Introduction
Postpartum hemorrhage (PPH) is the leading cause of maternal morbidity and maternal mortality globally. The effect it has on the maternal health and its social impact is circumstances of maternal death are devastating. In view of this, universal use of uterotonic drugs during delivery has been advised by the World Health Organization (WHO) as a part of active management of third stage of labor, in the prevention of PPH. The use of 10 IU oxytocin IM or IV has been recommended by the WHO universally within one minute of delivery of the baby during either vaginal delivery or cesarean delivery. Recently carbetocin has been added to the list of essential drugs for PPH prevention by WHO.1, 2
Carbetocin is a heat stable uterotonic. It is a long acting oxytocin analogue. It has longer duration of action, half -life being 40 minutes. This drug has been used since 1997 in a few countries and has been used in its heat stable form since 2018.3
The heat stable nature of carbetocin is useful for its use where refrigeration and electricity supply is a concern which would be needed for the storage of oxytocin.4 Its longer half - life has an advantage over oxytocin, especially in elective cesearean delivery cases as the need for giving additional oxytocin for a couple of hours after the surgery would be circumvented.5
The major drawback of carbetocin is that it is expensive in comparison to oxytocin.
When the use of prophylactic uterotonics are described, there are no consensus on the dose of uterotonics separately for caesarean delivery vs vaginal delivery. The elective caesarean poses a challenge to the obstetrician as the uterus is not in labour, therefore the oxytocin receptors on the uterus are more sensitive to a smaller dose of uterotonic. Lower doses are said to be as effective as standard dose in elective caesarean delivery. However, there is no consensus on doses of uterotonics for elective vs emergency caesarean delivery.6, 7
This study aims to compare the effectiveness and safety of 50 mcg carbetocin (lower dose) to 100mcg carbetocin (standard dose) for the prevention of postpartum hemorrhage during elective cesarean delivery.
Materials and Methods
This study was conducted at Bijapur Lingayat District Education (Deemed to be University) Shri BM Patil Medical College, Hospital, and Research Center, in the Department of Obstetrics and Gynecology. It was conducted on consenting women with term pregnancies (37-42 weeks of gestation) who were over 18 years undergoing elective LSCS under subarachnoid block (Spinal Anesthesia). Women who were in labor, or those who had coagulopathies, hypertension, cardiovascular disorders, hepatic, renal disorders, epilepsy were excluded. Women with conditions predisposing to uterine atony such as hydramnios, multiple gestation, abruption, placenta previa and severe anemia were also excluded from the study. The study was conducted between July 2022 to December 2023.
Sample size calculation
The anticipated means of estimated blood loss (ml) with 40 and 100 mg dose of carbetocin 806±310 and 697±453 respectively. (3) the required minimum sample size is 106 per Group (i.e. a total sample size of 212, assuming equal group Sizes) to achieve a power of 80% and a level of significance of 5% (two-sided), for detecting a true difference in means between two groups. Level of significance = 95%. The power of the study=80%, d = clinically significant difference between two parameters, SD = Common standard deviation.
Statistical analysis
The data obtained was entered in a Microsoft Excel Sheet, and statistical analysis was performed using statistical package for the social sciences (Version 21). Results will be presented as means, counts and percentages. For normally distributed continuous variables between two groups Independent t test was used. For not normally distributed variables Mann Whitney U test was used. Categorical variables between two groups were compared using Chi square test.
A p <0.05 was considered statistically significant.
Study design
The study was a randomized parallel single blinded group trial.
The study was conducted in accordance with the Declaration of Helsinki. It had obtained the Ethical clearance from the Institute Ethical committee, bearing Reference No. BLDE (DU)/IEC/575/2021-22 and was registered at Clinical Trials Registry of India CTRI/2022/03/041222.
The primary outcome of the study was to assess the blood loss in both groups by assessing intraoperative blood loss and the difference in preoperative and post-operative hemoglobin levels.
The secondary outcome was to assess the tone of the uterus, use of additional uterotonics or styptics, requirement of blood transfusions and adverse effects of the drug.
Method
A total of 2465 women were screened for inclusion into the study. After meeting the inclusion criteria and obtaining written and informed consent, the participants were assigned to either Group I or Group II as per predetermined randomization chart. Randomization was done by computerized randomization chart obtained from www.randomizer.org. Pre-operative pulse, blood pressure (BP) and complete blood count was obtained. Spinal anesthesia was given using bupivacaine 0.5% and cesarean delivery was performed. Group I was administered 50 mcg of carbetocin as a bolus dose IV within one minute of the delivery of the neonate. The drug was administered over 1 minute. Group II was administered 100mcg of carbetocin IV within one minute after the delivery of the baby. The drug was administered over one minute. The uterine one was recorded at one, five and ten minutes. It was assessed on a scale of one to five, where in the uterine tone corresponded to the following 1. Atonic, 2. Partial, inadequate uterine contractions, 3.Adequate contractions of the uterus 4. Well contracted uterus, 5.Very well contracted uterus. Blood loss was assessed by collection of blood in the suction bottle and weighing the wet mops. Mops were weighed pre-operatively and post operatively and the difference was calculated. The estimated blood loss was calculated using the formula 1 gm = 1ml of blood. The total blood loss was calculated by adding the blood in the suction apparatus and the blood from the mops. Pulse rate and blood pressure of the participants were recorded at beginning of the procedure and at one, five, ten minutes and at end of procedure. In case of use of any additional uterotonic or tranexamic acid or blood transfusion, it was recorded. The Complete Blood Count (CBC) was repeated between 48-72 hours after the caesarean delivery.
Table 1
Showing basic variables
Table 2
Showing clinical parameters on enrolment to the study
Table 3
Showing the uterine tone at various time after delivery of the drug
Table 4
Comparison of blood loss between the groups
Result
A total of 2456 women were screened. A were excluded due to unwillingness to participate in the study or not meeting the inclusion criteria. 108 participants were in Group I (carbetocin 50 mcg) and 104 in Group II (carbetocin 100mcg).
There was no significant difference between both the groups with respect to age of the participant (p=0.860), gestational period (p = 0.399), prior history of vaginal or cesarean delivery. (p=0.828, 0.266 respectively) (Table 1).
There were no statistically significant differences between both the groups with respect to pulse rate, systolic and diastolic blood pressure on admission, weight of the patient, uterine size and fetal heart rate (p>0.05). (Table 2)
Comparing the two groups with respect to the tone of the uterus after administering the carbetocin in the specified dose, there was no statistical significance. Most of the participants had a good tone by 1 minute. The mean tone was 4 at 10 minutes in both the groups. (Table 3)
Adverse effects of the drugs like nausea, vomiting, headache, chills, back pain, hypotension, flushing, dyspnea, and chest pain were not seen in any patient in both the groups
There was no statistical difference in blood loss, (Table 4) need for uterotonics, and additional procedures blood transfusion in both the groups. The average blood loss in both the groups was less than 350 ml.
There was no need for surgical intervention like brace sutures, revascularization, uterine artery ligation, internal iliac ligation, per partum hysterectomy in both the groups.
None of the patients required any blood transfusion or additional drugs.
Discussion
This study aimed to study the effectiveness of a lower dose of carbetocin during elective cesarean delivery. The study showed that the blood loss in both the 50mcg carbetocin and 100mcg carbetocin were similar. Various studies have used lower doses of carbetocin in the elective cesarean. Doses as low as 20mcg have shown to be as effective in maintaining the uterine tone, use of additional uterotonics and blood transfusion in comparison to the standard dose of 100 mcg.8 Even a dose of carbetocin as low as 14.8 mcg was considered non inferior to the standard dose.9 In comparison, lower doses of oxytocin have shown to be as effective as the standard dose of oxytocin in elective cesarean section. As carbetocin has a longer duration of action, it would not require the additional infusion after the bolus dose during elective cesarean delivery as in comparison to oxytocin.10
Other studies show that a dose of 62.9mcg of carbetocin was required for women with a BMI of more than 40 kg/m2.11
In a study conducted in Canada a total of 120 women were randomly allocated to groups receiving carbetocin doses of 20 μg, 40 μg, 60 μg, 80 μg and 100 μg. There was no difference in uterine tone among all dose groups and there still appeared to be an unacceptably high incidence of hypotension.12 Study did not find any significant difference in both the groups with respect to hemodynamic circulation or was there any significant hypotension. Carbetocin could be made as a choice in resource limited conditions.13 The cost of the drug is the main hinderence to its use. WHO has signed a memorandum with the manufacturers to reduce its price.14 Adverse effects of carbetocin are low and are similar to those of oxytocin.15
Carbetocin has been recently introduced in the India, in the year 2021, hence the studies conducted on carbetocin during cesarean delivery are less in number. This study shows that the 50mcg dose of carbetocin is non inferior to the standard dose of carbetocin.
Conclusion
Low dose carbetocin is as efficacious and safe as standard dose of carbetocin for the prevention of postpartum hemorrhage in elective cesarean delivery. This inference could reduce the cost of the drug used. It could lead to smaller packaging of the drug. It could potentially prevent cardiovascular adverse effects, though this study did not reveal any untoward cardiovascular effects of carbetocin.
Limitation
This study is limited to Indian ethnicity. The study did not blind the operating obstetrician or anesthesiologist. The study did not differentiate between primary or repeat cesarean deliveries.
