May 12, 2009 — New observational evidence supports previous evidence from a randomized controlled trial that folic acid–containing supplements lower the risk for pregnancies affected by neural tube defects, according to a US Preventive Services Task Force (USPSTF) statement and review of evidence reported in the May 5 issue of the Annals of Internal Medicine. The review suggests that the previously noted association of folic acid use with twin gestation may be confounded by fertility interventions.

Based on the evidence, the USPSTF has issued a grade A recommendation that all women planning or capable of pregnancy take a daily supplement containing 0.4 to 0.8 mg (400 - 800 µg) of folic acid.

Regarding benefits of this preventive measure, the USPSTF found convincing evidence that taking supplements containing 0.4 to 0.8 mg (400 - 800 µg) of folic acid during the periconceptional period lowers the risk for neural tube defects. Regarding potential harms, adequate evidence suggests that folic acid from supplementation at usual doses is not associated with serious harms.

For women who are planning or are capable of pregnancy, the USPSTF therefore concludes that there is high certainty that the net benefit of folic acid supplementation during pregnancy is substantial.

Tracy Wolff, MD, MPH, and colleagues from the USPSTF write, "Neural tube defects (NTDs) are among the most common birth defects in the United States,...In 1996, the...USPSTF recommended that all women planning a pregnancy or capable of conception take a supplement containing folic acid to reduce the risk for NTDs."

USPSTF Review Process

The goal of the review was to provide a basis for an updated USPSTF recommendation by searching for new evidence published since 1996 regarding the benefits and harms of folic acid supplementation for women of childbearing age, with the aim of preventing neural tube defects in offspring. The reviewers searched MEDLINE and Cochrane Central Register of Controlled Trials from January 1995 through December 2008, as well as recent systematic reviews and bibliographies cited in identified articles. Experts were also contacted for any pertinent suggestions.

Inclusion criteria for the studies were English-language articles describing the benefits and harms of folic acid supplementation in women of childbearing age to reduce neural tube defects in offspring. These included randomized controlled trials, cohort studies, case-control studies, systematic reviews, and meta-analyses. The investigators reviewed, abstracted, and rated the identified studies for methodologic quality using predefined USPSTF criteria.

The reviewers identified 4 observational studies that showed a benefit of reduction of the risk for neural tube defects associated with use of folic acid–containing supplements. However, a summary of the reduction in risk could not be calculated because of differences in study type and methods. There was only 1 included study on harms, which reported that the apparent association of twin pregnancies with folic acid intake disappeared after adjusting for in vitro fertilization and underreporting of folic acid intake.

Limitations of the review include studies with limited evidence on dose. Also, none of the studies that discussed B₁₂ supported or refuted the potential harm of masking vitamin B₁₂ deficiency in women of childbearing potential. The review did 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.

Furthermore, the review did not include a comprehensive picture of how folic acid–containing supplements may prevent other congenital abnormalities, consideration of the evidence on counseling to increase dietary intake of folic acid, or comparison of the effect of folic acid on neural tube defects among different ethnic groups or among groups with genetic differences that may affect folic acid metabolism.

"New observational evidence supports previous evidence from a randomized, controlled trial that folic acid–containing supplements reduce the risk for NTD-affected pregnancies," the review authors write. "The association of folic acid use with twin gestation may be confounded by fertility interventions."

Updates to 1996 Recommendation

The accompanying USPSTF statement is an update of the 1996 USPSTF recommendation that all women planning or capable of pregnancy take a multivitamin supplement containing folic acid to prevent neural tube defects. The statement is based on the evidence regarding folic acid supplementation in women of childbearing age published since the 1996 USPSTF recommendation, without review of evidence regarding food fortification with folic acid, counseling to increase dietary intake, or screening for neural tube defects.

"Approximately 1 in every 1000 pregnancies is affected by a neural tube defect," write USPSTF chair Ned Calonge, MD, MPH, from the Colorado Department of Public Health and Environment in Denver, and colleagues. "Although a personal or family history of a pregnancy affected by a neural tube defect is associated with an increased risk for having an affected pregnancy, most cases occur in the absence of any positive history."

Recommendations From Other Associations

This USPSTF recommendation is consistent with published guidelines of other specialty professional organizations. In 2003, the American College of Obstetrics and Gynecology recommended periconceptual use of a multivitamin supplement containing 0.4 mg of folic acid for most women of childbearing potential.

The American Academy of Family Physicians strongly recommends prescribing folic acid supplementation of 0.4 to 0.8 mg/day for women planning to become pregnant and without a history of neural tube defects, and 0.4 mg/day of folate supplementation to women of childbearing age who are not planning pregnancy.

"The American College of Obstetrics and Gynecology, AAFP [American Academy of Family Physicians], and most other organizations recommend 4 mg/d for women with a history of neural tube defects," the statement authors conclude.

"The American Academy of Pediatrics endorses the U.S. Public Health Service recommendation that all women capable of becoming pregnant consume 400 mcg of folic acid daily to prevent neural tube defects,' particularly for adolescent, ''sexually active women who do not plan to use effective contraception or abstain from sexual intercourse.' Because of teratogenesis and impaired folate metabolism associated with certain antiepileptic drugs, the American Academy of Neurology recommends folic acid supplementation of no less than 0.4 mg/d for women of childbearing age with epilepsy."

Ann Intern Med. 2009;150:626-631, 632-639