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Atrioventricular septal defects (AVSDs) have been identified as intriguingly infrequent among Hispanics with Down syndrome (DS) born in the United States. The aim of this study was to evaluate the effect of possible maternal risk factors in the presence of congenital heart defects (CHDs) in Mexican infants with DS. A total of 231 live birth infants born with DS during 2009-2018 at the "Dr. Juan I. Menchaca" Civil Hospital of Guadalajara (Guadalajara, Mexico) were ascertained in a case-control study. Patients with DS with any major CHD were included as cases and those without major CHD as controls. Potential risk factors were analyzed using logistic regression. Of eligible infants with DS, 100 (43.3%) had ≥1 major CHDs (cases) and were compared with a control group of 131 infants (56.7%) with DS without CHDs. Prevalent CHDs were ostium secundum atrial septal defects (ASDs) (46.9%), ventricular septal defects (27.3%), and AVSDs (14%). Lack of folic acid supplementation before pregnancy had a significant risk for CHDs in infants with DS (adjusted odds ratio [aORs] = 2.9 (95% confidence interval [95% CI]: 1.0-8.6) and in the analysis by subtype of CHDs, also, for the occurrence of ASDs (aOR = 11.5, 95% CI: 1.4-94.4). Almost half of the infants with DS in our sample had CHDs, being ASD the commonest subtype and AVSD the rarest. Our ethnic background alone or in concomitance with observed nutritional disadvantages seems to contribute differences in CHD subtype rates in our DS patients., (© 2019 Wiley Periodicals, Inc.)