Received: 19 January 2019 Revised: 1 June 2019 Accepted: 10 July 2019

DOI: 10.1002/ajmg.a.61300

ORIGINAL ARTICLE

Maternal risk factors for congenital heart defects in infants

with Down syndrome from Western Mexico

Jorge Román Corona-Rivera1,2 | Rafael Nieto-García3 | Andrea S. Gutiérrez-Chávez1 |

Lucina Bobadilla-Morales1,2 | Izabel M. Rios-Flores1 | Alfredo Corona-Rivera1,2 |
Gerardo E. Fabián-Morales1 | Ignacio Zavala-Cortés1 | Cynthia Lugo-Iglesias1 |
Christian Peña-Padilla1

1
Center for Registry and Research in
Congenital Anomalies (CRIAC), Service of Abstract
Genetics and Cytogenetics Unit, Pediatrics Atrioventricular septal defects (AVSDs) have been identified as intriguingly infre-
Division, Dr. Juan I. Menchaca Civil Hospital of
Guadalajara, Guadalajara, Jalisco, Mexico quent among Hispanics with Down syndrome (DS) born in the United States. The
2
Dr. Enrique Corona-Rivera Institute of aim of this study was to evaluate the effect of possible maternal risk factors in the
Human Genetics, Department of Molecular
presence of congenital heart defects (CHDs) in Mexican infants with DS. A total of
Biology and Genomics, Health Sciences
University Center, University of Guadalajara, 231 live birth infants born with DS during 2009–2018 at the “Dr. Juan I. Menchaca”
Guadalajara, Jalisco, Mexico
Civil Hospital of Guadalajara (Guadalajara, Mexico) were ascertained in a case–
3
Service of Cardiology, Pediatrics Division, Dr.
Juan I. Menchaca Civil Hospital of Guadalajara, control study. Patients with DS with any major CHD were included as cases and
Guadalajara, Jalisco, Mexico those without major CHD as controls. Potential risk factors were analyzed using

Correspondence
Jorge Román Corona-Rivera, Instituto de
Genética Humana “Dr. Enrique Corona-
Rivera,” Departamento de Biología Molecular y
Genómica, Centro Universitario de Ciencias de
la Salud, Universidad de Guadalajara, Sierra
Mojada 950, Edificio P, Nivel 2, 44340
Guadalajara, Jalisco, México.
Email: rocorona@cucs.udg.mx
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 with-
out CHDs. Prevalent CHDs were ostium secundum atrial septal defects (ASDs)
(46.9%), ventricular septal defects (27.3%), and AVSDs (14%). Lack of folic acid sup-
plementation 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 differ-
ences in CHD subtype rates in our DS patients.

KEYWORDS
atrioventricular septal defect, ethnicity, Hispanics, maternal obesity, ostium secundum atrial
septal defects

1 | I N T RO D UC T I O N Annerén, 1999). Atrioventricular septal defects (AVSDs) are the pre-

Congenital heart defects (CHDs) are the commonest major malforma-
tion in Down syndrome (DS) detected approximately in 50% of
patients, and constitutes an important prognostic factor in their asso-
ciated morbidity and mortality (Frid, Drott, Lundell, Rasmussen, &
dominantly mentioned CHDs in 45% of DS patients, followed by ven-
tricular septal defects (VSDs), atrial septal defects (ASDs), and
tetralogy of Fallot (TOF), constituting 35, 26, and 5% of cases, respec-
tively (Freeman et al., 1998). However, frequencies for each particular
subtype of CHDs clearly vary among large multicenter studies from

Am J Med Genet. 2019;1–9. wileyonlinelibrary.com/journal/ajmga © 2019 Wiley Periodicals, Inc. 1

2 CORONA-RIVERA ET AL.
the United States and Europe, mainly by ethnicity and gender (Källén,
Mastroiacovo, & Robert, 1996; Freeman et al., 1998; Torfs &
Christianson, 1999; Freeman et al., 2008; Morris et al., 2014; Stoll,
Dott, Alembik, & Roth, 2015). Particularly for AVSDs, black infants
with DS have a twofold risk than white infants, and Hispanics one-half
the risk than whites, respectively (Freeman et al., 2008; Khoury &
Erickson, 1992). By gender, CHDs has been more commonly found in
females than in males, particularly also for AVSDs (Freeman et al.,
2008; Morris et al., 2014; Santoro, Coi, Spadoni, Bianchi, &
Pierini, 2018).
At present, ethnic differences in frequency of the individual sub-
types of CHDs between infants with DS have not been explained only
by the karyotype or by a single gene or group of genes on chromo-
some 21 (Frid et al., 1999). Consequently, there have been proposed
further genetic or gene–environmental interactions involving SNPs
and CNVs located in chromosome 21 that can modify particularly the
risk for AVSDs (Sailani et al., 2013) or mutations in autosomal genes
not located on chromosome 21, such as GATA3, KCNH2, ENG, FLNA,
GUSB, SH3BGR, and CRELD1 (Alharbi et al., 2018; Kerstann et al.,
2004; Maslen et al., 2006), methylenetetrahydrofolate reductase
(MTHFR) variants (Brandalize, Bandinelli, dos Santos, Roisenberg, &
Schüler-Faccini, 2009), or even, dermatoglyphic differences
(Durham & Koehler, 1989). Besides, other maternal risk factors have
also been implicated including consanguinity (Mokhtar & Abdel-
Fattah, 2001; El-Gilany, Yahia, & Wahba, (2017), obesity (Bergström
et al., 2016), diabetes (Mokhtar & Abdel-Fattah, 2001), lack of folic
acid (FA) supplementation before pregnancy (Bean et al., 2011; El-
Gilany, Yahia, & Wahba, 2017), first-trimester exposure to oral contra-
ceptive pills (Mokhtar & Abdel-Fattah, 2001), and tobacco smoking
(Torfs & Christianson, 1999; El-Gilany, Yahia, & Wahba, 2017; Ber-
gström et al., 2016). Contrarily, advanced maternal age (Bergström
et al., 2016) and alcohol use (Khoury & Erickson, 1992) have been
associated with a reduced risk of CHDs. However, previously men-
tioned risks may have a variable contribution in CHD occurrence
among individuals with DS (Freeman et al., 2008; Khoury & Erickson,
1992), because they can vary depending on ethnicity or
sociodemographic conditions or it can be inclusively absent (Fixler &
Threlkeld, 1998). Intriguingly, infants of Hispanic mothers who immi-
grated to the United States––mainly from Mexico and Central Amer-
ica, have a lower risk for AVSDs than did infants of Hispanic mothers
born inside the United States (Freeman et al., 1998; Freeman et al.,
2008; Khoury & Erickson, 1992; Torfs & Christianson, 1999). Similarly,
very low rates of AVSDs have been reported in DS patients from
Mexico (de Rubens-Figueroa, del Pozzo-Magaña, Pablos-Hach, Cal-
derón-Jiménez, & Castrejón-Urbina, 2003; Rodríguez-Hernández &
Reyes-Núñez, 1984) and Guatemala (Vida et al., 2005). However,
effects of such potential maternal risk factors over CHDs in DS have
not been previously studied in Mexican patients. Here, we designed a
case–control study to evaluate several maternal risk factors in relation
to the presence of major CHDs in infants with DS, within a tertiary
university hospital in Western Mexico. Additionally, we review the
worldwide rates reported for the three major CHDs in infants
with DS.
2 | METHODS
2.1 | Study subjects
Patients with DS in this case–control study come from the Center for
Registry and Research in Congenital Anomalies (CRIAC), our hospital-
based birth defects surveillance program that covers all live births of
20 or more weeks of gestation and more than 500 g. All infants that
were born with DS from January 2009 to June 2018 at the “Dr. Juan
I. Menchaca” Civil Hospital of Guadalajara (Guadalajara, Jalisco, Mex-
ico) were retrospectively ascertained by the CRIAC. All of the partici-
pants' parents were Mexican mestizo origin from Western Mexico.
Trisomy 21 diagnosis was confirmed by peripheral blood karyotype
performed in our cytogenetics unit. As no correlation between the
karyotype and specific CHDs has been reported (Frid et al., 1999), all
patients cytogenetically confirmed were included. The Research
Council and Ethics Committee of our hospital approved this study.
2.2 | Study variables
The CRIAC register contains the records of cardiac evaluation per-
formed on all patients with DS within the first month of life. In all
cases, the echocardiography performed by a Pediatric Cardiologist
was used to document and confirm the definitive cardiac findings.
Patients with DS with any major CHD were included as cases.
Major CHDs were grouped in AVSDs, VSDs, ASDs, TOF, and
“others.” Only ostium secundum was included as ASDs. The patent
foramen ovale (PFO) was not included in the diagnosis of ASDs.
Also, patent ductus arteriosus (PDA) associated with the circulatory
adaptation after birth was not included as a major CHD. In accor-
dance with Freeman et al. (2008), each occurrence of CHD was
separately counted. For instance, in infants with both ASD and
VSD, both defects were recorded, however, if a VSD was part of a
TOF, then it was not counted separately. Infants with DS and a
structurally normal heart, PFO, or PDA were used as a control
group for comparisons.
The record used by the CRIAC was obtained by interviewing
mothers of cases and controls soon after delivery as well as from hos-
pital records. To evaluate potential maternal risk factors related to
CHDs in the studied population, we included family history evaluated
through a three-generation pedigree, including history of consanguin-
ity, and family history of CHDs; maternal and paternal age (years);
infant sex; low socioeconomic status, defined according to the highest
level of education attainment of the most educated parent when
parent(s) did not attend school, attended primary school, or attended
some secondary school (James, 2002); parity; exposure to chronic ill-
ness before pregnancy; self-reported use of FA supplementation
before pregnancy; inadequate prenatal care, defined when the mother
had fewer than five prenatal care visits during pregnancy; self-
reported prepregnancy body mass index (BMI), categorized as under-
weight (BMI < 18.5 kg/m2), normal weight (18.5–24.9 kg/m2), over-
weight (25–29.9 kg/m2), and obesity (≥30 kg/m2) (World Health
Organization BMI Classification, 2012); gestational weight gain
CORONA-RIVERA ET AL. 3

(kg) for each pre-pregnancy BMI category, classified as normal, insuffi- T A B L E 1 Major congenital heart defects in the sample of patients
cient or excessive weight gain, respectively (Institute of Medicine with Down syndrome
(US) and National Research Council (US) Committee to Reexamine Type of major congenital % of % of
IOM Pregnancy Weight Guidelines, Rasmussen, & Yaktine, 2009); heart defects (CHDs) n infants defects
antepartum BMI; exposure to acute illness during pregnancy; pres- Atrioventricular septal defects 18 7.8 14.0
ence of threatened abortion or first-trimester hemorrhage; anemia (AVSDs)
during pregnancy (hemoglobin <10 g/dL); hypertension or diabetes Complete 15 6.5 11.7
during pregnancy, whether developed before or after conception; Partial 3 1.3 2.3
and self-reported use of coffee, tobacco, alcohol, and illicit Atrial septal defects (ASDs)a 60 25.9 46.9
drugs/substances taken during the first trimester of pregnancy. Ventricular septal defects 35 15.2 27.3
(VSDs)b
Perimembranous 19 8.2 14.8
2.3 | Statistical methods
Muscular 9 3.9 7.0
We used standard summary statistics and bivariate analysis to NOS 7 3.1 5.5
describe the maternal and infant characteristics and associated CHDs. Others: 15 6.5 11.7
All quantitative variables were expressed as mean ± SD and compared
Double outlet right ventricle 4 1.7 3.1
by Student's t-test and/or Wilcoxon test, depending on whether they
Aortic coarctation 4 1.7 3.1
had a normal distribution. A p value <.05 was considered significant. c
Tetralogy of Fallot 3 1.3 2.3
Maternal and infant characteristics causing a >10% change in the OR
Pulmonary valve stenosis 2 0.9 1.6
were included as covariates in a multivariable logistic regression analy-
Ebstein anomaly 1 0.4 0.8
sis for each finding, using the enter method and expressed as adjusted
Total anomalous pulmonary 1 0.4 0.8
odds ratios (aORs) and its 95% confidence intervals (95% CIs), consid-
venous drainage
ered association when the OR was equal or more than 1 and the
Summary
lower bound of its 95% CI excluded the null value. Data analysis was
Number of major CHDs 128
performed using the Statistical Package for the Social Sciences (IBM
Patients with ≥1 of the above 100 43.3
Corp. released 2012; IBM SPSS Statistics, Version 21.0; IBM Corp.;
Patients without CHDs 131 56.7
Armonk, NY).
Total 231

Note: NOS, not otherwise specified.

3 | RESULTS a
Included only ostium secundum ASDs, excludes patent foramen
ovale (PFO).
b
During the study period, 243 cases of DS were identified. Of Excludes VSDs that is part of AVSDs or tetralogy of Fallot.
c
these, 12 were excluded because did not have karyotype or echo- Without AVSDs.

cardiography. Among the 231 who met the inclusion criteria

(214 with complete trisomy 21, nine with mosaic trisomy 21, six
with translocation trisomy, and two with other karyotypes),
100 (43.3%) were infants with at least one major CHD (cases) and
131 (56.7%) were infants without a major CHD (control group).
Among CHD cases, 59 (59%) were males and 41 (41%) females,
whereas in infants with DS without CHDs, 74 (56.5%) were males
and 57 (43.5%) females (p = .402). A total of 128 major CHDs
were observed in the 100 patients of the group of cases. Table 1
shows the distribution of specific subtypes of CHDs in our sample.
Eighty-eight percent of DS infants with recorded CHDs had one of
three diagnoses: ASDs (46.9%), followed by VSDs (27.3%) and
AVSDs (14%). Other CHDs including double-outlet right ventricle,
aortic coarctation, TOF, pulmonary valve stenosis, Ebstein anomaly,
and total anomalous pulmonary venous drainage constituted 11.7%
of cases. Table 2 provides a comparison of continuous variables in
the studied sample. Among the group of cases, father's average
schooling was significantly lower (p = .003) and mother's
antepartum BMI was significantly higher (p = .045), respectively.
No differences were found for the rest of assessed characteristics.
Sociodemographic, maternal, and infants evaluated variables and its
respective crude and aORs are presented in Table 3. The ORs
were adjusted for paternal education ≤9 years, pre-pregnancy BMI
≥30 kg/m2, and antepartum BMI ≥30 kg/m2. Lack of FA supple-
mentation before pregnancy in the mothers of infants of the group
of cases was associated with an increased risk of CHDs (aORs = 2.9,
95% CI: 1.0–8.6). For the remainder of possible risk factors, aORs
did not have any effects on the results. Illicit drugs/substances
(not included in Table 3) were only reported in one neonate in the
control group and in none of the infants in the group of cases,
respectively.
To investigate the effect of previous sociodemographic and repro-
ductive variables in the occurrence of each CHD subtype, we com-
pared separately the cases of ASDs, VSDs, and AVSDs (Table S1).
From this analysis, only ASDs showed statistically significant associa-
tion with the lack of FA supplementation before pregnancy
(aOR = 11.5, 95% CI: 1.4–94.4). In addition, no differences were
found for sex comparison of DS infants with ASDs, VSDs, and AVSDs
and DS infants without CHDs.
4 CORONA-RIVERA ET AL.

T A B L E 2 Demographic data and characteristics of our sample of Down syndrome patients in relation to the presence of major congenital
heart defects

Infants with Down syndrome (n = 231)

With CHD n = 100 Without CHD n = 131

Variables n Mean (SD) n Mean (SD) pa

Maternal age (years) 100 30.1 (9.5) 131 29.9 (8.9) .815
Maternal education (years) 92 8.6 (3.4) 117 8.7 (3.6) .751
Paternal age (years) 100 32.6 (10.9) 129 32.4 (9.5) .900
Paternal education (years) 97 7.8 (3.6) 124 9.2 (3.3) .003b
Pre-pregnancy weight (kg) 92 64.6 (13.5) 125 63.1 (14.4) .503
Antepartum weight (kg) 92 73.6 (12.5) 126 72.5 (13.9) .535
Maternal height (cm) 87 156.7 (7.1) 118 157.9 (6.3) .187
Gestational weight gain (kg) 92 8.9 (6.1) 123 9.1 (6.5) .830
2
Pre-pregnancy BMI (kg/m ) 85 26.6 (5.4) 115 25.4 (6.3) .188
Antepartum BMI (kg/m2) 85 30.2 (5.0) 116 28.8 (4.9) .045
Infants
Gestational age (weeks) 100 37.3 (2.3) 131 37.3 (2.1) .920
Birth weight (g) 100 2,528 (622) 131 2,586 (648) .358
Birth length (cm) 99 46.6 (5.3) 129 46.6 (3.4) .910
Occipitofrontal circumference (cm) 92 31.7 (2.2) 119 32.2 (2.3) .096

Abbreviation: CHD, congenital heart defects.

a
Student's t-test.
b
Wilcoxon test.

4 | DISCUSSION
The frequency for CHDs of 43.3% in our DS patients matches with
those reported in large multiethnic studies, which vary from 43% to
44% (Freeman et al., 2008; Morris et al., 2014). The multifactorial
hypothesis for CHDs in DS has been previously evaluated using sev-
eral maternal and environmental prenatal risk factors between DS
infants with CHDs and DS infants without CHDs, including consan-
guinity, maternal age, diabetes, first-trimester exposure to oral contra-
ceptive pills, tobacco smoking, alcohol use, and gender differences,
among others (Bean et al., 2011; El-Gilany et al., 2017; Freeman et al.,
2008; Khoury & Erickson, 1992; Kim et al., 2014; Mokhtar & Abdel-
Fattah, 2001; Morris et al., 2014; Torfs & Christianson, 1999). Most
of them, however, did not show statistical associations in our multi-
variate analysis (Table 3), excepting for the lack of FA supplementa-
tion before pregnancy in the mothers of infants in the group of cases
(aOR = 2.9, 95% CI: 1.0–8.6), reported also in a previous study in His-
panics from the United States (Bean et al., 2011) and in another from
Egypt (El-Gilany et al., 2017). This, besides to a statistically lower aver-
age schooling in fathers of infants with DS and CHDs, and a higher
antepartum BMI in mothers of infants with DS and CHDs (Table 2),
suggest certain socioeconomic and nutritional disadvantages in the
group of infants with DS and CHDs. In particular, our findings in rela-
tion to maternal BMI support previous statement of an increased risk
for CHDs in infants with DS whose mothers have obesity (Bergström
et al., 2016). In relation to maternal obesity, epigenetic factors have
been proposed to be related with the MTHFR pathway and DNA
methylation, since FA deficiency is common in obesity (Valdés, Tostes,
Anunciação, da Silva, & Sant'Ana, 2017), and also, because the risk for
nonsyndromic CHDs can be reduced by FA supplementation before
pregnancy (Huhta & Linask, 2015). The use of maternal supplements
with FA before pregnancy varies among ethnic groups and its fre-
quency was very low in our mothers (Table 3). The association
between the lack of FA and CHDs in DS differ by ethnicity (Bean
et al., 2011), and it can be probably influenced by MTHFR genotypes.
Particularly, the maternal MTHFR 677CT or TT genotypes increased
the risk for CHDs in infants with DS when their mothers did not have
periconceptional FA intake (Brandalize et al., 2009). Thus, although
FA-related risk appeared being causative for CHDs in infants with DS
(Tables 2 and 3), its inconsistency with other studies (Meijer et al.,
2006) may also reflect the complex interactions existing between
genetic and environmental factors implicated in FA metabolism among
different ethnic groups. Contrary to initial studies (Khoury & Erickson,
1992; Torfs & Christianson, 1999), no additional risks for CHDs in DS
infants were identified in our study sample (Tables 2 and 3). Even
though this may indicate that there are no significant differences on
environmental prenatal exposures among infants with DS with and
without CHDs (Fixler & Threlkeld, 1998), these few differences seem
to be important in our population.
Table S2 summarizes the rates for AVSDs, VSDs, and ASDs
reported in 60 studies including around 51,000 infants with DS
grouped according to the country of birth. There is a manifest
CORONA-RIVERA ET AL. 5

TABLE 3 Sociodemographic and reproductive characteristics and risk of congenital heart defects in infants with Down syndrome

Infants with Down syndrome (n = 231)

With CHDs Without CHDs Crude OR Adjusteda OR

Variables n = 100 (%) n = 131 (%) (95% CI) (95% CI)
Family history
Consanguinity 2 (2.0) 2 (1.5) 1.3 (0.2–9.5) 0.7 (0.1–5.4)
Relatives with CHDs 9 (9.0) 11 (8.4) 1.1 (0.4–2.7) 1.0 (0.4–2.9)
Pre-pregnancy and pregnancy
Maternal age (years)
≤19 19 (19.0) 24 (18.3) 1.1 (0.5–2.0) 0.9 (0.4–1.9)
≥35 39 (39.0) 50 (38.2) 1.0 (0.6–1.8) 1.1 (0.6–2.0)
Maternal education ≤9 yearsb 44 (47.8) 47 (40.2) 1.4 (0.8–2.4) 1.0 (0.5–2.0)
Paternal age (years)b
≤19 8 (8.0) 12 (9.3) 0.9 (0.3–2.2) 0.5 (0.2–1.8)
≥40 25 (25.0) 34 (26.3) 0.9 (0.5–1.7) 0.8 (0.4–1.5)
Paternal education ≤9 yearsb 48 (49.4) 42 (33.9) 1.9 (1.1–3.3) 1.7 (0.9–3.1)
Lower socioeconomic status 68 (68.0) 79 (60.3) 1.4 (0.8–2.4) 0.9 (0.4–1.8)
Any chronic disease before pregnancy 12 (12.0) 20 (15.3) 0.8 (0.4–1.6) 1.6 (0.6–3.8)
Pre-pregnancy BMI (kg/m2)b
<18.5 1 (1.2) 6 (5.2) 0.2 (0.1–1.8) 0.2 (0.0–1.8)
18.5–24.9 44 (51.8) 57 (49.6) 1.1 (0.6–1.9) 0.5 (0.2–1.0)
≥25 40 (47.0) 52 (45.2) 1.1 (0.6–1.9) 0.6 (0.3–1.3)
≥30 23 (27.1) 17 (14.8) 2.1 (1.1–4.3) 1.2 (0.4–3.3)
b
Gestational weight gain
Insufficient 43 (46.7) 50 (40.6) 1.3 (0.7–2.3) 1.2 (0.6–2.3)
Excessive 14 (15.2) 20 (16.3) 0.9 (0.4–1.9) 0.6 (0.2–1.4)
Antepartum BMI ≥30 kg/m 2‡
30 (35.3) 25 (21.6) 1.9 (1.1–3.7) 1.8 (0.7–4.4)
Parity ≥4 41 (41.0) 48 (36.6) 1.2 (0.7–2.1) 1.1 (0.6–1.9)
Lack of folic acid supplementation before pregnancyc 94 (94.0) 114 (87.0) 2.3 (0.9–6.1) 2.9 (1.0–8.6)
Inadequate prenatal care 11 (11.0) 23 (17.6) 0.6 (0.3–1.3) 2.6 (0.9–7.1)
First trimester hemorrhage 25 (25.0) 36 (27.5) 0.9 (0.5–1.6) 1.5 (0.8–2.9)
Anemia during pregnancy 3 (3.0) 3 (2.3) 1.3 (0.3–6.7) 0.2 (0.0–1.9)
Diabetes during pregnancy 8 (8.0) 7 (5.3) 1.5 (0.5–4.4) 0.9 (0.2–3.1)
Hypertension during pregnancy 6 (6.0) 10 (7.6) 0.8 (0.3–2.2) 1.5 (0.4–5.6)
Any disease during first trimester 11 (11.0) 19 (14.5) 0.7 (0.3–1.6) 1.4 (0.6–3.5)
Maternal first-trimester exposures
Hormonal contraceptives 21 (21.0) 25 (19.1) 1.7 (0.4–6.4) 0.5 (0.1–2.1)
Progestogens 1 (1.0) 5 (3.8) 0.3 (0.0–2.2) 4.0 (0.4–36.1)
Hyperthermia 4 (4.0) 5 (3.8) 1.1 (0.3–4.0) 3.0 (0.5–17.2)
Abdominal–pelvic diagnostic X-rays 4 (4.0) 2 (1.5) 2.7 (0.5–14.9) 0.1 (0.0–1.8)
Coffee consumption 64 (64.0) 80 (61.1) 1.1 (0.7–1.9) 0.9 (0.5–1.7)
Tobacco smoking 11 (11.0) 20 (15.3) 0.7 (0.3–1.5) 1.6 (0.6–4.0)
Alcohol consumption 12 (12.0) 20 (15.3) 0.8 (0.4–1.6) 1.3 (0.5–3.2)
Infants
Female sex 41 (41.0) 57 (43.5) 0.9 (0.5–1.5) 1.3 (0.7–2.4)
Gestational age <37 weeks 34 (34.0) 35 (26.7) 1.4 (0.8–2.5) 1.3 (0.7–2.6)
Birth weight <2,500 g 41 (41.0) 53 (40.5) 1.0 (0.6–1.7) 0.9 (0.5–1.7)

Abbreviations: CI, confidence interval; CHDs, congenital heart defects; OR, odds ratio.
a
The OR values were adjusted for paternal education ≤9 years, pre-pregnancy BMI ≥30 kg/m2, and antepartum BMI ≥30 kg/m2.
b
The total number of analyzed subjects match with the “n” showing its respective continuous variable in Table 2;
c
Use during the last 3 months prior to pregnancy.
6 CORONA-RIVERA ET AL.

diversity among these studies in relation to methods of cardiac evalu-
ation used, variable sample sizes, classification differences, and vary-
ing inclusion of transient or physiological CHDs. Even so, differences
on CHD subtypes among included countries are undeniable, indicating
that certain genetic or environmental risk factors occur more often in
certain populations. Ethnic variations are noted mostly for AVSDs,
highly prevalent in Caucasians and Black infants with DS. Also, this
study (Table 1) confirms a lower unusually frequency of AVSDs in
Mexico (de Rubens-Figueroa et al., 2003; Rodríguez-Hernández &
Reyes-Núñez, 1984), previously observed also in Mexican patients
with DS born in the US (Freeman et al., 2008; Khoury & Erickson,
1992) as well as in other Latin American countries, including Guate-
mala (Vida et al., 2005), Colombia (Ruz-Montes et al., 2017), and Brazil
(Bermudez, Medeiros, Bermudez, Novadzki, & Magdalena, 2015).
Notably, AVSDs in Asian population with DS are also fairly infrequent
(Hoe, Chan, & Boo, 1990; Jacobs, Leung, & Karlberg, 2000;
Jaruratanasirikul, Limpitikul, Dissaneevate, Booncharoen, & Tan-
tichantakarun, 2017; Kim et al., 2014; Masaki et al., 1981; Matsuo,
Oshima, Masuyoshi, Shimizu, & Okada, 1972; Sonoda et al., 2000; Tan
et al., 2013), indicating an ethnic linkage between this subtype of
CHD and Hispanic ethnicity as western Mexican Mestizos have an
Amerindian ancestry estimate of 31% (Rubi-Castellanos et al., 2009).
This common genetic background between Asian and Amerindian
populations could explain the likeliness in observed AVSD rates
between both populations. On the other hand, with the use of ances-
try informative markers in black patients with DS from the United
States, Freeman et al. (2008) found a higher proportion of sub-
Saharan African alleles among black infants with DS and AVSDs as
explanatory evidence for an African origin in the AVSDs. Thus,
previous data support that ethnicity may be pivotal in AVSD occur-
rence among DS patients of different populations. Particularly, AVSD
variations in rates between Blacks, Caucasians, Asians, and Hispanic
population shown in Table S2 suggest, firstly, that African ancestral
chromosomes might have initially introduced the mutational event
responsible for a high AVSD rate in the European populations and,
secondly, that Asian ancestral chromosomes might have also intro-
duced the low AVSD frequencies to the Amerindian populations and
these last to Latin American Mestizo populations, as illustrated in
Figure 1. Also, in relation to ethnicity, CRELD1 gene mutations have
been implicated in the occurrence of AVSDs in Caucasian infants with
DS (Maslen et al., 2006), but not in those born in Mexico (Alcántara-
Ortigoza et al., 2015). Other explanations for such differences could
include also the MTHFR alleles c.1298A and/or c.1298C, both pro-
posed as a risk marker for AVSDs in DS (Locke et al., 2010). Its fre-
quency variation among populations can be relevant because in
Mexicans the c.1298C allele has one of the lowest frequencies in the
world (Contreras-Cubas et al., 2016). Thus, further studies of these
alleles in DS infants with CHDs from our population would contribute
to explain why Hispanic patients with DS have protective odds for
AVSDs.
This report also confirms that the most frequent CHDs in Mexican
children with DS are ASDs (Table 1) (de Rubens-Figueroa et al., 2003;
Rodríguez-Hernández & Reyes-Núñez, 1984). ASDs are usually con-
sidered a less severe CHD, and its trends indicate that they have been
increasing over time among infants with DS (Bergström et al., 2016).
As a consequence, ASDs have been positioned as a prevalent CHD in
large population-based studies from Europe, and also in infants with
DS from the Middle East and from South Korea (Table S2). We

F I G U R E 1 Geographic distribution of atrioventricular septal defect (AVSD) frequencies informed in different worldwide populations with
Down syndrome. Rates over 30% are presented predominantly in Africans, Middle East, and Caucasian populations (blue), whereas rates under
20% are found in Asians and Latin American populations (green). Arrows indicate the probable ancestral relationship among populations (see the
text). Specific frequencies by country are available in Table S2 [Color figure can be viewed at wileyonlinelibrary.com]
CORONA-RIVERA ET AL.
identified increased odds for ASDs in infants with DS whose mothers
had a lack of FA supplementation before pregnancy in the analysis by
subtype of CHDs (Table S1). A similar finding has been previously
reported in female patients with DS born to Hispanic mothers from
the United States who did not take a supplement containing FA (Bean
et al., 2011). This association evidences an impaired FA or homocyste-
ine metabolism in the development of the heart, possibly by affecting
neural crest cells (Bean et al., 2011). However, as Meijer et al. (2006)
do not confirm this association, more studies are required, particularly
in Hispanics where lack of FA seems to have important negative
effects (Bean et al., 2011). Other associated risks for ASDs in infants
with DS such as female sex preponderance (Bean et al., 2011; Free-
man et al., 2008; Morris et al., 2014; Santoro et al., 2018), or maternal
smoking (Bean et al., 2011; El-Gilany et al., 2017), were not detected
in our study. No additional risks were identified for the other subtypes
of CHDs in our infants with DS. This may reveal a reduced statistical
power because of low sample size of our studied groups (Table S1) or
also could evidence ethnic or sociodemographic differences among
studied populations.
This was a case–control study based on information obtained by
interview and self-reporting, and thus, a recall bias cannot be excluded
as limitation inherent in the study design. A further weakness is that
population studied was confined to live birth infants with DS,
resulting in an underestimation of the rates and subtypes of associ-
ated CHDs. This is because our CRIAC does not register stillbirths
and, also, elective termination of pregnancy for fetal anomaly is not
legal in Western Mexico. Also, our numbers of specific subtypes of
CHDs were small—such as for AVSDs; this would lead that some of
our estimates of the evaluated risk could have been potentially
underestimated.
5 | CO NC LUSIO NS
Prevalent CHDs found in 88% of study cases were ASDs, VSDs, and
AVSDs, being ASD the commonest subtype and AVSD the rarest. This
study found few differences for evaluated maternal risks among
infants with DS with and without CHDs, excepting for findings sug-
gestive of socioeconomic and nutritional disadvantages in the group
of cases. With regard to the subtypes of CHDs, ASDs were associated
with risks related to lack of FA supplementation. No risks for AVSDs
and VSDs were identified in our sample. Upon our review (Table S2
and Figure 1), Asian ancestry in Latin American Mestizo infants with
DS remains the best explanation for our low AVSD rates. Effects of
the genetic makeup by ethnicity and/or its environmental interactions
over cardiac development of infants with DS are required to be con-
sidered in future studies, including its prevention aspects.
ACKNOWLEDGMENTS
We would like to thank to the CRIAC team for their enthusiastic oper-
ative support. We also acknowledge the staff of our Cytogenetics
Unit for its valuable assistance for chromosomal analysis.
7
CONFLIC T OF INT ER E ST
The authors declare no potential conflict of interest.
OR CID
Jorge Román Corona-Rivera https://orcid.org/0000-0002-4626-
148X
Lucina Bobadilla-Morales https://orcid.org/0000-0002-7035-7924
RE FE RE NCE S
Alcántara-Ortigoza, M. A., de Rubens-Figueroa, J., Reyna-Fabian, M. E.,
Estandía-Ortega, B., González-del Angel, A., Molina-Alvarez,  B., …
Díaz-García, L. (2015). Germline mutations in NKX2-5, GATA4, and
CRELD1 are rare in a Mexican sample of Down syndrome patients
with endocardial cushion and septal heart defects. Pediatric Cardiology,
36(4), 802–808. https://doi.org/10.1007/s00246-014-1091-3
Alharbi, K. M., Al-Mazroea, A. H., Abdallah, A. M., Almohammadi, Y.,
Carlus, S. J., & Basit, S. (2018). Targeted next-generation sequencing
of 406 genes identified genetic defects underlying congenital heart
disease in Down syndrome patients. Pediatric Cardiology, 39(8),
1676–1680. https://doi.org/10.1007/s00246-018-1951-3
Bean, L. J., Allen, E. G., Tinker, S. W., Hollis, N. D., Locke, A. E.,
Druschel, C., … Sherman, S. L. (2011). Lack of maternal folic acid sup-
plementation is associated with heart defects in Down syndrome: A
report from the National Down Syndrome Project. Birth Defects
Research Part A Clinical and Molecular Teratology, 91(10), 885–893.
https://doi.org/10.1002/bdra.22848
Bergström, S., Carr, H., Petersson, G., Stephansson, O., Bonamy, A. K.,
Dahlström, A., … Johansson, S. (2016). Trends in congenital heart
defects in infants with Down syndrome. Pediatrics, 138, e20160123.
https://doi.org/10.1542/peds.2016-0123
Bermudez, B. E., Medeiros, S. L., Bermudez, M. B., Novadzki, I. M., &
Magdalena, N. I. (2015). Down syndrome: Prevalence and distribution
of congenital heart disease in Brazil. Sao Paulo Medical Journal, 133(6),
521–524. https://doi.org/10.1590/1516-3180.2015.00710108
Brandalize, A. P. C., Bandinelli, E., dos Santos, P. A., Roisenberg, I., & Schüler-
Faccini, L. (2009). Evaluation of C677T and A1298C polymorphisms of
the MTHFR gene as maternal risk factors for Down syndrome and con-
genital heart defects. American Journal of Medical Genetics Part A, 149A
(10), 2080–2087. https://doi.org/10.1002/ajmg.a.32989
Contreras-Cubas, C., Sánchez-Hernández, B. E., García-Ortiz, H., Martínez-
Hernández, A., Barajas-Olmos, F., Cid, M., … Orozco, L. (2016). Heter-
ogenous distribution of MTHFR gene variants among mestizos and
diverse Amerindian groups from Mexico. PLoS One, 11(9), e0163248.
https://doi.org/10.1371/journal.pone.0163248
de Rubens-Figueroa, J., del Pozzo-Magaña, B., Pablos-Hach, J. L.,
Calderón-Jiménez, C., & Castrejón-Urbina, R. (2003). Heart mal-
formations in children with Down syndrome. Revista Española de Car-
diología, 56(9), 894–899. https://doi.org/10.1016/j.rec.2010.07.003
Durham, N. M., & Koehler, J. L. (1989). Dermatoglyphic indicators of con-
genital heart defects in Down's syndrome patients: A preliminary
study. Journal of Mental Deficiency Research, 33(Pt 4), 343–348.
https://doi.org/10.1111/j.1365-2788.1989.tb01485.x
El-Gilany, A. H., Yahia, S., & Wahba, Y. (2017). Prevalence of congenital
heart diseases in children with Down syndrome in Mansoura, Egypt: A
retrospective descriptive study. Annals of Saudi Medicine, 37(5),
386–392. https://doi.org/10.5144/0256-4947.2017.386
Fixler, D. E., & Threlkeld, N. (1998). Prenatal exposures and congenital
heart defects in Down syndrome infants. Teratology, 58(1), 6–12.
https://doi.org/10.1002/(SICI)1096-9926(199807)58:1<6::AID-
TERA4>3.0.CO;2-0
8 CORONA-RIVERA ET AL.
Freeman, S. B., Bean, L. H., Allen, E. G., Tinker, S. W., Locke, A. E.,
Druschel, C., … Sherman, S. L. (2008). Ethnicity, sex, and the incidence
of congenital heart defects: A report from the National Down Syn-
drome Project. Genetics in Medicine, 10(3), 173–180. https://doi.org/
10.1097/GIM.0b013e3181634867
Freeman, S. B., Taft, L. F., Dooley, K. J., Allran, K., Sherman, S. L.,
Hassold, T. J., … Saker, D. M. (1998). Population-based study of con-
genital heart defects in Down syndrome. American Journal of Medical
Genetics, 80(3), 213–217. https://doi.org/10.1002/(SICI)1096-8628
(19981116)80:3<213::AID-AJMG6>3.0.CO;2-8
Frid, C., Drott, P., Lundell, B., Rasmussen, F., & Annerén, G. (1999). Mortal-
ity in Down's syndrome in relation to congenital malformations. Jour-
nal of Intellectual Disability Research, 43(Pt 3), 234–241. https://doi.
org/10.1046/j.1365-2788.1999.00198.x
Hoe, T. S., Chan, K. C., & Boo, N. Y. (1990). Cardiovascular malformations
in Malaysian neonates with Down's syndrome. Singapore Medical Jour-
nal, 31(5), 474–476.
Huhta, J. C., & Linask, K. (2015). When should we prescribe high-dose folic
acid to prevent congenital heart defects? Current Opinion in Cardiology,
30(1), 125–131. https://doi.org/10.1097/HCO.0000000000000124
Institute of Medicine (US) and National Research Council (US) Committee
to Reexamine IOM Pregnancy Weight Guidelines, Rasmussen, K. M., &
Yaktine, A. L. (2009). Weight gain during pregnancy: Reexamining the
guidelines. Washington, DC: National Academies Press.
Jacobs, E. G., Leung, M. P., & Karlberg, J. (2000). Distribution of symptom-
atic congenital heart disease in Hong Kong. Pediatric Cardiology, 21(2),
148–157.
James, R. (2002). Background and higher education participation: An analysis
of school students' aspirations and expectations. Melbourne: Common-
wealth Department of Education Science & Training.
Jaruratanasirikul, S., Limpitikul, W., Dissaneevate, P., Booncharoen, P., &
Tantichantakarun, P. (2017). Comorbidities in Down syndrome
livebirths and health care intervention: An initial experience from the
birth defects registry in southern Thailand. World Journal of Pediatrics,
13(2), 152–157. https://doi.org/10.1007/s12519-016-0093-z
Källén, B., Mastroiacovo, P., & Robert, E. (1996). Major congenital mal-
formations in Down syndrome. American Journal of Medical Genetics,
65(2), 160–166. https://doi.org/10.1002/(SICI)1096-8628(19961016)
65:2<160::AID-AJMG16>3.0.CO;2-O
Kerstann, K. F., Feingold, E., Freeman, S. B., Bean, L. J., Pyatt, R., Tinker, S.,
… Sherman, S. L. (2004). Linkage disequilibrium mapping in trisomic
populations: Analytical approaches and an application to congenital
heart defects in Down syndrome. Genetic Epidemiology, 27(3),
240–251. https://doi.org/10.1002/gepi.20019
Khoury, M. J., & Erickson, J. D. (1992). Can maternal risk factors influence
the presence of major birth defects in infants with Down syndrome?
American Journal of Medical Genetics, 43(6), 1016–1022. https://doi.
org/10.1002/ajmg.1320430620
Kim, M. A., Lee, Y. S., Yee, N. H., Choi, J. S., Choi, J. Y., & Seo, K. (2014).
Prevalence of congenital heart defects associated with Down syn-
drome in Korea. Journal of Korean Medical Science, 29(11), 1544–1549.
https://doi.org/10.3346/jkms.2014.29.11.1544
Locke, A. E., Dooley, K. J., Tinker, S. W., Cheong, S. Y., Feingold, E.,
Allen, E. G., … Bean, L. J. (2010). Variation in folate pathway genes
contributes to risk of congenital heart defects among individuals with
Down syndrome. Genetic Epidemiology, 34(6), 613–623. https://doi.
org/10.1002/gepi.20518
Masaki, M., Higurashi, M., Iijima, K., Ishikawa, N., Tanaka, F., Fujii, T., …
Hashimoto, S. (1981). Mortality and survival for Down syndrome in
Japan. American Journal of Human Genetics, 33(4), 629–639.
Maslen, C. L., Babcock, D., Robinson, S. W., Bean, L. J., Dooley, K. J.,
Willour, V. L., & Sherman, S. L. (2006). CRELD1 mutations contribute
to the occurrence of cardiac atrioventricular septal defects in Down
syndrome. American Journal of Medical Genetics Part A, 140(22),
2501–2505. https://doi.org/10.1002/ajmg.a.31494
Matsuo, N., Oshima, M., Masuyoshi, N., Shimizu, K., & Okada, R. (1972).
Major and minor anomalies in Japanese children with Down's syn-
drome. Japanese Heart Journal, 13(4), 307–316.
Meijer, W. M., Werler, M. M., Louik, C., Hernandez-Diaz, S., de Jong-van
den Berg, L. T., & Mitchell, A. A. (2006). Can folic acid protect against
congenital heart defects in Down syndrome? Birth Defects Research
Part A Clinical and Molecular Teratology, 76(19), 714–717. https://doi.
org/10.1002/bdra.20312
Mokhtar, M. M., & Abdel-Fattah, M. (2001). Major birth defects among
infants with Down syndrome in Alexandria, Egypt (1995-2000): Trends
and risk factors. Eastern Mediterranean Health Journal, 7(3), 441–451.
Morris, J. K., Garne, E., Wellesley, D., Addor, M. C., Arriola, L., Barisic, I., …
Dolk, H. (2014). Major congenital anomalies in babies born with Down
syndrome: A EUROCAT population-based registry study. American
Journal of Medical Genetics Part A, 164A(12), 2979–2986. https://doi.
org/10.1002/ajmg.a.36780
Rodríguez-Hernández, L., & Reyes-Núñez, J. (1984). Congenital heart dis-
ease in Down's syndrome. Boletín Médico del Hospital Infantil de Méx-
ico, 41(11), 622–625.
Rubi-Castellanos, R., Martínez-Cortés, G., Muñoz-Valle, J. F., González-
Martín, A., Cerda-Flores, R. M., Anaya-Palafox, M., & Rangel-
Villalobos, H. (2009). Pre-Hispanic Mesoamerican demography
approximates the present-day ancestry of Mestizos throughout the
territory of Mexico. American Journal of Physical Anthropology, 139(3),
284–294. https://doi.org/10.1002/ajpa.20980
Ruz-Montes, M. A., Cañas-Arenas, E. M., Lugo-Posada, M. A., Mejía-
Carmona, M. A., Zapata-Arismendy, M., Ortiz-Suárez, L., & Henao-
Montaño, M. I. (2017). Cardiopatías congénitas más frecuentes en
niños con síndrome de Down. Revista Colombiana de Cardiología, 24(1),
66–70. https://doi.org/10.1016/j.rccar.2016.06.014
Sailani, M. R., Makrythanasis, P., Valsesia, A., Santoni, F. A., Deutsch, S.,
Popadin, K., … Antonarakis, S. E. (2013). The complex SNP and CNV
genetic architecture of the increased risk of congenital heart defects in
Down syndrome. Genome Research, 23(9), 1410–1421. https://doi.
org/10.1101/gr.147991.112
Santoro, M., Coi, A., Spadoni, I., Bianchi, F., & Pierini, A. (2018). Sex differ-
ences for major congenital heart defects in Down syndrome: A popula-
tion based study. European Journal of Medical Genetics, 61(9),
546–550. https://doi.org/10.1016/j.ejmg.2018.05.013
Sonoda, T., Kouno, K., Sawada, K., Koizumi, H., Takagi, J., & Yamasaki, S.
(2000). Increasing incidence of congenital heart disease in patients
with Down syndrome. Congenital Anomalies (Kyoto), 40, 112–116.
https://doi.org/10.1111/j.1741-4520.2000.tb00915.x
Stoll, C., Dott, B., Alembik, Y., & Roth, M. P. (2015). Associated congenital
anomalies among cases with Down syndrome. European Journal of
Medical Genetics, 58(12), 674–680. https://doi.org/10.1016/j.ejmg.
2015.11.003
Tan, M., Xu, C., Sim, S. K., Seow, A. L., Tan, T. H., & Quek, S. C. (2013).
Types and distribution of congenital heart defects associated with tri-
somy 21 in Singapore. Journal of Paediatrics and Child Health, 49(3),
223–227. https://doi.org/10.1111/jpc.12129
Torfs, C. P., & Christianson, R. E. (1999). Maternal risk factors and major
associated defects in infants with Down syndrome. Epidemiology, 10
(3), 264–270.
Valdés, S. T., Tostes, M. D. G. V., Anunciação, P. C., da Silva, B. P., &
Sant'Ana, H. M. P. (2017). Association between vitamin deficiency and
metabolic disorders related to obesity. Critical Reviews in Food Science
and Nutrition, 57(15), 3332–3343. https://doi.org/10.1080/1040839
8.2015.1117413
Vida, V. L., Barnoya, J., Larrazabal, L. A., Gaitan, G., de Maria-Garcia, F., &
Castañeda, A. R. (2005). Congenital cardiac disease in children with
Down's syndrome in Guatemala. Cardiology in the Young, 15(3),
286–290. https://doi.org/10.1017/S1047951105000582
World Health Organization BMI Classification. (2012). The International
Classification of adult underweight overweight and obesity according
CORONA-RIVERA ET AL.
to BMI; 2017. Retrieved from http://apps.who.int/bmi/index.jsp?
introPage=intro_3.html.
SUPPORTING INFORMATION
Additional supporting information may be found online in the
Supporting Information section at the end of this article.
9
How to cite this article: Corona-Rivera JR, Nieto-García R,
Gutiérrez-Chávez AS, et al. Maternal risk factors for congenital
heart defects in infants with Down syndrome from Western
Mexico. Am J Med Genet Part A. 2019;1–9. https://doi.org/10.
1002/ajmg.a.61300