Corticotropin-releasing hormone was measured in the plasma of 110 pregnant women and in the umbilical cord plasma of 25 premature infants and 43 infants born at term. Mean maternal plasma corticotropin-releasing hormone was undetectable (less than 41 pg/ml) until mid-second trimester, rose to a mean of 204 +/- 24 pg/ml by 30 weeks' gestation, to 326 +/- 41 by 35 weeks, and then rose sharply near term, with a mean of 2930 pg/ml at 38 to 40 weeks' gestation. Sequential measurements in seven pregnant women confirmed that plasma corticotropin-releasing hormone rose in a predictable pattern, with a dramatic increase in the final weeks of pregnancy. There was little hour-to-hour variability in maternal plasma concentrations. Corticotropin-releasing hormone was also detectable in umbilical cord plasma; mean corticotropin-releasing hormone was 194 +/- 44 in the preterm infants and 150 +/- 19 in the term infants. The corticotropin-releasing hormone extracted from both the maternal and fetal circulation was biologically active in vitro and caused the dose-dependent release of adrenocorticotropic hormone and beta-endorphin from cultured rat anterior pituitary cells. A significant correlation was found between maternal plasma corticotropin-releasing hormone and cortisol levels the morning after betamethasone administration, a finding that supports a physiologic role for maternal plasma corticotropin-releasing hormone. We conclude that the placenta secretes large amounts of biologically active corticotropin-releasing hormone into both the maternal and fetal circulation during pregnancy. We demonstrate that this corticotropin-releasing hormone is secreted into the maternal plasma in a reproducible pattern during normal term pregnancy and suggest that sequential corticotropin-releasing hormone measurements may prove to be of clinical utility. In addition, placental corticotropin-releasing hormone may be an important modulator of the hypothalamic-pituitary-adrenal axis during pregnancy.