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Folic Acid Supplementation for the Prevention of Neural Tube Defects: An Update of the Evidence for the U.S. Preventive Services Task Force
- Tracy Wolff, MD, MPH;
- Catherine Takacs Witkop, MD, MPH;
- Therese Miller, DrPH; and
- Shamsuzzoha B. Syed, MD, MPH, DPH (Cantab)
- From the U.S. Preventive Services Task Force, Agency for Healthcare Research and Quality, Rockville, Maryland.
Abstract
Background: Neural tube defects (NTDs) are among the most common birth defects in the United States. In 1996, the U.S. Preventive Services Task Force (USPSTF) recommended that all women planning a pregnancy or capable of conception take a supplement containing folic acid to reduce the risk for NTDs.
Purpose: To search for new evidence published since 1996 on the benefits and harms of folic acid supplementation for women of childbearing age to prevent neural tube defects in offspring, to inform an updated USPSTF recommendation.
Data Sources: MEDLINE and Cochrane Central Register of Controlled Trials searches from January 1995 through December 2008, recent systematic reviews, reference lists of retrieved articles, and expert suggestions.
Study Selection: English-language randomized, controlled trials; cohort studies; case–control studies; systematic reviews; and meta-analyses were selected if they provided information on the benefits and harms of folic acid supplementation in women of childbearing age to reduce NTDs in offspring.
Data Extraction: All studies were reviewed, abstracted, and rated for quality by using predefined USPSTF criteria.
Data Synthesis: Four observational studies reported benefit of reduction of risk for NTDs associated with folic acid–containing supplements. Differences in study type and methods prevent the calculation of a summary of the reduction in risk. The one included study on harms reported that the association of twinning with folic acid intake disappeared after adjustment for in vitro fertilization and underreporting of folic acid intake.
Limitations: The evidence on dose was limited. No evidence was found on the potential harm of masking vitamin B12 deficiency in women of childbearing age. The search focused on the association of NTDs with supplementation only and therefore does not provide a comprehensive review of the effects of folic acid on all possible outcomes or of the effects of dietary intake of folic acid.
Conclusion: New observational evidence supports previous evidence from a randomized, controlled trial that folic acid–containing supplements reduce the risk for NTD-affected pregnancies. The association of folic acid use with twin gestation may be confounded by fertility interventions.
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 100 000 live births and 11.11 per 100 000 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:
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); case–control studies; cohort studies; and systematic reviews that reported an overall effect on reduction of NTDs or an effect on harms associated with folic acid–containing 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.
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.
KQ = key question.
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, case–control, and meta-analytic studies that found statistically significant benefit; a small, fair-quality case–control 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 acid–containing multivitamins.
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 case–control 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 areas—most California counties and South Carolina. The Table details the study design. We rated the 1995 case–control 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 case–control 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 acid–containing 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 (CI, 0.25 to 1.22) for regular use (at least 3 times/wk) and an OR of 0.92 (CI, 0.55 to 1.55) for some use of folic acid–containing supplements, but neither of these findings was statistically significant. In both studies, it was difficult to accurately assess the dose and frequency of supplement intake because of the reliance on self-reporting and variability in supplement composition. Several differences in these case–control studies may explain differences in results. Thompson and colleagues' study (6) was smaller and adjusted for dietary folate intake. In addition, the exposure timeframes were different: Shaw and colleagues (5) measured exposure in 2 time frames, 3 months before and 3 months after conception, whereas Thompson and colleagues (6) combined these same 6 months of periconceptional time into 1 measure of exposure.
The fourth study was a meta-analysis of studies on pre- and periconceptional multivitamin use and congenital malformations. We rated this meta-analysis fair quality because it did not include consultation with expert informants to identify additional potential evidence not identified in the literature search and did not report a standard appraisal of study methodology (7). This meta-analysis may not fully meet strict systematic review inclusion criteria because it excluded studies on folate-only supplementation and included several studies that we excluded. We nevertheless include it here because it was published since the previous USPSTF review and the USPSTF may decide that it provides useful information as it deliberates on recommendations. The meta-analysis found that folic acid– containing multivitamins had a protective effect against NTDs, with an OR of 0.67 (CI, 0.58 to 0.77) in case–control studies and an OR of 0.52 (CI, 0.39 to 0.69) in RCTs and cohort studies. In addition, it found a significant effect of folic acid–containing multivitamin use on congenital limb defects. The meta-analysis found no consistent effect of folic acid–containing multivitamins on either orofacial clefts or urinary tract congenital abnormalities.
Key Question 2
Does folic acid supplementation in women of childbearing age increase the risk for any harmful outcomes for either the woman or the infant?
We found no studies that demonstrated an association of folic acid supplementation with twin pregnancy or masking of B12 deficiency. Of note, 1 fair-quality study suggested that confounding by infertility treatment explains previously reported associations of folic acid and twin pregnancy.
The retrospective cohort study (8) examined the association between risk for twinning in 176 042 women who gave birth in Norway between December 1998 and December 2001 and their history of multivitamin or folic acid supplementation before or during pregnancy. The Table provides details of this study. Twenty-four percent of women who became pregnant through in vitro fertilization (IVF) reported supplementation. Given the concern for underreporting of folic acid use (calculated to be about 45% when the investigators linked the pregnancies in this analysis to another large cohort study with more accurate assessment of folic acid exposure) and potential confounding by IVF, the investigators adjusted for these factors. We rated this study fair quality because it used reasonable, albeit not the best, methods for exposure assessments; recall by mothers was probably imperfect, given that exposure was assessed at delivery; mothers with or without twin pregnancies may have had differential recall of exposure; and the exact dose, timing, and duration of the interventions were not clearly described. After adjusting for age and parity, the investigators reported an OR of 1.59 (CI, 1.41 to 1.78) for twin delivery after preconceptional folic acid supplementation. In a subgroup analysis of women who did not report IVF, the risk for twinning was lower and nonsignificant (OR, 1.13 [CI, 0.97 to 1.33]). The investigators then adjusted for both a 45% underreporting of supplementation as well as an estimated 12.7% of unidentified IVF pregnancies. When the likely underreporting for folic acid use and IVF were accounted for, the OR for twin delivery after preconceptional supplementation decreased to 1.02 and was no longer significantly greater than the risk among women who did not take folic acid (CI, 0.85 to 1.24).
Discussion
New evidence from observational studies provides weight to previous evidence from controlled trials that folic acid supplementation provides benefit in reduction of risk for NTD-affected pregnancies. We found 4 fair- or good-quality studies of the benefits of supplementation published since the previous 1996 USPSTF report. Odds ratios for reductions in NTDs associated with periconceptional folic acid supplementation ranged from 0.11 to 0.65 in cohort and case–control studies; however, some of these studies had small samples, which limits our confidence in the statistical estimates. A meta-analysis reported ORs for NTDs inversely associated with multivitamin use of 0.67 in case–control studies and 0.52 in RCTs and cohort studies.
A study that we excluded from our review because it was performed in a population not generalizable to the United States deserves discussion. This cohort study evaluated the pregnancy outcomes of 130 142 women in 3 provinces in China who were asked during their premarital medical examination to take a 0.4-mg daily folic acid supplement (9). Periconceptional use of a folic acid supplement was associated with an approximately 40% to 80% reduction in risk for NTD-affected pregnancies; the reduction was greater in a region with higher prestudy rates of NTDs. Although the direct applicability of these specific rate reductions to the U.S. population is limited by the differences in the 2 countries' nutritional levels, these results nevertheless lend additional strength to the evidence on benefit.
The only RCT included in the 1996 USPSTF report on the prevention of first-occurrence NTDs noted an increase in the risk for twinning among multivitamin users (10). These findings were not statistically significant when the data were reanalyzed and twin deliveries were considered as the outcome instead of twin births (11). In our review, we attempted to identify all studies published since 1996 that examined twinning as an outcome. The 1 fair-quality study that we included found no association between preconceptional folic acid use and twinning; this study differed from previous studies because it accounted for both the high rate of underreporting of folic acid use (seen in many populations and studies) and the use of IVF. The previously discussed prospective study from China, which we excluded because of population, found no association with twinning; exposure assessment was probably fairly accurate and IVF and ovulation induction were not prevalent confounding factors (9).
Another potential concern about folic acid supplementation is masking of vitamin B12 deficiency. We found no evidence to support or refute this possible harm. However, given the low prevalence of vitamin B12 depletion in young women, it is unlikely that folic acid supplementation in women of childbearing age would result in a significant number of cases of neurologic sequelae due to masking of vitamin B12 deficiency. In a study that used data from the National Health and Nutrition Examination Survey and the Hispanic Health and Nutrition Examination Survey (12), the Centers for Disease Control and Prevention National Center for Health Statistics reported in 1998 that less than 1% of the total population between 4 and 50 years of age had a serum vitamin B12 level less than 100 pg/mL, the level below which vitamin B12 deficiency may occur. An ecologic study (13) that compared patients before and after folic acid fortification periods found no evidence of an increase in low vitamin B12 levels without anemia. Finally, folic acid supplementation is often given in the form of a multivitamin or prenatal vitamin that includes supplementation with vitamin B12, which reduces the likelihood that vitamin B12 deficiency would be masked in this population.
Gaps in the Evidence
Determining the most effective dose, form, and timing of folic acid supplementation to prevent first NTDs presents considerable difficulties. Randomized, controlled trials provide the best opportunity to make these determinations, but only 1 RCT (10) assessed women without a history of a previously affected child. In this study, women who were treated periconceptionally with 0.8 mg/d had a significantly lower risk for NTDs, but this RCT offered no opportunity to study other dosages. Observational studies have also attempted to answer these questions about dosage, but are plagued by difficulties with accurate exposure assessment (dose, form, and timing); heterogeneity with respect to whether studies accounted for supplements, fortified foods, and dietary intake of naturally occurring folate; and variability in bioavailability of various sources.
Limitations of the literature make it difficult to determine the combined effect of supplementation and dietary intake of folic acid on population rates of NTDs. Epidemiologic studies suggest that dietary intake varies by race or ethnicity. In addition, intake of dietary folic acid may be decreasing because of the recent popularity of low-carbohydrate diets, which eschew food products that are commonly fortified with folic acid.
Limitations of This Review
We looked specifically for studies on NTDs and therefore did not include a comprehensive picture of how folic acid–containing supplements may prevent other congenital abnormalities. We did not review the evidence on counseling to increase dietary intake of folic acid. We reviewed the overall effect of folic acid on NTDs and did not comprehensively review the evidence on how the effect may differ among ethnic groups or among groups with genetic differences that may affect the metabolism of folic acid.
Appendix: PubMed Search Terms and Exclusion Criteria
PubMed Search Terms and Limits
(“neural tube defects”[MeSH Terms] OR “spina bifida”[All Fields] OR “neural tube damage”[All Fields] OR “neural tube defect”[All Fields] OR “neural tube defects”[All Fields] OR “neural tube disorders”[All Fields] AND ((“1995/01/01”[PDAT]: “2007/11/30”[PDAT]) AND English[lang])) AND ((“folic acid”[MeSH Terms] OR folic acid[Text Word]) AND ((“1995/01/01”[PDAT]: “2007/11/30”[PDAT]) AND English[lang])) AND ((“pregnancy”[MeSH Terms] OR pregnancy[Text Word]) AND ((“1995/01/01”[PDAT]: “2007/11/30”[PDAT]) AND English[lang])) AND.
Exclusion Criteria for Folic Acid in Pregnancy Review
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Study not on folic acid supplementation.
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Incorrect study type.
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Setting not generalizable to U.S. population.
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Not in women of childbearing age.
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No outcomes of interest.
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High-risk or special population, such as women who had a previous NTD-affected pregnancy.
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Fewer than 100 participants.
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Duplicate study.
Article and Author Information
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Acknowledgment: The authors thank Gloria Washington, Coordinator of the USPSTF program; Caryn McManus, Agency for Healthcare Research and Quality librarian; Mary Barton, Scientific Director of the USPSTF program; and Task Force members Lucy Marion, Kimberly Gregory, and Tom DeWitt.
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Potential Financial Conflicts of Interest: None disclosed.
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Requests for Single Reprints: Reprints are available from the Agency for Healthcare Research and Quality Web site (http://www.preventiveservices.ahrq.gov).
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Current Author Addresses: Drs. Wolff and Miller: Agency for Healthcare Research and Quality, 540 Gaither Road, Rockville, MD 20850.
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Dr. Takacs Witkop: Preventive Medicine/OB/Gyn, 10 AMDS, 2355 Faculty Drive, Room 2N286, U.S. Air Force Academy, CO 80840.
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Dr. Syed: Johns Hopkins Bloomberg School of Public Health, Preventive Medicine Residency Program, 615 North Wolfe Street, Room WB602, Baltimore, MD 21205-1996.
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