Spontaneous preterm birth: Involvement of multiple feto-maternal tissues and organ systems, differing mechanisms, and pathways

Abstract

Survivors of preterm birth struggle with multitudes of disabilities due to improper in utero programming of various tissues and organ systems contributing to adult-onset diseases at a very early stage of their lives. Therefore, the persistent rates of low birth weight (birth weight < 2,500 grams), as well as rates of neonatal and maternal morbidities and mortalities, need to be addressed. Active research throughout the years has provided us with multiple theories regarding the risk factors, initiators, biomarkers, and clinical manifestations of spontaneous preterm birth. Fetal organs, like the placenta and fetal membranes, and maternal tissues and organs, like the decidua, myometrium, and cervix, have all been shown to uniquely respond to specific exogenous or endogenous risk factors. These uniquely contribute to dynamic changes at the molecular and cellular levels to effect preterm labor pathways leading to delivery. Multiple intervention targets in these different tissues and organs have been successfully tested in preclinical trials to reduce the individual impacts on promoting preterm birth. However, these preclinical trial data have not been effectively translated into developing biomarkers of high-risk individuals for an early diagnosis of the disease. This becomes more evident when examining the current global rate of preterm birth, which remains staggeringly high despite years of research. We postulate that studying each tissue and organ in silos, as how the majority of research has been conducted in the past years, is unlikely to address the network interaction between various systems leading to a synchronized activity during either term or preterm labor and delivery. To address current limitations, this review proposes an integrated approach to studying various tissues and organs involved in the maintenance of normal pregnancy, promotion of normal parturition, and more importantly, contributions towards preterm birth. We also stress the need for biological models that allows for concomitant observation and analysis of interactions, rather than focusing on these tissues and organ in silos.

Keywords: early delivery; inflammation; parturition; pregnancy; premature labor; preterm birth.

Figure 1

Disease states in the placenta contributing to preterm birth. Placental inflammation, endocrine dysfunction, and uteroplacental insufficiency can lead to inflammatory activation and propagation of inflammatory mediators towards other gestational tissues. CRH may play the predominant role in these placental disease states, with inflammation providing a feed-forward mechanism. This figure was created with BioRender.com.

Figure 2

Disease states in the fetal membranes contribute to preterm birth. Premature membrane senescence, chorioamnionitis, and uterine overdistension can all lead to dysfunctional membrane remodeling, generation of danger signals (senescence-associated secretory phenotype [SASP], and damage associate molecular pattern markers [DAMPs], and chemotaxis and immune cell activation. The localized presence of danger signals provides greater contributions toward untimely membrane rupture, while immune cell activation in the presence of danger signals may cause myometrial activation. This figure was created with BioRender.com.

Figure 3

Disease states in the decidua contribute to preterm birth. Deciduitis, decidual hemorrhage, and premature decidual senescence all eventually converge towards premature decidual activation characterized by leukocyte activation, inflammatory mediator production, and decidual apoptosis. This figure was created with BioRender.com.

Figure 4

Disease states in the myometrium contribute to preterm birth. Uterine overdistension and myometrial hemorrhage, and to a lesser extent, oxidative stress, may all lead to myometrial activation that produces contractions. This figure was created with BioRender.com.

Figure 5

Disease states in the cervix contribute to preterm birth. Cervical insufficiency and cervicitis may lead to localized inflammatory responses that can propagate towards other tissues. Similarly, a weakened epithelium may allow passage of bacteria leading to ascending infection, which also causes inflammation in seeded gestational tissues. This figure was created with BioRender.com.

Figure 6

An integrated model for PTB. Static risk factors may provide susceptibility to inherited dysregulations in the fetal and maternal tissues. An interaction with ‘pregnancy environment’ can contribute to dynamic risk factors, such as those from acquired disease states as discussed per tissue subsection, may occur throughout the pregnancy. Inflammation, and oxidative stress, provides the central tenet for PTB as they are inseparable in this process. As inflammation may propagate across different feto-maternal tissues, and tissue cross-talk may occur via various mechanisms, multiple contributions from affected tissues will eventually culminate to PTB. PTB is not a disease of a single system acting in silo but contributed by systems working together to produce an outcome. This figure was created with BioRender.com.