Preterm birth (PTB) is defined as all births occurring before 37 weeks of gestation (WG) by the Women Health Organization [1]. Preterm birth concerns 10.6% of livebirths worldwide in 2014 [2]. Spontaneous preterm birth (sPTB), due to spontaneous onset of labor represents 40 to 45% of PTB and premature rupture of membranes (PROM) represents 25 to 30% of preterm births [3]. To date, sPTB is the first cause of neonatal mortality and morbidity [4, 5]. The risk factors for sPTB are, a prior preterm birth, black race, periodontal disease, and low maternal body-mass index [3]. Prediction of sPTB in asymptomatic women remains a great challenge for the public health system. A short cervical length and a raised cervical-vaginal fetal fibronectin concentration are predictors of sPTB but their performance remains very low [6]. Effective and safety screening tools are still not available in clinical practice, such as the use of amniocentesis-based predictive risk models that are still under investigations [7, 8]. Early identification of women who will exhibit sPTB will allow intensification of the patient monitoring, tocolytic or vaginal progesterone medications, pessary and/or cervical cerclage placement, and decision taking for antenatal corticosteroid therapy.
Prokineticins (PROK) are secreted peptides with a capacity to control both angiogenic and inflammatory processes in humans and in other species [9–11]. The PROK family accounts two members, PROK1 and PROK2 [9]. The canonical member of this family, PROK1, is also known as Endocrine Gland-derived Vascular Endothelial Growth Factor (EG-VEGF). PROKs act through specific G protein-coupled receptors, PROK receptor 1 (PROKR1) and PROK receptor 2 (PROKR2) to control multiple biological functions such as, angiogenesis, circadian rhythm, neurogenesis of olfactory bulb, neuronal survival, reproduction, and inflammation [11]. EG-VEGF and PROKR1 are highly expressed in first trimester and in term placenta and fetal membranes [11–14]. Several studies reported increased levels of EG-VEGF and its direct involvement with its receptors in the etiology of recurrent pregnancy loss, gestational trophoblastic diseases and pregnancy pathologies such as fetal growth restriction and preeclampsia [15, 16]. These data strongly suggested that the increase in EG-VEGF levels may either contribute to the development of Placenta-Mediated Pregnancy Complications (PMC) or rather participates into the overall compensatory mechanism that occur to allow the pregnancy to progress.
In relation to preterm delivery and parturition, reports from the group of Jabbour [17–20] and from our group [12, 14] strongly suggested that deregulations in the levels of expression of members of the prokineticin family, including their receptors may be associated with the etiology of preterm and term births. In 2014, we demonstrated that circulating EG-VEGF and its expression in the fetal membranes increased towards term and significantly decreased at the time of labor [12]. In addition, the expression of its receptors exhibited the same profile towards term and an abrupt decrease at the time of labor [12]. Altogether, these results strongly suggested that EG-VEGF is a new cytokine that may act locally to ensure uterine quiescence during the third trimester of pregnancy. We believe that EG-VEGF’s contribution to the initiation of human labor is exhibited by the abrupt decrease in its levels and those of its receptors.
These findings highlight the role of EG-VEGF and its receptors as key actors that ensure quiescence of the intrauterine tissues in late pregnancy and further our understanding on their potential association with the physiopathology of preterm pregnancies. Nevertheless, no prospective study involving women at high-risk pregnancies has been conducted to determine whether EG-VEGF levels could be considered as indicators of the a subsequent occurrence of preterm birth.
The objective of this study was to determine the concentrations of EG-VEGF in the plasma of pregnant women at high risk in the second and third trimesters for the prediction of spontaneous preterm birth and the perspective of considering the usefulness of EG-VEGF as a new biomarker of sPTB.