Objective
Uterine atony is a leading cause of postpartum hemorrhage. Although most cases of postpartum hemorrhage respond to first-line therapy with uterine massage and oxytocin administration, second-line uterotonics including methylergonovine and carboprost are integral for the management of refractory uterine atony. Despite their ubiquitous use, it is uncertain whether the risk of hemorrhage-related morbidity differs in women exposed to methylergonovine or carboprost at cesarean delivery.
Study Design
We performed a secondary analysis using the Maternal-Fetal Medicine Units Network Cesarean Registry. We identified women who underwent cesarean delivery and received either methylergonovine or carboprost for refractory uterine atony. The primary outcome was hemorrhage-related morbidity defined as intraoperative or postoperative red blood cell transfusion or the need for additional surgical interventions including uterine artery ligation, hypogastric artery ligation, or peripartum hysterectomy for atony. We compared the risk of hemorrhage-related morbidity in those exposed to methylergonovine vs carboprost. Propensity-score matching was used to account for potential confounders.
Results
The study cohort comprised 1335 women; 870 (65.2%) women received methylergonovine and 465 (34.8%) women received carboprost. After accounting for potential confounders, the risk of hemorrhage-related morbidity was higher in the carboprost group than the methylergonovine group (relative risk, 1.7; 95% confidence interval, 1.2–2.6).
Conclusion
In this propensity score–matched analysis, methylergonovine was associated with reduced risk of hemorrhage-related morbidity during cesarean delivery compared to carboprost. Based on these results, methylergonovine may be a more effective second-line uterotonic.
Postpartum hemorrhage (PPH) is recognized as a leading cause of maternal mortality and morbidity worldwide. Data from epidemiologic studies indicate that the incidence of PPH has been steadily increasing in a number of well-resourced countries, with uterine atony identified as the main explanatory factor for this increase. The increase in rates of uterine atony has major clinical and public health relevance as atonic PPH has been linked to major hemorrhage-related morbidities, notably peripartum hysterectomy and massive transfusion.
Uterine massage and oxytocin administration are routinely performed prophylactically for the prevention of postdelivery uterine atony. Although pharmacologic prophylaxis with oxytocin is associated with a reduced risk of PPH compared to no uterotonics, refractory uterine atony can occur when the uterus fails to adequately contract after administration of oxytocin and uterine massage. In the setting of refractory uterine atony, second-line uterotonic agents, such as methylergonovine maleate (Methergine; Novartis, Basel, Switzerland) and carboprost (Hemabate; Pharmacia and Upjohn Company, New York, NY) are recommended by the American College of Obstetricians and Gynecologists (ACOG) and the Royal College of Obstetrics and Gynaecology and recent data suggest both agents are widely used in contemporary obstetric practice. Previous studies have compared methylergonovine vs carbroprost as prophylaxis against uterine atony and PPH in women undergoing vaginal delivery. However, data regarding the comparative effectiveness of these agents for uterine atony refractory to oxytocin are lacking, particularly in the setting of cesarean delivery. Because refractory uterine atony during cesarean delivery is often unanticipated, prospective randomized clinical investigations of methylergonovine and carboprost in this setting are logistically challenging to perform. However, the availability of large clinical datasets provides the opportunity to examine outcomes with a low prevalence, such as refractory uterine atony during cesarean delivery. The objective of this study was to examine whether the risk of hemorrhage-related morbidity differs between women who receive methylergonovine compared to carboprost during cesarean delivery.
Materials and Methods
Data source
Data were obtained from the Cesarean Registry that contains data collected for a multicenter study by the Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units (MFMU) Network. Details of this study have been previously summarized. From 1999 through 2000, investigators collected data from women who underwent delivery by primary cesarean delivery, repeat cesarean delivery, or vaginal delivery after cesarean delivery and who delivered infants ≥20 weeks or ≥500 g at 19 academic centers in the United States. From 2001 through 2002, only women who underwent repeat cesarean delivery or vaginal birth after cesarean delivery and who delivered infants ≥20 weeks or ≥500 g were enrolled. Patient and hospital identifiers were removed by the MFMU. Trained research nurses manually abstracted data from patients’ medical records. Data were submitted to a biostatistical coordinating center where audits were regularly performed to assess data quality. For the original study, ethics committees in each participating center approved the study protocol; informed consent was not required as data collection consisted only of abstraction from the medical records. Because of the deidentified data within the Cesarean Registry dataset, this secondary analysis received a waiver of exemption by the Stanford University Institutional Review Board.
Study cohort
For our study cohort, we selected women who had undergone cesarean delivery who received either methylergonovine or carboprost, but not both, for the treatment of uterine atony. Trained nurses abstracted relevant information about the presence of uterine atony and the administration of second-line uterotonics from medical records within each study site. No specific data on prophylactic regimens used at study sites were available in the Cesarean Registry. However, previously published data from Rouse et al indicate that oxytocin was routinely used as prophylaxis at 13 study sites, with 12 sites using 20 U oxytocin/L infused at 125-250 mL/h. Women who had abnormal placentation were excluded from our analysis. We also excluded women with any medical or pregnancy-related hypertensive disorder or asthma as these patients would not have been eligible for receiving either methylergonovine or carboprost. After accounting for these exclusions, the final study cohort comprised 1335 women ( Figure ).
Study outcomes
The primary study outcome was hemorrhage-related morbidity, which was defined by the presence of at least one of the following: intraoperative or postoperative red blood cell transfusion, uterine artery ligation or hypogastric artery ligation, or hysterectomy for the indication of uterine atony. These medical and surgical interventions have been previously defined as markers for severe atonic PPH and in prior studies were demonstrated to be important indicators of severe, hemorrhage-related obstetric morbidity during delivery hospitalizations. In addition, these nonpharmacological interventions have been described in treatment pathways for atonic PPH unresponsive to second-line uterotonic agents.
Covariates
Based on available data in the Cesarean Registry, 3 classes of potential confounders were included in our analysis: maternal demographics, obstetric characteristics, and perinatal factors. Maternal demographic characteristics included maternal age, race/ethnicity, and predelivery body mass index. Obstetric characteristics included gestational age at the time of delivery, type of pregnancy (singleton vs multiple gestation), and placenta previa. Perinatal factors included chorioamnionitis, the presence of labor or attempted induction prior to cesarean delivery, primary vs repeat cesarean delivery, and neonatal birthweight. Race/ethnicity were categorized as follows: Caucasian, African American, Hispanic, and non-Hispanic other. We constructed tertiles for neonatal birthweight: <3155 g, 3155-3696 g, and >3696 g.
Statistical analysis
To estimate the comparative effectiveness of methylergonovine vs carboprost, a propensity score–based method was used. A propensity score was estimated using nonparsimonious multivariable logistic regression with all covariates included; methylergonovine exposure was selected as the dependent variable. Patients receiving carboprost were matched 1:1 on propensity score to patients receiving methylergonovine using a nearest neighbor algorithm with a caliper of 0.02 difference in propensity score. Matching was performed using the psmatch2 command in software (Stata; StataCorp, College Station, TX). If ≥1 variables remained unbalanced after matching, we performed further multiple logistic regression analyses by including interaction terms until the matched cohorts were balanced for all baseline covariates. Covariate balance was assessed by calculating the absolute standardized difference in proportions. Absolute standardized differences allow the assessment of balance on potential confounders before and after matching patients receiving methylergonovine to those receiving carboprost. An absolute standardized difference of ≥10% was considered to show covariate imbalance.
We calculated risk differences for the unmatched and matched cohorts. We calculated the relative risk (RR) and 95% confidence interval (CI) for hemorrhage-related morbidity for women receiving carboprost; women receiving methylergonovine were considered as the referent group.
Secondary analyses
As previous studies have indicated that the risk of severe PPH is increased among women who experience spontaneous labor or labor induction prior to cesarean delivery, we also repeated our analysis in a subgroup of women who underwent an induction of labor or who experienced spontaneous labor prior to cesarean delivery (n = 840). Data analyses were performed using software (Stata, version 12).
Results
Cohort characteristics
In the Cesarean Registry, 57,182 women underwent cesarean delivery. After accounting for women who met the exclusion criteria, 1335 women received a second-line uterotonic: 870 women received methylergonovine and 465 women received carboprost ( Figure ). Within the cohort receiving a second-line uterotonic, 157 (11.8%) women had hemorrhage-related morbidity (115 required postoperative transfusion; 44 required intraoperative transfusion; 29 required uterine artery ligation; 18 required hysterectomy related to uterine atony; and no patients received hypogastic artery ligation).
Compared to women who received methylergonovine, women who received carboprost were younger, more likely to be Hispanic and less likely to be Caucasian or African American ( Table 1 ). Women who received carboprost were more likely to be obese prior to delivery and were less likely to undergo preterm delivery. They also had higher rates of singleton pregnancy, chorioamnionitis, placenta previa, and labor or attempted induction. The rate of repeat cesarean delivery was slightly higher in women who received methylergonovine.
| Characteristic | Carboprost (n = 465) | Methylergonovine (n = 870) | ASD, % |
|---|---|---|---|
| Maternal age, y | |||
| <20 | 53 (11.4%) | 89 (10.2%) | 3.9 |
| 20-34 | 337 (72.5%) | 585 (67.3%) | 11.3 |
| >34 | 75 (16.1%) | 196 (22.5%) | −16.3 |
| Race/ethnicity | |||
| African American | 63 (13.5%) | 195 (22.4%) | −23.3 |
| Caucasian | 132 (28.4%) | 369 (42.4%) | −29.6 |
| Hispanic | 249 (53.6%) | 249 (28.6%) | 52.5 |
| Other | 21 (4.5%) | 57 (6.6%) | −9.2 |
| Predelivery BMI, kg/m 2 | |||
| <30 | 167 (35.9%) | 365 (41.9%) | −12.3 |
| ≥30 | 254 (54.6%) | 473 (54.4%) | 0.4 |
| Missing | 44 (9.5%) | 32 (3.7%) | |
| Gestational age, wk | |||
| <37 | 70 (15.0%) | 176 (20.2%) | −13.6 |
| ≥37 | 391 (84.1%) | 693 (79.7%) | 11.4 |
| Missing | 4 (0.9%) | 1 (0.1%) | |
| Type of pregnancy | |||
| Singleton | 438 (94.2%) | 796 (91.5%) | 10.5 |
| Multiple | 27 (5.8%) | 74 (8.5%) | −10.5 |
| Chorioamnionitis | 108 (23.2%) | 132 (15.2%) | 20.4 |
| Placenta previa | 23 (4.9%) | 31 (3.7%) | 5.9 |
| Labor or attempted induction | 310 (66.7%) | 530 (60.9%) | 12.1 |
| Type of cesarean delivery | |||
| Primary | 271 (58.3%) | 506 (58.2%) | 2.0 |
| Repeat | 185 (39.6%) | 361 (41.5%) | −3.8 |
| Missing | 10 (2.1%) | 3 (0.3%) | |
| Neonatal birthweight tertiles, g | |||
| <3155 | 127 (27.3%) | 318 (36.5%) | −19.8 |
| 3155-3696 | 151 (32.5%) | 294 (33.8%) | −2.8 |
| >3696 | 187 (40.2%) | 258 (29.7%) | 22.2 |
The propensity matching resulted in 2 cohorts of 369 women who received methylergonovine and carboprost, respectively. The baseline characteristics in these 2 cohorts were well balanced ( Table 2 ). The standardized differences in the proportions for each covariate was <10% between women receiving methylergonovine compared to carboprost.
| Characteristic | Carboprost (n = 369) | Methylergonovine (n = 369) | ASD, % |
|---|---|---|---|
| Maternal age, y | |||
| <20 | 42 (11.4%) | 37 (10.0%) | 4.4 |
| 20-34 | 263 (71.3%) | 267 (72.4%) | −2.4 |
| >34 | 64 (17.3%) | 65 (17.6%) | −0.7 |
| Race/ethnicity | |||
| African American | 54 (14.6%) | 49 (13.3%) | 3.9 |
| Caucasian | 125 (33.9%) | 130 (35.2%) | −2.8 |
| Hispanic | 169 (45.8%) | 167 (45.3%) | 1.1 |
| Other | 21 (5.7%) | 23 (6.2%) | −2.3 |
| Predelivery BMI, kg/m 2 | |||
| <30 | 152 (41.2%) | 146 (39.6%) | 3.3 |
| ≥30 | 217 (58.8%) | 223 (60.4%) | −3.3 |
| Gestational age, wk | |||
| <37 | 57 (15.5%) | 61 (16.5%) | −3.0 |
| ≥37 | 312 (84.5%) | 308 (83.5%) | 3.0 |
| Type of pregnancy | |||
| Singleton | 18 (4.9%) | 15 (4.1%) | 3.9 |
| Multiple | 351 (95.1%) | 354 (95.9%) | −3.9 |
| Chorioamnionitis | 78 (21.1%) | 71 (19.2%) | 4.7 |
| Placenta previa | 16 (4.3%) | 20 (5.4%) | −5.0 |
| Labor or attempted induction | 238 (64.5%) | 234 (63.4%) | 2.3 |
| Type of cesarean delivery | |||
| Primary | 216 (58.5%) | 214 (58%) | 1.1 |
| Repeat | 153 (41.5%) | 155 (42%) | −1.1 |
| Neonatal birthweight tertiles, g | |||
| <3155 | 104 (28.2%) | 110 (29.8%) | −3.6 |
| 3155-3696 | 127 (34.4%) | 123 (33.3%) | 2.3 |
| >3696 | 138 (37.4%) | 136 (36.9%) | 1.1 |
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