Uterine overdistention induces preterm labor mediated by inflammation: observations in pregnant women and nonhuman primates

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 intraamniotic balloons (N = 6), which were compared to saline controls (N = 5). Cesarean delivery was performed due to preterm labor or at experimental end. Microarray, quantitative reverse transcriptase polymerase chain reaction, Luminex (Austin, TX), and enzyme-linked immunosorbent assay were used to measure messenger RNA (mRNA) and/or protein levels from monkey (amniotic fluid, myometrium, maternal plasma) and human (amniocytes, amnion, myometrium) tissues. Statistical analysis employed analysis of covariance and Wilcoxon rank sum. Biomechanical forces were calculated using the law of Laplace. RESULTS Preterm labor occurred in 3 of 6 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 (interleukin [IL]-1β, tumor necrosis factor [TNF]-α, IL-6, IL-8, CCL2, prostaglandin E2, prostaglandin F2α, all P < .05). A similar inflammatory response was observed in amniocytes in vitro following mechanical stretch (IL1β, IL6, and IL8 mRNA multiple time points, P < .05), in amnion of women with polyhydramnios (IL6 and TNF mRNA, P < .05) and in amnion (TNF-α) and myometrium of women with twins in early labor (IL6, IL8, CCL2, all P < .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. CONCLUSION Uterine overdistention by inflation of an intraamniotic 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.

Differential senescence in feto-maternal tissues during mouse pregnancy

“…We postulate that the changes in intrauterine environment (endocrine changes, for example, progesterone[29]) and mechanical factors (e.g. stretching as gestation progresses [21, 30, 31]), among others can potentially contribute to activation of stress associated p38MAPK. This then promotes the aging of the fetal tissues, thus preparing them for delivery.…”

“…One of the mediators of senescence associated inflammation is oxidative stress experienced at term due to increased metabolic demand of the growing fetus, depletion of antioxidants or reduced maternal supply of substrates required for redox balance[20]. It is likely that other factors such as increased stretch [21], endocrine changes and fetal stressors can also contribute to this process. Therefore, we posit that oxidative stress at term can perturb homeostatic balances of the intrauterine cavity, promoting senescence associated inflammation that can trigger parturition.…”

Preterm prelabor rupture of the membranes: A disease of the fetal membranes

“…Once the fetal development is complete, OS and inflammation build up at term is a factor responsible for triggering parturition. Oxidative stress and presence of ROS rises at term due to following factors: 1) increased metabolic demands from the fetus who is ready for its independent existence outside the uterus 78 , 2) depleted fetal antioxidant reserve in the intrauterine compartments 101 , 3) no change in supply of substrate to meet increased metabolic demands by the fetus 102,103 and 4) uterine over-distension and fetal stretching 104 . In preterm pregnancies, especially those complicated by pPROM, OS buildup can occur in response to risk factors such as infection, nutrient insufficiency (specifically antioxidants), behavioral factors (cigarette smoking, drug and alcohol abuse), and low or high BMI.…”

Human fetal membranes at term: Dead tissue or signalers of parturition?

“…Oxidative stress in the intrauterine cavity is expected to increase at term prior to labor. This increase may be due to increased fetal metabolic activity, decreased maternal supply of substrates to support fetal growth demands, depletion of antioxidants, stretching of the cavity by the fetus [55], or other yet unclear mechanisms. Oxidative stress-induced activation of p38 MAPK and its downstream effectors accelerates the development of an “aging fetal membrane phenotype,” which makes fetal membranes dysfunctional, accelerates damage, and generates signals like DAMPs and SASP that can be propagated to maternal side, as described above.…”