Placental hormones and identification of pregnancy at risk

A plethora of hormonal changes contribute to the physiological maternal adaptations during human gestation. Placenta represents a major source of hormones playing a relevant role in maternal–foetal physiological interactions, in the reprogramming of the maternal endocrine system and in the signaling mechanisms that determine the timing of parturition [1,2].Several placental hormones are hypersecreted in maternal circulation in pathological pregnancies, and their excessive release in association with gestational diseases may be part of an adaptive response of placenta to adverse environmental conditions.

Preterm delivery (PTD) is the best example: it is defined as delivery occurring before 37 completed gestational weeks and is the major cause of neonatal morbidity and mortality in developed countries [3]. It is a syndrome initiated by several causes, representing either a breakdown in the mechanisms responsible for maintaining uterine quiescence or an overwhelming of the normal parturition cascade: (i) the uterine pathway including myometrial contractility, cervical ripening and decidua/membrane activation [4] and (ii) the endocrine pathway regulating maternal/foetal mechanisms leading to labour and delivery [5]. The maternal/foetal hypothalamus–pituitary–adrenal (HPA) axis contains all the stress hormones, corticotropin-releasing hormone (CRH), Adrenocorticotropin hormone (ACTH) and cortisol, and during pregnancy, CRH and ACTH are also secreted by placenta [6]. They regulate several biological functions including the secretion of steroid hormones such as dehydroepiandrosteronesulphate (DHEA-S) and estriol.

Stress of delivery is associated with higher maternal levels of CRH, ACTH, cortisol, DHEAS-S and estriol, thus supporting the relevance of HPA axis hormones in the adaptive response of mother and foetus [7]. The same event has been shown in PTD, resulting in very high concentration of HPA axis hormones in maternal plasma [7]. CRH and estriol maternal levels have also been found to be high prior the onset of PTD and proposed as possible predictive markers [8]. This is of high clinical relevance since the tocolytic agents are poorly effective in the treatment of PTD [8], while new therapeutic strategies may be developed when women at risk are identified. The evolution of maternal serum CRH concentrations parallels the CRH curve of normal pregnancy but the level is displaced upward [9]. This discrimination is detectable before any clinical manifestation of uterine contractility, a fact that prompted the design of controlled studies focusing on the value of second-trimester CRH levels in predicting preterm birth. Maternal plasma levels of CRH are significantly elevated as early as 18–20 weeks' gestation in women who subsequently delivered preterm. It has been shown that changes in CRH from 18 to 20 weeks' gestation and 28 to 30 weeks' gestation are associated with maternal age and stress level at 18 to 20 weeks' gestation [10]. Other studies confirm a possible value of CRH as predictive marker of PTD [11–13]. Maternal plasma CRH beyond 28 weeks is an accurate biomarker in predicting preterm birth within 48 h [14]. Although CRH maternal levels increase at mid trimester, there are no sufficient data supporting the routine clinical use of plasma CRH as a predictor of preterm labour. A previous study following a low-risk women starting at 15–20 weeks of gestation demonstrated that CRH levels were higher in the group who delivered before 34 weeks but not in the whole preterm group [15].

Moreover, it is shown that a single measurement of plasma CRH, towards the end of the second trimester, may identify a group at risk for PTD, but over 50% of such deliveries will be unpredicted [16]. Several studies evaluated the ability of maternal estriol to predict PTD in populations of asymptomatic or symptomatic women. Estriol originates almost exclusively from foetal DHEA-S [17]. Thus, estriol in the mother serves as a marker of the activity of the foetal adrenal gland. Saliva estriol levels reflect the concentrations of free, unconjugated estriol in plasma and therefore correspond to the biologically active fraction of the circulating hormone [18,19]. Several studies have shown that a single salivary estriol value higher than 2.1 ng/ml between 21 weeks and 25 weeks in asymptomatic women is associated with an increased risk of preterm birth, and in this regard the estriol measurement achieves greater sensitivity than a standard clinical test [18,19]. A potential contribution of salivary estriol measurement comes from negative tests in high-risk populations. Among patients considered at high risk, two consecutive weekly estriol tests in the normal range suggest that the patient is likely to proceed to term, either without threatened preterm labour or by responding to tocolysis [19,20]. In symptomatic women, salivary estriol is associated with an increased risk of delivery within 2 weeks, but its predictive power is modest [20,21]. Maternal serum estriol levels accurately reflect activation of the foetal HPA axis, which occurs before the onset of premature uterine contractions [17]. Recent studies demonstrates that 2 weeks before PTD there is critically altered P/E3 and E3/E2 ratios in maternal plasma that create an estrogenic environment for the onset of labour [18,21].

Recently, a new member of CRH family, urocortin (Ucn) has been described to be involved in the mechanisms leading to PTD. Maternal plasma Ucn levels are significantly higher at term and preterm labour compared with those after elective caesarean section [22]. Moreover, foetal Ucn concentrations are higher than maternal concentrations, suggesting that the foetus is a major source of Ucn. Maternal plasma Ucn levels are increased in patients with threatened preterm labour who delivered before 34 completed weeks of pregnancy [23]. At the second trimester amniocentesis, in healthy pregnancies, amniotic fluid concentration of Ucn is low in women later undergoing PTD [24].

On the basis of these evidences, it is suggested that foetus, through Ucn and placenta and through CRH secretion and estriol, deriving from foeto-placental unit, may exert its biologic roles at the time of delivery, emphasising the possible enhancement in the mechanism of PTD. In conclusion, few evidences are available to recommend the routine use of hormone tests to predict PTD but, their clinical usefulness may enhance the sensitivity of the risk assessment only based on clinical and ultrasound examination. Cervicovaginal foetal fibronectin [25] and transvaginal sonographic cervical length measurements [26] represent useful factor-predictors of PTD in clinical practice, especially when their use is combined [27]. Therefore, the goal will be to combine these multiple approaches in a predictive test for PTD.