Preconception folic acid supplementation use and the occurrence of neural tube defects in Japan.

Abstract

With great interest, we read the paper titled “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” by Nishigori et al1 in Congenital Anomalies (July 2019 issue). Neural tube defects (NTDs) are among the common congenital anomalies that result in defects of the vertebrae, spinal cord, cranium, and/or brain. Folic acid supplementation before conception is the global strategy for preventing NTDs and is recommended for all women of reproductive age.2 A previous meta-analysis demonstrated a 69% reduction in NTD incidence with daily folic acid supplementation compared with no intervention or placebo without folic acid.3 According to the study by Nishigori et al who examined a large nationwide prospective cohort (the Japan Environment and Children's Study [JECS]), the risk of NTDs among women who did and did not take preconception folic acid supplements was 5.24 and 8.27 per 10 000 births, respectively; these values were nearly equivalent to those in previous data reported worldwide.4, 5 However, Nishigori et al concluded that there was no association between preconceptional folic acid supplementation and the NTD incidence. We suggest that the study by Nishigori et al included an important methodological limitation. In consideration of the low NTD incidence as well as the low prevalence of folic acid supplementation in this study, the sample size was too small to detect statistically significant association between preconceptional folic acid supplementation and NTD incidence; the current statistical power calculated by Pearson's chi-squared test was 0.10 (STATA14-MP, Stata Corp LP, College Station, Texas). In the JECS cohort, the proportion of women who took folic acid supplements before conception was low: only 8.3% (7634/92 269). In view of the prevalence of folic acid supplementation in Japan, at least 67 145 women who took folic acid supplements before conception and 744 408 who did not would have been needed to detect a significant difference in the proportion of offspring/fetuses with NTDs (ie, 5.24 and 8.27, respectively, per 10 000), with 80% power at a significance level of 5%. Thus, it would be practically impossible to demonstrate significant associations between folic acid supplementation and current incidence of NTDs in this observational study in Japan.1 In conclusion, we believe that Nishigori et al's findings should be interpreted carefully because the sample size was not sufficient to assess associations between preconceptional folic acid supplementation and NTD incidence. None.