Effectiveness of prophylactic carbetocin versus oxytocin following vaginal delivery for preventing severe postpartum hemorrhage

To compare the effectiveness of prophylactic carbetocin with prophylactic oxytocin for preventing severe postpartum hemorrhage (PPH) following vaginal delivery.

In France, the two most commonly used uterotonics are oxytocin and carbetocin. Carbetocin is used almost exclusively after cesarean deliveries as the trials conducted in high-income countries to assess its effectiveness included only cesareans. 5 More recently, the effectiveness of carbetocin has been studied after vaginal deliveries, first, in low-and middle-income countries, particularly because it can be used at ambient temperatures, unlike oxytocin, which requires cold storage. [6][7][8] Among these studies, the most robust data come from the CHAMPION (CardioMEMS Heart Sensor Allows Monitoring of Pressure to Improve Outcomes in NYHA Class III Heart Failure Patients) randomized controlled trial, which showed that carbetocin was no different to oxytocin for the prevention of blood loss of at least 500 mL or the use of additional uterotonic agents. Lack of power, however, prevented a showing of noninferiority for blood loss of at least 1000 mL. 7 Carbetocin might thus also be beneficial in high-income countries. Nonetheless, studies are required to analyze its effectiveness in different care settings that may be associated with different levels of risk. The few studies conducted in high-income countries have shown that the effectiveness of carbetocin after vaginal delivery is similar to oxytocin for preventing PPH [8][9][10] and probably for reducing the use of second-line treatment for PPH. 11 However, these studies have some limitations, including debatable and variable outcomes depending on the study, failure to evaluate more severe maternal morbidity, small sample sizes, and different interventions in control groups with the use of different uterotonics (substances, doses, and routes of administration).
In 2021, our maternity unit decided to change the prophylactic uterotonic used following vaginal deliveries because of the potential benefits of carbetocin and because it is both easier to administer and requires less clinical monitoring than oxytocin. At the introduction of the protocol, we planned to assess its effectiveness after 1 year of implementation.
Our objective was to compare the effectiveness of prophylactic carbetocin with prophylactic oxytocin in preventing severe PPH after vaginal delivery.

| Study population
We designed a before and after single-center cohort study for our French university maternity unit, which performs approximately 3100 deliveries per year. Among the 5940 women who delivered in the maternity unit in 2020 and 2021, we included all patients with vaginal births (n = 4832). The only exclusion criterion was cesarean delivery before or during labor (n = 1108).
The study compared two groups. The "oxytocin" study group comprised the patients who received prophylactic oxytocin for the prevention of PPH immediately after vaginal delivery from January 1, 2020, through January 17, 2021. The "carbetocin" study group was composed of patients who received prophylactic carbetocin, i.e., those giving birth from January 18, 2021, after the protocol changed, until the end of 2021.

| Protocol for active management of the third stage of labor
A postpartum drape containing a calibrated bag was used to collect postpartum blood and measure blood loss immediately after each vaginal delivery.
Before 2021, the nurse present in the labor room during delivery administered oxytocin to prevent PPH after placental delivery. The dose was 5 IU intravenously over 5 minutes, for patients without PPH risk factors, and 10 IU for those with one or more risk factors.
All patients then received an oxytocin infusion (10 IU in 1 L, i.e., a rate of 270 mL/h) for 2 h postpartum. Monitoring in the labor room during these 2 h included uterine expression to control blood loss and uterine tonus, as well as monitoring of vital signs every 15 min by a nurse and midwife. After this initial monitoring, patients were admitted to the postpartum ward without additional oxytocin infusion, except for those with major risk factors for PPH (previous PPH, macrosomia, or multiple pregnancy); these women could then receive a 12-h infusion of oxytocin.
In January 2021, carbetocin replaced oxytocin for the prevention of PPH after vaginal delivery. As for oxytocin, the nurse present at delivery administered the carbetocin in the labor room, just after delivery of the placenta, at a dose of 100 μg, i.e., 1 mL diluted in 10 mL of physiological saline, by a slow 1-min intravenous injection.
Postpartum monitoring was identical to that in the "before" period.
The decision to use carbetocin for the prevention of PPH was reached jointly by all staff anesthesiologists and obstetricians, after their review of the literature. The protocol change was effective on January 18, 2021. The nursing and midwifery teams were informed and trained to the new protocol prior to its clinical application.

| Management of PPH
The treatment of PPH, if it occurred, followed a protocol based on the 2014 national guidelines. 12 Only during the "before" period did management include the administration of additional oxytocin, up to a maximum dose of 40 IU. In case of persistent bleeding after additional oxytocin, sulprostone was administered. During the after period, if the bleeding persisted or began after the carbetocin injection, no oxytocin was used and sulprostone was immediately administered. During both periods, if bleeding persisted despite the administration of the uterotonic drugs, an intrauterine balloon was placed to attempt tamponade. If it was unsuccessful, arterial embolization or vascular ligation was attempted. At the same time, anesthesiologic management and resuscitation were performed.
The data were collected prospectively in the medical file at each follow-up visit, at delivery, and in the postpartum period by the professionals caring for the patient. The entire medical record was computerized in dedicated software packages internal to the Robert Debré maternity unit. Data for all women were checked during the daily staff meeting the day after their delivery. For this study, the data were extracted from the software anonymized on January 2022 and analyzed retrospectively.

| Outcomes
The primary outcome was the occurrence of severe PPH, defined as one or more of the following, based on the EPIMOMS definition 13 : estimated blood loss ≥1500 mL (clinically by means of a systematic postpartum drape containing a calibrated bag), blood transfusion ≥4 U of red blood cells, intrauterine balloon tamponade, embolization, vascular ligation, hysterectomy, or maternal death.
Secondary outcomes were PPH, defined as an estimated blood loss ≥500 mL, administration of tranexamic acid, and manual removal of the placenta if retained tissue remained.

| Statistical analysis
We compared the two groups for maternal, obstetric, labor, and neonatal characteristics with a Fisher or χ 2 test. The association between prophylactic carbetocin and the occurrence of PPH was studied by multivariate logistic regression with adjustment for confounding factors. After the univariate analysis and a review of the literature, the confounding factors we considered were multiple pregnancy, placenta previa, and episiotomy. All tests were two-sided with P values of ≤0.05 defined as statistically significant. Analyses were conducted with STATA 15 software (StataCorp LLC).

| Ethics
Women were informed since the beginning that their records could be used for the evaluation of medical practices and were allowed to opt out of these studies. The CNIL (Commission Nationale de l'Informatique et des Libertés) approved data collection from medical file in the maternity unit (n° 2020-526). The local institutional review board, CEERB Paris Nord (IRB 00006477) of HUPNVS, Paris 7 University, AP-HP, approved the research project and confirmed that the investigation was an observational study using anonymized data from medical records and therefore not covered by the Jardé law.

| RE SULTS
The current study included 4832 women: 2417 received oxytocin and 2415 carbetocin. The groups were similar for maternal characteristics and for obstetric and labor characteristics except that women in the carbetocin group were significantly more often obese, had placenta previa significantly more often, and had fewer twin pregnancies and episiotomies than the oxytocin group (Tables 1 and 2).   (Table 3).
During the study period, no women underwent embolization or surgical management for PPH and no women died.
Rates of PPH ≥500 mL (5.8% vs. 4.0%; P = 0.004) and the use of tranexamic acid (2% vs. 3%; P = 0.016) were significantly lower in the carbetocin group than in the oxytocin group. The transfusion rates were similar in both groups.

| DISCUSS ION
The rate of severe PPH in this study did not change significantly after the protocol change from prophylactic oxytocin to carbetocin; however, there was a decrease in the rate of PPH of ≥500 mL. There The principal limitation of the current study is that we had no data on the cause of the PPH (uterine atony or perineal wound), but atony is the main cause of PPH in France and in the literature so we surmised that it was also the case in our population. In addition to taking into account this missing information, we adjusted for episiotomy. Because of the retrospective design, not randomized, the absence of sample size calculation limits the results.
Side effects were not analyzed in the current study because they had not been collected in the before period; accordingly, no comparison between the two groups was possible. The number of patients was too small to analyze the subgroups at high risk for PPH, such as multiple pregnancy or macrosomia, to assess the effectiveness of carbetocin in these patients. Another limitation is that hemoglobin was not routinely measured in the postpartum period after vaginal delivery for women without PPH and therefore delta hemoglobin or hematocrit could not be compared, nevertheless we compared the transfusion rate as a proxy.
Our results suggest that carbetocin could be used as a routine alternative to oxytocin for the prevention of PPH after vaginal delivery in high-resource countries. Carbetocin, while ensuring effectiveness, can be stored more easily and simplifies the work for nurses, The absence of a second administration of the first uterotonic before the administration of a second-line uterotonic could lead to more rapid administration of sulprostone instead of repeated oxytocin administrations and therefore be more effective in management and reduce the occurrence of severe PPH. Olivier Sibony and Anne Laure Hörlin: Validation and review.

ACK N OWLED G M ENTS
The authors thank Jo Ann Cahn for editorial assistance.

CO N FLI C T O F I NTER E S T S TATEM ENT
All authors declare no conflicts of interest.

DATA AVA I L A B I L I T Y S TAT E M E N T
Research data are not shared. Abbreviations: CI: confidence interval; OR: odds ratio. a Severe postpartum hemorrhage (PPH) defined as one or more of the following: estimated blood loss ≥1500 mL, transfusion ≥4 U of red blood cells (RBCs), Bakri balloon, embolization, vascular ligation, hysterectomy, or maternal death. b Adjustment for multiple pregnancy, placenta previa, and episiotomy.