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The cerebra of fetal rats from dams given 0.04 or 0.02% caffeine in drinking water ad libitum before and/or during pregnancy were examined on gestational day 21. A low placental weight was induced by caffeine ingestion for a long time throughout premating and pregnancy. A greater reduction in the fetal weight of the cerebrum than that of the body was observed with caffeine ingestion during pregnancy of levels of 1.5–3.0 μg caffeine/ml or g wet weight in dams and fetuses. In the cerebra of offspring, the levels of caffeine and theophylline did not change for 4 h after birth, and theophylline was not detected at all after intraperitoneal injection of caffeine. Thus, maternal caffeine should be warned against the fetal cerebral function.

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At various gestational periods, caffeine was injected intra-arterially or intraperitoneally into pregnant rats. The teratogenic effects of caffeine on the fetal heart were dose dependent and detectable at relatively low concentrations. The most susceptible stage was during septation of the heart. The most common cardiovascular malformation was ventricular septa1 defect. Extracardiovascular anomalies, such as decreased thymic weight and degeneration of the lens, were found in all fetuses; skeletal malformations were found in some fetuses.

As a possible preventative measure for brain dysfunction in the fetal alcohol syndrome, the effect of zinc or vitamin E supplementation together with ethanol on the fetal cerebrum was investigated in rats. Contrary to our previously published data showing the good effect of 0.01% zinc with 30% ethanol on fetuses, the administration of 0.01% zinc with 20% ethanol, 0.03% vitamin E with 20% ethanol or 0.02% vitamin E with 10% ethanol during pregnancy did not result in a good effect on the body and cerebral weights of fetuses on gestational day 21. The development of dendritic branches on frontal cerebral neurons in fetuses was decreased in the order of the control, zinc with ethanol and ethanol groups. The concentration and content of α-tocopherol were increased, but those of zinc were not, in the fetal cerebrum with the maternal administration of vitamin E or zinc together with ethanol, respectively. These results suggest that the improvement of the brain function might depend on the deficient agent induced by maternal ethanol ingestion.

The pharmacokinetics of caffeine and its metabolites were studied in pregnant rats in order to clarify the effects of maternal caffeine ingestion on the caffeine disposition. On gestational day 18 the single intravenous or oral 10 mg/kg dose of caffeine was administered to pregnant rats who had received drinking water containing 0.04% caffeine or water ad lib during the premating and/or pregnant periods. Concentrations of caffeine and its dimethylxanthines were simultaneously determined by high-performance liquid chromatography. The caffeine plasma concentration-time curves were analyzed by assumption of a one-compartment model. The apparent volume of distribution of caffeine in rats given caffeine only during pregnancy was decreased. The elimination rate constant (kel) of caffeine in most of the rats taking caffeine during pregnancy was increased. The rats which had received caffeine throughout the premating and pregnant periods had a relatively high total body plasma clearance (CL) of caffeine. The kel and the CL widely varied in the rats taking caffeine during pregnancy. The individual values of kel or CL in pregnant rats were significantly correlated with the molar concentration ratios of the metabolites to caffeine in plasma at 8 h after administration of caffeine. It is concluded that the caffeine disposition is influenced by the different modes of maternal caffeine ingestion during the premating and/or pregnant periods.