Nongenetic Risk Factors and CHD - Patel, Pediatr Cardiol, 2013

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Nongenetic Risk Factors and Congenital Heart

Defects
ARTICLE in PEDIATRIC CARDIOLOGY AUGUST 2013
Impact Factor: 1.55 DOI: 10.1007/s00246-013-0775-4 Source: PubMed
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Pediatr Cardiol (2013) 34:15351555

DOI 10.1007/s00246-013-0775-4
REVIEW ARTICLE
Nongenetic Risk Factors and Congenital Heart Defects

Sonali S. Patel Trudy L. Burns
Received: 14 May 2013 / Accepted: 31 July 2013 / Published online: 21 August 2013
Springer Science+Business Media New York 2013
Abstract Advances have been made in identifying

genetic etiologies of congenital heart defects. Through this
knowledge, preventive strategies have been designed and
instituted, and prospective parents are counseled regarding
their risk of having an affected child. Great strides have
been made in genetic variant identification, and genetic
susceptibility to environmental exposures has been
hypothesized as an etiology for congenital heart defects.
Unfortunately, similar advances in understanding have not
been made regarding strategies to prevent nongenetic risk
factors. Less information is available regarding the potential adverse effect of modifiable risk factors on the fetal
heart. This review summarizes the available literature on
these modifiable exposures that may alter the risk for
congenital heart disease. Information regarding paternal
characteristics and conditions, maternal therapeutic drug
exposures, parental nontherapeutic drug exposures, and
parental environmental exposures are presented. Factors
are presented in terms of risk for congenital heart defects as
a group. These factors also are broken down by specific
defect type. Although additional investigations are needed
in this area, many of the discussed risk factors present an
opportunity for prevention of potential disease.
Keywords Heart defects Congenital Heart
disease Risk factors Epidemiology
S. S. Patel (&) T. L. Burns
Department of Pediatrics, Division of Pediatric Cardiology,
Carver College of Medicine, University of Iowa, Childrens
Hospital, 200 Hawkins Drive, Iowa City, IA 52242, USA
e-mail: sonalipatelmd@gmail.com; sonali-patel@uiowa.edu
T. L. Burns
Department of Epidemiology, College of Public Health,
University of Iowa, Iowa City, IA, USA
Birth defects, defined as abnormalities of structure, function, or body metabolism, affect 33 of 1,000 babies in the
United States [24, 32, 107]. Congenital heart defects
(CHDs) constitute a major proportion of clinically significant birth defects and are an important component of
pediatric cardiovascular disease, with an estimated prevalence of 69 CHDs per 1,000 live births [19, 76, 129].
During the first year of life, CHDs are the leading cause of
death from birth defects, with more than 91,000 life-years
lost each year in the United States [66, 130].
Although advances in understanding genetic risk factors
have been made, little is known regarding nongenetic risk
factors for the development of CHDs. Defect prevention
has been limited by a lack of information about modifiable
risk factors for abnormalities in cardiac development [80].
The proportion of CHDs potentially preventable through
changes in the fetal environment is unknown, but it is
suggested that the fraction of cases attributable to identifiable and potentially modifiable factors may be as high as
30 % for some defects [165]. The lack of information
regarding modifiable risk factors has made it difficult to
develop population-based strategies targeting CHD development and to assist couples in making lifestyle choices to
reduce the likelihood of having a child with a CHD [80].
Because the critical period for cardiac development is
between 2 and 7 weeks of gestational age, the risk factors
discussed in this report are limited to parental conditions
and environmental exposures during the periconceptional
period, which is defined as the 3 months before pregnancy
through the third month (first trimester) of pregnancy [80,
144]. Although the term environmental exposure conjures up the image of smog or a toxic waste dump, it refers
more broadly to any factor that is not genetic, and more
specifically to the fetal-placental-maternal environment
[95].
123
1536
This article aims to provide a current review of the literature to assist in providing guidance to pregnant women
and potential parents regarding their likelihood of having a
child with a CHD. Whereas numerous risk factors for CHD
have been implicated, this statement identifies those with
potential to be targeted for public health measures aimed at
reducing the burden of disease and assisting healthcare
providers in identifying common types of CHD associated
with the presence of risk factors.
Methods
Publications investigating the risk of CHD for children
after exposure to parental conditions or environmental
exposures were identified using Medline searches, references from individual articles, and reviews of scientific
journals. Combinations of the following terms were used as
search criteria: birth defect, congenital heart disease,
congenital heart defect, cardiovascular malformation,
risk factor(s), maternal exposure, paternal exposure, environmental exposure, and etiology. In
addition to these search terms, individual risk factors also
were included in the search terms (e.g., maternal age,
prepregnancy weight).
Each publication was assessed to determine the quality
of information presented with respect to consistency of
findings and study design. Case reports and case series
were not considered for inclusion in the review. Publications considered for inclusion were those published
between 1990 and 2013. Investigations before 1990 have
been summarized in previous publications [80]. The most
recent publication is discussed when a newer version of the
same database was used for additional investigations.
Studies that evaluated broad categories of defects (e.g.,
conotruncal defects, septal defects, left-sided obstructive
defects) were not included in the review unless information
regarding specific defects also was presented.
Confidence limits for the crude odds ratio (OR) or relative risk (RR) are included in this report if available.
Confidence limits that contain the value 1.0 indicate that
the estimate does not statistically differ from the null value,
suggesting no association.
The patient databases used among the referenced studies
are varied. Two population-based studies merit further
mention because they are the source for the majority of
information regarding risk factors for the development of
CHD. The Baltimore-Washington Infant Study (BWIS),
conducted between 1981 and 1989, was a casecontrol
study designed to further characterize the epidemiology of
CHD. The case infants were live-born infants with a CHD
from the Baltimore-Washington area. The diagnosis of
CHD was determined and confirmed within 1 year of birth
123
via echocardiography, cardiac catheterization, surgery, or

autopsy. Preterm infants (infants born at \38 weeks gestation) with patent ductus arteriosus as an isolated heart
defect and infants with arrhythmias in the absence of
structural heart defects were excluded from the review.
The control subjects comprised a random sample of liveborn infants without birth defects born in the same region
and frequency-matched to the cases by month, year, hospital of birth, and age at interview. Home interviews with
the case and control parents were conducted within
18 months the study subjects birth. A structured, standardized questionnaire obtained information on sociodemographic, medical, genetic, and environmental factors.
The latter included reports on parental smoking, alcohol
and recreational drug use, therapeutic drugs and caffeine
intake, diagnostic chest and abdominal radiography, and
potential exposures to pesticides, dyes, metals, and solvents
during the periconceptional exposure window (critical
period).
During the study period, 4,390 cases and 3,572 control
patients were enrolled in the study. The National Birth
Defects Prevention Study (NBDPS), which began in 1997,
is designed to identify infants with and without major birth
defects and to evaluate genetic and environmental factors
associated with the occurrence of birth defects [35].
This ongoing case-control study includes case and
control infants from birth defect surveillance registries in
10 states (Arkansas, California, Georgia [Centers for Disease Control and Prevention], Iowa, Massachusetts, New
Jersey, New York, North Carolina, Texas, and Utah). The
cases have one or more of over 30 eligible birth defects
reviewed by clinical geneticists at each site to determine
study eligibility. Infants with recognized or strongly suspected chromosomal abnormalities or single gene conditions are excluded from the study.
After inclusion in the study, all cases are classified by
clinical geneticists to establish defect consistency. Infants
used as control subjects (100 per birth year per site) are
randomly selected from birth certificates or birth hospital
records. The control subjects are unmatched to the cases.
Selected from the same base population as the cases, the
control subjects have no major birth defects and have an
estimated date of delivery during the same year as the
cases. As of December 2009, 27,812 cases and 10,200
control subjects are included in the database.
Results
The findings from this review are summarized in Tables 1,
2, 3 and 4, which summarize the literature regarding the
risk factors that may be associated with an increased or
decreased risk of CHDs as a group. Table 5 summarizes
1537
Table 1 Risk factors associated with congenital heart defects: characteristics and conditions
Exposure
Database
Cases (n)
Controls (n)
OR or RR (95 % CI)
Age
Advanced maternal age
Advanced paternal age
Young paternal age

Diabetes mellitus (pre-gestational)
Febrile illness
MACDP (19682005) [112]
739
1,301,143
1.2 (1.11.3)
PaRCM (19982002) [109]
4,337
8,683
1.1 (1.01.1)
4.0 (1.79.2)
PHHS (19881994) [78]
3,757
102,728
NSW/ACT (19811984) [86]
1,479
343,521
1.3 (1.11.4)
BWIS (19811989) [59]
3,377
3,572
1.3 (1.11.5)
FRCM (19821983) [147]
408
755
1.3 (1.01.6)
PRCM (19982002) [109]
3,933
8,683
1.1 (1.01.3)
NCHS (19992000) [167]
9,767
77,514
1.2 (1.11.4)
EHS (19951997) [13]
894
894
1.5 (1.22.0)
MBRN (19671998) [85]

Bei/Heb provinces (1988) [167]
3,656
497
1,869,388
6,222
1.5 (1.02.0)
2.3 (1.92.8)
EUROCAT (19902005) [62]
323
92,976
2.2 (1.92.6)
HCCSCA (19801996) [11]
4,480
38,151
2.5 (1.63.9)
NBDPS (19972003) [38]
3,519
4,689
4.6 (2.97.5)
Milwaukee (19971999) [169]
245
3,780
4.1 (1.511.2)
BWIS (19811989) [101]
3,377
3,572
3.0 (1.94.8)
WA State (19841991) [79]
1,511
8,934
4.0 (3.15.1)
SMBR (19811986) [121]
1,324
2,648
2.7 (1.45.0)
1.1 (0.91.5)
BWIS (19811989) [117]
2,361
3,435
HCCSCA (19801996)a [2]
4,480
38,151
2.6 (1.25.4)
Shan province (20042005)a [98]
164
328
5.9 (2.713.1)
NBDPS (19972003)b [34]
3,690
4,760
1.7 (1.03.0)
ABDCCS (19681980) [20]
829
3,029
1.8 (1.42.4)
SBDMP (19861987)c [171]
986
990
1.4 (0.72.9)
FRCM (19821983) [147]
583
756
1.5 (1.12.1)
HAVEN (20032010) [142]

ARHMS (19982008) [74]
229
417
320
250
1.5 (1.12.1)
1.5 (1.21.8)
Hypercholesterolemia
Hyperhomocysteinemia
Hypertension
Influenza
HAVEN (20032005) [156]
151
183
2.9 (1.46.0)
APGC (19881998) [160]
26
116
3.5 (1.210.2)
1.4 (1.31.5)
KPNCa (19952008) [94]
6,873
453,078
HCCSCA (19801996) [44]
4,480
38,151
1.3 (1.01.5)
NBDPS (19972003) [30]
5,021
4,796
1.8 (1.12.7)
Milwaukee (19971999) [169]
245
3,780
2.8 (1.26.7)
FRCM (19821983) [147]
583
756
2.6 (1.15.2)
BWIS (19811989) [117]
2,361
3,435
1.1 (0.91.4)
HCCSCA (19801996) [1]
4,480
38,151
1.7 (1.32.3)
ABDCCS (19681980) [20]
829
3,029
2.1 (0.85.5)
Prepregnancy weight
Overweight (BMI 2530)
Overweight ? obesity (BMI [ 25)
NBDPS (19972004) [63]
6,440
5,673
1.2 (1.11.3)
SMBR (19952007) [16]
11,163
1,235,877
1.1 (1.01.1)
ABDRFSS (19931997) [158]

ENN (19972008) [9]
195
797
330
322
2.0 (1.23.1)
1.1 (0.81.5)
NBDPS (19972004) [63]
6,440
5,673
1.2 (1.11.3)
ABDCCS (19681980) [157]
851
2,767
1.4 (1.01.9)
123
1538
Table 1 continued
Exposure
Obese (BMI [ 30)
Severely obese (BMI [ 40)
Database
Cases (n)
Controls (n)
OR or RR (95 % CI)
WCHARS (19922007) [103]
14,412
141,420
1.2 (1.21.3)
NBDPS (19972004) [63]
6,440
5,673
1.3 (1.21.4)
NYSCMR (19932003) [113]
7,392
56,304
1.2 (1.11.2)
1.2 (1.11.2)
SMBR (19952007) [16]
11,163
1,235,877
WABDR (19972000) [116]
111
418
1.3 (0.62.7)
ABDRFSS (19931997) [158]
195
330
2.0 (1.23.4)
ABDCCS (19681980) [157]
851
2,767
1.3 (0.82.1)
MBR (19901994) [124]
1,451
8,088
0.8 (0.31.9)
SMBR (19952007) [16]
11,163
1,235,877
1.5 (1.21.8)
PaRCM (19872006) [146]
5,493
3,104
1.4 (1.11.7)
NBDPS (19972007) [56]

PRCM (20052006) [110]
7,575
1,673
7,954
4,017
1.0 (0.91.1)
1.2 (1.11.4)
Shan province (20042005) [98]
164
328
2.5 (1.54.0)
BWIS (19811989) [59]
3,377
3,572
1.3 (1.11.5)
Reproductive history
Infertility/ART
Parity
Multiparous
Nulliparous
NBDPS (19972007) [56]
7,575
7,954
1.1 (1.01.2)
Socioeconomic status (low)
Kaunas (19992005) [90]
187
643
3.4 (1.57.6)
DNBC (19972002) [155]
659
81,453
1.6 (1.32.0)
Shan province (20042005) [98]
164
328
2.7 (1.54.8)
Stress
All exposures are maternal unless otherwise specified

Significant values are in bold
OR odds ratio, RR relative risk, CI confidence interval, BMI body mass index, ART assisted reproductive technique, ABDCCS Atlanta Birth
Defects Case-Control Study, ABDRFSS Atlanta Birth Defects Risk Factor Surveillance Study, ARHMS Arkansas Reproductive Health Monitoring System, APGC University of Alabama Prenatal Genetics Clinic, Bei/Heb provinces Beijing and Hebei provinces, BWIS BaltimoreWashington Infant Study, DNBC Danish National Birth Cohort, EHS Egyptian Health Service, ENN Eurocat Northern Netherlands Birth
Registry, EUROCAT all 18 registries, FRCM Finnish Register of Congenital Malformations, HAVEN Heart Defects, Vascular Status, Genetic
Factors and Nutrition Study, HCCSCA Hungarian Case-Control Surveillance of Congenital Abnormalities, KPNCa Kaiser Permanente Northern
California, MACDP Metropolitan Atlanta Congenital Defects Program, MBR Mainz (Germany) Birth Registry, NBDPS National Birth Defect
Prevention Study, NCHS National Center for Health Statistics, MBRN Medical Birth Registry of Norway, NSW/ACT New South Wales/Australia
Capitol Territory, NYSCMR New York State Congenital Malformations Registry, PaRCM Paris Registry of Congenital Malformations, PHHS
Parkland Health and Hospital System, PRCM Polish Registry of Congenital Malformations, SBDMP Shanghai Birth Defects Monitoring
Program, Shan province Shandong province, SMBR Swedish Medical Birth Registry, WABDR Western Australia Birth Defect Registry,
WCHARS Washington Comprehensive Hospital Abstract Reporting System
a
Pelvic inflammatory disease
Urinary tract infection

URI upper respiratory infection
these risk factors by specific defect. For the remainder of

the review, risk factors are divided into four broad categories: parental characteristics or conditions (Table 1),
maternal therapeutic drug exposures (Table 2), parental
nontherapeutic drug exposures (Table 3), and parental
environmental exposures (Table 4).
Parental Characteristics or Conditions
Parental Age
Findings have shown that maternal age, both advanced and
younger, are associated with CHD [59, 78, 86, 109, 112,
123
147]. In the BWIS, advanced maternal age was found to be

associated with an increased risk of Ebsteins anomaly and
transposition of the great arteries (TGA), with younger
mothers more likely to have a child with tricuspid atresia
[60]. Using data from the Metropolitan Atlanta Congenital
Defects Program, investigators identified older mothers as
more likely to have a child with an atrial septal defect
(ASD), coarctation of the aorta (CoA), or TGA [112]. In a
detailed analysis of the NBDPS database, advanced
maternal age was associated with ASD, tetraology of Fallot, and ventricular septal defect (VSD), whereas younger
maternal age was associated with total anomalous pulmonary venous return and tricuspid atresia.
1539
Table 2 Risk factors associated with congenital heart defects: therapeutic drug exposures
Exposure
Anti-asthmatic medication
Source
Database
Cases (n)
Controls (n)
OR or RR (95 % CI)
2.4 (1.24.8)
Lin et al. [96]
NYSCMR (19881991)
502
1,066
Kallen et al. [83]
SMBR (19952004)
11,367
585,372
1.1 (1.01.3)
Bronchodilators
Lin et al. [96]
NYSCMR (19881991)
502
1,066
2.2 (1.14.6)
Kallen et al. [83]
SMBR (19952004)
11,367
585,372
1.4 (1.11.7)
Antibiotics (any)
Crider et al. [41]
NBDPS (19972003)
5,269
4,941
1.1 (1.01.3)
Kallen et al. [82]
SMBR (19952001)
5,565
577,730
1.1 (0.91.3)
Macrolides
Crider et al. [41]
NBDPS (19972003)
5,269
4,941
1.0 (0.71.3)
Penicillins
Crider et al. [41]
NBDPS (19972003)
5,269
4,941
1.0 (0.81.1)
Denker et al. [51]
NJC (19911998)
4,055
9,263
1.7 (0.83.7)
Ferencz et al. [59]
BWIS (19811989)
3,377
3,572
1.3 (1.11.6)
Crider et al. [41]

Matok et al. [111]
NBDPS (19972003)
Clalit HMO (19982007)
5,269
571
4,941
85,250
1.5 (1.02.2)
1.8 (1.13.0)
Czeizal et al. [47]
HCCSCA (19801996)
4,467
38,151
2.1 (1.43.3)
Hernandez-Diaz et al. [72]
SEUBDS (19761988)
3,870
8,387
3.4 (1.86.4)
Czeizal et al. [47]
HCCSCA (19801996)
4,467
38,151
1.2 (0.91.6)
SEUBDS (19761988)
3,870
8,387
1.5 (0.63.8)
Sulfonamides
Sulfonamide with folic acid

Anticonvulsants
Werler et al. [162]
NBDPS (19972005)
7,093
6,052
1.4 (1.02.1)
Matok et al. [111]
Clalit HMO (19982007)
571
85,250
0.7 (0.22.9)
Kallen et al. [82]
SMBR (19952001)
5,565
577,730
1.6 (1.02.5)
SEUBDS (19761988)
3,870
8,387
2.2 (1.43.5)
SEUBDS (19761988)
3,870
8,387
2.3 (1.14.7)
Antidepressants (any)
Ferencz et al. [59]
BWIS (19811989)
3,377
3,572
3.0 (1.27.6)
Buproprion
Alwan et al. [6]
NBDPS (19972004)
6,853
5,869
1.1 (0.71.9)
SSRI (any)
Malm et al. [106]
FRCM (19962003)
8,253
635,583
1.3 (1.11.6)
Reis et al. [128]
SMBR (19952007)
14,821
1,062,190
1.0 (0.81.2)
With folic acid
Paroxetine
Fluoxetine
Alwan et al. [5]
NBDPS (19972002)
4,268
4,092
0.9 (0.71.2)
Louik et al. [102]

Malm et al. [106]
SEUBDS (19932004)
3,724
5,860
1.2 (0.91.6)
FRCM (19962003)
8,253
635,583
1.3 (0.82.1)
Bakker et al. [10]
ENN (19972006)
678
615
1.5 (0.64.2)
Reis et al. [128]
SMBR (19952007)
1,208
1,062,190
1.7 (1.12.5)
Louik et al. [102]
SEUBDS (19932004)
3,724
5,860
1.4 (0.82.5)
Louik et al. [106]
FRCM (19962003)
8,253
635,583
1.6 (1.12.2)
Malm et al. [102]
SEUBDS (19932004)
3,724
5,860
0.9 (0.61.5)
SNRI (Venlafaxine)
Polen et al. [120]
NBDPS (19972007)
8,069
8,002
2.7 (1.55.0)
TCA
Reis et al. [128]
SMBR (19952007)
1,662
1,062,190
1.6 (1.12.4)
Antifungals (metronidazole)
Ferencz et al. [59]
BWIS (19811989)
3,377
3,572
2.5 (1.15.8)
Antihypertensives
Banhidy et al. [12]
HCCSCA (19801996)
4,480
38,151
1.3 (1.01.5)
Li et al. [94]
KPNCa (19952008)
6,873
453,078
1.5 (1.02.2)
Caton et al. [30]
NBDPS (19972003)
5,021
4,796
1.8 (1.12.7)
Lennestal et al. [93]
SMBR (19822006)
1,418
1,045,425
2.6 (1.93.5)
b-Blockers
Caton et al. [30]
NBDPS (19972003)
5,021
4,796
2.6 (1.25.3)
ACE inhibitors
Kallen et al. [82]

Li et al. [94]
SMBR (19952001)
KPNCa (19952008)
5,565
6,873
577,730
453,078
1.9 (1.22.8)
1.5 (0.92.6)
1.9 (0.57.2)
Caton et al. [30]
NBDPS (19972003)
5,021
4,796
Lennestal et al. [93]
SMBR (19822006)
1,418
1,045,425
2.9 (0.96.8)
Cooper et al. [36]
TN Medicaid (19852000)
209
29,096
3.7 (1.97.3)
123
1540
Table 2 continued
Exposure
Folic acid (multivitamin)
Source
Database
Cases (n)
Controls (n)
OR or RR (95 % CI)
Correa et al. [39]
NBDPS (19972004)
5,206
4,737
0.9 (0.81.0)
Van Beynum et al. [153]
EUROCAT (19962005)
611
3,343
0.7 (0.60.9)
Smedts et al. [141]
HAVEN (20032006)
276
324
1.3 (0.91.9)
Czeizel et al. [48]
HPS (19931996)
31
50
0.6 (0.41.0)
Kallen et al. [82]
SMBR (19952001)
5,565
577,730
1.2 (1.01.6)
Botto et al. [18]
ABDCCS (19681980)
958
3,029
0.8 (0.61.0)
Czeizel et al. [45]
HCCSCA (19801991)
2,976
30,663
0.9 (0.81.0)
NSAIDs (any)
van Gelder et al. [154]
MoBa (19992007)
435
66,662
1.0 (0.71.6)
Kallen et al. [82]
SMBR (19952001)
5,565
577,730
1.2 (1.01.6)
Aspirin
MoBa (19992007)
435
66,662
1.6 (0.55.2)
1.4 (0.92.1)
Czeizel et al. [46]
HCCSCA (19801996)
4,056
38,151
Ibuprofen
MoBa (19992007)
435
66,662
0.9 (0.51.5)
Naproxen
Ferencz et al. [59]

Kallen et al. [82]
BWIS (19811989)
SMBR (19952001)
3,377
5,565
3,572
577,730
1.4 (1.11.8)
1.7 (1.12.5)
Thyroid replacement
Winker et al. [163]
SMBR (19952004)
11,028
848,468
1.3 (1.11.5)

OR odds ratio, RR relative risk, CI confidence interval, SSRI selective serotonin receptor inhibitors, SNRI selective serotonin receptor inhibitors,
TCA tricyclic antidepressants, ACE angiotensin-converting enzyme, NSAIDs nonsteroidal anti-inflammatory drugs, ABDCCS Atlanta Birth
Defects Case-Control Study, WIS Baltimore-Washington Infant Study, ENN Eurocat Northern Netherlands Birth Registry, EUROCAT all 18
registries, FRCM Finnish Register of Congenital Malformations, HAVEN Heart Defects, Vascular Status, Genetic Factors and Nutrition Study,
HCCSCA Hungarian Case-Control Surveillance of Congenital Abnormalities, HPS Hungarian Periconceptional Service, KPNCa Kaiser Permanente Northern California, MoBa Norwegian Mother and Child Cohort Study, NBDPS National Birth Defect Prevention Study, NJC North
Jutland County, Denmark, NYSCMR New York State Congenital Malformations Registry, SEUBDS Sloane Epidemiology Unit Birth Defects
Study, SMBR Swedish Medical Birth Registry, TN Medicaid Tennessee Medicaid
Table 3 Risk factors associated with congenital heart defects: nontherapeutic drug exposures
Exposure
Database
Cases (n)
Controls (n)
OR or RR (95 % CI)
Alcohol
PRAMS (19962005) [108]
237
948
3.0 (1.27.5)
BWIS (19811989) [4]
2,525
3,435
1.1 (1.01.2)
Patras (20062009) [84]
157
208
2.8 (1.84.6)
Cigarette smoking
Maternal use
NBDPS (19972002) [105]
3,067
3,947
1.2 (1.11.4)
ARHMS 19982004) [73]
275
118
1.7 (1.03.1)
SMBR (19831996) [81]
3,384
1,413,811
1.1 (1.01.2)
Italy (20082010) [40]
360
360
1.7 (1.12.6)
Maternal use
BWIS (19811989) [59]
3,377
3,572
1.6 (1.12.3)
Paternal use
Boston City (19881990) [97]

BWIS (19811989) [59]
49
3,377
505
3,572
3.7 (1.49.4)
1.7 (1.32.2)
Marijuana (paternal)
BWIS (19811989) [59]
3,377
3,572
1.2 (1.11.4)
Vitamin E
HAVEN (20032006) [141]
276
324
1.7 (1.02.6)
Paternal use
Cocaine

OR odds ratio, RR relative risk, CI confidence interval, ARHMS Arkansas Reproductive Health Monitoring System, BWIS Baltimore-Washington
Infant Study, HAVEN Heart Defects, Vascular Status, Genetic Factors and Nutrition Study, NBDPS National Birth Defect Prevention Study,
Patras University of Patras, Greece, PRAMS Pregnancy Risk Assessment Monitoring System, SMBR Swedish Medical Birth Registry
123
The role of paternal age in the occurrence of CHD also

has been investigated. Similar to maternal age, findings
have shown both advanced and younger paternal age to be
associated with CHD [13, 85, 109, 167, 170]. A matched
case-control study performed in Egypt identified an association between advanced paternal age and VSDs [13].
Diabetes Mellitus
Multiple studies have consistently demonstrated an association between CHD and maternal pre-gestational diabetes
[11, 38, 62, 79, 101, 121]. Pre-gestational diabetes appears
to induce malformation before the seventh week of gestation, during the critical period of organogenesis [89].
Pre-gestational diabetes has been associated with multiple types of CHD including ASD, atrioventricular septal
defect, CoA, double-outlet right ventricle, pulmonary
atresia, total anomalous pulmonary venous return, TGA,
tetralogy of Fallot, truncus arteriosus, and VSD, as determined using the BWIS, NBDPS, and EUROCAT databases
[38, 60, 62, 101]. Findings also have determined maternal
pre-gestational diabetes to be an independent risk factor for
mortality among infants with CHD [101].
Although the mechanisms underlying the association
between diabetes and CHD are not well understood, it
appears that hyperglycemia plays a critical role [38]. A
positive association exists between hyperglycemia during
embryogenesis and the risk for congenital malformations
among infants of diabetic mothers [57, 87, 125]. The
prevalence of birth defects among diabetic women with
good glycemic control is similar to that in the general
population [55].
Although glycemic control has been shown to reduce the
risk of birth defects, achieving and maintaining euglycemia
early in pregnancy remains a challenge because many
women with diabetes do not plan their pregnancies and do
not achieve adequate glycemic control before conception
[77, 125]. Glycemic control has been proposed as a prevention strategy for birth defects, but as the prevalence of
diabetes and risk factors for diabetes continues to rise, it
appears that this may not be solely effective [61, 114].
Febrile Illnesses: Upper Respiratory Infection, Urinary
Tract Infection, and Influenza
Maternal febrile illness during the first trimester of pregnancy has been investigated for its role in the development
of CHDs [1, 2, 20, 34, 98, 117, 147, 171]. One difficulty in
evaluating febrile illness as a risk factor is defining a febrile
illness because defining it is complex. Fever can be a
symptom of varied etiologies including upper respiratory
infection, influenza, urinary tract infection, and pneumonia.
Even limiting the definition of fever to the presence of
1541
these etiologies has not identified consistent associations,

suggesting the need for further investigations examining
the role of maternal fever.
Hyperhomocysteinemia
Folate is a key factor in cardiovascular development.
Folate and vitamin B12 are involved in the remethylation
of homocysteine into methionine. A compromised folate
or vitamin B12 status results in hyperhomocysteinemia.
Homocysteine can be harmful to cells because it results
in oxidative stress through the production of reactive
oxygen species, binds to nitric oxide, or leads to the
accumulation of its precursor, a potent inhibitor of biologic transmethylations [119]. Increased levels of homocysteine have been shown to produce cardiac defects in
chick embryos [132]. Given this finding, the role of
homocysteine levels as a risk factor for CHD development was investigated.
All three studies demonstrated increased risk of CHD in
infants born to mothers with high homocysteine levels.
However, these studies had small sample sizes, again
suggesting that further investigation is warranted [74, 156,
160].
Hypertension
Hypertension is common in pregnancy. Multiple studies
have identified an approximate twofold increased risk of
CHDs among infants born to mothers with hypertension
during pregnancy [30, 94, 147, 169]. Interestingly, when
the databases were stratified by defect, no significant
associations remained. Studies also have begun to investigate the ultimate question whether the underlying
hypertension or the medications used to treat hypertension
is the basis for the increased risk. However, further
research must be performed [94].
Prepregnancy Weight
The prevalence of overweight and obesity is increasing in
the United States at an alarming rate [114]. Adult weight is
categorized by use of the body mass index (BMI). Overweight is defined as a BMI of 2530 kg/m2, obesity as a
BMI of 3040 kg/m2, and morbid or severe obesity as a
BMI greater than 40 kg/m2.
Given the dramatic increase in excess weight among
potential mothers, multiple studies have investigated the
role of prepregnancy weight in the development of CHDs.
Findings have demonstrated each category of increased
weight to be significantly associated with the development
of CHDs [16, 63, 103, 113, 158].
123
1542
Table 4 Risk factors associated with congenital heart defects: environmental exposures
Exposure
Database
Cases (n)
Controls (n)
OR or RR (95 % CI)
NCAS (19932003) [49]
2,140
14,256
1.2 (0.91.7)
Maternal cyanide exposure
San Francisco (19831985) [136]
5,046
20,882
2.2 (1.33.9)
Maternal heavy metal exposure
HAVEN (20032010) [143]
424
480
0.9 (0.23.8)
5,046
20,882
1.5 (1.12.3)
Air pollution
Carbon monoxide
Chemical exposures
Maternal pesticide exposure
HAVEN (20032010) [143]
424
480
0.8 (0.32.1)
5,046
20,882
1.6 (1.02.5)
Maternal phthalate exposure
HAVEN (20032010) [143]
424
480
2.2 (0.95.2)
Paternal phthalate exposure
HAVEN (20032010) [143]
424
480
1.7 (1.12.5)
HAVEN (20032010) [143]
424
480
1.8 (1.13.0)
Dichloroethylene
New Jersey (19851988) [21]
108
52,334
2.8 (1.35.9)*
Trichloroethylene
Milwaukee (19971999) [169]
245
3,780
6.2 (2.614.5)
Hazardous waste site
Dallas County (19791984) [104]
1,283
2,292
1.2 (1.11.4)
Paternal alkylphenolic compound exposure

Drinking water contaminants

OR odds ratio, RR relative risk, CI confidence interval, HAVEN Heart Defects, Vascular Status, Genetic Factors and Nutrition Study, NCAS
Northern Congenital Abnormality Survey
*
90 % CI
Stratification by defect showed that overweight mothers

were more likely to have an infant with a CoA [158].
Mothers with a BMI greater than 30 kg/m2 were identified
as more likely to have an infant with ASD, aortic valve
stenosis, hypoplastic left heart syndrome, pulmonary valve
stenosis, or truncus arteriosus, whereas infants born to
mothers with a BMI greater than 40 kg/m2 were more
likely to have a double-outlet right ventricle [31, 103, 113,
123].
Reproductive History
Mothers with a history of infertility and use of assisted
reproductive techniques, including fertility medications,
have been identified as at an increased risk of having an
infant with any type of CHD [146]. This finding, however,
has not been replicated to date using other databases. When
stratified by defect, ASD, aortic valve stenosis, CoA,
tetralogy of Fallot, and VSD continued to demonstrate an
association [60, 126, 127, 146].
The number of previous pregnancies also has been
evaluated for its role in the development of CHDs. Findings have shown that multiparous women are at a greater
risk of having an infant with a CHD than mothers of infants
without structural heart defects [56, 59, 98, 110]. Although
nulliparous mothers were not found to have an elevated
risk of having an infant with any type of CHD using the
NBDPS database, stratification by defect identified
123
significant associations for infants with ASD, tetralogy of

Fallot, and VSD [56].
Socioeconomic Status
Socioeconomic status has been investigated as a potential
risk factor in the development of CHDs. In an investigation
of more than 81,000 births in Denmark, low maternal and
paternal sociooccupational status was associated with
infant CHDs. A small case-control study in Lithuania
showed a 3.4-fold elevation in risk for an infant with a
CHD born to mothers with low socioeconomic status [90].
Using the NBDPS database, the relationship between
parental socioeconomic status and the development of
TGA and tetralogy of Fallot was investigated [168].
Although no marker of socioeconomic status was statistically significant, many characteristics such as an unemployed mother, an unemployed father, or a low education
level of either parent were associated with increased risks
[168].
Stress
The relationship between maternal stress and birth defects
has been examined in multiple studies. One potential
mechanism whereby maternal stressors may lead to birth
defects is through increased production of corticosteroids
[27]. Findings have demonstrated that corticosteroids are
1543
Table 5 Risk Factors Associated with Specific Congenital Heart Defects

Defect
Exposure
Database
ASD
NBDPS (19972007) [65]

MACDP (19682005) [112]
Pre-gestational diabetes mellitus
EUROCAT (19902005) [62]
Febrile illness
Infertility/ART
Nulliparous
Cases (n)
Controls (n)
OR or RR (95 % CI)
468
8,169
2.5 (1.54.1)
398
1,301,143
1.4 (1.11.8)
101
26,228
2.3 (1.82.8)
NBDPS (19972003) [38]
419
4,689
8.5 (4.416.4)
BWIS (19811989)a [60]
187
3,572
1.7 (1.22.5)
NBDPS (19972003) [126]
1,080
5,008
3.4 (1.86.2)
NBDPS (19972007) [56]
1,422
7,954
1.3 (1.11.5)
Overweight ? obesity
NBDPS (19972004) [63]
621
5,673
1.3 (1.11.6)
Obese
WCHARS (19922007) [103]
1,690
141,420
1.2 (1.01.4)
Prepregnancy weight
NYSCMR (19932003) [113]
2,075
56,304
1.2 (1.11.4)
SMBR (19922001) [31]
639
812,457
1.4 (1.11.7)
Cephalosporins
NBDPS (19972003) [41]
1,225
4,941
1.9 (1.13.2)
SSRI
ENN (19972006) [10]
53
5.7 (1.423.7)
NBDPS (19972002) [5]
768
4,092
1.1 (0.61.9)
Paroxetine
ENN (19972006) [10]
56
615
5.7 (1.423.5)
SNRI (venlafaxine)
NBDPS (19972007) [120]
2,181
8,002
2.9 (1.26.9)
Antihypertensives
NBDPS (19972003) [30]
1,137
4,796
2.4 (1.34.4)
Alcohol use
FRCM (19821983) [149]
50
756
2.0 (1.13.4)
Cigarette use
BWIS (19811989) [4]
186
3,435
1.4 (1.01.8)
NBDPS (19972002) [105]
338
3,947
2.0 (1.52.6)
SMBR (19831996) [81]
100
1,413,811
1.6 (1.02.6)
BWIS (19811989) [60]
65,187
3,572
2.3 (1.34.2)
Nitrogen dioxide
MACDP (19862003) [145]
379
715,500
1.6 (1.22.1)
Particulate matter
Brisbane (19972004) [69]
127
2,860
1.1 (1.01.3)
TBDR (19972000) [64]
977
3,431
1.3 (1.01.6)
Sulphur dioxide
Brisbane (19972004) [69]
127
2,860
1.3 (1.01.7)
Cocaine use (paternal)

Air pollution
AVS
NBDPS (19972003) [38]
113
4,689
5.0 (1.122.9)
Infertility/ART
NBDPS (19972005) [127]
243
6,500
2.6 (1.25.3)
NBDPS (19972004) [63]
154
5,673
0.8 (0.61.2)
Obesity
NYSCMR (19932003) [113]
288
56,304
2.0 (1.42.9)
EUROCAT (19902005) [62]
11
26,228
2.2 (1.24.0)
NBDPS (19972003) [38]
66
4,689
12.4 (3.741.5)
BWIS (19811989) [101]
31
3,572
22.8 (7.470.5)
BWIS (19811989) [117]
244
3,435
1.7 (1.02.8)
Prepregnancy WEIGHT
AVSD
Febrile illness
NBDPS (19972003)a [34]
98
4,760
2.3 (1.14.7)
NBDPS (19972005) [152]
166
6,328
2.4 (1.26.6)
NBDPS (19972004) [63]
81
5,673
0.9 (0.61.5)
Obesity
WCHARS (19922007) [103]
120
141,420
0.5 (0.31.1)
Injuries
Prepregnancy weight
NYSCMR (19932003) [113]
125
56,304
1.0 (0.61.7)
SMBR (19922001) [31]
905
812,457
1.2 (1.01.5)
Antibacterials
NBDPS (19972003) [41]
128
4,941
1.7 (1.12.6)
Cough medications
BWIS (19811989) [60]
76
3,572
8.9 (2.630.6)
Cigarette use
NBDPS (19972007) [118]
187
6,703
1.5 (1.12.1)
BWIS (19811989) [4]
57
3,435
1.5 (1.02.3)
NBDPS (19972007) [118]
187
6,703
1.5 (1.12.1)
Cocaine use
BWIS (19811989) [60]
76
3,572
3.5 (1.111.4)
Paternal polychlorinated compound exposure
HAVEN (20032010) [143]
44
480
4.2 (1.214.4)
Febrile illness
BWIS (19811989) [117]
187
3,435
1.9 (1.13.4)
Ibuprofen
BWIS (19811989)a [60]
190
3,572
2.4 (1.14.2)
Passive smoke exposure
DS-AVSD
123
1544
Table 5 continued
Defect
CoA
Exposure
Database
Cases (n)
Controls (n)
OR or RR (95 % CI)
MACDP (19682005) [112]
256
1,301,143
1.5 (1.12.2)
EUROCAT (19902005) [62]
18
26,228
1.9 (1.23.1)
NBDPS (19972003) [38]
196
4,689
2.1 (0.59.5)
Epilepsy
BWIS (19811989) [60]
120
3,572
6.5 (1.823.0)
Febrile illness
ABDCCS (19681980) [20]
60
3,029
2.7 (1.26.0)
Infertility/ART
NBDPS (19972005) [127]
603
6,500
2.3 (1.43.8)
BWIS (19811989) [60]
120
3,572
6.1 (2.118.2)
Prepregnancy weight
Overweight
ABDRFSS (19931997) [158]
12
330
3.9 (1.113.8)
NBDPS (19972004) [63]
257
5,673
1.2 (0.91.5)
Obesity
DORV
NYSCMR (19932003) [113]
433
56,304
1.3 (1.01.7)
SMBR (19922001) [31]
117
812,457
1.5 (0.92.5)
Influenza
ABDCCS (19681980) [20]
60
3,029
3.8 (1.68.8)
Sulfonamides
NBDPS (19972003) [41]
431
4,941
2.7 (1.35.6)
Buproprion
NBDPS (19972004) [6]
546
5,869
2.6 (1.06.9)
SNRI (venlafaxine)
NBDPS (19972007) [120]
768
8,002
4.5 (1.412.5)
Antihypertensive
NBDPS (19972003) [30]
406
4,796
3.0 (1.36.6)
Mineral oil exposure
FRCM (19821983) [151]
50
756
5.9 (1.819.2)
Organic solvents
BWIS (19811989) [60]
120
3,572
3.2 (1.37.9)
Paternal alkylphenolic compound exposure
HAVEN (20032010) [143]
44
480
3.9 (1.212.7)
BWIS (19811989) [60]
27
3,572
12.3 (2.855.2)
Febrile illness
BWIS (19811989)b [60]
27
3,572
2.8 (1.26.4)
Severe obesity
NYSCMR (19932003) [113]
117
56,304
2.5 (1.15.8)
Ibuprofen
BWIS (19811989) [60]
27
3,572
3.6 (1.112.2)
BWIS (19811989) [60]
44
3,572
2.6 (1.44.8)
BWIS (19811989) [60]
44
3,572
1.8 (1.03.5)
Prepregnancy weight
Ebsteins
Prepregnancy weight
HLHS
NBDPS (19972004) [63]
56
5,673
1.8 (1.01.3)
Benzodiazepines
BWIS (19811989) [60]
44
3,572
5.3 (1.518.5)
Antihypertensives
NBDPS (19972003) [30]
65
4,796
11.4 (2.834.1)
Marijuana use
BWIS (19811989) [60]
34
3,572
3.6 (1.68.5)
Febrile illness
FRCM (19821983)b [147]
34
756
2.5 (1.25.4)
EUROCAT (19902005) [62]
26,228
0.7 (0.31.8)
NBDPS (19972003) [38]
203
4,689
2.5 (0.78.8)
BWIS (19811989) [60]
138
3,572
3.4 (1.011.5)
NBDPS (19972005) [152]
338
6,328
1.7 (1.03.0)
NBDPS (19972004) [63]
268
5,673
1.3 (1.01.7)
Obese
WCHARS (19922007) [103]
174
141,420
1.9 (1.11.3)
NYSCMR (19932003) [113]
241
56,304
1.7 (1.22.5)
1.4 (0.92.2)
Injuries
Prepregnancy weight
IAA
PA
SMBR (19922001) [31]
166
812,457
Sulfonamides
NBDPS (19972003) [41]
4,941
3.2 (1.37.6)
Metronidazole
NBDPS (19972003) [29]
176
4,581
2.3 (1.05.1)
Organic solvents
3.4 (1.66.9)
BWIS (19811989) [60]
138
3,572
Injuries
NBDPS (19972005) [152]
22
6,328
5.9 (1.720.0)
Aspirin
BWIS (19811989) [100]
46
3,572
2.1 (1.14.0)
BWIS (19811989) [60]
45
3,572
7.2 (1.631.4)
Prepregnancy weight
NBDPS (19972004) [63]
83
5,673
1.6 (1.02.5)
Influenza
BWIS (19811989) [117]
39
3,435
2.7 (1.26.3)
Injuries
NBDPS (19972005) [152]
140
6,328
2.9 (1.55.5)
TBDR (19972000) [64]
96
3,448
2.0 (1.13.6)
Air pollution
Particulate matter
123
1545
Table 5 continued
Defect
Exposure
Database
Cases (n)
Controls (n)
OR or RR (95 % CI)
PVS
Young maternal age
MACDP (19682005) [112]
262
1,301,143
0.7 (0.41.0)
NBDPS (19972004) [63]
495
5,673
1.4 (1.11.7)
Obesity
NYSCMR (19932003) [113]
957
56,304
1.3 (1.11.6)
Febrile illness
NBDPS (19972003)a [34]
448
4,760
3.0 (1.27.6)
BWIS (19811989) [60]
112
3,572
2.9 (1.55.4)
Antihypertensives
NBDPS (19972003) [30]
534
4,796
2.6 (1.35.4)
Naproxen
NBDPS (19972004) [71]
519
5,546
2.4 (1.34.5)
Cigarette use
BWIS (19811989) [4]
205
3,435
1.4 (1.11.7)
NBDPS (19972002) [105]
386
3,947
2.3 (1.14.8)
Carbon monoxide
NCAS (19932003) [49]
259
14,256
2.7 (1.35.5)
Organic solvents
BWIS (19811989) [60]
112
3,572
5.0 (1.38.7)
EUROCAT (20002004) [99]
167
1,177
2.6 (1.45.1)
BWIS (19811989) [60]
30
3,572
2.8 (1.36.4)
Febrile illness
BWIS (19811989) [117]
26
3,435
7.5 (2.621.8)
ABDCCS (19681980) [20]
12
3,029
5.2 (1.320.2)
Influenza
BWIS (19811989) [117]
26
3,435
6.0 (2.415.4)
Injuries
NBDPS (19972005) [152]
2296
6,328
2.5 (1.15.7)
Paternal cocaine use
BWIS (19811989) [60]
30
3,572
4.8 (1.614.0)
Paternal marijuana use
BWIS (19811989) [60]
30
3,572
2.7 (1.35.8)
Young maternal age
NBDPS (19972007) [65]
190
8,169
2.3 (1.34.0)
NBDPS (19972003) [38]
102
4,689
7.1 (2.025.4)
NBDPS (19972004) [63]
119
5,673
1.5 (1.02.3)
Maternal pesticide exposure
BWIS (19811989) [60]
56
3,572
6.8 (1.531.5)
MACDP (19682005) [112]
177
1,301,143
1.7 (1.12.5)
BWIS (19811989) [60]
214
3,572
1.7 (1.12.3)
EUROCAT (19902005) [62]
17
26,228
2.0 (1.23.2)
NBDPS (19972003) [38]
254
4,689
3.3 (1.110.1)
BWIS (19811989) [60]
106
3,572
2.2 (1.24.1)
NBDPS (19972004) [63]
314
5,673
1.0 (0.81.3)
Obesity
WCHARS (19922007) [103]
177
141,420
1.1 (0.71.8)
NYSCMR (19932003) [113]
331
56,304
0.9 (0.61.2)
SMBR (19922001) [31]
164
812,457
1.5 (1.02.3)
Stress
CBDMP (19871988) [25]
77
464
1.9 (1.13.1)
Benzodiazepines
BWIS (19811989) [60]
189
3,572
4.1 (1.98.6)
Folic acid
NBDPS (19972004)[39]
320
4,737
0.7 (0.51.0)
BWIS (19811989) [134]
53
679
1.0 (0.52.2)
ABDCCS (19681980) [17]
79
1,610
0.4 (0.20.9)
Ibuprofen
BWIS (19811989) [60]
106
3,572
2.5 (1.24.9)
Alcohol use
LA/SF/SC (19992004) [67]
106
425
1.9 (1.13.2)
Cigarette use
SMBR (19831996) [81]
307
1,413,811
1.3 (1.01.71)
Vitamin A
BWIS (19871989) [20]
47
679
2.4 (1.15.1)
Prepregnancy weight
Air pollution
TA
TAPVR
Young maternal age
Prepregnancy weight
TGA
Influenza
Prepregnancy weight
Organic solvents
TOF
BWIS (19811989) [60]
189
3,572
3.4 (1.57.5)
Gill et al. [65]
750
8,169
2.2 (1.43.3)
NBDPS (19972003) [38]
351
4,689
4.9 (2.211.0)
BWIS (19871989) [101]
294
3,572
6.6 (3.213.3)
Infertility/ART
BWIS (19811989) [60]
204
3,572
3.6 (1.96.9)
Nulliparous
NBDPS (19972007) [56]
711
7,954
1.3 (1.11.6)
Prepregnancy weight
Overweight
NYSCMR (19932003) [113]
487
56,304
1.3 (1.01.7)
NBDPS (19972004) [63]
447
5,673
1.2 (1.01.5)
123
1546
Table 5 continued
Defect
Exposure
Obese
Database
Cases (n)
Controls (n)
OR or RR (95 % CI)
WCHARS (19922007) [103]
377
141,420
1.1 (0.81.5)
SMBR (19922001) [31]
223
812,457
1.1 (0.71.6)
Stress
CBDMP (19871988) [25]
82
464
1.3 (0.82.1)
Anti-asthmatic medication
SMBR (19952004) [83]
405
585,372
1.7 (1.12.6)
Folic acid (multivitamin)
CBDMP (19871988) [137]
90
481
0.5 (0.31.0)
Metronidazole
BWIS (19811989) [60]
341
3,572
6.0 (1.820.7)
Air pollution
Truncus
Carbon monoxide
TBDR (19972000) [64]
136
3,343
2.0 (1.33.3)
Sulphur dioxide
England (19911999) [54]
146
759,993
1.4 (1.11.8)
EUROCAT (19902005) [62]
229
2.8 (1.26.9)
BWIS (19811989) [60]
38
3,572
13.2 (3.846.1)
Prepregnancy weight
VSD
Obesity
MBR (19901994) [124]
NA
8,088
6.3 (1.624.8)
Cigarette use
BWIS (19811989) [4]
20
3,435
1.9 (1.03.5)
Hazardous waste site
TBDR (19962000) [91]
101
4,965
2.8 (1.26.5)
NBDPS (19972007) [65]
1,293
8,169
2.5 (1.83.5)
EHS (19951997) [13]
453
894
1.7 (1.32.3)
Prepregnancy weight
NBDPS (19972004) [63]
734
5,673
1.1 (0.91.3)
Obesity
WCHARS (19922007) [103]
2,915
141,420
1.0 (0.91.1)
4,081
56,304
1.0 (0.91.1)
SMBR (19922001) [31]
2,676
812,457
1.1 (1.01.3)
1.5 (1.21.8)
EUROCAT (19902005) [62]
134
26,228
NBDPS (19972003) [38]
571
4,689
2.9 (1.36.6)
BWIS (19811989) [101]
563
3,572
3.1 (1.56.3)
NBDPS (19971998) [33]
168
692
0.9 (0.61.3)
ABDCCS (19681980) [20]
209
3,029
1.8 (1.12.9)
PaRCM (19872006) [146]
2,248
3,104
1.4 (1.11.8)
NBDPS (19972005) [127]
1,333
6,500
1.6 (1.12.4)
Hypertension
HCCSCA (19801996) [42]
1,661
38,151
1.3 (1.01.6)
Influenza
HCCSCA (19801996) [42]
1,661
38,151
1.3 (1.01.6)
ABDCCS (19681980) [20]
209
3,029
2.0 (1.13.6)
Nulliparous
NBDPS (19972007) [56]
1,237
7,954
1.4 (1.21.6)
SSRI
NBDPS (19972002) [5]
797
4,092
1.1 (0.61.9)
Paroxetine
ENN (19972006) [10]
183
615
0.6 (0.14.6)
Fluoxetine
FRCM (19962003) [106]
143
1,818
1.7 (1.12.4)
Cough and cold medications
Northern England (1995) [14]
296
296
2.2 (1.43.5)
BWIS (19811989) [60]
87
3,572
5.5 (1.618.7)
HCCSCA (19801991) [42]
1,661
38,151
0.8 (0.80.9)
Febrile illness
Infertility/ART
Folic acid
Metronidazole
123
NYSCMR (19932003) [113]
HPS (19931996) [48]
19
0.3 (0.10.7)
SEUBDS (19931996) [161]
186
521
1.2 (0.81.8)
HCCSCA (19801996) [42]
1,661
38,151
1.6 (1.22.3)
BWIS (19811989) [60]
640
3,572
3.5 (1.110.8)
Ibuprofen
BWIS (19811989) [60]
640
3,572
1.5 (1.02.3)
Alcohol use
ABDCCS (19681980) [164]
122
3,029
3.1 (1.28.2)
BWIS (19811989) [60]
73
3,572
1.8 (1.03.3)
Alcohol use (paternal)
ABDCCS (19681980) [164]
122
3,029
4.0 (1.69.9)
Cigarette use
NBDPS (19972002) [105]
584
3,947
1.3 (1.11.7)
Cocaine use
BWIS (19811989) [60]
640
3,572
2.9 (1.74.8)
Cocaine use (paternal)
BWIS (19811989) [60]
640
3,572
2.3 (1.63.3)
Marijuana use
ABDCCS (19681980) [164]
122
3,029
2.4 (1.43.9)
Marijuana use (paternal)
ABDCCS (19681980) [164]
122
3,029
2.2 (1.14.4)
BWIS (19811989) [58]
491
3,549
1.4 (1.11.8)
1547
Table 5 Risk Factors Associated with Specific Congenital Heart Defects

Defect
Exposure
Database
Cases (n)
Controls (n)
OR or RR (95 % CI)
NCAS (19932003) [49]
1,154
14,256
2.6 (1.93.7)
TBDR (19972000) [64]
1,757
3,342
1.2 (1.01.4)
CBDMP (19891993) [131]
260
9,106
1.6 (1.12.5)
MACDP (19862003) [145]
1,108
715,500
1.2 (1.01.4)
Air pollution
Carbon monoxide
Nitrogen
Particulate matter
Brisbane (19972004) [69]
222
2,860
1.2 (1.01.3)
Sulfur dioxide
TBDR (19972000) [64]
1,007
1,991
1.3 (1.11.6)
Paternal phthalate exposure
HAVEN (20032010) [143]
113
480
2.8 (1.45.9)

OR odds ratio, RR relative risk, CI confidence interval, NA not available, ASD atrial septal defect, ART assisted reproductive techniques, SSRI selective serotonin
receptor inhibitors, SNRI serotonin-norepinephrine reuptake inhibitor, AVS aortic valve stenosis, AVSD atrioventricular septal defect, DS-AVSD Down syndrome
atrioventricular septal defect, CoA coarctation of the aorta, DORV double-outlet right ventricle, HLHS hypoplastic left heart syndrome, IAA interrupted aortic arch, PA
pulmonary atresia, PVS pulmonary valve stenosis, TA tricuspid atresia, TAPVR total anomalous pulmonary venous return, TGA transposition of the great arteries, TOF
tetralogy of Fallot, VSD ventricular septal defect, ABDCCS Atlanta Birth Defects Case-Control Study, ABDRFSS Atlanta Birth Defects Risk Factor Surveillance Study,
BWIS Baltimore-Washington Infant Study, CBDMP California Birth Defects Monitoring Program, EHS Egyptian Health Service, ENN Eurocat Northern Netherlands
Birth Registry, EUROCAT all 18 registries, FRCM Finnish Register of Congenital Malformations, HAVEN Heart Defects, Vascular Status, Genetic Factors and Nutrition
Study, HCCSCA Hungarian Case-Control Surveillance of Congenital Abnormalities, HPS Hungarian Periconceptional Service, LA/SF/SC Los Angeles, San Francisco,
and Santa Clara counties, MACDP Metropolitan Atlanta Congenital Defects Program, MBR Mainz (Germany) Birth Registry, NBDPS National Birth Defect Prevention
Study, NCAS Northern Congenital Abnormality Survey, NYSCMR New York State Congenital Malformations Registry, PaRCM Paris Registry of Congenital Malformations, SEUBDS Sloane Epidemiology Unit Birth Defects Study, SMBR Swedish Medical Birth Registry, TBDR Texas Birth Defect Registry, WCHARS Washington
Comprehensive Hospital Abstract Reporting System
a
Urinary tract infection
Upper respiratory infection
teratogenic for various organ systems in animal models

[133]. Stressful life events have been shown to result in
elevated levels of maternal corticotrophin-releasing hormone and corticosteroid levels during pregnancy [75].
Increased glucocorticoid levels are associated with hyperinsulinemia and insulin resistance, which may be associated with increased risk of CHDs [7]. Additionally, stress
results in increased catecholamine production, which in
turn leads to decreased uterine blood flow and increased
fetal hypoxia.
The majority of previous studies have focused on orofacial cleft or neural tube defects, with only two studies
examining the effects of maternal stress on the development of CHDs [25, 98]. A case-control study performed in
China identified a threefold greater risk for infants with
CHDs born to mothers who reported stressful life events
during the periconceptional period [98]. Using data from
the California Birth Defects Monitoring Program, an
association of CHDs with TGA was identified [25]. This
represents another area in which further investigations are
needed to replicate the findings from these smaller studies.
with CHDs [59]. Given the increase in treatment of

depressive symptoms with medication, additional investigations into the effect of antidepressant medications on
CHDs have been performed. Rather than examine antidepressants as a group, investigations have focused on evaluating categories of medications including selective
serotonin-reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and tricyclic antidepressants (TCAs). All three categories have been
identified as significantly associated with CHD development [106, 120, 128]. When all antidepressant medications
are evaluated by defect, ASD, VSD, and CoA remain
significantly associated with their use [10, 106, 120].
Whereas these studies represent positive associations
between antidepressant categories and CHDs, numerous
studies have not identified a significant association between
maternal antidepressant use and CHDs [5, 6, 10, 102, 128].
Given the weak associations noted, additional investigations are needed to define the absolute risk better so
mothers and health care practitioners can make informed
decisions.
Maternal Therapeutic Drug Exposures
Antihypertensive Medications
Antidepressant Medications
Antihypertensive medications are commonly prescribed

during the periconceptional period. Studies investigating
the maternal use of these medications and CHD development have yielded conflicting results. Analyses of the
According to the BWIS data, maternal use of any antidepressants during the periconceptional period is associated
123
1548
Swedish Medical Birth Register and the NBDPS databases

identified a two- to three-fold increase in the risk for CHDs
as a group [30, 93].
More recent studies, however, have not reported significant associations with antihypertensive medications as a
class of drugs [12, 94]. When the NBDPS database was
stratified by defect, associations were identified between
maternal antihypertensive medication use and ASD, CoA,
Ebsteins anomaly, and pulmonary valve stenosis [30].
Additional investigations have been performed examining specific types of antihypertensive medications including
beta-blockers and angiotensin-converting enzyme (ACE)
inhibitors. Again, conflicting results have been reported [30,
36, 82, 93, 94]. Interestingly, the most recent study using the
Kaiser Permanente database postulated that the apparent
increased risk from ACE inhibitor use was due to the
underlying hypertension rather than the medications, highlighting the need for further investigation [94].
42]. Numerous studies, however, have failed to demonstrate a significant association between folic acid and CHD
risk reduction [39, 48, 82, 141].
The timing of multivitamin initiation within the periconceptional period also was found to be critical. Reduction in risk was present when the multivitamin
supplementation was used at about the time of conception
or early in the first month of pregnancy but not when use
started during the second or third months of pregnancy,
suggesting that the underlying mechanism of folate is most
effective during the critical period of cardiac development
[18, 48].
The exact mechanism of folic acids protective effect
has yet to be elucidated. One hypothesis is that folic acid
prevents congenital defects by stimulating cellular methylation reactions. Folic acid-deficient rats have been
reported to produce offspring with VSDs and defects of the
outflow tract and great vessels [18].
Anti-infection Medications
Nonsteroidal Antiinflammatory Medications
Anti-infection medications, including antibiotics and antifungals, are commonly prescribed during the periconceptional period of pregnancy. Two large studies using the
NBDPS and the Swedish Medical Birth Register were
unable to identify a significant association between general
maternal use of antibiotics and the development of CHDs
[41, 82]. However, increased risk of CHD, CoA, and
hypoplastic left heart syndrome have been reported for
mothers using sulfonamide medications [47, 72, 111].
These increased risks also were reduced if the mother
concomitantly took folic acid supplementation [47, 72].
Antifungal medications are another common class of
medications prescribed during the periconceptional period.
The BWIS identified a significant association between
metronidazole use and the development of CHDs [59].
Two metaanalyses showed no increased risk of congenital
anomalies, including CHDs, associated with maternal use
of metronidazole [23, 28]. More recently, examination of
the NBDPS did not identify an increased risk among
mothers who reported using metronidazole [29].
No consistent associations between maternal use of any

type of NSAID and the development of CHDs have been
reported [82, 154]. Various types of NSAIDs also have
been evaluated for their role in CHD formation. Although
aspirin is not significantly associated with CHDs as a
group, maternal use of aspirin is reported to be associated
with interrupted aortic arch [46, 100, 154].
The BWIS data showed an association between ibuprofen use and an increased risk of CHDs [59]. Stratification by defect identified a significant association between
ibuprofen and Down syndrome, atrioventricular septal
defect, double-outlet right ventricle, and TGA [60]. A more
recent study using the Norwegian Mother and Baby Cohort
with more than 66,000 study participants did not confirm
this association [154].
An association between maternal use of naproxen and
CHDs overall has been demonstrated using the Swedish
Medical Birth Register [82]. In addition, using the NBDPS
database, increased risk for pulmonary valve stenosis has
been reported [71].
Folic Acid
Parental Nontherapeutic Drug Exposures
Multivitamin supplements containing folic acid may

reduce the risk for some types of CHD, similar to the
known risk reduction of neural tube defects seen with folic
acid [43]. In a randomized trial, the use of multivitamins
containing folate was associated with an *60 % overall
reduction in the risk of CHDs [43]. Similar findings were
noted using the Atlanta Birth Defects Case-Control Study
and EUROCAT databases [18, 153]. Among the subtypes,
TGA and VSDs exhibited significant risk reduction [17,
Alcohol
123
Several studies have documented the wide-ranging teratogenic effects of alcohol consumption during pregnancy on
birth outcomes, including CHDs. Alcohol may have an
impact on heart development through its contribution to
impaired conversion of retinol to retinoic acid, antagonism of
the N-methyl-D-aspartate (NMDA) receptor, compromised
nutritional status, and vascular disruptive events [50, 88, 122].
Conflicting results have been reported for maternal

alcohol consumption during the periconceptional period. A
majority of studies have not reported a significant association between maternal alcohol use and CHDs. However,
two large studies did demonstrate a significant relationship
[3, 26, 59, 148]. A case-control study using the Pregnancy
Risk Assessment Monitoring System database also recently
reported a threefold risk for CHDs among mothers who
reported periconceptional alcohol use [108]. When study
databases were stratified by defect, increased risks were
observed for ASD, TGA, and VSD [67, 149, 164].
The majority of studies evaluating the adverse outcomes
related to alcohol have focused on maternal consumption,
but paternal consumption also has been investigated for its
role in CHDs. Although no reports have described a significant association for any type of CHD, one study identified a fourfold increase in risk for VSDs among fathers
who reported alcohol use [164].
1549
factor for the development of CHDs, analysis of NBDPS

data demonstrated a significant association between
maternal passive smoke exposure and atrioventricular
septal defects [105, 118].
Few studies have evaluated the effect of paternal smoking, and the results have been conflicting, similar to the
results for maternal smoking. The BWIS did not identify a
significant association between paternal cigarette smoking
and CHDs as a group or any CHD subtype [59]. A recent
study performed in Italy demonstrated an increased risk of
CHDs as a group among fathers who reported smoking [40].
The mechanisms by which cigarette smoke or the
chemical compounds contained within the smoke might
result in CHDs remain to be elucidated. However, given
the complexity of cardiovascular development, such
mechanisms are likely to involve genegene, geneenvironment, or environmentenvironment interaction effects.
Illicit Drugs
Caffeine
Caffeine is known to cross the placenta, and concern that
maternal ingestion of caffeine may lead to birth defects
prompted the Food and Drug Administration (FDA) to
caution pregnant women to limit their caffeine intake [80].
Using data from the NBDPS, the consumption of coffee,
tea, soda, and chocolate was examined for an association
with select CHDs [22]. No evidence for a teratogenic effect
of caffeine was identified [22]. Multiple other studies have
failed to identify an association between caffeine consumption and CHD risk [59, 150].
Cigarette Smoking
Maternal cigarette smoking has been investigated for a
possible role in CHD development, with conflicting results.
Analyses of the Swedish Medical Birth Register, Arkansas
Reproductive Health Monitoring System, and BWIS databases did not identify a significant association between
maternal periconceptional cigarette smoking and the
development of CHDs as a group [4, 73, 81]. However, a
study using the NBDPS database did identify an increased
risk for the development of CHDs among mothers who
reported use of cigarettes [105]. A second small study
based on data from the University of Patras in Greece
replicated these results [84].
Two recent metaanalyses demonstrated a modest association of cigarette use and an increased risk of CHDs
overall [68, 92]. Detailed analysis of the NBDPS data also
identified subtypes at increased risk, including ASD,
atrioventricular septal defect, pulmonary valve stenosis,
and VSD [105, 118]. In addition, although passive smoke
exposure was not previously identified as a significant risk
A review of all neonatal drug screens performed at Boston

City Hospital showed an increased risk of CHDs for infants
born to mothers who used cocaine prenatally [97]. Data
from the BWIS showed an association between maternal
and paternal cocaine use and CHDs, more specifically,
VSDs [59, 60]. Cocaine may exert direct toxic effects on
fetal myocytes. Primary cultures of myocardial cells from
near-term fetal rats exposed to cocaine resulted in apoptotic
cell death, which may play a role in the development of
structural malformations [166]. An additional hypothesis
for the mechanism is induction of coronary occlusion in the
developing fetal heart [140].
Although maternal marijuana use is not reported to be
associated with CHDs as a group, findings have demonstrated its association with VSDs [164]. However, data
from the BWIS have demonstrated that paternal marijuana
is associated with an increased risk for the development of
any type of CHDs [59]. Analysis of the birth defects registry in Atlanta and a stratified analysis of the BWIS also
have demonstrated an increased risk for development of
VSDs among infants whose fathers reported the use of
marijuana [58, 164]. Although these studies did demonstrate positive associations, it should be noted that the
number of individuals who reported illicit drug use was
extremely small, making interpretation of these results
limited.
Parental Environmental Exposures
Air Pollution
Observational studies have reported associations between
maternal exposure to environmental air pollution and
123
1550
congenital malformations [53]. More recent studies have

examined the effects of maternal environmental air pollutant exposure and subsequent CHD development [49, 54,
64, 69, 131, 145]. These studies have shown little or no
association with CHD development.
Chemical Exposures
Exposure to occupational chemicals, especially during the
periconceptional period, influences the reproductive system
in both men and women and may lead to adverse health
effects in children. Plausible mechanisms include reduced
sperm quality, disrupted epigenetic programming during
maturation of sperm cells, impaired maturation of oocytes,
and impaired embryogenesis [8, 115].
Multiple studies have demonstrated associations between
infant birth defects and parental exposure to occupational
chemicals, but the relationship between chemical exposure
and CHDs is not clear [15, 37, 52, 138, 139]. The BWIS
investigated the role of organic solvents with respect to
CHDs. Associations between maternal exposure to organic
solvents during the periconceptional period were observed
for CoA, hypoplastic left heart syndrome, and TGA [60].
Findings based on more than 25,000 births showed that
maternal exposure to cyanide or heavy metals is associated
with CHDs [136].
More recently, a Dutch case-control study showed an
association between paternal exposure to phthalates or alkylphenolic compounds during the periconceptional period
and an increased risk of infant CHDs in general [143]. In
this study, paternal exposure to phthalates was associated
with VSDs, exposure to polychlorinated compounds was
associated with atrioventricular septal defects, and exposure to alkylphenolic compounds was associated with CoA
[143]. Chemical exposures were difficult to define in these
studies, and the associations identified were weak, suggesting that these results need to be replicated for a definition of the true risk they represent.
Water Contamination
Multiple studies have examined the relationship between
maternal exposure to contaminated water and CHDs. Trichloroethylene, a hydrocarbon solvent used as a metal
degreasing agent, is an intermediate product in the production of polyvinyl chloride [159]. It also has uses as an
anesthetic, antiseptic, solvent for dry cleaning, and coffee
decaffeination. Dichloroethylene is a chemical used for
synthesis of polyvinyl chloride and plastic packaging.
Because both chemicals are volatile, the majority of these
chemicals released into the environment will evaporate.
However, in some groundwater environments, they can
persist for years, causing contamination of water supplies.
123
Animal studies of these chemicals have demonstrated

conflicting results. In small mammals, trichloroethylene
inhalation has not resulted in teratogenesis. However,
studies of chick embryos have demonstrated significant
cardiac teratogenesis, particularly if the trichloroethylene
exposure was early in gestation [70]. Gestational dichloroethylene exposure also has been demonstrated to result in
a significant proportion of abnormal hearts [70].
A recent case-control study performed in Milwaukee,
Wisconsin identified an increased risk of CHD in infants
born to mothers exposed to trichloroethylene compared
with those born to nonexposed younger mothers [169]. In a
study examining more than 80,000 births in New Jersey,
dichloroethylene exposure was associated with CHD [21].
Analysis of the California Birth Defects Monitoring Program database showed a possible association between
CHDs in infants and mothers who consumed tap water
versus bottled water after water contamination [135].
It is important to note that these studies were performed
with small samples, and exposure definitions were difficult,
suggesting that these results must be interpreted with caution. In addition, two large reviews have reported no association between maternal exposure to trichloroethylenecontaminated water and CHDs [70, 159].
Conclusion
Little is known regarding the risk factors for CHDs.
Numerous factors and exposures have been examined for
their role in the development of CHDs. As summarized in
Tables 1, 2, 3, 4, 5, significant associations between
multiple risk factors and CHDs have been identified.
Studies investigating a majority of these risk factors have
yielded conflicting results, suggesting that additional
investigations need to be performed. The limitations of
these studies overall need to be discussed. Recall bias is
of concern because most mothers of infants with CHDs
have a more detailed recollection of exposures than
mothers of healthy children. In addition, because most
exposures of interest are those during the periconceptional
period, recall of exposures may be difficult due to the
intervening time.
Most of the studies have had small samples due to the
rarity of specific types of CHDs. It also is difficult to
perform precise measurements of some exposures, such as
occupational and environmental exposures.
It is interesting to note that a large proportion of the risk
factors were observed to be associated with a variety of
CHDs, suggesting that chance associations may have been
observed as opposed to true associations. Mechanisms for
these associations are difficult to define because multiple
categories of defects were found to be associated with a
specific risk factor, further implying that these associations

occurred by chance.
Confounding in the interpretation of these results also is
a large concern. It is unclear whether maternal illnesses or
the medications used to treat these illnesses have independent effects. Finally, the majority of the significant
findings demonstrated weak associations or wide confidence intervals, suggesting that the results presented should
be interpreted with caution.
As previously discussed, the investigations presented in
this review had significant limitations. However, the presented information highlights some some principles for
prevention that could be useful. These principles include
the use of a multivitamin containing folate early in pregnancy or even beforehand, avoidance of individuals with a
febrile illness to minimize the chance of infection, avoidance of organic solvents, and avoidance of alcohol,
tobacco, and illicit drugs. Health care providers should
provide close monitoring of women receiving regular
medications for depression, hypertension, and infections,
as well as careful management of women with diabetes. In
addition, screening for CHDs should be performed when
these situations or exposures are present.
Further epidemiologic investigations to contribute
information necessary for the development of prevention
policies and interventions are warranted. As previously
mentioned, the NBDPS is an ongoing study, which will
continue to provide this information and ultimately may
lead to policies aimed at reducing the burden of CHDs.
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Nongenetic Risk Factors and Congenital Heart

Available from: Sonali Patel

Pediatr Cardiol (2013) 34:15351555

Nongenetic Risk Factors and Congenital Heart Defects

Abstract Advances have been made in identifying

Pediatr Cardiol (2013) 34:15351555

via echocardiography, cardiac catheterization, surgery, or

Pediatr Cardiol (2013) 34:15351555

Advanced paternal age

Young paternal age

MACDP (19682005) [112]

PaRCM (19982002) [109]

PHHS (19881994) [78]

NSW/ACT (19811984) [86]

BWIS (19811989) [59]

FRCM (19821983) [147]

PRCM (19982002) [109]

NCHS (19992000) [167]

EHS (19951997) [13]

MBRN (19671998) [85]

EUROCAT (19902005) [62]

HCCSCA (19801996) [11]

NBDPS (19972003) [38]

Milwaukee (19971999) [169]

BWIS (19811989) [101]

WA State (19841991) [79]

SMBR (19811986) [121]

BWIS (19811989) [117]

HCCSCA (19801996)a [2]

Shan province (20042005)a [98]

NBDPS (19972003)b [34]

ABDCCS (19681980) [20]

SBDMP (19861987)c [171]

FRCM (19821983) [147]

HAVEN (20032010) [142]

HAVEN (20032005) [156]

APGC (19881998) [160]

KPNCa (19952008) [94]

HCCSCA (19801996) [44]

NBDPS (19972003) [30]

Milwaukee (19971999) [169]

FRCM (19821983) [147]

BWIS (19811989) [117]

HCCSCA (19801996) [1]

ABDCCS (19681980) [20]

Overweight ? obesity (BMI [ 25)

NBDPS (19972004) [63]

SMBR (19952007) [16]

ABDRFSS (19931997) [158]

NBDPS (19972004) [63]

ABDCCS (19681980) [157]

Pediatr Cardiol (2013) 34:15351555

Severely obese (BMI [ 40)

WCHARS (19922007) [103]

NBDPS (19972004) [63]

NYSCMR (19932003) [113]

SMBR (19952007) [16]

WABDR (19972000) [116]

ABDRFSS (19931997) [158]

ABDCCS (19681980) [157]

MBR (19901994) [124]

SMBR (19952007) [16]