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

PLoS One. 2018 Mar 14;13(3):e0193127. doi: 10.1371/journal.pone.0193127. eCollection 2018.


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 During the post- FAF period, unpublished routine reports have indicated changes in the sex ratio for these defects while some descriptive reports are controversial.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.

Publication types

  • Clinical Trial
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Argentina / epidemiology
  • Chile / epidemiology
  • Cross-Sectional Studies
  • Female
  • Folic Acid / administration & dosage*
  • Follow-Up Studies
  • Food, Fortified*
  • Humans
  • Male
  • Neural Tube Defects / epidemiology*
  • Neural Tube Defects / prevention & control*
  • Sex Characteristics*
  • Sex Factors


  • Folic Acid

Grants and funding

The research program was supported by Agencia Nacional de Promoción Científica y Tecnológica (ANPCyT-MINCyT), grant number PICT-2016-0952 (PI: Lopez-Camelo JS) and PICT-2016-3869 (PI: Poletta FA), Argentina; Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET-MINCyT), Argentina. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.