Landscape of Preterm Birth Therapeutics and a Path Forward

Abstract

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.

Social Isolation Stress Modulates Pregnancy Outcomes and the Inflammatory Profile of Rat Uterus

“…Preterm labour is a complication that remains the leading cause of death during infancy with potentially lifelong neurodevelopmental and chronic consequences [ 49 , 50 ]. Current PTB therapeutics cannot provide a long-lasting delay of PTB and are ineffective in reducing neonatal morbidities [ 51 ]. Our primary finding was that SIS reduces pregnancy duration of the parental generation but not enough to cause PTB.…”

A Leukocyte Migration Assay Assists Understanding of Interleukin-1β-Induced Leukocyte Migration Into Preterm Mouse Uterus

“…The translational implications of this work are significant. Rytvela, our IL-1R allosteric inhibitor, is a formidable therapeutic candidate against PTB and the accompanying long-term physiological consequences on the offspring ( Nadeau-Vallee et al, 2017 ; Coler et al, 2021 ; Leimert et al, 2021 ). It selectively inhibits IL-1R signaling down the mitogen-activated protein kinase/p38 pathway that signals for the amplification of the inflammatory cascade that leads to parturition ( Nadeau-Vallee et al, 2015 ).…”

The contribution of racism-related stress and adversity to disparities in birth outcomes: evidence and research recommendations

“…Another area that requires more research is on mechanisms through which racism-related stress and adversity impact birth outcomes. Importantly, biomechanisms linking stress to adverse birth outcomes have been identified ( 64 , 65 , 66 , 67 ), and some of these biological profiles have also been associated with racism-related stress, including altered endocrine function (e.g., placental corticotropin-releasing hormone and cortisol), impaired immune function, and cardiovascular profiles ( 68 , 69 , 70 , 71 , 72 , 73 , 74 ). The prenatal maternal microbiome (including vaginal, gut, oral, and cervical) is also gaining increasing recognition for its relation to experiences of stress and adversity, birth outcomes, and fetal development ( 64 , 75 , 76 ).…”