IMPORTANCE: Neural tube defects are among the most common congenital anomalies in the United States. Periconceptional folic acid supplementation is a primary care-relevant preventive intervention.
OBJECTIVE: To review the evidence on folic acid supplementation for preventing neural tube defects to inform the US Preventive Services Task Force for an updated Recommendation Statement.
DATA SOURCES: MEDLINE, Cochrane Library, EMBASE, and trial registries through January 28, 2016, with ongoing surveillance through November 11, 2016; references; experts.
STUDY SELECTION: English-language studies of folic acid supplementation in women. Excluded were poor-quality studies; studies of prepubertal girls, men, women without the potential for childbearing, and neural tube defect recurrence; and studies conducted in developing countries.
DATA EXTRACTION AND SYNTHESIS: Two investigators independently reviewed abstracts, full-text articles, and risk of bias of included studies. One investigator extracted data and a second checked accuracy. Because of heterogeneity, data were not pooled.
MAIN OUTCOMES AND MEASURES: Neural tube defects, harms of treatment (twinning, respiratory outcomes).
RESULTS: A total of 24 studies (N > 58 860) were included. In 1 randomized clinical trial from Hungary initiated in 1984, incidence of neural tube defects for folic acid supplementation compared with trace element supplementation was 0% vs 0.25% (Peto odds ratio [OR], 0.13 [95% CI, 0.03-0.65]; n = 4862). Odds ratios from cohort studies recruiting participants between 1984 and 1996 demonstrated beneficial associations and ranged from 0.11 to 0.27 (n = 19 982). Three of 4 case-control studies with data from 1976 through 1998 reported ORs ranging from 0.6 to 0.7 (n > 7121). Evidence of benefit led to food fortification in the United States beginning in 1998, after which no new prospective studies have been conducted. More recent case-control studies drawing from data collected after 1998 have not demonstrated a protective association consistently with folic acid supplementation, with ORs ranging from 0.93 to 1.4 and confidence intervals spanning the null (n > 13 990). Regarding harms, 1 trial (OR, 1.40 [95% CI, 0.89-2.21]; n = 4767) and 1 cohort study (OR, 1.04 [95% CI, 0.91-1.18]; n = 2620) found no statistically significant increased risk of twinning. Three systematic reviews found no consistent evidence of increased risk of asthma (OR, 1.06 [95% CI, 0.99-1.14]; n = 14 438), wheezing, or allergy.
CONCLUSIONS AND RELEVANCE: In studies conducted before the initiation of food fortification in the United States in 1998, folic acid supplementation provided protection against neural tube defects. Newer postfortification studies have not demonstrated a protective association but have the potential for misclassification and recall bias, which can attenuate the measured association of folic acid supplementation with neural tube defects.
PURPOSE: To assess the benefits and harms of folic acid supplementation in reproductive-age women for the prevention of neural tube defects (NTDs).
DATA SOURCES: Systematic review of studies from MEDLINE, the Cochrane Library, EMBASE unpublished literature, and trial registries through January 28, 2016; bibliographies from retrieved articles, outside experts, and reviewers.
STUDY SELECTION: Two investigators independently selected studies using a priori inclusion and exclusion criteria. We included studies that focused on the use of folic acid supplementation (by itself or in multivitamin or prenatal supplement form) for the prevention of NTD-affected pregnancies in women of childbearing age. We limited the evaluation of benefits to NTDs. We excluded poor-quality studies and studies of prepubertal girls, men or women without the potential for childbearing, and NTD recurrence prevention, and studies in developing countries.
DATA EXTRACTION: One investigator extracted data and a second checked accuracy. Two reviewers independently rated the quality for all included studies, using predefined criteria.
DATA SYNTHESIS: We included 24 studies: 12 on the effect of folic acid supplementation on NTDs, three on variation in the effect on NTDs by race/ethnicity, and eight on variation by dosage or timing. For harms, we focused on two recent systematic reviews on respiratory outcomes, which reported on several included studies. One systematic review also provided data on variation in harms by timing and dose. We paid particular attention in the analysis to variation in effect by study design and over time, particularly before and after food fortification in the United States (1998). For the question of benefits of folic acid supplementation on NTDs, we found a single randomized, controlled trial (RCT), initiated in 1984 in Hungary, reporting a Peto odds ratio (OR) for NTDs of 0.131 (95% confidence interval [CI], 0.026 to 0.648; p=0.013). Two older cohort studies provided an OR of 0.11 (95% CI, 0.011 to 0.91) and 0.27 (95% CI, 0.11 to 0.63). Older case-control studies were also generally consistent with the evidence from the older RCT and cohort studies; odds ranged from 0.6 to 0.7 in three of four case-control studies. This evidence led to food fortification in the United States in 1998, after which no new trials or prospective cohort studies have been conducted. All newer evidence arises from case-control studies only. These newer studies, with inherently weaker designs, are consistent in not demonstrating a protective effect of folic acid supplements on NTDs, with odds ranging from 0.9 to 1.4 and CIs spanning the null. Regarding variations in benefits by race/ethnicity, we found three eligible studies. One found no effect by race/ethnicity, a second found a higher but nonsignificant risk of NTDs with folic acid supplementation among Hispanic women (adjusted OR for consistent users compared with nonusers, 2.20 [95% CI, 0.98 to 4.92]), and a third found that the risk reduction was of smaller magnitude for Hispanic women compared with white or black women. These inconsistent results could have occurred by chance. Regarding variation in benefits, eight studies provided information. Of these, four studies provided information on dose, none on duration, and five on timing. We found no indication of a dose-response relationship in three of four studies. One study showed lower odds for daily versus less than daily use (OR, 0.57 [95% CI, 0.35 to 0.93]). Regarding timing, two older studies consistently showed no effect. Two newer studies found no effect of timing for spina bifida, while one showed a protective effect with supplement use before pregnancy for anencephaly. Regarding harms, one trial and one cohort study did not find evidence of statistically significant increased risk of twinning in women. The cohort study found that any increased risk of twinning was attenuated when the confounding effects of in vitro fertilization were accounted for. Three systematic reviews evaluated childhood asthma, wheezing, or allergy and found no consistent evidence of harm. One trial evaluated the risks of adverse events in women and found a higher risk of some events (weight gain, diarrhea, constipation) and not others (increased appetite, lack of appetite, exanthema, heartburn, and vertigo), but the event rate was very low and could have occurred by chance or as consequence of pregnancy. One systematic review did not find consistent evidence of an effect of folic acid supplementation on childhood asthma, wheezing, and allergy by timing or dose of intake.
LIMITATIONS: We restricted interventions to folic acid supplementation and did not include interventions such as food fortification, counseling to increase dietary intake, or screening for NTDs. We found very limited information on differences in benefits and risks of folic acid supplementation by race/ethnicity, dose, and timing and no information on duration. Regarding the overall quality of evidence, ethical considerations limit the use of RCTs to answer questions of efficacy. Observational studies carry limitations of case ascertainment and recall bias, and these two sources of bias can serve to reduce the observed effect of NTDs.
CONCLUSIONS: Studies conducted before food fortification in the United States in 1998, with fewer design flaws, show that folic acid supplementation provides protection against NTDs. Newer studies, conducted after food fortification with folic acid, do not demonstrate this protective effect. These studies, however, have the potential for misclassification and recall bias, both of which can serve to attenuate the effect of folic acid supplementation on NTDs. Although mandatory food fortification in the United States has been accompanied by a decline in NTD prevalence, variations in intake continue to leave nearly a quarter of the U.S. population with suboptimal red blood cell folate concentrations, suggesting continued importance of folic acid supplement use. Evidence of variations in effectiveness by race/ethnicity is inconsistent and could have occurred due to chance. We found no evidence of a dose-response effect, but studies had small numbers of cases for subanalyses. We did not find consistent evidence on timing of folic acid for benefits. We also did not find consistent evidence of harms, specifically twinning, respiratory outcomes, and other harms.
Neural tube defects are among the most common congenital anomalies in the United States. Periconceptional folic acid supplementation is a primary care-relevant preventive intervention.
OBJECTIVE:
To review the evidence on folic acid supplementation for preventing neural tube defects to inform the US Preventive Services Task Force for an updated Recommendation Statement.
DATA SOURCES:
MEDLINE, Cochrane Library, EMBASE, and trial registries through January 28, 2016, with ongoing surveillance through November 11, 2016; references; experts.
STUDY SELECTION:
English-language studies of folic acid supplementation in women. Excluded were poor-quality studies; studies of prepubertal girls, men, women without the potential for childbearing, and neural tube defect recurrence; and studies conducted in developing countries.
DATA EXTRACTION AND SYNTHESIS:
Two investigators independently reviewed abstracts, full-text articles, and risk of bias of included studies. One investigator extracted data and a second checked accuracy. Because of heterogeneity, data were not pooled.
MAIN OUTCOMES AND MEASURES:
Neural tube defects, harms of treatment (twinning, respiratory outcomes).
RESULTS:
A total of 24 studies (N > 58 860) were included. In 1 randomized clinical trial from Hungary initiated in 1984, incidence of neural tube defects for folic acid supplementation compared with trace element supplementation was 0% vs 0.25% (Peto odds ratio [OR], 0.13 [95% CI, 0.03-0.65]; n = 4862). Odds ratios from cohort studies recruiting participants between 1984 and 1996 demonstrated beneficial associations and ranged from 0.11 to 0.27 (n = 19 982). Three of 4 case-control studies with data from 1976 through 1998 reported ORs ranging from 0.6 to 0.7 (n > 7121). Evidence of benefit led to food fortification in the United States beginning in 1998, after which no new prospective studies have been conducted. More recent case-control studies drawing from data collected after 1998 have not demonstrated a protective association consistently with folic acid supplementation, with ORs ranging from 0.93 to 1.4 and confidence intervals spanning the null (n > 13 990). Regarding harms, 1 trial (OR, 1.40 [95% CI, 0.89-2.21]; n = 4767) and 1 cohort study (OR, 1.04 [95% CI, 0.91-1.18]; n = 2620) found no statistically significant increased risk of twinning. Three systematic reviews found no consistent evidence of increased risk of asthma (OR, 1.06 [95% CI, 0.99-1.14]; n = 14 438), wheezing, or allergy.
CONCLUSIONS AND RELEVANCE:
In studies conducted before the initiation of food fortification in the United States in 1998, folic acid supplementation provided protection against neural tube defects. Newer postfortification studies have not demonstrated a protective association but have the potential for misclassification and recall bias, which can attenuate the measured association of folic acid supplementation with neural tube defects.
