Etiological aspects of esophageal atresia

Esophageal atresia (EA) is a severe congenital malformation, characterized by a discontinuity of the esophagus. To identify possible preventive measures, it is important to understand the etiology of EA, but little is known about risk factors. The principal aim of the present thesis is to contribute to a better understanding of the etiology of EA. The role of potential etiological maternal risk factors for EA in the infant has been approached. Studies I and II also concerned aspects of EA that warrant being addressed in a large and population-based investigation, covering the incidence, mortality, and cancer risk as well as the characteristics of an unselected cohort of patients. EA is rare, which makes it difficult to study. In Sweden, however, there is a unique possibility of conducting large population-based studies through the nationwide registers available. In all studies included in the present thesis, Swedish nationwide population-based registers were used, linked through personal identity numbers.

In study I, a population-based cohort study of 1,126 EA patients, the incidence of EA and the associated mortality and cancer risk were assessed. The mean incidence was found to be 3.16 per 10,000 live births, without any temporal changes (p for trend=0.94). EA patients had an almost 12 times higher risk of mortality compared to the background population (SMR 11.8, 95% CI 10.3-13.5). Survival improved substantially, however, during the study period (p for trend=0.0001). Occurrence of associated anomalies and very low birth weight were linked with a worse prognosis. Although uncertain, the risk of cancer did not seem to be increased in patients operated on for EA (SIR 0.9; 95% CI 0.2-2.6).

Studies II, III, and IV were all population-based, nested case-control studies, including over 700 cases of EA, conducted to assess the association between selected maternal exposures and the risk of EA in the infant.

In study II the risk factors maternal parity, age and ethnicity were approached. There seemed to be an increased risk of EA among infants of mothers having their first delivery. An over 30% decrease in risk of EA was found for mothers delivering their second (OR 0.68; 95% CI 0.56-0.83) or third child (OR 0.64; 95% CI 0.49-0.83), compared to first time mothers. The risk of having an infant with EA was found to increase with maternal age. Infants of women giving birth when 35-40 years and >40 years old showed a 2-fold (OR 2.09; 95% CI 1.09-3.99) and 3-fold (OR 3.04; 95% CI 1.37-6.74) increase in risk of EA, respectively, compared to those of mothers <20 years. There was a 66% increase in risk of isolated EA in infants of mothers of Caucasian (OR 1.66; 95% CI 1.06-2.61), compared to non-Caucasian ethnicity. In study II the characteristics of an unselected cohort of infants born with EA were described. Infants born with EA had a lower birth weight and were more often prematurely born, of male gender and twins, compared to infants born without this malformation.

In study III the potential maternal risk factors tobacco smoking, obesity and low socioeconomic status were assessed. No associations were found between these exposures and the risk of having an infant with EA.

In study IV we addressed the risk of having an infant with EA among women with diabetes. Maternal diabetes during pregnancy seemed to increase the risk of EA in the child. The adjusted risk of EA was 70 % higher among infants of women with diabetes than among those of women without the disease (OR 1.7; 95% CI 1.0- 2.9).

List of scientific papers

I. Oddsberg J, Lu Y, Lagergren J (2010). "Aspects of esophageal atresia in a population-based setting: Incidence, mortality, and cancer risk" (Submitted)

II. Oddsberg J, Jia C, Nilsson E, Ye W, Lagergren J (2008). "Influence of maternal parity, age, and ethnicity on risk of esophageal atresia in the infant in a population-based study." J Pediatr Surg 43(9): 1660-5
https://pubmed.ncbi.nlm.nih.gov/18779003

III. Oddsberg J, Jia C, Nilsson E, Ye W, Lagergren J (2008). "Maternal tobacco smoking, obesity, and low socioeconomic status during early pregnancy in the etiology of esophageal atresia." J Pediatr Surg 43(10): 1791-5
https://pubmed.ncbi.nlm.nih.gov/18926209

IV. Oddsberg J, Lu Y, Lagergren J (2010). "Maternal diabetes and risk of esophageal atresia" (Submitted)