Draft Recommendation Statement
Folic Acid for the Prevention of Neural Tube Defects: Preventive Medication
This opportunity for public comment expired on June 6, 2016 at 8:00 PM EST
Note: This is a Draft Recommendation Statement. This draft is distributed solely for the purpose of receiving public input. It has not been disseminated otherwise by the USPSTF. The final Recommendation Statement will be developed after careful consideration of the feedback received and will include both the Research Plan and Evidence Review as a basis.
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.
Neural tube defects are major birth defects of the brain and spine that occur early in pregnancy as a result of improper closure of the embryonic neural tube, which may lead to a range of disability or death. The two most common neural tube defects are anencephaly and spina bifida.1 Based on 2009–2011 data, the estimated average annual prevalence of anencephaly and spina bifida was 6.5 cases per 10,000 live births.1, 2 Folic acid supplementation in the periconceptional period is a primary prevention intervention that can be implemented in primary care settings to prevent neural tube defects.
Recognition of Risk Status
A personal or family history of a pregnancy affected by a neural tube defect is associated with an increased risk of having an affected pregnancy. However, most cases occur in the absence of any personal or family history.
Benefits of Preventive Medication
The USPSTF found convincing evidence that folic acid supplementation in the periconceptional period provides substantial benefits in reducing the risk of neural tube defects in the developing fetus. The USPSTF found inadequate evidence that the benefits of folic acid supplementation vary by dosage, timing relative to pregnancy, duration of therapy, or race/ethnicity.
Harms of Preventive Medication
The USPSTF found adequate evidence that the harms to the mother or infant from folic acid supplementation taken at the usual doses are no greater than small.
The USPSTF concludes with high certainty that the net benefit of daily folic acid supplementation to prevent neural tube defects in the developing fetus is substantial for women who are planning or capable of pregnancy.
Draft: Clinical Considerations
Patient Population Under Consideration
This recommendation applies to women who are planning or capable of pregnancy. It does not apply to women who have had a previous pregnancy affected by neural tube defects.
Assessment of Risk
Although all women of childbearing age are at risk of having a pregnancy affected by neural tube defects and should take folic acid supplementation, some factors substantially increase their risk, including a personal or family history (first- or second-degree relative) of neural tube defects. Women with a personal history of an affected pregnancy require special management and are not within the scope of this recommendation statement. Other reported risk factors include the use of certain antiseizure medications (e.g., valproic acid or carbamazepine), mutations in folate-related enzymes, maternal diabetes, and obesity.1
Evidence suggests that some racial/ethnic groups seem to be at an increased risk of neural tube defects. Birth prevalence rates are highest among Hispanics, followed by non-Hispanic whites and non-Hispanic blacks.1 Dietary folic acid intake varies by ethnicity. Mexican American women may be at increased risk because of decreased consumption of fortified foods and greater intake of corn masa–based diets. Fewer Hispanic women (17%) report consuming 400 µg or greater of folic acid daily through fortified food or supplements compared to 30% of non-Hispanic white women (30%).1, 2 Hispanic women may also be at increased risk of neural tube defects because they are more likely to have a genetic polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene, which has been associated with decreased intracellular folate metabolism.1, 2
One half of all pregnancies in the United States are unplanned.3 Therefore, clinicians should advise all women who are capable of pregnancy to take daily folic acid supplements. The critical period for supplementation starts 1 month before conception and continues through the first 2 to 3 months of pregnancy.1, 4, 5
Randomized trials conducted in settings without food fortification suggest that supplementation with a multivitamin containing 0.8 mg (800 µg) of folic acid reduces the risk of neural tube defects. Observational studies done before the implementation of food fortification laws report a reduction in neural tube defects in women taking a supplement containing 0.4 mg (400 µg) of folic acid.4, 5
Draft: Other Considerations
Research Needs and Gaps
Study results on the effectiveness of folic acid supplementation in reducing neural tube defects among Hispanic women compared to white or black women are inconsistent. Future research should continue to evaluate differences in subpopulations.1
Burden of Disease
During early fetal development, a neural tube forms that later becomes the spinal cord, brain, and neighboring protective structures (e.g., spinal column), with complete closure by the fourth week of pregnancy. Incomplete neural tube closure results in defects such as anencephaly and spina bifida. These defects vary in level of disability and may lead to death. Neural tube defects are the second most common major congenital anomaly in the United States.1 Based on 2009–2011 data from the Centers for Disease Control and Prevention (CDC), the estimated average annual prevalence of anencephaly and spina bifida was 6.5 cases per 10.000 live births.1, 2 About 1,300 annual births that would have otherwise been affected by neural tube defects are prevented by folic acid supplementation, according to recent estimates.2
Since widespread recommendations on folic acid supplementation and the 1998 implementation of food fortification laws by the U.S. Food and Drug Administration, prevalence rates of infants born with neural tube defects have decreased.1, 2 The prevalence of neural tube defects declined from 10.7 cases per 10,000 live births before the implementation of food fortification (1995 to 1996) to 7.0 cases per 10,000 live births after fortification (1999 to 2011).2 Although supplementation recommendations and food fortification have reduced the prevalence of neural tube defects, it is still difficult for most women to consume the daily requirement of 0.4 mg of folic acid from food alone. 2007–2012 National Health and Nutrition Examination Survey data reported that 48% of respondents of childbearing age consumed folic acid from mandatorily fortified foods only, and that only 29% took a folic acid supplement (72% were not taking folic acid daily).6 Of those women who took a folic acid supplement, about one half (14.6% of all women) took supplements containing less than the daily recommended dose of 400 µg.1, 6
Scope of Review
In 2009, the USPSTF reviewed the effectiveness of folic acid supplementation in women of childbearing age for the prevention of neural tube defects in their infants.4 The current review assessed new evidence on the benefits and harms of folic acid supplementation. The USPSTF did not review the evidence on folic acid supplementation among women who have a history of pregnancy affected by neural tube defects. Evidence on folate fortification, counseling to increase dietary intake of folate, or screening for neural tube defects is also outside the scope of this review.
Effectiveness of Preventive Medication
In 2009, the USPSTF reviewed the evidence on folic acid supplementation in women of childbearing age and found that the benefits were well-established and outweighed the harms.
In the current review, the USPSTF evaluated one randomized, controlled trial (RCT); two cohort studies; and eight case-control studies for evidence of effectiveness of folic acid supplementation. Results were not pooled due to study heterogeneity and the differences in food fortification over time.
A fair-quality RCT conducted in Hungary (1984–1992) assessed women (n=5,453) without a personal history of an affected pregnancy. Participants were randomized to receive either a daily vitamin supplement containing 0.8 mg of folic acid (experimental group) or a daily trace-element supplement (control group) in the periconceptional period. The trial reported no cases of neural tube defects in the experimental group and 6 cases in the control group (Fisher’s exact p=0.014).7 These results indicate a statistically significant lower odds of neural tube defects with folic acid supplementation (Peto’s odds ratio [OR], 0.131 [95% CI, 0.0263 to 0.648]; p=0.013).1
Evidence from older, fair-quality observational studies provide additional support that folic acid supplementation is beneficial. A fair-quality prospective cohort study (n=6,112) conducted in Hungary compared women who were provided a vitamin supplement containing 0.8 mg of folic acid before conception to unsupplemented women at the first prenatal visit (between 8 and 12 weeks of pregnancy) and showed a statistically significant effect on the odds of neural tube defects (OR, 0.11 [95% CI, 0.011 to 0.91]).8
A fair-quality retrospective cohort study conducted in the United States in women undergoing alpha-fetoprotein testing or amniocentesis between 15 and 20 weeks of pregnancy showed a statistically significant effect on the odds of neural tube defects among 10,713 women who took multivitamins containing folic acid in weeks 1 through 6 compared to 3,157 women who did not take any supplements (OR, 0.27 [95% CI, 0.12 to 0.59]).1, 9
The eight remaining studies were fair-quality case-control studies of births occurring over three decades, from 1976 through 2008. Studies compared neural tube defect cases to either nonmalformed infants or infants with malformations not caused by neural tube defects. Data were drawn from multistate (National Birth Defects Prevention Study, Slone Epidemiology Center Birth Defects Study), two-state (National Institute of Child Health and Human Development Neural Tube Defects Study), and single-state (Texas Neural Tube Defect Project, California Birth Defects Monitoring Program) studies.1 Older case-control studies conducted before implementation of food fortification laws were generally consistent with the evidence from the RCT and two cohort studies in showing that folic acid supplementation is beneficial for the prevention of neural tube defects (ORs ranged from 0.6 to 0.7). Newer case-control studies conducted after food fortification did not show a protective effect of folic acid supplementation on neural tube defects (ORs ranged from 0.934 to 1.4, with 95% CIs spanning the null).1
Ethical considerations limited the use of RCTs after food fortification. The newer studies are more subject to design issues than the older ones, which had fewer design flaws.1 Case-control studies have the potential for selection and recall bias, both of which can reduce the observed effect of folic acid supplementation on neural tube defects. A further issue with all study designs is the relative rarity of the outcome and the challenge of adequately powering studies to determine benefits. Another potential explanation for the findings from the evidence is that the majority of cases of neural tube defects due to folate deficiency have now been prevented and subsequent cases result from a different etiology. Despite this possible rationale, evidence indicates that most women are not consuming fortified foods at the level needed for optimal benefit. Inadequate folate intake continues to leave nearly one quarter of the U.S. population with suboptimal red blood cell folate concentrations.1, 6
Three fair-quality case-control studies examined the effects of folic acid supplementation by race/ethnicity.1, 10-12 One study found that folic acid supplementation may be less protective among Hispanic women compared to white or black women. A second study showed a higher risk of neural tube defects with supplementation among Hispanic women (adjusted OR for consistent users vs. nonusers, 2.20 [95% CI, 0.98 to 4.92]). A third study found no effect. These inconsistent results among Hispanic women could be a result of chance due to small sample size.
Eight fair-quality case-control studies addressed dose, timing, or duration of therapy. Of these eight studies, four provided information on dose, five provided information on timing, and none provided information on duration. Across the studies, evidence was inconsistent that the benefits of folic acid supplementation differ by dosage or timing.
Potential Harms of Preventive Medication
There is adequate evidence that folic acid supplementation does not have serious harms. One fair-quality trial and one fair-quality cohort study did not find evidence of a statistically significant increased risk with supplementation of twinning in women.1
In the Hungarian trial (n=5,453), the rate of twin pregnancies was not statistically significantly different between the multivitamin and trace element groups (relative risk, 1.4 [95% CI, 0.97 to 2.25]).13 In a retrospective, population-based cohort study in Norway (n=176,042), no association was found between folic acid supplementation and twinning (OR, 1.02 [95% CI, 0.85 to 1.24]) after adjusting for use of in vitro fertilization, maternal age, and parity.14
The Hungarian trial examined adverse events in women and found a potential increased risk of maternal weight gain, diarrhea, and constipation at 12 weeks of pregnancy. However, there was a low event rate, and these symptoms could have occurred by chance. These symptoms are also associated with pregnancy.1, 7
Two systematic reviews of observational studies evaluated childhood asthma, wheezing, or allergies and found inconsistent evidence of harms.1, 15, 16 Evidence was also inconsistent on the harms of folic acid supplementation differing by dosage and timing. No evidence was found on harms differing by duration of therapy.1
Estimate of Magnitude of Net Benefit
The USPSTF found no new substantial evidence on the benefits and harms of folic acid supplementation that would lead it to change its recommendation from 2009.5 The USPSTF assessed the balance of the benefits and harms of folic acid supplementation in women of childbearing age and determined that the net benefit is substantial. Evidence is adequate that the harms to the mother or infant from folic acid supplementation taken at the usual doses are no greater than small. Therefore, the USPSTF reaffirms its 2009 recommendation that all women planning or capable of pregnancy take a daily supplement containing 0.4 to 0.8 mg (400 to 800 µg) of folic acid.
How Does Evidence Fit With Biological Understanding?
Genetic predisposition and environmental influences are thought to contribute to neural tube defects. An important environmental influence is the consumption of folic acid. Low concentrations of folate may limit the number of methyl groups available for DNA replication and methylation. Evidence suggests that women with a pregnancy complicated by a neural tube defect are more likely to carry a gene mutation that encodes the MTHFR gene. Methylenetetrahydrofolate reductase is an enzyme that regulates folate and homocysteine levels. Persons who have this gene mutation have lower folate levels, which reduces the conversion of homocysteine to methionine and may increase the risk of neural tube defects.1
Draft: Update of Previous USPSTF Recommendation
This recommendation reaffirms the 2009 recommendation statement on folic acid supplementation in women of childbearing age.5 The current statement recommends that all women planning or capable of pregnancy take a daily supplement containing 0.4 to 0.8 mg (400 to 800 µg) of folic acid.
Draft: Recommendations of Others
The Health and Medicine Division of the National Academies (formerly the Institute of Medicine), American College of Obstetricians and Gynecologists, American Academy of Family Physicians, U.S. Public Health Service, CDC, American Academy of Pediatrics, American Academy of Neurology, and American College of Medical Genetics and Genomics recommend that women capable of becoming pregnant should take at least 400 µg of folic acid daily.17-25 The American College of Obstetricians and Gynecologists, CDC, and several other organizations recommend 4 mg of folic acid daily for women with a history of neural tube defects.18, 24, 25
1. Viswanathan M, Treiman KA, Kish Doto J, Middleton JS, Coker-Schwimmer EJ, Nicholson WS. Folic Acid Supplementation: An Evidence Review for the U.S. Preventive Services Task Force. Evidence Synthesis No. 145. AHRQ Publication No. 14-05214-EF-1. Rockville, MD: Agency for Healthcare Research and Quality; 2016.
2. Williams J, Mai CT, Mulinare J, Isenburg J, Flood TJ, Ethen M, et al; Centers for Disease Control and Prevention. Updated estimates of neural tube defects prevented by mandatory folic acid fortification: United States, 1995-2011. MMWR Morb Mortal Wkly Rep. 2015;64(1):1-5.
3. Finer LB, Zolna MR. Unintended pregnancy in the United States: incidence and disparities, 2006. Contraception. 2011;84(5):478-85.
4. Wolff T, Witkop CT, Miller T, Syed SB. Folic Acid Supplementation for the Prevention of Neural Tube Defects: An Update of the Evidence for the U.S. Preventive Services Task Force. Evidence Synthesis No. 70. AHRQ Publication No. 09-051132-EF-1. Rockville, MD: Agency for Healthcare Research and Quality; 2009. http://www.ncbi.nlm.nih.gov/books/NBK43412/
5. U.S. Preventive Services Task Force. Folic acid for the prevention of neural tube defects: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2009;150(9):626-31.
6. Tinker SC, Hamner HC, Qi YP, Crider KS. U.S. women of childbearing age who are at possible increased risk of a neural tube defect-affected pregnancy due to suboptimal red blood cell folate concentrations, National Health and Nutrition Examination Survey 2007 to 2012. Birth Defects Res A Clin Mol Teratol. 2015;103(6):517-26.
7. Czeizel AE, Dudás I. Prevention of the first occurrence of neural-tube defects by periconceptional vitamin supplementation. N Engl J Med. 1992;327(26):1832-5.
8. Czeizel AE, Dobó M, Vargha P. Hungarian cohort-controlled trial of periconceptional multivitamin supplementation shows a reduction in certain congenital abnormalities. Birth Defects Res A Clin Mol Teratol. 2004;70(11):853-61.
9. Milunsky A, Jick H, Jick SS, Bruell CL, MacLaughlin DS, Rothman KJ, et al. Multivitamin/folic acid supplementation in early pregnancy reduces the prevalence of neural tube defects. JAMA. 1989;262(20):2847-52.
10. Ahrens K, Yazdy MM, Mitchell AA, Werler MM. Folic acid intake and spina bifida in the era of dietary folic acid fortification. Epidemiology. 2011;22(5):731-7.
11. Shaw GM, Schaffer D, Velie EM, Morland K, Harris JA. Periconceptional vitamin use, dietary folate, and the occurrence of neural tube defects. Epidemiology. 1995;6(3):219-26.
12. Mosley BS, Cleves MA, Siega-Riz AM, Shaw GM, Canfield MA, Waller DK, et al; National Birth Defects Prevention Study. Neural tube defects and maternal folate intake among pregnancies conceived after folic acid fortification in the United States. Am J Epidemiol. 2009;169(1):9-17.
13. Czeizel AE, Métneki J, Dudás I. The higher rate of multiple births after periconceptional multivitamin supplementation: an analysis of causes. Acta Genet Med Gemellol (Roma). 1994;43(3-4):175-84.
14. Vollset SE, Gjessing HK, Tandberg A, Rønning T, Irgens LM, Baste V, et al. Folate supplementation and twin pregnancies. Epidemiology. 2005;16(2):201-5.
15. Crider KS, Cordero AM, Qi YP, Mulinare J, Dowling NF, Berry RJ. Prenatal folic acid and risk of asthma in children: a systematic review and meta-analysis. Am J Clin Nutr. 2013;98(5):1272-81.
16. Yang L, Jiang L, Bi M, Jia X, Wang Y, He C, et al. High dose of maternal folic acid supplementation is associated to infant asthma. Food Chem Toxicol. 2015;75:88-93.
17. Institute of Medicine. Dietary reference intakes: folate, other B vitamins, and choline. In: Dietary Reference Intakes for Thiamin, Riboflavin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. Washington, DC: National Academy Press; 1998.
18. Cheschier N; ACOG Committee on Practice Bulletins-Obstetrics. ACOG practice bulletin no. 44. Neural tube defects. Int J Gynaecol Obstet. 2003;83(1):123-33.
19. American Academy of Family Physicians. Clinical Preventive Service Recommendation: Neural Tube Defects. 2009. http://www.aafp.org/patient-care/clinical-recommendations/all/neural-tube-defects.html
20. Centers for Disease Control and Prevention. Recommendations for the use of folic acid to reduce the number of cases of spina bifida and other neural tube defects. MMWR Recomm Rep. 1992;41(RR-14):1-7.
21. American Academy of Pediatrics, Committee on Genetics. Folic acid for the prevention of neural tube defects. Pediatrics. 1999;104(2 Pt 1):325-7.
22. Harden CL, Pennell PB, Koppel BS, Hovinga CA, Gidal B, Meador KJ, et al; American Academy of Neurology; American Epilepsy Society. Practice parameter update: management issues for women with epilepsy—focus on pregnancy (an evidence-based review): vitamin K, folic acid, blood levels, and breastfeeding. Report of the Quality Standards Subcommittee and Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and American Epilepsy Society. Neurology. 2009;73(2):142-9.
23. Toriello HV; Policy and Practice Guideline Committee of the American College of Medical Genetics. Policy statement on folic acid and neural tube defects. Genet Med. 2011;13(6):593-6.
24. American College of Obstetricians and Gynecologists. ACOG Committee Opinion no. 313: the importance of preconception care in the continuum of women's health care. Obstet Gynecol. 2005;106(3):665-6.
25. Centers for Disease Control (CDC). Use of folic acid for prevention of spina bifida and other neural tube defects—1983–1991. MMWR Morb Mortal Wkly Rep. 1991;40(30):513-6.
Internet Citation: Draft Recommendation Statement: Folic Acid for the Prevention of Neural Tube Defects: Preventive Medication. U.S. Preventive Services Task Force. May 2016.