Postpartum hemorrhage (PPH) remains a leading cause of maternal mortality and severe morbidity worldwide.1 The increased rate of PPH has been noted in many countries and the primary reason is still uterine atony.2 Compared with physiological expectation, active management of the third stage of labor had been reported to be associated with a 50% reduction in the incidence of PPH.3 There are three components of the active management of the third stage of labor involving oxytocin administration, uterine massage and umbilical cord traction. Though, oxytocin is the most effective medication with few adverse effects, long-acting oxytocin agent (carbetocin) had emerged and was recommended by some institutional guidelines to prevent PPH for women after vaginal delivery or cesarean section.4
Carbetocin is a synthetic oxytocin analogue with similar side effects as oxytocin. However, the molecular structure of carbetocin is different from that of oxytocin. Due to the modification of its molecular structure, carbetotocin can avoid the cleavage of aminopeptidase and disulfide compounds, thereby enhancing its stability and its higher affinity for the receptor. For it born long acting and tetanic uterine contraction produced in postpartum uterus, carbetocin had been expected to be more effective than oxytocin in PPH management.5,6 Unfortunately, no previous randomized controlled trial had been provided direct evidence to show the decreased PPH following carbetocin infusion after birth. Compared with oxytocin, prophylactic effect of carbetocin showed reduced the need for additional uterotonics by half following cesarean section.7 Two studies based on economic analysis model further demonstrated that cost-effectiveness of carbetocin which would reduce the work load in busy units after cesarean.8–10 However, the advantages of carbetocin in the setting after vaginal delivery have not been clearly defined, and to date studies were small and of poor quality.7
According to the manufacturer's instructions, oxytocin should be given as a short-infusion while carbetocin in a single bolus intravenously over one minute to lower the side effects of cardiovascular responses. From a practical point of view, administering a 1 mL bolus over 1 minute can be a challenge for a midwife in the busy time immediately after fetus delivery. Laboring women in high risk at most hospitals receive intravenous fluids as a part of their intrapartum care, short infusion on gravity would be more convenience than slow manual injection. Meanwhile, short infusion of carbetocin showed similar uterine tone and comparable cardiovascular side-effects when compared with bolus injection in women undergoing cesarean delivery.11 In this work, we compared the effectiveness of the short infusion carbetocin (instead of boluses) to oxytocin in the active management of the third stage of labor targeting women with at least one risk factor of atonic PPH.
Materials and methods
This prospective, single-center, randomized double-blind controlled study was held in the Nanjing Drum Tower Hospital, a referral center in Jiangsu Province, China, from March to May 2018. There are approximately 7 500 deliveries annually after the government ending its one-child policy. No interim analyses were planned. The study was approved by the Drum Tower Hospital's Institutional Ethics Committee, and the trial was registered with China Clinical Trials Registry (ChiCTR1800015040, http://www.chictr.org.cn). Written informed consent was obtained from all women entering the research.
Women for whom a vaginal delivery was expected were recruited in the antenatal clinic or early in labor (<6 cm cervical dilatation in nulliparous or <2 cm in multiparous). The inclusion criteria were: (1) at or beyond 28 gestational weeks; (2) cephalic presentation; (3) 18–45 years old; (4) at least one risk factor for developing atony.
Risk factors included: (1) uterine over extension (i.e., suspected macrosomia, amnion fluid index ≥250 mm, multiple pregnancy); (2) intrapartum fever (above 37.8°C); (3) prolonged labor >12 hours (including the first and the second labor stage); (4) labor induction or augmentation; (5) epidural analgesia; (6) tocolysis utility; (7) precipitate delivery; (8) operative vaginal delivery; (9) antepartum hemorrhage including marginal placental previa and placental abruption (Grade I); (10) pregnancy complications as hypertensive disorders, gestational diabetes.12 Participants with serious cardiovascular disorders, serious hepatic or renal disease, epilepsy, known allergies to oxytocin or carbetocin and those without risk factors were excluded.
Randomization and double-blind
According to superiority test, Statistical Calculator Medical Version 3.0 Program (Vanderbilt, Nashville, TN) was used for calculations of sample size. As the primary outcome in the study, power analysis was based on the occurrence of PPH, which was 30% in our previous study (unpublished). Accordingly, 318 women per group were sufficient to detect a decrease in the primary outcome from 30.0% in the oxytocin group to 21.0% in the carbetocin group with a level of significance of 95% (α = 0.05), a power of 80% (β = 0.2).
Randomization was performed using a computer randomization sequence generation program and the results were kept in antenatal ward in a closed study box. At active stage of labor (cervical dilated at or beyond 6 cm), participants were randomized assigned to carbetocin or oxytocin group in a 1:1 ratio. Both 100 μg carbetocin (Ferring, St. Prex, Switzerland) and 10 IU oxytocin (Hefeng Pharmaceutical, China) were diluted into 100 mL normal saline in consecutively numbered treatment packs. Apart from the randomization number, all trial packs were identical in shape, size, and weight to ensure that the midwives, obstetricians and the participants were unaware of the individual treatment assignments. Packs were stored in refrigerate at 4 oC within 12 hours before administration. The random allocation sequence was revealed to the women just before discharge, and was revealed to the investigators at the end of the trial.
Immediately after delivery of the anterior shoulder and before placental delivery, prepared carbetocin or oxytocin were intravenously administered in women in the carbetocin group or in the oxytocin group, respectively. In cases of twin pregnancy, the medicines were given after delivery of the second fetus. Additional management of PPH was at the discretion of the obstetrician and midwife in line with routine practice at our institution. Briefly, if estimated blood loss had been over 500 mL, or vital sign was instable increased the rate of infusion and tranexamic acid (0.5–1.0 g) would be applied. If hemorrhage from atony after placenta delivered, and free of reminiscent in the uterus, second line uterotonics as ergometrine 0.2–0.4 mg or Hemabate 250 μg intramuscular injection (IM) should be given. Intrauterine balloon tamponade could be applied if necessary. Mothers were followed up to 42 days postpartum.
The primary outcome of the study was the incidence of blood loss more than 500 mL within 24 hours after delivery. The secondary outcomes were amount of total blood loss, blood loss within 2 hours after delivery, the rate of blood loss more than 1 000 mL postpartum, need for a second-line uterotonics and interventions, blood transfusion, difference between hemoglobin and hematocrit before and 48 hours after delivery, adverse maternal events attributed to the trial medication. Hemodynamic status (blood pressure and pulse) was measured 0 minutes, 30 minutes, 60 minutes, and 120 minutes after delivery.
Blood loss was collected into a plastic basin placed under the mother's pelvis and measured by the volume. After the delivery of placenta and lacerations repaired, a napkin specific designed for postpartum blood collection was maintained in place for 24 hours for continuous monitoring of blood loss. Blood from blood-soaked pads was weighted and calculated in milliliters. Patient demographics, antepartum and labor course, clinical outcomes and days in hospital were extracted from the electronic medical records.
Quantitative data were statistically described in terms of means ± standard deviation (SD) or median (interquartile range), and differences were compared using independent t test. While categorical data were presented as numbers and percentages (%) and differences between the two groups were compared using the chi-square test or Fisher's exact test. Differences in proportions and medians between the groups (with 95% confidence interval (CI)) were also calculated. P < 0.05 was considered to be statistical significance. Statistical analysis was performed using the SPSS Statistics version 20.0(SPSS, Inc., Chicago, IL, USA).
During the study period, a total of 693 women were assessed for eligibility, 57 (8.2%) of whom were excluded because they did not fulfill the eligibility criteria. Among 318 women in randomization, 12 (1.7%) women were further excluded from analysis: 10 of them were transverse to intrapartum cesarean, 2 of them were found lack of risk of atonic PPH during data collection. Of the women who participated in the trial, none were lost to follow-up. The trial profile was shown in the Figure 1.
Baseline characteristics between the two groups were broadly similar, regarding maternal age, gravidity, parity, body mass index before delivery, gestational age, birth weight, initial hemodynamic and hemoglobin before delivery. Induced labor was found in about 60% of all the women in the trial, labor augmentation in one-fourth. Risk factors for atonic PPH were not significantly different between the groups, as were the duration of the first, the second stage of labor (Table 1).
The primary outcome of blood loss of at least 500 mL within 24 hours postpartum occurred in 93 cases (29.6%) in the carbetocin group, as compared with 83 cases (26.8%) in the oxytocin group (relative risk (RR): 0.87, 95% CI: 0.61–1.23, P = 0.48, in Table 2). Either the amount of intrapartum blood loss ((329.1 ± 236.4) mL vs. (307.9 ± 242.2) mL, P = 0.27) or that of blood loss within 24 hours ((422.9 ± 241.4) mL vs. (406.0 ± 257.5) mL, P = 0.40) were identical between two groups.
However, manual removal of the placenta was applied in 19 women (6.1%) in the oxytocin group, significantly more than 6 women (1.9%) in the carbetocin group (RR. 3.35, 95% CI: 1.32–8.51, P = 0.01). Two-thirds of women who received manual removal in both groups were for uterine bleeding. Manual removal for uterine bleeding was more often indicated in women in the oxytocin group than in the carbetocin group (4.3% vs. 1.3%, RR: 3.39, 95% CI: 1.09–10.52, P = 0.03). No difference was found in women for manual removal indicated for prolonged third stage of labor between the two groups (1.9% vs. 0.6%, RR: 3.08, 95% CI: 0.62–15.37, P = 0.17).
Subgroup analysis was also performed among women received induced and/or augmented labor (272 in the carbetocin group vs. 262 in the oxytocin group, with equal baseline). There was still a highly significant difference between the two groups regarding the rate of manually placenta remove (1.8% vs. 6.5%, RR: 3.71, 95% CI: 1.35–10.2, P = 0.01) and the reason was also for uterine bleeding (in Supplementary Appendix Table S1, http://links.lww.com/MFM/A6). When tested in women without labor induced and/or augmented, the difference was disappeared (in Supplementary Appendix Table S2, http://links.lww.com/MFM/A7).
The rate of additional interventions in terms of the need for the second line uterotonics (23.9% vs. 23.5%, RR: 0.93, 95% CI: 0.68–1.42, P = 0.93), blood transfusion (0.3% vs. 0.6%, RR: 2.03, 95% CI: 0.18–22.53, P = 0.62), and fluid resuscitation (10.2% vs. 8.7%, RR: 0.84, 95% CI: 0.49–1.44, P = 0.59) were low overall and did not differ between the carbetocin and oxytocin groups. The frequency of postpartum hemoglobin less than 80 g/L was more happened in the oxytocin group than carbetocin group with no significant different (1.9% vs. 0.3%, P = 0.07). This may be attributed to the hemoglobin of 2 cases in oxytocin group were only 82 g/L and 83 g/L before delivery. Actually, there were only 4 cases in oxytocin group and 1 case in carbetocin group with postpartum hemoglobin less than 80 g/L due to PPH (1.3% vs. 0.3%, P = 0.21).
Vital signs were regularly monitored postpartum (Fig. 2). After uterotonics infusion, the blood pressure in the carbetocin group tend to be lower than that in the oxytocin group (P > 0.05), especially at 30 minutes postpartum (P < 0.05), while pulse tend to be simultaneously higher (P > 0.05, in Supplementary Appendix Table S3, http://links.lww.com/MFM/A8). No severe adverse event was reported, and no maternal death or perinatal death. All participants were followed-up until 42 days discharged from the hospital, and one case in oxytocin group readmission for late PPH.
Two large-scale multi-center studies were designed as noninferiority trial, and to determine if the use of carbetocin was as effective as conventional oxytocin for the prevention of PPH in vaginal delivery.13,14 However, the purpose of our superiority trial was to expect that carbetocin was superior to oxytocin in preventing PPH in vaginal delivery, with the suitable routes of administration and optimal doses of oxytocin. Because in some trials, the carbetocin was administered as 100 μg dosage IM, while oxytocin was administered IV or IM at varied dosages (5-10 IU).5,15,16
This study showed that prophylactic intravenous infusion of carbetocin was not better than oxytocin to reduce the risk of PPH during vaginal delivery in high risks women. Meanwhile, we found carbetocin was superior to oxytocin in decrease the risks of manually remove the placental, especially in women with induced or augmented labor. Carbetocin has a longer half-life than oxytocin and could be of value. Based on moderate-certainty evidence, a new network meta-analysis suggested that carbetocin has the 83.1% probability of being the best agent to reduce PPH ≥500 mL after vaginal delivery.7 However, the effect of carbetocin on the delivery of placenta had not been tested in clinical scenario. Earlier study found retained placenta increased with large doses of carbetocin (200 μg IM) given immediately after birth and many subsequent studies had delayed administration until after delivery of the placenta.17 The advantage of its application at the end of the third stage of labor did find in many secondary outcomes, like decreased need for uterine massage and other therapeutic uterotonics, narrower hemoglobin fallen but not placenta delivery.15 In a small double-blind randomized controlled trial where carbetocin was administered after infant delivery, less requirements of instrumental curettage of the uterine cavity had been reported in the carbetocin group (8.0% vs. 13.8%) though no significant difference. Mohammed et al. reached a similar conclusion that carbetocin infusion helped to delivery placenta and avoid evacuation and curettage in second-trimester abortion.18 The findings that carbetocin decreased manual removal of placenta in our trial are consistent with the results of previous studies and also reflected on the frequency of postpartum hemoglobin less than 80 g/L. The incidence of manual removal of placenta following vaginal delivery is an infrequent outcome. This study and all the other studies were not powered to determine the correlation.
Carbetocin exerts its role via oxytocin receptor which showed desensitization phenomenon after oxytocin preexposure. Compared with non-laboring women, nine times more does of oxytocin (2.99 IU) or at least eight times more amount of carbetocin (121 μg) were required in women received exogenous oxytocin during labor to obtain effective uterine contraction in 90% women (90% effective dose, ED90). Yet, in this trial, the effect of one ED90 carbetocin dose was similar to that of three times of oxytocin ED90 dose suggesting more efficacious of carbetocin in the prevention of PPH. The pharmaceutical characteristics of carbetocin is more complex that both agonist and antagonistic properties against the contractile effect of oxytocin were displayed in myometrium strips. The effect of carbetocin in the control of the uterine atony is not fully understood. Because carbetocin costs 10 times more than oxytocin now in our area and is not widely available, oxytocin remains the mainstay for prevention of PPH.
The mode of uterotonics administration is a practical issue in the delivery room. In several studies, carbetocin had been applied in the different route of administration (i.e., intramuscular, intravenous bolus, shot, or infusion), with varies injection speed (over 1 or 10 seconds, 30–60 seconds or over 60 seconds).17 Our study is the first to compare the preventive effect of intravenous infusion of carbetocin to oxytocin after vaginal delivery. The average time for infusion is 12 minutes. Although no major adverse event was found, non-invasive hemodynamic measurement did detect a small decreased in blood pressure after carbetocin infusion. Recently, intramuscular injection of heat stable carbetocin had been showed noninferior to oxytocin in the prevention of PPH after vaginal delivery with little side effects.13 This formulation of carbetocin has been recommended as a good alternative uterotonic in PPH prevention where maintaining a cold chain is difficult.13 Further studies on the route of administration of heat stable carbetocin are needed.
The measurement of blood loss during and after delivery was strictly followed the study protocol. The incidence of blood loss over 500 mL was about 30% which was in consistence with our previous study, but much higher than several other studies. To reduce bias, we maintained blinding until the statistical analysis was performed. Data was uploaded to web-based medical research public management platform ResMan (http://www.medresman.org) timely and objectively. All women were followed-up to 42 days postpartum.
This trial has several limitations. First, this trial was conducted in a single referral center. The results of this study might not be suitable at community level. Second, the rate of PPH interventions used in the work were higher than many other researches. We attribute this to the high rate of PPH resulting from objective measurement of blood loss which in turn leading to early intervention. Third, the requirement for additional uterotonic agents or manual removal of placenta was based on the subjective assessment atony and the speed of bleeding to determine.
Carbetocin could be considered as a good alternative agent to oxytocin in the PPH prevention in the third stage of labor in women with induced or augmented labor to reduce the need for manually remove the placental. Intravenous infusion injection of carbetocin allows midwife to have her hands free to focus on the other more important procedures after fetus delivery in busy clinical practice.
The authors would like to thank all participants, and the residents for their assistance in conducting the study.
Hua Li analysed the data and wrote the manuscript. Xiu-Yun Xu, Ning Gu, Xiao-Dong Ye and Zhi-Qun Wang carried out the analysis. Ya-Li Hu reviewed the manuscript. Yi-Min Dai made the contribution to the study design and reviewed the text. All authors read and approved the final manuscript.
Conflicts of Interest
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