Fetal-to-maternal signaling in the timing of birth

Abstract

Preterm birth remains the major cause of neonatal morbidity and mortality throughout the world. This is due, in part, to our incomplete understanding of the mechanisms that underlie the maintenance of pregnancy and the initiation of parturition at term. In this article, we review our current knowledge of the complex, interrelated and concerted mechanisms whereby progesterone maintains myometrial quiescence throughout most of pregnancy, as well as those that mediate the upregulation of the inflammatory response and decline in progesterone receptor function leading to parturition. Herein, we review findings that demonstrate a role of the fetus in the timing of birth. Specifically, we focus on our own studies indicating that maturation of the fetal lung and enhanced secretion of the surfactant components, surfactant protein A (SP-A), and the potent inflammatory glycerophospholipid, platelet-activating factor (PAF) initiate a signaling cascade culminating in parturition. Our studies suggest an essential role of steroid receptor coactivators, SRC-1 and SRC-2, which activate expression of genes encoding SP-A and LPCAT1. LPCAT1 is a key enzyme in the synthesis of PAF, as well as DPPC, a highly surface-active glycerophospholipid component of surfactant. Thus, we describe a novel pathway through which the fetus contributes to the initiation of labor by signaling the mother when its lungs have achieved sufficient maturity for survival in an aerobic environment.

Estimated date of delivery based on second trimester fetal head circumference: A population‐based validation of 21 451 deliveries

“…12 Such systematically skewed bias 23,24 could not be shown in the current study of second trimester HC dating. 28 Several hormonal axes are thought to be involved in the initiation of parturition on the one side, 27 and on the other side are targets for psycho-neuro-immunological modulation during pregnancy. 23,24 The pregnant women had been assigned and informed about an EDD based on a different term prediction model.…”

“…23,24 The pregnant women had been assigned and informed about an EDD based on a different term prediction model. This approach ignores the complexity of the initiation of labor in humans, 27 which is far from well understood. Psychological stress during pregnancy is associated with preterm delivery and has been estimated to account for 23%-27% of the variance in gestational age at birth.…”

“…Psychological stress during pregnancy is associated with preterm delivery and has been estimated to account for 23%-27% of the variance in gestational age at birth. 28 Several hormonal axes are thought to be involved in the initiation of parturition on the one side, 27 and on the other side are targets for psycho-neuro-immunological modulation during pregnancy. 29 Thus, maternal expectations of the given due date may affect the initiation of parturition.…”

Spontaneous premature birth as a target of genomic research

“…promote labor (21). In human pregnancy, the appearance of SP-A in amniotic fluid and the onset of labor may not coincide (22).…”

Progesterone Receptor Signaling in Uterine Myometrial Physiology and Preterm Birth

“…Emerging evidence suggests that the prostaglandin-STAR pathway is modulated in part by fetal-maternal crosstalk via Surfactant Protein-A and Platelet-Activating Factor that are secreted by fetal lungs under the control of Steroid Receptor Coactivators 1 and 2 (SRC-1 and SRC-2) (Gao et al, 2015). It is proposed that, at maturation, signals from fetal lungs down-regulate ovarian P4 synthesis that leads to reduction of P4 signaling, and subsequent initiation of parturition (Mendelson et al, 2016). Moreover, prostaglandin also elevates transcription factor Nur77 (also known as nuclear receptor subfamily 4, group A, member 1, Nr4a1 ) levels to promote expression of 20α-hydroxysteroid dehydrogenase (20α-HSD, also known as aldo-keto reductase family 1, member C18, Akr1c18 ) for P4 degradation (Stocco et al, 2000).…”