Interactions in developmental toxicology: Combined action of restraint stress, caffeine, and aspirin in pregnant mice

Background Stress can result in an increased use of substances such as caffeine and aspirin. The effect of maternal stress on concurrent exposure to caffeine and aspirin on prenatal development was assessed in mice. Methods On gestational day 9, mice were assigned to three treatment groups orally exposed to caffeine (30 mg/kg), aspirin (250 mg/kg), or a combination of caffeine (30 mg/kg) and aspirin (250 mg/kg). Three additional groups of pregnant animals received similar caffeine and aspirin doses and were immediately subjected to restraint for 14 hr. Control groups included unrestrained and restrained pregnant mice not exposed to caffeine or aspirin. All dams were euthanized on gestational day 18. Live fetuses were evaluated for sex, body weight, and external, internal, and skeletal malformations and variations. Results A single oral dose of caffeine or aspirin did not cause significant maternal toxicity. However, coadministration of these drugs with restraint produced some adverse maternal effects (i.e., reduction in maternal weight gain and food consumption on gestational days 9–11). In relation to embryo/fetal toxicity, the incidence of some skeletal defects was significantly increased after exposure to caffeine, aspirin, or maternal restraint, and their binary and ternary combinations. Conclusions Although caffeine and aspirin were given in a single dose in this study, the results suggest that prenatal stress could slightly exacerbate the maternal and developmental toxicity of the combination of these drugs in mice. Teratology 63:144–151, 2001. © 2001 Wiley-Liss, Inc.