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.

Keywords: fetus; neonate; pregnancy; prematurity; preterm birth; preterm labor; progesterone; therapeutic; tocolytic.

Figure 1

The potential mechanisms of selective P4 receptor modulator action on uterine muscle during pregnancy and term/preterm labor. (Left panel) During pregnancy, P4 liganding of P4 receptors (PR-A and PR-B) inhibits pro-inflammatory (cytokines and chemokines) and pro-contractile (CAPs) uterine genes, thereby maintaining myometrial relaxation. (Middle panel) During term and preterm labor, myometrial 20α-hydroxysteroid dehydrogenase (20α-HSD) enzyme expression and activity is upregulated, which results in local intracellular metabolism of P4 into its PR-inactive metabolite, 20α-hydroxyprogesterone (20αOHP). This leads to un-liganding of PRs (unbounding of P4). Un-liganded PR-A activates myometrial expression of pro-inflammatory and pro-contractile genes (i.e., oxtr and gja1) and induces labor contractions. (Right panel) Administration of SPRM compounds such as R5020 (aka: Promegestone), which is not a substrate for 20α-HSD, has higher affinity for PRs, longer half-life than P4, keeps the PRs constitutively liganded, maintains uterine quiescence, and prevents labor contractions. Note: this figure was created with Biorender.com.

Figure 2

Conceptual model showing BSCI actions in vivo and in vitro as a preterm labor therapeutic. (1) In vivo administration of BSCI (FX125L) using a nonhuman primate model of preterm labor induced by Group B Streptococcus (GBS) led to the powerful suppression of uterine activity and a complete blockade of PTB. BSCI treatment led to reduced maternal plasma IL-8 and IL-1β inhibited myometrial gap junction protein connexin 43 mRNA levels and reduced pro-inflammatory cytokines in amniotic fluid, chorioamniotic membrane, fetal plasma, lungs, and brain compared to GBS alone [210]. (2) Prophylactic in vivo administration of BSCI (BN83470) decreased LPS-induced PTB in pregnant mice, significantly inhibited neutrophil infiltration in the mouse myometrium, and significantly attenuated multiple cytokine/chemokine expression in maternal tissues (myometrium, decidua, plasma, and liver) [211]. (3) We hypothesize that pre-treatment with BSCI (FX125L) of human primary leukocytes isolated from peripheral blood of pregnant people will also prevent the in vitro trans-endothelial migration of neutrophils towards media containing multiple cytokines secreted from the pregnant human decidua and myometrium. Note: this figure was created with Biorender.com.

Figure 3

Conceptual model for the role of IL-1β in preterm labor and fetal inflammation. This model illustrates that IL-1β is the apex cytokine in the inflammatory cascade of preterm birth and fetal inflammatory injury, thereby presenting an attractive molecular target for drug discovery. PR-A/PR-B, P4 receptors A and B; PGs, prostaglandins; MMPs, matrix metalloproteinases; PGF_2α, prostaglandin F_2α; PLV, periventricular leukomalacia; BPD, bronchopulmonary dysplasia; and NEC, necrotizing enterocolitis. Increasing color intensity represents increasing inflammatory response. The level where Rytvela acts is identified by red arrows. Courtesy of Han Lee.

Figure 4

Schematic of non-targeted and uterine-targeted nanoliposomes. (A) The nanoliposomes are composed primarily of 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) and cholesterol but also include PEGylated lipid (PEG2000 phosphoethanolamine; ~2% of total lipids), which produces steric hindrance that improves circulation time, but without a targeting moiety. Indomethacin and lipophilic markers partition into the lipid bilayer. (B) Oxytocin receptor (OTR)-targeted nanoliposomes, whereby PEGylated 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE, ~2% of total lipids) is conjugated to either an OTR-binding antibody (via maleimide linkage) or peptide (Atosiban, via amine linkage).