Progestin therapy to prevent preterm birth: History and effectiveness of current strategies and development of novel approaches

Mesiano, Sam; Peters, Gregory A.; Amini, Peyvand; Wilson, Rachel; Tochtrop, Gregory P.; Akker, F. van den

doi:10.1016/j.placenta.2019.01.018

Cited by 17 publications

(13 citation statements)

References 108 publications

(91 reference statements)

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“…The first studies on the use of P4 to prevent PTB were in the 1960s, demonstrating a potential protective effect of P4 administration [184,185]. Studies of P4 as a PTB therapeutic dwindled throughout the 1990s, until two studies in 2003 reinvigorated interest in P4 as a viable preventative strategy [184,[186][187][188].…”

Section: Progesterone (P4) Analogsmentioning

confidence: 99%

Landscape of Preterm Birth Therapeutics and a Path Forward

Coler

Shynlova

Boros-Rausch

et al. 2021

JCM

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Preterm birth (PTB) remains the leading cause of infant morbidity and mortality. Despite 50 years of research, therapeutic options are limited and many lack clear efficacy. Tocolytic agents are drugs that briefly delay PTB, typically to allow antenatal corticosteroid administration for accelerating fetal lung maturity or to transfer patients to high-level care facilities. Globally, there is an unmet need for better tocolytic agents, particularly in low- and middle-income countries. Although most tocolytics, such as betamimetics and indomethacin, suppress downstream mediators of the parturition pathway, newer therapeutics are being designed to selectively target inflammatory checkpoints with the goal of providing broader and more effective tocolysis. However, the relatively small market for new PTB therapeutics and formidable regulatory hurdles have led to minimal pharmaceutical interest and a stagnant drug pipeline. In this review, we present the current landscape of PTB therapeutics, assessing the history of drug development, mechanisms of action, adverse effects, and the updated literature on drug efficacy. We also review the regulatory hurdles and other obstacles impairing novel tocolytic development. Ultimately, we present possible steps to expedite drug development and meet the growing need for effective preterm birth therapeutics.

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Section: Progesterone (P4) Analogsmentioning

confidence: 99%

Landscape of Preterm Birth Therapeutics and a Path Forward

Coler

Shynlova

Boros-Rausch

et al. 2021

JCM

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“…Beyond the scope of this review is the nuanced controversy about whether progesterone is effective for treatment of preterm birth or childhood consequences. Much has been written on this topic (150)(151)(152)(153), though far less is known about consequences on the characteristics of remodeling or immune cells in the cervix. In mice, progesterone or progestational agents clearly regulate inflammatory characteristics associated with cervix remodeling (Figure 2 as discussed earlier).…”

Section: Immunobiologic Perspective On Cervix Remodeling With Pretermmentioning

confidence: 99%

Immunobiology of Cervix Ripening

Yellon

2020

Front. Immunol.

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The cervix is the essential gatekeeper for birth. Incomplete cervix remodeling contributes to problems with delivery at or post-term while preterm birth is a major factor in perinatal morbidity and mortality in newborns. Lack of cervix biopsies from women during the period preceding term or preterm birth have led to use of rodent models to advanced understanding of the mechanism for prepartum cervix remodeling. The critical transition from a soft cervix to a compliant prepartum lower uterine segment has only recently been recognized to occur in various mammalian species when progesterone in circulation is at or near the peak of pregnancy in preparation for birth. In rodents, characterization of ripening resembles an inflammatory process with a temporal coincidence of decreased density of cell nuclei, decline in cross-linked extracellular collagen, and increased presence of macrophages in the cervix. Although a role for inflammation in parturition and cervix remodeling is not a new concept, a comprehensive examination of literature in this review reveals that many conclusions are drawn from comparisons before and after ripening has occurred, not during the process. The present review focuses on essential phenotypes and functions of resident myeloid and possibly other immune cells to bridge the gap with evidence that specific biomarkers may assess the progress of ripening both at term and with preterm birth. Moreover, use of endpoints to determine the effectiveness of various therapeutic approaches to forestall remodeling and reduce risks for preterm birth, or facilitate ripening to promote parturition will improve the postpartum well-being of mothers and newborns. The maternal immune system in mammals adapts to tolerate the differentiation of novel structures associated with the fetal allograft. Development of two interfaces protect the fetus from rejection and assault by the ecology of the external environment. The internal fetal-maternal interface, as represented by the fetal membranes, placenta, and decidua, is crucial for maintaining maternal inflammatory reactivity for surveillance and responses to pathogens. Discussion of the internal interface is elsewhere and in this special volume (1-3). However, the present review is focused on the external fetal-maternal interface consisting of an amniotic fluid buffer, in a forebag region later in pregnancy as the fetal head engages the lower uterus, and the fetal membranes as they press against the internal os of the cervix. This description of a singleton pregnancy in primates near term applies to rodents, despite anatomical differences in the uterus described below, because observations indicate a single fetal sac engages the internal os of the cervix shortly before labor. The success of this external interface to fend off the biome and virome in the vagina reflects the barrier function of the cervix to protect both the fetus and maternal host structures in the uterus. The cervix barrier function has both immunological and structural components. One part of the mate...

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“…There has been a growing advancement in the understanding of progesterone signaling pathways lately, which has shed light into novel targets for progestin-based therapies to prevent PTB. It has been suggested that new selective progestin agents can boost anti-inflammatory activities that prevent preterm labor [ 17 ].…”

Section: Discussionmentioning

confidence: 99%

Comparison of oral Dydrogesterone and 17-α hydroxyprogesterone caprate in the prevention of preterm birth

Alizadeh

Mahmoudinia

Mirteimoori

et al. 2022

BMC Pregnancy Childbirth

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Background Preterm birth (PTB) remains a significant problem in obstetric care. Progesterone supplements are believed to reduce the rate of preterm labor, but formulation, type of administration, and dosage varies in different studies. This study was performed to compare oral Dydrogesterone with intramuscular 17α-hydroxyprogesterone caproate (17α-OHPC) administration in prevention of PTB. Methods In this randomized clinical trial, we studied 150 women with singleton pregnancy in 28Th-34Th Gestational week, who had received tocolytic treatment for preterm labor. Participants were divided to receive 30 mg oral Dydrogesterone daily, 250 mg intramuscular 17α-OHPC weekly, or no intervention (control group). All treatments were continued until 37Th Week or delivery, whichever occurred earlier. Obstetric outcomes, including latency period, gestational age at delivery, birth weight, neonatal intensive care unit (NICU) admission, and neonatal mortality were recorded. All patients were monitored biweekly until delivery. Results Baseline gestational age was not significantly different between groups. Latency period was significantly longer in the progesterone group compared with Dydrogesterone and control groups (41.06 ± 17.29 vs. 29.44 ± 15.6 and 22.20 ± 4.51 days, respectively; P < 0.001). The progesterone group showed significantly better results compared with the other two groups, in terms of gestational age at delivery, birth weight, and Apgar score (P < 0.001). None of the participants showed severe complications, stillbirth, or gestational diabetes. Conclusion Progesterone caproate can strongly prolong the latency period and improve neonatal outcomes and therefore, is superior to oral Dydrogesterone in the prevention of PTB.

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Progestin therapy to prevent preterm birth: History and effectiveness of current strategies and development of novel approaches

Cited by 17 publications

References 108 publications

Landscape of Preterm Birth Therapeutics and a Path Forward

Landscape of Preterm Birth Therapeutics and a Path Forward

Immunobiology of Cervix Ripening

Comparison of oral Dydrogesterone and 17-α hydroxyprogesterone caprate in the prevention of preterm birth

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