Uterine Overdistention Induces Preterm Labor Mediated by Inflammation: Observations in Pregnant Women and Nonhuman Primates.

Publication Type:

Journal Article

Source:

American journal of obstetrics and gynecology (2015)

Abstract:

OBJECTIVE: Uterine overdistention is thought to induce preterm labor in women with twin and multiple pregnancies, but the pathophysiology remains unclear. We investigated for the first time the pathogenesis of preterm birth associated with rapid uterine distention in a pregnant nonhuman primate model. STUDY DESIGN: A nonhuman primate model of uterine overdistention was created using preterm chronically catheterized pregnant pigtail macaques (Macaca nemestrina) by inflation of intra-amniotic balloons (N=6), which were compared to saline controls (N=5). Cesarean section was performed due to preterm labor or at experimental end. Microarray, quantitative reverse transcriptase polymerase chain reaction, Luminex, and enzyme-linked immunosorbent assay were used to measure mRNA and/or protein levels from monkey (amniotic fluid, myometrium, maternal plasma) and human tissues (amniocytes, amnion and myometrium). Statistical analysis employed Analysis of Covariance, Wilcoxon rank sign and rank sum. Biomechanical forces were calculated using the Law of Laplace. RESULTS: Preterm labor occurred in three of six animals after balloon inflation and correlated with greater balloon volume and uterine wall stress. Significant elevations of inflammatory cytokines and prostaglandins occurred following uterine overdistention in an "inflammatory pulse" that correlated with preterm labor (IL-1beta, TNF-alpha, IL-6, IL-8, CCL2, PGE2, PGEF2alpha, all p<0.05). A similar inflammatory response was observed in amniocytes in vitro following mechanical stretch (IL1beta, IL6, and IL8 mRNA multiple timepoints, p<0.05), in amnion of women with polyhydramnios (IL-6 and TNF mRNA, p<0.05) and in amnion (TNF-alpha) and myometrium of women with twins in early labor (IL-6, IL-8, CCL2, all p<0.05). Genes differentially expressed in the nonhuman primate after balloon inflation and in women with polyhydramnios and twins are involved in tissue remodeling and muscle growth. CONCLUSIONS: Uterine overdistention by inflation of an intra-amniotic balloon is associated with an inflammatory "pulse" that precedes and correlates with preterm labor. Our results indicate that inflammation is an early event after a mechanical stress on the uterus and leads to preterm labor when the stress is sufficiently great. Further, we find evidence of uterine tissue remodeling and muscle growth as a common, perhaps compensatory, response to uterine distension.