Maternal Toxicity of Drugs and Metabolic Disorders—A Possible Etiologic Factor in the Intrauterine Death and Congenital Malformation: A Critique on Human Data

Human data were searched to determine whether an association of metabolically or drug-induced maternal toxicity with congenital malformations and intrauterine death would be valid for the human species. Intrauterine death was found to occur in association with maternal homeostatic alterations resulting from phenylketonuria and diabetes, and with maternal toxicity from toxemia of pregnancy, leukemia, burns, alcohol, aminopterin, isotretinoin, and possibly trimethadione. A pattern of anomalies found similar (except for minor differences) and thus suggestive of a possible common cause, was observed among anomalies to phenylketonuria, diabetes mellitus, aminopterin, alcohol, warfarin, phenytoin, phenobarbital, trimethadione, valproic acid, and isotretinoin. The pattern usually consisted of deficiencies in pre- and postnatal development, mid-facial hypoplasia, cleft palate, atrial or ventricular septal defects, patent ductus arteriosus, hypospadias, hernias, and other less frequent anomalies. The pattern is tentatively associated with alterations in maternal physiology resulting from phenylketonuria and diabetes; maternal toxicity of aminopterin, alcohol, and diverse factors co-occurring with warfarin use; and therapeutic doses (generally toxic in adults) of phenytoin, phenobarbital, trimethadione, and valproic acid. Whether these fetal malformations and intrauterine deaths would occur at nonmaterno-toxic levels of the above teratogenic agents, and, consequently, the strength of the associations could not be estimated for lack of data. However, human data seem to provide some, though weak, support and not to contradict the previous assumption formulated from animal studies that maternal toxicity may be causally related to fetal malformations and embryo-fetal mortality.