Click here for an Adobe PDF version of this document. (184KB PDF, Viewing Information)
NEW: Please take a moment to evaluate our birth defects risk factor series. Click here to take survey.
Hypoplastic left heart syndrome is characterized by several cardiac malformations. These include hypoplasia or underdevelopment of the left ventricle, atresia or hypoplasia of the aortic valve, atresia or hypoplasia of the mitral valve, and atresia or hypoplasia of the aorta. Due to these defects, the heart is not able to maintain systemic circulation (Cronk 2004).
The severity of this defect can vary; most often the condition is fatal unless treated. Some hypoplastic left heart syndrome cases are associated with chromosomal abnormalities (Boldt 2002, Ferencz 1997, Pradat 1992, Morris 1990, Natowicz1988). This defect does not appear to be among the heart defects commonly associated with the 22q11 microdeletion linked to DiGeorge syndrome and velocardiofacial anomaly (Trost 1999). This defect can also be associated with biliary atresia, a condition in which the bile ducts are obstructed or absent (Becker 2004).
Over the past several decades, ultrasonography and fetal echocardiography have allowed hypoplastic left heart syndrome to be identified in utero (Allan 1998, Hafner 1998, Reis 1998, Kirk 1997, Stoll 1997, Montana 1996). In regions where elective termination is allowed, prenatal diagnosis and elective termination may reduce the birth prevalence of hypoplastic left heart syndrome (Boldt 2002, Garne 2001, Brackley 2000, Riley 1998, Julian-Reynier 1994, Stoll 1993, Allan 1991, Blake 1991).
There have been several suggested causes for the manifestation of hypoplastic left heart syndrome. An early study indicated that there was an immunoreactive response by the heart tissues to specific growth factors as the heart tissues were under- or overreacting to the presence of growth factors, they were not able to form or grow properly ( Burton 1991). Further research has indicated that there is a genetic component to this defect. Families with other known cardiac defects are more likely to have offspring with hypoplastic left heart syndrome (Cronk 2004). This defect is also associated with the CATCH 22 (cardiac defects, abnormal facies, thymic hypoplasia, cleft palate, hypocalcemia) syndrome, caused by a chromosomal deletion within 22q11 (Consevage 1996). It is likely that another gene, Cited 2, also contributes to this defect. However, research related to this gene was limited to a small number of cases (Volcik 2003). It has also been suggested that children with the MTHFR 677TT genotype are also more likely to have cardiac defects. This gene is involved with homocystine regulation; when this gene is present in combination with low folate levels, cardiac defects and neural tube defects can develop (Junker 2001).
DEMOGRAPHIC AND REPRODUCTIVE FACTORS
Various studies have reported no differences in hypoplastic left heart syndrome rates with respect to race/ethnicity (Shaw 2002, Botto 2001a, Ferencz 1997, Storch 1992, Correa-Villansenor 1991, Maron 1973), although one investigation reported the rate among Mexican-Americans to be lower than the rates among non-Hispanic whites and African Americans (Fixler 1993). A recent study out of Wisconsin indicated that rates of this defect were higher among Caucasians than other groups, including African Americans and Hispanics (Cronk 2004).
Several studies reported a decrease in hypoplastic left heart syndrome rates over time (Ferencz 1997, Francannet 1993), but in one study this secular trend was observed in only one birth defects registries (Francannet 1993). Another investigation reported an increase in rates of the heart defect, although it was suggested that this trend might be due to increased use of echocardiography for making diagnoses (Cronk 2004, Morris 1990). Yet other reports found hypoplastic left heart syndrome rates to remain relatively constant over time (Botto 2001a, Wren 2000).
Several studies failed to find any seasonal variation in hypoplastic left heart syndrome rates (Cronk 2004, Tikkanen 1994, Tikkanen1992, Morris 1990), while another study reported rates to be highest in the spring and summer and lowest in the autumn (Ferencz 1997). Another study reported seasonal differences in hypoplastic left heart syndrome rates in Czechoslovakia (Samanek 1991a).
One investigation reported geographic variation in hypoplastic left heart syndrome risk, with rates for the defect being lower in suburban areas than in urban or rural areas (Ferencz 1997). No variation by county was reported for hypoplastic left heart syndrome in Oregon (Morris 1990); however, rates of this defect were found to be higher in eastern Wisconsin than in other portions of that state (Cronk 2004).
Hypoplastic left heart syndrome varies by sex, being more common among males than among females (Cronk 2004, Lary 2001, Ferencz 1997, Samanek 1994, Sampayo 1994, Francannet 1993, Pradat 1992, Morris 1990, Fyler 1980, Rothman 1976, Nadas 1972).
There appears to be no association between hypoplastic left heart syndrome and maternal age (Ferencz 1997, Tikkanen 1991, Francannet 1993, Tikkanen 1990, Rothman 1976) or paternal age (Ferencz 1997). Parity has not been found to influence hypoplastic left heart syndrome (Rothman).
Hypoplastic left heart syndrome risk is higher with lower birth weight (Jacobs 2003, Riley 1998, Ferencz 1997, Tikkanen 1994, Francannet 1993, Rosenthal 1991). The relationship between the heart defect and gestational age appears to be conflicted (Rasmussen 2001, Ferencz 1997, Tikkanen 1994, Francannet 1993). Hypoplastic left heart syndrome has been associated with intrauterine growth retardation (Jacobs 2003, Khoury 1988). There is no apparent relationship between hypoplastic left heart syndrome and macrosomia (Waller 2001). One investigation reported increased risk of hypoplastic left heart syndrome with multiple births (Tikkanen a1994), while other studies failed to find any association between plurality and the heart defect (Mastroiacovo 1999, Riley 1998, Ferencz 1997).
FACTORS IN LIFESTYLE OR ENVIRONMENT
One investigation observed that hypoplastic left heart syndrome rates were not influenced by socioeconomic factors such as parental education, income, or parental occupation (Ferencz 1997). An article that reviewed recent studies of paternal occupation and birth defects reported increased risk of hypoplastic left heart syndrome with paternal occupation of paint stripping (Chia 2002).
There is increased risk of hypoplastic left heart syndrome with first trimester maternal respiratory infection (Tikkanen 1994, Tikkanen 1991, Tikkanen 1990). Investigations into the relationship between maternal diabetes and hypoplastic left heart syndrome have been inconsistent (Loffredo 2001, Moore 2000, Ferencz 1997, Becerra 1990), however one study indicated maternal insulin dependent diabetes was a significant risk factor for this defect (Abu-Sulaimain 2004).
One study reported a higher than expected rate of hypoplastic left heart syndrome among infants born to mothers with untreated phenylketonuria (Levy 2001). Neither maternal fever in early pregnancy, hypothyroidism, or hyperthyroidism appears to impact risk of hypoplastic left heart syndrome (Botto 2001b, Tikkanen 1991, Khoury 1989).
Maternal obesity does not appear to be associated with risk of hypoplastic left heart syndrome (Moore 2000). However, one study indicated that maternal obesity combined with African-American race/ethnicity did increase the risk of cardiac defects (Mikhail 2002).
A study reported increased risk of hypoplastic left heart syndrome with maternal salbutamol (an asthma medication) use, although exposure was reported for only one case (Correy 1991). Hypoplastic left heart syndrome risk does not appear to be associated with maternal use of ampicillin (Czeizel 2001). One investigation reported increased risk of hypoplastic left heart syndrome with paternal exposure to general anesthesia and paternal and maternal exposure to solvents (Cronk 2004, Ferencz 1997), while another study found no association between maternal exposure to deodorants, hair sprays, dust, or glues (Tikkanen 1994, 1990). Hypoplastic left heart syndrome risk does not appear to be influenced by maternal exposure to dyes, lacquers, paints, or organic solvents at work (Tikkanen 1992). An increased risk of cardiac defects was noted with use of chlorine dioxide or trihalomethane to purify drinking water when concentrations were high (Cedergren 2002).
Hypoplastic left heart syndrome has not been linked to maternal use of alcohol, smoking, or coffee (Kallen 1999, Ferencz 1997, Tikkanen 1994). No association has been reported for hypoplastic left ventricle and Bendectin (Zierler 1985) or aspirin (Werler 1989, Zierler 1985). Additionally, this defect has not been linked to maternal use of marijuana (Fried 2002), coroticosteroids (Park-Wyllie 2000), antihistamine drugs (Kallen 2002), or fluoxetine (Prozac™) (Chambers 1996).
One study failed to find any impact of maternal multivitamin use on hypoplastic left heart syndrome risk (Botto 2000). A more recent study indicated that periconceptional use of multivitamins reduced the overall risk of birth defects, and therefore the risk of hypoplastic left heart syndrome (Botto 2004).
The hypoplastic left heart syndrome birth prevalence in Texas among 1999-2003 deliveries was 2.04 cases per 10,000 live births (Texas Department of State Health Services 2006). Birth prevalence in the United States is 2.43 per 10,000 live births (Canfield 2006).
Please Note: The primary purpose of this report is to provide background necessary for conducting cluster investigations. It summarizes literature about risk factors associated with this defect. The strengths and limitations of each reference were not critically examined prior to inclusion in this report. Consumers and professionals using this information are advised to consult the references given for more in-depth information.
- Abu-Harb M, Wyllie J, Hey E, Richmond S, Wren C. Presentation of obstructive left heart malformations in infancy. Arch Dis Child Fetal Neonatal Ed 1994;71:F179-83.
- Abu-Sulaiman RM, Subraih B. Congenital heart disease in infants of diabetic mothers: echocardiographic study. Pediatric Cardiology 25:137-140, 2004.
- Allan LD, Apfel HD, Printz BF. Outcome after prenatal diagnosis of the hypoplastic left heart syndrome. Heart 1998;79:371-374.
- Allan LD, Cook A, Sullivan I, Sharland GK. Hypoplastic left heart syndrome: effects of fetal echocardiography on birth prevalence. Lancet 1991;959-961.
- Becerra JE, Khoury MJ, Cordero JF, Erickson JD. Diabetes mellitus during pregnancy and the risks for specific birth defects: a population-based case-control study. Pediatrics 1990;85:1-9.
- Becker D, Islam S, Geiger J. Biliary atresia associated with hypoplastic left heart syndrome: a case report and review of the literature. Journal of Pediatric Surgery, Vol. 39, No. 9, 2004.
- Blake DM, Copel JA, Kleinman CS. Hypoplastic left heart syndrome: prenatal diagnosis, clinical profile, and management. Am J Obstet Gynecol 1991;165:529-534.
- Boldt T, Andersson S, Eronen M. Outcome of structural heart disease diagnosed in utero. Scand Cardiovasc J 2002;36:73-79.
- Botto LD, Correa A, Erickson JD. Racial and temporal variations in the prevalence of heart defects. Pediatrics 2001a;107:e32.
- Botto LD, Lynberg MC, Erickson JD. Congenital heart defects, maternal febrile illness, and multivitamin use: a population-based study. Epidemiology 2001b;12:485-490.
- Botto LD, Mulinare J, Erickson JD. Occurrence of congenital heart defects in relation to maternal mulitivitamin use. Am J Epidemiol 2000;151:878-884.
- Botto LD, Olney R, Erickson JD. Vitamin supplements and the risk for congenital anomalies other than neural tube defects. American Journal of Medical Genetics Part C (Semin. Med. Genet.) 125C:12-21, 2004.
- Brackley KJ, Kilby MD, Wright JG, Brawn WJ, Sethia B, Stumper O, Holder R, Wyldes MP, Whittle MJ. Outcome after prenatal diagnosis of hypoplastic left-heart syndrome: a case series. Lancet 2000;356:1143-1147.
- Burton PBJ, Hauck A, Nehlsen-Cannarella SL, Gusewitch GA, Sorensen CM, Gundry SR, Bailey LL. Hypoplasic left heart syndrome : some clues to its aetiology. The Lancet, Vol. 338, 1991.
- Canfield MA, Honein MA, Yuskiv N, Xing J, Mai CT, Collins JS, Devine O, Petrini J, Ramadhani TA, Hobbs CA, Kirby RS. National estimates and race/ethnic-specific variation of selected birth defects in the United States, 1999-2001. Birth Defects Res A Clin Mol Teratol. 2006 Nov;76(11):747-56.
- Cedergren M, Selbing A, Lofman O, Kallen B. Chlorination byproducts and nitrate in drining water and risk for congenital cardiac defects. Environmental Research Section A, 89, 124-130, 2002.
- Chambers CD, Johnson KA, Dick LM, Felix RJ, Jones, KL. Birth outcomes in pregnant women taking fluoxetine. New England Journal of Medicine, Vol. 335, No. 14, 1996.
- Chia SE, Shi LM. Review of recent epidemiological studies on paternal occupations and birth defects. Occup Environ Med. 2002;59:149-155.
- Consevage MW, Seip JR, Belchis DA, Davis AT, Baylen BG, Rogan PK. Association of a mosaic chromosomal 22q11 deletion with hypoplastic left heart syndrome. American Journal of Cardiology, Vol. 77, 1996.
- Correa-Villansenor A, McCarter R, Downing J, Ferencz C, Baltimore-Washington Infant Study Group. White-black differences in cardiovascular malformation in infancy and socioeconomic factors. Am J Epidemiol 1991;134:393-402.
- Correy JF, Newman NM, Collins JA, Burrows EA, Burrows RF, Curran JT. Use of prescription drugs in the first trimester and congenital malformations. Aust N Z J Obstet Gynaecol 1991;31:340-344.
- Cronk CE, Pelech AN, Malloy ME, McCarver DG. Excess birth prevalence of hypoplastic left heart syndrome in eastern Wisconsin for birth cohorts 1997-1999. Birth Defects Research (Part A): Clinidal and Molecular Teratology, 70:114-120, 2004.
- Czeizel AE, Rockenbauer M, Sorensen HT, Olsen J. A population-based case-control teratologic study of ampicillin treatment during pregnancy. Am J Obstet Gynecol 2001;185:140-147.
- Ferencz C, Loffredo CA, Correa-Villasenor A, Wilson PD, eds. Left-sided obstructive lesions. In: Genetic and Environmental Risk Factors of Major Cardiovascular Malformations: The Baltimore-Washington Infant Study 1981-1989. Armonk, NY: Fuytura Publishing Co., Inc; 1997: pp. 165-225.
- Ferencz C, Rubin JD, McCarter RJ, Brenner JI, Neill CA, Perry LW, Hepner SI, Downing JW. Congenital heart disease: prevalence at livebirth. Am J Epidemiol 1985;121:31-36.
- Fixler DE, Pastor P, Sigman E, Eifler CW. Ethnicity and socioeconomic status: Impact on the diagnosis of congenital heart disease. J Am Coll Cardiol 1993;21:1722-1726.
- Francannet C, Lancaster PA, Pradat P, Cocchi G, Stoll C. The epidemiology of three serious cardiac defects a joint study between five centres. Eur J Epidemiol 1993;9:607-616.
- Fried P. The consequences of marijuana use during pregnancy: a review of the medical literature. Women and Cannabus: Medicine, Science, and Sociology, Haworth Integrative Healing Press, 2002.
- Fyler DC. Report of the New England Regional Infant Cardiac Program. Pediatrics 1980;65 (suppl):375-461.
- Garne E, EUROCAT Working Group. Prenatal diagnosis of six major cardiac malformations in Europe--a population based study. Acta Obstet Gynecol Scand 2001;80:224-228.
- Garne E, Stoll C, Clementi M, Euroscan Group. Evaluation of prenatal diagnosis of congenital heart diseases by ultrasound: experience from 20 European registries. Ultrasound Obstet Gynecol 2001;17:386-391.
- Grech V. Decreased prevalence of hypoplastic left heart syndrome in Malta. Pediatr Cardiol 1999;20:355-357.
- Hafner E, Scholler J, Schuchter K, Sterniste W, Philipp K. Detection of fetal congenital heart disease in a low-risk population. Prenat diagn 1998;18:808-815.
- Jacobs EGJ, Leung MP, Karlberg J. Birthweight distrubution in southern Chinese infants with symptomatic congenital heart disease. J. Paediatr. Child Health, Vol.29, 191-196, 2003.
- Julian-Reynier C, Philip N, Scheiner C, Aurran Y, Chabal F, Maron A, Gombert A, Ayme S. Impact of prenatal diagnosis by ultrasound on the prevalence of congenital anomalies at birth in southern France. J Epidemiol Community Health 1994;48:290-296.
- Junker R, Kotthoff S, Vielhaber H, Halimeh S, Kosch A, Koch HG, Kassenborhmer R, Heineking B, Nowak-Gottl U. Infant methylenetetrahydrofolate reductase 677TT genotype is a risk factor for congenital heart disease. Cardiovascular Research 51, 2001, 251-254.
- Kallen B. Use of antihistamine drugs in early pregnancy and delivery outcomes. Journal of Maternal-Fetal and Neonatal Medicine, 2002, 11: 146-152.
- Kallen K. Maternal smoking and congenital heart defects. Eur J Epidemiol 1999;15:731-737.
- Khoury MJ, Becerra JE, d'Almada PJ. Maternal thyroid disease and risk of birth defects in offspring: a population-based case-control study. Paediatr Perinat Epidemiol 1989;3:402-420.
- Khoury MJ, Erickson JD, Cordero JF, McCarthy BJ. Congenital malformations and intrauterine growth retardation: a population study. Pediatrics 1988;82:83-90.
- Kidd SA, Lancaster PA, McCredie RM. The incidence of congenital heart defects in the first year of life. J Paediatr Child Health 1993;29:344-349.
- Kirk JS, Comstock CH, Lee W, Smith RS, Riggs TW, Weinhouse E. Sonographic screening to detect fetal cardiac anomalies: A 5-year experience with 111 abnormal cases. Obstet Gynecol 1997;89:227-232.
- Lary JM, Paulozzi LJ. Sex differences in the prevalence of human birth defects: a population-based study. Teratology 2001;64:237-251.
- Levy HL, Guldberg P, Guttler F, Hanley WB, Matalon R, Rouse BM, Trefz F, Azen C, Allred EN, de la Cruz F, Koch R. Congenital heart disease in maternal phenylketonuria: report from the Maternal PKU Collaborative Study. Pediatr Res 2001;49:636-642.
- Loffredo CA, Wilson PD, Ferencz C. Maternal diabetes: An independent risk factor for major cardiovascular malformations with increased mortality of affected infants. Teratology 2001;64:98-106.
- Maron BJ, Applefeld JM, Krovetz LJ. Racial frequencies in congenital heart disease. Circulation 1973;47:359-361.
- Mastroiacovo P, Castilla EE, Arpino C, Botting B, Cocchi G, Goujard J, Marinacci C, Merlob P, Metneki J, Mutchinick O, Ritvanen A, Rosano A. Congenital malformations in twins: an international study. Am J Med Genet 1999;83:117-124.
- Mikhail LN, Walker C, Mittendorf R. Association between maternal obesity and fetal cardiac malformations in African Amercians. Journal of the National Medical Association, Vol. 94, No. 8, 2004.
- Montana E, Khoury MJ, Cragan JD, Sharma S, Dhar P, Fyfe D. Trends and outcomes after prenatal diagnosis of congenital cardiac malformations by fetal echocardiography in a well defined birth population, Atlanta, Georgia, 1990-1994. J Am Coll Cardiol 1996;28:1805-1809.
- Moore LL, Singer MR, Bradlee ML, Rothman KJ, Milunsky A. A prospective study of the risk of congenital defects associated with maternal obesity and diabetes mellitus. Epidemiology 2000;11:689-694.
- Morris CD, Outcalt J, Menashe VD. Hypoplastic left heart syndrome: natural history in a geographically defined population. Pediatrics 1990;85:977-983.
- Nadas AS, Fyler DC. Pediatric Cardiology. Philadelphia: W.B. Sounders Company. 1972.
- Natowicz M, Chatten J, Clancy R, Conard K, Glauser T, Huff D, Lin A, Norwood W, Rorke LB, Uri A, et al. Genetic disorders and major extracardiac anomalies associated with the hypoplastic left heart syndrome. Pediatrics 1988;82:698-706.
- Papp Z, Toth-Pal E, Papp C, Toth Z, Szabo M, Veress L, Torok O. Impact of prenatal mid-trimester screening on the prevalence of fetal structural anomalies: a prospective epidemiological study. Ultrasound Obstet Gynecol 1995;6:320-326.
- Park-Wyllie L, Mazzotta P, Pastuszak A, Moretti M, Beique L, Hunnisett L, Friesen M, Jacobson S, Kasapinovic S, Chang D, Diav-Citrine O, Chitayat D, Nulman I, Einarson TR, Koren G. Birth defects after maternal exposure to corticosteroids: prospective cohort study and meta-analysis of epidemiological studies. Teratology 62; 385-392, 2000.
- Pradat P. Epidemiology of major congenital heart defects in Sweden, 1981-1986. J Epidemiol Community Health 1992;46:211-215.
- Rasmussen SA, Moore CA, Paulozzi LJ, Rhodenhiser EP. Risk for birth defects among premature infants: A population-based study. J Pediatr 2001;138:668-673.
- Reis PM, Punch MR, Bove EL, van de Ven CJ. Obstetric management of 219 infants with hypoplastic left heart syndrome. Am J Obstet Gynecol 1998;179:1150-1154.
- Riley MM, Halliday JL, Lumley JM. Congenital malformations in Victoria, Australia, 1983-95: an overview of infant characteristics. J Paediatr Child Health 1998;34:233-240.
- Rosenthal GL, Wilson PD, Permutt T, Boughman JA, Ferencz C. Birth weight and cardiovascular malformations: A population-based study. Am J Epidemiol 1991;133:1273-1281.
- Rothman KJ, Fyler DC. Sex, birth order, and maternal age characteristics of infants with congenital heart defects. Am J Epidemiol 1976;104:527-534.
- Samanek M, Voriskova M. Congenital heart disease among 815,569 children born between 1980 and 1990 and their 15-year survival: a prospective Bohemia survival study. Pediatr Cardiol 1999;20:411-417.
- Samanek M. Boy:girl ratio in children born with different forms of cardiac malformation: a population-based study. Pediatr Cardiol 1994;15:53-57.
- Samanek M, Slavik Z, Krejcir M. Seasonal differences in the incidence of congenital heart defects. Czech Med 1991a;14:146-155.
- Samanek M, Slavik Z, Balatka J, Bartakova H, Goetzova J, Homola J, Rusava I, Smrcka J, Krejcir M. Krajove rozdily vyskytu vrozenych srdecnich vad. Cesk Pediatr 1991b;46:65-70.
- Sampayo F, Pinto FF. Distribuicao por sexos das cardiopatias congenitas. Acta Med Port 1994;7:413-418.
- Sekhobo JP, Druschel CM. An evaluation of congenital malformations surveillance in New York State: an application of Centers for Disease Control and Prevention (CDC) guidelines for evaluating surveillance systems. Public Health Rep 2001;116:296-305.
- Shaw GM, Carmichael SL, Nelson V. Congenital malformations in offspring of Vietnamese women in California, 1985-97. Teratology 2002;65:121-124.
- Stoll C, Dott B, Alembik Y, De Geeter B. Evaluation and evolution during time of prenatal diagnosis of congenital heart diseases by routine fetal ultrasonographic examination. Ann Genet 2002;45:21-27.
- Stoll C, Alembik Y, Dott B, Meyer MJ, Pennerath A, Peter MO, De Geeter B. Evaluation of prenatal diagnosis of congenital heart disease. Prenat Diagn 1998;18:801-807.
- Stoll C, Alembik Y, Dott B, De Geeter B, Meyer MJ, Peter PO, Pennerath A. Evaluation of prenatal diagnosis of congenital heart disease. Teratology 1997;55:49.
- Stoll C, EUROCAT Working Group. Distribution of single organ malformations in European populations. Ann Genet 1995;38:32-43.
- Stoll C, Alembik Y, Dott B, Roth PM, De Geeter B. Evaluation of prenatal diagnosis of congenital heart disease. Prenat Diagn 1993;13:453-461.
- Stoll C, Alembik Y, Roth MP, Dott B, De Geeter B. Risk factors in congenital heart disease. Eur J Epidemiol 1989;5:382-391.
- Storch TG, Mannick EE. Epidemiology of congenital heart disease in Louisiana: an association between race and sex and the prevalence of specific cardiac malformations. Teratology 1992;46:271-276.
- Texas Department of State Health Services. Texas birth defects registry report of birth defects among 1999-2003 deliveries. 2006.
- Tikkanen J, Heinonen OP. Risk factors for cardiovascular malformations in Finland. Eur J Epidemiol 1990;6:348-356.
Tikkanen J, Heinonen OP. Maternal hyperthermia during pregnancy and cardiovascular malformations in the offspring. Eur J Epidemiol 1991;7:628-635.
- Tikkanen J, Heinonen OP. Occupational risk factors for congenital heart disease. Int Arch Occup Environ Health 1992;64:59-64.
- Tikkanen J, Heinonen OP. Risk factors for hypoplastic left heart syndrome. Teratology 1994;50:112-117.
- Torfs CP, Christianson RE. Anomalies in Down syndrome individuals in a large population-based registry. Am J Med Genet 1998;77:431-438.
- Trost D, Engels H, Bauriedel G, Wiebe W, Schwanitz G. Angeborene kardiovaskulare Fehlbildungen und chromosomale mikrodeletionen in 22q11.2. Dtsch Med Wochenschr 1999;124:3-7.
- Volcik, KA, Zhu H, Finnell RH, Shaw GM, Canfield M, Lammer EJ. Evaluation of the Cited 2 gene and risk for spina bifida and congenital heart defects. American Journal of Medical Genetics, published online 2002.
- Waller DK, Keddie AM, Canfield MA, Scheuerle AE. Do infants with major congenital anomalies have an excess of macrosomia? Teratology 2001;64:311-317.
- Werler MM, Mitchell AA, Shapiro S. The relation of aspirin use during the first trimester of pregnancy to congenital cardiac defects. N Engl J Med 1989;321:1639-1642.
- Wren C, Richmond S, Donaldson L. Temporal variability in birth prevalence of cardiovascular malformations. Heart 2000;83:414-419.
- Zierler S, Rothman KJ. Congenital heart disease in relation to maternal use of Bendectin and other drugs in early pregnancy. N Engl J Med 1985;313:347-352.