ABSTRACT
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.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
Conflict of Interest The authors report no conflict of interest.
Funding Sources Arvind Palanisamy was supported by departmental start-up funds.
Sarah K. England was supported by grants from the National Institute of Child Health and Human Development (R01 HD088097 and R01 HD096737).
Carmen M. Halabi was supported by NIH grant K08 HL135400.
RNA-seq experiments conducted at the Genome Technology Access Center (GTAC) were partially supported by the National Cancer Institute Cancer Center Support grant P30 CA91842 to the Siteman Cancer Center; by the Institute of Clinical and Translational Sciences/Clinical and Translational Sciences Award grant UL1TR002345 from the National Center for Research Resources, a component of the NIH; and by the NIH Roadmap for Medical Research.
The funding sources had no role in the design, collection or interpretation of data, and the decision to submit for publication.
Paper presentation information: This abstract was presented for Oral Presentation at the 50th Annual Meeting of the Society for Obstetric Anesthesia and Perinatology, Miami, FL, May 9-13, 2018.