Environmental Factors

3.5.1 The Effect of Drugs in Pregnancy

Although there is very little objective evidence of drugs in the pathogenesis of ARM, Stoll et al. [23] suggested from their relatively small sample that mothers of children with congenital anal atresia took drugs more often during pregnancy than did controls. Previous reports have implicated thalidomide [161] and tridione as possible aetiological agents [2]. More recently, Bonnot et al. [175] have reported 6 cases of anal atresia out of 262 congenital malformations identified in 13,703 patients exposed to benzodiaz-epines during pregnancy. They then demonstrated a significant association (p = 0.01) between lorazepam and anal atresia (five out of six patients)

3.5.2 Associations with Toxins

The known associations with toxins have been used to develop animal models as well as indicate possible involved pathways. The adriamycin-exposed animal model is well established [103] and ETU toxicity is the basis of a current animal model of ARM [104].

Retinoic acid is thought to be involved in the development of patterns in the developing embryo. Teratogenic doses of retinoic acid results in truncation of the embryonic body axis in the mouse, which corresponds to caudal regression syndrome as described in humans [146]. All-transretinoic acid has been used as an animal model of high ARM with fistula, suggesting that it interferes with the normal caudal migration along the urogenital system posterior wall [176].

In a further study on the effects of retinoic acid in the developing foetus, 100% of offspring had craniofacial anomalies, 94% anorectal, 90% limb and 55% neural tube defects [177]. Etretinate (which targets the tail bud) produces a mouse model of Currarino syndrome [178]. Although it is not clear at this stage whether this is a toxic effect or has to do with blocking of receptors during normal development, this association appears to indicate that (retinoic acid and other drug) teratogenesis affects the neural crest developmental pathway. Retinoic acid is of particular interest as it appears to inhibit Shh signalling and downstream bone morphogenetic protein 4 synthesis [179].

An association with thalidomide [161] has been reported, which reopens the possibility of a vascular component to the aetiology, because of its recently discovered anti-angiogenic properties. This raises the possibility of a genetically based vascular hypothesis for ARM, which may combine the two hypotheses.

3.5.3 Association with Infectious Agents

Associations with infectious agents remain uncommon, but foetal exposure to cytomegalovirus and toxoplasmosis have been reported as possible aetio-logical factors [29].

3.5.4 Environmental Exposure and ARM

The results of epidemiological studies are inconsistent as far as environmental exposure is concerned, but only weak potential associations with risk factors have been identified. The adverse effects of smoking, previous abortions and cycle disorders before pregnancy could not be established [180].

Stoll et al. [23] suggested that in their relatively small sample, fathers of ARM babies were more exposed to hazardous substances than fathers of controls. Other environmental factors such as exposure to electromagnetic radiation have proved to be difficult to determine from an epidemiological point of view.

3.5.5 Environmental Versus Genetic

Factors - Increased Susceptibility to Environmental Factors

Epidemiologic techniques are not infrequently used to study risk factors and interactions between gene susceptibility and environmental factors. The role of environmental factors in the development of ARM is probably small. Events during pregnancy or parental exposure (maternal or paternal) could theoretically be of significance and further research is clearly warranted. A clear distinction between environmental and genetic factors is not necessarily justified, as demonstrated in the concept of ecogenetics [181].

Although a considerable spectrum of anorectal maldevelopment has been shown to result from the toxic effects of ETU administration to timed-pregnant rats [104], another study demonstrated that discordance among twin animals suggested that te-ratogens could be eliminated as a major aetiological factor [182].


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