Maternal toxicity in humans and animals: effects on fetal development and criteria for detection

Evaluation of published human and animal teratology data revealed associations between maternal toxicity and congenital malformations and embryofetal death. This has been reported elsewhere in detail and is herein summarized. Regarding human data, intrauterine deaths were observed to occur in association with 1) maternal homeostatic changes due to phenylketonuria and diabetes and 2) maternal toxicity resulting from alcohol abuse, use of aminopterin, and, possibly, trimethadione. A pattern of malformations that was similar and thus suggestive of a common cause was noticed among malformations attributed to phenylketonuria, diabetes mellitus, aminopterin, alcohol, warfarin, phenytoin, phenobarbital, trimethadione, and valproic acid. On reviewing 234 studies of agents tested in hamsters, mice, rats and rabbits, a fairly strong association between maternal toxicity and embryo-fetal mortality was observed. Further, a consistent pattern of fetal malformations associated with maternotoxic effects was discovered in a survey of 476 studies of agents tested in these four species. In these reviews, it was postulated that maternal toxicity per se could possibly cause such fetal effects. For evaluating maternotoxic effects in experimental studies, the minimum maternal data required would be frequent measurements of maternal body weight and food consumption, signs of altered behavior, death, and gross lesions at necropsy.