Multiple gastrointestinal atresias result from disturbed morphogenesis

Abstract

Multiple gastrointestinal atresias (MGA) have been reported to account for 6% to 32% of all intestinal atresias. Controversy exists regarding the pathogenesis. Many investigators believe MGA to be the result of multiple ischemic infarctions of the intestinal tract. However, some have suggested that MGA results from a malformative process early in fetal life. Prenatal exposure to adriamycin in a rat model has been reported to lead to a spectrum of tracheoesophageal and associated malformations of the gastrointestinal tract, including intestinal atresias, identical to these observed in humans. The aim of this study was to determine the incidence and histopathologic findings of MGA in order to understand the pathogenesis. Timed-pregnant Sprague-Dawley rats were injected with adriamycin (1.75 mg/kg) in nine different gestational-day protocols. MGA was only seen in those rats who received adriamycin on gestational days 7, 8, and 9. The litters were recovered on day 21 by cesarean section. The digestive tracts (DT) of the fetuses were harvested for macroscopic and microscopic examination. Ten rats who received adriamycin on gestational days 7, 8, and 9 produced 87 newborns; 1 was damaged during dissection. DT anomalies occurred in 80 (93%) of the 86 newborns; 94% of these demonstrated MGA. There was a very high incidence of associated anomalies in newborns with MGA. Histologically, the blind-ending atresias showed different degrees of villous hyperplasia with or without intraluminal material. This is the first report demonstrating a high rate of occurrence of MGA in the adriamycin rat model. The injection of adriamycin early in gestation, the high incidence of associated malformations, and the anatomic and histologic findings in MGA indicate that MGA is a result of a malformative rather than an ischemic process.