[Skip to Content]

Claim CME

Nutrition

Folic Acid Supplementation to Prevent Neural Tube DefectsUpdated Evidence Report and Systematic Review for the US Preventive Services Task Force

To identify the key insights or developments described in this article

1 Credit CME

JAMA

Published Online: August 1, 2023

US Preventive Services Task Force

Article Information and Disclosures

Meera Viswanathan, PhD^1,2;

Rachel Peragallo Urrutia, MD, MS³;

Kesha N. Hudson, PhD^1,2;

Jennifer Cook Middleton, PhD^1,4;

Leila C. Kahwati, MD, MPH^1,2

Author Affiliations

¹RTI International–University of North Carolina at Chapel Hill Evidence-based Practice Center
²RTI International, Research Triangle Park, North Carolina
³Department of Obstetrics and Gynecology, University of North Carolina at Chapel Hill
⁴Cecil G. Sheps Center for Health Services Research, University of North Carolina at Chapel Hill

Read article on JAMA Network

Read Article Claim CME

Abstract

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.

Claim CME

Sign in to take quiz and track your certificates

Buy This Activity

Article Information

Accepted for Publication: June 19, 2023.

Corresponding Author: Meera Viswanathan, PhD, RTI International, 3040 E Cornwallis Rd, PO Box 12194, Research Triangle Park, NC 27709 (viswanathan@rti.org).

Author Contributions: Dr Viswanathan had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Viswanathan, Urrutia, Kahwati.

Acquisition, analysis, or interpretation of data: Viswanathan, Urrutia, Hudson, Middleton.

Drafting of the manuscript: Viswanathan, Urrutia, Hudson, Middleton.

Statistical analysis: Viswanathan.

Obtained funding: Viswanathan, Kahwati.

Administrative, technical, or material support: Viswanathan, Hudson, Middleton, Kahwati.

Supervision: Viswanathan.

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.

Editorial Disclaimer: This evidence report is presented as a document in support of the accompanying USPSTF recommendation statement. It did not undergo additional peer review after submission to JAMA.

AMA CME Accreditation Information

Credit Designation Statement: The American Medical Association designates this Journal-based CME activity activity for a maximum of 1.00  AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to:

1.00 Medical Knowledge MOC points in the American Board of Internal Medicine's (ABIM) Maintenance of Certification (MOC) program;;
1.00 Self-Assessment points in the American Board of Otolaryngology – Head and Neck Surgery’s (ABOHNS) Continuing Certification program;
1.00 MOC points in the American Board of Pediatrics’ (ABP) Maintenance of Certification (MOC) program;
1.00 Lifelong Learning points in the American Board of Pathology’s (ABPath) Continuing Certification program; and
1.00 credit toward the CME [and Self-Assessment requirements] of the American Board of Surgery’s Continuous Certification program

It is the CME activity provider's responsibility to submit participant completion information to ACCME for the purpose of granting MOC credit.