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Folic Acid for the Prevention of Neural Tube Defects, Preventive Medication, 2017

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Recommendations: Preventive Medication for Folic Acid for the Prevention of Neural Tube Defects

Discussion:

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 occurring 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 among the most common major congenital anomalies in the United States.1 Based on 2009–2011 data from the Centers for Disease Control and Prevention, the estimated average annual prevalence of anencephaly and spina bifida combined was 6.5 cases per 10,000 live births.12

Since widespread recommendations on folic acid supplementation and the implementation of food fortification laws by the US Food and Drug Administration in 1998, prevalence rates of infants born with neural tube defects have decreased.12 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 Folic acid supplementation prevents about 1300 annual births from being affected by neural tube defects, according to recent estimates.2 Although supplementation recommendations and food fortification laws have reduced the prevalence of neural tube defects, it is still difficult for most women to consume the daily requirement of 0.4 mg (400 μg) of folic acid from food alone. The 2007–2012 NHANES found that 48% of respondents of childbearing age reported consuming folic acid from mandatorily fortified foods only. Only 29% of all respondents reported taking a daily folic acid supplement.9 Among women who were taking a daily folic acid supplement, about half (14.6% of all women) were taking a supplement containing less than the daily recommended dose of 0.4 mg (400 µg).19

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 infants.7 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 in women with a history of pregnancy affected by neural tube defects or other high-risk factors. Evidence on folic acid fortification, counseling to increase dietary intake of folic acid or naturally occurring food 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 are well-established and outweigh the harms.8

In the current review, the USPSTF evaluated 1 randomized clinical trial (RCT), 2 cohort studies, 8 case-control studies, and 2 publications from the previous USPSTF review for evidence of effectiveness of folic acid supplementation (n = at least 41,802 participants). Results were not pooled because of study heterogeneity and differences in food fortification over time.

A fair-quality RCT conducted in Hungary (1984–1992) assessed women (n = 5453) without a personal history of pregnancy affected by neural tube defects.115 Participants were randomized to receive either a daily vitamin supplement containing 0.8 mg (800 μg) 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 (0% vs 0.25%; P = 0.014 by Fisher exact test).15 These results indicate a statistically significant lower odds of neural tube defects with folic acid supplementation (Peto odds ratio [OR], 0.131 [95% CI, 0.0263 to 0.648]; P = 0.013).115

Evidence from older, fair-quality observational studies provide additional support that folic acid supplementation is beneficial.15 A fair-quality prospective cohort study (n = 6112) conducted in Hungary compared women who were provided a vitamin supplement containing 0.8 mg (800 μg) of folic acid before conception with 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, 0.01 to 0.91]).116. A fair-quality retrospective cohort study conducted in the United States in women undergoing ɑ-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 of pregnancy compared with 3157 women who did not take any supplements (OR, 0.27 [95% CI, 0.11 to 0.63]).117

The 8 remaining studies were fair-quality case-control studies of births occurring over 3 decades, from 1976 through 2008.1 Studies compared infants who had malformations caused by neural tube defects to either nonmalformed infants or infants who had malformations not caused by neural tube defects. Data were drawn from 2 multistate studies (National Birth Defects Prevention Study and the Slone Epidemiology Center Birth Defects Study), a 2-state study (National Institute of Child Health and Human Development Neural Tube Defects Study), and 2 single-state studies (Texas Neural Tube Defect Project and the California Birth Defects Monitoring Program).1 Older case-control studies conducted before implementation of food fortification laws were generally consistent with the more recent evidence showing that folic acid supplementation is beneficial for the prevention of neural tube defects (OR range, 0.6 to 0.7 [in 3 of 4 studies]). Newer case-control studies conducted after food fortification did not show a protective effect of folic acid supplementation on neural tube defects (OR range, 0.93 to 1.40 [95% CI included the null]).1

Ethical considerations limited the use of RCT methods to study the effects of folic acid supplementation 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. Another 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 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-fourth of the US population with suboptimal red blood cell folate concentration.19

Three fair-quality case-control studies (n = 11,154) examined the effects of folic acid supplementation by race/ethnicity.118-20 One study found that folic acid supplementation may be less protective among Hispanic women compared with white or black women.18 A second study found a statistically nonsignificant increased risk of neural tube defects with supplementation among Hispanic women (OR adjusted for consistent users vs nonusers, 2.20 [95% CI, 0.98 to 4.92]).19. A third study found that periconceptional supplementation did not decrease the risk of neural tube defects and reported no differences in effect by race/ethnicity.20 These inconsistent results among Hispanic women could be a result of chance due to small sample sizes.

Eight fair-quality case-control studies addressed dose, timing, or duration of therapy.1 Of these 8 studies, 4 (n = 26,791) provided information on dose, 5 (n = 26,808) 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.1

Potential Harms of Preventive Medication

The USPSTF found adequate evidence that folic acid supplementation does not have serious harms. One fair-quality trial and 1 fair-quality cohort study did not find evidence of a statistically significant increased risk of pregnancy with twins in women.1

In the Hungarian trial (n = 5453), the rate of twin pregnancy was not statistically significantly different between the multivitamin and trace-element groups (OR, 1.4 [95% CI, 0.97 to 2.25]).121 In a retrospective, population-based cohort study in Norway (n = 176,042), no association was found between folic acid supplementation and twin pregnancy (OR, 1.04 [95% CI, 0.89 to 2.21]) after adjusting for use of in vitro fertilization, maternal age, and parity.22

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.115

Three systematic reviews of observational studies (n = at least 14,438 participants) evaluated childhood asthma, wheezing, or allergies and found inconsistent evidence of harms.12324 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.

Other potential hypothesized harms of folic acid supplementation include the masking of symptoms of vitamin B12 deficiency and subsequent neurologic complications, carcinogenic effects, asthma/allergic reactions, and interactions with medications.1710 The USPSTF found no significant evidence of these potential harms.

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 to a change in its recommendation from 2009.7 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 who are planning or capable of pregnancy take a daily supplement containing 0.4 to 0.8 mg (400 to 800 µg) of folic acid.8

How Does Evidence Fit With Biological Understanding?

Genetic predisposition and environmental influences are thought to contribute to neural tube defects. These environmental influences are being investigated. An important environmental influence is the consumption of folate. The mechanism of action of folate in the prevention of neural tube defects is unknown. Folate acts as a coenzyme in the synthesis of nucleic acids and the metabolism of amino acids. An important function of folate is its role in single-carbon transfers, which are important in methylation reactions and in purine and pyrimidine synthesis. Folate is necessary for the regulation of DNA synthesis and function; reduced concentrations of folate may limit the number of methyl groups available for DNA replication and methylation.1710

Evidence suggests that mutation in the MTHFR gene, which encodes the enzyme methylenetetrahydrofolate reductase, is a risk factor for neural tube defects. This enzyme regulates folate and homocysteine levels. Persons who have this gene mutation have decreased folate levels, which reduces the conversion of homocysteine to methionine and may increase the risk of neural tube defects.125 Folic acid consumption may help diminish the effects of the gene mutation.

Response to Public Comment

A draft version of this recommendation statement was posted for public comment on the USPSTF website from May 10 to June 6, 2016. Some comments requested a more detailed definition of “excessive” folic acid. In response, the USPSTF added information about tolerable upper intake levels for folic acid. Other comments suggested emphasizing that many women do not meet daily recommended amounts of folic acid and adding language on the potential harms of folic acid supplementation. The USPSTF added language about the harms of supplementation and the difficulty of consuming enough folic acid from food alone.

Other Sections:

Update of Previous USPSTF Recommendation

This recommendation reaffirms the 2009 recommendation statement on folic acid supplementation in women of childbearing age.8 The current statement recommends that all women who are planning or capable of pregnancy take a daily supplement containing 0.4 to 0.8 mg (400 to 800 µg) of folic acid.

 

Recommendation 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, US Public Health Service, Centers for Disease Control and Prevention, American Academy of Pediatrics, American Academy of Neurology, and American College of Medical Genetics and Genomics recommend that women who are capable of becoming pregnant should take at least 0.4 mg (400 µg) of folic acid daily.1026-30 The American College of Obstetricians and Gynecologists, Centers for Disease Control and Prevention, and several other organizations recommend that women with a history of neural tube defects or other high-risk factors take 4 mg (4000 μg) of folic acid daily.31-33

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