Randomized Parallel Trial of Intramyometrial Injection of Heat-stable Carbetocin vs Intramyometrial Injection of Oxytocin for the Prevention of Postpartum Hemorrhage during Cesarean Delivery

INTRODUCTION

Worldwide, postpartum hemorrhage, or PPH, is the leading cause of maternal death. Uterine atony has been the commonest cause of PPH. Guidelines for the use of preventive uterotonics in the avoidance of PPH have been provided by the WHO. Carbetocin, oxytocin, methergine, carboprost and misoprostol have been used in the prophylaxis of postpartum haemorrhage.¹ There is, however no mention of any varied dose or route for cesarean delivery. Intramyometrial route has been used to deliver uterotonic drugs such as oxytocin and carboprost by operating obstetricians during cesarean delivery.² Studies have shown that the intramyometrial route of uterotonic may cause immediate uterine contractions due to the local action of the absorbed drug. This may be helpful in preventing blood loss. Carbetocin is the synthetic counterpart of oxytocin which is longer acting compared to oxytocin (t_1/2 85–100 minutes). Unlike oxytocin, carbetocin does not require cold storage and remains stable for 1.5 years at thirty degrees Celsius temperature and relative humidity of 75%. Heat stable carbetocin was introduced in India in 2021. Carbetocin has been used via intramyometrial route during myomectomy in open and laparoscopic surgeries but not for cesarean sections. Hence, a Novel study was designed for intramyometrial injection of heat stable carbetocin vs intramyometrial injection of oxytocin for the prevention of postpartum bleeding during cesarean delivery.

MATERIALS AND METHODS

This 1 year study, a randomized parallel trial, was conducted in the Obstetrics and Gynecology Department at the Shri BM Patil Medical College, Hospital and Research Centre, BLDE (DU), in Vijayapura, Karnataka, India. The Institutional Ethics Committee (IEC) has granted the study ethical clearance. BLDE(DU)/IEC/562/2021-2022. Clinical Trials of India CTRI/2021/09/036792 has the trial registered.

RESULTS

A total of 857 pregnant women underwent cesarean sections during the study period. The first 100 pregnant women who fit the study requirements were included in the study. Informed written consent was obtained and randomized into group I (Carbetocin group) and group II (Oxytocin group). There were no drop-outs after inclusion in the study. Group I and group II were homogeneous with respect to patient characteristics. There was no statistically significant difference across the two groups in the women’s age, parity, obstetric score, or weight (Table 1). This study excluded women in active labor. We included the women in early labor defined as less than 6 cm cervical dilation. In both study groups, the proportion of these women was comparable (p-value 0.335 - not significant). Hemoglobin levels prior to operation and the postoperative hemoglobin levels on day 2 of surgery were measured. The drop in the hemoglobin levels was measured and found to be similar, and although there was a statistically significant difference between the two groups, the difference is not substantial in terms of clinical outcomes (Table 2). The uterine tone was assessed at 1, 3, 5, and 10 minutes in both the groups after administration of the drug on a scale of 1–5. It was found to be similar in the both the groups over the time intervals (p-value > 0.05) (Table 3). The variations in vital parameters heart rate, systolic BP, diastolic BP and SpO₂ were recorded at 1, 5, and 10 minutes. No significant variability was noted in both the groups (Table 4). The adverse events following the administration of drugs, such as nausea, PPH, tachysystole, uneasiness in chest/chest pain, were looked out for. One case in group II had nausea. No other cases in both the groups reported any adverse reactions (p-value 0.315) (Table 5). In two cases in group I and four cases in group II, additional uterotonics were delivered. Two cases in group I and one case in group II involved the transfusion of blood and blood components.

DISCUSSION

Studies have been conducted on the dosage and delivery method of uterotonics during elective cesarean sections. Though the use of intramyometrial route has not been licensed for oxytocin, the use has been advocated for over 30 years. Intramyometrial route is said to be faster in action in comparison to the intramuscular route due to local action of the drug. However, the comparison of intramyometrial route to the intravenous route in the use of oxytocin has not shown to have any benefits other than reducing nausea and vomiting.⁵ This is the first study to assess the use of carbetocin intramyometrially during a cesarean surgery. Compared to oxytocin, carbetocin has a longer half-life, which results in a longer duration of effect. The intramyometrial route of carbetocin has been less studied. This study highlights that when administered intramyometrially, carbetocin is just as efficient as oxytocin in preventing postpartum hemorrhage. The blood loss was nearly equal in both the study groups, 0.943 gm/dL in group I vs 0.912 gm/dL in group II. A large multicentric trial showed that the amount of blood loss of at least 500 mL or additional uterotonic agents used were similar in both the carbetocin group, and oxytocin group.⁴ The tone of the uterus was well contracted for 5 minutes in both the groups. Just 4% of cases in group I and 8% of cases in group II warranted the administration of additional uterotonics. These findings are consistent with non-inferiority, as seen in the Champion trial.⁴ Blood transfusion was done for 4 percent of cases in group I and 2 percent of cases in group II. About the dosage of carbetocin, one study that used 100 micrograms of the drug intravenously during a cesarean section right after the baby was delivered reported that only 3.3% of patients experienced significant bleeding. The usefulness of carbetocin in preventing postpartum hemorrhage during cesarean sections was highlighted in this study.⁶ No adverse effects were observed in group I, and only one case in group II had an adverse event, which is statistically not significant. Studies on the intramyometrial route suggest that this route would deliver an immediate effect on the uterus, with lesser systemic effects. Our study did not show any significant variations among the two groups with respect to hemodynamics after administering the drug. In a study using 20 IU oxytocin intramyometrially, they observed that there was more hypotension in comparison to the intravenous route.⁷ Other studies have not shown significant hypotension after administering intramyometrial oxytocin. However, the study could not conclude any advantage of the intramyometrial route. The tone of the uterus was similar after administering intramyometrial carbetocin or oxytocin. Studies conducted in Japan have observed a delay in the tone in the intramyometrial group.⁸ Studies on the use of intramyometrial carbetocin are few. One study has used the intramyometrial carbetocin during myomectomy and concluded that the blood loss was less in comparison to rectal misoprostol or the use of nothing.⁹ A literature review was done on the implementation of heat-stable carbetocin for PPH prophylaxis in poor-resource countries. They observed that heat stable carbetocin can be affordably used in low-income economies for public sector use and that it has demonstrated efficacy in reducing postpartum bleeding in vaginal and cesarean sections in tertiary level hospitals.¹⁰

CONCLUSION

In terms of effectiveness and safety in preventing postpartum hemorrhage during cesarean sections, intramyometrial injection of carbetocin is comparable to intramyometrial injection of oxytocin. Heat stable carbetocin has the advantage of a long half-life along with not requiring cold transportation and storage. With competitive pricing, carbetocin could be projected as an appropriate replacement for oxytocin in the prophylaxis of PPH.

ORCID

Rajasri G Yaliwal https://orcid.org/0000-0002-9740-6300

Preeti S Malapure https://orcid.org/0000-0002-9214-1147

REFERENCES

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