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.
Similar content being viewed by others
References
Acs N, Banhidy F, Puho E, Czeizel AE (2005) Maternal influenza during pregnancy and risk of congenital abnormalities in offspring. Birth Defects Res A Clin Mol Teratol 73:989–996
Acs N, Banhidy F, Puho EH, Czeizel AE (2008) Possible association between acute pelvic inflammatory disease in pregnant women and congenital abnormalities in their offspring: a population-based case-control study. Birth Defects Res A Clin Mol Teratol 82:563–570
Adams MM, Mulinare J, Dooley K (1989) Risk factors for conotruncal cardiac defects in Atlanta. J Am Coll Cardiol 14:432–442
Alverson CJ, Strickland MJ, Gilboa SM, Correa A (2011) Maternal smoking and congenital heart defects in the Baltimore-Washington Infant Study. Pediatrics 127:e647–e653
Alwan S, Reefhuis J, Rasmussen SA, Olney RS, Friedman JM, National Birth Defects Prevention Study (2007) Use of selective serotonin-reuptake inhibitors in pregnancy and the risk of birth defects. N Engl J Med 356:2684–2692
Alwan S, Reefhuis J, Botto LD, Rasmussen SA, Correa A, Friedman JM, National Birth Defects Prevention Study (2010) Maternal use of bupropion and risk for congenital heart defects. Am J Obstet Gynecol 203:52 e51–52 e56
Andrews RC, Walker BR (1999) Glucocorticoids and insulin resistance: old hormones, new targets. Clin Sci Lond 96:513–523
Anway MD, Skinner MK (2008) Epigenetic programming of the germ line: effects of endocrine disruptors on the development of transgenerational disease. Reprod Biomed Online 16:23–25
Baardman ME, Kerstjens-Frederikse WS, Corpeleijn E, de Walle HE, Hofstra RM, Berger RM, Bakker MK (2012) Combined adverse effects of maternal smoking and high body mass index on heart development in offspring: evidence for interaction? Heart 98:474–479
Bakker MK, Kerstjens-Frederikse WS, Buys CH, de Walle HE, de Jong-van den Berg LT (2010) First-trimester use of paroxetine and congenital heart defects: a population-based case-control study. Birth Defects Res A 88:94–100
Banhidy F, Acs N, Puho EH, Czeizel AE (2010) Congenital abnormalities in the offspring of pregnant women with type 1, type 2, and gestational diabetes mellitus: a population-based case-control study. Congenit Anom Kyoto 50:115–121
Banhidy F, Acs N, Puho EH, Czeizel AE (2011) Chronic hypertension with related drug treatment of pregnant women and congenital abnormalities in their offspring: a population-based study. Hypertens Res 34:257–263
Bassili A, Mokhtar SA, Dabous NI, Zaher SR, Mokhtar MM, Zaki A (2000) Risk factors for congenital heart diseases in Alexandria. Egypt. Eur J Epidemiol 16:805–814
Bateman DN, McElhatton PR, Dickinson D, Wren C, Matthews JN, O’Keeffe M, Thomas SH (2004) A case-control study to examine the pharmacological factors underlying ventricular septal defects in the North of England. Eur J Clin Pharmacol 60:635–641
Blatter BM, Roeleveld N, Zielhuis GA, Gabreels FJ, Verbeek AL (1996) Maternal occupational exposure during pregnancy and the risk of spina bifida. Occup Environ Med 53:80–86
Blomberg MI, Kallen B (2010) Maternal obesity and morbid obesity: the risk for birth defects in the offspring. Birth Defects Res A Clin Mol Teratol 88:35–40
Botto LD, Khoury MJ, Mulinare J, Erickson JD (1996) Periconceptional multivitamin use and the occurrence of conotruncal heart defects: results from a population-based, case-control study. Pediatrics 98:911–917
Botto LD, Mulinare J, Erickson JD (2000) Occurrence of congenital heart defects in relation to maternal mulitivitamin use. Am J Epidemiol 151:878–884
Botto LD, Correa A, Erickson JD (2001) Racial and temporal variations in the prevalence of heart defects. Pediatrics 107:E32
Botto LD, Lynberg MC, Erickson JD (2001) Congenital heart defects, maternal febrile illness, and multivitamin use: a population-based study. Epidemiology 12:485–490
Bove FJ, Fulcomer MC, Klotz JB, Esmart J, Dufficy EM, Savrin JE (1995) Public drinking water contamination and birth outcomes. Am J Epidemiol 141:850–862
Browne ML, Bell EM, Druschel CM, Gensburg LJ, Mitchell AA, Mitchell AA, Lin AE, Romitti PA, Correa A, National Birth Defects Prevention Study (2007) Maternal caffeine consumption and risk of cardiovascular malformations. Birth Defects Res A 79:533–543
Burtin P, Taddio A, Ariburnu O, Einarson TR, Koren G (1995) Safety of metronidazole in pregnancy: a meta-analysis. Am J Obstet Gynecol 172:525–529
Canfield MA, Honein MA, Yuskiv N, Xing J, Mai CT, Collins JS, Devine O, Petrini J, Ramadhani TA, Hobbs CA, Kirby RS (2006) National estimates and race/ethnic-specific variation of selected birth defects in the United States, 1999–2001. Birth Defects Res A Clin Mol Teratol 76:747–756
Carmichael SL, Shaw GM (2000) Maternal life event stress and congenital anomalies. Epidemiology 11:30–35
Carmichael SL, Shaw GM, Yang W, Lammer EJ (2003) Maternal periconceptional alcohol consumption and risk for conotruncal heart defects. Birth Defects Res A Clin Mol Teratol 67:875–878
Carmichael SL, Shaw GM, Yang W, Abrams B, Lammer EJ (2007) Maternal stressful life events and risks of birth defects. Epidemiology 18:356–361
Caro-Paton T, Carvajal A, Martin de Diego I, Martin-Arias LH, Alvarez Requejo A, Rodriguez Pinilla E (1997) Is metronidazole teratogenic? A meta-analysis. Br J Clin Pharmacol 44:179–182
Carter TC, Druschel CM, Romitti PA, Bell EM, Werler MM, Mitchell AA, National Birth Defects Prevention Study (2008) Antifungal drugs and the risk of selected birth defects. Am J Obstet Gynecol 198:e191–e197
Caton AR, Bell EM, Druschel CM, Werler MM, Lin AE, Browne ML, McNutt LA, Romitti PA, Mitchell AA, Olney RS, Correa A, Defects NB (2009) Antihypertensive medication use during pregnancy and the risk of cardiovascular malformations. Hypertension 54:63–70
Cedergren MI, Kallen BA (2003) Maternal obesity and infant heart defects. Obes Res 11:1065–1071
Centers for Disease Control, Prevention (2008) Update on overall prevalence of major birth defects–Atlanta, Georgia, 1978–2005. MMWR Morb Mortal Wkly Rep 57:1–5
Cleves MA, Savell VH Jr, Raj S, Zhao W, Correa A, Werler MM, Hobbs CA (2004) Maternal use of acetaminophen and nonsteroidal antiinflammatory drugs (NSAIDs), and muscular ventricular septal defects. Birth Defects Res Part A Clin Mol Teratol 70:107–113
Cleves MA, Malik S, Yang S, Carter TC, Hobbs CA (2008) Maternal urinary tract infections and selected cardiovascular malformations. Birth Defects Res A Clin Mol Teratol 82:464–473
Cogswell ME, Bitsko RH, Anderka M, Caton AR, Feldkamp ML, Hockett Sherlock SM, Meyer RE, Ramadhani T, Robbins JM, Shaw GM, Mathews TJ, Royle M, Reefhuis J, National Birth Defects Prevention Study (2009) Control selection and participation in an ongoing, population-based, case-control study of birth defects: the National Birth Defects Prevention Study. Am J Epidemiol 170:975–985
Cooper WO, Hernandez-Diaz S, Arbogast PG, Dudley JA, Dyer S, Gideon PS, Hall K, Ray WA (2006) Major congenital malformations after first-trimester exposure to ACE inhibitors. N Engl J Med 354:2443–2451
Cordier S, Ha MC, Ayme S, Goujard J (1992) Maternal occupational exposure and congenital malformations. Scand J Work Environ Health 18:11–17
Correa A, Gilboa SM, Besser LM, Botto LD, Moore CA, Hobbs CA, Cleves MA, Riehle-Colarusso TJ, Waller DK, Reece EA (2008) Diabetes mellitus and birth defects. Am J Obstet Gynecol 199(237):e231–e239
Correa A, Gilboa SM, Botto LD, Moore CA, Hobbs CA, Cleves MA, Riehle-Colarusso TJ, Waller DK, Reece EA, National Birth Defects Prevention Study (2012) Lack of periconceptional vitamins or supplements that contain folic acid and diabetes mellitus-associated birth defects. Am J Obstet Gynecol 206:218 e211–218 e213
Cresci M, Foffa I, Ait-Ali L, Pulignani S, Gianicolo EA, Botto N, Picano E, Andreassi MG (2011) Maternal and paternal environmental risk factors, metabolizing GSTM1 and GSTT1 polymorphisms, and congenital heart disease. Am J Cardiol 108:1625–1631
Crider KS, Cleves MA, Reefhuis J, Berry RJ, Hobbs CA, Hu DJ (2009) Antibacterial medication use during pregnancy and risk of birth defects: the National Birth Defects Prevention Study. Arch Pediatr Adolesc Med 163:978–985
Csaky-Szunyogh M, Vereczkey A, Kosa Z, Urban R, Czeizel AE (2013) Association of maternal diseases during pregnancy with the risk of single ventricular septal defects in the offspring: a population-based case-control study. J Matern Fetal Neonatal Med 26:738–747
Czeizel AE (1998) Periconceptional folic acid containing multivitamin supplementation. Eur J Obstet Gynecol Reprod Biol 78:151–161
Czeizel AE, Banhidy F (2011) Chronic hypertension in pregnancy. Curr Opin Obstet Gynecol 23:76–81
Czeizel AE, Toth M, Rockenbauer M (1996) Population-based case-control study of folic acid supplementation during pregnancy. Teratology 53:345–351
Czeizel AE, Rockenbauer M, Mosonyi A (2000) A population-based case-control teratologic study of acetylsalicylic acid treatments during pregnancy. Pharmacoepidemiol Drug Saf 9:193–205
Czeizel AE, Rockenbauer M, Sorensen HT, Olsen J (2001) The teratogenic risk of trimethoprim-sulfonamides: a population-based case-control study. Reprod Toxicol 15:637–646
Czeizel AE, Dobo M, Vargha P (2004) Hungarian cohort-controlled trial of periconceptional multivitamin supplementation shows a reduction in certain congenital abnormalities. Birth Defects Res A Clin Mol Teratol 70:853–861
Dadvand P, Rankin J, Rushton S, Pless-Mulloli T (2011) Ambient air pollution and congenital heart disease: a register-based study. Environ Res 111:435–441
DeJonge MH, Zachman RD (1995) The effect of maternal ethanol ingestion on fetal rat heart vitamin A: a model for fetal alcohol syndrome. Pediatr Res 37:418–423
Dencker BB, Larsen H, Jensen ES, Schonheyder HC, Nielsen GL, Sorensen HT (2002) Birth outcome of 1,886 pregnancies after exposure to phenoxymethylpenicillin in utero. Clin Microbiol Infect 8:196–201
Desrosiers TA, Herring AH, Shapira SK, Hooiveld M, Luben TJ, Herdt-Losavio ML, Lin S, Olshan AF, National Birth Defects Prevention Study (2012) Paternal occupation and birth defects: findings from the National Birth Defects Prevention Study. Occup Environ Med 69:534–542
Dolk H, Vrijheid M (2003) The impact of environmental pollution on congenital anomalies. Br Med Bull 68:25–45
Dolk H, Armstrong B, Lachowycz K, Vrijheid M, Rankin J, Abramsky L, Boyd PA, Wellesley D (2010) Ambient air pollution and risk of congenital anomalies in England, 1991–1999. Occup Environ Med 67:223–227
Dunne F, Brydon P, Smith K, Gee H (2003) Pregnancy in women with type 2 diabetes: 12 years outcome data 1990–2002. Diabet Med 20:734–738
Duong HT, Hoyt AT, Carmichael SL, Gilboa SM, Canfield MA, Case A, McNeese ML, Waller DK, National Birth Defects Prevention Study (2012) Is maternal parity an independent risk factor for birth defects? Birth Defects Res A 94:230–236
Eriksson UJ, Cederberg J, Wentzel P (2003) Congenital malformations in offspring of diabetic mothers: animal and human studies. Rev Endocr Metab Disord 4:79–93
Ewing CK, Loffredo CA, Beaty TH (1997) Paternal risk factors for isolated membranous ventricular septal defects. Am J Med Genet 71:42–46
Ferencz C, Rubin JD, Loffredo C, Magee CA (1993) Epidemiology of congenital heart disease: the Baltimore-Washington Infant Study: 1981–1989. Futura Publishing Co., Mount Kisco, NY
Ferencz C, Correa-Villasenor A, Loffredo CA (1997) Genetic and environmental risk factors of major cardiovascular malformations: the Baltimore-Washington Infant Study: 1981–1989. Futura Publishing Co., Armonk, NY, p 463
Ferrara A, Kahn HS, Quesenberry CP, Riley C, Hedderson MM (2004) An increase in the incidence of gestational diabetes mellitus: Northern California, 1991–2000. Obstet Gynecol 103:526–533
Garne E, Loane M, Dolk H, Barisic I, Addor MC, Arriola L, Bakker M, Calzolari E, Matias Dias C, Doray B, Gatt M, Melve KK, Nelen V, O’Mahony M, Pierini A, Randrianaivo-Ranjatoelina H, Rankin J, Rissmann A, Tucker D, Verellun-Dumoulin C, Wiesel A (2012) Spectrum of congenital anomalies in pregnancies with pregestational diabetes. Birth Defects Res A Clin Mol Teratol 94:134–140
Gilboa SM, Mendola P, Olshan AF, Langlois PH, Savitz DA, Loomis D, Herring AH, Fixler DE (2005) Relation between ambient air quality and selected birth defects, seven county study, Texas, 1997–2000. Am J Epidemiol 162:238–252
Gilboa SM, Mendola P, Olshan AF, Langlois PH, Savitz DA, Loomis D, Herring AH, Fixler DE (2005) Relation between ambient air quality and selected birth defects, seven county study, Texas, 1997–2000. Am J Epidemiol 162:238–252
Gill SK, Broussard C, Devine O, Green RF, Rasmussen SA, Reefhuis J, National Birth Defects Prevention Study (2012) Association between maternal age and birth defects of unknown etiology–United States, 1997–2007. Birth Defects Res Part A 94:1010–1018
Gillum RF (1994) Epidemiology of congenital heart disease in the United States. Am Heart J 127:919–927
Grewal J, Carmichael SL, Ma C, Lammer EJ, Shaw GM (2008) Maternal periconceptional smoking and alcohol consumption and risk for select congenital anomalies. Birth Defects Res A Clin Mol Teratol 82:519–526
Hackshaw A, Rodeck C, Boniface S (2011) Maternal smoking in pregnancy and birth defects: a systematic review based on 173,687 malformed cases and 11.7 million controls. Hum Reprod Update 17:589–604
Hansen CA, Barnett AG, Jalaludin BB, Morgan GG (2009) Ambient air pollution and birth defects in Brisbane. Australia. PLoS One 4:e5408
Hardin BD, Kelman BJ, Brent RL (2005) Trichloroethylene and dichloroethylene: a critical review of teratogenicity. Birth Defects Res A Clin Mol Teratol 73:931–955
Hernandez RK, Werler MM, Romitti P, Sun L, Anderka M, National Birth Defects Prevention Study (2012) Nonsteroidal antiinflammatory drug use among women and the risk of birth defects. Am J Obstet Gynecol 206:228 e221
Hernandez-Diaz S, Werler MM, Walker AM, Mitchell AA (2000) Folic acid antagonists during pregnancy and the risk of birth defects. N Engl J Med 343:1608–1614
Hobbs CA, James SJ, Jernigan S, Melnyk S, Lu Y, Malik S, Cleves MA (2006) Congenital heart defects, maternal homocysteine, smoking, and the 677 C>T polymorphism in the methylenetetrahydrofolate reductase gene: evaluating gene-environment interactions. Am J Obstet Gynecol 194:218–224
Hobbs CA, MacLeod SL, Jill James S, Cleves MA (2011) Congenital heart defects and maternal genetic, metabolic, and lifestyle factors. Birth Defects Res A Clin Mol Teratol 91:195–203
Hobel CJ, Dunkel-Schetter C, Roesch SC, Castro LC, Arora CP (1999) Maternal plasma corticotropin-releasing hormone associated with stress at 20 weeks’ gestation in pregnancies ending in preterm delivery. Am J Obstet Gynecol 180:S257–S263
Hoffman JI, Kaplan S, Liberthson RR (2004) Prevalence of congenital heart disease. Am Heart J 147:425–439
Holing EV, Beyer CS, Brown ZA, Connell FA (1998) Why don’t women with diabetes plan their pregnancies? Diabetes Care 21:889–895
Hollier LM, Leveno KJ, Kelly MA, MCIntire DD, Cunningham FG (2000) Maternal age and malformations in singleton births. Obstet Gynecol 96:701–706
Janssen PA, Rothman I, Schwartz SM (1996) Congenital malformations in newborns of women with established and gestational diabetes in Washington State, 1984–91. Paediatr Perinat Epidemiol 10:52–63
Jenkins KJ, Correa A, Feinstein JA, Botto L, Britt AE, Daniels SR, Elixson M, Warnes CA, Webb CL, American Heart Association Council on Cardiovascular Disease in the Young (2007) 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 115:2995–3014
Kallen K (1999) Maternal smoking and congenital heart defects. Eur J Epidemiol 15:731–737
Kallen BA, Otterblad Olausson P (2003) Maternal drug use in early pregnancy and infant cardiovascular defect. Reprod Toxicol 17:255–261
Kallen B, Otterblad Olausson P (2007) Use of anti-asthmatic drugs during pregnancy. Eur J Clin Pharmacol 63:383–388
Karatza AA, Giannakopoulos I, Dassios TG, Belavgenis G, Mantagos SP, Varvarigou AA (2011) Periconceptional tobacco smoking and isolated congenital heart defects in the neonatal period. Int J Cardiol 148:295–299
Kazaura M, Lie RT, Skjaerven R (2004) Paternal age and the risk of birth defects in Norway. Ann Epidemiol 14:566–570
Kidd SA, Lancaster PA, McCredie RM (1993) The incidence of congenital heart defects in the first year of life. J Paediatr Child Health 29:344–349
Kitzmiller JL, Buchanan TA, Kjos S, Combs CA, Ratner RE (1996) Preconception care of diabetes, congenital malformations, and spontaneous abortions. Diabetes Care 19:514–541
Klotz JB, Pyrch LA (1999) Neural tube defects and drinking water disinfection by-products. Epidemiology 10:383–390
Kousseff BG (1999) Diabetic embryopathy. Curr Opin Pediatr 11:348–352
Kuciene R, Dulskiene V (2009) Maternal socioeconomic and lifestyle factors during pregnancy and the risk of congenital heart defects. Medicina Kaunas 45:904–909
Langlois PH, Brender JD, Suarez L, Zhan FB, Mistry JH, Scheuerle A, Moody K (2009) Maternal residential proximity to waste sites and industrial facilities and conotruncal heart defects in offspring. Paediatr Perinat Epidemiol 23:321–331
Lee LJ, Lupo PJ (2013) Maternal smoking during pregnancy and the risk of congenital heart defects in offspring: a systematic review and metaanalysis. Pediatr Cardiol 34:398–407
Lennestal R, Otterblad Olausson P, Kallen B (2009) Maternal use of antihypertensive drugs in early pregnancy and delivery outcome, notably the presence of congenital heart defects in the infants. Eur J Clin Pharmacol 65:615–625
Li DK, Yang C, Andrade S, Tavares V, Ferber JR (2011) Maternal exposure to angiotensin converting enzyme inhibitors in the first trimester and risk of malformations in offspring: a retrospective cohort study. BMJ 343:d5931
Lin AE, Ardinger HH (2005) Genetic epidemiology of cardiovascular malformations. Prog Pediatr Cardiol 20:113–126
Lin S, Herdt-Losavio M, Gensburg L, Marshall E, Druschel C (2009) Maternal asthma, asthma medication use, and the risk of congenital heart defects. Birth Defects Res A Clin Mol Teratol 85:161–168
Lipshultz SE, Frassica JJ, Orav EJ (1991) Cardiovascular abnormalities in infants prenatally exposed to cocaine. J Pediatr 118:44–51
Liu S, Liu J, Tang J, Ji J, Chen J, Liu C (2009) Environmental risk factors for congenital heart disease in the Shandong Peninsula, China: a hospital-based case-control study. J Epidemiol 19:122–130
Loane M, Dolk H, Morris JK, EWG (2009) Maternal age-specific risk of nonchromosomal anomalies. BJOG 116:1111–1119
Loffredo CA, Ferencz C, Wilson PD, Lurie IW (2000) Interrupted aortic arch: an epidemiologic study. Teratology 61:368–375
Loffredo CA, Wilson PD, Ferencz C (2001) Maternal diabetes: an independent risk factor for major cardiovascular malformations with increased mortality of affected infants. Teratology 64:98–106
Louik C, Lin AE, Werler MM, Hernandez-Diaz S, Mitchell AA (2007) First-trimester use of selective serotonin-reuptake inhibitors and the risk of birth defects. N Engl J Med 356:2675–2683
Madsen NL, Schwartz SM, Lewin MB, Mueller BA (2013) Prepregnancy body mass index and congenital heart defects among offspring: a population-based study. Congenit Heart Dis 8:131–141
Malik S, Schecter A, Caughy M, Fixler DE (2004) Effect of proximity to hazardous waste sites on the development of congenital heart disease. Arch Environ Health 59:177–181
Malik S, Cleves MA, Honein MA, Romitti PA, Botto LD, Yang S, Hobbs CA, National Birth Defects Prevention Study (2008) Maternal smoking and congenital heart defects. Pediatrics 121:e810–e816
Malm H, Artama M, Gissler M, Ritvanen A (2011) Selective serotonin reuptake inhibitors and risk for major congenital anomalies. Obstet Gynecol 118:111–120
Martin JA, Kung HC, Mathews TJ, Hoyert DL, Strobino DM, Guyer B, Sutton SR (2008) Annual summary of vital statistics: 2006. Pediatrics 121:788–801
Mateja WA, Nelson DB, Kroelinger CD, Ruzek S, Segal J (2012) The association between maternal alcohol use and smoking in early pregnancy and congenital cardiac defects. J Womens Health Larchmt 21:26–34
Materna-Kiryluk A, Wisniewska K, Badura-Stronka M, Mejnartowicz J, Wieckowska B, Balcar-Boron A, Czerwionka-Szaflarska M, Gajewska E, Godula-Stuglik U, Krawczynski M, Limon J, Rusin J, Sawulicka-Oleszczuk H, Szwalkiewicz-Warowicka E, Walczak M, Latos-Bielenska A (2009) Parental age as a risk factor for isolated congenital malformations in a Polish population. Paediatr Perinat Epidemiol 23:29–40
Materna-Kiryluk A, Wisniewska K, Badura-Stronka M, Mejnartowicz J, Wieckowska B, Balcar-Boron A, Czerwionka-Szaflarska M, Gajewska E, Godula-Stuglik U, Krawczynski M, Limon J, Rusin J, Sawulicka-Oleszczuk H, Szwalkiewicz-Warowicka E, Walczak M, Latos-Bielenska A (2009) Parental age as a risk factor for isolated congenital malformations in a Polish population. Paediatr Perinat Epidemiol 23:29–40
Matok I, Gorodischer R, Koren G, Landau D, Wiznitzer A, Levy A (2009) Exposure to folic acid antagonists during the first trimester of pregnancy and the risk of major malformations. Br J Clin Pharmacol 68:956–962
Miller A, Riehle-Colarusso T, Siffel C, Frias JL, Correa A (2011) Maternal age and prevalence of isolated congenital heart defects in an urban area of the United States. Am J Med Genet A 155A:2137–2145
Mills JL, Troendle J, Conley MR, Carter T, Druschel CM (2010) Maternal obesity and congenital heart defects: a population-based study. Am J Clin Nutr 91:1543–1549
Mokdad AH, Bowman BA, Ford ES, Vinicor F, Marks JS, Koplan JP (2001) The continuing epidemics of obesity and diabetes in the United States. JAMA 286:1195–1200
Nafee TM, Farrell WE, Carroll WD, Fryer AA, Ismail KM (2008) Epigenetic control of fetal gene expression. BJOG 115:158–168
Oddy WH, De Klerk NH, Miller M, Payne J, Bower C (2009) Association of maternal prepregnancy weight with birth defects: evidence from a case-control study in Western Australia. Aust N Z J Obstet Gynaecol 49:11–15
Oster ME, Riehle-Colarusso T, Alverson CJ, Correa A (2011) Associations between maternal fever and influenza and congenital heart defects. J Pediatr 158:990–995
Patel SS, Burns TL, Botto LD, Riehle-Colarusso TJ, Lin AE, Shaw GM, Romitti PA, National Birth Defects Prevention Study (2012) Analysis of selected maternal exposures and nonsyndromic atrioventricular septal defects in the National Birth Defects Prevention Study, 1997–2005. Am J Med Genet A 158A:2447–2455
Perna AF, Ingrosso D, De Santo NG (2003) Homocysteine and oxidative stress. Amino Acids 25:409–417
Polen KN, Rasmussen SA, Riehle-Colarusso T, Reefhuis J, National Birth Defects Prevention Study (2013) Association between reported venlafaxine use in early pregnancy and birth defects: the National Birth Defects Prevention Study, 1997–2007. Birth Defects Res A Clin Mol Teratol 97:28–35
Pradat P (1992) A case-control study of major congenital heart defects in Sweden: 1981–1986. Eur J Epidemiol 8:789–796
Pullarkat RK (1991) Hypothesis: prenatal ethanol-induced birth defects and retinoic acid. Alcohol Clin Exp Res 15:565–567
Queisser-Luft A, Kieninger-Baum D, Menger H, Stolz G, Schlaefer K, Merz E (1998) Does maternal obesity increase the risk of fetal abnormalities? Analysis of 20,248 newborn infants of the Mainz Birth Register for detecting congenital abnormalities. Ultraschall Med 19:40–44
Queisser-Luft A, Kieninger-Baum D, Menger H, Stolz G, Schlaefer K, Merz E (1998) Does maternal obesity increase the risk of fetal abnormalities? Analysis of 20,248 newborn infants of the Mainz Birth Register for detecting congenital abnormalities. Ultraschall Med 19:40–44
Ray JG, O’Brien TE, Chan WS (2001) Preconception care and the risk of congenital anomalies in the offspring of women with diabetes mellitus: a meta-analysis. QJM 94:435–444
Reefhuis J, Honein MA, Schieve LA, Correa A, Hobbs CA, Rasmussen SA, National Birth Defects Prevention Study (2009) Assisted reproductive technology and major structural birth defects in the United States. Hum Reprod 24:360–366
Reefhuis J, Honein MA, Schieve LA, Rasmussen SA, National Birth Defects Prevention Study (2011) Use of clomiphene citrate and birth defects: the National Birth Defects Prevention Study, 1997–2005. Hum Reprod 26:451–457
Reis M, Kallen B (2010) Delivery outcome after maternal use of antidepressant drugs in pregnancy: an update using Swedish data. Psychol Med 40:1723–1733
Reller MD, Strickland MJ, Riehle-Colarusso T, Mahle WT, Correa A (2008) Prevalence of congenital heart defects in metropolitan Atlanta, 1998–2005. J Pediatr 153:807–813
Retrieved from www.americanheart.org. Accessed May 2013
Ritz B, Yu F, Fruin S, Chapa G, Shaw GM, Harris JA (2002) Ambient air pollution and risk of birth defects in Southern California. Am J Epidemiol 155:17–25
Rosenquist TH, Ratashak SA, Selhub J (1996) Homocysteine induces congenital defects of the heart and neural tube: effect of folic acid. Proc Natl Acad Sci U S A 93:15227–15232
Rowland JM, Hendrickx AG (1983) Corticosteroid teratogenicity. Adv Vet Sci Comp Med 27:99–128
Scanlon KS, Ferencz C, Loffredo CA, Wilson PD, Correa-Villasenor A, Khoury MJ, Willett WC (1998) Preconceptional folate intake and malformations of the cardiac outflow tract. Baltimore-Washington Infant Study Group. Epidemiology 9:95–98
Shaw GM, Swan SH, Harris JA, Malcoe LH (1990) Maternal water consumption during pregnancy and congenital cardiac anomalies. Epidemiology 1:206–211
Shaw GM, Schulman J, Frisch JD, Cummins SK, Harris JA (1992) Congenital malformations and birth weight in areas with potential environmental contamination. Arch Environ Health 47:147–154
Shaw GM, O’Malley CD, Wasserman CR, Tolarova MM, Lammer EJ (1995) Maternal periconceptional use of multivitamins and reduced risk for conotruncal heart defects and limb deficiencies among offspring. Am J Med Genet 59:536–545
Shaw GM, Velie EM, Katz EA, Morland KB, Schaffer DM, Nelson V (1999) Maternal occupational and hobby chemical exposures as risk factors for neural tube defects. Epidemiology 10:124–129
Shaw GM, Wasserman CR, O’Malley CD, Nelson V, Jackson RJ (1999) Maternal pesticide exposure from multiple sources and selected congenital anomalies. Epidemiology 10:60–66
Shepard TH, Fantel AG, Kapur RP (1991) Fetal coronary thrombosis as a cause of single ventricular heart. Teratology 43:113–117
Smedts HP, Rakhshandehroo M, Verkleij-Hagoort AC, de Vries JH, Ottenkamp J, Steegers EA, Steegers-Theunissen RP (2008) Maternal intake of fat, riboflavin, and nicotinamide and the risk of having offspring with congenital heart defects. Eur J Nutr 47:357–365
Smedts HP, van Uitert EM, Valkenburg O, Laven JS, Eijkemans MJ, Lindemans J, Steegers EA, Steegers-Theunissen RP (2012) A derangement of the maternal lipid profile is associated with an elevated risk of congenital heart disease in the offspring. Nutr Metab Cardiovasc Dis 22:477–485
Snijder CA, Vlot IJ, Burdorf A, Obermann-Borst SA, Helbing WA, Wildhagen MF, Steegers EA, Steegers-Theunissen RP (2012) Congenital heart defects and parental occupational exposure to chemicals. Hum Reprod 27:1510–1517
Srivastava D (2001) Genetic assembly of the heart: implications for congenital heart disease. Annu Rev Physiol 63:451–469
Strickland MJ, Klein M, Correa A, Reller MD, Mahle WT, Riehle-Colarusso TJ, Botto LD, Flanders WD, Mulholland JA, Siffel C, Marcus M, Tolbert PE (2009) Ambient air pollution and cardiovascular malformations in Atlanta, Georgia, 1986–2003. Am J Epidemiol 169:1004–1014
Tararbit K, Houyel L, Bonnet D, De Vigan C, Lelong N, Goffinet F, Khoshnood B (2011) Risk of congenital heart defects associated with assisted reproductive technologies: a population-based evaluation. Eur Heart J 32:500–508
Tikkanen J, Heinonen OP (1990) Risk factors for cardiovascular malformations in Finland. Eur J Epidemiol 6:348–356
Tikkanen J, Heinonen OP (1991) Maternal exposure to chemical and physical factors during pregnancy and cardiovascular malformations in the offspring. Teratology 43:591–600
Tikkanen J, Heinonen OP (1992) Risk factors for atrial septal defect. Eur J Epidemiol 8:509–515
Tikkanen J, Heinonen OP (1992) Risk factors for conal malformations of the heart. Eur J Epidemiol 8:48–57
Tikkanen J, Heinonen OP (1993) Risk factors for coarctation of the aorta. Teratology 47:565–572
Tinker SC, Reefhuis J, Dellinger AM, Jamieson DJ (2011) Maternal injuries during the periconceptional period and the risk of birth defects: the National Birth Defects Prevention Study, 1997–2005. Paediatr Perinat Epidemiol 25:487–496
van Beynum IM, Kapusta L, Bakker MK, den Heijer M, Blom HJ, de Walle HE (2010) Protective effect of periconceptional folic acid supplements on the risk of congenital heart defects: a registry-based case-control study in the northern Netherlands. Eur Heart J 31:464–471
van Gelder MM, Roeleveld N, Nordeng H (2011) Exposure to nonsteroidal antiinflammatory drugs during pregnancy and the risk of selected birth defects: a prospective cohort study. PLoS One 6:e22174
Varela MM, Nohr EA, Llopis-Gonzalez A, Andersen AM, Olsen J (2009) Socio-occupational status and congenital anomalies. Eur J Public Health 19:161–167
Verkleij-Hagoort AC, Verlinde M, Ursem NT, Lindemans J, Helbing WA, Ottenkamp J, Siebel FM, Gittenberger-de Groot AC, de Jonge R, Bartelings MM, Steegers EA, Steegers-Theunissen RP (2006) Maternal hyperhomocysteinaemia is a risk factor for congenital heart disease. BJOG 113:1412–1418
Watkins ML, Botto LD (2001) Maternal prepregnancy weight and congenital heart defects in offspring. Epidemiology 12:439–446
Watkins ML, Rasmussen SA, Honein MA, Botto LD, Moore CA (2003) Maternal obesity and risk for birth defects. Pediatrics 111:1152–1158
Watson RE, Jacobson CF, Williams AL, Howard WB, DeSesso JM (2006) Trichloroethylene-contaminated drinking water and congenital heart defects: a critical analysis of the literature. Reprod Toxicol 21:117–147
Wenstrom KD, Johanning GL, Johnston KE, DuBard M (2001) Association of the C677T methylenetetrahydrofolate reductase mutation and elevated homocysteine levels with congenital cardiac malformations. Am J Obstet Gynecol 184:806–812 discussion 812–807
Werler MM, Hayes C, Louik C, Shapiro S, Mitchell AA (1999) Multivitamin supplementation and risk of birth defects. Am J Epidemiol 150:675–682
Werler MM, Ahrens KA, Bosco JL, Mitchell AA, Anderka MT, Gilboa SM, Holmes LB (2011) Use of antiepileptic medications in pregnancy in relation to risks of birth defects. Ann Epidemiol 21:842–850
Wikner BN, Sparre LS, Stiller CO, Kallen B, Asker C (2008) Maternal use of thyroid hormones in pregnancy and neonatal outcome. Acta Obstet Gynecol Scand 87:617–627
Williams LJ, Correa A, Rasmussen S (2004) Maternal lifestyle factors and risk for ventricular septal defects. Birth Defects Res A Clin Mol Teratol 70:59–64
Wilson PD, Loffredo CA, Correa-Villasenor A, Ferencz C (1998) Attributable fraction for cardiac malformations. Am J Epidemiol 148:414–423
Xiao Y, Xiao D, He J, Zhang L (2001) Maternal cocaine administration during pregnancy induces apoptosis in fetal rat heart. J Cardiovasc Pharmacol 37:639–648
Yang Q, Wen SW, Leader A, Chen XK, Lipson J, Walker M (2007) Paternal age and birth defects: how strong is the association? Hum Reprod 22:696–701
Yang J, Carmichael SL, Canfield M, Song J, Shaw GM, National Birth Defects Prevention Study (2008) Socioeconomic status in relation to selected birth defects in a large multicentered US case-control study. Am J Epidemiol 167:145–154
Yauck JS, Malloy ME, Blair K, Simpson PM, McCarver DG (2004) Proximity of residence to trichloroethylene-emitting sites and increased risk of offspring congenital heart defects among older women. Birth Defects Res A Clin Mol Teratol 70:808–814
Zhan SY, Lian ZH, Zheng DZ, Gao L (1991) Effect of fathers’ age and birth order on occurrence of congenital heart disease. J Epidemiol Community Health 45:299–301
Zhang J, Cai WW (1993) Association of the common cold in the first trimester of pregnancy with birth defects. Pediatrics 92:559–563
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Patel, S.S., Burns, T.L. Nongenetic Risk Factors and Congenital Heart Defects. Pediatr Cardiol 34, 1535–1555 (2013). https://doi.org/10.1007/s00246-013-0775-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00246-013-0775-4