Investigating the Effect of Extracellular Calcium on Oxytocin-induced Human Myometrial Contractility In-vitro

Overview

Postpartum hemorrhage (PPH) is a leading cause of maternal morbidity and mortality worldwide and is caused most commonly by poor uterine muscle tone after delivery. The first line agent used in the prevention and treatment of PPH is oxytocin, which acts by binding with the oxytocin receptor (OTR) found on myometrial cells to cause uterine contraction. It does this by increasing levels of calcium within the myometrial cell, which promotes contraction. Women who require augmentation of labor with intravenous oxytocin because of inadequate labor progression have been shown to be at increased risk of PPH. In-vitro human myometrial models have shown that following prolonged exposure to oxytocin there is desensitization of the myometrium resulting in a significant reduction in contractility upon delivery of further oxytocin. Optimal levels of calcium are very important for contraction of the uterine muscle. Too little calcium results in a reduced contraction. Too much calcium may result in either stronger contractions, or even possibly relaxation of the muscle and therefore a reduced contraction. The investigators currently do not know the effects of calcium on the desensitized uterine muscle. The investigators hypothesize that myometrial contractility following desensitization of the myometrium would be reduced in myometrial samples exposed to low calcium, when compared to normal calcium or high calcium exposure. These results will help in establishing whether myometrial contraction can be augmented by increasing calcium levels within the body, or by optimizing normal physiological calcium levels, in the setting of a augmented prolonged labor, which is at higher risk of poor uterine contraction and PPH.

The increased incidence of uterine atony and PPH following exogenous oxytocin administration during labor augmentation is related to myometrial OTR desensitization to oxytocin. Calcium is an important messenger required within the uterine muscle cell to result in muscle contraction following administration of oxytocin. A physiological level of calcium is known to provide optimal contractility to normal myometrium. Characterization of the importance of low, normal or high calcium levels in a setting of prolonged exogenous oxytocin administration may provide guidance for the use of exogenous calcium as a uterotonic adjunct; or for the optimization of serum calcium levels during augmented labor. In the clinical setting of failed labor augmentation and OTR desensitization, the role of serum calcium levels is not currently known. The investigators' previously validated in-vitro model provides a solid foundation for the study of myometrial contractility under controlled conditions, without any confounders that could be encountered in clinical settings. The results of this study will provide insight into the effect of low, normal or high calcium levels on the oxytocin pretreated (desensitized) and non-pretreated myometrium. Based on oxytocin dose-response curves after pretreatment to oxytocin and then subsequent exposure to either low, normal or high levels of calcium, the investigators will be able to determine the role of calcium on desensitized myometrium.