nongenetic risk factors and congenital heart defects

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 poten-

tial 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

Birth defects, defined as abnormalities of structure, func-

tion, 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 signifi-

cant birth defects and are an important component of

pediatric cardiovascular disease, with an estimated preva-

lence of 6–9 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 identi-

fiable 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 devel-

opment 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’’ con-

jures 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].

S. S. Patel (&) � T. L. Burns

Department of Pediatrics, Division of Pediatric Cardiology,

Carver College of Medicine, University of Iowa, Children’s

Hospital, 200 Hawkins Drive, Iowa City, IA 52242, USA

e-mail: [email protected]; [email protected]

T. L. Burns

Department of Epidemiology, College of Public Health,

University of Iowa, Iowa City, IA, USA

123

Pediatr Cardiol (2013) 34:1535–1555

DOI 10.1007/s00246-013-0775-4

This article aims to provide a current review of the lit-

erature 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, refer-

ences 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 expo-

sure,’’ ‘‘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. Publica-

tions 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 rel-

ative 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 case–control

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

via echocardiography, cardiac catheterization, surgery, or

autopsy. Preterm infants (infants born at \38 weeks ges-

tation) 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 live-

born infants without birth defects born in the same region

and frequency-matched to the cases by month, year, hos-

pital 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, stan-

dardized questionnaire obtained information on sociode-

mographic, 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 Dis-

ease 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 sus-

pected chromosomal abnormalities or single gene condi-

tions 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

1536 Pediatr Cardiol (2013) 34:1535–1555

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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 MACDP (1968–2005) [112] 739 1,301,143 1.2 (1.1–1.3)

PaRCM (1998–2002) [109] 4,337 8,683 1.1 (1.0–1.1)

PHHS (1988–1994) [78] 3,757 102,728 4.0 (1.7–9.2)

NSW/ACT (1981–1984) [86] 1,479 343,521 1.3 (1.1–1.4)

BWIS (1981–1989) [59] 3,377 3,572 1.3 (1.1–1.5)

FRCM (1982–1983) [147] 408 755 1.3 (1.0–1.6)

Advanced paternal age PRCM (1998–2002) [109] 3,933 8,683 1.1 (1.0–1.3)

NCHS (1999–2000) [167] 9,767 77,514 1.2 (1.1–1.4)

EHS (1995–1997) [13] 894 894 1.5 (1.2–2.0)

Young paternal age MBRN (1967–1998) [85] 3,656 1,869,388 1.5 (1.0–2.0)

Bei/Heb provinces (1988) [167] 497 6,222 2.3 (1.9–2.8)

Diabetes mellitus (pre-gestational) EUROCAT (1990–2005) [62] 323 92,976 2.2 (1.9–2.6)

HCCSCA (1980–1996) [11] 4,480 38,151 2.5 (1.6–3.9)

NBDPS (1997–2003) [38] 3,519 4,689 4.6 (2.9–7.5)

Milwaukee (1997–1999) [169] 245 3,780 4.1 (1.5–11.2)

BWIS (1981–1989) [101] 3,377 3,572 3.0 (1.9–4.8)

WA State (1984–1991) [79] 1,511 8,934 4.0 (3.1–5.1)

SMBR (1981–1986) [121] 1,324 2,648 2.7 (1.4–5.0)

Febrile illness BWIS (1981–1989) [117] 2,361 3,435 1.1 (0.9–1.5)

HCCSCA (1980–1996)a [2] 4,480 38,151 2.6 (1.2–5.4)

Shan province (2004–2005)a [98] 164 328 5.9 (2.7–13.1)

NBDPS (1997–2003)b [34] 3,690 4,760 1.7 (1.0–3.0)

ABDCCS (1968–1980) [20] 829 3,029 1.8 (1.4–2.4)

SBDMP (1986–1987)c [171] 986 990 1.4 (0.7–2.9)

FRCM (1982–1983)c [147] 583 756 1.5 (1.1–2.1)

Hypercholesterolemia HAVEN (2003–2010) [142] 229 320 1.5 (1.1–2.1)

Hyperhomocysteinemia ARHMS (1998–2008) [74] 417 250 1.5 (1.2–1.8)

HAVEN (2003–2005) [156] 151 183 2.9 (1.4–6.0)

APGC (1988–1998) [160] 26 116 3.5 (1.2–10.2)

Hypertension KPNCa (1995–2008) [94] 6,873 453,078 1.4 (1.3–1.5)

HCCSCA (1980–1996) [44] 4,480 38,151 1.3 (1.0–1.5)

NBDPS (1997–2003) [30] 5,021 4,796 1.8 (1.1–2.7)

Milwaukee (1997–1999) [169] 245 3,780 2.8 (1.2–6.7)

FRCM (1982–1983) [147] 583 756 2.6 (1.1–5.2)

Influenza BWIS (1981–1989) [117] 2,361 3,435 1.1 (0.9–1.4)

HCCSCA (1980–1996) [1] 4,480 38,151 1.7 (1.3–2.3)

ABDCCS (1968–1980) [20] 829 3,029 2.1 (0.8–5.5)

Prepregnancy weight

Overweight (BMI 25–30) NBDPS (1997–2004) [63] 6,440 5,673 1.2 (1.1–1.3)

SMBR (1995–2007) [16] 11,163 1,235,877 1.1 (1.0–1.1)

ABDRFSS (1993–1997) [158] 195 330 2.0 (1.2–3.1)

Overweight ? obesity (BMI [ 25) ENN (1997–2008) [9] 797 322 1.1 (0.8–1.5)

NBDPS (1997–2004) [63] 6,440 5,673 1.2 (1.1–1.3)

ABDCCS (1968–1980) [157] 851 2,767 1.4 (1.0–1.9)

Pediatr Cardiol (2013) 34:1535–1555 1537

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these risk factors by specific defect. For the remainder of

the review, risk factors are divided into four broad cate-

gories: 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,

147]. In the BWIS, advanced maternal age was found to be

associated with an increased risk of Ebstein’s 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 Fal-

lot, and ventricular septal defect (VSD), whereas younger

maternal age was associated with total anomalous pul-

monary venous return and tricuspid atresia.

Table 1 continued


Obese (BMI [ 30) WCHARS (1992–2007) [103] 14,412 141,420 1.2 (1.2–1.3)

NBDPS (1997–2004) [63] 6,440 5,673 1.3 (1.2–1.4)

NYSCMR (1993–2003) [113] 7,392 56,304 1.2 (1.1–1.2)

SMBR (1995–2007) [16] 11,163 1,235,877 1.2 (1.1–1.2)

WABDR (1997–2000) [116] 111 418 1.3 (0.6–2.7)

ABDRFSS (1993–1997) [158] 195 330 2.0 (1.2–3.4)

ABDCCS (1968–1980) [157] 851 2,767 1.3 (0.8–2.1)

MBR (1990–1994) [124] 1,451 8,088 0.8 (0.3–1.9)

Severely obese (BMI [ 40) SMBR (1995–2007) [16] 11,163 1,235,877 1.5 (1.2–1.8)

Reproductive history

Infertility/ART PaRCM (1987–2006) [146] 5,493 3,104 1.4 (1.1–1.7)

Parity

Multiparous NBDPS (1997–2007) [56] 7,575 7,954 1.0 (0.9–1.1)

PRCM (2005–2006) [110] 1,673 4,017 1.2 (1.1–1.4)

Shan province (2004–2005) [98] 164 328 2.5 (1.5–4.0)

BWIS (1981–1989) [59] 3,377 3,572 1.3 (1.1–1.5)

Nulliparous NBDPS (1997–2007) [56] 7,575 7,954 1.1 (1.0–1.2)

Socioeconomic status (low) Kaunas (1999–2005) [90] 187 643 3.4 (1.5–7.6)

DNBC (1997–2002) [155] 659 81,453 1.6 (1.3–2.0)

Stress Shan province (2004–2005) [98] 164 328 2.7 (1.5–4.8)

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 Mon-

itoring System, APGC University of Alabama Prenatal Genetics Clinic, Bei/Heb provinces Beijing and Hebei provinces, BWIS Baltimore-

Washington 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 Systema Pelvic inflammatory diseaseb Urinary tract infectionc URI upper respiratory infection

1538 Pediatr Cardiol (2013) 34:1535–1555

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Table 2 Risk factors associated with congenital heart defects: therapeutic drug exposures

Exposure Source Database Cases (n) Controls (n) OR or RR (95 % CI)

Anti-asthmatic medication Lin et al. [96] NYSCMR (1988–1991) 502 1,066 2.4 (1.2–4.8)

Kallen et al. [83] SMBR (1995–2004) 11,367 585,372 1.1 (1.0–1.3)

Bronchodilators Lin et al. [96] NYSCMR (1988–1991) 502 1,066 2.2 (1.1–4.6)

Kallen et al. [83] SMBR (1995–2004) 11,367 585,372 1.4 (1.1–1.7)

Antibiotics (any) Crider et al. [41] NBDPS (1997–2003) 5,269 4,941 1.1 (1.0–1.3)

Kallen et al. [82] SMBR (1995–2001) 5,565 577,730 1.1 (0.9–1.3)

Macrolides Crider et al. [41] NBDPS (1997–2003) 5,269 4,941 1.0 (0.7–1.3)

Penicillins Crider et al. [41] NBDPS (1997–2003) 5,269 4,941 1.0 (0.8–1.1)

Denker et al. [51] NJC (1991–1998) 4,055 9,263 1.7 (0.8–3.7)

Ferencz et al. [59] BWIS (1981–1989) 3,377 3,572 1.3 (1.1–1.6)

Sulfonamides Crider et al. [41] NBDPS (1997–2003) 5,269 4,941 1.5 (1.0–2.2)

Matok et al. [111] Clalit HMO (1998–2007) 571 85,250 1.8 (1.1–3.0)

Czeizal et al. [47] HCCSCA (1980–1996) 4,467 38,151 2.1 (1.4–3.3)

Hernandez-Diaz et al. [72] SEUBDS (1976–1988) 3,870 8,387 3.4 (1.8–6.4)

Sulfonamide with folic acid Czeizal et al. [47] HCCSCA (1980–1996) 4,467 38,151 1.2 (0.9–1.6)


Anticonvulsants Werler et al. [162] NBDPS (1997–2005) 7,093 6,052 1.4 (1.0–2.1)

Matok et al. [111] Clalit HMO (1998–2007) 571 85,250 0.7 (0.2–2.9)

Kallen et al. [82] SMBR (1995–2001) 5,565 577,730 1.6 (1.0–2.5)


With folic acid Hernandez-Diaz et al. [72] SEUBDS (1976–1988) 3,870 8,387 2.3 (1.1–4.7)

Antidepressants (any) Ferencz et al. [59] BWIS (1981–1989) 3,377 3,572 3.0 (1.2–7.6)

Buproprion Alwan et al. [6] NBDPS (1997–2004) 6,853 5,869 1.1 (0.7–1.9)

SSRI (any) Malm et al. [106] FRCM (1996–2003) 8,253 635,583 1.3 (1.1–1.6)

Reis et al. [128] SMBR (1995–2007) 14,821 1,062,190 1.0 (0.8–1.2)

Alwan et al. [5] NBDPS (1997–2002) 4,268 4,092 0.9 (0.7–1.2)

Louik et al. [102] SEUBDS (1993–2004) 3,724 5,860 1.2 (0.9–1.6)

Paroxetine Malm et al. [106] FRCM (1996–2003) 8,253 635,583 1.3 (0.8–2.1)

Bakker et al. [10] ENN (1997–2006) 678 615 1.5 (0.6–4.2)

Reis et al. [128] SMBR (1995–2007) 1,208 1,062,190 1.7 (1.1–2.5)

Louik et al. [102] SEUBDS (1993–2004) 3,724 5,860 1.4 (0.8–2.5)

Fluoxetine Louik et al. [106] FRCM (1996–2003) 8,253 635,583 1.6 (1.1–2.2)

Malm et al. [102] SEUBDS (1993–2004) 3,724 5,860 0.9 (0.6–1.5)

SNRI (Venlafaxine) Polen et al. [120] NBDPS (1997–2007) 8,069 8,002 2.7 (1.5–5.0)

TCA Reis et al. [128] SMBR (1995–2007) 1,662 1,062,190 1.6 (1.1–2.4)

Antifungals (metronidazole) Ferencz et al. [59] BWIS (1981–1989) 3,377 3,572 2.5 (1.1–5.8)

Antihypertensives Banhidy et al. [12] HCCSCA (1980–1996) 4,480 38,151 1.3 (1.0–1.5)

Li et al. [94] KPNCa (1995–2008) 6,873 453,078 1.5 (1.0–2.2)

Caton et al. [30] NBDPS (1997–2003) 5,021 4,796 1.8 (1.1–2.7)

Lennestal et al. [93] SMBR (1982–2006) 1,418 1,045,425 2.6 (1.9–3.5)

b-Blockers Caton et al. [30] NBDPS (1997–2003) 5,021 4,796 2.6 (1.2–5.3)

Kallen et al. [82] SMBR (1995–2001) 5,565 577,730 1.9 (1.2–2.8)

ACE inhibitors Li et al. [94] KPNCa (1995–2008) 6,873 453,078 1.5 (0.9–2.6)

Caton et al. [30] NBDPS (1997–2003) 5,021 4,796 1.9 (0.5–7.2)

Lennestal et al. [93] SMBR (1982–2006) 1,418 1,045,425 2.9 (0.9–6.8)

Cooper et al. [36] TN Medicaid (1985–2000) 209 29,096 3.7 (1.9–7.3)

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Table 3 Risk factors associated with congenital heart defects: nontherapeutic drug exposures


Alcohol PRAMS (1996–2005) [108] 237 948 3.0 (1.2–7.5)

Cigarette smoking

Maternal use BWIS (1981–1989) [4] 2,525 3,435 1.1 (1.0–1.2)

Patras (2006–2009) [84] 157 208 2.8 (1.8–4.6)

NBDPS (1997–2002) [105] 3,067 3,947 1.2 (1.1–1.4)

ARHMS 1998–2004) [73] 275 118 1.7 (1.0–3.1)

SMBR (1983–1996) [81] 3,384 1,413,811 1.1 (1.0–1.2)

Paternal use Italy (2008–2010) [40] 360 360 1.7 (1.1–2.6)

Cocaine

Maternal use BWIS (1981–1989) [59] 3,377 3,572 1.6 (1.1–2.3)

Boston City (1988–1990) [97] 49 505 3.7 (1.4–9.4)

Paternal use BWIS (1981–1989) [59] 3,377 3,572 1.7 (1.3–2.2)

Marijuana (paternal) BWIS (1981–1989) [59] 3,377 3,572 1.2 (1.1–1.4)

Vitamin E HAVEN (2003–2006) [141] 276 324 1.7 (1.0–2.6)



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

Table 2 continued

Exposure Source Database Cases (n) Controls (n) OR or RR (95 % CI)

Folic acid (multivitamin) Correa et al. [39] NBDPS (1997–2004) 5,206 4,737 0.9 (0.8–1.0)

Van Beynum et al. [153] EUROCAT (1996–2005) 611 3,343 0.7 (0.6–0.9)

Smedts et al. [141] HAVEN (2003–2006) 276 324 1.3 (0.9–1.9)

Czeizel et al. [48] HPS (1993–1996) 31 50 0.6 (0.4–1.0)

Kallen et al. [82] SMBR (1995–2001) 5,565 577,730 1.2 (1.0–1.6)

Botto et al. [18] ABDCCS (1968–1980) 958 3,029 0.8 (0.6–1.0)

Czeizel et al. [45] HCCSCA (1980–1991) 2,976 30,663 0.9 (0.8–1.0)

NSAIDs (any) van Gelder et al. [154] MoBa (1999–2007) 435 66,662 1.0 (0.7–1.6)

Kallen et al. [82] SMBR (1995–2001) 5,565 577,730 1.2 (1.0–1.6)

Aspirin van Gelder et al. [154] MoBa (1999–2007) 435 66,662 1.6 (0.5–5.2)

Czeizel et al. [46] HCCSCA (1980–1996) 4,056 38,151 1.4 (0.9–2.1)

Ibuprofen van Gelder et al. [154] MoBa (1999–2007) 435 66,662 0.9 (0.5–1.5)

Ferencz et al. [59] BWIS (1981–1989) 3,377 3,572 1.4 (1.1–1.8)

Naproxen Kallen et al. [82] SMBR (1995–2001) 5,565 577,730 1.7 (1.1–2.5)

Thyroid replacement Winker et al. [163] SMBR (1995–2004) 11,028 848,468 1.3 (1.1–1.5)



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 Per-

manente 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

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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 asso-

ciation between advanced paternal age and VSDs [13].

Diabetes Mellitus

Multiple studies have consistently demonstrated an asso-

ciation 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 gesta-

tion, during the critical period of organogenesis [89].

Pre-gestational diabetes has been associated with mul-

tiple 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 deter-

mined 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 pre-

vention 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 preg-

nancy 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

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 bio-

logic transmethylations [119]. Increased levels of homo-

cysteine 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 develop-

ment 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 inves-

tigate 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). Over-

weight is defined as a BMI of 25–30 kg/m2, obesity as a

BMI of 30–40 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].

Pediatr Cardiol (2013) 34:1535–1555 1541

123

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. Find-

ings 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

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 statisti-

cally significant, many characteristics such as an unem-

ployed 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

Table 4 Risk factors associated with congenital heart defects: environmental exposures


Air pollution

Carbon monoxide NCAS (1993–2003) [49] 2,140 14,256 1.2 (0.9–1.7)

Chemical exposures

Maternal cyanide exposure San Francisco (1983–1985) [136] 5,046 20,882 2.2 (1.3–3.9)

Maternal heavy metal exposure HAVEN (2003–2010) [143] 424 480 0.9 (0.2–3.8)

San Francisco (1983–1985) [136] 5,046 20,882 1.5 (1.1–2.3)

Maternal pesticide exposure HAVEN (2003–2010) [143] 424 480 0.8 (0.3–2.1)

San Francisco (1983–1985) [136] 5,046 20,882 1.6 (1.0–2.5)

Maternal phthalate exposure HAVEN (2003–2010) [143] 424 480 2.2 (0.9–5.2)

Paternal phthalate exposure HAVEN (2003–2010) [143] 424 480 1.7 (1.1–2.5)

Paternal alkylphenolic compound exposure HAVEN (2003–2010) [143] 424 480 1.8 (1.1–3.0)

Drinking water contaminants

Dichloroethylene New Jersey (1985–1988) [21] 108 52,334 2.8 (1.3–5.9)*

Trichloroethylene Milwaukee (1997–1999) [169] 245 3,780 6.2 (2.6–14.5)

Hazardous waste site Dallas County (1979–1984) [104] 1,283 2,292 1.2 (1.1–1.4)



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

1542 Pediatr Cardiol (2013) 34:1535–1555

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Table 5 Risk Factors Associated with Specific Congenital Heart Defects

Defect Exposure Database Cases (n) Controls (n) OR or RR (95 % CI)

ASD Advanced maternal age NBDPS (1997–2007) [65] 468 8,169 2.5 (1.5–4.1)

MACDP (1968–2005) [112] 398 1,301,143 1.4 (1.1–1.8)

Pre-gestational diabetes mellitus EUROCAT (1990–2005) [62] 101 26,228 2.3 (1.8–2.8)

NBDPS (1997–2003) [38] 419 4,689 8.5 (4.4–16.4)

Febrile illness BWIS (1981–1989)a [60] 187 3,572 1.7 (1.2–2.5)

Infertility/ART NBDPS (1997–2003) [126] 1,080 5,008 3.4 (1.8–6.2)


Prepregnancy weight

Overweight ? obesity NBDPS (1997–2004) [63] 621 5,673 1.3 (1.1–1.6)

Obese WCHARS (1992–2007) [103] 1,690 141,420 1.2 (1.0–1.4)

NYSCMR (1993–2003) [113] 2,075 56,304 1.2 (1.1–1.4)

SMBR (1992–2001) [31] 639 812,457 1.4 (1.1–1.7)

Cephalosporins NBDPS (1997–2003) [41] 1,225 4,941 1.9 (1.1–3.2)

SSRI ENN (1997–2006) [10] 3 53 5.7 (1.4–23.7)

NBDPS (1997–2002) [5] 768 4,092 1.1 (0.6–1.9)

Paroxetine ENN (1997–2006) [10] 56 615 5.7 (1.4–23.5)

SNRI (venlafaxine) NBDPS (1997–2007) [120] 2,181 8,002 2.9 (1.2–6.9)

Antihypertensives NBDPS (1997–2003) [30] 1,137 4,796 2.4 (1.3–4.4)

Alcohol use FRCM (1982–1983) [149] 50 756 2.0 (1.1–3.4)

Cigarette use BWIS (1981–1989) [4] 186 3,435 1.4 (1.0–1.8)

NBDPS (1997–2002) [105] 338 3,947 2.0 (1.5–2.6)

SMBR (1983–1996) [81] 100 1,413,811 1.6 (1.0–2.6)

Cocaine use (paternal) BWIS (1981–1989) [60] 65,187 3,572 2.3 (1.3–4.2)

Air pollution

Nitrogen dioxide MACDP (1986–2003) [145] 379 715,500 1.6 (1.2–2.1)

Particulate matter Brisbane (1997–2004) [69] 127 2,860 1.1 (1.0–1.3)

TBDR (1997–2000) [64] 977 3,431 1.3 (1.0–1.6)

Sulphur dioxide Brisbane (1997–2004) [69] 127 2,860 1.3 (1.0–1.7)

AVS Pre-gestational diabetes mellitus NBDPS (1997–2003) [38] 113 4,689 5.0 (1.1–22.9)

Infertility/ART NBDPS (1997–2005) [127] 243 6,500 2.6 (1.2–5.3)

Prepregnancy WEIGHT


Obesity NYSCMR (1993–2003) [113] 288 56,304 2.0 (1.4–2.9)

AVSD Pre-gestational diabetes mellitus EUROCAT (1990–2005) [62] 11 26,228 2.2 (1.2–4.0)

NBDPS (1997–2003) [38] 66 4,689 12.4 (3.7–41.5)

BWIS (1981–1989) [101] 31 3,572 22.8 (7.4–70.5)

Febrile illness BWIS (1981–1989) [117] 244 3,435 1.7 (1.0–2.8)

NBDPS (1997–2003)a [34] 98 4,760 2.3 (1.1–4.7)

Injuries NBDPS (1997–2005) [152] 166 6,328 2.4 (1.2–6.6)

Prepregnancy weight


Obesity WCHARS (1992–2007) [103] 120 141,420 0.5 (0.3–1.1)

NYSCMR (1993–2003) [113] 125 56,304 1.0 (0.6–1.7)

SMBR (1992–2001) [31] 905 812,457 1.2 (1.0–1.5)

Antibacterials NBDPS (1997–2003) [41] 128 4,941 1.7 (1.1–2.6)

Cough medications BWIS (1981–1989) [60] 76 3,572 8.9 (2.6–30.6)

Cigarette use NBDPS (1997–2007) [118] 187 6,703 1.5 (1.1–2.1)

BWIS (1981–1989) [4] 57 3,435 1.5 (1.0–2.3)

Passive smoke exposure NBDPS (1997–2007) [118] 187 6,703 1.5 (1.1–2.1)

Cocaine use BWIS (1981–1989) [60] 76 3,572 3.5 (1.1–11.4)

Paternal polychlorinated compound exposure HAVEN (2003–2010) [143] 44 480 4.2 (1.2–14.4)

DS-AVSD Febrile illness BWIS (1981–1989) [117] 187 3,435 1.9 (1.1–3.4)

Ibuprofen BWIS (1981–1989)a [60] 190 3,572 2.4 (1.1–4.2)

Pediatr Cardiol (2013) 34:1535–1555 1543

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Table 5 continued


CoA Advanced maternal age MACDP (1968–2005) [112] 256 1,301,143 1.5 (1.1–2.2)


NBDPS (1997–2003) [38] 196 4,689 2.1 (0.5–9.5)

Epilepsy BWIS (1981–1989) [60] 120 3,572 6.5 (1.8–23.0)

Febrile illness ABDCCS (1968–1980) [20] 60 3,029 2.7 (1.2–6.0)

Infertility/ART NBDPS (1997–2005) [127] 603 6,500 2.3 (1.4–3.8)

BWIS (1981–1989) [60] 120 3,572 6.1 (2.1–18.2)

Prepregnancy weight

Overweight ABDRFSS (1993–1997) [158] 12 330 3.9 (1.1–13.8)


Obesity NYSCMR (1993–2003) [113] 433 56,304 1.3 (1.0–1.7)

SMBR (1992–2001) [31] 117 812,457 1.5 (0.9–2.5)

Influenza ABDCCS (1968–1980) [20] 60 3,029 3.8 (1.6–8.8)

Sulfonamides NBDPS (1997–2003) [41] 431 4,941 2.7 (1.3–5.6)

Buproprion NBDPS (1997–2004) [6] 546 5,869 2.6 (1.0–6.9)

SNRI (venlafaxine) NBDPS (1997–2007) [120] 768 8,002 4.5 (1.4–12.5)

Antihypertensive NBDPS (1997–2003) [30] 406 4,796 3.0 (1.3–6.6)

Mineral oil exposure FRCM (1982–1983) [151] 50 756 5.9 (1.8–19.2)

Organic solvents BWIS (1981–1989) [60] 120 3,572 3.2 (1.3–7.9)

Paternal alkylphenolic compound exposure HAVEN (2003–2010) [143] 44 480 3.9 (1.2–12.7)

DORV Pre-gestational diabetes mellitus BWIS (1981–1989) [60] 27 3,572 12.3 (2.8–55.2)

Febrile illness BWIS (1981–1989)b [60] 27 3,572 2.8 (1.2–6.4)

Prepregnancy weight

Severe obesity NYSCMR (1993–2003) [113] 117 56,304 2.5 (1.1–5.8)

Ibuprofen BWIS (1981–1989) [60] 27 3,572 3.6 (1.1–12.2)

Ebstein’s Advanced maternal age BWIS (1981–1989) [60] 44 3,572 2.6 (1.4–4.8)

Advanced paternal age BWIS (1981–1989) [60] 44 3,572 1.8 (1.0–3.5)

Prepregnancy weight


Benzodiazepines BWIS (1981–1989) [60] 44 3,572 5.3 (1.5–18.5)

Antihypertensives NBDPS (1997–2003) [30] 65 4,796 11.4 (2.8–34.1)

Marijuana use BWIS (1981–1989) [60] 34 3,572 3.6 (1.6–8.5)

HLHS Febrile illness FRCM (1982–1983)b [147] 34 756 2.5 (1.2–5.4)


NBDPS (1997–2003) [38] 203 4,689 2.5 (0.7–8.8)

BWIS (1981–1989) [60] 138 3,572 3.4 (1.0–11.5)

Injuries NBDPS (1997–2005) [152] 338 6,328 1.7 (1.0–3.0)

Prepregnancy weight


Obese WCHARS (1992–2007) [103] 174 141,420 1.9 (1.1–1.3)

NYSCMR (1993–2003) [113] 241 56,304 1.7 (1.2–2.5)

SMBR (1992–2001) [31] 166 812,457 1.4 (0.9–2.2)

Sulfonamides NBDPS (1997–2003) [41] 6 4,941 3.2 (1.3–7.6)

Metronidazole NBDPS (1997–2003) [29] 176 4,581 2.3 (1.0–5.1)


IAA Injuries NBDPS (1997–2005) [152] 22 6,328 5.9 (1.7–20.0)

Aspirin BWIS (1981–1989) [100] 46 3,572 2.1 (1.1–4.0)

PA Pre-gestational diabetes mellitus BWIS (1981–1989) [60] 45 3,572 7.2 (1.6–31.4)

Prepregnancy weight


Influenza BWIS (1981–1989) [117] 39 3,435 2.7 (1.2–6.3)

Injuries NBDPS (1997–2005) [152] 140 6,328 2.9 (1.5–5.5)

Air pollution

Particulate matter TBDR (1997–2000) [64] 96 3,448 2.0 (1.1–3.6)

1544 Pediatr Cardiol (2013) 34:1535–1555

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Table 5 continued


PVS Young maternal age MACDP (1968–2005) [112] 262 1,301,143 0.7 (0.4–1.0)

Prepregnancy weight


Obesity NYSCMR (1993–2003) [113] 957 56,304 1.3 (1.1–1.6)

Febrile illness NBDPS (1997–2003)a [34] 448 4,760 3.0 (1.2–7.6)

BWIS (1981–1989) [60] 112 3,572 2.9 (1.5–5.4)

Antihypertensives NBDPS (1997–2003) [30] 534 4,796 2.6 (1.3–5.4)

Naproxen NBDPS (1997–2004) [71] 519 5,546 2.4 (1.3–4.5)


NBDPS (1997–2002) [105] 386 3,947 2.3 (1.1–4.8)

Air pollution

Carbon monoxide NCAS (1993–2003) [49] 259 14,256 2.7 (1.3–5.5)


TA Young maternal age EUROCAT (2000–2004) [99] 167 1,177 2.6 (1.4–5.1)

BWIS (1981–1989) [60] 30 3,572 2.8 (1.3–6.4)

Febrile illness BWIS (1981–1989) [117] 26 3,435 7.5 (2.6–21.8)

ABDCCS (1968–1980) [20] 12 3,029 5.2 (1.3–20.2)

Influenza BWIS (1981–1989) [117] 26 3,435 6.0 (2.4–15.4)

Injuries NBDPS (1997–2005) [152] 2296 6,328 2.5 (1.1–5.7)

Paternal cocaine use BWIS (1981–1989) [60] 30 3,572 4.8 (1.6–14.0)

Paternal marijuana use BWIS (1981–1989) [60] 30 3,572 2.7 (1.3–5.8)

TAPVR Young maternal age NBDPS (1997–2007) [65] 190 8,169 2.3 (1.3–4.0)

Pre-gestational diabetes mellitus NBDPS (1997–2003) [38] 102 4,689 7.1 (2.0–25.4)

Prepregnancy weight


Maternal pesticide exposure BWIS (1981–1989) [60] 56 3,572 6.8 (1.5–31.5)

TGA Advanced maternal age MACDP (1968–2005) [112] 177 1,301,143 1.7 (1.1–2.5)

BWIS (1981–1989) [60] 214 3,572 1.7 (1.1–2.3)


NBDPS (1997–2003) [38] 254 4,689 3.3 (1.1–10.1)

Influenza BWIS (1981–1989) [60] 106 3,572 2.2 (1.2–4.1)

Prepregnancy weight


Obesity WCHARS (1992–2007) [103] 177 141,420 1.1 (0.7–1.8)

NYSCMR (1993–2003) [113] 331 56,304 0.9 (0.6–1.2)

SMBR (1992–2001) [31] 164 812,457 1.5 (1.0–2.3)

Stress CBDMP (1987–1988) [25] 77 464 1.9 (1.1–3.1)

Benzodiazepines BWIS (1981–1989) [60] 189 3,572 4.1 (1.9–8.6)

Folic acid NBDPS (1997–2004)[39] 320 4,737 0.7 (0.5–1.0)

BWIS (1981–1989) [134] 53 679 1.0 (0.5–2.2)

ABDCCS (1968–1980) [17] 79 1,610 0.4 (0.2–0.9)

Ibuprofen BWIS (1981–1989) [60] 106 3,572 2.5 (1.2–4.9)

Alcohol use LA/SF/SC (1999–2004) [67] 106 425 1.9 (1.1–3.2)

Cigarette use SMBR (1983–1996) [81] 307 1,413,811 1.3 (1.0–1.71)

Vitamin A BWIS (1987–1989) [20] 47 679 2.4 (1.1–5.1)


TOF Advanced maternal age Gill et al. [65] 750 8,169 2.2 (1.4–3.3)

Pre-gestational diabetes mellitus NBDPS (1997–2003) [38] 351 4,689 4.9 (2.2–11.0)

BWIS (1987–1989) [101] 294 3,572 6.6 (3.2–13.3)

Infertility/ART BWIS (1981–1989) [60] 204 3,572 3.6 (1.9–6.9)

Nulliparous NBDPS (1997–2007) [56] 711 7,954 1.3 (1.1–1.6)

Prepregnancy weight

Overweight NYSCMR (1993–2003) [113] 487 56,304 1.3 (1.0–1.7)


Pediatr Cardiol (2013) 34:1535–1555 1545

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Table 5 continued


Obese WCHARS (1992–2007) [103] 377 141,420 1.1 (0.8–1.5)

SMBR (1992–2001) [31] 223 812,457 1.1 (0.7–1.6)

Stress CBDMP (1987–1988) [25] 82 464 1.3 (0.8–2.1)

Anti-asthmatic medication SMBR (1995–2004) [83] 405 585,372 1.7 (1.1–2.6)

Folic acid (multivitamin) CBDMP (1987–1988) [137] 90 481 0.5 (0.3–1.0)

Metronidazole BWIS (1981–1989) [60] 341 3,572 6.0 (1.8–20.7)

Air pollution

Carbon monoxide TBDR (1997–2000) [64] 136 3,343 2.0 (1.3–3.3)

Sulphur dioxide England (1991–1999) [54] 146 759,993 1.4 (1.1–1.8)

Truncus Pre-gestational diabetes mellitus EUROCAT (1990–2005) [62] 5 229 2.8 (1.2–6.9)

BWIS (1981–1989) [60] 38 3,572 13.2 (3.8–46.1)

Prepregnancy weight

Obesity MBR (1990–1994) [124] NA 8,088 6.3 (1.6–24.8)


Hazardous waste site TBDR (1996–2000) [91] 101 4,965 2.8 (1.2–6.5)

VSD Advanced maternal age NBDPS (1997–2007) [65] 1,293 8,169 2.5 (1.8–3.5)

Advanced paternal age EHS (1995–1997) [13] 453 894 1.7 (1.3–2.3)

Prepregnancy weight


Obesity WCHARS (1992–2007) [103] 2,915 141,420 1.0 (0.9–1.1)

NYSCMR (1993–2003) [113] 4,081 56,304 1.0 (0.9–1.1)

SMBR (1992–2001) [31] 2,676 812,457 1.1 (1.0–1.3)


NBDPS (1997–2003) [38] 571 4,689 2.9 (1.3–6.6)

BWIS (1981–1989) [101] 563 3,572 3.1 (1.5–6.3)

Febrile illness NBDPS (1997–1998) [33] 168 692 0.9 (0.6–1.3)

ABDCCS (1968–1980) [20] 209 3,029 1.8 (1.1–2.9)

Infertility/ART PaRCM (1987–2006) [146] 2,248 3,104 1.4 (1.1–1.8)

NBDPS (1997–2005) [127] 1,333 6,500 1.6 (1.1–2.4)

Hypertension HCCSCA (1980–1996) [42] 1,661 38,151 1.3 (1.0–1.6)

Influenza HCCSCA (1980–1996) [42] 1,661 38,151 1.3 (1.0–1.6)

ABDCCS (1968–1980) [20] 209 3,029 2.0 (1.1–3.6)


SSRI NBDPS (1997–2002) [5] 797 4,092 1.1 (0.6–1.9)

Paroxetine ENN (1997–2006) [10] 183 615 0.6 (0.1–4.6)

Fluoxetine FRCM (1996–2003) [106] 143 1,818 1.7 (1.1–2.4)

Cough and cold medications Northern England (1995) [14] 296 296 2.2 (1.4–3.5)

BWIS (1981–1989) [60] 87 3,572 5.5 (1.6–18.7)

Folic acid HCCSCA (1980–1991) [42] 1,661 38,151 0.8 (0.8–0.9)

HPS (1993–1996) [48] 5 19 0.3 (0.1–0.7)

SEUBDS (1993–1996) [161] 186 521 1.2 (0.8–1.8)

Metronidazole HCCSCA (1980–1996) [42] 1,661 38,151 1.6 (1.2–2.3)

BWIS (1981–1989) [60] 640 3,572 3.5 (1.1–10.8)

Ibuprofen BWIS (1981–1989) [60] 640 3,572 1.5 (1.0–2.3)

Alcohol use ABDCCS (1968–1980) [164] 122 3,029 3.1 (1.2–8.2)

BWIS (1981–1989) [60] 73 3,572 1.8 (1.0–3.3)

Alcohol use (paternal) ABDCCS (1968–1980) [164] 122 3,029 4.0 (1.6–9.9)

Cigarette use NBDPS (1997–2002) [105] 584 3,947 1.3 (1.1–1.7)

Cocaine use BWIS (1981–1989) [60] 640 3,572 2.9 (1.7–4.8)

Cocaine use (paternal) BWIS (1981–1989) [60] 640 3,572 2.3 (1.6–3.3)

Marijuana use ABDCCS (1968–1980) [164] 122 3,029 2.4 (1.4–3.9)

Marijuana use (paternal) ABDCCS (1968–1980) [164] 122 3,029 2.2 (1.1–4.4)

BWIS (1981–1989) [58] 491 3,549 1.4 (1.1–1.8)

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teratogenic for various organ systems in animal models

[133]. Stressful life events have been shown to result in

elevated levels of maternal corticotrophin-releasing hor-

mone and corticosteroid levels during pregnancy [75].

Increased glucocorticoid levels are associated with hyper-

insulinemia and insulin resistance, which may be associ-

ated 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 oro-

facial cleft or neural tube defects, with only two studies

examining the effects of maternal stress on the develop-

ment 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.

Maternal Therapeutic Drug Exposures

Antidepressant Medications

According to the BWIS data, maternal use of any antide-

pressants during the periconceptional period is associated

with CHDs [59]. Given the increase in treatment of

depressive symptoms with medication, additional investi-

gations into the effect of antidepressant medications on

CHDs have been performed. Rather than examine antide-

pressants as a group, investigations have focused on eval-

uating categories of medications including selective

serotonin-reuptake inhibitors (SSRIs), serotonin-norepi-

nephrine reuptake inhibitors (SNRIs), and tricyclic anti-

depressants (TCAs). All three categories have been

identified as significantly associated with CHD develop-

ment [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 investiga-

tions are needed to define the absolute risk better so

mothers and health care practitioners can make informed

decisions.

Antihypertensive Medications

Antihypertensive medications are commonly prescribed

during the periconceptional period. Studies investigating

the maternal use of these medications and CHD develop-

ment have yielded conflicting results. Analyses of the

Table 5 Risk Factors Associated with Specific Congenital Heart Defects


Air pollution

Carbon monoxide NCAS (1993–2003) [49] 1,154 14,256 2.6 (1.9–3.7)

TBDR (1997–2000) [64] 1,757 3,342 1.2 (1.0–1.4)

CBDMP (1989–1993) [131] 260 9,106 1.6 (1.1–2.5)

Nitrogen MACDP (1986–2003) [145] 1,108 715,500 1.2 (1.0–1.4)

Particulate matter Brisbane (1997–2004) [69] 222 2,860 1.2 (1.0–1.3)

Sulfur dioxide TBDR (1997–2000) [64] 1,007 1,991 1.3 (1.1–1.6)

Paternal phthalate exposure HAVEN (2003–2010) [143] 113 480 2.8 (1.4–5.9)



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 Mal-

formations, SEUBDS Sloane Epidemiology Unit Birth Defects Study, SMBR Swedish Medical Birth Registry, TBDR Texas Birth Defect Registry, WCHARS Washington

Comprehensive Hospital Abstract Reporting Systema Urinary tract infectionb Upper respiratory infection

Pediatr Cardiol (2013) 34:1535–1555 1547

123

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 sig-

nificant 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,

Ebstein’s anomaly, and pulmonary valve stenosis [30].

Additional investigations have been performed examin-

ing 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, high-

lighting the need for further investigation [94].

Anti-infection Medications

Anti-infection medications, including antibiotics and anti-

fungals, are commonly prescribed during the periconcep-

tional 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].

Folic Acid

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,

42]. Numerous studies, however, have failed to demon-

strate a significant association between folic acid and CHD

risk reduction [39, 48, 82, 141].

The timing of multivitamin initiation within the per-

iconceptional period also was found to be critical. Reduc-

tion 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 acid’s protective effect

has yet to be elucidated. One hypothesis is that folic acid

prevents congenital defects by stimulating cellular meth-

ylation reactions. Folic acid-deficient rats have been

reported to produce offspring with VSDs and defects of the

outflow tract and great vessels [18].

Nonsteroidal Antiinflammatory Medications

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 ibu-

profen use and an increased risk of CHDs [59]. Stratifica-

tion 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].

Parental Nontherapeutic Drug Exposures

Alcohol

Several studies have documented the wide-ranging terato-

genic 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].

1548 Pediatr Cardiol (2013) 34:1535–1555

123

Conflicting results have been reported for maternal

alcohol consumption during the periconceptional period. A

majority of studies have not reported a significant associ-

ation 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 sig-

nificant association for any type of CHD, one study iden-

tified a fourfold increase in risk for VSDs among fathers

who reported alcohol use [164].

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 con-

sumption 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 dat-

abases 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 asso-

ciation 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

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 smok-

ing, 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 gene–gene, gene–envi-

ronment, or environment–environment interaction effects.

Illicit Drugs

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 demon-

strated 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 reg-

istry 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 demon-

strate 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

Pediatr Cardiol (2013) 34:1535–1555 1549

123

congenital malformations [53]. More recent studies have

examined the effects of maternal environmental air pollu-

tant 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 al-

kylphenolic 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 expo-

sure to alkylphenolic compounds was associated with CoA

[143]. Chemical exposures were difficult to define in these

studies, and the associations identified were weak, sug-

gesting that these results need to be replicated for a defi-

nition of the true risk they represent.

Water Contamination

Multiple studies have examined the relationship between

maternal exposure to contaminated water and CHDs. Tri-

chloroethylene, a hydrocarbon solvent used as a metal

degreasing agent, is an intermediate product in the pro-

duction 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.

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 dichlo-

roethylene 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 Pro-

gram 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 cau-

tion. In addition, two large reviews have reported no asso-

ciation between maternal exposure to trichloroethylene-

contaminated 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

1550 Pediatr Cardiol (2013) 34:1535–1555

123

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 inde-

pendent effects. Finally, the majority of the significant

findings demonstrated weak associations or wide confi-

dence 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 pre-

sented information highlights some some principles for

prevention that could be useful. These principles include

the use of a multivitamin containing folate early in preg-

nancy or even beforehand, avoidance of individuals with a

febrile illness to minimize the chance of infection, avoid-

ance 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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