Carbetocin versus oxytocin for prevention of postpartum hemorrhage after vaginal delivery in high risk women 

Postpartum hemorrhage (PPH) is best defined and diagnosed clinically as excessive bleeding that makes the patient symp- tomatic and/or results in signs of hypovolemia [1]. The most common definition of PPH is estimated blood loss 500 ml after vaginal birth. The inadequacy of this definition was illustrated in studies that assessed blood loss using various objective methods: the mean blood loss reported after vaginal delivery was approximately 400 to 600 ml, and clinicians were likely to underestimate the volume of blood loss [2].

The incidence of PPH has been reported to be 3.9% in women who delivered vaginally [3].

Risk factors for PPH include prolonged labor (412h), severe anemia, preeclampsia, antepartum hemorrhage, intra- partum blood loss, history of PPH or retained placenta, body mass index (BMI) 435, polyhydramnios, multiple gestation and difficult instrumental delivery [4,5]

Systematic reviews have concluded that active manage- ment of the third stage of labor, particularly the prophylactic use of uterotonic agents can significantly decrease the incidence of PPH compared with that of expectant manage- ment [6–8].

Oxytocin is the most widely used uterotonic agent [9–11], but has a half-life of only 4–10min [12], that is why it is better administered as a continuous intravenous infusion to achieve sustained uterotonic activity [7,13].

Carbetocin is a synthetic long-lasting oxytocin agonistic analogue with prolonged half-life prolonging its pharmaco- logical effects [14]. Its prolonged uterine activity may theoretically offer advantages over oxytocin in the manage- ment of the third stage of labor. The side-effect profile of carbetocin was not found to be different from that of oxytocin [15], but may prove to be advantageous when compared to Syntometrine [10].

The aim of this study was to compare the effectiveness and tolerability of carbetocin versus oxytocin in the prevention of PPH after vaginal delivery in women with at least two risk factors of atonic PPH.

Material and methods

This study was a prospective double-blinded randomized, with balanced randomization (1:1) and parallel grouped study, it was conducted on 200 pregnant women attending Kasr Al Ainy and Benisuef maternity hospitals during the period from May 2013 to December 2014. A control group was not included for ethical reasons.

The study was approved by local ethics committee and informed consents about the study and expected value and outcome were obtained. All participants were at 37–40 weeks of gestation with at least two risk factors for developing atonic PPH. Women were approached in the antenatal clinic or early in labor if appropriate. Risk factors included previous PPH, Primipara 440 years, BMI 435, multiple pregnancy, prolonged labor412h, and ultrasound estimated fetal weight

44 kg. Participants with placenta previa, coagulopathy, preeclampsia, cardiac, renal, liver diseases, epilepsy, and known hypersensitivity to oxytocin or carbetocin were excluded.

All patients were subjected to full history taking, general, abdominal and obstetric examination. Ultrasound scan, com- plete blood picture, liver functions and coagulation profile were also done.

Participants were equally randomized using automated web-based randomization system ensuring allocation con- cealment into two groups: Group 1 included 100 women who received a single 100mg IM dose of carbetocin (PabalÕ Ferring, West Drayton, UK ) and group 2 included 100 women who received 5 IU IM oxytocin (SyntocinonÕ , Novartis, Basel, Switzerland). Both drugs were administered after delivery of the posterior shoulder, in cases of twin pregnancy the drugs were given after delivery of the second twin.

All participants were followed-up for 24h. The uterine tone and amount of bleeding were noted and the need for further uterotonic agents was checked 2 min after giving the drug. Blood loss was estimated by weighing the swabs and using pictorial charts. PPH was defined as bleeding 4500 ml and major PPH was defined as bleeding 4100ml. Blood hemoglobin was assessed 24 h after delivery.

Systolic and diastolic blood pressures were measured immediately after delivery, 30 and 60 min after delivery. We recorded possible complications like nausea, vomiting, tachycardia, flushing, dizziness, headache, shivering, metallic taste, dyspnea, palpitation and itching.

Data were statistically described in terms of mean ± stand- ard deviation (±SD), or frequencies (number of cases) and percentages when appropriate. Comparison of numerical variables between the study groups was done using inde- pendent t-test. For comparing categorical data, Chi square ( 2) test was performed. Exact test was used instead when the expected frequency is less than 5. p values less than 0.05 were considered statistically significant. All statistical calculations were done using computer program SPSS (Statistical Package for the Social Science; SPSS Inc., Chicago, IL) release 15 for Microsoft Windows (2006).

Results 

The 200 patients were classified into two groups: Group 1 included 100 patients who received carbetocin and group 2 included 100 patients who received oxytocin.

Baseline characteristics of the groups are summarized in Table 1. There was no significant difference between the groups in age, gravidity, parity, body mass index, gestational age and fetal birth weight.

Risk factors for atonic and traumatic PPH were not significantly different between the groups (Table 1).

There was no significant difference between the groups regarding the duration of 1st, 2nd and 3rd stages of labor (Table 1).

The amount of bleeding, occurrence of PPH, need for other uterotonics, the difference between blood hemoglobin levels before delivery and 24h after delivery were significantly lower in the carbetocin group. On the other hand, there was no significant difference between the two groups regarding occurrence of major PPH and the need for blood transfusion (Table 2).

Women in the carbetocin group had a statistically signifi- cant lower systolic and diastolic blood pressure immediately after delivery, at 30 and 60 min after delivery (Table 3).

Regarding drugs side effects, there was no significant difference between the two groups regarding occurrence of nausea, vomiting, flushing, dizziness, headache, shivering, metallic taste, dyspnea, palpitations and itching. The inci- dence of tachycardia was significantly higher in the carbetocin group (Table 4).

Discussion

Our results have shown that carbetocin is superior to oxytocin in prevention of PPH after vaginal delivery in women with at least two risk factors for developing atonic PPH. This fact can be explained by the known longer half-life of Carbetocin when compared to Oxytocin causing a more uterine response, in terms of frequency and amplitude of uterine contractions [14].

Table 1. Baseline characteristics of the groups*. 

*Data are presented as mean ± SD.
BMI, body mass index; PPH, postpartum hemorrhage. 

Two substantive studies comparing active management of third stage with expectant management have clearly indicated the advantages of active management. The Bristol trial [16], in which active management had been the norm, and the Hinchingbrooke trial [17], in which expectant management had been the norm, both studies demonstrated significant reductions in the incidence of PPH with active management compared with expectant management (5.9% versus 17.9% and 6.8% versus 16.5%, respectively). Both studies were terminated after interim analysis because the difference in PPH rate was so great.

Reyes et al. performed a prospective double-blinded randomized controlled trial in 60 women with severe preeclampsia who were randomized to receive either oxytocin or carbetocin during the third stage of labor. They found that carbetocin was as effective as oxytocin in the prevention of PPH. Carbetocin had a safety profile similar to that of oxytocin, and it was not associated with the development of oliguria or hypertension. They concluded that carbetocin is an appropriate alternative to oxytocin for the prevention of PPH in women with severe preeclampsia [18].

That difference between our results and those of Reyes et al. may be attributed to the difference in the studied population. Reyes et al were studying women with severe preeclampsia but we have excluded women with preeclampsia from our study.

In our study, we found that the amount of bleeding after delivery was significantly lower in women who received carbetocin than those who received oxytocin (Figure 1). We also found less need for additional uterotonics and less difference between hemoglobin before and after delivery among women in the carbetocin group.

Boucher et al. have randomized 160 women undergoing vaginal delivery with at least one risk factor for PPH to

Table 2. Bleeding and Hb results of the groups* 

*Data are presented as mean ± standard deviation.
Data are presented as number and percent. 

Table 3. Blood pressure measurements in the groups*. 

*Data are presented as mean ± SD. 

Table 4. Drug complications*.

*Data are presented as number and percent. 

Figure 1. Amount of bleeding in the groups. 

in the difference in the studied populations, we studied women with risk factors for atonic PPH undergoing vaginal delivery, but Attilakos et al studied women undergoing cesarean sections with or without risk factors for PPH [15].

Leung et al. compared the efficacy and safety of intramuscular (IM) carbetocin with IM syntometrine in preventing primary PPH in a prospective, double-blinded, randomized controlled trial. They found that IM carbetocin was as effective as IM syntometrine in preventing primary PPH after vaginal delivery. It was less likely to induce hypertension and had a low incidence of adverse effect. So, it should be considered as a good alternative to conventional uterotonic agents used in managing the third stage of labor [20].

In our study, there was a significantly lower blood pressure (affecting both systolic and diastolic blood pressure) imme- diately after delivery and at 30 and 60min after delivery among women in carbetocin group than women in oxytocin group. These results agree with those of Samimi et al. who randomized 200 women undergoing vaginal delivery to receive either carbetocin or syntometrine, they found that the systolic BP measurements at 0, 30, and 60min after delivery were significantly higher in the syntometrine group [21].

Moertl et al. studied 56 women undergoing elective cesarean section after spinal anesthesia. They measured hemodynamic parameters taken for 500s upon administra- tion of a slow intravenous bolus of 100mg of carbetocin or 5IU of oxytocin to prevent PPH. They found a non- significant difference in the hemodynamic effects of both drugs, with a maximal effect at about 30–40s: HR increased 17.98 ± 2.53 bpm for oxytocin and 14.20 ± 2.45 bpm for carbetocin. Systolic blood pressure (sBP) decreased ( 26.80 ± 2.82 mmHg for oxytocin versus 22.98 ± 2.75mmHg for carbetocin). Following the maximal effect, women treated with carbetocin recovered slowly to baseline values asymptotically (HR and BP), whereas women treated with oxytocin displayed a slight rebound bradycardia at 200 s ( 6.8 ± 1.92 bpm). Patients under both treatments showed a similar profile of side effects without any indication of unexpected adverse effects. They concluded that both oxyto- cins have comparable hemodynamic effects and are uterotonic drugs with an acceptable safety profile for prophylactic use. Minimal differences in the recovery phase beyond 70 s are in keeping with the fact that carbetocin has an extended half-life compared with oxytocin [22].

The difference between our results and those of Moertl et al. can be attributed to the difference in sample size between the studies. We studied 200 women but Moertl et al. studied 56 women only. The difference can be also due to the use of spinal anesthesia in the study of Moertl et al. Another difference is in the studied population, Moertl et al. studied women undergoing elective cesarean section, but we have studied women undergoing vaginal delivery with at least two risk factors of atonic PPH.

We did not find a significant difference between the two study groups regarding drugs side effects apart from tachy- cardia being more common in women who received carbetocin than those who received oxytocin. These results agree with those of Moertl et al. [22] and Attilakos et al. [15], who found no significant difference in the side effects between carbetocin and oxytocin.

To the best of our knowledge, our study is the first study comparing carbetocin effectiveness, safety and hemodynamic effects with oxytocin after vaginal delivery in women with at least two risk factors of developing atonic PPH.

We concluded that carbetocin is a better alternative to traditional oxytocin in prevention of PPH after vaginal delivery in women with at least two risk factors for atonic PPH with minimal hemodynamic changes and similar side effects and could be routinely used to prevent PPH, which represents the main deaths among parturient women.

Declaration of interest

The authors declare no conflicts of interests. 

References

1. Prata N, Gerdts C. Measurement of postpartum blood loss. BMJ 2010;340:c555.

2. Stafford I, Dildy GA, Clark SL, Belfort MA. Visually estimated and calculated blood loss in vaginal and cesarean delivery. Am J Obstet Gynecol 2008;199:519. e1–7.

3. Naef III RW, Chauhan SP, Chevalier SP, et al. Prediction of hemorrhage at cesarean delivery. Obstet Gynecol 1994;83:923–6.

4. Jansen AJ, van Rhenen DJ, Steegers EA, et al. Postpartum hemorrhage and transfusion of blood and blood components. Obstet Gynecol Surv 2005;60:663–71.

5. Combs CA, Murphy EL, Laros Jr RK. Factors associated with postpartum hemorrhage with vaginal birth. Obstet Gynecol 1991; 77:69–76.

6. Prendiville WJ, Elbourne D, McDonald S. Active versus expectant management in the third stage of labour (Cochrane review). The Cochrane library. Oxford, UK: Update Software; 2003.

7. McDonald S, Abbott JM, Higgins SP. Prophylactic ergometrine- oxytocin versus oxytocin for the third stage of labour. Cochrane Database Syst Rev 2004;(1):CD000201.

8. Elbourne DR, Prendiville WJ, Carroli G. Prophylactic use of oxytocin in the third stage of labour (Cochrane Review). The Cochrane Library. Oxford, UK: Update Software; 2003.

9. Bouwmeester FW, Boltc AC, van Geijn HP. Pharmacological and surgical therapy for primary postpartum haemorrhage. Curr Pharm Des 2005;11:759–73.

10. Chong Y-S, Su L-L, Arulkumaran S. Current strategies for the prevention of postpartum haemorrhage in the third stage of labour. Curr Opin Obstet Gynecol 2004;16:143–50.

11. Wedisinghe L, Macleod M, Murphy DJ. Use of oxytocin to prevent haemorrhage at caesarean section–a survey of practice in the United Kingdom. Eur J Obstet Gynecol Reprod Biol 2008;137:27–30. J Matern Fetal Neonatal Med, 2016; 29(4): 532–536

12. Chard T, Boyd N, Forsling M. The development of a radio- immunoassay for oxytocin: the extraction of oxytocin from plasma, and its measurement during parturition in human and goat blood. J Endocrinol 1970;48:223–34.

13. Liabsuetrakul T, Choobun T, Peeyanajarassri K, Islam QM. Prophylactic use of ergot alkaloids in the third stage of labour. Cochrane Database Syst Rev 2007;18: CD005456.

14. Hunter DJ, Schulz P, Wassenaar W. Effect of carbetocin, a long- acting oxytocin analog on the postpartum uterus. Clin Pharmacol Ther 1992;52:60–7.

15. Attilakos G, Psaroudakis D, Ash J, et al. Carbetocin versus oxytocin for the prevention of postpartum haemorrhage following caesarean section: the results of a double-blind randomised trial. BJOG 2010; 117:929–36.

16. Prendiville W, Harding JE, Elbourne DR, Stirrat GM. The Bristol third stage trial: active versus physiological management of the third stage of labor. BMJ 1988;297:1295–300.

17. Rogers J, Wood J, McCandlish R, et al. Active versus expectant management of third stage of labor: the Hinchingbrooke randomized controlled trial. Lancet 1998; 351:693–9.

18. Reyes OA, Gonzalez GM. Carbetocin versus oxytocin for preven- tion of postpartum hemorrhage in patients with severe preeclamp- sia: a double-blind randomized controlled trial. J Obstet Gynaecol Can 2011;33:1099–104.

19. Boucher M, Nimrod CA, Tawagi GF, et al. Comparison of carbetocin and oxytocin for the prevention of postpartum hemor- rhage following vaginal delivery: a double-blind randomized trial. J Obstet Gynaecol Can 2004;26:481–8.

20. Leung SW, Ng PS, Wong WY, Cheung TH. A randomised trial of carbetocin versus syntometrine in the management of the third stage of labour. BJOG 2006;113:1459–64.

21. Samimi M, Harsini AI, Kalahroudi M. Carbetocin vs. syntometrine in prevention of postpartum hemorrhage: a double blind randomized control trial. Iran Red Crescent Med J 2013;15: 817–22.

22. Moertl MG, Friedrich S, Kraschl J, et al. Haemodynamic effects of carbitocin and oxytocin given as IV bolus on women undergoing CS. BJOG 2011;118:1349–56.