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Maternal Age and Prevalence of Isolated Congenital

Heart Defects in an Urban Area of the United States
Assia Miller,1,2 Tiffany Riehle-Colarusso,1 Csaba Siffel,1,3 Jaime L. Fras,1,4 and Adolfo Correa1*
Division of Birth Defects and Developmental Disabilities, National Center on Birth Defects and Developmental Disabilities, Centers for Disease
Control and Prevention, Atlanta, Georgia
Research Triangle Institute International, Atlanta, Georgia
Computer Sciences Corporation, Atlanta, Georgia
McKing Consulting Corporation, Fairfax, Virginia

Received 2 September 2010; Accepted 1 May 2011

Although maternal age has been associated with a number of

birth defects in several reports, the literature on the association How to Cite this Article:
of maternal age with isolated congenital heart defect (CHD) Miller A, Riehle-Colarusso T, Siffel C, Fras JL,
phenotypes has been limited. We evaluated CHD prevalence Correa A. 2011. Maternal age and prevalence
based on a cohort of 5,289 infants and fetuses with isolated of isolated congenital heart defects in an
CHDs born during the period 19682005 and ascertained by the urban area of the United States.
Metropolitan Atlanta Congenital Defects Program (MACDP)
Am J Med Genet Part A 9999:19.
among residents of ve central counties in Atlanta. For our
denominator, we obtained information on births to residents
of the same counties from vital records (n 1,301,143). We
calculated prevalence ratios for 23 CHD phenotypes by several Most CHDs have a multifactorial etiology, involving interactions
maternal age categories, using the group 2529 years of age as a between genetic and nongenetic factors. Previous studies have
reference group. We used Poisson regression models to estimate identied possible risk factors, including maternal pregestational
adjusted prevalence ratios (aPRs) and 95% condence intervals diabetes and rubella [Jenkins et al., 2007], gestational age
(CIs), controlling for maternal race, infant sex, and birth cohort. [Rasmussen et al., 2001; Tanner et al., 2005] and intrauterine
A maternal age of 35 years or older was associated with an growth restriction [Malik et al., 2007], infant sex [Rothman and
increased prevalence for several CHD phenotypes: laterality Fyler, 1976; Pradat, 1992; OMalley et al., 1996; Ferencz et al., 1997;
defects (aPR 2.06; CI 1.223.48), all conotruncal defects Pradat et al., 2003], and maternal race [Francannet et al., 1993;
(aPR 1.30; CI 1.031.65), and specically for dextro-trans- Ferencz et al., 1997]. In addition some investigators have shown an
position of the great arteries (aPR 1.65; CI 1.102.48), coarc- increased prevalence of CHD among children born to women
tation of the aorta (aPR 1.54; CI 1.102.16), ventricular septal 35 years and older [Rothman and Fyler, 1976; Croen and Shaw,
defects (aPR 1.20; CI 1.061.36), and atrial septal defects 1995; Hollier et al., 2000; Pradat et al., 2003; Reefhuis and Honein,
(aPR 1.36; CI 1.051.77). Our ndings suggest that the birth 2004; Garg et al., 2008]. Evaluating the effect of maternal age on
prevalence of specic isolated CHDs varies with maternal age. CHD prevalence is of particular importance because during the past
Further studies are warranted to corroborate these observations, decade the proportion of women in the United States who gave
taking into account potential confounding by known modiable
risk factors. Published 2011 Wiley-Liss, Inc.
Additional supporting information may be found in the online version of
Key words: congenital heart defects; maternal age; epidemiology this article.
of congenital heart defects The ndings and conclusions in this report are those of the authors and do
not necessarily represent the ofcial position of the Centers for Disease
Control and Prevention.
INTRODUCTION *Correspondence to:
Adolfo Correa, M.D., Ph.D., National Center on Birth Defects and
Congenital heart defects (CHDs) are the most common type of
Developmental Disabilities, Centers for Disease Control and Prevention,
birth defects, occurring in approximately 39 of every 1,000 live Mailstop E-86, 1600 Clifton Road, Atlanta, GA 30333
births [Wilson et al., 1993; Wren et al., 2000; Botto et al., 2001; E-mail: acorrea@cdc.gov
Dastgiri et al., 2002; Pradat et al., 2003; Correa et al., 2007; Reller Published online 00 Month 2011 in Wiley Online Library
et al., 2008], and account for a signicant proportion of infant (wileyonlinelibrary.com).
mortality due to birth defects [Yang et al., 1997; Lee et al., 2001]. DOI 10.1002/ajmg.a.34130

Published 2011 Wiley-Liss, Inc.

This article is a US Government work and, as such, is in the public domain in the United States of America.


birth after age 35 increased signicantly [Hamilton and Ventura, Atlanta on behalf of the Georgia Division of Public Health, Georgia
2006]. Department of Human Resources, and has CDCs Institutional
However, there has been little consistency in the literature Review Board approval. Further details about this system have been
regarding the strength and direction of the association with mater- published elsewhere [Correa et al., 2007].
nal age [Hollier et al., 2000; Cedergren et al., 2002; Reefhuis and
Honein, 2004; Amorim et al., 2008; Garg et al., 2008] (see Supple-
mentary Appendix). While some authors have reported a U-shaped Case Classication
effect [Cedergren et al., 2002; Reefhuis and Honein, 2004], others All MACDP records on case infants with nonchromosomal CHDs
have described a linear relationship with increasing strength of the (ICD9-CM codes 745.0747.9) were reviewed and their CHDs were
association with increasing maternal age [Hollier et al., 2000; classied by experts in pediatric cardiology according to a standard
Amorim et al., 2008; Garg et al., 2008]. Furthermore, information clinical nomenclature from the Society of Thoracic Surgeons (STS)
on the variation in prevalence of specic CHD phenotypes with and a presumed embryological developmental schema described
maternal age is limited by the inconsistency in the type of CHDs elsewhere [Riehle-Colarusso et al., 2007]. The records reviewed on
examined and the mixed results observed across studies. For each CHD case consisted of information abstracted from medical
example, while one investigator [Pradat et al., 2003] found a records by trained medical abstractors. Such information included
signicant association between advanced maternal age and tetral- cardiac diagnoses, presence of other defects, methods of diagnosis
ogy of Fallot and atrioventricular septal defects (AVSDs), other (e.g., echocardiography, catheterization, surgery or autopsy), and
investigators did not [Baird et al., 1991; OMalley et al., 1996; Loane results of laboratory tests (e.g., genetic tests). Normal physiologic
et al., 2009]. Furthermore, very few studies have been population- ndings in premature or newborn infants less than 6 weeks of age
based and have accounted for possible effect modiers such as low such as patent ductus arteriosus (PDA), patent foramen ovale, or
birth weight (LBW), preterm delivery, maternal race, and infant sex. valve insufciency unrelated to structural valve abnormality were
In a previous analysis Reefhuis and Honein [2004] reported sig- not considered structural abnormalities and were excluded from
nicant associations between maternal age 3540 and tricuspid analysis (n 613). PDA was only considered a CHD if occurring in
atresia and right ow tract defects, but, even though they excluded term infants, persisting beyond 6 weeks of life, and not maintained
case infants with chromosomal abnormalities, they did not exclude patent to ensure survival due to another cardiac condition. For this
those with nonchromosomal syndromes or with nonsyndromic study, 23 CHD phenotypes were grouped into nine broad categories
associated extra-cardiac anomalies. (cardiac looping, conotruncal defects, AVSDs, left or right ven-
Our study expands on previous work by utilizing an extended tricular tract obstruction (LVOTO or RVOTO) defects, ventricular
birth cohort and a current, standard CHD classication system, and septal defects (VSDs), atrial septal defects (ASDs), laterality defects,
by examining isolated CHDs without associated major noncardiac and cell growth defects). Inlet-type VSDs were included in the
malformations. In this study, we used population-based surveil- AVSD category and malaligned or conotruncal type VSDs in the
lance data to: (1) examine the effect of increasing maternal age on conotruncal group. The cell growth defects category comprised
the prevalence for several isolated (nonsyndromic) CHD pheno- total and partial anomalous pulmonary venous return, ASD sinus
types, while accounting for selected maternal and infant character- venosus, and cor triatrium. Phenotypes with fewer than ve cases
istics; and (2) explore potential effect modication of the maternal per maternal age category were excluded.
age group-specic CHD prevalence estimates by preterm birth, We rst identied all cases with CHDs in the MACDP (ICD-9
LBW, maternal race, and infant sex. codes) born between January 1, 1968 and December 31, 2005. We
used ICD-9 codes starting with 758 to exclude cases with chromo-
METHODS somal abnormalities within this set of cases with CHDs. To further
exclude cases with multiple malformations, we used codes 756.4
Study Population and 756.5 that identify chondrodystrophies and osteodystrophies,
We identied singleton live born and stillborn infants and fetuses respectively. In addition, a clinical geneticist (JLF) manually
diagnosed with CHDs during the period January 1, 1968 reviewed the records of all remaining cases with multiple codes
December 31, 2005 using data from the Metropolitan Atlanta to identify and exclude cases with multiple congenital anomalies
Congenital Defects Program (MACDP). MACDP is an ongoing and specic syndromes. Noncardiac defects were dened as
population-based birth defects surveillance system established in major if they had surgical, medical, or serious cosmetic impor-
1968 to actively ascertain birth defects among live born and stillborn tance (Rasmussen et al., 2003).
infants of 20 weeks gestation or >500 g birth weight born to
residents of ve counties in metropolitan Atlanta, Georgia. This
program routinely collects demographic characteristics and clinical Denominator
information of structural birth defects, chromosomal abnormal- For the denominator of our prevalence estimates, we obtained vital
ities, and syndromes from several data sources. The defects are records information on all infants born in ve counties in metro-
coded using a modied 6-digit code from the International Clas- politan Atlanta from the same birth cohort that gave rise to the CHD
sication of Diseases (ICD), Ninth Revision, Clinical Modication, cases (n 1,301,143). Our denominator was limited to infants who
and the British Paediatric Association Classication of Diseases were singleton and live born at 20 weeks of gestation. Since we had
developed for MACDP. MACDP was granted authority to conduct a limited ability to link individual cases to their underlying birth
birth defect surveillance in the ve central counties of metropolitan records, we applied rate-based methodology for analyzing MACDP

population-based design. Our analyses employed grouped case and and prematurity-associated heart conditions (e.g., PDA, patent
live birth counts to produce both crude and model adjusted foramen ovale, peripheral pulmonic stenosis; n 613) resulted in a
prevalence estimates and prevalence ratio (PR) estimates. total of 5,289 infants with isolated CHDs and a prevalence of 40.6
per 10,000 live births. Table I shows the number of case infants with
isolated CHDs and their prevalence rates per 10,000 live births
Covariates among maternal age categories and for all births by birth cohort,
We used MACDP data to obtain information on maternal age, maternal race or ethnicity, infant sex, gestational age, and birth
parity, gestational age, birth weight, maternal race or ethnicity, and weight. The prevalence of CHDs increased among all groups of
infant sex for case infants and used birth certicate data to obtain women, regardless of age, across successive birth cohorts, partic-
information on maternal age, parity, gestational age, birth weight, ularly among infants born to women 35 years of age or older from
maternal race or ethnicity, and infant sex for the denominator. We prevalence per 10,000 live births of 32.5 (CI 23.843.3) for birth
grouped maternal age at birth into the following categories: cohort 19681980 to 63.0 (CI 57.868.4) for birth cohort
younger than 20, 2024, 2529 (reference), and 3034 years of 19932005.
age, and 35 years of age or older. Infants of mothers with missing age Prevalence rate ratios for all selected CHDs in the aggregate
information were excluded from analysis (n 21). We created increased monotonically with maternal age, from the group
categories for birth cohort (19681980, 19811992, and younger than 20 years of age (aPR 0.93; CI 0.811.06) to the
19932005), infant sex (male and female), and maternal race group 35 years of age or older (aPR 1.17; CI 1.051.31; Table II).
(White and Nonwhite). The race category Nonwhite comprised Table II shows the aPRs for CHDs across maternal age categories,
all other racial and ethnic categories (as dened by the U.S. Ofce of adjusted for infant sex, maternal race or ethnicity, and birth
Management and Budget). We dened parity as number of prior period. Compared with infants born to mothers 2529 years of
live births, and grouped women without previous live births as age, infants born to mothers 35 years of age or older, had an
nulliparous and women with one or more live births as increased prevalence for several broad categories of CHD, including
multiparous. laterality defects (aPR 2.03; CI 1.014.10); conotruncal defects
(aPR 1.30; CI 1.031.65), VSDs (aPR 1.20; CI 1.061.36);
ASDs (aPR 1.36; CI 1.051.77); as well as for specic phenotypes
Statistical Analysis such as D-TGA (aPR 1.65; CI 1.102.48), and coarctation of the
We calculated prevalence rates per 10,000 live births within each aorta (aPR 1.54; CI 1.102.16). Infants born to younger mothers
maternal age group relative to those within the reference group. We (<20 years of age) had a decreased prevalence of valvar pulmonic
applied Pearson Chi-squared statistics and Poisson regression stenosis (aPR 0.66; CI 0.440.98), and an increased prevalence of
models to estimate adjusted prevalence ratios (aPRs) and 95% laterality defects (aPR 2.06; CI 1.223.48). Additionally, infants
condence intervals (CIs) for each of the different age categories, born to mothers 2024 years of age had a decreased prevalence of
comparing them with the reference category [Cameron and Triv- aortic stenosis (aPR 0.50; CI 0.280.89), membranous VSDs
edi, 1998], adjusting for birth cohort (19681980, 19811992, or (aPR 0.78; CI 0.610.99), and muscular VSDs (aPR 0.83; CI
19932005), infant sex (male or female), and maternal race (White 0.700.99). We examined the association of CHD and paternal
or Nonwhite). We used Cochran-Armitage trend test for analysis of age and found no difference in specic associations compared
trend. to the analysis of CHD and maternal age. We performed addi-
Maternal age was grouped into larger categories [1530 tional analyses comparing PRs before folate supplementation
(reference), 3035, and 3555 years of age] to increase the sample (19681996) and after mandatory folate supplementation
size of the maternal age groups, and stratied by maternal race, (19992005) for each specic CHD selected for the study and
infant sex, preterm delivery (<37 weeks or 37 weeks), and LBW for CHD in the aggregate and we found no differences between
(<2,500 g or 2,500 g) to examine variations in PRs among strata the two cohorts.
of these covariates. For examination of statistical interaction There were several signicant ndings for CHDs among infants
between covariates and maternal age categories, we used a Chi- born to mothers in the older age groups, stratied by various
squared test in Poisson regression. In our study of statistical covariates (Table III). Compared with infants with normal birth
interactions between maternal age and covariates, we used multi- weight, infants with LBW born to mothers 3034 years of age had
plicative terms in Poisson models [Rothman et al., 2008]. We signicantly increased prevalence of all selected CHDs
present both crude and stratied PRs, and P-values for signicant (P 0.0005), LVOTOs (P 0.0320), and VSDs (P 0.0064),
interactions (P < .05). We used SAS-PC for computation (9.01 v, and those born to mothers 35 years of age or older had a signicantly
SAS Institute, Inc, Raleigh, NC). increased prevalence of RVOTO (P 0.0079; Table III). Preterm
infants born to mothers 30 years of age or older were more likely to
have an increased risk for total CHDs (P 0.0007 for the maternal
RESULTS group 3034 years of age; P < 0.0000 for the group 35 years of age or
We identied 8,277 live born and stillborn infants and fetuses with older); specically, premature infants born to mothers 3034 years
nonchromosomal CHDs born during the period January 1, 1968- of age had a higher risk of all VSDs (P 0.0013). There were
December 31, 2005, among 1,301,143 live births in metropolitan signicant variations in prevalence estimates among infants born
Atlanta. Exclusion of infants with syndromes or undened patterns to White women and infants born to Nonwhite women, all of whom
of associated major noncardiac congenital anomalies (n 2,375), were 35 years of age or older, for the broad categories of cardiac
TABLE I. Number of Cases and Prevalence of Isolated Congenital Heart Defects per 10,000 Livebirths by Demographic and Clinical Descriptive Characteristics, Metropolitan
Atlanta, 19682005
Maternal age <20 years Maternal age 2024 years Maternal age 2529 years Maternal age 3034 years Maternal age 35 years Total Armitage
trend test
Cases Prevalence Cases Prevalence Cases Prevalence Cases Prevalence Cases Prevalence Cases Prevalence
no. (95% CIa) no. (95% CI) no. (95% CI) no. (95% CI) no. (95% CI) no. (95% CI) P-Values
Birth cohort
19681980 191 29.5 (25.534.0) 296 27.2 (24.230.5) 282 29.5 (26.133.1) 116 26.8 (22.132.1) 46 32.5 (23.843.3) 931 28.5 (26.730.4) 0.8875
19811992 161 31.8 (27.137.2) 336 32.9 (29.536.6) 421 35.0 (31.738.5) 305 35.6 (31.739.8) 143 44.0 (37.151.8) 1,366 34.9 (33.136.8) 0.0060
19932005 261 43.2 (38.148.8) 564 44.3 (40.748.1) 798 51.7 (48.155.4) 819 53.2 (49.757.0) 550 63.0 (57.868.4) 2,992 51.3 (49.553.1) <0.0001
Race or ethnicity
White 273 36.5 (32.341.1) 666 36.3 (33.639.2) 971 41.7 (39.144.4) 849 45.0 (42.048.1) 500 56.9 (52.062.1) 3,259 42.4 (41.043.9) <0.0001
Nonwhite 339 33.7 (30.237.5) 528 34.3 (31.537.4) 523 38.4 (35.241.9) 388 41.7 (37.646.1) 238 52.2 (45.859.3) 2,016 38.1 (36.539.8) <0.0001
Infant sex
Male 308 34.2 (30.538.3) 590 34.2 (31.537.1) 765 40.4 (37.643.3) 635 43.9 (40.647.5) 380 55.4 (50.061.3) 2,678 40.3 (38.741.8) <0.0001
Female 304 35.5 (31.639.7) 606 36.6 (33.839.7) 736 40.7 (37.843.7) 604 43.7 (40.347.3) 359 54.8 (49.360.8) 2,609 41.0 (39.542.6) <0.0001
Gestational age
Term 484 39.6 (36.243.3) 963 38.9 (36.541.5) 1,239 43.9 (41.546.4) 995 44.0 (41.346.8) 571 51.8 (47.656.2) 4,252 43.0 (41.744.3) <0.0001
Preterm 118 49.7 (41.159.5) 217 64.5 (56.273.7) 245 77.3 (68.087.7) 220 93.6 (81.7106.8) 160 126.3 (107.5147.4) 960 76.6 (71.981.7) <0.0001
Birth weight
2,500 g 476 31.8 (29.034.8) 988 32.5 (30.534.6) 1,261 36.9 (34.939.0) 1,026 39.0 (36.641.4) 600 48.7 (44.952.8) 4,351 36.8 (35.737.9) <0.0001
<2,500 g 135 64.6 (54.276.5) 205 72.4 (62.883.0) 235 97.1 (85.1110.3) 212 121.1 (105.4138.6) 134 133.1 (111.5157.7) 921 91.2 (85.497.3) <0.0001
Nulliparous 460 34.7 (31.638.0) 584 35.3 (32.538.3) 648 42.6 (39.446.0) 391 42.8 (38.747.3) 192 58. 0(50.166.8) 2,275 39.6 (38.041.2) <0.0001
Multiparous 140 35.8: (30.142.3) 581 34.9 (32.137.8) 831 39.0 (36.441.8) 833 44.1 (41.247.2) 541 54.2 (49.759.0) 2,926 41.4 (39.942.9) <0.0001

Total 613 34.9 (32.237.8) 1,196 35.4 (33.437.4) 1,501 40.5 (38.542.6) 1,240 43.8 (41.446.4) 739 55.1 (51.259.3) 5,289 40.6 (39.641.8) <0.0001
Condence interval.

TABLE II. Adjusted Prevalence Ratios for Isolated Congenital Heart Defects Among Maternal Age Groups, Adjusted for Sex, Time Cohort, and Maternal Race or Ethnicity, Metropolitan
Atlanta Congenital Defects Program, 19682005

Maternal age <20 years Maternal age 2024 years Maternal age 3034 years Maternal age 35 years
Congenital heart defects Cases no. aPR (95% CIa) Cases no. aPR (95% CI) Cases no. aPR (95% CI) Cases no. aPR (95% CI)
Laterality defect 31 2.06 (1.223.48)b 37 1.41 (0.872.30) 27 1.51 (0.872.62) 15 2.03 (1.014.10)
Cardiac looping 13 1.12 (0.552.28) 32 1.29 (0.762.19) 34 1.69 (1.002.86) 12 1.54 (0.763.11)
Any single ventricle 10 1.18 (0.542.60) 23 1.12 (0.612.06) 24 1.64 (0.893.01) 9 1.57 (0.703.55)
Conotruncal defect 105 0.96 (0.761.22) 200 0.94 (0.771.13) 164 0.89 (0.731.09) 109 1.30 (1.031.65)
Tetralogy of Fallot 48 0.95 (0.661.37) 92 0.91 (0.681.21) 77 0.98 (0.721.32) 46 1.30 (0.901.86)
D-TGA 32 0.83 (0.551.26) 58 0.80 (0.571.12) 48 0.76 (0.531.10) 39 1.65 (1.102.48)
Vascular ring 9 1.24 (0.562.76) 14 0.87 (0.441.71) 22 1.61 (0.872.98) 8 1.11 (0.472.60)
AVSDs 11 1.00 (0.492.03) 24 0.67 (0.401.14) 20 0.67 (0.381.18) 14 1.30 (0.662.54)
Complete AVSDs 9 1.54 (0.594.07) 15 0.91 (0.431.93) 14 1.27 (0.572.82) 6 1.73 (0.456.73)
LVOTOs 76 0.77 (0.591.01) 171 0.84 (0.691.03) 179 1.00 (0.821.22) 94 1.12 (0.871.44)
HLHS 34 1.00 (0.661.54) 66 1.05 (0.741.48) 53 1.09 (0.751.57) 21 1.17 (0.691.98)
Coarctation of the aorta 25 0.66 (0.421.03) 83 0.86 (0.651.15) 91 1.09 (0.821.45) 57 1.54 (1.102.16)
Aortic stenosis 13 0.88 (0.451.72) 16 0.50 (0.280.89) 29 0.88 (0.541.44) 12 1.01 (0.521.96)
RVOTOs 57 0.79 (0.581.08) 123 0.91 (0.711.15) 105 0.84 (0.651.08) 74 1.15 (0.861.53)
Valvar pulmonic stenosis 31 0.66 (0.440.98) 83 0.81 (0.611.08) 82 0.86 (0.651.15) 66 1.33 (0.971.82)
VSDs 283 0.91 (0.801.05) 560 0.89 (0.801.00) 638 1.02 (0.921.14) 379 1.20 (1.061.36)
Membranous VSDs 55 0.81 (0.601.11) 111 0.78 (0.610.99) 124 0.86 (0.681.09) 91 1.21 (0.931.58)
Muscular VSDs 95 0.82 (0.651.03) 218 0.83 (0.700.99) 351 1.03 (0.881.19) 212 1.11 (0.941.32)
ASDs 72 0.97 (0.731.29) 117 0.81 (0.641.03) 118 0.85 (0.671.08) 91 1.36 (1.051.77)
Secundum ASDs 39 0.89 (0.611.31) 76 0.90 (0.671.21) 82 0.87 (0.651.17) 64 1.32 (0.961.82)
Ebsteins anomaly 6 1.79 (0.684.73) 13 1.22 (0.582.54) 12 1.20 (0.552.60) 10 1.94 (0.834.53)
Cell growth defects 13 1.23 (0.642.37) 29 0.86 (0.531.40) 30 1.06 (0.641.73) 12 1.20 (0.592.43)
Total and partial anomalous 11 1.25 (0.622.56) 22 0.88 (0.511.51) 24 1.42 (0.812.52) 10 1.51 (0.693.29)
pulmonary venous return
Total heart defects 613 0.93 (0.811.06) 1,196 0.91 (0.821.00) 1,240 0.98 (0.891.07) 739 1.17 (1.051.3)
aPR, adjusted prevalence ratio (reference group is maternal age 2529 years); CI, condence interval; D-TGA, dextro-transposition of the great arteries; AVSDs, atrioventricular septal defects; HLHS, hypoplastic left heart syndrome; LVOTOs,
left ventricular outow tract obstructions; RVOTOs, right ventricular outow tract obstructions; VSDs, ventricular septal defects; ASDs, atrial septal defects; TOF, tetralogy of Fallot; TAPVR, total anomalous pulmonary venous return.
Condence interval.
Bolded results indicate statistically signicant values (P < 0.05).

TABLE III. Crude and Stratied Prevalence Ratios for Isolated Congenital Heart Defects Among Maternal Age Groups by Maternal Race or
Ethnicity, Sex, Birth weight, and Preterm Delivery, Metropolitan Atlanta Congenital Defects Program, 19682005
Maternal age
Defect (years) PR crude (95% CI) Cofactor PR stratied (95% CI) P-Valuesa
Laterality defects 35 1.01 (0.591.74) Male 1.74 (0.873.48) 0.0496
Female 0.55 (0.221.37)
Cardiac looping defects 3035 1.46 (0.972.19) White 0.95 (0.561.61) 0.0136
Nonwhite 2.80 (1.425.50)b
Conotruncal defects 3035 0.95 (0.801.13) Preterm 1.52 (0.962.39) 0.0205
Term 0.85 (0.701.02)
AVSDs 3035 0.92 (0.561.51) Preterm 2.71 (0.868.53) 0.0454
Term 0.73 (0.421.29)
LVOTOs 3035 1.18 (0.991.40) LBW 1.94 (1.213.12) 0.0320
Normal BW 1.11 (0.921.34)
RVOTOs 35 1.46 (1.131.87) LBW 2.57 (1.624.10) 0.0079
Normal BW 1.21 (0.901.64)
35 1.46 (1.131.87) Preterm 2.28 (1.443.61) 0.0117
Term 1.12 (0.821.52)
VSDs 3035 1.27 (1.161.39) LBW 1.71 (1.372.13) 0.0064
Normal BW 1.22 (1.101.35)
3035 1.27 (1.161.39) Preterm 1.68 (1.352.10) 0.0013
Term 1.13 (1.021.25)
35 1.59 (1.421.78) Preterm 2.01 (1.552.60) 0.0113
Term 1.39 (1.221.57)
35 1.59 (1.421.78) White 1.69 (1.481.93) 0.0458
Nonwhite 1.31 (1.051.62)
Total heart defects 3035 1.17 (1.101.25) LBW 1.55 (1.321.81) 0.0005
Normal BW 1.14 (1.061.22)
3035 1.17 (1.101.25) Preterm 1.44 (1.231.68) 0.0007
Term 1.07 (0.991.15)
35 1.47 (1.361.60) Preterm 1.94 (1.632.31) 0.0000
PR, prevalence ratios (reference group is maternal age <30 years); CI, condence interval; LBW, low birthweight; D-TGA, dextro-transposition of the great arteries; AVSDs, atrioventricular
septal defects; HLHS, hypoplastic left heart syndrome; LVOTOs, left ventricular outow tract obstructions; RVOTOs, right ventricular outow tract obstructions; VSDs, ventricular septal defects; ASDs,
atrial septal defects; PDA, patent ductus arteriosus; TOF, tetralogy of Fallot.
P < 0.05 of Chi-squared test for interaction term of maternal age category and cofactor for specic CHDs in Poisson regression.
Bolded results indicate statistically signicant values P < 0.05.

looping (P 0.0136) and all VSDs (P 0.0458). We found a addition, our study included cases of CHDs among liveborns,
predominance of laterality defects among males born to women stillborns, and fetuses from a dened population ascertained by
35 years of age or older (Table III). an active surveillance system with high sensitivity; thus, it repre-
sents a more inclusive group of case infants than reported by most
other surveillance programs. Furthermore, a clinical, standardized
DISCUSSION nomenclature and developmental schema were used to classify
Our ndings suggest that the birth prevalence of isolated CHDs in heart defects and eliminate nonstructural and newborn or
the aggregate might be associated with advanced maternal age, prematurity-associated cardiac conditions [Riehle-Colarusso
especially 35 years of age or older. Infants born to mothers older et al., 2007], and cases with associated noncardiac anomalies
than 35 years of age seemed to be at 20% increased risk of CHDs, were carefully reviewed by a dysmorphologist to exclude those
while infants born to younger mothers tended to be at decreased risk with major anomalies and syndromes. Comparing to the study by
of CHDs. Our results also suggest an effect of advanced maternal age Reefhuis and Honein [2004] we included only cases of CHD
on the prevalence of specic groups of CHDs, such as laterality without associated major noncardiac malformations, used a differ-
defects, conotruncal defects, LVOTOs, RVOTOs, AVSDs, and ent CHD classication and groups of CHD [Riehle-Colarusso et al.,
VSDs. 2007], had an extended birth cohort, and also accounted for
To our knowledge, our study is the rst population-based study possible effect modiers such as LBW, preterm delivery, maternal
to assess the associations between various maternal age groups and race, and infant sex. Syndromic cases and cases with additional
different phenotypic categories of isolated CHDs, and to investigate noncardiac major malformations were excluded from our analysis.
possible variation of these associations by potential effect modiers Our study had several limitations. First, the sample size for some
such as birth weight, preterm birth, maternal race, and infant sex. In of the CHD phenotypes was relatively small. Consequently, we

might not have had an adequate statistical power to detect real pulmonary stenosis. We also observed a decreased aPR for mem-
associations or evaluate the cumulative effect of birth weight and branous and muscular VSDs among offspring of mothers in the
gestational age on specic CHD phenotypes among maternal 2024 years of age group, which is consistent with a previous
categories 3539 and 4045 years of age. Second, our reference publication [Pradat et al., 2003]. Further studies are warranted
population did not include stillbirths and elective terminations. to corroborate these ndings and, if conrmed, to elucidate pos-
Also, we were able to stratify maternal race or ethnicity only as sible reasons for these associations.
White versus Nonwhite because we did not have more detailed Our nding of an association of ASDs with advanced maternal
information on race or ethnicity categories for the earlier years of age is consistent with several previous reports [Rothman and Fyler,
the study data. Thus, we could not determine if racial or ethnic 1976; Ferencz et al., 1997; Pradat et al., 2003; Forrester and Merz,
disparity in our results reected disparities for Hispanics/Latinos, 2008]. Our ndings also corroborated other studies showing an
Black or African-American, or for Asian or other ethnic subgroups. effect of advanced maternal age on VSDs [Rothman and Fyler, 1976;
Although advanced paternal age may be an additional confounder, Forrester and Merz, 2008], coarctation of the aorta [McBride et al.,
as it is associated with increased mutation rate for autosomal 2005], and D-TGA [Rothman and Fyler, 1976; Ferencz et al., 1997;
dominant diseases, we were not able to study it because MACDP Reefhuis and Honein, 2004]. Some discrepancies between our study
did not start collecting paternal age information until 1984. Con- and previous reports regarding the association between maternal
sequently, paternal age information was missing in 44% of cases. age and increased risk of selected CHD phenotypes might be due in
Furthermore, this information is often missing on vital records, part to differences in study populations, methods, and unaccounted
which are the main source of data on paternal age. Lastly, our confounding or effect modication [Correa-Villase~ nor et al., 1994;
ascertainment of CHDs relied heavily on hospital charts and their Pradat et al., 2003; Reefhuis and Honein, 2004; McBride et al., 2005;
related diagnostic evaluations (roentgenograms, color Doppler Forrester and Merz, 2008]. For example, a casecontrol study
echocardiography, or autopsies when available). We have opted designed to evaluate the effects of exposure to trichloroethylene
for not using any of the methods to account for multiple compar- (TCE) on the risk of CHDs found maternal age to be an effect
isons because such methods have not proven to be widely accepted modier for the relationship between TCE and CHDs [Yauck et al.,
or used, particularly in situations where the inferential process may 2004]. So differences in exposure to possible effect modiers among
be more complex and involve a sequential exploratory approach studies could potentially result in apparent null effects when in fact
(e.g., going from the aggregate to subgroups to more specic the level of association might differ across strata of the effect
phenotypes) in an effort to determine possible sources of variation. modier of interest. Advanced maternal age has also been asso-
Our results suggest that the prevalence of isolated CHDs as a ciated with the use of assisted reproductive technology, which in
group increases with increasing maternal age, as has also been noted turn has been associated with septal heart defects [Reefhuis et al.,
by other authors [Croen and Shaw, 1995; Hollier et al., 2000; 2009]. So differences in exposure to assisted reproductive technol-
Reefhuis and Honein, 2004; Forrester and Merz, 2008]. In the ogy or prevalence of infertility among study populations could also
maternal age category 35 years of age or older, our estimates were explain some of the differences in ndings between studies. We had
within the ranges previously reported by others [Hollier et al., 2000; no information on the use of assisted reproductive technology in
Reefhuis and Honein, 2004; Reller et al., 2008]. However, Reefhuis our study population, so we were not able to address this issue. We
and Honein [2004] found a U-shaped relationship, resulting from a did examine parity as a covariate by conducting analyses stratied
slightly increased PR for all CHDs among younger maternal age by parity and found no effect of parity (data not shown). Addi-
categories. This discrepancy with our ndings could be explained in tionally, several maternal co-morbidities such as diabetes [Wren
part by the fact that we used a different cohort of CHD case infants et al., 2003; Correa et al., 2008], obesity [Gilboa et al., 2010],
and a different CHD classication system. While four previous hypertension [Caton et al., 2009], medication use (e.g., selective
studies did not nd an association of CHDs in the aggregate with serotonin-reuptake inhibitors [Louik et al., 2007]), and smoking
maternal age [Baird et al., 1991; Ferencz et al., 1997; Cedergren et al., [Malik et al., 2008; Alverson et al., 2011] could be related to
2002; Amorim et al., 2008], Baird et al. [1991] and Ferencz et al. advanced maternal age and explain the association between
[1997] did report associations of maternal age with specic CHD advanced maternal age and CHD. We had no information on these
phenotypes. However, Ferencz et al. [1997] relied on data from factors and, therefore, could not account for them in our analyses.
1981 to 1987, in which the proportion of births to older mothers was Although we observed a signicantly stronger maternal age
low, and the oldest maternal age category in their study was 30 years association among LBW and preterm infants for several groups
of age or older. Thus, the maternal age effect among older age of CHD among offspring of women in the 3034 years and in the 35
groups might have been underestimated. This also might have been years of age or older categories (Table III), we did not identify a
true for the population-based study by Baird that covered the consistent pattern in the estimates of associations. The association
period 19661981 [Baird et al., 1991]. Cedergren et al. [2002], in of CHD with LBW and prematurity has been reported previously
a hospital-based study with small sample size found a nonsigni- [Mili et al., 1991; Rosenthal et al., 1991; Rosenthal, 1996; Rasmussen
cant U-shaped curve without clear cut dependency. et al., 2001; Tanner et al., 2005; Malik et al., 2007], but the reasons
With regard to young maternal age and specic CHD pheno- for such association are not known. One plausible explanation is
types, a previous study had shown a decreased aPR for RVOTO that the presence of CHD might impair normal fetal growth.
among infants of women younger than 20 years of age group However, although we could suggest that impaired fetal circulation
[Reefhuis and Honein, 2004], while in our study we found a may cause LBW, no consistent hemodynamic pattern with respect
signicant association only for one major type of RVOTO, valvar to oxygen saturations or hemoperfusion can explain our sugges-

tion. Another possibility is that both altered fetal growth and CHD Botto LD, Correa A, Erickson JD. 2001. Racial and temporal variations in
represent co-outcomes associated with a common but yet unde- the prevalence of heart defects. Pediatrics 107:E32.
ned genetic susceptibility or prenatal factor (e.g., alcohol con- Cameron AC, Trivedi PK. 1998. Regression analysis of count data.
sumption, infection, and nutritional status) and that the effect of Cambridge, UK: Cambridge University Press.
this factor could vary with maternal age and vice versa. Caton AR, Bell EM, Druschel CM, Werler MM, Lin AE, Browne ML,
We found signicant racial or ethnic variations for some of the McNutt LA, Romitti PA, Mitchell AA, Olney RS, Correa A. 2009.
maternal age and CHD associations (Table III). Our ndings for Antihypertensive medication use during pregnancy and the risk of
LVOTOs, VSDs, and AVSDs, were consistent with previously cardiovascular malformations. Hypertension 54:6370.
reported observations [Ferencz et al., 1997; Botto et al., 2001; Cedergren MI, Selbing AJ, Kallen BAJ. 2002. Risk factors for cardiovascular
Pradat et al., 2003], but not for conotruncal defects [Ferencz malformationA study based on prospectively collected data. Scand J
Work Environ Health 28:1217.
et al., 1997] and ASDs [Pradat et al., 2003]. Variability in rates
by race or ethnicity might reect variations in genetic susceptibility, Correa A, Cragan JD, Kucik JE, Alverson CJ, Gilboa SM, Balakrishnan R,
socioeconomic status, and/or access to health care. For example, a Strickland MJ, Duke CW, OLeary LA, Riehle-Colarusso T, Siffel C,
Gambrell D, Thompson D, Atkinson M, Chitra J. 2007. Reporting birth
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Correa A, Gilboa SM, Besser LM, Botto LD, Moore CA, Hobbs CA, Cleves
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associated with socioeconomic factors [Correa-Villasenor et al., black differences in cardiovascular malformations in infancy and socio-
1991]. Our results on specic phenotypes on variation by infant sex economic factors. The Baltimore-Washington Infant Study Group. Am J
are conrmed by some studies [Samanek, 1994; Correa et al., 2007], Epidemiol 134:393402.
but differ from others [Ferencz et al., 1997; Lary and Paulozzi, Correa-Villase~
nor A, Ferencz C, Neill CA, Wilson PD, Boughman JA. 1994.
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