Despite advancements in the obstetric management of postpartum hemorrhage, hemorrhage after delivery remains a significant contributor to maternal morbidity and mortality. Approximately 20% of pregnancy-related deaths in developing countries are related to postpartum hemorrhage.1 Similarly, in the United States, approximately 11% of maternal deaths are from postpartum hemorrhage.2 Uterine atony is the most common cause of maternal postpartum hemorrhage.3 Prolonged labor and intrapartum oxytocin exposure are known risk factors for uterine atony.4,5
Worldwide, prophylactic administration of oxytocin is recommended during the third stage of labor after both vaginal and cesarean birth.6,7 However, the laboring uterus exposed to intrapartum exogenous oxytocin may exhibit an unpredictable response to oxytocin administration at the time of delivery. Methylergonovine, a semisynthetic ergot alkaloid, is currently approved by the U.S. Food and Drug Administration for the prevention and control of postpartum hemorrhage.8
The aim of this study was to test the hypothesis that administration of prophylactic methylergonovine in addition to oxytocin in laboring patients undergoing intrapartum cesarean birth reduces the need for additional uterotonic agents by improving uterine tone.
This randomized, placebo-controlled trial was approved by the University of Iowa’s Institutional Review Board. This study was designed and reported using CONSORT (Consolidated Standards of Reporting Trials) guidelines. Written consent was obtained from a convenience sample of eligible laboring patients (recruited when the study investigator was available) shortly after admission to the hospital for planned vaginal delivery. Inclusion criteria were laboring patients aged 18 years or older in whom the decision was made to perform cesarean birth. Patients with placental or uterine anomalies, including placenta accreta spectrum, were excluded from study participation. Additionally, patients with contraindications to methylergonovine, including a history of chronic or pregnancy-induced hypertension, coronary artery disease, human immunodeficiency virus (HIV) infection and taking a protease inhibitor, or known hypersensitivity to methylergonovine, were excluded. Hypertension was defined as preexisting chronic hypertension diagnosed before 20 weeks of gestation or pregnancy-induced hypertension diagnosed after 20 weeks of gestation using standard blood pressure and laboratory criteria.9Intraamniotic infection was defined as fever greater than 38.0°C, initiation of antibiotics, and either uterine tenderness, maternal tachycardia, or fetal tachycardia. A history of postpartum hemorrhage was assessed through review of the obstetric history in the electronic health record. A variety of participant characteristics were recorded (Table 1).
Eligible patients were approached and consented to participate in the study shortly after their arrival on the labor and delivery unit for planned vaginal delivery; patients were enrolled in the study and allocated to a study group at the time that intrapartum cesarean birth was recommended by the obstetric care physician. Patients were randomized to receive either intravenous oxytocin at 300 mL/minute plus intramuscular methylergonovine 0.2 mg (1 mL) (study group) or intravenous oxytocin at 300 mL/minute plus intramuscular normal saline (1 mL) (placebo group). Rigorous data to support the use of any one single uterotonic agent as an additional drug to treat uterine atony are lacking. Methylergonovine was associated with reduced risk of hemorrhage-related morbidity during cesarean birth compared with 15-methyl prostaglandinF2ɑ in a secondary analysis using data from the Maternal-Fetal Medicine Units Network Cesarean Registry.10
Using nQuery Advisor to develop a computer-generated sequence, a one-to-one allocation was used with a randomized block design and mixed block sizes (4 and 6). Opaque, sealed envelopes were prepared with the allocation sequence. The unblinded anesthesiologist caring for the patient during the cesarean birth opened the sealed envelope shortly before delivery and prepared the study drug. Per institutional protocol, immediately after delivery, a 500-mL bag containing 30 units of oxytocin was infused at 300 mL/hour (5 mL/minute) for 1 hour, followed by 150 mL/hour (2.5 mL/minute) for the second hour. The study drug was administered into the deltoid muscle immediately after the initiation of oxytocin. The delivering physician, patient, and nursing staff were blinded to the group assignment. The oxytocin infusion was continued throughout the procedure and during the patient's postoperative recovery stay for a total of 2 hours after delivery.
Uterine tone was assessed 4 minutes after delivery of the placenta.8 The delivering physician was instructed to evaluate uterine tone as either satisfactory or unsatisfactory. If the uterine tone was judged unsatisfactory, the delivering physician was unblinded to facilitate administration of an appropriate additional uterotonic agent. Uterotonics were administered in accordance with the dose and frequency recommended by the American College of Obstetricians and Gynecologists (ACOG).11 Intravenous oxytocin was initiated at 300 mL/minute immediately after the delivery of the neonate in all patients.12,13 In general, if the patient had received methylergonovine as the study drug and was deemed to have unsatisfactory uterine tone, a treatment dose of 15-methyl prostaglandinF2ɑ was administered, unless contraindicated. If the patient had received placebo, methylergonovine was administered. At the delivering physician’s discretion, the oxytocin infusion rate was increased to 600 mL/minute intravenously. An increase in the oxytocin infusion rate was not considered an additional uterotonic agent.
As per the normal routine at our institution, the circulating nurse was responsible for measuring and documenting quantitative blood loss by quantifying blood suctioned off the surgical field and weighing surgical sponges and blood collected on the underbody pad.14 Total quantitative blood loss was calculated at the conclusion of the procedure. Additionally, preoperative hemoglobin levels (sampled on admission to the hospital for labor) and postoperative day 1 hemoglobin levels were measured and recorded, as well as blood transfusions administered during the delivery hospitalization.
The primary outcome was the administration of additional uterotonic agents, including administration of methylergonovine, 15-methyl prostaglandinF2ɑ, and misoprostol, for the treatment of uterine atony. The administration of additional uterotonic agents was chosen as the primary outcome because this is a pragmatic outcome used in a clinical setting that indicates concern for uterine atony. To detect a twofold decrease in the need for additional uterotonics (from a baseline of 42–21%)15 with a two-sided type 1 error of 5% and power of 80%, a sample size of 76 patients per group was necessary (asymptotic Pearson χ2 test). To account for dropout and deviation from protocol, we planned to enroll 80 participants in each group. Secondary outcomes included surgical assessment of uterine tone 4 minutes after delivery of the placenta, quantitative blood loss, incidence of postpartum hemorrhage, difference between the preoperative and postoperative day 1 hemoglobin value, and blood transfusion. Postpartum hemorrhage was defined as quantitative blood loss greater than 1 L within the first 24 hours after delivery. Because methylergonovine may lead to hypertension, we assessed the incidence of postpartum pregnancy-induced hypertension.
The association between the need for additional uterotonic agents and treatment group was assessed using Fisher exact test. For our secondary outcomes, categorical variables were assessed using Fisher exact tests, and continuous variables were compared using Student’s t tests with unequal variances. Relative risk (RR) or mean difference and 95% CIs are reported. An intent-to-treat analysis was performed. Chi-squared and t tests were used to assess for the association of intraamniotic infection, parity, history of postpartum hemorrhage, prior cesarean birth, induction of labor, maximum oxytocin infusion rate during labor, duration of time in labor, and indication for cesarean birth with the primary outcome. The primary outcome was also evaluated using Poisson regression and robust variance estimation to control for history of postpartum hemorrhage. P<.05 was considered statistically significant. Stata 17.0 was used for analyses.
From June 2019 through February 2021, 1,088 eligible patients were approached for study participation shortly after arrival to the labor and delivery unit (study recruitment was paused between March 2020 and June 2020 because of the coronavirus disease 2019 [COVID-19] pandemic and the subsequent moratorium on clinical research.) A total of 160 women who underwent intrapartum cesarean birth were randomized, 80 to the study group and 80 to the placebo group (Fig. 1, Table 1). There were no multiple gestations in the study cohort. All patients received the study drugs.
Significantly fewer patients who received methylergonovine received additional uterotonic agents as compared with patients who received oxytocin alone (20% vs 55%, RR 0.4, 95% CI 0.2–0.6, Table 2). The number needed to treat to avoid additional uterotonic agents was 2.9 (95% CI 2.0–4.8). Using a parsimonious model, we adjusted for history of postpartum hemorrhage, the sole baseline characteristic that was found to be associated with the primary outcome. After adjusting for history of postpartum hemorrhage, prophylactic methylergonovine was still found to be associated with a decreased need for additional uterotonic agents (RR 0.4, 95% CI 0.2–0.6). Participants receiving methylergonovine were more likely to have satisfactory uterine tone 4 minutes after delivery of the placenta, less quantitative blood loss, lower incidence of postpartum hemorrhage, decreased frequency of blood transfusion, and a smaller difference between preoperative and postoperative day 1 hemoglobin concentrations. There was no significant difference between study groups in the incidence of hypertension (9% vs 11%, P=.8).
Prophylactic methylergonovine and oxytocin compared with oxytocin alone at the time of intrapartum cesarean birth in laboring patients was found to decrease the need for additional uterotonic agents and improve uterine tone. Furthermore, prophylactic methylergonovine reduced quantitative blood loss, which in turn decreased the rates of postpartum hemorrhage and the frequency of blood transfusion.
Prolonged labor exposure to oxytocin in the intrapartum period is a known risk factor for postpartum hemorrhage. Patients whose labor was complicated by postpartum hemorrhage have been found to receive more oxytocin during labor compared with patients who did not hemorrhage.16,17 Prior studies have noted oxytocin resistance in laboring patients undergoing intrapartum cesarean birth.12,13 Continuous exposure of human myometrial cells to oxytocin leads to a loss in their capacity to respond to oxytocin. This effect is especially pronounced when comparing the concentration of oxytocin receptors in patients who present for scheduled cesarean birth with that in patients with augmented or induced labor who undergo intrapartum cesarean birth.18 Prior studies have suggested an increase in the requirement for prophylactic and therapeutic uterotonic agents in patients undergoing intrapartum compared with scheduled cesarean birth.12,19 In one study, 34% of laboring patients undergoing intrapartum cesarean birth required supplemental uterotonic agents compared with 8% of patients presenting for scheduled cesarean birth.12 The administration of prophylactic methylergonovine in patients requiring intrapartum cesarean birth could therefore serve to improve uterine tone and decrease postpartum hemorrhage by facilitating uterine contraction through an alternative, non–oxytocin receptor–dependent pathway. Methylergonovine is thought to elicit its uterotonic effects through stimulation of the α-adrenergic and serotonin receptors in the myometrium.20
In contrast to the positive findings of our study, Balki et al15 report no difference in the need for additional uterotonic agents in patients undergoing cesarean birth for arrest of labor who received intraoperative methylergonovine plus oxytocin compared with oxytocin (33% vs 35%). Similarly, no difference was found in a group that received 15-methyl prostaglandinF2α 0.25 mg with oxytocin compared with oxytocin alone. An intravenous bolus injection of methylergonovine 0.2 mg was used in the Balki et al study, and oxytocin was administered as an initial intravenous bolus (5 units) followed by in infusion of 40 mL/minute for 6 hours. In contrast, we administered intramuscular methylergonovine and a higher oxytocin infusion rate, with no initial bolus dose. It is important to note that intravenous methylergonovine and intravenous bolus oxytocin are not recommended by ACOG.11 Intravenous methylergonovine increases the risk of severe hypertension, and boluses of oxytocin are associated with hypotension.8 Although the variation between the results of the two studies can be attributed to the relatively small sample size of the respective studies, the discrepancies could also be a result of the differences in the doses and routes of administration of methylergonovine and oxytocin.
Although methylergonovine should be avoided in patients with pregnancies complicated by hypertension, in the absence of preexisting hypertension in pregnancy, our results suggest that prophylactic methylergonovine can be given without concern for a clinically significant rise in blood pressure.
A strength of this study lies in its design as a randomized controlled trial. Additionally, uterotonic agents were administered as currently recommended by ACOG, making the study clinically applicable to most U.S. institutions.
A major limitation of our study is the subjectivity of our primary outcome. However, assessment of uterine tone is the method currently used by clinicians to determine whether additional uterotonic agents are necessary. The delivering physician was unblinded if additional uterotonic agents were required. Unblinding, however, was necessary to facilitate administration of an appropriate additional uterotonic agent. Our study focused on the prophylactic use of methylergonovine and did not assess the effects of other uterotonic agents such as 15-methyl prostaglandinF2α. Currently, no rigorous data support the use of any one uterotonic agent as an additional drug to treat uterine atony, and current choice among the available agents is typically dictated by physician preference and patient contraindications to specific medications.21 We administered an oxytocin infusion at 300 mL/hour. Studies have shown that women undergoing intrapartum cesarean birth may require a higher dose of oxytocin to prevent uterine atony.12,13,17 It is possible that a higher prophylactic oxytocin dose may have mitigated the need for additional uterotonic agents. Lastly, compared with most studies, which report transfusion rates between 2% and 4%, an unusually higher rate of blood transfusions (23%) was noted in the placebo group.22
In conclusion, the addition of prophylactic methylergonovine to oxytocin immediately after delivery in patients undergoing intrapartum cesarean birth decreased the need for additional uterotonic agents compared with oxytocin alone.
Authors' Data Sharing Statement
- Will individual participant data be available (including data dictionaries)? No.
- What data in particular will be shared? Not available.
- What other documents will be available? Not available.
- When will data be available (start and end dates)? Not applicable.
- By what access criteria will data be shared (including with whom, for what types of analyses, and by what mechanism)? Not applicable.
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