Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Clinical Trial
. 2018 Mar 14;13(3):e0193127.
doi: 10.1371/journal.pone.0193127. eCollection 2018.

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

Fernando A Poletta  1   2 , Monica Rittler  3 , Cesar Saleme  4 , Hebe Campaña  1 , Juan A Gili  1 , Mariela S Pawluk  1 , Lucas G Gimenez  1 , Viviana R Cosentino  1 , Eduardo E Castilla  1   2 , Jorge S López-Camelo  1   2
Affiliations
Clinical Trial

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

Fernando A Poletta et al. PLoS One. .

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 During the post- FAF period, unpublished routine reports have indicated changes in the sex ratio for these defects while some descriptive reports are controversial.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

PubMed Disclaimer

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Fig 1
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
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.
See this image and copyright information in PMC

References

    1. Lopez-Camelo JS, Castilla EE, Orioli IM. Folic acid flour fortification: Impact on the frequencies of 52 congenital anomaly types in three South American countries. Am J Med Genet A. 2010. Epub 2010/09/04. doi: 10.1002/ajmg.a.33479 . - DOI - PubMed
    1. Rittler M, Lopez-Camelo J, Castilla EE. Sex ratio and associated risk factors for 50 congenital anomaly types: clues for causal heterogeneity. Birth Defects Res A Clin Mol Teratol. 2004;70(1):13–9. doi: 10.1002/bdra.10131 . - DOI - PubMed
    1. Michalski AM, Richardson SD, Browne ML, Carmichael SL, Canfield MA, VanZutphen AR, et al. Sex ratios among infants with birth defects, National Birth Defects Prevention Study, 1997–2009. American Journal of Medical Genetics Part A. 2015;167(5):1071–81. - PubMed
    1. Lary JM, Paulozzi LJ. Sex differences in the prevalence of human birth defects: A population‐based study. Teratology. 2001;64(5):237–51. doi: 10.1002/tera.1070 - DOI - PubMed
    1. Shaw GM, Carmichael SL, Kaidarova Z, Harris JA. Differential risks to males and females for congenital malformations among 2.5 million California births, 1989–1997. Birth Defects Research Part A: Clinical and Molecular Teratology. 2003;67(12):953–8. doi: 10.1002/bdra.10129 - DOI - PubMed

Publication types