Preterm Birth and Corticotrophin-Releasing Hormone as a Placental Clock

Abstract

Preterm birth worldwide remains a significant cause of neonatal morbidity and mortality, yet the exact mechanisms of preterm parturition remain unclear. Preterm birth is not a single condition, but rather a syndrome with a multifactorial etiology. This multifactorial nature explains why individual predictive measures for preterm birth have had limited sensitivity and specificity. One proposed pathway for preterm birth is via placentally synthesized corticotrophin-releasing hormone (CRH). CRH is a peptide hormone that increases exponentially in pregnancy and has been implicated in preterm birth because of its endocrine, autocrine, and paracrine roles. CRH has actions that increase placental production of estriol and of the transcription factor nuclear factor-κB, that likely play a key role in activating the myometrium. CRH has been proposed as part of a placental clock, with early activation of placental production resulting in preterm birth. This article will review the current understanding of preterm birth, CRH as an initiator of human parturition, and the evidence regarding the use of CRH in the prediction of preterm birth.

Keywords: corticotrophin-releasing hormone; parturition; placental clock; preterm birth.

Figure 1.

Potential compartments and pathologic pathway(s) involved in preterm birth. Preventive treatment(s) of preterm birth are also shown.

Figure 2.

Regulatory elements in the CRH gene in humans. An endogenous retrovirus long-term repeat enhancer sequence (ERV-LTR), NF-κB enhancer sequence, negative glucocorticoid response element (nGRE), cAMP response element (CRE), caudal-type homeobox response element (CDXRE), and a TATA element are present in the promoter region of the human CRH gene.

Figure 3.

CRH pathways and feedback loops in the maternal, placental, and fetal compartments. Solid lines represent potential roles for CRH in parturition. Dashed lines represent positive feedback loops that could lead to progressive amplification of CRH. Adapted from Herrera 2021.