We report the existence of a 'placental clock', which is active from an early stage in human pregnancy and determines the length of gestation and the timing of parturition and delivery. Using a prospective, longitudinal cohort study of 485 pregnant women we have demonstrated that placental secretion of corticotropin-releasing hormone (CRH) is a marker of this process and that measurement of the maternal plasma CRH concentration as early as 16-20 weeks of gestation identifies groups of women who are destined to experience normal term, preterm or post-term delivery. Further, we report that the exponential rise in maternal plasma CRH concentrations with advancing pregnancy is associated with a concomitant fall in concentrations of the specific CRH binding protein in late pregnancy, leading to a rapid increase in circulating levels of bioavailable CRH at a time that coincides with the onset of parturition, suggesting that CRH may act directly as a trigger for parturition in humans.

Asthma during pregnancy is associated with a low birth weight, although the mechanisms contributing to this outcome remain unknown. The relationship between maternal asthma and its treatment, placental function, fetal sex, and low birth weight was examined to establish the effect of asthma on fetal growth. Glucocorticoid intake by women with asthma was assessed throughout pregnancy. The placenta was collected after delivery, and 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) activity was measured. Fetal cortisol and estriol were measured in the umbilical vein plasma at delivery. Those with asthma were compared with a nonasthmatic control group. In women with asthma who did not use inhaled steroids and were pregnant with a female fetus, we observed significantly reduced birth weights, whereas male birth weights were unaffected. The presence of a female fetus was associated with significantly increased maternal circulating monocytes, significantly reduced placental 11beta-HSD2 activity and fetal estriol, and a trend toward elevated fetal plasma cortisol. This study provides evidence that in pregnancies complicated by asthma there is a fetal sex-specific effect on the maternal immune system with adverse effects on placental function and female fetal growth.

The very rapid rise of CRH in late pregnancy is associated with an E3 surge and critically altered P/E3 and E3/E2 ratios that create an estrogenic environment at the onset of labor. Our evidence provides a rationale for the use of CRH in predicting preterm birth and informs approaches to delaying labor using P supplementation.

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