Documente Academic
Documente Profesional
Documente Cultură
org
OBSTETRICS
Second-line uterotonics and the risk of
hemorrhage-related morbidity
Alexander J. Butwick, MBBS, FRCA, MS; Brendan Carvalho, MB ChB, FRCA; Yair J. Blumenfeld, MD;
Yasser Y. El-Sayed, MD; Lorene M. Nelson, MS, PhD; Brian T. Bateman, MD, MSc
OBJECTIVE: Uterine atony is a leading cause of postpartum hemor- hysterectomy for atony. We compared the risk of hemorrhage-
rhage. Although most cases of postpartum hemorrhage respond to related morbidity in those exposed to methylergonovine vs car-
first-line therapy with uterine massage and oxytocin administration, boprost. Propensity-score matching was used to account for
second-line uterotonics including methylergonovine and carboprost potential confounders.
are integral for the management of refractory uterine atony. Despite
RESULTS: The study cohort comprised 1335 women; 870 (65.2%) women
their ubiquitous use, it is uncertain whether the risk of hemorrhage-
received methylergonovine and 465 (34.8%) women received carboprost.
related morbidity differs in women exposed to methylergonovine or
After accounting for potential confounders, the risk of hemorrhage-related
carboprost at cesarean delivery.
morbidity was higher in the carboprost group than the methylergonovine
STUDY DESIGN: We performed a secondary analysis using the group (relative risk, 1.7; 95% confidence interval, 1.2e2.6).
Maternal-Fetal Medicine Units Network Cesarean Registry. We
CONCLUSION: In this propensity scoreematched analysis, methyl-
identified women who underwent cesarean delivery and received
ergonovine was associated with reduced risk of hemorrhage-related
either methylergonovine or carboprost for refractory uterine
morbidity during cesarean delivery compared to carboprost. Based
atony. The primary outcome was hemorrhage-related morbidity
on these results, methylergonovine may be a more effective second-
defined as intraoperative or postoperative red blood cell trans-
line uterotonic.
fusion or the need for additional surgical interventions including
uterine artery ligation, hypogastric artery ligation, or peripartum Key words: cesarean delivery, hemorrhage, morbidity, uterine atony
Cite this article as: Butwick AJ, Carvalho B, Blumenfeld YJ, et al. Second-line uterotonics and the risk of hemorrhage-related morbidity. Am J Obstet Gynecol
2015;212:x.ex-x.ex.
From the Departments of Anesthesia (Drs Butwick and Carvalho), Obstetrics and Gynecology (Drs Blumenfeld and El-Sayed), and Health Research Policy
(Dr Nelson), Stanford University School of Medicine, Stanford, CA, and Division of Pharmacoepidemiology and Pharmacoeconomics, Department of
Medicine, Brigham and Women’s Hospital, Department of Anesthesiology, Critical Care Medicine, and Pain Medicine, Massachusetts General Hospital,
Harvard Medical School, Boston, MA (Dr Bateman).
Received Sept. 19, 2014; revised Nov. 10, 2014; accepted Jan. 6, 2015.
This study was supported and funded internally by the Departments of Anesthesia and Obstetrics and Gynecology, Stanford University School of
Medicine. A.J.B. and B.T.B. are supported by Eunice Kennedy Shriver National Institute of Child Health and Human Development grant numbers
1K23HD070972 and K08HD075831, respectively.
The authors report no conflict of interest.
Presented in oral format at the 34th annual meeting of the Society for Obstetric Anesthesia and Perinatology, Toronto, Ontario, Canada, May 5-9, 2014.
We acknowledge the assistance of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), the Maternal-Fetal
Medicine Units (MFMU) Network, and the Protocol Subcommittee in making the database available on behalf of the project. The contents of this report
represent the views of the authors and do not represent the views of the NICHD, MFMU Network, or the National Institutes of Health.
Corresponding author: Alexander J. Butwick, MBBS, FRCA, MS. ajbut@stanford.edu
0002-9378/$36.00 ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ajog.2015.01.008
In the setting of refractory uterine atony, cesarean delivery and who delivered in- indication of uterine atony. These med-
second-line uterotonic agents, such as fants 20 weeks or 500 g were ical and surgical interventions have been
methylergonovine maleate (Methergine; enrolled. Patient and hospital identifiers previously defined as markers for severe
Novartis, Basel, Switzerland) and carbo- were removed by the MFMU. Trained atonic PPH18 and in prior studies were
prost (Hemabate; Pharmacia and Upjohn research nurses manually abstracted data demonstrated to be important indicators
Company, New York, NY) are recom- from patients’ medical records. Data of severe, hemorrhage-related obstetric
mended by the American College of Ob- were submitted to a biostatistical coor- morbidity during delivery hospitaliza-
stetricians and Gynecologists (ACOG) dinating center where audits were regu- tions.19-23 In addition, these non-
and the Royal College of Obstetrics and larly performed to assess data quality. pharmacological interventions have
Gynaecology9,10 and recent data suggest For the original study, ethics committees been described in treatment pathways
both agents are widely used in contem- in each participating center approved the for atonic PPH unresponsive to second-
porary obstetric practice.11 Previous study protocol; informed consent was line uterotonic agents.24,25
studies have compared methylergonovine not required as data collection consisted
vs carbroprost as prophylaxis against only of abstraction from the medical Covariates
uterine atony and PPH in women un- records. Because of the deidentified data Based on available data in the Cesarean
dergoing vaginal delivery.12-15 However, within the Cesarean Registry dataset, this Registry, 3 classes of potential con-
data regarding the comparative effective- secondary analysis received a waiver of founders were included in our analysis:
ness of these agents for uterine atony exemption by the Stanford University maternal demographics, obstetric char-
refractory to oxytocin are lacking, parti- Institutional Review Board. acteristics, and perinatal factors. Maternal
cularly in the setting of cesarean delivery. demographic characteristics included
Because refractory uterine atony during Study cohort maternal age, race/ethnicity, and prede-
cesarean delivery is often unanticipated, For our study cohort, we selected women livery body mass index. Obstetric char-
prospective randomized clinical inves- who had undergone cesarean delivery acteristics included gestational age at the
tigations of methylergonovine and car- who received either methylergonovine or time of delivery, type of pregnancy
boprost in this setting are logistically carboprost, but not both, for the treat- (singleton vs multiple gestation), and
challenging to perform. However, the ment of uterine atony. Trained nurses placenta previa. Perinatal factors included
availability of large clinical datasets pro- abstracted relevant information about the chorioamnionitis, the presence of labor
vides the opportunity to examine out- presence of uterine atony and the or attempted induction prior to cesarean
comes with a low prevalence, such as administration of second-line uterotonics delivery, primary vs repeat cesarean de-
refractory uterine atony during cesarean from medical records within each study livery, and neonatal birthweight. Race/
delivery. The objective of this study was to site. No specific data on prophylactic ethnicity were categorized as follows:
examine whether the risk of hemorrhage- regimens used at study sites were available Caucasian, African American, Hispanic,
related morbidity differs between women in the Cesarean Registry. However, pre- and non-Hispanic other. We constructed
who receive methylergonovine compared viously published data from Rouse et al17 tertiles for neonatal birthweight: <3155 g,
to carboprost during cesarean delivery. indicate that oxytocin was routinely used 3155-3696 g, and >3696 g.
as prophylaxis at 13 study sites, with 12
M ATERIALS AND M ETHODS sites using 20 U oxytocin/L infused at 125- Statistical analysis
Data source 250 mL/h. Women who had abnormal To estimate the comparative effectiveness
Data were obtained from the Cesarean placentation were excluded from our of methylergonovine vs carboprost, a
Registry that contains data collected for a analysis. We also excluded women with propensity scoreebased method was used.
multicenter study by the Eunice Kennedy any medical or pregnancy-related hyper- A propensity score was estimated using
Shriver National Institute of Child tensive disorder or asthma as these pa- nonparsimonious multivariable logistic
Health and Human Development tients would not have been eligible for regression with all covariates included;
Maternal-Fetal Medicine Units (MFMU) receiving either methylergonovine or methylergonovine exposure was selected
Network.16 Details of this study have carboprost. After accounting for these as the dependent variable. Patients
been previously summarized.16 From exclusions, the final study cohort receiving carboprost were matched 1:1 on
1999 through 2000, investigators comprised 1335 women (Figure). propensity score to patients receiving
collected data from women who under- methylergonovine using a nearest
went delivery by primary cesarean de- Study outcomes neighbor algorithm with a caliper of 0.02
livery, repeat cesarean delivery, or The primary study outcome was difference in propensity score. Matching
vaginal delivery after cesarean delivery hemorrhage-related morbidity, which was performed using the psmatch2 com-
and who delivered infants 20 weeks or was defined by the presence of at least mand in software (Stata; StataCorp, Col-
500 g at 19 academic centers in the one of the following: intraoperative or lege Station, TX). If 1 variables remained
United States. From 2001 through 2002, postoperative red blood cell transfusion, unbalanced after matching, we performed
only women who underwent repeat ce- uterine artery ligation or hypogastric further multiple logistic regression ana-
sarean delivery or vaginal birth after artery ligation, or hysterectomy for the lyses by including interaction terms until
the matched cohorts were balanced for all Secondary analyses Association between second-line
baseline covariates. Covariate balance was As previous studies have indicated that uterotonics and hemorrhage-related
assessed by calculating the absolute stan- the risk of severe PPH is increased morbidity
dardized difference in proportions. Abso- among women who experience sponta- Hemorrhage-related morbidity was
lute standardized differences allow the neous labor or labor induction prior to more common among women who
assessment of balance on potential con- cesarean delivery,27,28 we also repeated received carboprost: 81 (17.4%) women
founders before and after matching pa- our analysis in a subgroup of women in the carboprost group vs 76 (8.8%)
tients receiving methylergonovine to those who underwent an induction of labor or women in the methylergonovine group.
receiving carboprost. An absolute stan- who experienced spontaneous labor Compared to women who received
dardized difference of 10% was consid- prior to cesarean delivery (n ¼ 840). methylergonovine, those who received
ered to show covariate imbalance.26 Data analyses were performed using carboprost were at significantly higher
We calculated risk differences for the software (Stata, version 12). risk of hemorrhage-related morbidity
unmatched and matched cohorts. We (unadjusted RR, 2.0; 95% CI, 1.5e2.7).
calculated the relative risk (RR) and 95% After adjusting for confounders using
confidence interval (CI) for hemorrhage- R ESULTS propensity-score matching, the risk of
related morbidity for women receiving Cohort characteristics hemorrhage-related morbidity re-
carboprost; women receiving methyl- In the Cesarean Registry, 57,182 women mained increased for women who
ergonovine were considered as the referent underwent cesarean delivery. After ac- received carboprost (RR, 1.7; 95% CI,
group. counting for women who met the 1.2e2.6) (Table 3).