Neural tube defects: Sex ratio changes after fortification with folic acid

Abstract

Background: Historically, neural tube defects (NTDs) have predominated in female infants but the reasons remain unclear. In South America, the pre- folic acid fortification (FAF) rates of NTDs were around 18/10,000 births for females and 12/10,000 births for males, with an estimated sex ratio (male/female) of 0.67. During the post- FAF period, unpublished routine reports have indicated changes in the sex ratio for these defects while some descriptive reports are controversial. To date and to our knowledge, however, no studies specifically focusing on these changes to test this hypothesis directly have been undertaken. The aim of this study was to analyze changes in the sex ratio of infants with NTDs after FAF in South American countries.

Materials and methods: With a descriptive cross-sectional study design, 2,597 infants with isolated NTDs born between 1990 and 2013 in 3 countries participating in the Latin American Collaborative Study of Congenital Malformations (ECLAMC) network were included: (Chile N = 521 and Argentina N = 1,619 [with FAF policies]; Venezuela N = 457 [without FAF policies; used as control]; total births = 2,229,561). The differences-in-differences method and Poisson regressions were used to evaluate the sex ratio shift from female to male before vs. after FAF, and to assess whether these differences were related to the fortification.

Results and conclusions: In Chile and Argentina the prevalence of NTDs, particularly anencephaly and cervico-thoracic spina bifida, showed a greater reduction rate in females than in males after FAF, resulting in a change of the sex ratio of infants with NTDs. Some mechanisms possibly involved in this differential reduction are proposed which might be useful to identify the pathogenesis of NTDs as a whole and specifically of those susceptible to the protective effect of folic acid.

Fig 1. Sex ratio changes for NTD cases and total births in Chile, Argentina, and Venezuela (1990–2013).

NTD: neural tube defect; FAF: folic acid fortification; M/F: male/female; Sex ratio (male/female) for neural tube defect cases (full blue line), sex ratio for total births (dashed red line). Sex ratios estimated by multivariate regression models adjusted by hospital.

Fig 2. Changes in NTD rates by sex in Chile, Argentina and Venezuela (1990–2013).

NTD: neural tube defect; FAF: folic acid fortification; Neural tube defects rates (per 10,000 births) for females (dashed orange line), and males (full blue line). Rates estimated by multivariate regression models adjusted by hospital.