MON-130 - Circadian Regulation of Oxytocin Responsiveness Defines Oxytocin Uterotonic Efficacy and Labor Induction Outcomes Across Metabolic States

Background:
Parturition exhibits circadian organization, with spontaneous birth peaking during the late evening and early morning hours. Despite this, the timing of synthetic oxytocin administration for labor induction is not guided by circadian biology. Oxytocin efficacy is highly variable and frequently reduced in pregnancies complicated by obesity and gestational diabetes mellitus (GDM), conditions associated with molecular clock disruption. We hypothesized that circadian regulation of the molecular clock gates oxytocin receptor expression and uterine responsiveness, thereby shaping labor-induction outcomes.

Methods:
We employed a translational approach combining mechanistic mouse models, human cells, and a retrospective clinical cohort. Uterine contractility was assessed ex vivo across circadian phases in late-gestation wild-type mice, smooth muscle–specific circadian molecular clock Bmal1 conditional knockout mice, and a food-induced gestational diabetes model. Circadian regulation of oxytocin receptor (Oxtr) expression was evaluated using bioluminescence reporters, and in situ hybridization. Human relevance was tested using synchronized term human myometrial cells exposed to oxytocin at defined circadian time points. Clinically, we analyzed >3,300 term inductions of labor to determine how time-of-day of induction interacts with maternal BMI, parity, and GDM status to influence labor duration, delivery method, and neonatal outcomes.

Results:
In mice, oxytocin-induced uterine contractions displayed time-of-day dependence (p = 0.004), coinciding with circadian oscillations in Oxtr expression (p = 0.04). Conditional deletion of Bmal1 abolished myometrial circadian rhythms and significantly reduced oxytocin responsiveness, despite preserved spontaneous contractility. Gestational diabetes suppressed uterine clock expression and impaired oxytocin efficacy (Ctr, p < 0.001; diabetes, p > 0.05). In human myometrial cells, oxytocin-induced contractions varied by circadian timing, confirming intrinsic circadian regulation. Clinically, induction of labor duration followed a significant circadian rhythm (Lomb-Scargle, p< 0.05), with induction during early morning hours associated with the shortest total induction duration and induction near midnight associated with the longest induction (p < 0.01), the latter which significantly increased rates of cesarean delivery. These effects were most pronounced during early labor and were amplified in obese, nulliparous, and GDM pregnancies, without increased NICU admission or adverse neonatal outcomes.

Conclusion:
The uterine clock is a critical regulator of oxytocin responsiveness and labor progression. Aligning labor induction with maternal circadian biology represents a novel, precision strategy to improve obstetric outcomes, particularly in metabolically vulnerable pregnancies.

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