Maternal caffeine consumption during pregnancy does not affect preimplantation development but delays early postimplantation growth in rat embryos

Models for studying prenatal drug-induced intrauterine growth retardation (IUGR) have, without exception, measured growth-related factors in the postimplantation embryo, fetus or neonate. Therefore, it is not known whether effects of drug exposure on growth and metabolism begin early in the preimplantation embryo, or whether IUGR is exclusively a postimplantation phenomenon. The present study investigates whether caffeine, a drug known to induce a dose-dependent fetal IUGR, affects embryo development before and/or after implantation or is exclusively a fetal phenomenon. Preimplantation embryo assessment (with treatment from Days 2 to 4 of pregnancy) included glucose utilization, cell number evaluation and stage of development (morula to hatched blastocyst); whereas, postimplantation embryo assessment (treatment from Days 2 to 10, 10.5 or 11 of pregnancy) included somite number evaluation and extent of neural tube closure, as seen using scanning electron microscopy. Comparing control preimplantation embryos with those exposed to 30 and 60 mg kg^-1 caffeine did not reveal any effects of caffeine exposure, as assessed on Day 5 of gestation. However, postimplantation embryo development assessed on Day 12 of gestation revealed that caffeine exposure of 15 and 30 mg kg^-1 significantly reduced, at both dosage levels, somite number and the extent of neural tube closure. In addition, comparisons of control and experimental groups revealed that in the high-dose caffeine group the forebrain cavity was significantly enlarged and bounded by a reduced, irregularly aligned neuroepithelium. The findings suggest that IUGR is a phenomenon first identifiable during late postimplantation embryogenesis and continues in fetal life.