Next generation strategies for preventing preterm birth

Abstract

Preterm birth (PTB) is defined as delivery before 37 weeks of gestation. Globally, 15 million infants are born prematurely, putting these children at an increased risk of mortality and lifelong health challenges. Currently in the U.S., there is only one FDA approved therapy for the prevention of preterm birth. Makena is an intramuscular progestin injection given to women who have experienced a premature delivery in the past. Recently, however, Makena failed a confirmatory trial, resulting the Center for Drug Evaluation and Research's (CDER) recommendation for the FDA to withdrawal Makena's approval. This recommendation would leave clinicians with no therapeutic options for preventing PTB. Here, we outline recent interdisciplinary efforts involving physicians, pharmacologists, biologists, chemists, and engineers to understand risk factors associated with PTB, to define mechanisms that contribute to PTB, and to develop next generation therapies for preventing PTB. These advances have the potential to better identify women at risk for PTB, prevent the onset of premature labor, and, ultimately, save infant lives.

Keywords: Drug delivery; Nanomedicine; Nanoparticles; Pregnancy; Preterm birth; Vaginal drug delivery.

Figure 1:

Labeled schematic of the womb.

Figure 2:

Risk factors associated with preterm birth include short sonographic cervix, a previous spontaneous preterm birth, bacterial vaginosis, the presence of fetal fibronectin in cervicovaginal fluid, the use of tobacco and/or narcotics, and high levels of stress during pregnancy. Despite these associations, it remains difficult to predict, and prevent preterm birth.

Figure 3:

Preclinical animal models of PTB have been useful for understanding mechanisms of PTB, as well as for testing therapies capable of preventing PTB.

Figure 4:

A summary of drug candidates and formulations used in recent clinical and preclinical PTB prevention studies. Further work should be done to understand drug mechanisms and optimal formulations to best prevent PTB.

Figure 5:

Drug administration during pregnancy is altered due to changes in maternal physiology. These changes must be taken into account when considering drugs, formulations, and dosing regimens for PTB prevention.

Figure 6:

(A) Schematic of oxytocin receptor targeted liposome structure. (B) Fluorescent detection of in vivo liposome biodistribution. Systemically delivered non-targeted liposomes were transported to the liver, whereas systemically delivered oxytocin receptor-targeted liposomes were transported to the uterus. (C-E) Contraction traces for mouse uterine tissue after systemic administration of (C) oxytocin receptor (OTR)-targeted, drug-free liposomes, (D) salbutamol (SAL) loaded non-targeted liposomes, or (E) OTR-targeted SAL-loaded liposomes. The effects of the OTR-targeted SAL-loaded liposomes was reversed after tissue washing and contractions resumed. Reprinted with permission from Paul, et al. [149]

Figure 7:

Ex vivo fluorescent imaging and immunohistochemistry to monitor trafficking of Cy5-labeled dendrimer (DCy5). On gestational day 17 (E17), pregnant CD-1 dams were given intrauterine injections of LPS or PBS. DCy5 (10 mg/kg) was administered intraperitoneally 1 hour later. After 6 hours, uterus and embryos were isolated, imaged to monitor the fluorescent signal from DCy5, and prepared for histochemical verification. (A) Histochemistry confirmed the presence of DCy5 in the maternal side of the placenta. (D) DCy5 was present in the fetal tissue of the placenta, but was restricted to the yolk sac membranes. The presence of DCy5 in the yolk sac increased with LPS exposure. Images are 40× magnifications, and scale bars represent 50 μm. Reprinted with permission from Lei, et al. [198]

Figure 8:

Area under the curve (AUC) in plasma, cervix, proximal uterus, and distal uterus for up to 6 h (AUC_0–6) and over 24 h (AUC_last) after a single vaginal dose of Crinone gel (“Gel”, black bars) or an equivalent dose of progesterone nanosuspension (“NS”, white bars) administered to healthy pregnant mice on embryonic day 15 (E15). Data is presented as average ± SE for n=4–5 mice per time point. * p < .05, ** p < .01, *** p < .001. Reprinted with permission from Hoang, et al. [52]

Figure 9:

Cervical tissue sections stained with (A) mucicarmine to visualize mucus and (B) hematoxylin & eosin (H&E) to examine cell/tissue histology. 12 h after vaginal gel (Crinone) dosing, there was a marked decrease in the amount of secreted mucus and evidence of cell apoptosis (marked in images with black arrowheads). The cervical changes observed with vaginal gel treatment were not evident in healthy E15 mice, RU-486 treated E15 mice injection, healthy E19 mice, or in NS treated E15 mice. Images are representative of n = 6 total mice from 2 replicates (mucicarmine) and n = 3 mice (H&E) per group. Scale bars = 50 μm. Reprinted with permission from Hoang, et al. [52]

Figure 10:

(A) In an adapted model of inflammation induced PTB, neither Crinone nor Makena were able to prevent PTB. (B) In the same model, a combination of vaginal nanosuspensions of progesterone and trichostatin A were able to prevent PTB, whereas an intraperitoneal injection of the same drugs did not prevent PTB. (C) In an in vitro model, the same concentrations of progesterone and trichostatin A that prevented PTB in mice, prevented human myometrial cell contractions. Reprinted with permission from Zierden, et al. [150]