Folic Acid Supplementation for the Prevention of Neural Tube Defects: An Update of the Evidence for the U.S. Preventive Services Task Force

Neural tube defects (NTDs) are among the most common birth defects in the United States (1). It is difficult to estimate disease burden because affected pregnancies are sometimes spontaneously or electively aborted and are underreported on birth certificates (2). The Centers for Disease Control and Prevention estimate that the rates in 2005 for 2 of the most common NTDs, spina bifida and anencephaly, were 17.96 per 100000 live births and 11.11 per 100000 live births, respectively (3). The U.S. Preventive Services Task Force (USPSTF) last issued a recommendation on the use of folic acid in women of childbearing age in 1996. At that time, it recommended that all women planning a pregnancy or capable of conception take a supplement that contained folic acid. They found insufficient evidence to recommend for or against counseling women to increase their dietary folate consumption as an alternative to taking a folic acid supplement. The purpose of this review is to update the evidence on folic acid supplementation in women of childbearing age. The USPSTF decided to focus its new review on folic acid supplementation; therefore, this update does not include a review of the evidence on fortification, counseling to increase dietary intake, or screening for neural tube defects. We include only literature published since 1995 because it is an update of the previous USPSTF review. Figure 1 shows the analytic framework developed for this review, which follows USPSTF methods. The USPSTF developed 2 key questions (KQs) from the analytic framework to guide its consideration of the evidence on folic acid supplementation: Figure 1. Analytic framework for the U.S. Preventive Services Task Force review on folic acid supplementation for the prevention of NTDs. KQ = key question; NTD = neural tube defect. KQ1: Does folic acid supplementation in women of childbearing age reduce the risk for a pregnancy affected by a neural tube defect? KQ2: Does folic acid supplementation in women of childbearing age increase the risk for any harmful outcomes for either the woman or the infant? Methods Data Sources and Searches We performed a systematic search in MEDLINE for English-language articles published between January 1995 and December 2008 by using the terms neural tube defects, folic acid, pregnancy, twinning, and twins. We identified additional studies by searching the Cochrane Central Register of Controlled Trials, having discussions with experts, and hand-searching reference lists from included studies and major review articles and studies. Study Selection Two reviewers independently reviewed the titles and abstracts and selected articles for inclusion on the basis of predetermined inclusion and exclusion criteria. In general, we selected randomized, controlled trials (RCTs); casecontrol studies; cohort studies; and systematic reviews that reported an overall effect on reduction of NTDs or an effect on harms associated with folic acidcontaining supplements and provided new evidence that was not in the 1996 USPSTF report. We excluded studies that did not include new evidence since the 1996 review; did not report outcome data on NTDs or harms associated with folic acid supplementation; did not report on the effect of supplements separate from dietary effects; were letters, editorials, or nonsystematic reviews; were performed in special or high-risk populations; or were performed in a country or population with widespread malnutrition or that was otherwise not generalizable to the United States. The Appendix provides more details on search terms and inclusion and exclusion criteria. We discussed and settled disagreements about inclusion of an article by consensus; if necessary, we involved a third reviewer for disagreements. Data Extraction and Quality Assessment For all citations that met initial eligibility criteria, 2 reviewers reviewed, abstracted, and independently quality-rated the full articles. We ultimately included studies that were rated fair or good on the basis of USPSTF criteria. We achieved consensus about article abstraction data and quality through discussion by the 2 reviewers and resolved disagreements by involving a third reviewer. We extracted data from included studies on the following items: methods; exposure assessment; case ascertainment; selection of participants; dose of folic acid; sample size; size of effect on NTDs, other congenital abnormalities, and twinning; and information on confounders. We used standard USPSTF methodology on internal and external validity to quality-rate the articles for all KQs. We evaluated the quality of RCTs and cohort studies on initial assembly of comparable groups, maintenance of comparable groups, important differential loss to follow-up or overall high loss to follow-up, measurements (equality, reliability, and validity of outcome measurements), clear definition of interventions, and appropriateness of outcomes. We evaluated systematic reviews and meta-analyses on comprehensiveness of sources considered, search strategy, standard appraisal of included studies, validity of conclusions, recency, and relevance. Appendix Table 1 lists more complete criteria and definitions for USPSTF quality ratings. Appendix Table 1. U.S. Preventive Services Task Force Hierarchy of Research Design and Quality Rating Criteria Data Synthesis and Analysis We qualitatively synthesized data from studies included for KQ1 and KQ2 in tabular and narrative format. We organized synthesized evidence by key question. Role of the Funding Source The general work of the USPSTF is supported by the Agency for Healthcare Research and Quality. This specific review did not receive separate funding. Results We identified 1083 articles, of which 4 met our inclusion criteria for benefits and 1 for harms. Figure 2 details the reasons for exclusions. Appendix Tables 2 and 3 discuss studies that initially met inclusion criteria and were abstracted and quality-rated but were ultimately excluded for KQ1 (benefits) and KQ2 (harms), respectively. Figure 2. Study flow diagram. KQ = key question. Appendix Table 2. Studies Excluded After Abstraction and Quality Rating for Key Question 1 (Benefits) Appendix Table 3. Studies Excluded After Abstraction and Quality Rating for Key Question 2 (Harms) Key Question 1 Does folic acid supplementation in women of childbearing age reduce the risk for a pregnancy affected by a neural tube defect? Our literature search to answer this question returned 4 articles that met the inclusion criteria, were published within the search time frame, and were of appropriate methodological quality. The Table lists detailed study characteristics and outcomes. Observational studies on the benefits of folic acid supplementation provide generally consistent evidence that folic acid supplementation in the periconceptional period reduces the risk for neural tube defects in offspring. This evidence was provided by 3 fair- or good-quality cohort, casecontrol, and meta-analytic studies that found statistically significant benefit; a small, fair-quality casecontrol study reported benefit that was not statistically significant. In addition to NTDs, the cohort and meta-analysis found reductions in cardiovascular congenital abnormalities associated with folic acidcontaining multivitamins. Table. Characteristics and Results of Studies Included for Key Questions 1 and 2 The first study, by Czeizel and colleagues (4), recruited a cohort of 6112 women from the Hungarian Preconception Service. Women in the supplementation group received 0.8 mg of folic acid per day beginning 1 month before planned conception. Women who presented at 8 to 12 weeks of gestation with no periconception folic acid supplementation served as control participants and were matched 1-to-1 by age, socioeconomic status, and employment status with 3056 women who received supplements. We rated this study fair quality because women in the supplementation group were more likely than control participants to have congenital abnormalities or a history of congenital abnormalities among family or offspring and because exposure to folic acid supplementation was assessed earlier in the supplementation group than in the control group. One NTD occurred in the supplementation group and 9 in the control group, of 3056 women in each group. Although this difference was statistically significant after adjustment for birth order, chronic maternal disorders, and history of previous fetal death or congenital abnormality, our confidence in the statistical estimates is reduced, given the small number of events. Of note, this study also reported that women who received supplements had infants with significantly fewer cardiovascular congenital abnormalities than did control participants. We found 2 casecontrol studies in the literature search. These studies explored the association between exposure to folic acid supplementation in the periconceptional period and NTD in women residing in 2 areasmost California counties and South Carolina. The Table details the study design. We rated the 1995 casecontrol study by Shaw and colleagues (5) good quality because it accurately ascertained cases, selected case-patients and control participants without obvious biases, had response rates of 88% among both case patients and control participants, applied exposure measurement equally to case-patients and control participants, and explored reporting bias. We rated the 2003 casecontrol study by Thompson and colleagues (6) fair quality because it had a small sample size, differential measurement assessments, and differential response rates among case patients and control participants. Shaw and colleagues (5) reported an odds ratio (OR) of 0.65 (95% CI, 0.45 to 0.94) for any reported use of folic acidcontaining supplements in the 3 months before conception and an OR of 0.60 (CI, 0.46 to 0.79) for supplement use in the 3 months after conception. Thompson and colleagues (6) reported an OR of 0.55