A NOVEL PREGNANT RAT MODEL FOR LABOR INDUCTION AND AUGMENTATION WITH OXYTOCIN

2021 
Background: Despite the widespread use of oxytocin for induction of labor, mechanistic insights into maternal and neonatal wellbeing are lacking because of the absence of an animal model that recapitulates modern obstetric practice. Objective: The objectives of this research were to create and validate a hi-fidelity animal model that mirrors labor induction with oxytocin in parturients and to assess its translational utility. Study Design: The study was performed in timed-pregnant Sprague Dawley dams. The model consisted of a subcutaneously implanted microprocessor-controlled infusion pump on gestational day 18 that was pre-programmed to deliver an escalating dose of intravenous oxytocin on gestational day 21 to induce birth. Once predictable delivery of healthy pups was achieved, we validated the model with molecular biological experiments on the uterine myometrium and telemetry-supported assessment of changes in intrauterine pressure. Finally, we applied this model to test the hypothesis that labor induction with oxytocin was associated with oxidative stress in the newborn brain with a comprehensive array of biomarker assays and oxidative stress gene expression studies. Results: During the iterative model development phase, we confirmed the optimal gestational age for pump implantation, the concentration of oxytocin, and the rate of oxytocin administration. Exposure to anesthesia and surgery during pump implantation was not associated with significant changes in the cortical transcriptome. Activation of pump with oxytocin on gestational day 21 resulted in predictable delivery of pups within 8-12 hours. Increased frequency of change of oxytocin infusion rate was associated with dystocic labor. Labor induction and augmentation with oxytocin was associated with increased expression of the oxytocin receptor gene in the uterine myometrium, decreased expression of the oxytocin receptor protein on the myometrial cell membrane, and cyclical increases in intrauterine pressure. Examination of the frontal cortex of vaginally delivered newborn pups born after oxytocin-induced labor did not reveal an increase in oxidative stress compared to saline-treated control pups. Specifically, there were no significant changes in oxidative stress biomarkers involving both the oxidative stress (reactive oxygen/nitrogen species, 4-hydroxynonenal, protein carbonyl) and the antioxidant response (total glutathione, total antioxidant capacity). In addition, there were no significant differences in the expression of 16 genes emblematic of the oxidative stress response pathway. Conclusions: Collectively, we provide a viable and realistic animal model for labor induction and augmentation with oxytocin. We demonstrate its utility in addressing clinically relevant questions in obstetric practice that could not be mechanistically ascertained otherwise. Based on our findings, labor induction with oxytocin is not likely to cause oxidative stress in the fetal brain. Adoption of our model by other researchers would enable new lines of investigation related to the impact of perinatal oxytocin exposure on the mother-infant dyad.
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