Folic Acid Supplementation to Prevent Neural Tube Defects: Preventive Medication

The U.S. Preventive Services Task Force (USPSTF) makes recommendations about the effectiveness of specific preventive care services for patients without obvious related signs or symptoms in order to improve the health of people nationwide. 

It bases its recommendations on the evidence of both the benefits and harms of the service and an assessment of the balance. The USPSTF does not consider the costs of providing a service in this assessment. 

The USPSTF recognizes that clinical decisions involve more considerations than evidence alone. Clinicians should understand the evidence but individualize decision making to the specific patient or situation. Similarly, the USPSTF notes that policy and coverage decisions involve considerations in addition to the evidence of clinical benefits and harms. 

The USPSTF is committed to mitigating the health inequities that prevent many people from fully benefiting from preventive services. Systemic or structural racism results in policies and practices, including healthcare delivery, that can lead to inequities in health. The USPSTF recognizes that race, ethnicity, and gender are all social rather than biological constructs. However, they are also often important predictors of health risk. The USPSTF is committed to helping reverse the negative impacts of systemic and structural racism, gender-based discrimination, bias, and other sources of health inequities, and their effects on health, throughout its work.

Neural tube defects are among the most common congenital malformations in the United States, with an estimated 3,000 pregnancies affected each year.¹ Many of these neural tube defects are caused by low folate levels in the body. The Centers for Disease Control and Prevention estimated that spina bifida occurs in 3.9 out of 10,000 live births in the United States, anencephaly in 2.5 out of 10,000 live births, and encephalocele in 1 out of 10,000 live births.² Neural tube defects can result in death and a range of disabilities affecting children. Children with encephaloceles have an increased mortality rate, with many survivors having neurologic and developmental deficits.^3-5 Common disabilities from spina bifida include lower limb weakness and paralysis, sensory loss, bowel and bladder dysfunction, orthopedic abnormalities (e.g., clubfoot, contractures, hip dislocation, scoliosis, or kyphosis), and ventriculomegaly (which may require placement of ventricular-peritoneal shunts).^6-8 Anencephaly is life-limiting in early infancy.⁹

Folate refers to the water-soluble B vitamin (B₉) that occurs in many chemical forms, including naturally in foods. Folic acid is the term applied to the synthetic form of folate that is found in supplements and added to fortified foods. Folic acid supplementation has been found to reduce the risk of neural tube defects.^10,11 Despite folic acid fortification of food and supplementation guidelines, folic acid deficiency remains a concern in the United States. Low levels of maternal folate may be due to inadequate dietary intake, poor intestinal absorption, medication use that interferes with folic acid function, and impaired folate metabolism.¹² Survey data from 1998 to 2016 found that approximately 20% to 40% of women who were recently pregnant or trying to get pregnant reported taking periconceptional folic acid supplements, and those with an unintended pregnancy were 4 to 5 times less likely to have taken periconceptional folic acid supplements.¹²

In 2017, the U.S. Preventive Services Task Force (USPSTF) reviewed the evidence for folic acid supplementation and issued an A recommendation.¹¹ The USPSTF has decided to use a reaffirmation deliberation process to update this recommendation. The USPSTF uses the reaffirmation process for well-established, evidence-based current standards of practice in primary care for which only a very high level of evidence would justify a change in the grade of the recommendation. In its deliberation of the evidence, the USPSTF considers whether the new evidence is of sufficient strength and quality to change its previous conclusions about the evidence.

Using a reaffirmation process, the USPSTF concludes that, for persons who are planning to or could become pregnant, there is high certainty that folic acid supplementation has a substantial net benefit.

See the Table for more information on the USPSTF recommendation rationale and assessment. For more details on the methods the USPSTF uses to determine net benefit, see the USPSTF Procedure Manual.¹³

Patient Population Under Consideration

This recommendation applies to persons who are planning to or could become pregnant. It does not apply to persons who have had a previous pregnancy affected by neural tube defects or who are at very high risk because of other factors (e.g., use of certain antiseizure medications or family history). It does not apply to persons taking certain medications known to block the function of folic acid (e.g., methotrexate, carbamazepine, and valproic acid).

Definitions

Neural tube defects are caused by a failure of closure of the embryonic neural tube, which results in birth defects of the brain, spinal cord, and overlying tissues. The most common forms of neural tube defects are anencephaly, encephalocele, and spina bifida.¹⁴ Anencephaly occurs when the cranial portion of the neural tube fails to close. Affected babies are born without portions of the brain and skull. Anencephaly is life-limiting in early infancy. Encephalocele occurs when cranial defects allow portions of the brain and meninges to protrude. Spina bifida is a group of conditions that vary in severity and include myelomeningocele (protrusion of the spinal cord and meninges through a spinal defect), meningocele (protrusion of meninges through a spinal defect), and spina bifida occulta (spinal defect without any protrusion).¹²

Assessment of Risk

All pregnancies are at risk for neural tube defects, and persons who are planning to or could become pregnant should take folic acid supplements. Certain risk factors convey a higher risk and individuals with these risk factors should talk to their healthcare professional. These factors include personal, partner, or family history of neural tube defects, malabsorption caused by bariatric procedures, the use of certain antiseizure medicines, and genetic mutations in folate-related enzymes.^15-19 Pregestational diabetes and obesity have been associated with an increased risk of neural tube defects.^20,21 Certain ethnic groups such as First Nation persons in Canada and Hispanic persons in California are thought to be at higher risk of neural tube defects.^22,23 It is unclear, however, whether this is related to a higher risk of genetic mutation among these groups or due to differential intake of folic acid–fortified foods.¹²

Timing

The neural plate completes its formation and closure early in pregnancy (usually 26 to 28 days post-fertilization).¹⁷ This means the critical period for folic acid supplementation starts at least 1 month before conception and continues through the first 2 to 3 months of pregnancy. Approximately half of all pregnancies in the United States are unplanned; in order to gain the full benefits of supplementation, clinicians should advise all persons who plan to or who could become pregnant to take daily folic acid.²⁴

Dosage

Good evidence from studies in settings without fortification of food suggests that an over-the-counter multivitamin with between 0.4 mg (400 μg) (the generally available dose) and 0.8 mg (800 μg) of folic acid reduces the risk for neural tube defects.^11,12 Clinical practice guidelines from professional medical and public health organizations recommend a minimum folic acid supplementation daily intake of 400 µg for all persons who are planning a pregnancy or could become pregnant.^25-28

Since 1998, specific enriched cereal grain products in the United States have been fortified with folic acid. In 2016, the U.S. Food and Drug Administration began allowing corn masa flour to be voluntarily fortified with folic acid.¹² It is unclear if persons in the United States are ingesting fortified foods at a level adequate to provide optimal benefit for prevention of neural tube defects.¹²

Additional Tools and Resources

The Community Preventive Services Task Force recommends community-wide education campaigns to promote the use of folic acid supplements among persons of childbearing age (https://www.thecommunityguide.org/findings/pregnancy-health-community-wide-campaigns-promote-use-folic-acid-supplements.html).

This recommendation is a reaffirmation of the USPSTF 2017 recommendation statement. In 2017, the USPSTF reviewed the evidence for folic acid supplementation to prevent neural tube defects and found convincing evidence that the benefits of supplementation substantially outweighed the harms (A recommendation).¹¹ In the current update, the USPSTF found no new substantial evidence that could change its recommendation and, therefore, reaffirms its recommendation that all persons planning to or who could become pregnant take a daily supplement of folic acid.

Scope of Review

To reaffirm its recommendation, the USPSTF commissioned a reaffirmation evidence update.¹² The aim of evidence updates that support the reaffirmation process is to identify new and substantial evidence sufficient to change the prior recommendation.¹³ The reaffirmation update focuses on targeted key questions on the benefits and harms of folic acid supplementation.

Benefits of Folic Acid Supplementation

In 2017, the USPSTF reviewed the evidence on the benefits of folic acid supplementation to prevent neural tube defects and found convincing evidence that the benefits of supplementation were significant. Three fair-quality observational studies (reported in four publications) published since the last USPSTF recommendation reported on the association between folic acid supplementation and neural tube defects (n=990,372).¹² Two cohort studies were in populations without food fortification (Norway and Japan) and the third was a case-control study set in the United States and Canada prior to and after the introduction of food fortification. The Norwegian cohort study (n=896,674 live births and stillborn infants) reported results by time periods (1999–2005, 2006–2013, and overall, 1999–2013).^29,30 The authors hypothesized that these periods corresponded to lesser (1999–2005) and greater adherence (2006–2013) to recommendations regarding folic acid supplementation. The study reported a statistically significant reduction in neural tube defects in women taking folic acid supplementation in the period corresponding to greater adherence (2006 to 2013) but not in other time periods. The Japanese cohort (n=92,269) compared adequate users of folic acid supplements (started before conception) with inadequate users (started after pregnancy recognition or nonuse of folic acid supplements). Neural tube defect outcomes included spina bifida, anencephaly, and encephalocele. The study reported no statistically significant differences associated with folic acid supplementation.³¹ Both cohort studies drew from general populations. The case-control study set in the United States and Canada (111 cases and 1,243 controls) in the period following food fortification focused on participants with pregestational diabetes and prepregnancy obesity. This study reported no statistically significant associations between daily or less than daily folic acid supplementation compared with no supplementation and neural tube defects.³²

The USPSTF also reviewed data on whether the benefits of folic acid supplementation differ by timing. In the previously mentioned Norwegian study, there was no effect of folic acid supplementation regardless of the timing of folic acid supplementation in the period corresponding to lesser adherence (1999–2013) and in the overall period (1999–2013). In the second period, the results demonstrated a benefit of folic acid supplementation regardless of timing (before pregnancy only: adjusted relative risk [aRR], 0.54 [95% CI, 0.31 to 0.91]; before and during pregnancy: aRR, 0.49 [95% CI, 0.29 to 0.83]; and during pregnancy only: aRR, 0.62 [95% CI, 0.39 to 0.97]).¹²

Harms of Folic Acid Supplementation

In 2017, the USPSTF reviewed the evidence on the harms of folic acid supplementation to prevent neural tube defects and found adequate evidence that folic acid supplementation at usual doses is not associated with serious harms. Six fair-quality cohort studies and one fair-quality case-control study published since the 2017 USPSTF recommendation examined the potential association between folic acid supplementation and autism spectrum disorder (ASD) (N=761,125). No study reported statistically significant associations between supplementation and increased risk of ASD. Two studies reported statistically significant reductions of autism associated with folic acid supplementation. Other studies in similar geographic settings or populations that used different measures of exposure or comparators reported no association between folic acid supplementation and autism. Three studies reported on associations between folic acid supplementation and ASD by dose and found no differences. Two studies reported on associations between folic acid supplementation and ASD by timing. Neither reported harms; however, one reported a statistically significant reduction of ASD associated with folic acid supplementation initiation in weeks 5 to 8 of the pregnancy.¹²

One high-quality trial reported on the differences in twin deliveries based on the dosage of folic acid. It found no differences between an exposure of 4 mg vs. 0.4 mg of folic acid. No studies reported on the overall risk, timing, or duration of twin gestations and folic acid supplementation.¹² One cohort study (n=429,004) found no association between folic acid supplementation and maternal cancer.¹²

How Does Evidence Fit With Biological Understanding?

Adequate maternal folate levels are important in preventing neural tube defects; however, the mechanism by which folate reduces this risk is not well understood. Folate is necessary for nucleotide synthesis and DNA and RNA function.¹² Inadequate folate levels impair nucleotide synthesis and DNA and RNA replication, and may lead to incomplete neural folds and subsequent neural tube defects.

Studies are needed that provide more information on the following.

• The understanding of how genetic polymorphisms related to slower folate metabolism relate to folic acid supplementation strategies.
• The effectiveness of folic acid supplementation in reducing neural tube defects among Hispanic persons.
• Factors that contribute to variations in supplementation.

The American College of Obstetricians and Gynecologists, American Academy of Family Physicians, and American Academy of Pediatrics all recommend folic acid supplementation of 400 µg (0.4 mg) per day for persons of reproductive age who are planning to become pregnant and are at average risk of neural tube defects (i.e., without a prior pregnancy with a neural tube defect).^25-27

1. Centers for Disease Control and Prevention. Spina bifida and anencephaly before and after folic acid mandate--United States, 1995-1996 and 1999-2000. MMWR Morb Mortal Wkly Rep. 2004;53(17):362-365.
2. Mai CT, Isenburg JL, Canfield MA, et al. National population-based estimates for major birth defects, 2010-2014. Birth Defects Res. 2019;111(18):1420-1435.
3. Markovic I, Bosnjakovic P, Milenkovic Z. Occipital encephalocele: cause, incidence, neuroimaging and surgical management. Curr Pediatr Rev. 2020;16(3):200-205.
4. Centers for Disease Control and Prevention. Encephalocele. Accessed February 3, 2023. https://www.cdc.gov/ncbddd/birthdefects/surveillancemanual/quick-reference-handbook/encephalocele.html
5. Huang SB, Doherty D. Congenital malformations of the central nervous system. In: Gleason CA, Juul SE (eds.). Avery’s Diseases of the Newborn. 10th ed. New York: Elsevier; 2018. p. 857-878.
6. Centers for Disease Control and Prevention. Spina Bifida. Accessed February 3, 2023. https://www.cdc.gov/ncbddd/birthdefects/surveillancemanual/quick-reference-handbook/spinaBifida.html
7. Mitchell LE, Adzick NS, Melchionne J, et al. Spina bifida. Lancet. 2004;364(9448):1885-1895.
8. Wiener JS, Suson KD, Castillo J, et al. Bladder management and continence outcomes in adults with spina bifida: results from the National Spina Bifida Patient Registry, 2009 to 2015. J Urol. 2018;200(1):187-194.
9. Centers for Disease Control and Prevention. Anencephaly. Accessed February 3, 2023. https://www.cdc.gov/ncbddd/birthdefects/surveillancemanual/quick-reference-handbook/anencephaly.html
10. Prevention of neural tube defects: results of the Medical Research Council Vitamin Study. MRC Vitamin Study Research Group. Lancet. 1991;338(8760):131-137.
11. US Preventive Services Task Force. Folic acid supplementation for the prevention of neural tube defects: US Preventive Services Task Force recommendation statement. JAMA. 2017;317(2):183-189.
12. Viswanathan M, Urrutia RP, Hudson KN, Cook Middleton J, Kahwati LC. Folic Acid Supplementation to Prevent Neural Tube Defects: A Limited Systematic Review Update for the U.S. Preventive Services Task Force. Evidence Synthesis No. 230. Rockville, MD: Agency For Healthcare Research and Quality; 2023. AHRQ Publication 22-05302-EF-1.
13. U.S. Preventive Services Task Force. Procedure Manual. Accessed February 3, 2023. https://uspreventiveservicestaskforce.org/uspstf/about-uspstf/methods-and-processes/procedure-manual
14. Centers for Disease Control and Prevention. Congenital Anomalies of the Nervous System: Neural Tube Defects. Accessed February 3, 2023. https://www.cdc.gov/ncbddd/birthdefects/surveillancemanual/quick-reference-handbook/neuralTubeDefects.html
15. Hernández-Díaz S, Werler MM, Walker AM, Mitchell AA. Neural tube defects in relation to use of folic acid antagonists during pregnancy. Am J Epidemiol. 2001;153(10):961-968.
16. Agopian AJ, Tinker SC, Lupo PJ, et al. Proportion of neural tube defects attributable to known risk factors. Birth Defects Res A Clin Mol Teratol. 2013;97(1):42-46.
17. Greene ND, Copp AJ. Neural tube defects. Annu Rev Neurosci. 2014;37:221-242.
18. El Khoury L, Benvenga R, Roussel J, et al. Fetal spina bifida in a pregnant woman following omega gastric bypass: case report and literature review. Int J Surg Case Rep. 2020;70:137-139.
19. Li J, Feng D, He S, Yang H, Su Z, Ye H. Association of MTHFR 677C > T gene polymorphism with neonatal defects: a meta-analysis of 81444 subjects. J Obstet Gynaecol. 2022;42(6):1811-1822.
20. Garne E, Loane M, Dolk H, et al. Spectrum of congenital anomalies in pregnancies with pregestational diabetes. Birth Defects Res A Clin Mol Teratol. 2012;94(3):134-40.
21. Racusin D, Stevens B, Campbell G, Aagaard KM. Obesity and the risk and detection of fetal malformations. Semin Perinatol. 2012;36(3):213-221.
22. Ray JG, Vermeulen MJ, Meier C, Cole DE, Wyatt PR. Maternal ethnicity and risk of neural tube defects: a population-based study. CMAJ. 2004;171(4):343-345.
23. Feuchtbaum L, Currier RJ, Riggle S, Roberson M, Lorey FW, Cunningham JC. Neural tube defect prevalence in California (1990-1994): eliciting patterns by type of defect and maternal race/ethnicity. Genet Test. 1999;3(3):265-272.
24. Finer LB, Zolna MR. Declines in unintended pregnancy in the United States, 2008-2011. N Engl J Med. 2016;374(9):843-852.
25. ACOG Committee Opinion No. 762: prepregnancy counseling. Obstet Gynecol. 2019;133(1):e78-e89.
26. American Academy of Pediatrics Committee on Genetics: folic acid for the prevention of neural tube defects. Pediatrics. 1999;104(2 Pt 1):325-327.
27. American Academy of Family Physicians. Clinical Preventive Service Recommendation: Neural Tube Defects. Accessed February 3, 2023. https://www.aafp.org/family-physician/patient-care/clinical-recommendations/all-clinical-recommendations/neural-tube-defects.html
28. From the Centers for Disease Control and Prevention. Recommendations for use of folic acid to reduce number of spina bifida cases and other neural tube defects. JAMA. 1993;269(10):1233, 1236-1238.
29. Gildestad T, Bjørge T, Haaland ØA, Klungsøyr K, Vollset SE, Øyen N. Maternal use of folic acid supplements and infant risk of neural tube defects in Norway 1999-2013. Scand J Public Health. 2016;44(6):619-626.
30. Gildestad T, Bjørge T, Haaland ØA, Klungsøyr K, Vollset SE, Øyen N. Maternal use of folic acid and multivitamin supplements and infant risk of birth defects in Norway, 1999-2013. Br J Nutr. 2020;124(3):316-329.
31. Nishigori H, Obara T, Nishigori T, et al. Preconception folic acid supplementation use and the occurrence of neural tube defects in Japan: a nationwide birth cohort study of the Japan Environment and Children’s Study. Congenit Anom (Kyoto). 2019;59(4):110-117.
32. Petersen JM, Parker SE, Benedum CM, Mitchell AA, Tinker SC, Werler MM. Periconceptional folic acid and risk for neural tube defects among higher risk pregnancies. Birth Defects Res. 2019;111(19):1501-1512.