Caffeine-induced limb malformations: Description of malformations and quantitation of placental transfer

Caffeine was administered intraperitoneally to CD‐1 mice on days 11 and 12 of pregnancy at doses of 80–250 mg/kg. A dose‐related pattern of malformations was seen that included mainly cleft palate, limb malformations, and hematomas. Many of the limb malformations were examined in preparations stained for cartilage and bone and a number of unique structural arrangements were found. As in previous studies, an asymmetric response was seen, the left limbs being affected more often than the right. Transplacental passage of caffeine was also studied. Caffeine and many metabolites pass into the embryo and attain concentrations slightly below those in maternal plasma. A peak caffeine concentration of 1 mM is attained after a teratogenic dose, which is at least an order of magnitude greater than that of any of the metabolites.