Carbetocin Monotherapy Versus Carbetocin Plus Oxytocin Infusion in Elective Cesarean Delivery: A Non-Inferiority Trial

PHARMACOLOGICAL RATIONALE:

Carbetocin exerts its uterotonic effect through sustained occupancy of myometrial oxytocin receptors (OTRs). Continuous stimulation of OTRs triggers homologous receptor desensitization, progressively reducing myometrial responsiveness. The addition of an oxytocin infusion following carbetocin raises three competing hypotheses: (1) incremental benefit from residual unoccupied receptors; (2) receptor counterproductivity through accelerated downregulation; or (3) pharmacological redundancy. No published RCT has resolved this uncertainty.

TRIAL DESIGN:

The trial uses a non-inferiority design because the combination regimen is already practiced without evidence. Demonstrating non-inferiority of monotherapy would provide the first evidence to safely simplify uterotonic regimens, reduce drug costs, nursing workload, and unnecessary receptor stimulation.

BLOOD LOSS MEASUREMENT:

Intraoperative blood loss measured by gravimetric quantification: [Weight soaked materials minus Weight dry materials] divided by 1.05, plus suction canister volume, minus irrigation volume, minus amniotic fluid volume. Secondary measurement uses the Gross formula: ABL = EBV x (Hb preoperative minus Hb postoperative) divided by Hb preoperative, where EBV = body weight (kg) x 85 mL/kg.

UTERINE TONE ASSESSMENT:

Assessed using the 11-point Verbal Numerical Rating Scale (VNRS 0-10) with predefined anchor definitions, by the blinded operating obstetrician via bimanual palpation at 2, 5, and 10 minutes following carbetocin bolus. Pre-study inter-rater calibration session with intraclass correlation coefficient target of 0.80 or more.

STANDARDIZED FLUID PROTOCOL:

All patients receive a standardized intravenous fluid protocol to eliminate hemodilution as a confounding variable: spinal coload Ringer's Lactate 500 mL; intraoperative maintenance 100 mL/hour; study infusion 500 mL over 4 hours identical in both groups; postoperative Ringer's Lactate 80 mL/hour for 8 hours. Total 24-hour fluid volume recorded as a statistical covariate.

STATISTICAL ANALYSIS:

Non-inferiority declared if the upper bound of the two-sided 95% confidence interval of the risk difference does not exceed +0.10. Both per-protocol and intention-to-treat analyses performed; concordance of both required per ICH E9(R1). IRB approval: Subcommittee of Health and Bioethics Research Ethics, Qassim University, Approval No. 26-23-4, dated June 02, 2026.

Inclusion criteria

• Adult women aged 18 to 45 years
• Scheduled for elective non-emergency cesarean delivery
• Spinal anesthesia planned and administered as the sole anesthetic technique
• Singleton pregnancy at gestational age of 37 completed weeks or more
• ASA physical status II
• Preoperative hemoglobin of 9 g/dL or more
• Able to provide written informed consent in Arabic or English

Exclusion criteria

• Emergency or crash cesarean delivery
• Placenta previa, placenta accreta spectrum disorder, or other abnormal placentation
• Known uterine anomalies likely to impair contractility including fibroids greater than 5 cm, bicornuate or unicornuate uterus
• Grand multiparity defined as 5 or more previous deliveries
• Multiple gestation including twins or higher order
• Polyhydramnios defined as amniotic fluid index greater than 24 cm
• Prior oxytocin augmentation in current pregnancy for more than 6 hours
• Known hypersensitivity to carbetocin, oxytocin, or any formulation excipient
• Severe preeclampsia, eclampsia, or HELLP syndrome
• Cardiovascular disease including arrhythmia, valvular disease, cardiomyopathy, or ischemic heart disease
• Known coagulopathy or thrombocytopenia with platelets less than 100 x 10^9/L
• Hepatic or renal impairment
• Body mass index greater than 40 kg/m2 at time of delivery
• Enrollment in another interventional clinical trial