Hypothesis: Estrogen related thrombosis explains the pathogenesis and epidemiology of gastroschisis

Abstract

A three-part hypothesis is proposed to explain the unusual epidemiology of gastroschisis, a congenital abnormality of the abdominal wall, which has a rising frequency, a higher rate in first and young mothers in whites but not blacks, and a unique negative correlation with obesity. The hypothesis involves: (1) An early estrogenic thrombophilia, (2) racial differences in thrombosis, and (3) thrombotic by-products interfering with early developmental signaling. For the first: (1) An estrogenic thrombophilia is a known effect. (2) A mouse model links excess estrogen to thromboses affecting the fetus. (3) Young and first mothers have higher first trimester estrogen levels. (4) A negative correlation between body mass index and pregnancy estradiol accounts for the weight relationship. (5) Maternal alcohol raises estrogen levels in premenopausal women. (6) A link with atrazine, an estrogenic endocrine disruptor, has been found, and rising frequencies of gastroschisis make this and other such chemicals a particular concern if estrogen is indeed involved. For the second: Blacks have a different thrombophilic gene background and less of a thrombotic response to estrogen than whites, explaining racial differences. For the third: Protein palmitoylation affects cell signaling in development, and lipid rafts, a major aspect of thromboses, facilitate this process. Such thrombotic byproducts could be the source of palmitic acid rich amniotic vacuoles with gastroschisis. Similar vacuoles can occur with limb-body wall defects, another early developmental anomaly associated with decreased maternal age that may have a similar pathogenesis. Later thrombotic related anomalies with a similar epidemiology seem to primarily involve vascular disruptions, but localized signaling anomalies may also occur.

The association between maternal parity and birth defects

“…Sharpe et al (1993) has proposed that exposure to high levels of estrogen during pregnancy may reduce the number of Leydig-cells (clusters of testosterone secreting cells in the testis), which may lead to impaired masculinization of the reproductive tract and genitalia resulting in hypospadias (Sharpe et al, 1993). Also, a recent study by Lubinsky found that higher estrogen levels in first time mothers are significantly correlated with the risk of gastroschisis (Lubinsky, 2012), a birth defect that our study and three previous studies have observed to be associated with first birth (Vu et al, 2008;Benjamin et al, 2010;Doung et al, 2012). It has also been proposed that maternal hormone levels may act in similar ways on other organ systems resulting in birth defects (Panagiotopoulou et al, 1990;Cederroth et al, 2007).…”

Comprehensive Developmental Mechanisms in Gastroschisis

“…Inadequate obliteration of the right umbilical vein [2] , or of the right omphalomesenteric artery [3] , would lead to either weakness or necrosis of the forming abdominal wall. Epidemiological support has been given to such views 228 [19] . However, the right rectus muscle is always well developed in gastroschisis, and the cord itself appears split on the right as we described in figure 3 .…”

Abdominal wall defects: Prenatal diagnosis, newborn management, and long-term outcomes

“…38 Finally, an interesting three-part hypothesis has been proposed that links the early estrogenic thrombophilia, racial differences in thrombosis, and thrombotic by-products interfering with early developmental signaling with the incidence of gastroschisis. 39 In this theory, different interconnected aspects are in charge such as the high levels of estrogen in young mother with low body mass index, the lower frequencies of thrombotic known genes in blacks, and palmitic acid by-products of thrombosis affecting cell signaling.…”