We sought to determine the effect of maternal infections on the fetal hypothalamic-pituitary-adrenal axis. Umbilical cord blood was collected at vaginal delivery after labor (24-44 wk. gestation) from 361 infants of women having normal pregnancy (apart from preterm delivery in some) and 110 infants of women diagnosed with infections: 86% of these women had amnionitis. Infants exposed to antenatal corticosteroids, being growth retarded, or having developmental abnormalities that would be expected to alter function of the hypothalamic-pituitary unit were excluded. Umbilical cord serum was assayed for dehydroepiandrosterone sulfate (DS) and for cortisol. The data were analyzed by use of SAS. The gestational age of the infants of normal women (35.8 ± 0.2 wk., Mean ± SE) was greater than that of the infants of women having infections (34.3 ± 0.4 wk., P = 0.003). Umbilical cord serum levels of DS and cortisol rose as a function of gestational age in both groups of infants (P<0.01). Despite being, on average, 1 wk younger than the normal infants are, the infants of women having infections during pregnancy had higher serum levels of cortisol and DS than did those infants of the normal women. These data are consistent with activation of the fetal hypothalamic-pituitary-adrenal axis in pregnancies complicated by maternal infections. Such a fetal response could be the consequence of transplacental passage of products of the activated maternal immune system.