Interaction between time-of-day and oxytocin efficacy in mice and humans with and without gestational diabetes

Management of labor in women with diabetes is challenging due to the high risk of peri- and postpartum complications. To avoid cesarean section and assist with labor progression, Pitocin, a synthetic oxytocin, is frequently used to induce and augment labor. However, the efficacy of Pitocin is often compromised in diabetic pregnancies, leading to increased cesarian delivery. As diabetes deregulates the body's circadian timekeeping system and the time-of-day of the first Pitocin administration contributes to labor duration, our objective was to determine how the time of day and the circadian clock gene, Bmal1, gates oxytocin efficacy. Our studies in mice show that, compared to the rest phase of the day (lights on), the uterotonic efficacy of oxytocin is significantly increased during the active phase (lights off). Using in vitro studies, a myometrium-specific Bmal1 conditional knockout mouse model, and a mouse model of food-induced gestational diabetes, we find that Bmal1 is crucial for maintaining oxytocin receptor expression and response in the myometrium in mice. These findings also translate to humans, where oxytocin-induced human myometrial cell contraction is time-of-day dependent, and retrospective clinical data suggest that administration of Pitocin in the morning should be considered for pregnant women with gestational diabetes.