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BIRTH DEFECT RISK FACTOR SERIES: Hypoplastic Left Heart Syndrome

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DEFINITION

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).

ETIOLOGY

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).

PREVALENCE

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).

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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. 

This report is for information purposes only and is not intended to diagnose, cure, mitigate, treat, or prevent disease or other conditions and is not intended to provide a determination or assessment of the state of health. Individuals affected by this condition should consult their physician and when appropriate, seek genetic counseling.

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Document E58-10957B                    Revised March 2007

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Last updated February 10, 2012