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Epilepsy65 Prepregnancy overweight/obesity66 MATERNAL THERAPEUTIC DRUG EXPOSURE Anticonvulsants67,68 Ibuprofen69 Sulfasalazine70 Thalidomide71 Trimethoprim-sulfonamide70,72,c Vitamin A congeners/retinoids73,74,c b 1.13–1.40 4.2 1.86 3.4 b 2.1–4.8 b aExposures associated with definite or possible risk of offspring with any congenital cardiovascular defect bOdds ratio not available c Risk reduced if mother took folic acid simultaneously Modified from Jenkins KJ, Correa A, Feinstein JA, et al Noninherited risk factors and congenital cardiovascular defects: current knowledge: a scientific statement from the American Heart Association Council on Cardiovascular Disease in the Young: endorsed by the American Academy of Pediatrics Circulation 2007;115:2995–3014 Maternal exposure to organic solvents has frequently and consistently been reported to be associated with relatively high odds ratios for the development of specific congenital cardiac malformations In contrast to maternal illnesses and use of medications, it is feasible to avoid exposure to organic solvents, and prevention strategies might be directed at reducing maternal exposures to these materials Other maternal exposures, including pesticides, air pollutants, and lead, have been reported to have an association with congenital heart defects.9,10 The Baltimore-Washington Infant Study was a large population-based surveillance with careful verification of maternal exposures.1 The attributable fraction, which is the proportion of cases of specific heart defect that might be attributable to specific exposure, is summarized in Table 13.4 Note that some of the significant exposures were paternal rather than maternal Table 13.4 Attributable Fraction of Congenital Cardiac Lesions to Potential Risk Factors Malformation and Potential Risk Factors Transposition with intact ventricular septum (n = 106) Influenza P < 01 AF (%) 12.1 7.0 95% CI 8.5–15.8 3.6–10.3 Relative Risk 2.2 Miscellaneous solvents Tetralogy of Fallot (n = 204) Paternal anesthesia Clomiphene Atrioventricular septal defect with Down syndrome (n = 190) Ibuprofen Hypoplastic left heart syndrome (n = 138) Solvent/degreasing agent Family history of congenital heart disease Coarctation of the aorta (n = 120) Family history of congenital heart disease Macrodantin Clomiphene Isolated/simple perimembranous VSD (n = 459) Paternal use of marijuana Maternal use of cocaine Multiple/multiplex perimembranous VSD (n = 181) Paternal use of cocaine Diabetes mellitus Metronidazole Atrial septal defect (n = 187) Gestational diabetes mellitus Paternal use of cocaine Family history of congenital heart disease Corticosteroids 4.8 6.5 3.9 2.4 4.6 4.6 8.6 4.6 4.0 9.4 4.6 2.3 2.0 7.9 6.0 1.7 8.3 4.8 2.1 1.4 14.1 4.4 3.7 3.4 2.6 3.0–6.6 4.8–8.3 2.4–5.5 1.5–3.4 2.7–6.5 2.7–6.5 6.9–10.3 3.2–6.0 3.1–4.9 8.1–10.8 3.5–5.7 1.8–2.8 1.4–2.7 4.2–11.6 2.2–9.7 0.9–2.5 6.0–10.5 2.6–6.9 1.4–2.8 1.1–1.7 11.3–17.0 2.5–6.2 1.9–5.4 2.4–4.3 1.9–3.2 3.2 2.5 3.0 2.4 3.4 4.8 4.6 6.7 4.5 1.4 2.4 2.3 3.9 7.6 2.4 2.3 3.9 4.8 AF, Attributable fraction; CI, confidence interval; VSD, ventricular septal defect From Wilson PD, Loffredo CA, Correa-Villasenor A, Ferencz C Attributable fraction for cardiac malformations Am J Epidemiol 1998;148:414–423 Genetic Factors The prevalence of congenital cardiac disease is increased in children with specific chromosomal abnormalities and syndromes, and the knowledge of these associations is expanding These genetic factors are further explored in other chapters A high prevalence of congenital cardiac disease has been observed among children with trisomy 21 (Down syndrome),11 trisomy 18 (Edwards syndrome),12,13 trisomy 13 (Patau syndrome),12,14 and monosomy XO (Turner syndrome) With the average maternal age increasing, the prevalence of infants with chromosomal abnormalities is likely to rise, in particular the number of infants with trisomy 21 This is associated with congenital cardiac disease in 40% to 50% of pregnancies.15,16 After the age of 30 years, a mother's risk of having a child with trisomy 21 increases exponentially, such that by the time she is 35 years, the risk is 1 in 365 pregnancies.17 The deletion of the 22q11 gene has been implicated as an important contributor to the development of congenital cardiac disease.18 Studies have estimated the prevalence of the deletion to be approximately 1.5 cases in each 10,000 live births.18,19 It has been suggested that more than 1% of all congenitally malformed hearts are associated with this deletion, accounting for half of the cases with interrupted aortic arch, 20% of those with common arterial trunk, and approximately 16% of those with tetralogy of Fallot.18 The risk of recurrence is also higher in families and mothers with nonsyndromic congenital heart disease, as summarized in Table 13.5.20,21 The prevalence of a congenital heart defect in at least one twin of a monochorionic pair is estimated at almost 10%,22 with the prevalence in the second twin increasing to more than 25% if the first twin is affected.23,24 Furthermore, assisted reproduction techniques may result in a modest increase in the risk of congenital heart disease, with a recent meta-analysis showing an odds ratio of 1.3 compared with fetuses conceived spontaneously.25 Table 13.5 Nonsyndromic Congenital Heart Defects and Implicated Modes of Inheritance, Risks of Recurrence, and Genes Congenital Heart Defect Atrioventricular canal defect Tetralogy of Fallot Transposition of the great arteries Congenitally corrected transposition of the great arteries Left-sided obstructions Atrial septal defect Recurrence Risk Genes (%) Multifactorial 3–4 – Autosomal dominant 50 p93 CRELDI GATA4 PTPN11 Multifactorial 2.5–3 — Autosomal dominant 50 NKX2.5 Autosomal recessive 25 Jagged 1 Three-gene model 2.5–3 FOG2 — — Multifactorial 1–1.8 – Autosomal 50 CFC1 dominant Multifactorial 5.8 – Mode of Inheritance Multifactorial Autosomal dominant 50 Autosomal recessive 25 Multifactorial – NOTCH1 NKX2.5 — – References 81–84 85 86,87 88 89 83,84,90,91 92 93 94 97 90,95,96 97–99 100 101 102 103 104 105–107 102