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Clinical Trial Summary

Postpartum hemorrhage (PPH) is the leading cause of maternal morbidity and mortality worldwide. Up to 80% of PPH is caused by uterine atony, the failure of the uterine smooth muscle to contract and compress the uterine vasculature after delivery. Laboratory and epidemiological studies show that low extracellular and serum calcium levels, respectively, decrease uterine contractility. A pilot study performed by the investigators supports the hypothesis that intravenous calcium chloride is well tolerated and may have utility in preventing uterine atony. The proposed research will establish the relationship between uterine tone and calcium through a clinical trial with an incorporated pharmacokinetic and pharmacodynamic (PK/PD) study. In a randomized, placebo-controlled, double-blind trial, investigators will establish the effect of 1 gram of intravenous calcium chloride upon quantitative blood loss and uterine tone during cesarean delivery in parturients with high risk of uterine atony. Investigators will concurrently collect serial venous blood samples to measure calcium for PK/PD modeling in this pregnant study cohort. High-quality clinical research and development of novel therapeutics to manage uterine atony are critical to reduce the high maternal morbidity and mortality from PPH.

Clinical Trial Description

This randomized controlled trial (RCT) assesses calcium chloride as a novel intervention to prevent hemorrhage from uterine atony with nested PK/PD analysis. PPH is the leading cause of maternal morbidity and mortality worldwide. Uterine atony, defined as failure of the uterus to adequately contract after placental delivery, causes approximately 80% of PPH. Current medications used to prevent or treat uterine atony are limited by poor efficacy, adverse side effects, expense, and contraindications to use. As such, there is a critical need for effective, safe, and inexpensive pharmacologic measures for uterine atony. Intravenous calcium chloride is an inexpensive, shelf-stable drug with good biologic and epidemiological plausibility to treat and/or prevent uterine atony. Calcium is already frequently utilized in obstetric anesthesia for indications such as hypocalcemia from massive transfusion and overcoming magnesium toxicity. Multiple in vitro studies have demonstrated that adequate extracellular calcium levels are necessary for forceful myometrial contraction in response to oxytocin. Epidemiological studies show that low ionized calcium levels predict the development of severe postpartum hemorrhage in a dose-response fashion. The investigators recently conducted a 40-patient placebo-controlled, double-blind pilot RCT assessing a one-gram dose of intravenous calcium chloride as a novel agent to prevent uterine atony during cesarean delivery. This pilot demonstrated the feasibility of enrollment and good patient tolerance of the intervention. Moreover, there were trends suggestive of efficacy of calcium to prevent uterine atony in patients who received calcium as compared to placebo infusion (p=0.07, relative risk 0.38, 95% CI 0.15-1.07, number needed to treat 3.3). Building upon the promising results from the pilot study, the aims of this study are to: AIM 1: Establish the effect of a calcium chloride infusion on blood loss and uterine tone during cesarean delivery in parturients at heightened risk for uterine atony in a double-blind, randomized, placebo-controlled trial. Hypothesis: Calcium chloride infusion will reduce quantitative blood loss (QBL, primary outcome) and improve a numerical rating score for uterine tone (secondary outcome) compared to placebo without significant safety or tolerability concerns. AIM 2: Measure pharmacokinetics and pharmacodynamics of intravenous calcium chloride in pregnant patients. Establishing the pharmacokinetics of intravenous calcium chloride in parturients is of relevance whether or not it is shown to be effective in preventing atony in Aim 1, given the multiple indications for calcium administration in obstetric patients. Meanwhile, pharmacodynamic modeling of calcium's effect upon uterine tone will allow quantification of calcium's effect on myometrial function. Investigators will generate a pharmacokinetic and pharmacodynamic model for calcium in pregnancy that includes estimates of covariate effects and intra-and inter-individual variability using non-linear mixed effects modeling. Significance: If calcium chloride, an inexpensive, widely available drug, has efficacy in the prevention or treatment of uterine atony, it has the potential to decrease the leading cause of maternal morbidity and mortality. Investigators will also leverage the intervention tested in the RCT, the infusion of calcium chloride, to define the pharmacokinetics and pharmacodynamics of calcium in pregnant women at term. This has potential relevance in defining approaches for administering calcium in various obstetrical contexts and will facilitate dose optimization. ;

Study Design

Related Conditions & MeSH terms

NCT number NCT05027048
Study type Interventional
Source Stanford University
Contact Jessica Ansari, MD
Phone 760-845-0328
Email [email protected]
Status Not yet recruiting
Phase Phase 3
Start date January 2023
Completion date June 2027

See also
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