Atenolol developmental toxicity: animal-to-human comparisons

Atenolol, 4-2'-hydroxy-3'-isopropyl-aminopropoxy) phenylacetamide, is a beta-adrenoreceptor blocker used for treatment of hypertension in pregnancy. Beta-blockers are reported to cause fetal harm (such as decreased birth weight) when administered to a pregnant woman. We evaluate published human and animal evidence of atenolol developmental toxicity and compare the manifestations in humans and in routinely-used animal models.

The comparison is based on the following criteria: comparability of pharmacokinetic/pharmacodynamic characteristics, type of adverse outcome, lowest adverse effect levels, and specificity and selectivity of effect.

Manifestations of atenolol prenatal toxicity (placental changes, intrauterine growth retardation and changes in fetal weight in the absence of structural malformations) are similar in the tested animal species (rats and rabbits) and humans. The human seems to be more sensitive, however, because adverse embryo-fetal effects are reported at doses much lower than those in the tested species. In humans and rats, adverse embryo-fetal effects are induced by doses that are not maternally toxic. In the rabbit, however, such effects are seen only at maternally toxic doses, suggesting that in this species, developmental toxicity may be maternally mediated.

The available data suggest animal-human concordance with regard to the nature and manifestations of atenolol prenatal toxicity. The animal models "predicted" developmental toxicity manifests as placental changes, intrauterine growth retardation and fetal weight decrease in the absence of structural malformations. Thus far, this is concordant with the data from humans, in whom intrauterine growth retardation has been observed but not structural abnormalities.