Carbetocin Use during Caesarean Deliveries in Preventing Postpartum Haemorrhage (PPH) In Enugu: A 15-Case Series and Review of Literature

ABSTRACT


INTRODUCTION
Primary postpartum haemorrhage (PPH) is one of the most feared complications in pregnancy and a leading cause of maternal mortality globally with an incidence of 2-11%. 1-3It is defined as the loss of blood from the genital tract of up to 500ml following vaginal delivery or 1000ml following caesarean delivery or any amount of blood loss that could lead to a woman's cardiovascular instability or reduction of haemoglobin by 10% or more from the baseline within the first 24 hours after delivery. 4-6It is estimated that globally about 14 million women experience PPH and 70,000 maternal deaths arise from it yearly. 7It is also known that about 70 to 80% of PPH are caused by uterine atony. 8- 11 Therefore, preventing uterine atony especially among women undergoing caesarean delivery and other high risk pregnant women will go a long way in reducing maternal morbidity and mortality arising from PPH.Over the years, and across generations, history is filled with various attempts by birth attendants and accoucheurs to enhance uterine tone postpartum and reduce the risk of PPH.The first drugs to be used for their uterotonic properties were ergot-alkaloids, followed by oxytocin and at last the prostaglandins. 12The ergot alkaloids have a lot of side-effects and complications that have limited their use.The active management of the third stage of labour using oxytocin has reduced the occurrence of PPH by 60-70%. 13In the present day obstetrics the use of oxytocin is firmly established but it appears that the maximum possibilities of the drug have been reached, hence, the need for a more effective uterotonic drug that can meet the need of uterine tone especially among women with high risk pregnancies for PPH such as those undergoing cesarean deliveries.Carbetocin is a long-acting synthetic oxytocin analogue: 1deamino-1-monocarbo-(2-O-Methyltyrosine)-oxytocin, first described in 1987 with a half-life of 40 minutes (around 4-10 minutes) longer than oxytocin; and uterine contraction occurs in less than 2 minutes after intravenous administration of optimal dose of 100µg. 14It is a medication used for preventing PPH after childbirth especially following caesarean section and appears to work as well as oxytocin. 15It works as an oxytocic, antihaemorrhagic and uterotonic drug and functions as an agonist at peripheral oxytocin receptors, particularly in the myometrium with less affinity for myoepithelial cells.Unlike oxytocin, it does not require constant refrigeration and a cold chain system of storage. 16This makes it suitable in the resource-poor countries where electricity may not be sufficiently available.The oxytocin receptors are G-protein coupled and the mechanism of action involves second messengers and production of inositol phosphates. 17It can be administered intravenously or intramuscularly and the recommended dose in an adult is 100µg.Carbetocin is essentially safe but some minor side-effects have been reported such as nausea, vomiting, abdominal pain, itching, increased body temperature trembling and weakness. 18Others include back and chest pain, dizziness, chills, sweating, tachycardia and respiratory distress.The average blood loss during caesarean section is estimated at about 500-600ml by various investigators 19,20 and some recorded even higher values.A systemic review and metaanalysis in 2022 concluded that for patients undergoing caesarean section and vaginal delivery, Carbetocin was superior to oxytocin in effectiveness and similar in safety and therefore recommended Carbetocin as an alternative for oxytocin in preventing PPH. 21An analysis of the costeffectiveness of Carbetocin versus oxytocin in the UK concluded that Carbetocin utilization leads to lower prophylactic treatment cost and less PPH events versus oxytocin when utilized for the prevention of PPH following vaginal birth. 22It was also found that prophylactic single dose of Carbetocin use reduces the need for additional uterotonic agents when compared with standard dose of oxytocin, also reduced the incidence of PPH 23 and similar results were gotten when compared with a combination of oxytocin and ergometrine and fewer side-effects were also observed. 24However, only 100µg of Carbetocin (a 1 dose fits all preparation) is available despite the differences in body/mass indices and hence, the anticipated weights of our prospective parturient.A smaller dose formulation to meet the need of smaller women may reduce the cost per ample and further make the drug pocket friendly, increase availability and uptake in resource poor countries.This area needs further studies especially in low resource countries like ours.The above findings showed that a lot of works have been done on Carbetocin lately and the need to present our experiences with this novel drug that promises a lot of comparative advantage over the existing uterotonics.

AIM
The aim was to analyze our experiences with Carbetocin during caesarean section in preventing PPH.

OBJECTIVES
The objectives were to determine the: 1.Average estimated blood loss following the use of Carbetocin 2. Average reduction in PCV 3. The proportion that had need for additional uterotonics 4.

METHODOLOGY
This was a case series of 15 patients who had caesarean delivery in one of the above listed centres.Most of these women had a high risk for PPH.High risk pregnancy in this study refers to pregnancies with increased tendencies to bleeding after delivery such as placenta praevia, placental abruption, multiple gestation, macrosomia, previous Corresponding Author Onyekpa IJ caesarean deliveries, prolonged labour, grand multiparous women, previous PPH etc.The enrollees were selected and counseled on the drug and their consent obtained.They were also informed that should bleeding occur, they will be treated in accordance to standard PPH management globally.The pre-operative PCV was done and the values noted.All the surgeries were under spinal anaesthesia after preloading with at least 1 litre of normal saline.After the delivery of the baby 100µg of the PABAL ® brand of Carbetocin injection was given intravenously and the placenta delivered.The intra-operative blood loss was visually estimated by the obstetrician and the anaesthetist, the average was determined and the value documented.A repeat PCV was done on the 2 nd day post-operatively and the values noted.In a situation where the single dose of Carbetocin could not control the bleeding other uterotonics such as oxytocin, prostaglandins and ergot-alkaloids were used to control the bleeding.Any observed side-effects were noted, treated and documented

DATA ANALYSIS
Data was collated using a proforma and analyzed with Statistical Package for Social Sciences, SPSS version 25.0 for Windows.Frequencies, means and percentages were calculated and represented in tables.

RESULTS
The result showed that 15 subjects were involved in the study.
Table 1 below revealed the socio-demographic distribution of the subjects.Out of the fifteen subjects analyzed, 5(33.3%) were less than 30 years while 10(66.7%)were more than 30 years.Majority of them were Igbo 14(93.3%)whereas only 1(6.7%) was Yoruba Table 2 below showed some clinical characteristics of the subjects.Seven of them (46.7%) were primipara whereas 1(6.7%) was para 4 or more and 7(46.7%) were either para-2 or para-3.Intra-operatively 12(80%) had no uterine fibroid and 3(20%) had uterine fibroid of different sizes and numbers.It also revealed that 6(40%) were delivered at a gestational age of 38 weeks, 3(20%) at 37 weeks and 1(6.7%) each at 35 and 40 weeks.Only 1(6.7%) had need for additional uterotonics whereas the remaining 14(93.3%)had no need for additional uterotonics during and after the surgery.There was no record of any side-effects in any of the subjects.Table 3 below showed the distribution based on the different indications for the surgery.Prolonged labour and placenta previa with previous caesarean delivery topped the list with each having 3(20%) whereas breech presentation and previous caesarean deliveries were 2(13.3%)each; the others constituted the remaining 5(33.3%)

DISCUSSION
The aim of this15-case series was to analyze our experiences during caesarean section with Carbetocin in preventing PPH following caesarean deliveries in our centres.It is thought that Carbetocin, a long-acting oxytocin analogue promises to be of better effect in maintaining uterine tone and reducing PPH arising from uterine atony.The estimated mean blood loss from the study was 335.33ml±140.80.This was significantly lower than the average estimated blood loss during caesarean deliveries pegged at 500-600ml by Abdulrahim G et al and Khan FA et al. 19,20 While Abdulkarim and his team worked on 97 full-term pregnant women and compared different methods of estimating blood loss to arrive at their value under standard uterotonic agents, ours was a simple case-series of just 15 women who had cesarean deliveries under Carbetocin and we used only visual estimation to arrive at our value.These variables might have contributed to the differences in the amount of blood loss.On the other hand, Khan et al worked on 126 patients who had caesarean delivery under standard oxytocic agent.The estimation of blood loss also was via different methods including visual by both the anaesthetist and the obstetrician, intra-operative and post-operative transfusion and pre-and post-operative haemoglobin and haematocrit whereas our study was a case-series of 15 subjects under Carbetocin using only one method of estimation(visual method) these differences could also have accounted for the differences.However, one outstanding difference between the quoted studies above and ours is the type of uterotonic agent used.The mean reduction in the PCV in our study was found to be 3.27±1.28.This differed from the finding of Singh B et al who found an average haematocrit drop of 5.49±1.27under standard uterotonic cover in a tertiary hospital setting. 25This difference in the PCV above could be due to the fact that theirs was a prospective, observational study unlike ours and their sample size of 121 was way higher than our sample size of 15.Secondly, this difference may be due to the difference in the choice of uterotonic agents used.
The common side-effects associated with Carbetocin use during caesarean section in our centres

Table 3 : Indication for CS
Table4below showed the distribution based on the amount of estimated blood loss (EBL).The mean EBL was 335.33ml±140.80withp-value of 0.001 and confidence interval of 4.68-8.26,theaverage pre-operative packed cell volume (PCV), 34.2%±2.73whereas the mean post-operative PCV was 30.93%±2.21 with p-value of 0.001 and confidence interval of 2.55-3.90