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BIRTH DEFECT RISK FACTOR SERIES: Esophageal Atresia

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DEFINITION

Esophageal atresia is the absence, closure, or constriction of the esophagus at any point along its length. Tracheoesophageal fistula is an abnormal connection between the trachea and the esophagus. Esophageal atresia and tracheoesophageal fistula most frequently occur together, with isolated tracheoesophageal fistula being much less common and isolated esophageal atresia being the least common condition (Torfs 1995).

Esophageal obstructions are isolated in 40-60% of cases (Garne 2002, Haeusler 2002, Sparey 2000, Stoll 1996, Harris 1995, Robert 1995, Torfs 1995, Castilla 1990). Less than 20% of cases are associated with chromosomal anomalies, usually trisomy 18, trisomy 21, and trisomy 13 (Haeusler 2002, Sparey 2000, Torfs 1998, Kallen 1996, Robert 1995, Torfs 1995, Harris 1995, Robert 1993, Depaepe 1993). Esophogeal atresia and tracheoesophageal fistula are also associated with the VATER (vertebral defects, anal malformations, tracheoesophageal fistula, esophageal atresia, renal defects and radial bone dysplasia) complex and/or the VACTRL ( vertebral anomalies, vascular anomalies, anal atresia, cardiac anomalies, tracheo-esophageal fistula, esophageal atresia, renal anomalies, and limb anomalies association (Kluth 2003). These conditions are usually diagnosed shortly after delivery.

EMBRYOLOGY

The primitive foregut divides into the trachea and esophagus during the 4 th week of gestation. If this division fails to occur, esophageal atresia and tracheoesophageal fistula result. However, new research indicates that there may be separate origins for the development of the esophagus and the development of the fistula. Spilde found that the tracheoesophageal fistula is likely to be a third bronchial bud that does not develop properly (2003). This conclusion was drawn based upon the fact that the gene known as Sonic Hedgehog (Shh) did not produce signals in the fistula tract, while this is present in the esophageal tract and other gut components (Spilde 2003). Mutations in three genes, NMYC, SOX2 and CHD7 have been identified that cause syndromic forms of esophageal atresia (Brunner 2005).

DEMOGRAPHIC AND REPRODUCTIVE FACTORS

With respect to race/ethnicity, several studies have reported esophageal atresia and tracheoesophageal fistula to be more common in whites than in nonwhites or Hispanics (Canfield 2006, Torfs 1995, Harris 1995). However, one investigation reported no link between race/ethnicity and esophageal atresia (Yang 1994), and another found the rate of esophageal atresia/fistula to be higher in Europeans and South Asians than in Caribbeans (Leck 1995). One study observed risk of tracheoesophageal atresia/stenosis to be lower in offspring of Vietnamese mothers when compared with offspring of non-Hispanic white mothers (Shaw 2002).

Most investigations have found no secular trends in the rate of esophageal atresia and tracheoesophageal fistula, although several birth defect registries have reported an increase in esophageal atresia rates and yet one reported a decrease in esophageal atresia and tracheoesophageal fistula rates (Torfs 1995, Yang 1994, Robert 1993, Depaepe 1993). Studies show that esophageal atresia and tracheoesophageal fistula do not appear to exhibit seasonal variation (Torfs 1995, Castilla 1990, Bound 1989, Fraser 1987).

The impact of geographic location on esophageal atresia and tracheoesophageal fistula risk has not been extensively examined. One study reported risk to be higher in urban areas than in rural areas for esophageal atresia with tracheoesophageal fistula and for isolated tracheoesophageal fistula, but not for isolated esophageal atresia (Torfs 1990). One investigation failed to identify any association between esophageal atresia and altitude (Castilla 1999).

The influence of maternal age on esophageal atresia and tracheoesophageal fistula risk has been variously reported to be U-shaped (higher rates among both older and younger mothers) or increasing with greater maternal age (Torfs 1995, Harris 1995, Depaepe 1993), although several investigations found no effect of maternal age on esophageal atresia rates either with and without tracheoesophageal fistula (Yang 1994, Robert 1993). No clear association between tracheoesophageal fistula and paternal age has been identified (McIntosh 1995).

Infant sex has been reported to influence esophageal atresia and tracheoesophageal fistula risk, with the conditions being more common among males than among females (Haeusler 2002, Lary 2001, Harris 1995, Robert 1993, Depaepe 1993). However, several studies failed to identify infant sex as a risk factor (Riley 1998, Torfs 1995, Yang 1994, Lowry 1986).

Risk for esophageal atresia and tracheoesophageal fistula increases with lower birth weight and lower gestational age (Rasmussen 2001, Riley 1998, Torfs 1995, Harris 1995, Robert 1993, Depaepe 1993). Esophageal atresia has been associated with intrauterine growth retardation (Khoury 1988). There is decreased risk of these esophageal and tracheal conditions with increasing parity (Harris 1995, Robert 1993). One study indicated that these defects, either alone or in combination, were more likely to occur when parity was less than 1 or greater than 3 (Bianca 2003, 2002). Both esophageal atresia and tracheoesophageal fistula are more common among multiple gestation pregnancies (Mastroiacovo 1999, Riley 1998, Torfs 1995, Harris 1995, Robert 1993, Depaepe 1993, Doyle 1991, Ramos-Arroyo 1991, Kallen 1986).

One investigation found no association between parental consanguinity and esophageal atresia (Rittler 2001).

FACTORS IN LIFESTYLE OR ENVIRONMENT

Although one investigation reported an increased risk of tracheoesophageal anomalies with socioeconomic deprivation, the difference was not statistically significant (Vrijheid 2000).

Esophageal atresia and tracheoesophageal fistula have not been linked to maternal infections such as hepatitis, rubella, salmonella, and rubeola (Fraser 1987). Women with phenylketonuria (PKU) may have a higher risk for having infants with esophageal atresia (Jones 1988). A population-based case-control study found no association between hyperthyroidism or hypothyroidism and tracheoesophageal fistula or esophageal atresia (Khoury 1989). One study identified no association between maternal diabetes and esophageal atresia and tracheoesophageal fistula (Becerra 1990) while another study observed increased rates of esophageal/intestinal atresia with both preexisting diabetes and gestational diabetes (Aberg 2001). Esophageal atresia and tracheoesophageal fistula do not appear to be linked to maternal smoking (Honein 2001, Van Den Eeden 1990, Shiono 1986).

It has been suggested that methimazole (a medication for hypethyroidism) use during pregnancy may cause esophageal atresia and tracheoesophageal fistula (Ramirez 1992), although further corroboration of this link is needed. Esophageal atresia has been reported among infants born to mothers who took thalidomide (Warkany 1971). Studies have reported no association between cephalosporin antibiotics, nalidixic acid, calcium channel blockers, ampicillin, or the benzodiazepines nitrazepam, medazepam, tofisopam, alprazolum, and clonazepam and esophageal atresia or stenosis (Eros 2002, Czeizel 2001a, Czeizel 2001b, Czeizel 2001c, Sorensen 2001). Living in proximity to hazardous waste sites or a variety of industries has not been found to affect risk of esophageal atresia or tracheoesophageal fistula (Castilla 2000, Dolk 1998). One investigation reported no association between parental farming occupation and pesticide exposure and risk of esophageal atresia (Kristensen 1997).

There have been no associations found between the manifestation of these defects and the use of fluoxetine (Prozac ä) (Chambers 1996), antihistamine drugs (Kallen 2002), marijuana (Fried 2002), or corticosteroids (Park-Wyllie 2000). The use of chemotherapy does not appear to be a risk factor for esophageal atresia (Cardonic 2004).

One study found no association between maternal influenza during pregnancy and esophageal atresia or stenosis (Acs 2005).

No association between maternal folic acid use and esophageal atresia/stenosis has been identified (Czeizel 1996). Furthermore, a study that examined co-trimoxazole, a combination of trimethoprim and sulfamethoxazole that is a folic acid antagonist, failed to find any association between the medication and esophageal atresia/stenosis (Czeizel, 1990).

PREVALENCE

Birth prevalence in Texas for esophageal atresia/tracheoesophageal fistula for 1999-2003 deliveries was 2.11 cases per 10,000 live births (Texas Department of State Health Services 2006). Nationwide, rates range between 1.04 and 4.91 per 10,000 live births (National Birth Defects Prevention Network 2006). Differences in prevalence may be due to differences in case inclusion criteria.

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Yang P, Khoury MJ, Stewart WF, Beaty TH, Chee E, Beatty JC, Diamond EL, Gordis L. Comparative epidemiology of selected midline congenital abnormalities. Genet Epidemiol 1994;11:141-154.

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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