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

Date Published: March 14, 2018

Publisher: Public Library of Science

Author(s): Fernando A. Poletta, Monica Rittler, Cesar Saleme, Hebe Campaña, Juan A. Gili, Mariela S. Pawluk, Lucas G. Gimenez, Viviana R. Cosentino, Eduardo E. Castilla, Jorge S. López-Camelo, Cheryl S. Rosenfeld.


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 During the post- FAF period, unpublished routine reports have indicated changes in the sex ratio for these defects while some descriptive reports are controversial.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

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.

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.

Partial Text

Neural tube defects (NTDs), including spina bifida, anencephaly and cephalocele, are severe birth defects of the central nervous system that occur during embryonic development when the neural tube fails to close completely. In South America before folic acid fortification, as well as in other countries without fortification policies, the overall prevalence of NTDs varied between 10 and 20 per 10,000 births [1], and showed a historical female sex predisposition for the three malformations. The observed frequency in South America was 18/10,000 for females and 12/10,000 for males [2], with an estimated sex ratio (SR = male/female) of 0.67, which however differed among other studies. For the US NBDPS registry [3], it was closer to an equal male/female relationship, while Lary and Paulozzi [4], Shaw et al. [5], and Rittler et al. [2] found a greater female excess. Epigenetic phenomena [6], a relatively higher proportion of males with associated NTDs and lost during early gestation [7], and/or differences in susceptibility to environmental factors, based on the multifactorial theory [8], could explain the female excess.

By using a descriptive cross-sectional study, 2,597 live and stillborn infants with isolated NTDs among 2,229,561 total births (TB) from 95 maternity hospitals of 3 South American countries participating in the Latin American Collaborative Study of Congenital Malformations (ECLAMC)[21–22] between 1990 and 2013, were analyzed: (Chile N = 521, TB = 565,238; Argentina N = 1619, TB = 1,310,367; Venezuela N = 457, TB = 353,956). Venezuela, where no fortification policy has been implemented, was used as control group.

The number of cases by anomaly type, country, gender, and FAF period are shown in Table 1. The total number of births with specified sex was 2,229,561 (98.6%), and the population SR (M/F) of the 3 countries did not change during the whole study period (Chile: before FAF = 1.051, after FAF = 1.055, p = 0.1758; Argentina: before FAF = 1.041, after FAF = 1.049, p = 0.192; and Venezuela = 1.061) (Fig 1).

Up to date and to our knowledge, the sex-specific effect of folic acid on the prevalence of NTDs has not been explored.




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