A Blood Test to Predict Preterm Birth: Don’t Mess with Maternal-Fetal Stress

The timely onset of labor and birth is a critical determinant of perinatal outcome. The mean duration of human pregnancy is 40 wk (280 d) from the first day of the last normal menstrual period. Both preterm birth (PTB; defined as delivery before 37 wk gestation) and postterm pregnancy (delivery after 42 wk) are associated with adverse perinatal outcome. In developed countries, PTB complicates 7–12% of all deliveries but accounts for over 70% of perinatal morbidity and mortality (1). Although the incidence of PTB has continued to rise every year for the past three decades, perinatal survival and intact survival have increased steadily during this same time period due in large part to the appropriate and timely use of antenatal corticosteroids and to improvements in neonatal resuscitation and infant care. For these reasons, early and accurate identification of women at risk of PTB is critical to optimize perinatal outcome. Early identification of women at risk will become even more important if recent reports on the use of progesterone supplementation to prevent PTB can be replicated (2–4). Obstetric care providers have traditionally relied on clinical symptoms (regular uterine contractions, pelvic pressure) to identify women at risk of spontaneous PTB. Numerous studies have now shown that reliance on clinical symptoms alone is inaccurate and unreliable. Such an approach will fail to identify the majority of womenwhodeliverpreterm(5), and, contrary topopularbelief, the presence of symptoms is not associated with an increased risk of spontaneous PTB (6, 7). For these reasons, extensive efforts have been made to develop objective tests to identify women at risk of PTB. Two such tests are currently recommended by the American College of Obstetricians and Gynecologists (ACOG) for the prediction of PTB, namely cervicovaginal fetal fibronectin (fFN) and measurement of cervical length by transvaginal ultrasound (8). A number of other predictive tests are under investigation, the most promising of which are measurements of steroid and stress hormones in the maternal circulation. The biological plausibility behind the use of maternal serum stress and sex steroid hormone levels to predict PTB is well established. Considerable evidence suggests that the hormonal milieu of the fetoplacental unit is in control of the timing of labor, although maternal and genetic factors are also involved (9–11). It is likely that a “parturition cascade” exists at term that is responsible for the removal of mechanisms maintaining uterine quiescence and the recruitment of factors acting to promote uterine activity. Although a detailed review of the proposed cascade is beyond the scope of this editorial, it is clear that endocrine factors are involved. As in other mammalian viviparous species, the final common pathway toward parturition in the human appears to be maturation and activation of the fetal hypothalamic-pituitary-adrenal (HPA) axis, with an increase in the major adrenal glucocorticoid product in the fetal circulation in late gestation (cortisol in the sheep and human; corticosterone in the rat and mouse). The cellular and molecular factors responsible for the maturation of the fetal HPA axis are incompletely understood, but are associated with the gestational age-dependent up-regulation of a number of critical genes, most importantly fetoplacental CRH. Levels of CRH in the maternal circulation increase from 10–100 pg/ml in nonpregnant women to 500–3,000 pg/ml in the third trimester of pregnancy (12). The source of this excess CRH is the placenta. Shortly before the onset of labor, both at term and preterm, CRH levels increase and hepatic-derived CRH-binding protein levels decrease, resulting in a marked increase in free (biologically active) CRH (13). CRH, in turn, acts via specific nuclear receptors in the myometrium, placenta, and fetal membranes to differentially regulate target genes. Among its effects on term uterine tissues, CRH promotes myometrial contractility by stimulating prostaglandin production from the decidua and fetal membranes (14) and potentiates the contractile effects of oxytocin and prostaglandins on the myometrium (15). At term, CRH also directly stimulates the production of the C-19 steroid, dehydroepiandrostenedione sulfate, from the intermediate (fetal) zone of the fetal adrenal glands (16, 17). Dehydroepiandrostenedione sulfate is then 16-hydroxylated in the fetal liver and converted to estriol