Evidence Summary
Folic Acid Supplementation to Prevent Neural Tube Defects: Preventive Medication
August 01, 2023
Recommendations made by the USPSTF are independent of the U.S. government. They should not be construed as an official position of the Agency for Healthcare Research and Quality or the U.S. Department of Health and Human Services.
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By Meera Viswanathan, PhD; Rachel Peragallo Urrutia, MD, MS; Kesha N. Hudson, PhD; Jennifer Cook Middleton, PhD; Leila C. Kahwati, MD, MPH
The information in this article is intended to help clinicians, employers, policymakers, and others make informed decisions about the provision of health care services. This article is intended as a reference and not as a substitute for clinical judgment.
This article may be used, in whole or in part, as the basis for the development of clinical practice guidelines and other quality enhancement tools, or as a basis for reimbursement and coverage policies. AHRQ or U.S. Department of Health and Human Services endorsement of such derivative products may not be stated or implied.
This article was published online in JAMA on August 1, 2023 (JAMA. 2023;330(5):460-466. doi:10.1001/jama.2023.9864).
Importance: Neural tube defects are among the most common birth defects in the US.
Objective: To review new evidence on the benefits and harms of folic acid supplementation for the prevention of neural tube defects to inform the US Preventive Services Task Force.
Evidence Review: Sources included PubMed, Cochrane Library, Embase, and trial registries from July 1, 2015, through July 2, 2021; references; and experts, with surveillance through February 10, 2023. Two investigators independently reviewed English-language randomized studies and nonrandomized cohort studies in very highly developed countries that focused on the use of folic acid supplementation for the prevention of neural tube defect–affected pregnancies; methodological quality was dually and independently assessed.
Findings: Twelve observational studies (reported in 13 publications) were eligible for this limited update (N = 1,244,072). Of these, 3 studies (n = 990,372) reported on the effect of folic acid supplementation on neural tube defects. For harms, 9 studies were eligible: 1 randomized clinical trial (n = 431) reported on variations in twin delivery, 7 observational studies (n = 761,125) reported on the incidence of autism spectrum disorder, and 1 observational study (n = 429,004) reported on maternal cancer. Two cohort studies and 1 case-control study newly identified in this update reported on the association between folic acid supplementation and neural tube defects (n = 990,372). One cohort study reported a statistically significant reduced risk of neural tube defects associated with folic acid supplementation taken before pregnancy (adjusted relative risk [aRR], 0.54 [95% CI, 0.31-0.91]), during pregnancy (aRR, 0.62 [95% CI, 0.39-0.97]), and before and during pregnancy (aRR, 0.49 [95% CI, 0.29-0.83]), but this association occurred for only the later of 2 periods studied (2006-2013 and not 1999-2005). No other statistically significant benefits were reported overall. No study reported statistically significant harms (multiple gestation, autism, and maternal cancer) associated with pregnancy-related folic acid exposure.
Conclusions and Relevance: New evidence from observational studies provided additional evidence of the benefit of folic acid supplementation for preventing neural tube defects and no evidence of harms related to multiple gestation, autism, or maternal cancer. The new evidence was consistent with previously reviewed evidence on benefits and harms.
Neural tube defects are major congenital malformations often caused by low folate concentrations in the body at the time of conception. These defects frequently result in significant disability or death for affected fetuses and children. Strategies that enhance folic acid uptake before pregnancy offer the best chance of prevention.
In 2017, the US Preventive Services Task Force (USPSTF) concluded that folic acid supplementation in the periconceptional period has substantial benefits in reducing the risk of neural tube defects in the developing fetus1 and reaffirmed its 2009 recommendation that all persons who are planning or capable of pregnancy take a daily supplement containing 0.4 to 0.8 mg (400-800 μg) of folic acid (A recommendation). The 2017 USPSTF recommendation was based on previously reviewed evidence from a randomized clinical trial and observational studies reporting reduced neural tube defects with supplementation and no consistent evidence of harms such as multiple gestation, maternal adverse effects, or child respiratory illness.
This limited evidence update aimed to identify studies published since the previous (2017) evidence review2 conducted for the USPSTF to inform a reaffirmation of the current recommendation.
An analytic framework and 2 key questions guided the limited evidence update (Figure). A literature search of PubMed/MEDLINE, the Cochrane Library, Embase, and trial registries was conducted from July 1, 2015, through July 2, 2021. Additional sources included reference lists of retrieved articles, outside experts, and public commenters, with ongoing surveillance of the literature through February 10, 2023. Two investigators independently evaluated the eligibility of all abstracts and articles and rated study quality using predefined criteria.4 Detailed methods and results are available in the full evidence report.4
English-language randomized and nonrandomized studies that focused on the use of folic acid supplementation (by itself or in multivitamins) for the prevention of neural tube defect–affected pregnancies in persons capable of getting pregnant were eligible. Studies conducted in very highly developed countries and that investigated potential harms of folic acid supplementation, such as maternal cancer and autism spectrum disorder, were also eligible. Ineligible studies included poor-quality studies and those focusing solely on persons taking antiseizure medications or with a history of neural tube defects in previous pregnancies.
Twelve observational studies (reported in 13 publications5-17) (Table) were eligible for this limited update (N = 1,244,072 [from nonoverlapping cohorts]). Of these, 3 studies (n = 990,372) assessed the effect of folic acid supplementation on neural tube defects.5-8 No studies examined differences by race or ethnicity.
For harms, 9 studies were eligible; 1 randomized clinical trial (n = 431) assessed variations in twin delivery,9 7 observational studies (n = 761,125) examined the incidence of autism spectrum disorders,10-16 and 1 observational study (n = 429,004) reported on maternal cancer.17 The Table also reports details on studies from the 2017 evidence review.18-47
Benefits of Folic Acid Supplementation
Regarding the benefits of folic acid supplementation, 2 cohort studies and 1 case-control study in this update examined the association between folic acid supplementation and neural tube defects (n = 990,372).5-8 Food fortification and supplementation practices varied by setting. Of these studies, 1 cohort study set in Norway (no mandatory fortification) reported on neural tube defects among live births and stillborn infants from 1999 to 2013 overall and also stratified results into 2 separate periods: 1999 to 2005 and 2006 to 2013.6 The authors performed this stratified analysis because they found that the overall adjusted relative risk (aRR) was affected by year of birth. Several external events of importance were cited to explain differences by period: the introduction of folic acid recommendations in 1999, inclusion of 0.2 mg of folic acid in multivitamin supplements from 2004 onward (before 2004, most multivitamins did not include folic acid), and increased adherence to folic acid recommendations in the second half of the period analyzed (2006-2013).6
The authors reported no statistically significant benefits in the first of the 2 periods (1999-2005), regardless of timing of supplementation (before pregnancy, during pregnancy, or before and during pregnancy). In contrast, in the second period (2006-2013), the authors reported a statistically significant reduced risk of neural tube defects associated with folic acid supplementation taken before pregnancy (aRR, 0.54 [95% CI, 0.31-0.91]), during pregnancy (aRR, 0.62 [95% CI, 0.39-0.97]), and before and during pregnancy (aRR, 0.49 [95% CI, 0.29-0.83]).6
The second cohort study, set in Japan (no mandatory food fortification), reported no statistically significant differences associated with adequate (preconception) folic acid supplementation (adjusted odds ratio [aOR], 0.62 [95% CI, 0.23-1.71]) when compared with inadequate use (use after pregnancy recognition or no use).5 The third study, a case-control study set in the US and Canada in the period following food fortification, reported on participants with pregestational diabetes and prepregnancy obesity.8 The study reported that cases occurred more often among persons with unplanned pregnancies.8 Authors reported a statistically significant reduction in neural tube defects in women with prepregnancy obesity taking 0.4 mg to 1 mg of folic acid, when compared with women taking no supplementation and adjusting for maternal age (aOR, 0.54 [95% CI, 0.29-0.95]).8 Results adjusting for planned pregnancy rather than maternal age were similar but not statistically significant (aOR, 0.57 [95% CI, 0.30-1.02]).8 Across all 3 studies, no other statistically significant benefits were reported overall or by dose (1 study8) or timing (1 study6,7).
Harms of Folic Acid Supplementation
No study of harms (multiple gestation, autism, and maternal cancer) reported significant associations with pregnancy-related folic acid exposure.9-17
This evidence review identified 3 new observational studies reporting on the association between folic acid supplementation before or during pregnancy and neural tube defects in offspring. Mandatory food fortification and supplementation practices varied by geography and period of investigation and contributed to heterogeneity across studies. Nevertheless, these new studies provided additional evidence of the benefit of folic acid supplementation for preventing neural tube defects. Nine new observational studies found no evidence of harms related to multiple gestation, autism, or maternal cancer. This new evidence is consistent with previously reviewed evidence on the benefits and harms of folic acid supplementation to prevent neural tube defects.
Source: This article was published online in JAMA on August 1, 2023 (JAMA. 2023;330(5):460-466. doi:10.1001/jama.2023.9864).
Conflict of Interest Disclosures: None reported.
Funding/Support: This research was funded under contract 75Q80120D00007, Task Order 01, from the Agency for Healthcare Research and Quality (AHRQ), US Department of Health and Human Services, under a contract to support the USPSTF.
Role of the Funder/Sponsor: Investigators worked with USPSTF members and AHRQ staff to develop the scope, analytic framework, and key questions for this review. AHRQ had no role in study selection, quality assessment, or synthesis. AHRQ staff provided project oversight, reviewed the report to ensure the analysis met methodological standards, and distributed the draft for peer review. Otherwise, AHRQ had no role in the conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript findings. The opinions expressed in this document are those of the authors and do not represent the official position of AHRQ or the US Department of Health and Human Services.
Additional Contributions: We thank the following individuals for their contributions to this project: Justin Mills, MD, MPH (AHRQ medical officer); Tina Fan, MD, MPH (previous associate scientific director, AHRQ); and Tracy Wolff, MD, MPH (scientific director, AHRQ USPSTF program); current and former members of the USPSTF; peer and federal partner reviewers; RTI International– University of North Carolina Evidence-based Practice Center staff: Christiane Voisin, MSLS (research librarian); Roberta Wines, MPH, and Carol Woodell, BSPH (current and former Evidence-based Practice Center program managers); Nila Sathe, MA, MLIS (quality assurance); Sharon Barrell, MA (editor); and Teyonna Downing and Alex Cone (publications specialists). USPSTF members, peer reviewers, and federal partner reviewers did not receive financial compensation for their contributions.
Additional Information: A draft version of the full evidence report underwent external peer review from 3 content experts (Nancy Rose, MD, University of Utah; Jorge Chavarro, MD, ScD, Harvard University; Kimberly Gregory, MD, MPH, Cedars-Sinai Medical Center) and 3 individuals from 2 federal partners (Centers for Disease Control and Prevention, National Institutes of Health). Comments from reviewers were presented to the USPSTF during its deliberation of the evidence and were considered in preparing the final evidence review.
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3. U.S. Preventive Services Task Force Procedure Manual. US Preventive Services Task Force. Published May 2021. Accessed July 11, 2023. https://uspreventiveservicestaskforce.org/uspstf/about-uspstf/methods-and-processes/procedure-manual
4. Viswanathan M, Urrutia RP, Hudson KN, Middleton JC, Kahwati LC. Folic Acid Supplementation to Prevent Neural Tube Defects: A Limited Systematic Review Update for the US Preventive Services Task Force. Evidence Synthesis No. 230. Agency for Healthcare Research and Quality; 2023. AHRQ publication 22-05302-EF-1.
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33. Granell R, Heron J, Lewis S, Davey Smith G, Sterne JA, Henderson J. The association between mother and child MTHFR C677T polymorphisms, dietary folate intake and childhood atopy in a population-based, longitudinal birth cohort. Clin Exp Allergy. 2008;38(2):320-328. doi:10.1111/j.1365-2222.2007.02902.x
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37. Martinussen MP, Risnes KR, Jacobsen GW, Bracken MB. Folic acid supplementation in early pregnancy and asthma in children aged 6 years. Am J Obstet Gynecol. 2012;206(1):72.e71-77. doi:10.1016/j.ajog.2011.07.03
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Evidence reviews for the US Preventive Services Task Force (USPSTF) use an analytic framework to visually display the key questions that the review will address to allow the USPSTF to evaluate the effectiveness and safety of a preventive service. The questions are depicted by linkages that relate to interventions and outcomes. Further details are available from the USPSTF procedure manual.3 NTD indicates neural tube defect.
| Key question | Evidence summary in 20172 | Summary of new evidence | Limitations of new evidence | Consistency of new evidence with prior evidence findings |
|---|---|---|---|---|
| KQ1: Benefits of folic acid supplementation | ||||
| 1a: Effects of folic acid supplements on risk of NTDs | 12 Studies (1 RCT, 2 cohort, 8 case-control, 1 previous review); n >41,802
Generally consistent evidence within the prefortification (indicating benefit) and postfortification (no statistically significant differences) eras; inconsistent over time 1 RCT (prefortification): Peto OR for NTD, 0.131 (95% CI, 0.026-0.648); P = .0129,42-47 2 Cohort studies (prefortification): aOR for NTD, 0.11 (95% CI, 0.01-0.91)18 OR, 0.27 (95% CI, 0.11-0.63)19,20 4 Case-control studies (prefortification): aOR for NTD, 0.7 (95% CI, 0.5-0.8)21 RR for NTD, 0.6 (95% CI, 0.4-0.8)22 OR for NTD, 0.65 (95% CI, 0.45-0.94)23 OR for NTD, 1.00 (95% CI, 0.73-1.40); P = .9724 1 Case-control study (spanning prefortification and postfortification eras): aOR for NTD, 1.12 (95% CI, 0.22-5.78)25 3 Case-control studies (postfortification): OR for NTD, 1.11 (95% CI, 0.74-1.65) for consistent users26 aOR for NTD (anencephaly + spina bifida), 0.93 (95% CI, 0.82-1.06)27 aOR (anencephaly), 1.2 (95% CI, 0.8-1.9)28 aOR (spina bifida), 1.4 (95% CI, 1.0-1.8)28 No new trials can be conducted on this topic New studies must rely on observational data with inherent risks of case ascertainment bias (in prospective cohort studies) or exposure recall bias (in retrospective studies) |
3 Studies (2 cohort [3 publications]5-7, 1 case-control8); N = 990,372
Norwegian cohort (no mandatory fortification) study reported no statistically significant associations in overall analysis (1999-2013) or the first period (1999-2005) with low adherence to folic acid supplementation recommendations Statistically significant associations from 2006-2013 with higher adherence to folic acid recommendations: Before pregnancy only (aRR, 0.54 [95% CI, 0.31-0.91])6 During pregnancy only (aRR, 0.62 [95% CI, 0.39-0.97])7 Before and during pregnancy (aRR, 0.49 [95% CI, 0.29-0.83])7 No consistently and statistically significant associations in Japanese cohort of general population (no mandatory fortification) (aOR, 0.62 [95% CI, 0.23-1.71] for preconceptional use when compared with use after pregnancy recognition or no use)5 or US and Canadian case-control study (postfortification study) of participants with prepregnancy diabetes or pregestational obesity for exposures measured as less than daily, daily, <0.4 mg, 0.4 mg to <1.0 mg8 |
Heterogenous populations with different levels of food fortification and diet patterns; methodological limitations in foundational evidence also apply | New studies have some evidence of benefit for reducing NTDs and do not change conclusions from foundational evidence |
| 1b: Differences in effect of folic acid supplements on NTDs by race or ethnicity | 3 Case-control studies; n = 11,154
Inconsistent and imprecise findings from fair-quality studies suggesting no differences: No effect in first study28 Higher risk in second study (aOR for Hispanic women with consistent use compared with nonuse, 2.20 [95% CI, 0.98-4.92])26 Less protective effect in third study (OR, 0.96 [95% CI, 0.44-2.10] for Hispanic women vs 0.62 [95% CI, 0.35-1.10] for non-Hispanic White women vs 0.54 [95% CI, 0.09-3.20] for Black women)23 Small numbers in each comparison, differences in direction of estimate of effects possibly due to chance |
No new evidence | NA | NA |
| 1c: Differences in effect of folic acid supplements on NTDs by dosage, duration, and timing |
Dosage: 4 studies (1 cohort, 3 case-control); n = 26,791 No indication of dose response in 3 of 4 studies;19,20,22-24 1 study showed lower odds for daily use vs less than daily use (OR, 0.57 [95% CI, 0.35-0.93])22 Duration: 0 studies Timing: 5 studies (1 cohort, 4 case-control); n = 26,808 Calculated OR from cohort study for use weeks 1-6 vs weeks 7 and later, 0.29 (95% CI, 0.14-0.60)19,20 Older studies consistently showed no effect of timing;23,25 1 new study (postfortification) showed a protective effect of use before pregnancy vs initiation in the first month of pregnancy on anencephaly but not spina bifida;28 the other new study did not find a protective effect for spina bifida for consistent periconceptional use vs initiation in the first month of pregnancy26 Small numbers in each comparison, effects possibly due to chance, studies used different measures of dose and timing |
Dosage: 1 case-control study of women with prepregnancy obesity; n = 1429
Statistically significantly reduced association between NTD risk and exposure of 0.4 mg to <1.0 mg of folic acid supplementation daily (aOR, 0.54 [95% CI, 0.29-0.95]) but not for exposures of <0.4 mg (aOR, 1.29 [95% CI, 0.40-3.37]) or <0.4 mg or ≥1.0 mg (aOR, 0.84 [95% CI, 0.38-1.68]);8 differences did not persist in sensitivity analysis Duration: 0 studies Timing: 1 cohort study (2 publications6,7); n = 896,674 Consistent benefits regardless of timing in 1 of 3 periods examined (2006-2013) (aRR before pregnancy only, 0.54 [95% CI, 0.31-0.91];6 during pregnancy only, 0.62 [95% CI, 0.39-0.97];7 and before and during pregnancy, 0.49 [95% CI, 0.29-0.83];7 consistently no statistically significant differences for the other periods [1999-2013, 1999-2005]) |
Small numbers in each comparison, effects possibly due to chance | New studies do not change conclusions regarding dosage or timing |
| KQ2: Harms of folic acid supplementation | ||||
| 2a: Harms associated with folic acid supplements: multiple gestation (twinning) | 2 Studies (1 trial, 1 cohort); n = 7387
Trial found no statistically significant differences in twin pregnancy rate (RR, 1.4 [95% CI, 0.87-2.26])29 Cohort study found higher risk of twin birth for folate use (OR, 1.59 [95% CI, 1.41-1.78]) that was attenuated once potential misclassification was accounted for (OR, 1.04 [95% CI, 0.91-1.18])30 Low event rate, wide CIs |
No new evidence | NA | NA |
| 2a: Harms associated with folic acid supplements: childhood asthma, allergy, wheezing |
3 Systematic reviews, 8 observational studies; n >14,438 No effect for a large majority of comparisons and outcomes31-41 Variable measures of outcomes and exposure, all observation studies with risks of bias from case ascertainment and recall |
No new evidence | NA | NA |
| 2a: Harms associated with folic acid supplements: other adverse events in women | 1 RCT; n = 4862
Increased risk for weight gain, diarrhea, constipation; reduced risk for irregular defecation; no difference for increased appetite, lack of appetite, exanthema, heartburn, and vertigo42 Low event rate, wide CIs |
No new evidence | NA | NA |
| 2a: Harms associated with folic acid supplements: autism | No eligible evidence | 7 Studies (6 fair-quality cohort10-15 and 1 fair-quality case-control16); n = 761,125
Studies set in 4 countries (Israel, Sweden, Denmark, Norway); varied measures of exposure, comparators, and outcomes; generally no statistically significant associations; 3 publications on 2 populations in Israel15 and Norway,12,14 respectively, reported some benefits |
No study reported harms, but differences in statistically significant associations (benefits vs no evidence of difference may stem from differences in measurement of exposure, choice of comparator, and controls for confounding | NA |
| 2a: Harms associated with folic acid supplements: maternal cancer | No eligible evidence | 1 Cohort study;17 n = 429,004
HR for 1 pregnancy with exposure to folic acid supplementation vs no exposure in pregnancy, 1.08 (95% CI, 1.00-1.18)17 HR for ≥2 pregnancies with exposure to folic acid supplementation vs no exposure in pregnancy, 1.06 (95% CI, 0.91-1.22)17 |
Potential for unmeasured confounding and recall bias in the classification of the intervention | NA |
| 2b: Differences in harms associated with folic acid supplements by dosage, timing, and duration: twinning | No eligible evidence | 1 Trial;9 n = 431
RR, 0.45 (95% CI, 0.11-1.77) for twin deliveries with exposure to 4-mg folic acid supplementation vs exposure to 0.4-mg folic acid supplementation; both groups exposed before conception and through 12 weeks of gestation |
Applicability uncertain to unplanned pregnancies | NA |
| 2b: Differences in harms associated with folic acid supplements by dosage, timing, and duration: childhood asthma, allergy, wheezing | Dosage: 1 systematic review, 1 observational study; n = 484
No consistent increase in the risk of childhood asthma, wheezing, or allergies by timing32,41 Duration: 0 studies Timing: 2 systematic reviews, 3 observational studies; N varies by outcome No consistent increase in the risk of childhood asthma, wheezing, or allergies by timing31,33,34,40,41 Variable measures of outcomes and exposure, all observational studies with risks of bias from case ascertainment and recall |
No new evidence | NA | NA |
| 2b: Differences in harms associated with folic acid supplements by dosage, timing, and duration: autism | No eligible evidence | Dosage: 3 studies (2 cohort,11,12 1 case-control);16 n = 194,281
Overlap in CIs with exposure to folic acid supplementation in different doses vs no or very low exposure to folic acid supplementatn in pregnancy, all not statistically significant Duration: 0 studies Timing: 2 cohort studies,11,12 n = 120,235 Overlap in CIs with exposure to folic acid supplementation in different time intervals vs no exposure to folic acid supplementation in pregnancy, all but 1 estimate not statistically significant; initiation in weeks 5 to 8 associated with benefit (14/16,184 vs 32/14,721; aOR, 044 [95% CI, 0.23-0.83])12 |
Potential for unmeasured confounding and recall bias in the classification of the intervention | NA |