Funding: Gov 

Women with newly diagnosed breast cancer (invasive and in-situ) 

Case control study design Follow-up duration nd 

Cases were women newly diagnosed with a first primary in situ or invasive breast cancer between August 1, 1996, and July 31, 1997, confirmed by the physician and the medical record, who were residents of either Nassau or Suffolk counties in New York at the time of their diagnosis, and who spoke English. (Over 97% of all residents in these two counties are 

English-speaking.) Controls: Control women were a sample of current residents of Nassau and Suffolk counties who spoke English, who did not have a personal history of breast cancer, and who were frequency matched to the expected distribution of case women by 5-year age group. 

By duration<2 months 2-5 months 6-13 month14+ months 

Gammon 2002 [12206514] 

Outcome Definition Statistical analyses and confounders adjusted Results 

Risk for breast cancer among those who donated a blood sample 

Unconditional and multiple logistic regression model identified using backward selection model 

Among parous women lactation for 14 or more months decreased the odds of breast cancer (n=102) 0.70 (0.54, 0.92) compared to those who never lactated (ref group) or less than lactated <14 mo Lactation <2 mo, 2-5 mo, and 6-13 mo when compared to never lactated group had non significant results for the odds of breast cancer development. 

A: smodwea

SelStuConBlinDatWitdroAnaInteinte

Over

C-134
Jernstrom 2004 [15265971] 

Study 

characteristics 

Subjects’ 

health 

conditions 

Study design and 

follow-up duration Eligibility criteria Breastfeeding Exposures or Interventions 

Mean age (range): 39 Menopause: ND Race: Jewish 30% cases French Canadian 10% Other white 59% Black1% Other 0.5% Enrolled/Evaluate: 1927/1830 Location: hospital based Sites: Multi Funding: ND 

Women with carriers of gene mutation BRCA1 and BRCA2 

Case-control study design Follow-up 8.2 (time between breast cancer diagnosis and the completion of study questionnaire. 

Selected Eligible subjects who carried a mutation in either the BRCA1 or the BRCA2 gene were drawn from a database 

For women who gave an approximate length of breastfeeding (e.g., 3–5 months), the midpoint of duration was used. The year of breast cancer diagnosis and years of all pregnancies were recorded. If both occurred during the same calendar year, it was not possible to establish the sequence of breast cancer and pregnancy. Only live births that occurred at least one calendar year before a diagnosis of breast cancer were captured. Twin births were considered to be one birth with respect to breast-feeding. 

Espbbc

Jernstrom 2004 [15265971] 

Outcome 

Definition 

Statistical analyses and confounders 

adjusted Results Bia

Breast cancer among BRCA1 and BRCA 2 

Conditional logistic regression for odds ratios (ORs) in the univariate and multivariate analyses. In the first analysis, parity and oral contraceptive use were used as covariate variables. Because of the strong association between parity and breast-feeding, secondary analysis was performed a that excluded all nulliparous women. All analyses were adjusted for oral contraceptive use. 

In univariate analyses subjects who had breastfed their kids >1y and had BRCA1 gene polymorphism (OR 0.56; 95% CI 0.41 to 0.76) had statistically significant reduced odds of breast cancer compared to none breastfeeding. Breastfeeding ≤1 yr + BRCA1 (OR 0.89; 95% CI 0.70, 1.15; p<.001) and breastfeeding + BRCA2 were not associated with reduced odds. In multivariate subjects who had breastfed their kids >1y and had BRCA1 gene polymorphism (OR 0.55; 95% CI 0.38 to 0.80) had statistically significant reduced odds of breast cancer compared to none breastfeeding. The trend per month of breast feeding also decreased the odds of breast cancer 

A: strong, B: modera

Selection Study design Confounder Blinding Data collection Withdraw and dropoAnalyses Intervention integrity 

Overall grade: B 

C-135
Lee SY, 2003 [12704674] 

Study 

characteristics 

Subjects’ health 

conditions 

Study design and 

follow-up duration Eligibility criteria 

Breastfeeding 

Exposures or 

Interventions 

Mean age (range): 33-44 Menopause: Pre Race: Asian 100% Enrolled/Evaluate: 110604 Location: population based Sites: Multi Funding: Gov 

Earlier menarche Oral contraceptive use Ever smoke Alcohol use Exercise (yes) [data available by duration of lactation] 

Prospective observational cohort Follow-up 6 yrs 

Premenopausal women who were enrolled in the Korean Medical Insurance Corporation (KMIC) and participated in the Korean Women’s cohort 

Ever vs Never Periods of lactation 1-12 months 13-24 months 

Lee SY, 2003 [12704674] 

Outcome 

Definition 

Statistical analyses and 

confounders adjusted Results 

Incident breast cancers 

In bivariate analyses, the authors examined the relation between lactation and traditional breast cancer risk factors, adjusting for age. In these bivariate analyses, the authors tested for trends across categories of duration of lactation, using parous women who never breastfed as the reference. In Cox proportional hazard models, age, age at menarche, number of children, age at first pregnancy, oral contraceptives, smoking, exercise and obesity were controlled to delineate the independent effects of lifetime lactation. In all analyses, a 2-sided alpha level of 0.05 was considered statistically significant.

Compared to parous women who had no history of lactation, periods of lactation of 1–12 months or 13–24 months were associated with decreased risk of breast cancer (RR, 0.8; 95% CI, 0.7–1.0 or RR, 0.7; 95% CI, 0.5–1.1, respectively), and this risk decreased even further for those with who breastfed for more than 24 months (RR, 0.6; 95% CI, 0.3–1.0)

Person- Multivariate model 

years 

Breast 

cancer RR 

(95%CI) 

Never 263,472 161 Ref 1-12 256,199 149 0.8 

(0.7-1.0) 

NS 

13-24 39,125 32 0.7 

(0.5-1.1) 

NS 

>24 23,556 18 0.6 

(0.3-1.0) 

p = 0.0438 

p for trend <0.001

C-136
Evidence table for Systematic Reviews of Breastfeeding 

Author, Year[UI] Topic Lipworth, 2000 [10675379] Breast Cancer

Literature search (Dates) Medline (1966-1998); Other databases searched? (no); unpublished data used? (no) 

Countries where primary 

studies conducted 

International studies including developed and developing nations 

Study eligibility / inclusion 

criteria 

Studies that included more than 200 cases overall and explicitly controlled for number of 

full-term pregnancies and age at first birth 

Study design [No. Of studies] Case-control studies 

No. of subjects 23461/52948 

Study population (definition in 

included studies) 

Premenopausal women with breast cancer and controls (nd) 

Intervention/Exposure 

(definition in included 

studies) 

Breastfeeding (ever) 

Comparator (definition in 

included studies) 

Breastfeeding (never) 

Outcomes (definition in 

included studies) 

Breast cancer (nd) 

Heterogeneity assessments None 

Quality assessments ND 

Publication bias assessments ND 

Statistical Analysis or metaanalytic methods 

No meta-analysis; only qualitative review 

Results “Ever” breastfeeding effect remains inconclusive with results indicating either no 

association or a weak protective effect against breast cancer. Few studies also reported 

an inverse association between increasing life-time breastfeeding and breast cancer risk 

in parous women. 

Quality of the systematic 

review 

B 

Author’s interpretations of the 

results 

“Evidence supporting protective factor of breastfeeding for breast cancer is limited and 

should be interpreted with caution.” 

Comments / Limitations 

C-137
Author, yr: Lipworth, 2000 [10675379] 

Topic of the systematic review*/MA: Breast Cancer

Reporting yes/no 

Reporting of Background 

1 Description of study outcomes Yes 

2 Types of exposure or intervention used Yes 

3 Types of study designs used Yes 

4 Study population Yes 

Reporting of Search strategy 

5 Search strategy, including time period and key words Yes 

6 Effort to include all available studies (contact with authors) Partially 

7 Databases and registries searched Partially 

8 Method of addressing published articles other than English No 

9 Method of handling abstracts and unpublished studies No 

Reporting of Methods 

10 Rationale for selection and/or coding of data Yes 

11 Assessment of confounding Yes 

12 Assessment of quality No 

13 Assessment of heterogeneity Yes 

14 Description of statistical methods sufficient to replicate Not applicable 

15 Provision of appropriate tables and graphs Partially 

Reporting of Results 

16 Graphic summarizing of individual study estimates and overall Not applicable 

17 Tables giving descriptive information of each study included Yes 

18 Results of sensitivity testing (subgroup analysis) Not applicable 

19 Indication of statistical uncertainty of findings Not applicable 

20 Quantitative assessment of bias (eg. publication bias) Not applicable 

Overall quality B 

*When grading a systematic review, please skip item #14, 18-20 

Please fill the white areas only 

Evaluation of quality of a systematic review or meta-analysis 

Yes /No 

/Partially 

1 Is search strategy appropriate/relevant to the key question(s)? yes 

2 Did authors give justifications for inclusion/exclusion criteria pertaining to the studies of 

interest? 

no 

3 Were Population, Intervention/Exposure, Comparator/Control, Outcomes, and Study 

Designs well-defined? 

yes 

4 Did authors attempt to minimize errors in data extraction (such as collecting the 

relevant data, double data extraction, verification of data extraction...etc.)? 

nd 

5 Was individual study quality (such as sample size, study design, blinding, various 

biases and confounders, study subject attrition rate...etc.) assessed? 

Partially 

6 Did authors consider appropriate confounders and justification for adjusting or not 

adjusting for those confounders? 

yes 

7 Was the justification for combining or not-combining data for meta-analysis, or the use 

of a particular analytic method or model appropriate? 

no 

8 Was heterogeneity explored (this is in addition to any statistical test of heterogeneity, 

did the authors look at the actual differences in PICOS, for example?)? 

no 

8 Were results reported accurately (eg, no discrepancies between text and tables)? no 

9 Were conclusions justified by the reported/collected data and analysis? yes 

C-138
Appendix C. Evidence Tables 

Part III. Maternal Outcomes 

Osteoporosis-BMD 

Hansen 1991 

Matsushita 2002 

Sowers 1992 

Uusi-Rasi 2002 

Osteoporosis-Fracture

Alderman 1986 

Chan 1996 

Cumming 1993 

Hoffman 1993 

Kreiger 1982 

Michaelsson 2001 

C-139
Hansen, 1991 [UI#1790399] 

Study 

characteristics 

Subjects’ 

health 

conditions 

Study design 

and follow-up 

duration 

Eligibility criteria Breastfeeding Expo

Intervention

Mean age (range): 51 Menopause: post Race: ND Enrolled/Evaluate: 178/121 Location: Denmark Sites: Single Funding: 

healthy Prospective 

cohort (12 years) 

In 1979, 178 women completed a 2-year, prospective study receiving placebo. They had been selected by questionnaire and a medical screening examination. All had passed a natural menopause 6 months to 3 years earlier and were free of disease or medications known to influence the calcium metabolism. In 1989, 12 years after the start of the original study, all 178 women were re-contacted for a follow-up examination. Of these, 24 (13%) were unable to participate: 6 women had died, 9 suffered from diseases which made participation impossible, 6 unwilling to participate for personal reasons, 2 had emigrated, and 1 could not be located. Among the 154 women underwent the follow-up examination, 24 women were excluded due to owing to post-trial treatment with sex hormones for more than 1 year and another 9 women presenting with disease known to influence calcium metabolism were excluded as well. 

111 women (92%) haexperienced 1 or morpregnancies (mean: 2breast fed for a mean lactation period of 13 

Hansen, 1991 [UI#1790399] 

Outcome Definition 

Statistical 

analyses and 

confounders 

adjusted 

Results Bi

Lumbar spine BMD, measured by DEXA. BMD is calculated as BMC divided by the area of interest from L2 to L4 including the intervertebral discs. BMD only measured in the follow-up. Forearm BMC was measured by single photon absorptiometry (125I). The rate of postmenopausal bone loss (% per year) was 

determined as the difference in % between the measurement in 1979 and the measurement obtained in 1989 divided by 10 years. 

Student’s t test for unpaired data 

∆BMCarm% 

per year 

∆BMDspine

Lactation (-) 

-1.8±0.8 0.84±0.18 

Lactation (+) 

-1.7±0.8 0.88±0.14 

p-value NS NS 

A: strong, B: moweak 

Selection Study design Confounder Blinding Data collection Withdraw and dAnalyses Intervention inte

Overall: C Univariate analysand lactation. Ungroup including n

C-140
Matsushita, 2001 [UI#12200655] 

Study 

characteristics 

Subjects’ 

health 

conditions 

Study design and 

follow-up duration Eligibility criteria Breastfeeding Exposures or Interventions 

Mean age (range): 30.1 Menopause: pre Race: Asian (assumed) Enrolled/Evaluate: 113/113 Location: Japan Sites: Single Funding: ND 

Healthy, wellnourished Longitudinal cohort study 

Mean interval between each delivery = 2.5 years 

Postpartum Japanese women, aged 20-40 years, who delivered a singleton infant at the university hospital between 1994 and 1999. Women who had 2nd pregnancy were included. 

Exclusion criteria included complications and medications before or during pregnancy, that would affect bone metabolism, delivery before 36 weeks’ gestation, or bed rest in excess of 7 days. 

Lactation information including l(breast-fed or formula-fed) was immediately after the subsequeOnly 1 woman had formula-fed, (n=46) or without (n=66) formula Whether breast-feeding had beeon-demand, and when alternativwas not available because of am

Matsushita, 2001 [UI#12200655] 

Outcome Definition Statistical analyses and confounders adjusted Results 

BMD of the lumbar spine (L2-L4) was measured by DEXA within 7 days of delivery. 113 of women became pregnant again and they had 2nd BMD 

measurement within 7 days of the next delivery. 

The percent change in BMD (∆BMD%) was calculated by subtracting the value at the time of the first pregnancy from the value at the time of the second pregnancy. 

BMD and backgrounds of consecutive pregnancies were compared using a paired t-test. Multiple regression analysis was performed to look for independent predictors of 

∆BMD%. BMD after the initial 

delivery was included as an independent variable to adjust for regression toward the mean. 

Lumbar BMD of 110 women after the initial and the subsequent delivery was 1.006±0.117 and 1.019±0.115 g/cm2, respectively. BMD after the 

subsequent delivery was significantly higher than that after the initial delivery (p=0.001), with a ∆BMD% of 1.4±4.2%. 

Independent determinants of 

∆BMD% were explored 

by multiple regression analysis: the length of lactation between the scans showed no correlation with 

∆BMD% (coefficient=-0.06±0.157 SEM, 

p=0.702). Age was the most significant predictor for ∆BMD% in the model. 

Amw

SSCBDWdAIi

Ov

C-141
Sowers, 1992 [UI#4543] 

Study 

characteristics 

Subjects’ 

health 

conditions 

Study design 

and follow-up 

duration 

Eligibility criteria Breastfeeding Exp

or Intervention

Mean age (range): Menopause: mix Race: European Enrolled/Evaluate: 217/181 Location: US Sites: Single Funding: Government 

ND Prospective 

cohort (5 year) 

In 1984, BMD of women In aged 22-54 years living in a single rural community were measured by single-photon densitometry. The community was selected for study because of the mineral characteristics of the community water supply. Women were eligible to participate in the baseline study if they had lived in the community the previous 5 years, were able to complete face-to-face interview, were ambulatory and reported themselves to be of northern European heritage. In 1989, a follow-up survey reexamined 181 of the 217 women who participated in the baseline survey. Nonrespondents to the follow-up survey were less likely to be married, were younger, had a greater Quetelet index, and had a slightly greater BMD than participants at baseline 

Subjects were intervibaseline and follow-uvarious factors, inclulactation. 

Sowers, 1992 [UI#4543] 

Outcome Definition Statistical analyses and confounders adjusted Results 

BMD was expressed as the bone mineral to bone width ratio. Percent change was calculated as 100% - follow-up value/baseline value 

Multiple-variable regression analyses were used to assess relationships between BMD change or baseline BMD values and the explanatory variables adjusting for age and estrogen status. Stepwise regression was used to generate models considering all other important variables, including age, estrogen status, parity, age at first pregnancy, and weight. 

Nulliparous women (n=12) had significantly lower BMD at baseline and follow-up than parous women (n=169) before and after adjusting for age and estrogen status. A recalled history of breast-feeding in parous women did not predict significant differences in BMD level or amount of BMD change. We had insufficient sample size to test whether duration of breast-feeding in excess of 6 months for a single infant or 6 months cumulative time from breast-feeding multiple infants was associated with significant differences in BMD. 

Amw

SSCBDWdAIi

Ov

C-142
Uusi-Rasi, 2002 [UI#11991440] 

Study 

characteristics 

Subjects’ 

health 

conditions 

Study design 

and follow-up 

duration 

Eligibility criteria 

Breastfeed

Exposures 

Interventio

Mean age (range): 28.4 Menopause: pre Race: ND Enrolled/Evaluate: 132/92 Location: Finland Sites: Single/Multi Funding: private 

healthy Prospective 

cohort 

4.2 (range 3.2-5.4) years 

Healthy, non-smoking women willing to participate in original crosssectional study. Inclusion criteria were a daily dietary calcium intake of over 1200 mg (Ca+) or under 800 mg (Ca-) and vigorous physical activity more than twice a week, or light to moderate activity no more than once a week. Women who had intermediate levels of physical activity or calcium intake or used calcium supplements were excluded. Altogether 92 women out of the 132 original 25- to 30-year-old subjects participated in the follow-up measurements. 

Total duration of breastfeeding (operiod or sum of periods of breas

Uusi-Rasi, 2002 [UI#11991440] 

Outcome Definition Statistical analyses and confounders adjusted Results 

BMC at the proximal femoral neck and total trochanter region and the distal radius of the dominant side was measured with dual energy Xray absorptiometry. 

Repeated-measures analyses of variance were used to analyze the between group differences in changes in site-specific BMC. Regression models for % bone loss using a multivariate stepwise regression analysis that included baseline variables: age, body weight, muscle strength, estimated maximal oxygen uptake and calcium intake, the absolute changes in body weight, muscle strength, estimated maximal oxygen uptake, calcium intake, physical activity, duration of breastfeeding and time from weaning. 

The mean decrease in BMC (95% CI) was 1.5% 

(0.7% to 2.4%) for the femoral neck, 0.6% (-0.8% to 1.9%) for the trochanter and 6.0% (4.5% to 7.4%) for the distal radius during the follow-up 

According to the multiple stepwise regression 

analyses, the statistically significant independent predictors for site-specific bone loss were low calcium intake at the baseline and change in body weight both at the proximal femur and at the distal radius. High calcium intake, as well as an increase in body weight, were associated with less bone loss at all the measured bone site. 

In addition, breastfeeding was associated with 

radial bone loss; the longer the duration of breastfeeding the greater the bone loss (Multiple regression coefficient= -0.34 +- 0.14 SE, p=0.015). Breastfeeding was not associated with femoral neck or trochanter BMC loss 

O

C-143
Alderman, 1986 [UI#3728442] 

Study 

characteristics 

Subjects’ 

health 

conditions 

Study 

design 

and 

follow-up 

duration 

Eligibility criteria Breastfeeding Exposures 

Interventions 

Mean age (range): 50-74 Menopause: post (assumed) Race: White Enrolled/Evaluate: 355/344 for cases; 562/318 for controls Location: US Sites: Multi Funding: Government 

ND Casecontrol 

study 

Cases: Between 1976 and 1980, all women with hip 

fracture who sought care from a 62% sample of orthopedic surgeons were eligible. Women with forearm fracture who sought care from these orthopedists were eligible if the physician’s practice had records that allowed tracing of all outpatients. Women who sought care for vertebral fractures were not eligible because we believed that they represented a small and probably unrepresentative group of women with vertebral fracture. Exclusion: nonwhite, younger than 50 or older than 74 years of age, nonresidents of King County, residents of institutions at the time of fracture, or if they had multiple or pathologic fractures. 

Controls: unmatched control women were identified 

through 3 door-to-door area-based surveys of the general population of King Country conducted in 1976, 1977, and 1979. Comparable exclusion criteria were used. 

The duration of lactation was calby summing the number of montlactation associated with each biwas treated in separate analyses categorical variable (taking value12, 13 to 24 and more than 24 mand as continuous variable (takinfrom 0 to 109 months) 11/355 cases missing data on la

C-144
Alderman, 1986 [UI#3728442] 

Outcome 

Definition Statistical analyses and confounders adjusted Results 

Risk of hip or forearm fractures 

Logistic regression was used. The logistic model was evaluated for confounding by forward selection method. Only parity and variables with independent confounding effects were included in the final model. The same procedure was repeated to examine the association between fracture and duration of lactation. 

Logistic regression analysis did not reveal a substantial change in risk of fracture with increasing duration of lactation when lactation was treated as a categorical variable. Adjustment for confounding effects of age, relative weight, and duration of estrogen use did not alter these results. Similar results were obtained when lactation was treated as a continuous variable. Separate analysis of women with hip fracture suggested that an increase in months of breastfeeding was associated with an irregular decreased in risk of fracture. 

Amw

SSCBDWdAIi

Ov

C-145
Chan, 1996 [UI#8783297] 

Study 

characteristics 

Subjects’ 

health 

conditions 

Study design 

and follow-up 

duration 

Eligibility criteria Breastfeeding Exposures o

Interventions 

Mean age (range): 75 (70-79) Menopause: post Race: Chinese Enrolled/Evaluate: 481/481 Location: Hong Kong Sites: Single Funding: Government 

ND Case-control 

study 

Chinese women aged 70-79 years who were living in Geriatric Housing Scheme in Hong Kong. Subjects with a known history of metabolic bone disorder, cancer, or who were on long-term steroid treatment, were excluded. No subjects with such histories but 3 subjects on steroid therapy were excluded from the study. Cases: definite or doubtful vertebral fracture Control: the remaining enrolled subjects (women with no fractures) 

Home-visit interviews by a standarstructured questionnaire was administered by 2 trained research nurses who was blinded to the fracstatus. Period of lactation: less than 24 moor 24 months or more 

Chan, 1996 [UI#8783297] 

Outcome Definition 

Statistical analyses 

and confounders 

adjusted 

Results 

Diagnosis of vertebral fracture according to Black et al.: definite vertebral fracture: when any of the 3 vertebral ratios was 3 SD or more away from the mean; doubtful fracture: any of the 3 vertebral ratios was 2-2.99 SD away from the mean. A woman with 1 or more definite fractures was classified as a definite case, a woman with no definite fractures but one or more doubtful fractures as a doubtful case, and the rest as controls. 

Logistic regression: OR for vertebra fracture among definite case and control; doubtful cases and controls. Analysis adjusted for age. 

There were no significant differences in the age of menarche and menopause between definite cases, doubtful cases, and controls. The risk of definite fracture decreased with the number of children given birth to and the duration of breastfeeding. 

Period of Age-adj OR (95% CI) lactation 

% in definite cases (n=144) 

% in doubtful cases (n=174) 

% in controls (n=163) Definite cases & 

control 

Doubtful cases & control 

Never 63 45 53 1.0 1.0 <24 mo 18 22 20 0.7 

(0.4-1.3) 

1.3 (0.7-2.2) 

≥24 mo 19 33 27 0.6 

(0.3-1.0 

1.5 (0.9-2.4 

ODw

C-146
Cumming, 1993 [UI#8225744] 

Study 

characteristics 

Subjects’ health 

conditions 

Study design 

and follow-up 

duration 

Eligibility criteria 

Breastfee

Exposure

Interventi

Mean age (range): 65-100 Menopause: post Race: D Enrolled/Evaluate: Location: Australia Sites: Multi Funding: ND 

Self-reported heath (for directly interviewed subjects only: 104 cases and 114 controls) Cases: 23% excellent, 50% good, 20% fair; 6% poor Controls: 26% excellent, 51% good, 21% fair; 5% poor 

Populationbased casecontrol study All people aged ≥65 living in a postcode-defined area in Sydney between 3/1990 and 8/1991. Total of 11 hospitals were included in the study. 

Cases: People with hip fractures presenting to the 

hospitals. The case ascertainment varied across hospitals. 

Controls: People living in private homes in the community 

and from people living in nursing homes and hostels. The controls comprised a probability sample of people aged ≥65 

years living in the 11 postcodes of the study base during the same time period as the cases. 

Proxy respondents were used for elderly people with 

cognitive impairment and those with various other health problems. A shortened questionnaire was used to interview proxy respondents. 

For all womenEver breastfeeFor parous woonly: Average duratbreastfeeding child (months) 

C-147
Cumming, 1993 [UI#8225744] 

Outcome 

Definition 

Statistical analyses and confounders 

adjusted Results 

Risk of hip fracture 

Data analysis: crude, stratified and multivariate methods to produce OR for associations between hip fracture and exposure variables. Age is the strongest predictor of hip fracture and so all results were adjusted for age. Multiple logistic regressions were controlling for several confounding variables. Selection of confounders for inclusion in these models was based a priori knowledge of risk factors for hip fracture and the strength of univariate associations between exposure variables and hip fracture. Confounders (other than age) were entered into models as categorical variables. 

There were 311 women in this study: 174 cases and 137 controls. The 

response rate was 96% for cases and 82% for controls. Proxy interviews were required for 93 subjects. Most cases (78%) were recruited from 1 teaching hospital. A history of use of HRT was more common among controls than among cases (age-adj OR: 0.55, 95%CI 0.24-1.27). 

Age- and proxy-adjusted Multivariate-adjusted 

Cases Ctrl OR (95%CI) No. subjects in the model OR (95%CI) 

All women 

BF- N=176 Never 60 42 1.00 1.00 Ever 106 95 0.72 (0.43-1.20) 0.64 (0.30-1.38) 

Parous women 

BF- N=140 Never 25 12 1.00 1.00 Ever 106 95 0.47 (0.22-0.99) 0.55 (0.10-2.90) Average duration of BF per child (mo) N=136 0 19 11 1.00 1.00 0.5-3 17 16 0.56 (0.19-1.68) 0.64 (0.13-3.06) 3-6 17 24 0.41 (0.15-1.13) 0.79 (0.18-3.51) 6-9 18 23 0.47 (0.19-1.19) 0.41 (0.09-1.82) >9 7 10 0.28 (0.07-1.18) 0.24 (0.04-1.53) 

For women who had one or two children, breastfeeding markedly reduce the 

risk of hip fracture in later life. After adjusting for age and number of children, the OR in parous women for breastfeeding all children versus breastfeeding none was 0.26 (95%CI 0.10-0.69) 

A: smowea

SelStuConBlinDatWitdroAnaInteinte

OverMissmultiof su

C-148
Hoffman, 1993 [UI#8338971] 

Study characteristics 

Subjects’ 

health 

conditions 

Study design 

and follow-up 

duration 

Eligibility criteria 

Breastfeed

Exposures 

Interventio

Mean age (range): 50-103 Menopause: post Race: White Enrolled/Evaluate: 286/174 cases; 311/174 controls Location: USA Sites: Multi Funding: ND 

Hospital cases and controls 

Case-control study 

Cases: a sample of radiologically confirmed cases of first hip fracture among white women aged 45 years and older was drawn from among admissions to one of 30 hospitals between 9/1987 and 7/1989 Controls: white hospital controls, frequency-matched to cases by 10-year age group and by hospital of admission during the same time period. Exclude subjects with a prior hip fracture, pathological fracture secondary to cancer, evidence of bony metastases, severe cognitive, language, or hearing impairment, died in the hospital shortly after surgery, or medically unstable 

Ever lactated Lactated ≤ 12 mLactated > 12 m

Hoffman, 1993 [UI#8338971] 

Outcome 

Definition Statistical analyses and confounders adjusted Results 

Risk of hip fracture 

Conditional logistic regression models were used to remove the effect of matching cases and controls. Because the age intervals were wide, age was controlled for as continuous variable. Variables that changed crude estimates by 10% or greater were retained as confounding variables. For lactation, only the number of live births was retained. 

Lactation was associated with reduced odds of hip fracture among all women (OR=0.66 [0.41-1.05]) Restricting the analysis to parous women and controlling for number of live births, there was no association between ever having lactated or duration of lactation and hip fracture (OR for lactation of 12 months or less=0.80 [0.42-1.55]); OR for lactation of more than 12 months=1.08 [0.45-2.60]) Duration of lactation did not confound the negative association between parity and hip fracture. 

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C-149
Kreiger, 1982 [UI#7102649] 

Study characteristics 

Subjects’ 

health 

conditions 

Study design 

and followup duration Eligibility criteria Breastfeeding Exposures or Interventions 

Mean age (range): 45-74 Menopause: post Race: ND Enrolled/Evaluate: 149/98 for cases; 1345/884 Location: US Sites: Multi Funding: ND 

Hospital cases and controls 

Case-control study 

Women aged 45-74 years admitted to surgical services of 4 Connecticut hospitals between 9/1977 and 5/1979. Cases: women admitted to 1 of the 4 study hospitals with a first diagnosis of hip fracture, either intra- or extra- capsular, confirmed by x-ray. Controls: systematic sample of women admitted to the inpatient surgical services of the 3 largest hospitals. Controls included had a wide variety of diagnoses, and no more than 5% of the controls were in any single diagnostic category. Exclusion: women with reproductive cancers, who did not speak English, who lived outside of Connecticut, or last menstrual period was within 1 year of hospital admission or if the admitting diagnosis of a disease related to estrogen use. 

98 of 149 cases (66%) of hip fracture and 884 of 1345 controls (66%) were interviewed. Variable: Breastfeeding 12-month increase 

Bethe groan

Kreiger, 1982 [UI#7102649] 

Outcome Definition Statistical analyses and confounders adjusted Results Bias/

Co

Odds ratio of hip fracture, compared cases to trauma or nontrauma controls. 

Linear logistic regression, adjusted for age and for Quetelet index (similar to BMI), bilateral ovariectomy, and estrogen replacement therapy. 

Linear logistic regression, adjusted for age and for Quetelet index (0.01 increase), bilateral ovariectomy (yes/no), and estrogen replacement therapy (60-month increase): 

Cases and 

trauma control 

Cases and 

non-trauma 

control 

Variable Unit Adj OR 

(95% CI) 

Adj OR 

(95% CI) 

Breastfeeding 12-

month increase 

0.5 

(0.2, 0.9) 

0.6 

(0.3, 1.0) 

A: strong, B: moderate

Selection Study design Confounder Blinding Data collection Withdraw and dropout Analyses Intervention integrity 

Overall: C Sample size in breastfedescribed. Did not sepa

C-150
Michaelsson, 2001 [UI#2001082617] 

Study 

characteristics 

Subjects’ 

health 

conditions 

Study design and follow-up 

duration Eligibility criteria 

Breastfeed

Exposures 

Interventio

Mean age (range): Cases=72.5; Controls=70.5 Menopause: post Race: ND Enrolled/Evaluate: 715/664 for cases evaluated Location: Sweden Sites: Multi Funding: ND 

ND Case-control study; a 

comprehensive questionnaire at a mean interval of 95 days after the fracture; associations between lactation and hip fracture were only analyzed for parous women 

Cases: All fractures of the proximal femur that occurred 

between 10/ 1993 and 2/1995 among women resident in 6 counties in Sweden who were born after 1913. Using clinical records or operation registers in all 24 hospitals in the study area, a total of 1,597 possible incident cases were identified. Those with a fracture due to malignancy (n=26); high-energy trauma (n-4); incorrect diagnosis (n=41); old fracture (n-10); blindness (n=5); birth outside Sweden (n=202); excluded: severe alcoholic abuse, psychosis, or senile dementia (n=576); or death within 3 months of the fracture (n=123). After exclusions, 1,610 eligible cases remained and were approached with. The Swedish inpatient register identified 34 additional cases. 

Controls: Native-born women were randomly selected 

from the national population register in the month before the start of the study. Potential controls aged 70-80 years were frequency matched (2 controls per 1 case) to the expected hip fracture age distribution within county of residence. Controls aged 50-69 years were randomly selected from the population register as part of a breast cancer study being conducted at the same time with the same questionnaire. For these women, frequency matching to the expected number of breast cancer cases provided 2-4 times as many controls as hip fracture cases in each 5-year age group and country of residence. Of the 4,870 candidate controls in the hip fracture analysis, 4,059 were eligible for the study, 610 were born outside of Sweden, 257 died before being approached, 44 were senile or psychotic, and 2 were blind. 

Duration of brea4 classes definetotal duration obreastfeeding a

C-151
Michaelsson, 2001 [UI#2001082617] 

Outcome 

Definition 

Statistical analyses and confounders 

adjusted Results 

OR of hip fracture 

Unconditional logistic regression were used as measure of association. The multivariate analyses included the covariates age, BMI, oral contraceptive use, HRT use, and smoking status. Interactions were considered. Associations between lactation and hip fracture were only analyzed for parous women 

Long total duration of breastfeeding was associated with a reduction in risk (table 3 in paper), but this association disappeared after adjustment for parity, body mass index, and use of exogenous estrogens. There were no substantial risk differences in analyses that considered mean duration of breastfeeding per child (quartiles 0–2, 3–4, 5–6, and 7 months per child or more) (data not shown). Long duration of breastfeeding also had no substantial association with hip fracture risk among those with their first pregnancy as a teenager or among those with their first pregnancy after age 30 years. The relative risk estimates for lactation and parity were similar for cervical and trochanteric hip fracture (data not shown). 

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C-152
Appendix C. Evidence Tables 

Part III. Maternal Outcomes 

Ovarian Cancer 

Chiaffarino 2005 

Cramer 1983 

Greggi 2000 

Gwinn 1990 

Hartge 1989 

John 1993 

Modugno 2003 

Ness 2000 

Riman 2002 

Risch 1983

Risch 1994 

Siskind 1997 

Titus-ernstoff 2001 

Tung 2003, 2005 

West 1966 

Whittemore 1992 

Wynder 1969 

Yen 2003

C-153
Chiaffarino, 2005 [UI# 15975644] 

Study 

characteristics Subjects’ health conditions Study design and follow-up duration Eligibility criteria Breastfee

Exposure

Intervent

Median age (range): Cases: 56 (18-79) Controls: 57 median (17-79) Menopause: ND Race: ND Enrolled/Evaluate: Cases: 1031/1028 Controls: 2411/2390 Location: Italy Sites: Multi-center Funding: Private, government 

Cases: ND Controls: traumatic conditions 26%, nontraumatic orthopedic disorders 28%, acute surgical conditions mostly abdominal diseases 15%, miscellaneous illnesses (ear, nose throat, teeth) 31% 

Case-control Data collection by interviews using structured questionnaire 

Case: Histologicaly confirmed epithelial ovarian cancer diagnosed in past year, admitted to major or teaching hospital Control: residents of same geographic area, admitted to same network of hospitals for acute, non-neoplastic, unrelated to known or likely risk factors for ovarian cancer, exclusion include hormonal and gynecological diseases, or ovariectomized 

Breast feedinstatus determby questionn

C-154
Chiaffarino, 2005 [UI# 15975644] 

Outcome 

Definition 

Statistical analyses and confounders 

adjusted Results 

Ovarian cancer confirmed by histology 

Unconditioned multiple logistic regression adjusting for age, center, education, parity, oral contraceptive use, family history of ovarian/breast cancer in first degree relatives 

Exposure status Cases n (%) Controls n (%) ORadj (95% CI) 

Never breastfed 368(36) 878 (37) 1.0 Ever breastfed 660 (64) 1512 (63) 1.16 (0.93-

1.43) 

Breastfed 1-4 months 157 (15) 358 (15) 1.20 (0.91-

1.59) 

Breastfed 5-8 months 180 (18) 366 (15) 1.24 (0.95-

1.62) 

Breastfed 9-16 months 

195 (19) 451 (19) 1.01 (0.77-

1.33) 

Breastfed ≥17 

months 

128 (12) 337 (14) 1.21 (0.85-

1.71) 

x2 for trend 0.03 (p=0.87) 

Odds ratioadj 

Exposure (95% CI) status Serous Mucinous Other subtypes Never breastfed 1 1 1 Ever breastfed 1.1 (0.85-1.48) 1.59 (0.82-3.07) 1.08 (0.71-1.62) Breastfed 1-4 mo 1.3 (0.90-1.85) Breastfed 5-8 mo 1.16 (0.81-1.65) Breastfed 9-16 mo 1.06 (0.74-1.51) Breastfed ≥17 mo 0.87 (0.55-1.39) x2 for trend 0.14 

p=0.71 

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C-155
Cramer, 1983 [UI# 6578366] 

Study 

characteristics 

Subjects’ health 

conditions 

Study design and 

follow-up duration Eligibility criteria Breastfeeding Exposures or Interventions 

Mean age: 53 Menopause: ND Race: White Enrolled/Evaluate: Cases: 215 Controls: 215 Location: USA Sites: Multi-center Funding: Government 

ND Case-control 

Data collection by questionnaires 

Cases: white females with epithelial ovarian cancer residing in greater Boston area Controls: matched residents of same precinct, age within 2 years, race. Only bilateral oophorectomy excluded. 

Breastfeeding status determined by questionnaire 

Cramer, 1983 [UI# 6578366] 

Outcome Definition Statistical analyses and confounders adjusted Results 

All types of epithelial ovarian cancer 

Chi-square Crude relative risks 1.11 (0.70-1.76) never breastfed parous 

cases (86/137) vs controls (106/176) 

Non-significant trend in risk for ovarian cancer with number of children breastfed. 

A: strong, C: weak 

Selection Study desConfoundeBlinding Data colleWithdraw Analyses Interventio

Minimal repPotential rec

C-156
Greggi, 2000 [UI# 11006030] 

Study 

characteristics Subjects’ health conditions 

Study design 

and follow-up 

duration 

Eligibility criteria 

Breastfeed

Exposures 

Interventio

Median age (range): Cases: 54 (13-80) Controls: 55 (19-80) Menopause: mix Race: ND Enrolled/Evaluate*: Cases: 440/330 Controls 868/721 Location: Italy Sites: Single Funding: Private *Parous 

Cases: ND Controls: traumatic conditions 29%, nontraumatic orthopedic disorders 21%, acute abdominal diseases generally requiring surgery 17%, miscellaneous illnesses (ear, nose throat, teeth) 33% 

Case-control Data collection by hospital interviews 

Cases: admitted histologically confirmed diagnosis of epithelial ovarian cancer Controls: admitted to same hospital, similar age strata, acute nongynecological, nonhormonal, or nonneoplastic condition 

Breast feeding status determininterview 

Greggi, 2000 [UI# 11006030] 

Outcome 

Definition 

Statistical analyses and confounders 

adjusted Results 

Epithelial ovarian cancer confirmed by histology 

Mantel-Haenzel adjusted for age; unconditional multiple logistic regression estimates including terms for age, education, parity, oral contraceptive use, family history of ovarian cancer 

Exposure ORadj (95% CI) status* 

Cases 

330 (%) 

Controls 

721 (%) MantelHaenzel Multivariate regression 

Never breastfed 84 (25) 120 (17) 1.0 1.0 Breastfed ≤12 

months 

136 (41) 294 (41) 0.6 

(0.5-0.9) 

0.8 (1.0-

1.1) 

Breastfed >12 months 

110 (33) 307 (43) 0.5 

(0.3-0.7) 

0.5 

(0.4-0.8) 

*Parous 

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C-157
Gwinn, 1990 [UI# 2348208] 

Study 

characteristics 

Subjects’ 

health 

conditions 

Study design and 

follow-up duration Eligibility criteria Breastfeeding Exposures or Interventions 

Mean age (range): ND Menopause: mix Race: ND Enrolled/Evaluate: Cases: 494/436 Controls: 4236/3833 Location: USA Sites: Multi center Funding: 

ND Case-control 

Controls contacted by random telephone Data collection by interview of standard questionnaire 

Cases: 20-54 year, resides in 1 of 8 study areas, ovarian cancer by histology Controls: matched for age, resides in same 8 areas, no ovaries or unknown number of ovaries are exclusion 

Breast feeding status determined binterview, duration in months regardless of pattern 

Gwinn, 1990 [UI# 2348208] 

Outcome Definition Statistical analyses and confounders adjusted Results Bia

C

Epithelial ovarian cancer confirmed by histology 

Logistic regression adjusted for pregnancy, oral contraceptive use, age, and age-pregnancy interaction 

Breastfeeding duration (month)* 

Cases 

n (%) 

Controls 

n (%) 

RRadj 

(95% CI) 

0 184 

(57) 

1517 

(46) 

1.0 

1-2 40 (12) 552 (17) 0.6 

(0.5-0.9) 

3-5 32 (10) 330 (10) 0.8 6-11 33 (10) 379 (11) 0.8 12-23 25 (8) 321 (10) 0.7 ≥ 24 7 (2.2) 213 (6.4) 0.3 

* Parous women only β –0.024  Each month of breastfeeding reduced risk by 2.4% Most protection due to first exposure rather than number of pregnancies 

A: strong, B: modweak 

Selection Study design Confounder Blinding Data collection Withdraw and droAnalyses Intervention integ

Ovarian cancer comajority of cases 

C-158
Hartge, 1989 [UI# 2750791] 

Study characteristics Subjects’ health conditions Study design and follow-up duration Eligibility criteria Breastfeeding Exposures or Interventions 

Mean age (range): Cases: 54 (20-79) Controls: 55 Menopause: mix Race: Cases: 12% black Controls: 14% black Enrolled/Evaluate: Cases: 296/203* Controls: 343/257* Location: USA Sites: Multi Funding: Government *Parous women (evaluated) 

Serous 28% Serous, low malignant potential 12% Mucinous 6% Mucinous, low malignant potential 3% Endometrioid, low malignant potential 26% Clear cell 4% Mixed epithelial 8% Undifferentiated 10% Controls:  Infectious 2%  Neoplasm 5%  Endocrine-metabolic 5%  Blood disease or blood-forming organs 1% Nervous system 8%  Eye, ear, mastoid 8%  Varicose veins, hemorrhoids 1%  Respiratory 8%  Digestive system 16%  Urinary 5%  Skin 2%  Musculoskeletal 22%  Congenital 1%  Ill-defined 5%  Fractures/injuries 11% 

Case-control Data collection with interviewer of standard questionnaire and medical records review 

Cases: primary epithelial ovarian cancer confirmed by microscopic slides and medical records, included low malignant potential tumors as well as malignant tumors Controls: hospitalized for other conditions, matched for age, hospital, race, at least one ovary. Excluded if psychiatric diagnosis or related to major exposures of interest 

Breastfeeding status determined by intervie

C-159
Hartge, 1989 [UI# 2750791] 

Outcome Definition Statistical analyses and confounders adjusted Results 

Primary epithelial ovarian cancer confirmed by microscopic slides and medical records 

Rate ratio of ovarian cancer incidence in exposed group to corresponding unexposed group, adjusted for confounding variables by stratified contingency table analysis and by logistic regression models, adjustments for age and race, and parity, difficulty conceiving, oral contraceptives, surgical menopause, HRT, or family history of ovarian cancer as needed 

Breastfeeding duration (month)* 

Cases 

n (%) 

Controls 

n (%) 

Rate 

ratioadj 

(95% CI) 

0 112 

(55) 

121 

(47) 

1.0 

1-9 62 (31) 84 (33) 0.8 

(0.5-1.2) 

10-18 16 (7.9) 37 (18) 0.5 

(0.2-0.9) 

19-110 13 (6.4) 15 (7.4) 1.1 

(0.5-2.6) 

* Parous women only Adjusted for age and race Trend test p = 0.14 Number of months breastfeeding not related to risk 

C-160
John, 1993 [UI# 8418303] 

Study 

characteristics 

Subjects’ 

health 

conditions 

Study design and follow-up duration Eligibility criteria 

Breastfeeding 

Exposures or 

Interventions 

Mean age (range): Cases: Invasive 53 Borderline 37 Controls: ND Menopause: mix Race: Black Enrolled/Evaluate: Cases: 110/53 Controls: 365/259  69% population  31% hospital Location: USA Sites: 7 of 12 studies Funding: Government 

Invasive cancer 65% Low malignant 32% Unknown 3% 

Case-control Data from 7 studies of cases diagnosed between 1971 and 1986. Individual patient data collected by interview from 7 case-control studies conducted in US 

Epithelial ovarian cancer Controls: population and hospital subjects, bilateral oophorectomy excluded 

Breastfeeding statudetermined by interview 

John, 1993 [UI# 8418303] 

Outcome 

Definition 

Statistical analyses and 

confounders adjusted Results B

Epithelial ovarian cancer 

Conditional logistic regression adjusted for study, birth year, reference age, parity 

Breastfeeding duration (month)* 

Cases 

n (%) 

Controls 

n (%) 

RRadj 

(95% CI) 

Never breastfed 24 (45) 102 (39) 1.0 Ever breastfed 29 (55) 157 (61) 0.90 

(0.42-1.9) 

1-5 11 (21) 52 (20) 1.0 

(0.39-2.6) 

≥6 18 (34) 103 (40) 0.85 

(0.36-2.0) 

Trend per month 0.99 

p=0.57 

* Parous 

A: strong, B: weak 

Selection Study design Confounder Blinding Data collectiWithdraw anAnalyses Intervention 

Data unavailacontraceptives 

Overlap with Hartge 1989 and Cramer 1983 

C-161
Modugno, 2003 [UI# 12946038] 

Study 

characteristics 

Subjects’ 

health 

conditions 

Study design and follow-up duration Eligibility criteria 

Breastfeed

Exposure

Interventi

Mean age (range): BRCA1 51 BRCA2 61 BRCA- 58 Menopause: mix Race: 100% Jewish Enrolled/Evaluate: Cases: 95 Controls: 147 Location: USA, Israel Sites: Multi Funding: Government 

ND Case-control 

Cases screened for Ashkenazi founder mutations BRCA1 (185delAG or 5382insC) or BRCA2 (6174delT) Controls were ovarian cases without BRCA1/2 genotype Individual patient data collected by interview from 4 case-control studies. Two US population studies (100 cases), one hospital-based study from 11 US and Israel centers (208 cases), and one US genetic counseling center (14 cases) 

Jewish women with epithelial ovarian cancer, no breast cancer history, BRCA1/2 confirmed by data sequencing 

ND 

Modugno, 2003 [UI# 12946038] 

Outcome 

Definition 

Statistical analyses and 

confounders adjusted Results 

Invasive epithelial ovarian cancer confirmed by histology 

Unconditioned logistic regression adjusted for age at diagnosis, year of birth, number of live births, oral contraceptive use, history of tubal ligation. MantelHaenszel test for heterogeneity 

ORadj 

(95% CI) 

BRCA- 

(n=147) 

BRCA1/2 

(n=95) 

BRCA1 

(n=64) 

BRCA2 

(n=31) 

Breastfeeding 1.0 1.09 

(0.61-1.97) 

1.36 

(0.68-2.73) 

0.70 

(0.28-1.72) 

Breastfeeding duration* 

1.0 1.02 

(0.99-1.04) 

1.01 

(0.98-1.04) 

1.02 

(0.99-1.05) 

* Parous women 

A: strong, C: weak 

Selection Study desConfoundeBlinding Data collecWithdraw aAnalyses Interventio

10% overlap genetic centClassificatiostudies 

One population study, Ness 2000, has been reported 

C-162
Ness, 2000 [UI# 11021606] 

Modugno, 2001 [UI# 11308435]

Study 

characteristics 

Subjects’ health 

conditions 

Study design and 

follow-up duration Eligibility criteria Breastfeeding Exposures or Interventions 

Mean age (range): Cases:  Invasive 53  Borderline 45 Controls: 49 Menopause: mix Race: ND Enrolled/Evaluate: Cases: 767/531* Controls: 1215/1190* Location: USA Sites: Multi Funding: Government *Parous women (evaluated) 

Invasive epithelial 616 Serous 45% Mucinous 8% Endometrioid 22% Other 24% Borderline epithelial 151 Serous 52% Mucinous 40% Endometrioid 2% Other 6% Other includes clear cell, mixed cell, undifferentiated or poorly differentiated 

Case-control Data collection by interview Controls identified by random-digit dialing from HFCA lists 

Histologically confirmed epithelial ovarian cancer diagnosed past 6 months, 20-69 years Controls: ≤ 65 years, matched by 5 years and 3 digit exchange Exclusion: outside counties of referral hospital, prior diagnosis of ovarian cancer, non-English speaking, mentally incompetent, critically ill, prior bilateral oophorectomy 

Breastfeeding status determined by interview, length recorded on life calendar 

C-163
Ness, 2000 [UI# 11021606] 

Modugno, 2001 [UI# 11308435] 

Outcome 

Definition Statistical analyses and confounders adjusted Results 

Epithelial ovarian cancer confirmed by histology 

Multivariate unconditional logistic regression adjusted for age, number of pregnancies, family history of ovarian cancer, race, oral contraceptive use, tubal ligation, hysterectomy, breastfeeding For analyses by histology: multivariate unconditional logistic regression adjusted for age, number of live births, years of oral contraceptive use, years of noncontraceptive estrogen use and months breastfed, tubal ligation, hysterectomy, family history of ovarian and breast cancer, ethnicity 

Breastfeeding duration (month)* 

Cases 

n (%) 

Controls 

n (%) 

Odds 

ratioadj 

(95% CI) 

0 299 (56) 577 (48) 1.0 1-5 117 (22) 259 (22) 0.9 

(0.7-1.2) 

6-11 46 (8.7) 119 (10) 0.9 

(0.6-1.3) 

12-23 40 (7.5) 124 (10) 0.7 

(0.5-1.1) 

≥24 29 (5.5) 111 (9.3) 0.6 

(0.4-1.0) 

* Parous women only 

Histologic subgroup (N) Months breastfed 

Odds ratioadj 

(95% CI) 

Serous (357) 1.00 

(0.98-1.01) 

Mucinous (112) 1.00 

(0.98-1.02) 

Endometrioid (139) 0.97 

(0.94-1.00) 

Other (159) 0.97 

(0.94-1.00) 

All (767) 0.99 

(0.98-1.00) 

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Riman, 2002 [UI# 12181107] 

Study 

characteristics 

Subjects’ health 

conditions 

Study design and follow-up 

duration Eligibility criteria 

Breastfeeding 

Exposures or 

Interventions 

Mean age (range): Cases: 62 Controls: 63 Menopause: mix Race: ND Enrolled/Evaluate: Cases: 914/655 Controls: 4148/3899 Location: Sweden Sites:NA Funding: Private, government 

All invasive (655) Serous (337) Mucinous (60) Endometrioid (180) Clear cell (43) Other/undifferentiated (35) 

Case-control Data collected by self-administered questionnaires followed up by phone for missing or inconsistent details 

Swedish born women 50-74 years old with epithelial ovarian cancer confirmed by histology identified by national registry Controls: randomly selected population national registry Exclusion: previous ovarian malignancy or bilateral oophorectomy 

Breastfeeding statudetermined by questionnaires 

C-165
Riman, 2002 [UI# 12181107] 

Outcome 

Definition 

Statistical analyses and 

confounders adjusted Results B

Epithelial ovarian cancer confirmed by histology 

Unconditional logistic regression adjusted for age, bmi, parity, age at menopause, duration of oral contraceptive use, HRT use 

Breastfeeding duration (months) 

Cases 

n (%) 

Controls 

n (%) 

ORadj (95% 

CI) 

<1 33 (7.2) 161 (15) 1.0 1-5 134 (29) 612 (15) 0.99 

(0.64-1.52) 

6-11 134 (29) 840 (19) 0.77 

(0.50-1.19) 

≥12 158 (34) 1,024 (14) 0.87 

(0.56-1.35) 

Parous women 

Odds Ratioadj (95% CI) Breastfeeding duration 

(months) Serous Mucinous Endometrioid Clear cell <1 1.0 1.0 1.0 1.0 1-5 0.87 

(0.50-1.53) 

2.19 

(0.49-9.87) 

1.05 

(0.47-2.34) 

0.54 

(0.16-1.87) 

6-11 0.61 

(0.35-1.09) 

1.75 

(0.39-7.87) 

1.10 

(0.50-2.46) 

0.23 

(0.06-0.88) 

≥12 0.87 

(0.49.-1.54) 

0.83 

(0.49-1.54) 

1.02 

(0.44-2.37) 

0.24 

(0.06-0.97) 

A: strong, B: mweak 

Selection Study design Confounder Blinding Data collection Withdraw and dAnalyses Intervention int

50% of cases anphone for missinunknown if breasmonth includes nunavailable 

C-166
Risch, 1983 [UI# 6681935] 

Study 

characteristics 

Subjects’ 

health 

conditions 

Study design 

and follow-up 

duration 

Eligibility criteria 

Breastfeedin

Exposures 

Intervention

Mean age (range): Cases: 20-74 Controls: 21-75 Menopause: mix Race: white Enrolled/Evaluate: Cases: 284 Controls: 705 Location: USA Sites: Multi Funding: Government 

ND Case-control 

Data collection by interview Cases 

Epithelial ovarian cancer diagnosed in past 18 months, reside in 6 specified counties of Washington and Utah and identified by population-based cancer reporting systems, age 34-74 for Washington cases, age 20-74 for Utah cases Controls: household survey conducted in same counties by standard geographic sampling methods or telephone selected from directories. Utah samples matched for age and Washington samples matched for age range. Exclusion included bilateral oophorectomy ≤ 1 year Additional case-control exclusion: nonwhite, incomplete reproductive histories 

Breastfeeding sdetermined by interview 

Risch, 1983 [UI# 6681935] 

Outcome 

Definition Statistical analyses and confounders adjusted Results 

Epithelial ovarian cancer 

Linear logistic regression adjusted for age at diagnosis 20-44, nulliparous, no miscarriages, < 1 year total exposure to combined oral contraceptives, nonobese 

RR 0.79 per year of lactation p=0.034, is associated with decreased ovarian cancer risk Cases reported less time breastfeeding than controls 3+ total months lactation – RR 0.69 (0.50-0.96) p=0.026 

A: stromode

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C-167
Risch, 1994 [UI# 7942759] 

Study 

characteristics 

Subjects’ 

health 

conditions 

Study design and follow-up 

duration Eligibility criteria 

Breastfeed

Exposures 

Interventio

Mean age (range): Cases: 57 Controls: 58 Menopause: mix Race: 96% white Enrolled/Evaluate: Cases: 450 Controls: 564 Location: Canada Sites: Multi Funding: Government 

ND Case-control 

Data collection by interview using questionnaire incorporating life events calendar – conducted at subject’s home 

Primary malignant or borderline malignant epithelial ovarian cancer confirmed by histology, age 35-79, residents of Ontario located through Ontario Cancer Registry, living subjects 

Controls: obtained from Enumeration Composite Record listing compiled by Ontario Ministry of Revenue, matched for area of residence and age range, exclusion included bilateral oophorectomy < 1 year, living subjects 

Breastfeeding determined by interview 

Risch, 1994 [UI# 7942759] 

Outcome Definition Statistical analyses and confounders adjusted Results Bias/

Co

Primary malignant or borderline malignant epithelial ovarian cancer confirmed by pathology reports 

Multivariate unconditional continuous logistic regression adjusted for 3 age groups, continuous variables age, total duration of oral contraceptive use 

No of full-term Mean pregnancies Cases Controls 

Odds 

ratioadj 

(95% CI) 

Total duration* (year) 

0.51 0.65 0.89 

(0.75-1.05) 

Average duration of lactation/pregnancy* (months) 

2.24 2.72 0.87 

(0.76-0.99) 

*Adjusted for number of full-term pregnancies Inverse association with total duration of lactation Inverse association with average duration per pregnancy, p=0.030 Pregnancies with lactation slightly more protective than pregnancies without 

A: strong, B: moderate

Selection Study design Confounder Blinding Data collection Withdraw and dropout Analyses Intervention integrity 

Slightly greater number or US, smaller percentagever used OC and amonterm pregnancies and ustime 

C-168
Siskind, 1997 [UI# 9229212] 

Study 

characteristics 

Subjects’ 

health 

conditions 

Study design and follow-up duration Eligibility criteria 

Breastfeeding 

Exposures or 

Interventions 

Mean age* (range): Cases: 57 Controls: 56 Menopause: mix Premenopausal  Cases: 35%  Controls: 36% Race: ND Enrolled/Evaluate*: Cases: 824/618 Controls: 855/724 Location: Australia Sites: Multi Funding: Government, private *Parous 

ND Case-control 

Data collection by interviewer with questionnaire at discharge or clinic followup, in homes for all controls and homes or clinics for cases Controls randomly selected through electoral roll 

Cases: Histologically confirmed primary epithelial ovarian cancer, 18-79 years, ≥ 1 live birth Controls: similar age and region Exclusion: history of ovarian cancer or bilateral oophorectomy, incapable of completing questionnaire 

Breastfeeding status determined by questionnaire 

C-169
Siskind, 1997 [UI# 9229212] 

Outcome 

Definition 

Statistical analyses and 

confounders adjusted Results 

Primary epithelial ovarian cancer confirmed by histology 

Multiple logistic regression with covariates: age, parity, age at 1st

birth, education, oral contraceptive use, smoking history, menopausal status 

Breastfeeding duration (month) 

Cases 

n (%) 

Controls 

n (%) 

Odds ratioadj 

(95% CI) 

0 168 (27) 155 (21) 1.0 1-6 180 (29) 190 (26) 0.89 

(0.65-1.2) 

7-12 125 (20) 187 (26) 0.68 

(0.49-0.94) 

13-24 107 (17) 141 (19) 0.84 

(0.59-1.2) 

25-36 25 (4) 39 (5) 0.69 

(0.38-1.3) 

>36 13 (2) 12 (2) 0.77 

(0.34-1.8) 

Any 450 (73) 569 (79) 0.80 

(0.61-1.04) 

Per month 0.99 

(0.98-1.0) 

* Parous women only 

A: stronmodera

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C-170
Outcome 

Definition 

Statistical analyses and 

confounders adjusted Results 

Primary epithelial ovarian cancer confirmed by histology 

Multiple logistic regression with covariates: age, parity, age at 1st

birth, education, oral contraceptive use, smoking history, menopausal status 

Premenopausal Postmenopausal 

Cases 

n (%) 

Controls 

n (%) 

Cases 

n (%) 

Controls 

n (%) Breastfeeding duration (month) Odds ratioadj 

(95% CI) 

Odds ratioadj 

(95% CI) 

0 75 (35) 66 (25) 93 (23) 89 (19) 

1.00 1.00 

69 (32) 78 (29) 111 (27) 112 (24) 1-6 0.75 (0.46-1.21) 0.98 (0.65-1.47) 34 (16) 72 (27) 91 (23) 115 (25) 7-12 0.53 (0.31-0.94) 0.83 (0.54-1.26) 33 (15) 36 (14) 74 (18) 105 (23) 13-24 1.03 (0.54-1.95) 0.88 (0.56-1.38) 

4 (4) 12 (5) >24 0.29 (0.08-1.04) --- 

21 (5) 27 (6) 25-36 --- 0.93 (0.46-1.88) 13 (3) 12 (3) >36 --- 1.27 (0.50-3.2) 

* Parous women onl

y

A: stronmoderaSelectioStudy dConfouBlinding Data coWithdradropout AnalyseIntervenintegrity 

C-171
Titus-Ernstoff, 2001 [UI# 11237375] 

Study characteristics Subjects’ health conditions Study design and follow- up duration Eligibility criteria Breastfeed

Exposures 

Interventio

Mean age (%):  Cases Controls <30 29(5.2) 37(7.1) 30-39 78(14) 89(17) 40-49 159(28) 136(26) 50-59 126(22) 118(23) 60-69 118(21) 117(22) ≥70 53(9.4) 26(5.0) Menopause: mix Race: ND Enrolled/Evaluate: Cases: 563/378* Controls: 523/417* Location: USA Sites: Multi Funding: Government * Parous women only 

Serous borderline 86 Serous invasive 229 Mucinous 83 Endometrioid/clear cell 130 * Parous women only 

Case-control Data collection by interviewer with questionnaire in homes for all controls and case Controls selected by random digit dialing, >60 years by Town Books 

Cancer registry and hospital board cases of epithelial ovarian cancer including lesions of borderline malignancy, 20-74 years, Controls: matched by age within 4 years and telephone sampling unit, >60 years were matched by age and precinct, exclusion included bilateral oophorectomy 

Breastfeeding status determby interview 

C-172
Titus-Ernstoff 2001 [UI# 11237375] 

Outcome Definition 

Statistical analyses 

and confounders 

adjusted 

Results 

Epithelial ovarian cancer by pathology report or microscopy slides 

Unconditional logistic regression adjusted for age, state, parity 

Breastfeeding duration (month)* 

Cases 

n (%) 

Controls 

n (%) 

Odds ratioadj 

(95% CI) 

0 239 (63) 223 (53) 1.0 <3 43 (11) 48 (12) 0.9 

(0.6-1.4) 

3-6 54 (14) 76 (18) 0.7 

0.5-1.1) 

>6 42 (11) 70 (17) 0.7 

(0.4-1.0) 

Ever 139 (37) 194 (47) 0.7 

(0.5-1.0) 

P for trend 0.21 

* Parous women only 

Odds Ratioadj (95% CI) Breastfeeding Status 

Serous 

borderline 

(n=86) 

Serous 

invasive 

(n=229) 

Mucinous 

(n=83) 

Endometrioid 

/Clear cell 

(n=130) 

Never breastfed 1.0 1.0 1.0 1.0 Ever breastfed 

0.8 

(0.4-1.6) 

1.0 

(0.6-1.4) 

0.6 

(0.3-1.2) 

0.4 

(0.2-0.7) 

P for trend1 0.61 0.34 0.88 0.04 

1Average duration (months) per breastfed child

A: mweSeStCoBlDaWdrAnInin

C-173
Tung, 2003 [UI# 14507598], Tung 2005 [UI# 15692075] 

Study characteristics Subjects’ health conditions Study design and follow-up duration Eligibility criteria Breastfe

Exposu

Interven

Mean age (range): Cases: 50 Mucinous  55 Nonmucinous Controls: 56 Menopause: premenopausal 39% Race %:  Cases Cases  Mucinous Nonmucinous Controls Asian 51 34 42 White 30 50 44 Other 19 16 14 Enrolled/Evaluate: Cases: 558 Controls: 607 Location: USA Sites: Multi Funding: Government 

Invasive n=431 Mucinous 11% Serous 51% Endometrioid 17% Clear cell 11% Other(undifferentiated, squamous, transitional) 10% Borderline n=127 Mucinous 48% Serous 52% 

Case-control Data collection by interviewer with questionnaire including life calendar in homes for 95% of all interviewed 

Cases: 

≥18 years, epithelial ovarian 

cancer confirmed by histology, identified by population-based cancer registry, reside in Los Angeles, California or Hawaii for 1 year prior to diagnosis Controls: 

≥18 years, reside in Los 

Angeles, California or Hawaii for 1 year prior to Interview, no prior history of ovarian cancer, 

≥1 intact ovary, matched 

for age (±5 years), ethnicity, study site, randomly selected from neighborhood walk procedure in LA and Hawaii Department of Health state-wide annual survey list 

Breastfeedstatus deteby intervie

C-174
Epithelial 

ovarian cancer confirmed by histology 

Polytomous logistic model adjusted for age, ethnicity, study site, education, oral contraceptive use, tubal ligation Unconditional logistic regression adjusted for age, ethnicity, study site, education, tubal ligation, HRT, ovulation variables 

Odds ratioadj 

Breastfeeding (95% CI) 

All cases Mucinous Nonmucinous 

Never 1 1 1 Ever 0.6 (0.4-0.7) 0.8 (0.5-1.4) 0.5 (0.4-0.7) Breastfeeding duration (month)* 0 1 1 1 ≤5 0.6 

(0.4-0.9) 

0.6 

(0.4-1.4) 

0.7 

(0.4-0.9) 

6-16 0.6 

(0.4-0.9) 

0.7 

(0.3-1.3) 

0.5 

(0.3-0.7) 

>16 0.6 

(0.4-0.8) 

0.9 

(0.8-1.8) 

0.4 

(0.3-0.7) 

P for trend* 0.011 0.99 0.0005 

*Based on likelihood ratio test comparing models with and without a trend variable that was assigned median values for the categories 

Odds ratioadj 

(95% CI) 

Total breastfeeding duration (year)* 

Premenopausal Postmenopausal 

0 1 <0.5 0.96 (0.49-1.85) 0.64 (0.41-1.02) 0.5-1.0 0.81 (0.43-1.54) 0.60 (0.36-1.00) >1.0 0.46 (0.22-0.97) 0.69 (0.43-1.12) P for trend 0.003 0.08 

Odds ratioadj 

(95% CI 

Breastfeeding Breastfeeding duration (month)* 

Invasive cases 

Never Ever ≤5 6-16 >16 P for 

trend* 

All cases 1 0.5 

(0.4-

0.7) 

0.6 

(0.4-

0.9) 

0.5 

(0.4-0.8) 

0.5 

(0.3-

0.7) 

0.002 

Mucinous 1.2 

(0.6-

2.7) 

0.7 

(0.3-

1.8) 

1.1 

(0.5-2.6) 

1.2 

(0.5-

3.0) 

0.30 

Serous 0.5 

(0.3-

0.7) 

0.6 

(0.4-

0.9) 

0.5 

(0.3-0.8) 

0.4 

(0.2-

0.7) 

0.96 

Endometrioid 0.5 

(0.3-

0.9) 

0.6 

(0.3-

1.2) 

0.6 

(0.3-1.3) 

0.3 

(0.1-

1.0) 

0.10 

Clear cell 0.5 

(0.2-

1.0) 

0.6 

(0.3-

1.5) 

0.5 

(0.3-1.4) 

0.3 

(0.1-

1.1) 

0.40 

A: strong, B: mweak Selection Study design Confounder Blinding Data collection Withdraw and dAnalyses Intervention int

Controls were benumber of full-tecontraceptive moligation 

C-175
C-176
West, 1966 [UI# 5939299] 

Study 

characteristics 

Subjects’ health 

conditions 

Study design 

and follow-up 

duration 

Eligibility criteria 

Breastfeeding 

Exposures or 

Interventions 

Mean age (range): Cases: 53 Controls: 50 Menopause: mix Race: ND Enrolled/Evaluate: Cases: 97/76 Controls: 91/76 Location: USA Sites: Multi Funding: ND 

Cases: Pseudo-mucinous cystadenocarcinoma 23 Serous cystadenocarcinoma 16 Cystadenocarcinoma and adenocarcinoma 43 Carcinoma 6 Granulosa cell 5 Teratoma 1 Dysgerminoma 1 Meso-meta-nephroma 1 Unclassified 1 Controls: (25 diagnoses) Endometriosis 19 Simple cyst 10 Pseudo-mucinous cystadenoma 9 Dermoid cyst 8 

Case-control Data collection by interview 

Cases: malignancy of ovary, 50 mile radius of Boston, exclusion includes >75 years and co-existent malignancy of another organ that was not metastatic from ovary and recurrent cases Controls: female hospital patients matched for age 

± 5 

years, residence and date of surgery, next operated case of benign ovarian neoplasms from same hospital as malignant case 

Breast feeding stadetermined by interview 

C-177
West, 1966 [UI# 5939299] 

Outcome Definition 

Statistical analyses 

and confounders 

adjusted 

Results Bias/limitations Comments 

Malignant ovarian cancer confirmed by pathology 

T test with p level of 0.01 for significance 

76 matched pairs Lactation (months) Cases Controls 6.6 5.8 p > 0.3 

A: strong, B: moderate, C: weak A B C 

Selection X Study design X Confounder X Blinding X Data collection X Withdraw and dropout X Analyses X Intervention integrity 

Cases and controls classified as private and service with more contrimplying differ SES. Only descriptive statistics given for education. Nconfounders 

C-178
Whittemore, 1992 [UI# 1476141] 

Study characteristics 

Subjects’ 

health 

conditions 

Study design and follow-up 

duration Eligibility criteria 

Breastfeedi

Exposures 

Interventio

Mean age (range): Cases: ND Controls: ND Menopause: mix Race: White Enrolled/Evaluate: Cases: 2197/1071 Controls: 8893/5705 Location: USA Sites: 12 studies, of which 7 with breastfeeding data Funding: Government 

ND Case-control 

Data from 12 studies conducted from 1956-1986. 6 hospital and 6 population (random-digit dialing) controls. 

Breastfeeding data from 7 studies; 2 hospital- and 5 population-based studies 

Studies with individual patient data collected from personal interviews through structured questionnaires, data coded and stored electronically, variable definitions documented Cases: newly diagnosed invasive epithelial tumors at US hospital Controls: reside in US, during time of case ascertainment, no gynecological condition if hospital controls

Breastfeeding sdetermined by interview 

C-179
Whittemore, 1992 [UI# 1476141] 

Outcome 

Definition 

Statistical analyses and 

confounders adjusted Results 

Invasive epithelial tumors 

Conditional logistic regression with odds ratio adjusted for age, study, parity, oral contraceptive use 

Breastfeeding duration (month)* 

Cases 

n (%) 

Controls 

n (%) 

RRadj 

(95% CI) 

Hospital studies 

0 117 (58) 612 (57) 1.0 1-5 49 (24) 237 (22) 0.95 

(0.62-1.5) 

6-11 13 (6) 110 (10) 0.40† 

(0.20-0.78) 

12-23 16 (8) 78 (7) 0.70 

(0.36-1.4) 

≥24 6 (3) 44 (4) 0.59 

(0.22-1.6) 

Any breastfeeding 

84 (42) 469 (43) 0.73 

(0.51-1.0) 

Trend per month 0.99 

p=0.18 

Population studies 

0 478 (55) 2152 (47) 1.0 1-5 208 (24) 1188 (26) 0.87 

(0.72-1.1) 

6-11 88 (10) 567 (12) 0.74 

(0.57-0.96) 

12-23 61 (7) 449 (10) 0.69 

(0.51-0.94) 

≥24 35 (4) 268 (6) 0.74 

(0.49-1.1) 

Any breastfeeding 

392 (45) 2472 (53) 0.81† 

(0.68-0.95) 

Trend per month 0.99† 

* Parous † p<0.01 Risk reduction per month of breastfeeding within 6 months delivery exceeds that for subsequent breastfeeding Hospital 2.5% vs 1.4% Population 1.2% vs 0.9% 

A: stronC: weaSelectiStudy dConfouBlindinData coWithdraAnalyseInterve

Hospital-based studies overlap with Hartge 1989 Population-based studies overlap with Cramer 1983 

C-180
Wynder, 1969 [UI# 5764976] 

Study 

characteristics 

Subjects’ health 

conditions 

Study design and 

follow-up duration Eligibility criteria 

Breastfeeding 

Exposures or 

Interventions 

Mean age (range): Cases: 52 Controls: ND Menopause: mix Race: Cases:  91% White  9% Black Controls:  94% White  6% Black Enrolled/Evaluate: Cases: 158 Controls: 300 Location: USA Sites: Multi Funding: Government 

Serous cystadenocarcinoma 28 Pseudo-mucinous cystadenocarcinoma 10 Endometrioid carcinoma 11 Solid adenocarcinoma 91 Miscellaneous  Granulose cell tumor 4  Teratoma 1  Carcinoid 1  Others 2 Unspecified 10 

Case-control Hospital-based population Data collection by interview 

Epithelial ovarian cancer confirmed by histology, functionary or dysontogenetic tumors excluded Eight additional cases of diagnosis other than adenocarcinoma and endometrioid cancers Controls matched for age 

Breastfeeding status determined by interview 

Wynder, 1969 [UI# 5764976] 

Outcome Definition 

Statistical analyses 

and confounders 

adjusted 

Results 

Epithelial ovarian cancer confirmed by histology 

ND No difference between groups for age of first nursing or never nursing 

158 Cases 300 Controls 

Premenopausal 

(55) 

Postmenopausal 

(95) 

Premenopausal 

(95) 

Postmenopausal 

(205) 

BF ≥12 

months 

10% 24% 7% 21% 

A: smo

SelStuConBlinDatWitdroAnaInte

C-181
Yen, 2003 [UI# 12713998] 

Study 

characteristics 

Subjects’ health 

conditions 

Study design 

and follow-up 

duration 

Eligibility criteria 

Breastfeeding 

Exposures or 

Interventions 

Median age (range): Cases: 47 (20-75) Controls: 44 (20-75) Menopause: mix Race: ND Enrolled/Evaluate: Cases: 86 Controls: 369 Location: Taiwan Sites: Multi Funding: Government 

Cases: Serous (27%0 Mucinous (27%) Endometrioid (21%) Clear cell (15%) Unspecified adenocarcinoma (2%) Controls: Trauma (28%) Nontraumatic orthopedic conditions (30%) Surgery (19%) Miscellaneous (23%)  medical, eye, nose,  throat, dental 

Case-control Data collection by in-hospital interview 

Newly diagnosed primary invasive epithelial ovarian cancer confirmed by histology, Taiwan resident for > 20 years Controls: matched for age, same hospital admission at same time for nonmalignant, nongynecologic condition, nonhormonal or nondigestive tract diseases, no long term modification of diet Exclusion: major gynecologic operation including hysterectomy with or without oophorectomy or oophorectomy only, severe illness 

Breast feeding stadetermined by interview 

Yen, 2003 [UI# 12713998] 

Outcome Definition Statistical analyses and confounders adjusted Results 

Primary invasive epithelial ovarian cancer confirmed by histology 

Conditional multivariate logistic regression model adjusted for number of live birth 

Breastfeeding duration (years) 

Cases 

n (%) 

Controls 

n (%) 

ORadj 

(95% CI) 

0 41 (48) 176 (48) 1.0 ≤1 8 (9) 42 (11) 0.82 (0.35-

1.9) 

>1 37 (43) 151 (41) 0.55 (0.29-

1.01) 

Breastfeeding for more than one year is trend for protection 

A: stmod

SeleStudConfBlindData WithdropAnalInterinteg

C-182
Appendix C. Evidence Tables 

Part III. Maternal Outcomes 

Postpartum Depression 

Chaudron 2001 

Cooper 1993 

Hannah 1992 

Henderson 2003 

Murray 2003 

Seimyr 2004 

Warner 1996

C-183
Chaudron 2001, [UI# 1446151] 

Study 

characteristics 

Subjects’ 

health 

conditions 

Study design and follow-up duration Eligibility criteria 

Breas

Expos

Interv

Mean age (range): 29 yr (SD 4.4) Race: 69% white Enrolled/Evaluate: 465 Location: US Sites: Multi Funding: 

Prospective cohort; the study examined predictors of new-onset postpartum depression during postpartum months 1-4; data from the Wisconsin Maternity Leave and Health Project (WMLHP); subjects participated in a 90-minute home interviews during the second trimester, and at 1 and 4 months after delivery; both the DIS and CES-D were administered at each interview; DIS questions about fatigue and sleep were modified to account for disturbances caused by night-time infant care 

Between weeks 12 and 25 of a non-highrisk pregnancy; >18 yr; non-handicapped; living within Milwaukee or Dane counties; living with the baby’s father; one of the couple was employed; had a telephone; spoke English well enough to understand interviewer; able to complete questionnaire; not depressed at 1 month postpartum; Excluded subjects who did not complete follow up at 4 months 

Chaudron 2001, [UI# 1446151] 

Outcome Definition Statistical analyses and confounders adjusted Results 

Postpartum depression defined by: 

1. Diagnosis of major 

depression on NIMH Diagnostic Interview Schedule (DIS) per DSM-III-R criteria 

2. 

≥16 on the Center for Epidemiologic Studies Depression Scale (CES-D); and /or 

3. receiving 

antidepressants 

Age, depression during pregnancy, postpartum thoughts of death and dying, difficulty falling asleep (see full discussion in paper) 

327/465 breastfed; 27/465 became depressed between 1 and 4 months; Women who breastfed their infants were not significantly different in their development of depression from women who bottlefed their infants. Of those women who were breastfeeding at 1 month postpartum (n=327), women who worried about breastfeeding were significantly more likely to become depressed than those who did not worry (relative risk 3.0, CI 1.041-9.216, P=0.04) 

Amw

SSCBDWdAIi

C-184
Cooper, 1993 [UI# 8463993] 

Study characteristics 

Subjects’ 

health 

conditions 

Study design and 

follow-up duration Eligibility criteria Breastfeeding Exposures 

Interventions 

Mean age (range): Enrolled/Evaluate: 243 women at Oxford; 113 at Cambridge Location: UK Sites: Multi Funding: 

2 separate prospective cohort studies (Oxford and Cambridge) 

See ref 12 in paper for criteria for Oxford; For Cambridge: primiparous, 20-40 yr, had a partner, 37-42 wk gestation, infant 

≥ 2.5 Kg, and no gross 

congenital abnormality 

Of those who attempted to initiatbreastfeeding, those who terminbefore 8 wk were compared with who did not 

Cooper, 1993 [UI# 8463993] 

Outcome Definition 

Statistical 

analyses and 

confounders 

adjusted 

Results 

At Oxford, Present State Examination (PSE) was used to determine psychiatric symptoms. At Cambridge, prospective subjects were screened at 6 wk postpartum using the Edinburgh Postnatal Depression Scale (EPDS). All high scorers (≥13), 78% of the intermediate scorers (10-12), and a random sample of low scorers (≤ 9) received full psychiatric assessment 

between 2 and 3 months postpartum. 58 who met Research Diagnostic Criteria (RDC) criteria for major and minor depression, and 55 who were psychiatrically well were interviewed in full. 

At Cambridge, Standardized Psychiatric Interview (SPI) was used. 

Social class, age, and education 

At Oxford, 14/25 subjects (56%) with psychiatric symptoms versus 40/175 subjects (23%) without psychiatric symptoms had given up breastfeeding by 8 wk postpartum (P<0.01). In eight, depression preceded cessation of breastfeeding, in two depression was the subsequent event, and in four, the two events arose contemporaneously. Low social class and younger age were also determinants of early cessation of breastfeeding. Antenatal psychiatric status did not predict breastfeeding outcome. At Cambridge, 30/54 subjects (56%) with an episode of depression versus 10/48 subjects (21%) without depression postpartum had given up breastfeeding by 8 wk (P<0.001). Lower educational attainment was also associated with early cessation of breastfeeding. In all cases, the onset of depression preceded the cessation of breastfeeding. 

C-185
Hannah 1992, [UI# 1617360] 

Study 

characteristics 

Subjects’ 

health 

conditions 

Study design and follow-up duration Eligibility criteria 

Breastfeeding 

Exposures or 

Interventions 

Mean age (range): Evaluated: 231 Location: UK Sites: Multi Funding: 

ND Prospective cohort, questionnaires (general questionnaire and 

Edinburgh Postnatal Depression Scale (EPDS)) on 5th day 

postpartum and repeat EPDS at 6 weeks postpartum 

Women who had delivered a live baby 

ND 

Hannah 1992, [UI# 1617360] 

Outcome Definition Statistical analyses and confounders adjusted Results 

Postpartum depression defined by EPDS score ≥ 13 at 6 weeks. 

Chi-square At 6 weeks, 8/26 (31%) women with EPDS score ≥ 13 vs 

25/200 (12%) women with EPDS < 13 only did bottle feeding (P<0.04). [Or 18/26 (69%) women with EPDS score ≥ 13 vs 175/200 (88%) women with EPDS < 13 had ever breastfed.] 

A: stromodera

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C-186
Henderson 2003, [UI# 12911800] 

Study 

characteristics 

Subjects’ 

health 

conditions 

Study design and follow-up duration Eligibility criteria 

Breast

Expos

Interv

Mean age (range): Race: Enrolled/Evaluate: 1745 enrolled Location: Australia Sites: Multi Funding: 

Prospective cohort, population from a RCT on the effectiveness of maternal debriefing on the incidence of postnatal psychological morbidity; self-reported questionnaires were completed at 2, 6, and 12 months after birth; the questionnaire included a measure of current breastfeeding status; The Edinburgh Postnatal Depression Scale (EPDS) was used to screen for symptoms of depression at each of the follow-up intervals. All subjects who scored > 12 on the scale, subjects being treated for a psychological disorder, subjects taking antidepressants, and a stratified sample of women with low EPDS scores were offered a diagnostic interview. The interview enabled a diagnosis of depression to be made based on DSM IV. 

Before 72 hr postpartum, given birth to health infants >35 wk gestation, English speaking, >18 yrs, not under psychological care at the time of recruitment; cases were excluded if no information about breastfeeding status was given at any interval (n=56) 

Primary was durabreastfe

Henderson 2003, [UI# 12911800] 

Outcome Definition 

Statistical analyses 

and confounders 

adjusted 

Results 

Diagnosis of depression based on DSM IV (data obtained from diagnostic interview) 

Adjusted for demographic, perinatal, and postnatal factors 

Breastfeeding was initiated by 1670/1745 women (96%); 57% still breastfeeding at 6 months (30% fully); 22% still breastfeeding to some extent at 12 months. 314/1745 (18%) developed depression in the 12 months after birth, 63% showing the first symptom by 2 months. After adjustment for confounding factors, early cessation of breastfeeding was found to be associated with postnatal depression (adjusted hazard ratio 1.25, 95% CI 1.03 to 1.52). Onset of postnatal depression occurred before cessation of breastfeeding in most cases. 

A: mowe

SeStuCoBliDaWidroAnIntinte

C-187
Murray, 2003 [UI# 12848402] 

Study characteristics Subjects’ health conditions Study design and follow-up duration Eligibility criteria Breastf

Exposu

Interve

Mean age (range): 25 yr in self-exclusion group; 28 yr in take-up group Menopause: pre/post/mix Race: 75 in selfexclusion group; 81 in take-up group Location: UK Sites: Single/Multi Funding: 

History of depression was common, as were health problems, and depressed or anxious mood in pregnancy 

Cohort study; 403 women from a RCT of a preventive intervention for postpartum depression were identified as being high risk for depression from antenatal screening; 2 groups were formed; one group from the control arm (routine care) of the RCT was willing to receive additional home-based Health Visiting in the last 5 weeks of pregnancy and the first 8 weeks postpartum; the other group refused the intervention 

Vulnerable to postpartum depression per screening results 

Murray, 2003 [UI# 12848402] 

Outcome Definition Statistical analyses and confounders adjusted Results 

Predictive Index for Postpartum Depression 

Comparing the self-exclusion group (n=75) with the take-up group (n=81), the infants in the self-exclusion group were less likely to be breastfed, both immediately after birth (63% vs 83%, P=0.007) and at 10 days (31% vs 54%, P=0.01) 

A: smodwea

SeleStudConBlindData WithdropAnaInteinteg

C-188
Seimyr 2004, [UI# 15376402] 

Study 

characteristics 

Subjects’ 

health 

conditions 

Study design and follow-up duration Eligibility criteria 

Breastfeedi

Exposures 

Interventio

Mean age (range): 29 yr (18-43) Race: Enrolled/Evaluate: 352 women Location: Sweden Sites: Multi Funding: 

Prospective cohort, Edinburgh Postnatal Depression Scale (EPDS) result at 2 months before childbirth (I), 2 months (II )and 12 months (III) after childbirth 

All Swedish speaking pregnant women at six antenatal clinics were invited to participate, with their partners or alone 

Seimyr 2004, [UI# 15376402] 

Outcome Definition Statistical analyses and confounders adjusted Results 

Cut-off point of 9/10 on EPDS scale is used to set the threshold for vulnerability to depression 

Did not report actual adjustment, but reported that there was no difference with regards to age, education, parity, and length of marital relationship between low and high-scoring women 

63 women (21%) scored high on EPDS at the end of pregnancy; 54 (17%) at 2 months; 28 (12%) at 12 months. ~50% of the high EPDS (I) scorers also scored high on EPDS (II), and 39% of those who were high EPDS (II) scorers continued to score high on EPDS (III). Fewer high EPDS (I) scorers breastfed compared to the low scorers (82% vs 94%, P<0.02) Fewer high EPDS (II) scorers breastfed compared to the low scorers (85% vs 93%, P<0.08) High EPDS scorers experienced breastfeeding more negatively than the women scoring low on EPDS (I) (40% vs 20%, P<0.03) and on EPDS (II) (51% vs 16%, P<0.0001). High EPDS (II) scorers breastfed for a shorter time compared to the low-scoring women (4.6 months, SD 2.4 vs 5.3 months, SD 1.9, P<0.04) 

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Warner, 1996 [UI# 8733800] 

Study 

characteristics 

Subjects’ 

health 

conditions 

Study design and follow-up duration Eligibility criteria 

Breastfeed

Exposures 

Interventio

Mean age (range): 28 yr (15-46 yr) Race: Eligible/Enrolled: 2978/2375 Location: UK Sites: Multi Funding: 

Prospective cohort 

Recruited subjects over a 20-month period from two postnatal wards prior to discharge, subjects agreed to a home visit 6-8 wk after delivery; Edinburgh Postnatal Depression Scale (EPDS) was completed at the interview 

Living outside the district and insufficient English to understand the questionnaire 

Warner, 1996 [UI# 8733800] 

Outcome 

Definition Statistical analyses and confounders adjusted Results 

EPDS score > 12 

13 socio-demographic and obstetric variables were entered individually into a logistic regression analysis with high and low EPDS as the outcome variable using a threshold of 12/13; those variables showing a significant association with high EPDS scores were entered into a stepwise logistic regression analysis 

280/2375 scored >12 on EPDS; Unplanned pregnancy, not breastfeeding at 6 wk (OR 1.52, 95%CI 1.12-2.06), unemployment in mother or head of household were associated with an EPDS score >12 in a stepwise logistic analysis 

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Appendix C. Evidence Tables 

Part III. Maternal Outcomes 

Maternal Weight 

Brewer 1989 

Janney 1997 

Linne 2003 

Ohlin 1990 

Olson 2003 

Sichieri 2003 

Walker 2004

C-191
Brewer 1989 [2916446] 

Study 

characteristics Population Study design and follow-up duration Eligibility criteria Breastfe

Exposu

Interve

Mean age (range): Pre-pregnancy BW (range): ND Pre-pregnancy BMI (range): ND Race: white Enrolled/Evaluate: 70/56 Location: US Sites: Single Funding: 

Well-educated, middle to upper middle income range 

Prospective cohort; to study postpartum changes in body weight in lactating vs. nonlactating women up to 6 mo postpartum; mothers were visited in the hospital within 1 to 2 d of delivery and at home at 3 and 6 mo postpartum, weights were objectively measured; detailed information on infant diet was collected by monthly questionnaires completed by the mothers. Mother’s calorie intake measured. Three-day maternal food records were also completed at 3 and 6 months postpartum. Energy intake (kcal) was calculated by computer from food records with the Nutritional Analysis System (Louisiana State University, Baton Rouge, LA). 

Good health, ≥18 yr, mothers of full term infants 

Brewer 1989 [2916446] 

Outcome Definition Statistical analyses and confounders adjusted Results 

Exclusive breastfeeding; exclusive formula feeding; mixed breast and formula feeding 

ANCOVA; covariables included maternal age, parity, prepregnancy weight, initial postpartum measurement for each variable, and others 

“If weight change during the first 3 mo is corrected for an initial fluid loss of 2 kg, weight loss averaged 1.6, 2.1, and 1.5 kg/mo for exclusive breastfeed, exclusive formula feed, and mixed feed, respectively. Exclusive breastfeed resulted in an additional 0.43 kg/mo loss over the second 3 mo with mixed feed averaging a 0.27 kg loss and nonlactating women experiencing essentially no change.” No significant differences in total weight loss were observed between the lactating and non-lactating groups. Exclusive breastfeeding resulted in a significant decrease in weight between 3 and 6 months (P < 0.05). 

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Janney, 1997 [9356528] 

Study characteristics 

Subjects’ 

health 

conditions 

Study design and 

follow-up duration Eligibility criteria 

Breastfee

Exposur

Interven

Mean age (range): 29.3 (20-40) Pre-pregnancy BW (range): 59.7 (43.1-93.0) kg Pre-pregnancy BMI (range): 22.2 (16.9-33.7) kg/m2Race: 96% White Enrolled/Evaluate: 110/71 Location: US Sites: Single Funding: ND 

Prospective, longitudinal study (0.5, 2, 4, 6, 12, and 18 mo post-partum) 

Pregnant nulliparous and primiparous women aged 20-40 y in their 3rd trimester were recruited 

from birthing education classes and obstetric practices. To be eligible for participation, the women must have declared either that they had no intention of breastfeeding or that they intended to breast-feed for >= 6 months. 

Exclusion criteria were a history of endocrine, renal, liver, or chronic respiratory illness; complications of pregnancy, including HTN and GDM; fetal complications or complications at delivery; delivery of an infant small for gestational age; and delivery of twins. 

Fully breast-feedefined as provleast 2/3 of the energy intake pof the infant’s wbreast milk. Sehow this estimamade. 

Janney, 1997 [9356528] 

Outcome 

Definition 

Statistical 

analyses and 

confounders 

adjusted 

Results 

Postpartum weight retention over time 

Longitudinal regression analysis: proc mixed and glm procedures 

Most women (66.7%) fully breastfed for 6 mo. Duration of lactation practice was a significant predictor of postpartum weight retention over time -(P<0.001) - not only in the longitudinal regression model containing only lactation practice and months since parturition but also in the multiple-variable longitudinal regression model. Regardless of lactation practice, women consistently lost weight from 0.5 to 18 mo after parturition. The weight-retention curve appeared to be curvilinear, with slower rates of weight loss occurring after 12 mo postpartum. Overall, less weight was retained by lactating women than by nonlactating women. Even women who breast-fed for < 4 mo retained less weight than women who bottle-fed their infants. Additionally, women who switched to partly breast-feeding had weight retention rates intermediate between those of women fully breast-feeding and those bottle-feeding. Once lactation was discontinued, slower rates of weight loss were observed. Breast-feeding women achieved their prepregnancy weights about 6 month earlier than women who only bottle-fed their infants (see Figure 5 in original paper). 

C-193
Janney, 1997 [9356528] 

Outcome 

Definition 

Statistical 

analyses and 

confounders 

adjusted 

Results 

The following data were estimated from Figure 5 in the original paper: 

1) Time returned to prepregnancy weights: 

Bottle-feeding only: ~18 months postpartum Partly breast-feeding at 2 mo, and bottle-feeding or infant weaned at 4, 6, 12, and 18 months: ~12 months postpartum Fully breast-feeding for 6 month and bottle-feeding or infant weaned at 12 and 18 month: ~11 months postpartum Fully breastfeeding for 6 month, partly breast-feeding for 12 month, and bottle-feeding or infant weaned at 18 month: ~ 10 months postpartum 

2) Weight retention at 6 months postpartum: 

Fully breastfeeding for 6 months (n=57): ~ +3 kg Partly breastfeeding at 2 month and bottle-feeding at 4 and 6 months (n=10): ~ +3.5 kg Fully bottle-feeding for 6 months (n=12): ~ +5 kg 

A: smodSeleStudConBlinDatWithdropAnaInte

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C-194
Linne, 2003 [14634683] 

Study 

characteristics Population Study design and follow-up duration Eligibility criteria Breastfeeding Expo

Interventions 

Mean age (range): 45 yr (at 15 yr follow up) Pre-pregnancy BW (range): 59.8 kg Pre-pregnancy BMI (range): 21.5 kg/m2Race: Enrolled/Evaluate: 1423/563 (at 15 yr) Location: Stockholm Sites: Multi Funding: 

Cross section of the metropolitan population from both inner city of Stockholm and its suburbs; a range of socioeconomic groups 

Prospective cohort; longitudinal study of women’s weight gain during pregnancy, at 1 yr postpartum and at 15 yr follow up; feeding data were collected retrospectively by questionnaires at 2.5, 6, 12 mo and at 15 yr; for women who still lived in the Stockholm area, weights were measured in the University hospital (n=363); for women who lived far away, weights were self-reported (n=200) 

2 outliers were excluded: BMI of 47; first child at 49 yr 

Measured by lactation every month of full lactgiven 4 points, every mmixed lactation was givpoints; total sum (0-48indicated the individuaamount 

Linne, 2003 [14634683] 

Outcome 

Definition Statistical analyses and confounders adjusted Results 

Overweight (BMI > 25), normal weight (BMI 20-25); 

ANOVA was used to analyze weight change at four time points; women who were overweight at prepregnancy and at follow up and those who lost weight and regained a BMI in the normal range at 15 yr were excluded from the analysis 

Those women who became overweight had lower lactation scores than women who remained normal weight at 15 years follow up (21.7 ± 11.0 vs. 24.0 ± 9.4, t=2.25, df = 488, 

P < 0.05). 

Responders were slightly older, had higher educational attainment, and higher income than non-responders. Nonresponse was more common in non-Nordic citizens. 

A: strongmoderate

Selection Study deConfounBlinding Data collWithdraw Analyses Intervent

Overall: C 

C-195
Ohlin, 1990 [2341224]; Ohlin, 1996 [8732961] 

Study 

characteristics 

Subjects’ 

health 

conditions 

Study design and 

follow-up duration Eligibility criteria Breastfeeding Exposure

Interventions 

Mean age (range): 29.5 (17-49) Pre-pregnancy BW (range): 59.6 (39-129) kg Pre-pregnancy BMI (range): 21.5 (15.4-43.0) kg/m2Race: ND Enrolled/Evaluate: 2295 (at 2 mo) /1423 (at 1 yr) Location: Sweden Sites: Multi Funding: Government 

Women were studied retrospectively during pregnancy at maternity clinics, and monitored prospectively up to 1 year after delivery. 

All mothers who, during one year, came to the maternity clinic for the last routine control, i.e. 6-15 weeks after the delivery, were invited by their midwives to take part in the study. Women who were going to move within a short time and those with obvious language and communication problems were not invited. Exclusion: twin births, use of insulin during pregnancy, GI problems with severe energy losses (heavy vomiting or diarrhea) and prepregnant body weights were not available.

Lactation score: a scoring systeconstructed in order to express and intensity of breast feeding. month with full lactation was givpoints, and every month with mfeeding was given 2 points. The sum (0-48) indicated the individlactation amount. 

Ohlin, 1990 [2341224]; Ohlin, 1996 [8732961] 

Outcome 

Definition 

Statistical analyses 

and confounders 

adjusted 

Results 

The body weight 1 year after delivery (∆weight) 

Ranged influence of different factors on the 

∆ weight was 

analyzed by a multiple stepwise regression analysis 

30% lost weight, 56% gain 0-5 kg, 13% gained 5-10 kg and 1.5% gained >=10 kg 1 year after delivery. Frequency of overweight women (BMI>=23.9) increased from 13% before pregnancy to 21% 1 year post-partum (p<0.001) Ranged influence of different factors on the 

∆ weight: 

The coefficients between the 

∆ weight and lactation score, age, pre-pregnancy weight 

and parity were very low (multiple r=0.38, p<0.001) and significant correlations do not necessarily indicate causality. Weight gain during pregnancy had the strongest influence, and explained 12.7% of the variation of the 

∆ weight (p<0.001). 

Lactation and age increased the total proportion of explained variance by about 1% each. Simple correlation coefficient between the 

∆ weight and lactation score was –0.09 

(p<0.01) 

A: strongmoderate

Selection Study deConfounBlinding Data collWithdraw Analyses Intervent

C-196
Olson, 2003 [12532163] 

Study characteristics Population Study design and follow-up duration Eligibility criteria Breastfeeding Exposu

Interventions 

Mean age (range): Pre-pregnancy BW (range): kg Pre-pregnancy BMI (range): kg/m2Race: white (96%) Enrolled/Sample/Evaluate: 622/597/540 Location: US Sites: Single Funding: 

Rural, socioeconomically diverse 

Prospective cohort; to study the relative importance of gestational weight gain, postpartum exercise, food intake and breastfeeding to weight change from early pregnancy to 1 yr postpartum; weight was measured at antenatal and 1 yr postpartum visit (varied between 9 and 19 mo); 32/540 self-reported weight at 1 yr; breastfeeding data collected at 6 wk obstetric visit; 6 mo and 1 yr questionnaires. 

Food frequency questionnaires were completed at 1st

or 2nd trimester of pregnancy, 6 months postpartum, 

and 1 yr postpartum. 

≥ 18 yr; healthy, gave birth to fullterm singletons 

Breastfeeding after 6 mo wconsidered to be non-exclbreastfeeding score similaand Rossner’s was constrpoint for each wk of exclusbreastfeeding and 0.5 poineach wk of mixed feeding 

Olson, 2003 [12532163] 

Outcome Definition Statistical analyses and confounders adjusted Results 

Weight change from early pregnancy to 1 yr postpartum; major weight gain was defined as ≥4.55 kg at 1 yr postpartum 

Univariate and multiple linear regression; weights taken between 9 and 19 mo were eligible for inclusion, actual number of mo postpartum at the measurement of the “1 yr postpartum body weight” was entered into all of the regression models; variables in the initial model included age, education, smoking status, income, marital status, prepregnancy BMI category and parity; 3 subjects with poor fit were removed from the analysis; a model reduction method was applied at the 10% significance level to produce an inclusive, reduced model Using food frequency data, the difference in the daily energy intake from 6 months to 1 yr postpartum was calculated for each woman. The Wilcoxon rank sum test was used to assess change in total daily energy intake across the five categories of self-reported behavior change in amount of food intake. 

Only the 597 women who delivered full term infants were included in the sample; 540 had 1 yr weight recorded; Women who were breastfeeding at 1 yr retained less weight compared with the women who weren’t (P = 0.04). Breastfeeding at all other time points and the breastfeeding score were not significantly related to postpartum weight retention. 

O

C-197
Sichieri, 2003 [12821967]

Study characteristics Subjects’ health conditions Study design and follow-up duration Eligibility criteria 

Mean age (range): 24-40 yr Pre-pregnancy BW (range):  Stratified by BMI at  baseline Pre-pregnancy BMI (range): % BMI < 25kg/m2 in 1989: 81.5% 

BW mean, ALL: 58.0 kgs % BMI > 25kg/m2 in 1989: 18.5%

BW mean, ALL: 80.4 kgs Race: ND Enrolled/Evaluate: 1,538/1,538 nulliparous at baseline; 2,810/2,810 primiparous at baseline Location: USA Sites: Single/Multi: mailed questionnaire Funding: Supported by FundaCBo CAPESCoordenaq20 de Aperfeicoamento de Pessoal de Nivel Superior and Boston Obesity Nutrition Research Center (DK 46200) 

None documented The cohort of the Nurse's Health 

Study II, with analysis restricted to women who were aged 24 to 40 y at baseline (1989), who had a history of no more than one past full-term pregnancy at baseline, gave birth to one child between 1990 and 1991, but had no other pregnancies during the follow-up. SUBJECTS: 1,538 of the 33,082 nulliparous women and 2,810 of the 20,261 primiparous, in 1989. The NHS II Cohort has been followed up every 2 yr to ascertain incident diseases and exposures including parity and body weight. Individual breastfeeding data were collected retrospectively in the 1997 follow-up. Women were asked to recall their lifetime breastfeeding history. 

Excluded from analysis: those who reported use of insulin, hypoglycemic drugs, or thyroid disease at baseline or followup were excluded from analysis 

wo0

wat

aqq

C-198
Outcome Definition Statistical analyses and confounders adjusted Results 

To assess whether women who breastfed were different in terms of their weight changes than women who did not, weight change from prepregnancy (in 1989) to postpregnancy 

(in 1993) was estimated according to exclusive breastfeeding duration using linear regression models. 

The longitudinal models were based on mixed effects analysis. These models permitted the authors to test differences in prepregnancy weight at baseline (group effect), weight gain with pregnancy (time-dependent effect of period I), and weight change after pregnancy (time-dependent effect of period II) by breastfeeding status. If breastfeeding groups differed at baseline but had the same change in weight during follow-up, a group effect but not a time-dependent effect would be seen. 

After adjusting for age, physical 

activity, and BMI, lactation was associated with a weight gain from 1989 to 1993 of approximately 1 kg (statistically significant only for women nulliparous in 1989 with a BMI <25 kg/m2 (P=0.02) and for those women primiparous in 1989, with a BMI ≥25 kg/m2 (P=0.04)) comparing women who breastfed with women who did not. Duration of lactation was unrelated to the magnitude of weight change (P>0.40 for all comparisons). 

Maternal weight change associated 

with breastfeeding is minimal among normal weight women, and for overweight women the weight gained in pregnancy Is not reduced by breastfeeding. 

AmSSCBDWdAInin

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Walker, 2004 [15778139] 

Study characteristics 

Subjects’ 

health 

conditions 

Study design and follow-up 

duration Eligibility criteria 

Breastfeeding 

Exposures or 

Interventions 

Mean age (range): ND (>18 yr) Pre-pregnancy BW (range): ND Pre-pregnancy BMI (range): ND Race: 26% African American, 44% Hispanic, 30% White Enrolled/Evaluate: ND/382 Location: US Sites: Single Funding: Government 

healthy Prospective, longitudinal cohort 

(post-delivery, and 6 wk, and 3, 6, and 12 months postpartum). Energy intakes were measured at above times by average of one 24-hour recall and two food records at each observation. Fat intakes measured by Food Habits Questionnaire (Kristal, 1990). 

Healthy women, singleton pregnancies with prenatal care funded through Medicaid; had a parity not exceeding III; were conversant in English; and were age 18 or higher. 

Full (exclusive) or partfeeding, measured at pand 12 months postpa

Walker, 2004 [15778139] 

Outcome 

Definition 

Statistical analyses and confounders 

adjusted Results 

Postpartum BMI 

General linear mixed models, also known as hierarchical linear models, were used. Forward additive method (or forward selection) was used to select variables for inclusion in the model. 

Infant feeding method was not associated with postpartum BMI (p=0.140) when ethnicity, time, pre-pregnant BMI and a bunch of other variables (such as parity, gestational weight gain, Cesarean section, etc) were included in the model. 

A: smodwea

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C-200
Appendix C. Evidence Tables 

Part III. Maternal Outcomes 

Type 2 DM 

Stuebe 2005

C-201
Stuebe, 2005 [16304074] 

Study 

characteristics 

Subjects’ 

health 

conditions 

Study design 

and follow-up 

duration 

Eligibility criteria Breastfeeding Exposures or Interventions 

Mean age (range): 52 at follow-up Menopause: mix Race: ND Enrolled/Evaluate: see results Location: US Sites: Multi Funding: Government 

ND Prospective, 

longitudinal study 

The Nurses’ Health Studies consist of 2 

large cohorts enrolled in prospective, longitudinal studies of women’s health 

The Nurses’ Health Study (NHS) was 

initiated in1976 and enrolled 121,700 women from 11 states. Participants were between 30 and 55 years of age at baseline, and each woman completed a detailed baseline questionnaire regarding diseases and health related topics. 

The second cohort, the Nurses’ Health Study 

II (NHS II), began in 1989, enrolling 116,671 women from 14 states. Participants were between 25 and 42 years of age and completed a similar baseline questionnaire as well as biennial follow-up questionnaires. 

Women in the Nurses’ Health Studie

baseline in 1976. Lactation history was when women were asked to report total 

In NHS II, women reported the numb

more than 5 months at baseline and on Lactation history was assessed 3 timesInformation on parity was used to derive participant’s total cumulative lactation a

Total duration of lactation was calcul

months after birth that the participant rebreastfeeding altogether. Using the 199duration of exclusive lactation could be reported timing of introduction of formul

C-202
Stuebe, 2005 [16304074] 

Outcome Definition Statistical analyses and confounders adjusted Results 

Ascertainment of Type 2 Diabetes Mellitus

A case of diabetes was confirmed if a woman 

reported 1 of the following: (1) 1 or more classic symptoms plus either a fasting glucose of 

≥140 

mg/dL or random plasma glucose 

≥ 200 mg/dL 

; (2) at least 2 instances of elevated plasma glucose concentration (fasting glucose 

≥140 

mg/dL, random plasma glucose 

≥200 mg/dL, or 

oral glucose tolerance test 

≥200 mg/dL after 2 

hours) on different occasions in the absence of symptoms; or (3) treatment with insulin or an oral hypoglycemic agent.

The criteria for diagnosis of diabetes changed 

in 1997, when a fasting glucose level of 

≥126 

mg/dL was made the diagnostic threshold.

Ascertainment of Gestational Diabetes 

Women in the NHS II were asked to report 

the diagnosis of gestational diabetes on each biennial questionnaire. To validate the study’s diagnostic criteria, 20,422 participants completed a detailed questionnaire, and 92% corroborated their diagnosis. A review of medical records for 120 of these women 

Lifetime lactation history among parous 

women was stratified into 6 groups: None (referent), > 0 to 3 mo, > 3 to 6 mo, > 6 to 11 mo,> 11 to 23 mo, and > 23 mo. In the NHS, lactation information was used from the 1986 questionnaire. In the NHS II analysis, lactation history was derived from selfreported pregnancies assessed every 2 years and lactation reports in 1997 and 2003. Lifetime duration was updated every 2 years. 

Linear trend was assessed using 

midpoints of lactation categories. 

All models were age-adjusted. Potential 

confounders, including parity, body mass index at age 18 years, diet, physical activity, family history of diabetes, and smoking status, were included in the multivariate model. 

In the NHS cohort, 83,585 parous women 

reported lifetime duration of lactation; of these, 64% had ever breastfed. In the NHS II cohort, 73,418 parous women reported duration of lactation, and 85% had ever breastfed. 

In the NHS, women who had ever 

breastfed had a covariate-adjusted HR for type 2 diabetes of 0.97 (95%CI 0.91 - 1.02) compared with women who never breastfed. There was a modest but statistically significant inverse association between duration of lactation and the risk of type 2 diabetes. In the multivariate-adjusted model including current BMI, each additional year of lactation was associated with an HR of 0.96 (95%CI 0.92 - 0.99) for type 2 diabetes. 

Among women who had ever breastfed in 

the NHS II, the covariate-adjusted HR for type 2 diabetes was 0.90 (95%CI 0.77 - 1.04). Each year of lactation was associated with a covariate-adjusted HR of 0.84 (95%CI 0.78 - 0.89). When BMI was added to this model, the HR was 0.88 (95%CI 0.82 - 0.94) 

O

C-203
Outcome Definition Statistical analyses and confounders adjusted Results 

confirmed definite or probable gestational diabetes in 94%. To assess screening for gestational diabetes, a random sample of 100 study participants was surveyed, of whom 83% reported undergoing a 50-g, 1-hour glucose challenge test. Gestational diabetes history was not assessed in the NHS cohort.

for each additional year of lactation. 

Women with a history of GDM had an 

increased risk of type 2 diabetes in the NHS II cohort, with 624 cases per 100,000 person years compared with 118 cases per 100,000 person-years among those without such a history. Lactation had no effect on diabetes risk in the GDM group, with a covariateadjusted HR of 0.96 (95% CI 0.84 - 1.09) per additional year of lactation. 

The effects of exclusive versus total 

breastfeeding could be compared in the NHS II cohort data. In models controlling for age and parity, each year of lifetime exclusive breastfeeding was associated with an HR for type 2 diabetes of 0.63 (95%CI 0.54 - 0.73), while each year of total breastfeeding was associated with an HR of 0.76 (95%CI 0.71 - 0.81). 

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D-1

Appendix D. List of Excluded Studies 

AbouSaleh MT, Ghubash R, Karim L, et al. Hormonal 

aspects of postpartum depression. 

Psychoneuroendocrinology 1998 Jul;23(5):465-75. 

Developing country 

AbuSabha R, Greene G. Body weight, body 

composition, and energy intake changes in 

breastfeeding mothers. J Hum Lact 1998 

Jun;14(2):119-24. Non-comparative study 

Adair LS, Pollitt E, Mueller WH. Maternal 

anthropometric changes during pregnancy and 

lactation in a rural Taiwanese population. Hum Biol 

1983 Dec;55(4):771-87. Non-comparative study 

Affinito P, Tommaselli GA, di Carlo C, et al. Changes 

in bone mineral density and calcium metabolism in 

breastfeeding women: a one year follow-up study. J 

Clin Endocrinol Metab 1996 Jun;81(6):2314-8. Less 

than 1 year follow-up

Alder E, Bancroft J. The relationship between breast 

feeding persistence, sexuality and mood in postpartum 

women. Psychol Med 1988 May;18(2):389-96. 

N<100

Alder EM, Cox JL. Breast feeding and post-natal 

depression. J Psychosom Res 1983;27(2):139-44. 

N<100 

Alm B, Wennergren G, Norvenius SG, et al. Breast 

feeding and the sudden infant death syndrome in 

Scandinavia. Arch Dis Child 2002 June; 86(6): 400-2. 

Included in MA

Andreev A, Arjas E. Acute middle ear infection in 

small children: a Bayesian analysis using multiple 

time scales. Lifetime Data Anal 1998;4(2):121-37. 

Not relevant

Aniansson G, Svensson H, Becker M, et al. Otitis 

media and feeding with breast milk of children with 

cleft palate. Scand J Plast Reconstr Surg Hand Surg 

2002;36(1):9-15. Otitis media in children with cleft 

palate

Atalah E, Lagos I, Grez M, et al. [Effect of lactation 

on the weight and body composition of wet nurses]. 

[Spanish]. Archivos Latinoamericanos de Nutricion 

1983 Sep;33(3):649-63. Non-English language 

publication

Auestad N, Scott DT, Janowsky JS, et al. Visual, 

cognitive, and language assessments at 39 months: a 

follow-up study of children fed formulas containing 

long-chain polyunsaturated fatty acids to 1 year of 

age. Pediatrics 2003 Sep;112(3 Pt 1):e177-e183. Not 

relevant

Barbosa L, Butte NF, Villalpando S, et al. Maternal 

energy balance and lactation performance of 

Mesoamerindians as a function of body mass index. 

Am J Clin Nutr 1997 Sep;66(3):575-83. Not relevant

Bastian LA, West NA, Corcoran C, et al. Number of 

children and the risk of obesity in older women. Prev 

Med 2005 Jan;40(1):99-104. Case control study

Batstra L, Neeleman J, Hadders-Algra M. Can breast 

feeding modify the adverse effects of smoking during 

pregnancy on the child's cognitive development? J 

Epidemiol Community Health 2003 Jun;57(6):403-4. 

Not relevant

Bauer DC, Browner WS, Cauley JA, et al. Factors 

associated with appendicular bone mass in older 

women. The Study of Osteoporotic Fractures Research 

Group.[see comment]. Ann Intern Med 1993 May 

1;118(9):657-65. Cross-sectional study

Becher H, Schmidt S, ChangClaude J. Reproductive 

factors and familial predisposition for breast cancer by 

age 50 years. A case-control-family study for 

assessing main effects and possible gene-environment 

interaction.[see comment]. Int J Epidemiol 2003 

Feb;32(1):38-48. Included in MA

Bjorkelund C, Lissner L, Andersson S, et al. 

Reproductive history in relation to relative weight and 

fat distribution. Int J Obes Relat Metab Disord 1996 

Mar;20(3):213-9. Cross-sectional study

Boonyaratavej N, Suriyawongpaisal P, Takkinsatien 

A, et al. Physical activity and risk factors for hip 

fractures in Thai women. Osteoporos Int 

2001;12(3):244-8. Developing country

Bouwstra H, Dijck-Brouwer DA, Boehm G, et al. 

Long-chain polyunsaturated fatty acids and 

neurological developmental outcome at 18 months in 

healthy term infants. Acta Paediatr 2005 

Jan;94(1):26-32. Not relevant

Bouwstra H, DijckBrouwer DA, Wildeman JA, et al. 

Long-chain polyunsaturated fatty acids have a positive 

effect on the quality of general movements of healthy 

term infants. Am J Clin Nutr 2003 Aug;78(2):313-8. 

Not relevant
D-2

Bradshaw MK, Pfeiffer S. Feeding mode and 

anthropometric changes in primiparas. Hum Biol 

1988 Apr;60(2):251-61. Insufficient sample size

Butte NF, Garza C, Stuff JE, et al. Effect of maternal 

diet and body composition on lactational performance. 

Am J Clin Nutr 1984 Feb;39(2):296-306. Noncomparative study

Butte NF, Hopkinson JM. Body composition changes 

during lactation are highly variable among women. 

[Review] [45 refs]. J Nutr 1998 

Feb;128(2:Suppl):Suppl-385S. Review

Carranza-Lira S, Mera JP. Influence of number of 

pregnancies and total breast-feeding time on bone 

mineral density. Int J Fertil Womens Med 2002 

Jul;47(4):169-71. Developing country

Chan GM, Ronald N, Slater P, et al. Decreased bone 

mineral status in lactating adolescent mothers. J 

Pediatr 1982 Nov;101(5):767-70. Less than 1 year 

follow-up

Chan SM, Nelson EA, Leung SS, et al. Bone mineral 

density and calcium metabolism of Hong Kong 

Chinese postpartum women--a 1-y longitudinal study. 

Eur J Clin Nutr 2005 Jul;59(7):868-76. Less than 1 

year follow-up

Chang-Claude J, Eby N, Kiechle M, et al. 

Breastfeeding and breast cancer risk by age 50 among 

women in Germany. Cancer Causes Control 2000 

Sep;11(8):687-95. Pre 2001

Coitinho DC, Sichieri R, quino Benicio MH. Obesity 

and weight change related to parity and breast-feeding 

among parous women in Brazil. Public Health Nutr 

2001 Aug;4(4):865-70. Developing country

Cox JL, Chapman G, Murray D, et al. Validation of 

the Edinburgh Postnatal Depression Scale (EPDS) in 

non-postnatal women. J Affect Disord 1996 Jul 

29;39(3):185-9. Reference, not relevant

Cox JL, Connor Y, Kendell RE. Prospective study of 

the psychiatric disorders of childbirth. Br J Psychiatry 

1982 Feb;140:111-7. N<100

Cox JL, Holden JM, Sagovsky R. Detection of 

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Br J Psychiatry 1987 Jun;150:782-6. N<100

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Dalton K. Prospective study into puerperal depression. 

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Dennis KJ, Bytheway WR. Changes in body weight 

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relevant

Duffy SW, Jakes RW, Ng FC, et al. Interaction of 

dense breast patterns with other breast cancer risk 

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19;91(2):233-6. Population not well-defined

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expenditure of free-living, lactating Colombian 

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Mar;56(3):205-13. Developing country 

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Egan KM, Stampfer MJ, Rosner BA, et al. Risk 

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Erkkola M, Pigg HM, Virta-Autio P, et al. Infant 

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D-3

Findeisen M, Vennemann M, Brinkmann B, et al. 

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Climacteric 2002 Sep;5(3):277-85. Cross-sectional 

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D-4

Holt GM, Wolkind SN. Early abandonment of breast 

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Developing country

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Kamitsuka MD, Horton MK, Williams MA. The 

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relevant

Keeping JD, Najman JM, Morrison J, et al. A 

prospective longitudinal study of social, psychological 

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demographic characteristics of the 8556 respondents. 

Br J Obstet Gynaecol 1989 Mar;96(3):289-97. Not 

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Kendell RE, McGuire RJ, Connor Y, et al. Mood 

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Khedr EM, Farghaly WM, Amry S, et al. Neural 

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Koetting CA, Wardlaw GM. Wrist, spine, and hip 

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Cross-sectional study

Kramer FM, Stunkard AJ, Marshall KA, et al. Breastfeeding reduces maternal lower-body fat. J Am Diet 

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Laizner AM, Jeans ME. Identification of predictor 

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Lederman SA, Alfasi G, Deckelbaum RJ. Pregnancyassociated obesity in black women in New York City. 

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Lee CY, Ko IS, Kim HS, et al. Development and 

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No BF exposure, cross-sectional study
D-5

Lovelady CA, Garner KE, Moreno KL, et al. The 

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Lumachi F, Ermani M, Brandes AA, et al. Breast 

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Biomed Pharmacother 2002 Oct;56(8):416-20. 

Population not well-defined

Malloy MH, Berendes H. Does breast-feeding 

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Included in systematic review

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Am J Public Health 1999 Aug;89(8):1244-7. Pre 2001

Marini A, Vegni C, Gangi S, et al. Influence of 

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Matsumoto I, Kosha S, Noguchi S, et al. Changes of 

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Less than 1 year follow-up

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McCredie M, Paul C, Skegg DC, et al. Breast cancer 

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McKeown T, Aaby P. The influence of reproduction 

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No hormonal data given

Melton LJ, III, Bryant SC, Wahner HW, et al. 

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Mezzacappa ES, Katlin ES. Breast-feeding is 

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Mihatsch WA, von Schoenaich P, Fahnenstich H, et 

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Minami Y, Tsubono Y, Nishino Y, et al. The increase 

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Modugno F, Ness RB, Allen GO, et al. Oral 

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Montella M, De Marco MR, Romeo F, et al. Survival 

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Morley R. Breast feeding and cognitive outcome in 

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Morley R, Fewtrell MS, Abbott RA, et al. 

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D-6

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Morrison J, Najman JM, Williams GM, et al. Socioeconomic status and pregnancy outcome. An 

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Motil KJ, Sheng H, Kertz BL, et al. Lean body mass 

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Exclusive and mixed feeding data combined

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Naismith DJ, Ritchie CD. The effect of breast-feeding 

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Najman JM, Morrison J, Williams GM, et al. The 

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Najman JM, Morrison J, Williams GM, et al. 

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Nasca PC, Greenwald P, Chorost S, et al. An 

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Am J Epidemiol 1999 Jul 15;150(2):174-82. Pre 2001

Niemela M, Uhari M, Mottonen M. A pacifier 

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O'Neill T, Murphy P, Greene VT. Postnatal 

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Oddy WH. Breastfeeding and asthma in children. A 

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Orwoll ES, Bauer DC, Vogt TM, et al. Axial bone 

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Paine BJ, Makrides M, Gibson RA. Duration of 

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Parker JD. Postpartum weight change. [Review] [21 

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Paton LM, Alexander JL, Nowson CA, et al. 

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Peters RK, Kjos SL, Xiang A, et al. Long-term 

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D-7

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Pettitt DJ, Knowler WC. Long-term effects of the 

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Piers LS, Diggavi SN, Thangam S, et al. Changes in 

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Pitt B. "Atypical" depression following childbirth. Br 

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8. Not relevant

Potter S, Hannum S, McFarlin B, et al. Does infant 

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Retrospective study

Prentice AM, Whitehead RG, Roberts SB, et al. Longterm energy balance in child-bearing Gambian 

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Developing country

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Rami B, Schneider U, Imhof A, et al. Risk factors for 

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Richards M, Wadsworth M, Rahimi-Foroushani A, et 

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Rookus MA, Rokebrand P, Burema J, et al. The effect 

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Breastfeeding exclusivity unclear 

Rosenblatt KA, Thomas DB. Lactation and the risk of 

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Rossner S. Weight gain in pregnancy. [Review] [17 

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Rush D, Lumey LH, Ravelli AC, et al. The indirect 

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Sadurskis A, Kabir N, Wager J, et al. Energy 

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Schauberger CW, Rooney BL, Brimer LM. Factors 

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Schneider AP. Risk factor for ovarian cancer. N Engl 

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Schwartz SM, Weiss NS, Daling JR, et al. Incidence 

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Sheikh GN. Observations of maternal weight behavior 

during the puerperium. Am J Obstet Gynecol 1971 

Sep 15;111(2):244-50. Unclear exclusive 

breastfeeding
D-8

Singh Y, Sayami P, Sayami G, et al. Nepalese breast 

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Sinigaglia L, Varenna M, Binelli L, et al. Effect of 

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43. Cross-sectional study

Soltesz G, Jeges S, Dahlquist G. Non-genetic risk 

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Jul;83(7):730-5. Developing country 

Sowers M, Corton G, Shapiro B, et al. Changes in 

bone density with lactation.[see comment]. JAMA 

1993 Jun 23;269(24):3130-5. Less than 1 year 

follow-up 

Sowers M, Wallace RB, Lemke JH. Correlates of 

forearm bone mass among women during maximal 

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E-1

Appendix E. Peer Reviewers 

The peer reviewer comments on a preliminary draft of this report were considered by the EPC in 

preparation of this final report. Synthesis of the scientific literature presented here does not 

necessarily represent the views of individual reviewers. The authors gratefully acknowledge the 

peer reviewers. 

David Atkins, MD, MPH 

Chief Medical Officer 

Center for Outcomes and Evidence 

Agency for Healthcare Research and Quality 

Rockville, Maryland 

Pamela D. Hill, PhD, RN, CBE, FAAN 

Professor 

College of Nursing 

University of Illinois at Chicago 

Director, Quad Cities Regional Program 

Moline, Illinois 

Lawrence M. Gartner, MD 

Professor Emeritus 

Departments of Pediatrics and 

 Obstetrics/Gynecology 

The University of Chicago 

Chicago, Illinois 

 Representative for the 

 American Academy of Pediatrics 

 

International Formula Council 

Atlanta, Georgia 

 

Peer Reviewers 

 Russell Merritt, MD, PhD, FAAP 

 Carol Lynn Berseth, MD, FAAP 

 Jose Saavedra, MD, FAAP 

 John Wallingford, PhD 

Jeanne-Marie Guise, MD, MPH 

Associate Professor 

Director of Clinical Research 

Division of General Obstetrics & Gynecology 

Oregon Health and Science University 

Portland, Oregon 

Nanette Pazdernik, PhD 

Center for Breastfeeding Information 

La Leche League International 

Schaumberg, Illinois 

Jane Heinig, PhD, IBCLC 

Academic Administrator 

Department of Nutrition 

Director, Human Lactation Center 

University of California, Davis 

Laurie P. Shornick, PhD 

Assistant Professor 

Department of Biology 

Saint Louis University 

St. Louis, Missouri