Guidelines on optimal feeding of low birth-weight infants in low-and middle-income countries. 1.Infant nutrition. 2.Infant, Low birth weight. 3.Nutritional requirements. 4.Feeding methods. 5.Infant food. 6.Guidelines. 7.Developing countries. I. World Health Organization.#
early detection and treatment of complications, can substantially reduce mortality in this highly vulnerable group. Interventions to improve feeding are likely to improve the immediate and longerterm health and well-being of the individual infant and have a significant impact on neonatal and infant mortality levels in the population. Better feeding was one of the first interventions for preterm babies in the 1960s in the United Kingdom and was associated with reduced case fatality in hospitals before the advent of intensive care.
The objective of these guidelines is to improve the quality of care received by LBW infants in developing countries through improved capacity of health workers. These guidelines focus on the feeding of clinically stable LBW infants in low-and middle income countries. They do not specifically address the feeding of infants with a birth weight less than 1.0 kg (known as extremely LBW, ELBW), who are often clinically unstable and may require parenteral nutrition. Guidance on the management of clinically unstable infants is addressed in other WHO documents.
The guideline development group identified 18 research questions to be of the highest priority for development of recommendations. Most of the questions are relevant to all LBW infants (birth weight less than 2.5 kg) but some are specific to very LBW (VLBW) infants (birth weight less than 1.5 kg). The questions do not specifically address ELBW infants. For each question, the following four outcomes were considered to be critical: mortality, severe morbidity, neurodevelopment and anthropometric status. Benefits and harms in critical outcomes formed the basis of the recommendations for each question.
Studies from developing and developed countries that included infants with a birth weight less than 2500 g or gestation less than 37 weeks were considered for inclusion in this review. Efforts were made to identify relevant non-English language articles and abstracts also.
A standardized form was used to extract relevant information from studies. Systematically extracted data included: study identifiers, setting, design, participants, sample size, intervention or exposure, control or comparison group, outcome measures and results. The following quality characteristics were recorded for all studies: allocation concealment or risk of selection bias (observational studies), blinding of intervention or observers or risk of measurement bias, loss to follow up, intention to treat analysis or adjustment for confounding factors, and analysis adjusted for cluster randomization (the latter only for cluster-randomized controlled trials, RCTs).
We used a modified GRADE approach for assessing the quality of evidence and the recommendations (for details, see Methodology section). The quality of the set of included studies reporting results for an outcome was graded as: high, moderate, low or very low.
The strength of a recommendation reflects the degree of confidence that the desirable effects of adherence to a recommendation outweigh the undesirable effects. The decisions were made on the basis of evidence of benefits and harms; quality of evidence; values and preferences of policy-makers, health-care providers and parents; and whether costs are qualitatively justifiable relative to benefits in low-and middle-income countries.
Each recommendation was graded as strong when there was confidence that the benefits clearly outweigh the harms, or weak when the benefits probably outweigh the harms, but there was uncertainty about the trade-offs. A strong or weak recommendation was further classified as situational if the benefits outweigh the harms in some situations but not in others. For example, some recommendations were considered relevant only to settings in low-and middle-income countries where resources were very limited (e.g. Recommendations 3, 4, 5 and 12) while others were considered relevant only to settings where certain types of facilities were available (e.g.

# Recommendations 2 and 17).
Feeding of LBW infants 3 2011 WHO Recommendations on optimal feeding of low-birth-weight infants No.
Recommendation  Type of recommendation Quality of evidence (at least 1 critical outcome)
What to feed? a. Choice of milk
Low-birth-weight (LBW) infants, including those with very low birth weight (VLBW), should be fed mother's own milk.

# Strong Moderate
LBW infants, including those with VLBW, who cannot be fed mother's own milk should be fed donor human milk (recommendation relevant for settings where safe and affordable milk-banking facilities are available or can be set up).
Strong situational High
LBW infants, including those with VLBW, who cannot be fed mother's own milk or donor human milk should be fed standard infant formula (recommendation relevant for resource-limited settings).
VLBW infants who cannot be fed mother's own milk or donor human milk should be given preterm infant formula if they fail to gain weight despite adequate feeding with standard infant formula.

# Weak situational Low
LBW infants, including those withVLBW, who cannot be fed mother's own milk or donor human milk should be fed standard infant formula from the time of discharge until 6 months of age (recommendation relevant for resource-limited settings).

# Weak situational Low
-  VLBW infants who are fed mother's own milk or donor human milk should not routinely be given bovine milk-based humanmilk fortifier (recommendation relevant for resource-limited settings).
VLBW infants who fail to gain weight despite adequate breastmilk feeding should be given human-milk fortifiers, preferably those that are human milk based.

# Weak situational Low
b. Supplements 6.  VLBW infants should be given vitamin D supplements at a dose ranging from400 i.u to 1000 i.u. per day until 6 months of age.
Weak Very low 7.  VLBW infants who are fed mother's own milk or donor human milk should be given daily calcium (120-140 mg/kg per day) and phosphorus (60-90 mg/kg per day) supplementation during the first months of life.
Weak Low 8.  VLBW infants fed mother's own milk or donor human milk should be given 2-4 mg/kg per day iron supplementation starting at 2 weeks until 6 months of age.
Daily oral vitamin A supplementation for LBW infants who are fed mother's own milk or donor human milk is not recommended at the present time, because there is not enough evidence of

# Weak Low
benefits to support such a recommendation. 10. Routine zinc supplementation for LBW infants who are fed mother's own milk or donor human milk is not recommended at the present time, because there is not enough evidence of benefits to support such a recommendation.

# RESUME D'ORIENTATION
Selon la definition de l'Organisation mondiale de la Sante, le poids de naissance est faible lorsqu'il est inferieur a 2500 grammes. La prevalence mondiale du faible poids de naissance est de 15,5 %, ce qui signifie qu'environ 20,6 millions de nourrissons de cette categorie naissent chaque annee, dans les pays en developpement pour 96,5 % d'entre eux. Les taux varient beaucoup selon les regions des Nations Unies : l'incidence la plus elevee est observee en Asie centrale et du Sud (27,1 %) et la plus faible en Europe (6,4 %).
Le faible poids de naissance peut etre du a la prematurite (naissance avant 37 semaines revolues de grossesse), a une petite taille pour l'age gestationnel (hypotrophie neonatale, definie comme un poids pour l'age gestationnel inferieur au dixieme centile), ou a ces deux facteurs. De plus, selon la reference utilisee pour le poids de naissance, une proportion variable mais minime de nourrissons de faible poids de naissance sont nes a terme et ne presentent pas d'hypotrophie. Le retard de croissance intrauterine, defini comme un taux de croissance foetale inferieur a la normale, est generalement responsable de l'hypotrophie. Le faible poids de naissance delimite donc un groupe heterogene de nourrissons : certains sont prematures, d'autres sont nes a terme mais presentent une hypotrophie, et d'autres encore sont nes a la fois prematures et hypotrophiques.
Il est generalement admis qu'etre ne avec un faible poids est un desavantage pour le nourrisson. Les risques de retard de croissance precoce, de maladie infectieuse, de retard de developpement et de deces durant la premiere enfance et l'enfance sont majores chez les nourrissons de faible poids de naissance.
Les pays peuvent fortement reduire leurs taux de mortalite infantile en ameliorant les soins aux nourrissons de faible poids de naissance. Comme l'experience des pays developpes et des pays a revenu faible ou intermediaire l'a clairement demontre, le fait de leur prodiguer des soins appropries (y compris l'alimentation, le maintien de la temperature et des soins hygieniques du cordon et de la Ces lignes directrices ont pour objectif d'ameliorer la qualite des soins recus par les nourrissons de faible poids de naissance dans les pays en developpement, en renforcant pour cela les capacites des agents de sante. Elles portent principalement sur l'alimentation des nourrissons de faible poids de naissance cliniquement stables dans les pays a revenu faible ou intermediaire. Ces orientations ne concernent pas l'alimentation des nourrissons dont le poids de naissance est inferieur a 1,0 kg (on parle alors de poids de naissance extremement faible), lesquels sont souvent cliniquement instables et peuvent avoir besoin d'une nutrition parenterale. D'autres documents de l'OMS traitent de la prise en charge des nourrissons cliniquement instables.
Le groupe d'elaboration des lignes directrices a recense 18 questions de recherche pour lesquelles il a ete considere prioritaire de formuler des recommandations. La plupart de ces questions interessent tous les nourrissons de faible poids de naissance (moins de 2,5 kg), mais certaines sont propres aux nourrissons de tres faible poids de naissance (moins de 1,5 kg). Elles ne concernent pas specifiquement les nourrissons de poids de naissance extremement faible. Pour chacune d'elles, les quatre issues cles suivantes ont ete considerees : mortalite, morbidite severe, developpement neurologique et statut anthropometrique. Les recommandations reposaient a chaque fois sur les effets souhaitables et les effets indesirables sur ces quatre plans.
Ont ete considerees comme entrant dans le champ de cette revue les etudes realisees dans des pays en developpement et des pays developpes sur des nourrissons d'un poids de naissance inferieur a 2500 grammes ou nes avant 37 semaines de grossesse. Nous nous sommes efforces de recenser egalement les articles et resumes pertinents disponibles dans d'autres langues que l'anglais.
Les informations utiles ont ete extraites des etudes au moyen d'un formulaire standardise. Parmi les donnees systematiquement extraites figurent les identifiants de l'etude, sa structure, son contexte, les participants, la taille de l'echantillon, l'intervention ou l'exposition, le groupe temoin ou groupe de comparaison, les mesures et les resultats. Les caracteristiques de qualite suivantes ont ete consignees pour toutes les etudes : dissimulation de l'allocation ou risque de biais de selection (etudes d'observation), traitement a l'aveugle de l'intervention ou des observateurs ou risque de biais de mesure, perte de suivi, intention de prendre en compte les facteurs de confusion dans l'analyse ou l'ajustement, et ajustement de l'analyse en fonction de la randomisation en grappes (uniquement pour les essais controles randomises en grappe).
Une supplementation orale quotidienne en vitamine A n'est pas recommandee aujourd'hui pour les nourrissons de faible poids de naissance nourris avec le lait de leur mere ou d'une donneuse, car les preuves de ses avantages ne sont pas suffisantes.

# Faible Faible
- Une supplementation systematique en zinc n'est pas recommandee aujourd'hui pour les nourrissons de faible poids de naissance nourris avec le lait de leur mere ou d'une donneuse, car les preuves de ses avantages ne sont pas suffisantes.

# Faible Moderee
Quand et comment commencer l'alimentation ?
Les nourrissons de faible poids de naissance qui sont capables de prendre le sein devraient etre allaites des que possible apres la naissance des lors qu'ils sont cliniquement stables.

# Forte Faible
-  Les enfants de tres faible poids de naissance devraient recevoir une alimentation enterale de 10 ml/kg par jour, de preference du lait maternel exprime, a partir du premier jour de vie, les autres besoins en liquides etant satisfaits par voie intraveineuse (recommandation applicable la ou les ressources sont limitees).

# Faible (circonstancielle) Faible
Duree optimale de l'allaitement exclusif au sein 13. Les nourrissons de faible poids de naissance devraient etre exclusivement nourris au sein jusqu'a l'age de six mois.

# Forte Faible
Comment alimenter le nourrisson ?
- Lorsque les nourrissons de faible poids de naissance doivent etre nourris par une autre methode orale, on doit le faire au verre (ou au palladai, qui est un gobelet a bec) ou a la cuillere. Countries can reduce their neonatal and infant mortality rates by improving the care of LBW infants.
Experience from developed and low-and middle-income countries has clearly shown that appropriate care of LBW infants, including their feeding, temperature maintenance, hygienic cord and skin care, and early detection and treatment of problems such as infections can substantially reduce mortality.
Interventions to improve feeding are likely to improve the immediate and longer-term health and well-being of the individual infant and have a significant impact on neonatal and infant mortality at a population level. In the 1960s in the United Kingdom, better feeding was one of the first interventions for preterm babies that was associated with reduced case fatality in hospital settings before the advent of intensive care. V Kangaroo Mother Care for LBW infants weighing less than 2 kg, which includes exclusive and frequent breastfeeding in addition to skin-to-skin contact and support for the motherinfant dyad, has been shown to reduce mortality in hospital-based studies in low-and middle-income countries. VI Studies from India have shown that improved care of LBW infants in the community can be highly effective in improving their survival. VII-VIII LBW infants can be classified according to their gestation into term (born after 37 and before 42 completed weeks of gestation) and preterm (born up to 37 completed weeks of gestation). Infants in each of these categories can be further divided into two groups based on whether or not they are SGA.
LBW infants are classified as very low birth weight (VLBW) if their birth weight is less than 1.5 kg, and as extremely low birth weight (ELBW) if their birth weight is less than 1 kg. Preterm infants of less than 32 weeks gestation are at greatest mortality risk, followed by preterm infants of 32-36 weeks gestation who are also SGA, preterm infants of 32-36 weeks gestation who are not SGA, and term LBW infants. All these groups have a higher mortality risk than infants who do not have LBW.
WHO guidelines for feeding of LBW infants have not been available. The quality of care received by LBW infants in many low-and middle-income countries is inadequate. These infants are often not breastfed and many times not fed at all in the first hours and days of life. The objective of these guidelines is to improve the quality of care received by LBW infants through improved capacity of the health workers who care for these infants.
These guidelines were developed using funding to the Department of Maternal, Newborn, Child and Adolescent Health from the United States Agency for International Development. The guidelines will be reviewed and updated in 2014, i.e. three years from the date of their publication.

# Guideline Development Group
The following external experts were involved in the development of these guidelines: African

# SCOPE OF THE GUIDELINES

# Target audience
The primary audience for these guidelines is intended to be health-care workers in first-level health facilities and referral hospitals. However, the guidelines are expected to be used by policy-makers, programme managers and health-facility managers to set up a system for optimal care of LBW infants.
Further, many of the recommendations will be relevant for community health workers providing care to LBW infants at home. The information in these guidelines will be included in several capacity strengthening courses for health workers, such as for Essential Newborn Care and Integrated Management of Childhood Illness (IMCI), and in community health worker training on caring for the newborn at home.

# Population of interest
The guidelines focus on the feeding of clinically stable LBW infants in low-and middle-income countries. Some of the questions and recommendations focus only on VBLW infants (birth weight less than 1.5 kg). They do not specifically address the feeding of infants with a birth weight less than 1.0 kg (ELBW), who are often clinically unstable and may require parenteral nutrition. Guidance on the management of clinically unstable infants is addressed in other WHO documents. IX, X Further, the guidelines do not provide separate recommendations for the two groups of LBW infants, preterm and SGA, because of lack of evidence.

# Critical outcomes
Four outcomes were considered to be critical by the guideline development group: mortality, severe morbidity, neurodevelopment and anthropometric status. Mortality and severe morbidity over the short term (e.g. during initial hospital stay after birth) or longer term (e.g. infant mortality) were considered to be critical. However, neurodevelopment and anthropometric status were considered critical only if measured at age 6 months or more. Benefits and harms in critical outcomes formed the basis of the recommendations. When information on critical outcomes was not available, other non-critical outcomes were considered. Examples of these other outcomes include breastfeeding duration or exclusivity, short-term growth, duration of hospital stay, haemoglobin levels and bone mineralization.

# Priority questions
These guidelines address the following questions that were identified to be of the highest priority,

# Data abstraction and summary tables of individual studies
A standardized form was used to extract information from relevant studies. Systematically extracted data included: study identifiers, setting, design, participants, sample size, intervention or exposure, control or comparison group, outcome measures and results. The following quality characteristics were recorded for RCTs: allocation concealment, blinding of intervention or observers, loss to followup, intention to treat analysis, analysis adjusted for cluster randomization (the latter only for cluster-RCTs). The quality characteristics recorded for observational studies were likelihood of reverse causality, selection bias and measurement bias, loss to follow-up and analysis adjusted for confounding.
The studies were stratified according to the type of intervention or exposure, study design, birth weight and gestational age, where possible. Effects were expressed as relative risks (RR) or odds ratios (OR) for categorical data, and as mean differences (MD) or weighted mean differences (WMD) for continuous data where possible. Where results adjusted for potential confounders were available, particularly for observational studies, they were used in preference to unadjusted results. Where results adjusted for potential confounders were not available, unadjusted results were used. All studies reporting on a critical outcome were summarized in a table of individual studies (see Annexes).

# Pooled effects
Pooled effects for developing recommendations were considered, wherever feasible. If results of three or more RCTs were available for an outcome, and the overall quality of evidence using the GRADE approach was at least "low", observational studies were not considered. However, if there were less than three RCTs for an outcome or the quality of evidence was "very low", the effects from RCTs were pooled with those from available cohort and case-control studies.
Pooled effects from published systematic reviews were used if the meta-analysis was appropriately done, and the reviews were up to date. However, if any relevant published study not included in the systematic review or a methodological problem with the meta-analysis was identified, the results were pooled using the "metan" command in Stata 11.0. For pooling, the author-reported adjusted effect sizes and confidence intervals (CIs) were used as far as possible. Random effects models for metaanalysis were used if there was important inconsistency in effects, and the random effects model was not unduly affected by small studies. Where pooling of results was not possible, the range of effect sizes observed in the individual studies was used in the development of recommendations.

# Grading the quality of evidence
A modified GRADE approach for assessing the quality of evidence was used. The quality of the set of included studies reporting results for an outcome was graded as: high, moderate, low or very low. The interpretation of the grades in these guidelines is:
High: One can be sure that the intervention is beneficial, has no effect or is harmful. The results, including the magnitude of the pooled effect, are unlikely to change with new studies.
Moderate: One can be reasonably sure that the intervention is beneficial, has no effect or is harmful.
However, the magnitude of the pooled effect may change with new studies.
Low: Although it is likely that the intervention is beneficial, has no effect or is harmful, one cannot be sure. The magnitude of the pooled effect is uncertain and is likely to change with new studies.
Very low: One cannot be certain about the effects of the intervention.
One of the difficulties in using GRADE is that the evidence base for an outcome may include studies with varying methodological quality and sample size. Therefore, the weight of the studies in the estimation of the pooled effect was included to make judgments about the quality of the set of included studies. The criteria used to grade the quality of evidence are shown in Table I. The following briefly describes how these criteria were used:

# Study design
The included studies were classified as:
- RCTs -including RCTs or cluster-RCTs 2. non-randomized experimental studies 3. observational studies, including cohort studies and case-control studies (studies with other observational designs were not included)
If a majority of evidence was from RCTs, indicated by over 50% weight in the pooled effect, a score of 0 was given. A score of -0.5 was given if a majority of evidence was from non-randomized experimental studies, and -1.0 if the evidence was from observational studies.

# Limitations in methods
Four criteria were used for assessing limitations in the methods of included studies. A set of studies could receive a maximum of -2.0 points for limitations in methods. If a majority of evidence was from RCTs that reported adequate allocation concealment, a score of 0 was given. If allocation concealment was not done or was unclear in a majority of studies, a score of -0.5 was given. On reviewing the methods used in cohort or case-control studies, if the groups (exposed/unexposed in cohort studies, or cases/controls in case-control studies) were likely to be comparable at baseline and there was a low risk of reverse causality, a score of 0 was given; otherwise, the study was graded-0.5).
- Risk of measurement bias: Measurement bias can be minimized by blinding the participants and researchers to the intervention. If that is not possible, the observers measuring outcome can be blinded. Lastly, measurement bias is less likely if the outcome is "objective". If the majority of evidence was from studies where any of the above was done, a score of 0 was given (otherwise, the study was graded-0.5).

# Loss to follow-up:
A large loss to follow-up can lead to bias in results; 20% loss to follow-up was chosen arbitrarily as the cut-off point. If the majority of evidence was from studies where loss to follow-up was less than 20%, a score of 0 was given (otherwise, 0.5 was given).

# Appropriateness of analysis:
If the majority of evidence was from RCTs which had analysis by intention to treat, and additionally cluster adjustment was done when the design was cluster-RCT, a score of 0 was given (otherwise, -0.5 was given). If the majority of evidence was from observational studies with analysis adjusted for confounding, a score of 0 was given (otherwise, -0.5 was given).
Results are imprecise when studies include relatively few patients and few events and thus have wide CIs around the estimate of the effect. In this case, the quality of the evidence is lower than it otherwise would be due to resulting uncertainty in the results.
If the 95% CI around the pooled effect included no effect, and the upper or lower confidence limits do not include an effect that, if real, would represent a meaningful benefit or an unacceptable harm, a score of 0 was given. Otherwise, a score of -1.0 was given.
If the 95% CI around the pooled effect excluded no effect, and both the upper or lower confidence limits are an effect that, if real, would represent a meaningful benefit or an unacceptable harm, a score of 0 was given. Otherwise, a score of -0.5 was given.
Meaningful benefit or unacceptable harm: For the purposes of these guidelines, a RR of 0.9 or lower, or a MD greater than 0.1 standard deviation (SD) was used as a guide for meaningful benefit. This translated to 10% or greater relative reduction in mortality, 10% or greater relative reduction in severe morbidity, MD higher by 1 point in mental development scores, and MD in weight higher by 100 g and length by 0.3 cm (the last at 6-18 months of age). Similarly, unacceptable harm involved a 10% or greater increase in mortality or morbidity, at least 1 point lower mean mental development score, 100 g lower weight and 0.3 cm lower length.
Consistency refers to the similarity of estimates of effect across studies. If three or more studies were available, effect size was such that it indicated meaningful benefit or unacceptable harm, and >75% of evidence from at least two studies have effect sizes in the same direction as the pooled effect, a score of 0 was given. If the pooled effect size excluded meaningful benefit or unacceptable harm, and the effect size of studies with >75% of the total weight of evidence also excluded meaningful benefit and unacceptable harm (i.e. consistent with "no effect"), a score of 0 was also given. If the two above conditions were not satisfied, a score of -1.0 was given.
If only two studies were available, and the results were in the same direction, we gave a score of -0.5.
However, if the results of the two studies were in different directions, a score of -1.0 was given. In case only one study was available, a score of -1.0 was given.
Directness, generalizability, external validity of study results or their applicability were used as synonymous. If the majority of evidence was from studies with both population and intervention the same as the population and intervention of interest, a score of 0 was given. If the majority of evidence was from studies that had a population and intervention that were different from the population or intervention of interest for these guidelines, a score of -1.0 was given; if either of them were different a score of -0.5 was given.

# Upgrading quality of evidence from observational studies
The GRADE criteria were modified to start with a score of -1.0 (moderate quality) for observational studies rather than the usual -2.0 (low quality). Therefore, the quality of evidence from observational studies was not upgraded even if the effect sizes were large, there was a dose-response gradient or the confounding factors could only underestimate the true size of effect. However, the quality of evidence from observational studies was downgraded if there were serious limitations in methods, imprecision, inconsistency and indirectness as described above.

# Formulation of recommendations
The external guideline panel formulated the first version of the recommendations based on the technical review published in 2006. This version of guidelines was field tested in health facilities in four countries -Ghana, India, Pakistan and Uganda -in 2008-9.
After the evidence base was updated in 2010 and its quality graded using the modified GRADE approach, WHO staff prepared the second version of recommendations in a format consistent with the new WHO Handbook for Guideline Development 1. This version was sent to the external expert panel for their review and inputs, which was incorporated into the final version of the guidelines.
The GRADE system for grading recommendations was used. The strength of a recommendation reflects the degree of confidence that the desirable effects of adherence to a recommendation outweigh the undesirable effects. The decisions were made on the basis of evidence of benefits and harms, quality of evidence, values and preferences of policy-makers, health-care providers and parents, and whether costs are qualitatively justifiable compared to the benefits in low-and middle-income countries. The recommendations were graded as one of three types:
A strong recommendation is one for which there is confidence that the benefits either clearly outweigh the harms or do not. The quality of evidence required to make such a recommendation is at least moderate, although the panel may make exceptions. Similarly, the benefits are likely to be valued highly, and costs appear to be justified by the benefits of making such a recommendation. A strong recommendation can be in favor of an intervention or against it.
A weak recommendation is one for which the benefits probably outweigh the harms, but there is high quality evidence; uncertainty in how policy-makers, health workers and parents value the example, some recommendations were considered relevant only to settings in low-and middle-others were considered relevant only to settings where certain facilities were available (e.g.
Recommendations 2 and 17). Summary of evidence: No RCTs examining the effect of feeding mother's own milk to LBW infants on their mortality were identified. Therefore, evidence was considered from four observational studies, all from developed country settings. The quality of evidence for this outcome was graded as low. The pooled effect was 18% reduction in mortality (95% CI 7% to 28%).
Only two RCTs conducted in a developing country examined the effect of feeding mother's own milk on the risk of severe infections or necrotizing enterocolitis (NEC). Therefore, their results were pooled with those of six observational studies from developed country settings. The quality of evidence for this outcome was graded as moderate. The pooled effect was 60% reduction (95% CI 48% to 69%) in the risk of severe infections or NEC.
Eight observational studies evaluated the effect of feeding mother's own milk on neurodevelopment.
The outcome in six of these studies was the MD in mental development scores between breast-milkfed and formula-fed LBW infants at different ages ranging from 18 months to 8 years. The quality of evidence for this outcome was graded as low. The pooled MD in mental development scores was 5.2 points higher (95% CI 3.6 to 6.8) in those fed mother's own milk. Two studies could not be included in the meta-analysis. One of them reported higher mental development scores at 6 months of age in breast-milk-fed infants but did not report CIs of this difference (MD 10 points). The other study reported adjusted OR for higher-than-average scores in an English picture vocabulary test at 5 years of age (OR 1.06, 95% CI 0.86 to 1.32).
Only one observational study reported the effect of feeding mother's own milk on anthropometric status at 9 months of age. The quality of evidence for this outcome was graded as very low. This study found no significant difference in weight SD scores (MD -0.27, 95% CI -0.59 to 0.05) but significantly lower length SD scores in infants fed mother's own milk compared with formula (MD -0.47, 95% CI -0.79 to -0.15).
Long-term beneficial effects of breast-milk feeding on blood pressure, serum lipid profile and proinsulin levels have also been reported; these studies were not reviewed in detail.
In conclusion, there is low to moderate quality evidence that feeding mother's own milk to LBW infants of any gestation is associated with lower mortality, lower incidence of infections and NEC, and improved development scores as compared with feeding infant formula. There is very low quality evidence that feeding mother's own milk is associated with lower length at 9 months of age. (See GRADE profile, Table 1).
Balance of benefits and harms, values and preferences, and costs: Important benefits were found for mortality (18% reduction), severe infections or NEC (60% reduction), and mental development scores (5.2 points higher) associated with feeding mother's own milk compared with formula. The only apparent harm was lower length at 9 months in one study.
Policy-makers, health-care providers and parents in low-and middle-countries are likely to give a high value to the benefits in reduced mortality and severe morbidity. Benefits in terms of increased mental development scores would be valued in both developed and low-and middle-income countries.
Considering the low costs involved in implementation of feeding mother's own milk, the observed benefits are clearly worth the costs.

# RECOMMENDATION 1
LBW infants, including those with VLBW, should be fed mother's own milk.
(Strong recommendation, based on moderate quality evidence of reduced severe morbidity and low quality evidence of reduced mortality and improved neurodevelopment) Summary of evidence: All studies included in the evidence base for this question were RCTs. All had very few methodological limitations and most were conducted in developed country settings.
Evidence from 3 RCTs showed that there was no significant effect of feeding donor human milk compared with feeding infant formula on mortality (RR 0.81, 95% CI 0.46, 1.41). The evidence was judged to be of moderate quality largely because of the wide CI of effect which reflects lack of sufficient data for this outcome.
The pooled effect in five RCTs and one non-randomized experimental study was 61% reduction (95% CI 22% to 81%) in the risk of severe infections or NEC when LBW infants were fed donor human milk compared with feeding infant formula. The quality of evidence for this outcome was graded as high.
A multi-centre RCT conducted in the United States of America compared the effects of an exclusively human milk-based diet compared with a diet of both human milk and bovine milk-based products in infants with birth weight from 500 g to 1250 g. The intervention groups received mother's own milk (or donor human milk if mother's own milk was not available) with a human milk-based human-milk fortifier, while the control group received mother's own milk (or formula if mother's own milk was not available) with bovine milk-based human-milk fortifier. This study was not included in the GRADE profile (Table 2) because both groups received mother's own milk, if it was available. The study reported a 77% reduction (95% CI 34% to 92%) in the odds of developing NEC in the group that received an exclusive human-milk diet.
Only two RCTs have examined the effect of feeding donor human milk compared with feeding infant formula on mental development scores. There was no significant difference in scores (MD in scores -1.2 points, 95% CI -5.1 to 2.6) between the intervention and comparison groups. The quality of evidence for this outcome was low.
Similarly, only two RCTs were identified that examined the effect of donor human milk on anthropometric status at 18 months of age. There was no significant difference in weight (MD -0.1 kg, 95% CI -0.35 to 0.15) or length (MD -0.53 cm, 95% CI -1.2 to 0.14 cm) between infants fed donor human milk or infant formula. The quality of this evidence is low.
In conclusion, there is high quality evidence that feeding donor human milk to LBW infants is associated with lower incidence of infections and NEC during the initial hospital stay after birth.
There is moderate quality evidence for no significant effect on mortality, and low quality evidence of no effect on mental development scores and anthropometric status at 18 months of age.
Balance of benefits and harms, values and preferences, and costs: Important benefits were found for severe infections or NEC (61% reduction). There was no significant effect on mortality, neurodevelopment or anthropometric status (see GRADE profile, Table 2). The risks are related to transmission of infections, such as human immunodeficiency virus (HIV), in case safe milk-banking facilities are not available.
Given the high mortality in low-and middle-income country populations, particularly as a result of infections, the benefit in terms of reduction of severe infections or NEC would be highly valued by policy-makers, health-care providers and parents in these settings.
The observed benefits would be considered to be worth the costs in many settings. However, the necessity of safe milk-banking facilities for feeding of donor human milk to reduce the risk of HIV and other infections could make the costs of this intervention unaffordable in very resource-limited settings.

# RECOMMENDATION 2
LBW infants, including those with VLBW, who cannot be fed mother's own milk should be fed donor human milk.
(Strong situational recommendation relevant to settings where safe and affordable milk-banking facilities are available or can be set up, based on high quality evidence for benefit in reducing severe morbidity)
Table 2. GRADE profile summary for Question 2  (see annexes for detailed GRADE profiles and summary tables of individual studies). Short-term weight gain was higher in infants fed preterm infant formula than in those fed standard infant formula (13 g versus 16 g/kg per day). (See GRADE profile, Table 3).
Balance of benefits and harms, values and preferences, and costs: There was no significant difference in any critical outcome. However, confidence in this finding of equivalence is low given the low quality of evidence and wide CIs of all results. The cost of preterm infant formula is high, its availability in resource-limited settings is low, and evidence of benefits is unclear.

# RECOMMENDATION 3
LBW infants, including those with VLBW, who cannot be fed mother's own milk or donor human milk should be fed standard infant formula.
(Weak situational recommendation relevant for resource-limited settings, based on evidence of no significant benefit of preterm infant formula on mortality, neurodevelopment and long-term growth)
VLBW infants who cannot be fed mother's own milk or donor human milk should be given preterm infant formula if they fail to gain weight despite adequate feeding with standard infant formula.
(Weak situational recommendation relevant for resource-limited settings, based on benefit of preterm formula on short-term growth) Summary of evidence: No studies were found which examined the effect of the intervention on mortality or severe morbidity. Two RCTs were identified which reported the effect of nutrientenriched infant formula compared with that of standard infant formula on neurodevelopment. The quality of evidence was low. Five RCTs examined the effect of the intervention on anthropometric status at 12 to 18 months of age. The quality of evidence for this outcome was graded as low. There was no significant effect on mental development scores (MD o.2 points, 95% CI -3.0 to 3.4) or weight (MD 0.1 kg, 95% CI -0.3 to 0.4) and length at 18 months of age (MD 0.5 cm, 95% CI -0.5 to 1.4). (See GRADE profile, Table 4.)
Balance of benefits and harms, values and preferences, and costs: There was no significant effect on neurodevelopment or anthropometric status at 12 to 18 months of age. The cost of nutrientenriched infant formula is high and its availability in resource-limited settings is low. The observed lack of benefits does not justify the costs in such settings.

# RECOMMENDATION 4
LBW infants, including those with VLBW, who cannot be fed mother's own milk or donor human milk should be fed standard infant formula from the time of discharge until 6 months of age.
(Weak situational recommendation relevant for resource-limited settings, based on low quality evidence for no benefit of nutrient-enriched formula on critical outcomes) Summary of evidence: Two studies reported the impact of multi-component fortification on mortality rates in VLBW infants. The quality of evidence for this outcome was graded as low. There was no significant difference in the risk of mortality between infants who received human milk fortification and those who did not receive fortified milk (pooled RR 2.32, 95% CI 0.16 to 34.7).
A total of six studies, four RCTs from developed country settings and two quasi-RCTs from developing country settings, have evaluated the effect of human milk fortification on the risk of NEC in preterm neonates. The quality of evidence for this outcome was graded as very low. No significant difference in the risk of NEC was observed between the groups supplemented with a multi-component fortifier and the control groups (pooled RR 1.22, 95% CI 0.6 to 2.46).
A multi-centre RCT conducted in the United States of America compared the effects of an exclusively human milk-based diet compared with a diet of both human milk and bovine milk-based products in infants with birth weights of 500 g to 1250 g. The intervention groups received mother's own milk (or donor human milk if mother's own milk was not available) with a human milk-based human-milk fortifier, while the control group received mother's own milk (or formula if mother's own milk was not available) with bovine milk-based human-milk fortifier. This study was not included in the GRADE profile (Table 5) because both groups received a fortifier. The study reported a 77% reduction (95% CI 34% to 92%) in the odds of developing NEC in the group that received an exclusive human-milk diet (including human milk-based fortifier)
Only one RCT which examined the effect of multi-component fortification on long-term neurodevelopmental outcomes was identified. The study did not find any significant difference in mental development scores at 18 months of age between the fortified and unfortified groups of infants (MD 2.2 points, 95% CI -3.3 to 7.7). The quality of evidence was low.
Two RCTs looked at the impact of fortification of human milk on anthropometric status at 6 months of age or older. No significant effect was observed in either the weight (pooled MD -0.03 kg, 95% CIo.32 to 0.25 kg) or length (pooled MD -0.2 cm, 95% CI -1.0 to 0.6) at 12 to 18 months of age in infants who received fortified human milk during the neonatal period. The quality of evidence for this outcome was graded as low.
Evidence was also examined for a non-critical outcome -short-term growth during initial hospital stay. Nine RCTs examined the effect of multi-component fortification of human milk on the rate of weight gain. The quality of evidence was graded as moderate. The pooled result was that weight gain was 2.75 g/kg per day (95% CI 1.6 to 3.9) greater in infants receiving human-milk fortifier. Similarly, the pooled effect on rate of length gain was 0.18 cm per week (95% CI 0.09 to 0.28) greater than the control group.
In conclusion, there is low to very low quality evidence that feeding multi-component fortified human milk does not affect the risk of mortality and NEC, and does not improve neurodevelopmental outcomes and anthropometric status at 6 months of age or beyond. Human-milk fortifier improves the rates of weight and length gain during the initial hospital stay (see GRADE profile, Table 5).
Balance of benefits and harms, values and preferences, and costs: There was no evidence of significant benefits or harm in mortality, NEC, mental development scores, and anthropometric status associated with feeding fortified human milk. However, the possibility of harm in terms of increased risk of mortality and NEC cannot be entirely ruled out, because the point estimates were above 1 but with very wide CIs. The only benefit observed was in short-term growth during initial hospital stay.
Given the evidence of lack of benefits in any of the critical outcomes and a substantial improvement in weight gain during hospital stay, it is likely that clinicians would value this intervention but policymakers would not. The costs are significant and may not be justified in resource-limited settings by the small observed benefits. Also, the availability of multi-component fortifier might be an issue in many such settings.

# RECOMMENDATION 5
VLBW infants who are fed mother's own milk or donor human milk need not be given bovine milk-based human-milk fortifier. VLBW infants who fail to gain weight despite adequate breast-milk feeding should be given human-milk fortifiers, preferably those that are human milk based.
(Weak situational recommendation relevant to resource-limited settings, based on low to very low quality evidence for no benefits in critical outcomes and higher costs) Summary of evidence: Two RCTs examined the effect of 2-4 RDA vitamin D supplementation compared with 1 RDA supplementation on anthropometric status at 6 months of age or older. While one RCT reported weight percentiles and length SD scores at 9 to 11 years, the other study reported weight and length at 6 months of age. Neither of the studies found any significant effect on anthropometric status. The quality of evidence was graded as very low.
Two RCTs evaluated the effect of 2-4 RDA vitamin D supplements on bone mineralization status of preterm neonates at 6 months of age or older. The quality of evidence was very low. There was no difference in the bone mineral densities of infants who received 2-4 RDA and 1 RDA vitamin D supplements respectively (pooled MD 2.0 mg/cm 2 95% CI -8.0 to 12.0). Another study, an RCT from a developed country, ascertained the effect on radiographic bone disease at 6 weeks of age in preterm VLBW infants. The study did not find any difference in the scores (graded on a scale of 0 to 9, with 0 being normal and 9 indicating severe bone disease) between the two groups (median score 2 versus 2.5, P=0.36).
To conclude, there is very low quality evidence that giving 2-4 RDA oral vitamin D supplements does not affect anthropometric status or bone mineralization at or beyond 6 months of age in VLBW infants. (See GRADE profile, Table 6.)
Balance of benefits and harms, values and preferences, and costs: There is no evidence of benefits or harm associated with daily oral vitamin D supplementation in doses exceeding 1 RDA in VLBW infants. Given the evidence of lack of benefits in any of the critical outcomes, policy-makers and health-care providers from both low-and middle-income and developed countries are unlikely to give high value to high-dose vitamin D supplementation in VLBW infants. Further, availability of formulations containing only vitamin D for daily supplementation of LBW infants is low. The lack of evidence of benefit on any critical outcome does not justify the costs of making such formulations widely available.

# RECOMMENDATION 6
VLBW infants should be given vitamin D supplements at a dose ranging from400 i.u to 1000 i.u. per day until 6 months of age.
(Weak recommendation, based on very low quality evidence for lack of benefits) Table 6. GRADE profile summary for Question 6  (see annexes for detailed GRADE profiles and summary tables of individual studies)

# Summary of evidence:
No studies were identified that examined the effect of calcium and phosphorus supplementation on mortality, neurodevelopment or anthropometric status in preterm VLBW infants.
Only one RCT examined the effect of calcium and/or phosphorus supplementation on rickets of prematurity in VLBW infants. Therefore, additional evidence from an observational study was considered. Both the studies were from developed country settings. The quality of evidence for this outcome was graded as very low. There was no significant difference in the incidence of rickets between the intervention and control groups (pooled RR 0.35, 95% CI 0.03 to 4.75).
One RCT looked at the effect of mineral supplementation on the risk of active metabolic bone disease (high alkaline phosphatase levels) in preterm neonates. The quality of evidence for this outcome was graded as low. The study showed a 45% reduction (95% CI 18% to 63%) in the risk of metabolic bone disease following calcium and phosphorus supplementation. Another study -a historical cohort from a developed country -evaluated the effect on the alkaline phosphatase levels in ELBW infants. In conclusion, there is low quality evidence that routine calcium and phosphate supplementation reduces the risk of metabolic bone disease in preterm VLBW infants. There is, however, no evidence of reduction in the risk of rickets of prematurity. (See GRADE profile, Table 7.)
Balance of benefits and harms, values and preferences, and costs: There is lack of evidence for benefits or harm in mortality, neurodevelopment, and anthropometric status following routine calcium and phosphorus supplementation. The intervention has some benefit in reducing metabolic bone disease in preterm VLBW infants.
The benefit in terms of reducing metabolic bone disease is expected to be valued by health-care providers and parents. The associated costs are likely to be low and may be justified by the benefits.

# RECOMMENDATION 7
VLBW infants who are fed mother's own milk or donor human milk should be given daily calcium (120-140 mg/kg per day) and phosphorus (60-90 mg/kg per day) supplementation during the first months of life.
(Weak recommendation, based on low quality evidence for benefit in a non-critical outcome)
Table 7. GRADE profile summary for Question 7  (see annexes for detailed GRADE profiles and summary tables of individual studies) Summary of evidence: One RCT examined the effect of early iron supplementation on mortality in VLBW infants. There was no difference in the risk of mortality up to 2 months of age between the group of infants that received early iron supplementation and the group that received iron at a later age (RR 0.94, 95% CI 0.14 to 6.56). The quality of evidence was graded as very low. The wide CIs further reduce the confidence in this outcome.
Three RCTs evaluated the effect of supplements on late onset sepsis. The quality of evidence for this outcome was graded as very low. There was no significant difference in the incidence of sepsis between the two groups (pooled RR 1.06, 95% CI 0.86 to 1.30).
Three RCTs examined the effect of supplements on significant anaemia up to 2 months of age. The quality of evidence for this outcome was graded as low. The pooled effect was 30% reduction (95% CI 6% to 48%) in the need for blood transfusion with early iron supplementation. The effect could be an underestimate of the true effect size because one of the included studies initiated iron at 4 weeks of age in the control group, unlike the other two that started iron at 2 months. Another study, a quasi-RCT from a developed country setting, found a significant reduction in the proportion of infants with haemoglobin levels <9 g/dl at 3 months of age (RR 0.03, 95% CI 0 to 0.44). The results of this study were not included in the meta-analysis because the definition of severe anaemia in the other studies was anaemia requiring blood transfusion.
One RCT studied the effect on both neurodevelopment and malnutrition at 5 years of age. The quality of evidence for both outcomes was graded as very low. The study did not find any difference in either the mental processing composite score (MD 3.0 points, 95% CI -2.1 to 8.1) or the risk of stunting (RR 1.06, 95% CI 0.3 to 3.5) between infants who received early iron supplementation and those who received it later.
Three RCTs examined the effect of early iron supplementation on morbidities attributed to oxidative stress, particularly chronic lung disease (CLD) and retinopathy of prematurity (ROP), in preterm VLBW infants. The quality of evidence for this outcome was graded as low. There was a trend towards reduction in the risk of CLD in infants who received iron at an earlier age (pooled RR 0.61, 95% CI 0.37 to 1.0). No significant difference was found in the risk of ROP (pooled RR 0.41, 95% CI 0.14 to 1.18).
To conclude, there is low quality evidence that early iron supplementation reduces severe anaemia, defined as anaemia needing blood transfusion, in early infancy, and no evidence that it improves other critical outcomes. There is low to very low quality evidence that supplementing iron does not increase the risk of severe morbidities such as late onset sepsis, CLD and ROP. (See GRADE profile, Table 8.)
Balance of benefits and harms, values and preferences, and costs: There is benefit in terms of reduced risk of severe anaemia and no apparent harms associated with early iron supplementation of VLBW infants. Given the evidence for lack of harmful effects, policy-makers and health-care providers in both low-and middle-income and developed country settings are likely to give a high value to the intervention. The benefits observed with iron supplementation justify the marginal costs involved in administering early iron supplements to VLBW infants.

# RECOMMENDATION 8
VLBW infants fed mother's own milk or donor human milk should be given 2-4 mg/kg per day iron supplementation starting at 2 weeks (Weak recommendation, based on low quality evidence for benefit in one critical outcome and low to very low quality evidence for no harms in other critical outcomes Summary of evidence: A Cochrane review assessed the benefits and risks of vitamin A supplementation in VLBW infants. The meta-analysis of the eight eligible trials suggested a beneficial effect in reducing death or oxygen requirement at 1 month of age (RR 0.93, 95% CI 0.88 to 0.99) and oxygen requirement at 36 weeks postmenstrual age (RR 0.87, 95% CI 0.77 to 0.98). However, of the eight studies, only one trial used the oral route for vitamin A supplementation. This study did not find any significant effect on either mortality until discharge (RR 0.86, 95% CI 0.56 to 1.33) or chronic lung disease (RR 1.0, 95% CI 0.8 to 1.24) following daily oral vitamin A supplements of 5000 i.u./kg in ELBW infants. The quality of evidence for both the outcomes was graded as low. (See GRADE profile, Table 9).
To conclude, daily oral vitamin A supplementation at 2-3 times the RDA does not reduce the risk of mortality or CLD in VLBW infants. However, there is insufficient evidence (a single study) to have confidence in this conclusion.
Balance of benefits and harms, values and preferences, and costs: There is low quality evidence for no benefits or harm in any of the critical outcomes with daily oral vitamin A supplementation.
Given the lack of benefits and the additional costs involved in administering daily vitamin A supplements, policy-makers and health-care providers are not likely to give high value to routine oral vitamin A supplementation in VLBW infants.

# RECOMMENDATION 9
Daily oral vitamin A supplementation for LBW infants who are fed mother's own milk or donor human milk is not recommended at the present time because there is not enough evidence of benefits to support such a recommendation.
(Weak recommendation, based on low quality evidence for lack of benefits in critical outcomes) Table 9. GRADE profile summary for Question 9 58,59 (see annexes for detailed GRADE profiles and summary tables of individual studies)    Summary of evidence: Two observational studies examined the effect of early initiation of breastfeeding on mortality during the neonatal period. Both of these community-based studies were conducted in developing country settings. The quality of evidence for this outcome was graded as low.
The pooled effect was 42% reduction in mortality (95% CI 21% to 57%) with initiation of breastfeeding in the first day of life. There was evidence of a dose response, i.e. earlier initiation was associated with a greater benefit.
No studies were identified that evaluated the effect on any of the other critical outcomes in LBW infants.
To conclude, there is low quality evidence that initiation of breastfeeding in the first day of life is associated with a significant reduction in the risk of neonatal mortality when compared with delaying breastfeeding for more than 24 hours after birth. (See GRADE profile, Table 11.)
Balance of benefits and harms, values and preferences, and costs: There is evidence for significant benefit in neonatal mortality with early initiation of breastfeeding. Policy-makers, healthcare providers and parents in both low-and middle-income and developed country settings are likely to give a high value to the benefits observed in neonatal mortality. The observed benefits clearly outweigh the low costs involved in implementation of early initiation of breastfeeding. Further, this recommendation would be consistent with the recommendation for the general population of neonates to initiate breastfeeding as soon as possible within the first hour after birth.

# RECOMMENDATION 11
LBW infants who are able to breastfeed should be put to the breast as soon as possible after birth when they are clinically stable.
(Strong recommendation, based on low quality evidence for benefits)

# QUESTION 12:
In VLBW infants born in settings where total parenteral nutrition (TPN) is not possible (P), what is the effect of starting small amounts of oral feeds (about 10 ml/kg per day) in the first few days of life (I) compared with no enteral feeding (C) on mortality, severe morbidity, neurodevelopment and anthropometric status (O)?
Summary of evidence: Four RCTs, all from developed country settings, examined the effect of giving small feed volumes in the first week of life (trophic feeding) on mortality in VLBW infants. The quality of evidence was graded as low. No significant effect on the risk of mortality was observed (pooled RR 0.76, 95% CI 0.45 to 1.28).
Eight RCTs evaluated the effect on the risk of NEC. The quality of evidence for this outcome was graded as very low. There was no significant effect on the incidence of NEC (pooled RR 1.10, 95% CI 0.70 to 1.79).
Five RCTs examined the effect on the rate of weight gain during hospital stay. The outcome in these studies was the mean days to regain birth weight. The quality of evidence was graded as low. There was no significant difference in the outcome between the group of infants who received small volumes of feeds and the group that did not receive any feeds in the first few days of life (pooled MD -0.01 days, 95% CI -0.96 to 0.95).
Three RCTs evaluated the effect of trophic feeding on the length of hospital stay in VLBW infants. The quality of evidence for this outcome was graded as very low. There was no significant difference in the mean duration of hospital stay following trophic feeding (pooled MD -3.8 days, 95% CI -12.2 to 4.5).
Six RCTs studied the effect of minimal enteral nutrition on time to reach full enteral feeding. No significant difference in the mean number of days was observed (pooled MD -1.05 days, 95% CI -2.61 to
In conclusion, there is low to very low quality evidence that initiating small volumes of oral feeds in the first few days of life along with parenteral nutrition does not reduce or increase the risk of mortality and NEC in VLBW infants. It is also not associated with any benefits in short-term weight gain or length of hospital stay (see GRADE profile, Table 12).
Balance of benefits and harms, values and preferences, and costs: There is evidence for no significant benefits or harms in any of the critical and non-critical outcomes with feeding small volumes of human milk orally in the first week of life in VLBW infants.
Enteral fasting for even a few days has been shown to induce mucosal atrophy, decrease the secretion of gut hormones and enzymes, and impair mucosal immunity in both animals and human infants. Moreover, keeping the infants nil per oral in the first week of life means that they have to be given TPN. Most health facilities in low-and middle-income country settings would not have the necessary infrastructure to administer TPN. If these infants can be started on small volumes of oral feeds (along with intravenous fluids), one can possibly avoid using TPN in such settings. Also, the costs involved in implementing this intervention are not likely to be different from giving infants only intravenous fluids.
Given these considerations and the evidence for no significant harms, policy-makers and health-care providers from low-and middle-income country settings are likely to give high value to initiation of oral feeds in small amounts (trophic feeding) in the first few days of life in VLBW infants. In view of the advantages of breast milk (Recommendations 1 and 2) these small feeds should be breast milk wherever possible.

# RECOMMENDATION 12
VLBW infants should be given 10ml/kg per day of enteral feeds, preferably expressed breast milk, starting from the first day of life, with the remaining fluid requirement met by intravenous fluids.
(Weak situational recommendation relevant to resource-limited settings where TPN is not possible, based on low to very low quality evidence for no harm in critical outcomes) Table 12. GRADE profile summary for Question 12  (see annexes for detailed GRADE profiles and summary tables of individual studies) compared with an exclusive breastfeeding duration of 4 months or less (C) on mortality, severe morbidity, neurodevelopment and anthropometric status (O)? Summary of evidence: No studies were identified that evaluated the effect of duration of exclusive breastfeeding on mortality in LBW infants.
One cluster-RCT examining the effect of community-based promotion of exclusive breastfeeding on episodes of diarrhoeal illness during infancy was identified. Exclusive breastfeeding rates at 6 months of age in the intervention and control clusters were 41% and 4% respectively. The quality of evidence for this outcome was graded as low. There was no significant effect on the proportion of infants with diarrhoeal episodes between 3 and 6 months of age (OR 0.73, 95% CI 0.41 to 1.40). Another study, a quasi-RCT from a developing country setting, found a significant reduction in the percentage of days ill with diarrhoea between 4 and 6 months of age in term LBW infants (mean : 5.4  days and 2.8  days in infants who were exclusively breastfed for 6 and 4 months of age respectively; P<0.05).
Three RCTs examined the effect of exclusive breastfeeding duration of 6 months on significant anaemia at 6 months of age. The quality of evidence for this outcome was graded as very low. No significant effect on the incidence of anaemia was observed in infants who were exclusively breastfed until 6 months of age (pooled OR 1.38, 95% CI 0.81 to 2.35). Two of the three included studies supplemented infants with iron in addition to breast milk, but the largest study did not use any iron supplements.
One observational study ascertained the effect of breastfeeding duration on IQ scores at 7-8 years of age. The quality of evidence was graded as very low. The study found no significant difference in mean verbal IQ scores between infants who were exclusively breastfed for 4 to 7 months and those who were breastfed for less than 4 months (MD 2.0 points, 95% CI -4.4 to 8.4). Another study, a quasi-RCT, found no difference in either the proportion of infants walking by 12 months of age (RR 0.68, 95% CI 0.32 to 1.44) or the mean age at crawling between the two groups (MD -0.6 months, 95% CI -1.3 to 0.1).
The cluster-RCT on community-based promotion of exclusive breastfeeding that evaluated the effect on diarrhoeal illness also assessed the effect of the intervention on anthropometric status at 6 months of age. The quality of evidence was graded as very low. There was no difference in the proportions of infants with stunting (difference in proportion 9%, 95% CI -2 to 20%) or wasting (difference in proportion -2%, 95% CI -6% to 1%) at 6 months of age.
In conclusion, there is very low quality evidence that exclusive breastfeeding for 6 months compared with 4 months does not have a beneficial or harmful effect on anaemia at 6 months or mental development scores at 7-8 years of age. There is low quality evidence from a single study of breastfeeding promotion that there is no benefit or harm in terms of diarrhoeal morbidity or malnutrition. However, in this study an exclusive breastfeeding rate of only 41% was achieved at 6 months in the 'intervention' group. (See GRADE profile, Table 13.)
Balance of benefits and harms, values and preferences, and costs: There is low to very low quality evidence for no benefits or harms in long-term neurodevelopment, anthropometric status, significant anaemia or diarrhoeal morbidity.
The costs involved in starting complementary feeding from 4 months of age are higher than continuing exclusive breastfeeding until 6 months age. The risk of contamination involved in preparation of complementary foods is also a major consideration in low-and middle-income country settings. Further, the current global policy recommendation is to exclusively breastfeed all infants for 6 months. The available evidence does not justify a different recommendation for LBW infants. Given these RECOMMENDATION 13 LBW infants should be exclusively breastfed until 6 months of age.
(Strong recommendation based on very low quality evidence for no harm in critical outcomes and the lower costs involved) QUESTION 14: In LBW infants who need to be fed by an alternative oral feeding method (P), what is the effect of feeding by cup (I) compared with bottle-feeding (C) on mortality, severe morbidity, neurodevelopment and anthropometric status (O)?
Summary of evidence: No studies were identified that compared the effects of different alternative oral feeding methods on mortality, severe morbidity such as infections, neurodevelopment, or longterm anthropometric status in LBW infants.
Three RCTs studied the effects of cup-versus bottle-feeding on the rates of exclusive breastfeeding at hospital discharge. The quality of evidence for this outcome was graded as moderate. The breastfeeding rates were significantly higher in infants fed by cup than in those fed by bottle (pooled OR 1.80, 95% CI 1.12 to 2.91). Two RCTs evaluated the effects of cup-and bottle-feeding on any breastfeeding (exclusive or partial) at 3 months after hospital discharge. The quality of evidence for this outcome was low. There was no significant difference between the two groups (pooled OR 1.43, 95% CI 0.87 to 2.34).
One RCT from a developing country setting studied the effects of cup-and bottle-feeding on short-term weight gain. The quality of evidence for this outcome was graded as low. There was no significant difference in the rate of weight gain in the 1-week period after enrolment between the two groups of infants (MD 0.6 g/kg per day, 95% CI -3.2 to 2.0).
One RCT from a developed country compared the effects of cup-and bottle-feeding on length of hospital stay in LBW infants. The quality of evidence for this outcome was graded as low. Infants in the cupfeeding group had a significantly longer hospital stay than those in the bottle-feeding group (MD 10.1 days, 95% CI 3.9 to 16.3).
One RCT examined the effects of cup-and bottle-feeding on the proportion of infants with desaturation and/or apnoea during feeding. The quality of evidence for this outcome was graded as low. The proportion was significantly less in the cup-feeding group (OR 0.29, 95% CI 0.08 to 0.99). Another study, a cross-over study from a developed country setting, also found a significant reduction in the proportion of episodes of desaturation with cup-feeding (mean : 0.05  versus 0.13  in cup-and bottle-feeding groups respectively; P=0.02).
There is some evidence for less spilling and greater consumption when a palladai is used compared with a regular cup.
In conclusion, there is moderate to low quality evidence that cup-feeding improves exclusive breastfeeding rates at discharge and reduces the risk of apnoeic episodes during feeding. On the other hand, it was associated with prolonged hospital stay, and the benefit in breastfeeding rates was not sustained at 3 months of age. (See GRADE profile, Table 14).
Balance of benefits and harms, values and preferences, and costs: There is no evidence for benefits in any of the critical outcomes but some evidence for benefits in non-critical outcomes, such as exclusive breastfeeding rates, with cup-feeding. There is low quality evidence for harm in another noncritical outcome (length of hospital stay).
Since cups are much easier to clean than bottles, feeding by a cup could potentially reduce the risk of severe infections, such as diarrhoea, a major consideration in low-and middle-income countries. Given that cup-feeding is also associated with benefits in breastfeeding rates, policy-makers and health-care providers from resource-limited settings are likely to give a high value to this feeding method. On the other hand, the possible effect on duration of hospital stay might increase the costs and effort involved RECOMMENDATION 14 LBW infants who need to be fed by an alternative oral feeding method should be fed by cup (or palladai which is a cup with a beak) or spoon.
(Strong situational recommendation relevant to resource-limited settings, based on moderate quality evidence for benefits in a non-critical outcome) Table 14. GRADE profile summary for Question 14  (see annexes for detailed GRADE profiles and summary tables of individual studies)

# QUESTION 15:
In VLBW infants who need to be given intragastric tube feeding (P), what is the effect of bolus intermittent feeding (I) compared with continuous feeding (C) on mortality, severe morbidity, neurodevelopment and anthropometric status (O)?
Summary of evidence: No studies were found that compared the effects of intermittent feeding and continuous feeding through intragastric tube on mortality in VLBW infants.
Four studies (three RCTs and one quasi-RCT, all from developed country settings) compared the effects of bolus and continuous intragastric tube feeding on NEC. The quality of evidence for this outcome was graded as low. There was no significant difference in the incidence of NEC between the two feeding groups (RR 0.99, 95% CI 0.51 to 1.92). However, the CI is wide, and therefore the result should be interpreted with caution.
A total of four RCTs evaluated the effect on rate of weight gain during hospital stay. The outcome assessed was the number of days to regain birth weight. The quality of evidence was graded as very low.
No significant difference was found between the groups of infants receiving bolus feeding and continuous intragastric tube feeding (MD -0.46 days, 95% CI -1.48 to 0.55).
Five RCTs ascertained the effects of bolus and continuous intragastric tube feeding on the number of days to reach full feeds. The quality of evidence for this outcome was graded as low. There was no significant difference between the two groups (MD -1.86 days, 95% CI -5.8 to 2.1).
One RCT studied the effects on the number of apnoeic episodes during feeding. The quality of evidence was graded as low. There was no significant difference between the two feeding groups in the number of episodes during the entire study period (MD -14.0 episodes, 95% CI -28.2 to 0.2). Another study, an RCT from a developed country setting, also found no significant difference in the number of apnoeic episodes per day between the two groups (MD 0.6 episodes, 95% CI -0.79 to 1.99).
In conclusion, there is low to very low quality evidence that bolus or intermittent feeding and continuous feeding through intragastric tube are not different in the risk of NEC, days to regain birth weight or days to reach full feeds when compared with continuous feeding. (See GRADE profile, Table 15.)
Balance of benefits and harms, values and preferences, and costs: There is evidence for no significant benefits or harms in any of the critical and non-critical outcomes with bolus intragastric tube feeding.
Unlike continuous intragastric tube feeding, bolus or intermittent feeding does not require syringe pumps or other infusion pumps. Implementing bolus feeding might therefore be associated with lower costs than implementing continuous feeding. Given that there is no difference in benefits or harm between the two methods, policy-makers and health-care providers are likely to give high value to bolus, intermittent feeding through intragastric tube in VLBW infants.

# RECOMMENDATION 15
VLBW infants requiring intragastric tube feeding should be given bolus intermittent feeds.
(Weak recommendation, based on low to very low quality evidence for no difference in benefits or harm but lower costs) Summary of evidence: No studies were found that examined the effects of the different routes of intragastric tube placement (oral and nasal) on mortality, neurodevelopment and long-term growth in VLBW infants. Indeed, only one RCT was identified that ascertained the effects of oral and nasal routes of tube placement on severe morbidities and growth during hospital stay. This study found no significant differences in either the risk of NEC (RR 2.78, 95% CI 0.12 to 50.0), mean number of days to regain birth weight (MD -0.9 days, 95% CI -3.1 to 1.3) or in the duration of oxygen supplementation (MD -7.6 days, 95% CI -30.4 to 15.2) between the orogastric and nasogastric tube feeding groups. The quality of evidence for all three outcomes was graded as very low.
A descriptive study from a developed country setting reported a significant increase in nasal resistance and total airway resistance following insertion of a nasogastric tube in preterm infants born before 32 weeks gestation. There were, however, no differences in either the nasal resistance or total airway resistance between the nasogastric and orogastric tube feeding groups at one month after removal of the tubes.
In conclusion, there is very low quality evidence that orogastric tube feeding does not reduce the risk of NEC, days to regain birth weight or the duration of oxygen supplementation when compared with nasogastric tube feeding. (See GRADE profile, Table 16).
Balance of benefits and harms, values and preferences, and costs: There is no evidence for benefits or harms in any of the critical outcomes with orogastric tube feeding compared with nasogastric tube feeding.
Orogastric tubes are easier to insert but are relatively more difficult to fix than tubes placed through the nasal route. This might result in frequent change of feeding tubes, thereby increasing the costs. On the other hand, nasogastric tube feeding has been associated with some deterioration in physiological parameters, such as airway resistance, and carries a risk of injury to the nasal mucosa. Therefore, policy-makers, health-care providers, and parents are likely to be equivocal regarding the optimal route of placement of an intragastric tube.

# RECOMMENDATION 16
In VLBW infants who need to be given intragastric tube feeding, the intragastric tube may be placed either by the oral or nasal route, depending upon the preferences of health-care providers.
(Weak recommendation, based on lack of evidence for benefits or harm in any of the critical outcomes) QUESTION 17: In LBW infants who are fully or mostly fed by an alternative oral feeding method (P), what is the effect of feeding based on infants' hunger cues (I) compared with strict scheduled feeding (C) on mortality, severe morbidity, neurodevelopment and anthropometric status (O)?

# Summary of evidence:
No studies compared the effects of feeding based on infants' hunger cues and those of scheduled feeding on mortality, severe morbidity including hypoglycemia, neurodevelopment or anthropometric status (at or beyond 6 months of age). A Cochrane review included eight RCTs, all from developed country settings, involving 496 infants in total. One additional study was found (observational, from developed country settings). Feeding was initiated in response to infants' hunger cues in all studies and was stopped based on satiation cues or after a prescribed volume was administered. In many of these studies, infants were aroused to feed orally if they did not demonstrate Three studies (two RCTs and one observational) have ascertained the effects of feeding based on infants' hunger cues and scheduled feeding on weight gain during hospital stay. The quality of evidence for this outcome was graded as very low. There was no significant difference in the mean weight gain between the two groups (MD -0.47 g/kg per day, 95% CI -3.76 to 2.82). Another study, an RCT not included in the meta-analysis, also reported no difference in the mean weight gain between the two groups of infants (MD -2.8 g per day, 95% CI -6.55, 0.95). The other five studies also examined the effect on shortterm growth. However, they could not be included in the meta-analysis because of incomplete data. Four of these studies reported no significant differences in the rate of weight gain during the study period; the fifth study reported the mean daily weight gain in both the groups (26.4 g versus 34.1 g) but did not elaborate as to whether the difference was statistically significant.
Three RCTs evaluated the effect of feeding based on hunger cues on the length of hospital stay. The quality of evidence for this outcome was graded as moderate. The pooled MD in the postmenstrual age at discharge was 0.55 weeks shorter (95% CI -0.84, -0.26) in those receiving feeding based on hunger cues. However, these results have to be interpreted with caution, because the largest study included in the meta-analysis used a co-intervention (non-nutritive sucking) known to shorten the length of hospital stay in preterm infants. As with the previous outcome, the data from five RCTs were not included in the meta-analysis because of incomplete data. Of these, three studies reported no significant difference in either the mean duration of hospital stay or mean age at discharge while one study reported a significant difference in the number of days from enrolment until infants were ready for discharge (2.7 versus 8.9 days; P value not reported). The fifth study reported the duration of hospital stay in the two groups (31 versus 33 days) but did not mention whether the difference was statistically significant.
Two RCTs studied the effect of feeding based on infants' hunger cues on time to reach full feeds in preterm infants. The quality of evidence for this outcome was graded as moderate. The pooled MD is 2.8 days less (95% CI -3.6, -2.1) in infants who received feeding based on hunger cues. Another RCT reported that infants in the group fed based on hunger cues achieved full feeds earlier than the control group infants (2.7 versus 8.9 days), but did not comment on the statistical significance.
In conclusion, there is moderate quality evidence that feeding based on infants' hunger cues reduces the time to reach full enteral feeds and possibly the length of hospital stay. There is very low quality evidence that it does not increase the rate of weight gain during initial hospital stay. (See GRADE profile, Table 17).
Balance of benefits and harms, values and preferences, and costs: There is no evidence of benefits or harms in any of the critical outcomes. Policy-makers, health-care providers and parents are likely to value shorter hospital stays, but this observed benefit could have been confounded by another intervention (non-nutritive sucking). Since feeding based on infants' hunger cues requires a greater number of well-trained health providers to feed the babies and train the mothers to look for hunger cues, implementing this approach would be associated with higher costs.

# RECOMMENDATION 17
LBW infants who are fully or mostly fed by an alternative oral feeding method should be fed based on infants' hunger cues, except when the infant remains asleep beyond 3 hours since the last feed.
(Weak situational recommendation relevant to settings with adequate number of health care providers, based on moderate to low quality evidence for benefit in non-critical outcomes) QUESTION 18: In VLBW infants who need to be fed by an alternative oral feeding method or given intragastric feeds (P), what is the effect of rapid (>30 ml/kg per day) progression of feeds (I) compared with slow (<20 ml/kg per day) progression (C) on mortality, severe morbidity, neurodevelopment and anthropometric status (O)?
Summary of evidence: Three RCTs evaluated the effect of rapid progression of feeds (>30 ml/kg per day) on mortality in VLBW infants. Two of the studies were from developing country settings. The quality of evidence for this outcome was graded as moderate. There was no significant difference in the risk of mortality between the 'fast' and 'slow' feeding groups (pooled RR 0.67, 95% CI 0.36 to 1.22).
Four RCTs -two each from developed and developing country settings -examined the effect of rapid progression of enteral feeds on the incidence of NEC. The quality of evidence for this outcome was graded as low. There was no significant difference in the risk of NEC between the two groups, but the wide CI means that this finding is inconclusive (pooled RR 1.02, 95% CI 0.51 to 2.05).
No studies were found that examined the effects of rapid and slow progression of feeds on neurodevelopment and anthropometric status at 6 months of age or more in preterm LBW infants. We included four RCTs that studied the effects of rapid and slow progression of feeds on weight gain during initial hospital stay. Since the studies reported only median and range/inter-quartile ranges, the results could not be pooled. The quality of evidence for this outcome was graded as high. All four studies showed a significant reduction in the median days to regain birth weight -the reported median difference ranging from 2 to 6 days.
Three RCTs have looked at the effect of rapid feed progression on the duration of hospital stay in LBW infants. The results of these studies were also not pooled (only median and ranges available). The quality of evidence for this outcome was graded as low. Infants in the rapid feeding group from all the studies had shorter duration of stay in the hospital; however, the difference was not statistically significant in two studies. The third study reported a significant difference between the two groups (median  9.5 days In conclusion, there is moderate to low quality evidence that rapid progression of oral feeds does not reduce or increase the risk of mortality or NEC. The only benefit is that it reduces the time to regain birth weight in VLBW infants. (See GRADE profile, Table 18).
Balance of benefits and harms, values and preferences, and costs: There is no evidence of benefits or harms in any of the critical outcomes, but some benefit was observed in one 'other' noncritical outcome (rate of weight gain during hospital stay).
The benefit in short-term weight gain is likely to be given some value by parents and health-care providers. However, policy-makers are unlikely to give a high value to this benefit in the absence of evidence of benefit on critical outcomes. The costs of implementing faster progression of feeding are RECOMMENDATION 18 In VLBW infants who need to be fed by an alternative oral feeding method or given intragastric tube feeds, feed volumes can be increased by up to 30 ml/kg per day with careful monitoring for feed intolerance.
(Weak recommendation, based on high quality evidence for benefit in a non-critical outcome)
Table 18. GRADE profile summary for Question 18  (see annexes for detailed GRADE profiles and summary tables of individual studies)

# FIELD TESTING OF GUIDELINES
Recommendations for feeding LBW infants were first drafted in 2006, and a set of training materials for health workers who care for LBW infants was developed based on these recommendations. A field test with a pre-post design was conducted in two district-level hospitals each in Ghana, India, Pakistan and Uganda in 2008-9. The objectives of the field test were to evaluate the feasibility and acceptability of implementing the guidelines and to document the effect of guideline implementation on the knowledge and skills of health workers and mothers. The relatively small sample size of 120 infants per country was not sufficient to detect improvements in feeding practices.
In all countries, health providers who care for LBW infants were trained in a 3-day workshop comprised of self-reading sessions and classroom demonstrations using video and posters based on the guidelines, combined with clinical demonstrations and practice. A typical workshop included about 20 participants and 2-4 facilitators/trainers. In addition to training, supervision and on-the-job support was provided to the health workers, and efforts were made to improve facilities and supplies where possible.
The results of the field tests in all four countries were very encouraging. It was feasible to implement the guidelines in all the sites, and they were found to be acceptable to health workers and mothers. Both the health workers and mothers felt that implementation of the guidelines had improved the care of LBW infants. Finally, there was a substantial and statistically significant improvement in knowledge and skills of health providers related to optimal feeding of LBW infants in all the study sites.

# IMPLEMENTATION PLAN
These guidelines will be disseminated to Ministries of Health of relevant countries through the WHO Regional and Country offices. The draft training materials related to the guidelines, including the reading materials for sessions, posters and video, will be finalized and made available to countries through WHO Regional and Country Offices as reference material. However, the main implementation strategy for these guidelines and training materials will be through incorporation into the flagship tools and training materials of the Department of Maternal, Newborn, Child and Adolescent Health, including IMCI and Integrated management of pregnancy and childbirth (IMPAC) materials for community, first-level health facilities and referral hospitals. These materials are already in use in over