Effect of Heat stable Carbetocin vs Oxytocin for Preventing Postpartum Haemorrhage on Post Delivery Hemoglobin- A Randomized Controlled Trial

Post-partum haemorrhage is one of the major causes of maternal mortality in low- and middle-income countries. Oxytocin is the rst choice uterotonic for the PPH prevention but it requires cold storage. Heat stable carbetocin appears to be a promising agent for the prevention of PPH. The present study was an ancillary to the WHO CHAMPION Trial conducted to compare the effect of heat-stable carbetocin 100 µg IM versus oxytocin 10 IU IM on post-delivery hemoglobin level in one of the participating facilities in India. Methods This was a nested randomized controlled trial designed to compare the effect of heat-stable carbetocin 100 µg IM versus oxytocin 10 IU IM, administered within one minute of vaginal delivery of the baby for prevention of postpartum haemorrhage, on post-delivery 48–72 hours hemoglobin level, adjusted for pre-delivery hemoglobin level. 1,799 women from one hospital in India participated in this study. hemoglobin, slightly higher drop and higher percentage of women having a drop of 2 g/dL or larger, compared to 10 IU of oxytocin, but these differences are not clinically relevant. Post-delivery hemoglobin unadjusted or adjusted for pre-delivery hemoglobin was slightly lower for carbetocin compared to oxytocin. Correspondingly, the drop in hemoglobin was slightly higher for carbetocin. The proportion of participants with a drop in hemoglobin of 2 g/dL or more, both unadjusted and adjusted for pre-delivery hemoglobin, was higher for carbetocin. However, the magnitude of these differences was not clinically relevant. The present study also showed that there is a decrease in post-delivery hemoglobin with blood loss which was not signicantly different between carbetocin and oxytocin groups. Based on results from the present study, measurement of drop in hemoglobin might be eventually used as a proxy for post-partum blood loss, provided further studies are conducted to shed more light on other individual factors that can improve individual prediction of blood loss, for assessing the ecacy of intervention for prevention and treatment of post-partum hemorrhage.

further studies are conducted to shed more light on other individual factors that can improve individual prediction of blood loss, for assessing the e cacy of intervention for prevention and treatment of post-partum hemorrhage.

Background
Maternal mortality continues to be unacceptably high and in 2017, about 295,000 women died during and following pregnancy and childbirth. Almost all of these deaths occurred in low-resource settings, and most could have been prevented [1]. In 2015, United Nations adopted the Sustained Development Goals which aims at improving maternal health by reducing the global maternal mortality ratio to less than 70 per 100,000 livebirths by 2030 [1,2]. Postpartum haemorrhage (PPH) is one of the major causes of maternal mortality in low-and middle-income countries. PPH affects approximately 5% of all women who give birth [3]. It is associated with nearly one-fourth of all maternal deaths globally and uterine atony is the most common cause of PPH [3].
PPH is commonly de ned as a blood loss of 500 ml or more within 24 hours after birth, while severe PPH is de ned as a blood loss of 1000 ml or more within the same timeframe. The majority of deaths due to PPH could be avoided through the use of prophylactic good quality uterotonics during the third stage of labour and by timely and appropriate management. WHO recommendations, updated in 2018, mention ve effective drugs for the prevention of PPH namely oxytocin, carbetocin, misoprostol, ergometrine/ methylergometrine, and oxytocin with ergometrine xed-dose combination [3,4]. Oxytocin (IM/IV, 10 IU) is recommended as the uterotonic drug of choice [3]. The use of heat-stable (HS) carbetocin has been recommended for the prevention of PPH in settings where oxytocin is unavailable (or its quality cannot be guaranteed) and where the cost of HS carbetocin is comparable to other effective uterotonics [3,5,6]. HS carbetocin is a long-acting synthetic agonist analogue of the human oxytocin [7,8,9].
The World Health Organization conducted the WHO CHAMPION trial which was a phase III, randomized, double-blind, active controlled, multinational, multicentre, non-inferiority trial comparing the effectiveness of HS carbetocin with oxytocin for the prevention of postpartum haemorrhage during the third stage of labour in women delivering vaginally. The trial methods and results are described in detail elsewhere [10,11].
Although measured postpartum blood loss has been used as the primary outcome in a number of trials assessing the e cacy of strategies for prevention and treatment of PPH, post-delivery hemoglobin and decline from pre-delivery level have been regarded as more appropriate alternatives because they are theorized to be stronger indicators of risk for shock and death than postpartum blood loss [12]. Secondary analysis of data from three multi country randomized trials done by Anger H showed that there was a correlation between the blood loss after delivery and post-partum drop in hemoglobin They also found that the relation was not signi cant in cases where the blood loss was below 500 ml and was signi cant when the blood loss was more than 1000 ml [13,14]. Mean drop in pre-to-post hemoglobin of 2 g/dl or more is considered as a clinically important value to assess the correlation between blood loss and post-partum drop in haemoglobin in previous studies [12,15,16]. There are no studies assessing the effect of heat stable carbetocin for prevention of postpartum hemorrhage in low risk vaginal deliveries with post-delivery hemoglobin as the primary outcome. Even the large heat stable carbetocin trial coordinated by WHO has not incorporated post-delivery hemoglobin as an end point for assessing the e cacy of heat stable carbetocin. Hence, we conducted a nested randomized controlled study to compare the effect of heat-stable carbetocin 100 µg IM versus oxytocin 10 IU IM on post-delivery hemoglobin level in one of the participating facilities in India.

Methods
This is an ancillary study of the WHO CHAMPION trial which collected data on pre and post-delivery hemoglobin levels during the period of 12 months. The primary outcome was post-delivery 48-72 hours hemoglobin. The secondary outcome was the proportion of women with a drop in post-delivery hemoglobin ≥ 2 g/dl after 48-72 hours of delivery [11].
The WHO CHAMPION trial was a randomized, double-blind, non-inferiority trial comparing the effectiveness of HS carbetocin with oxytocin for the prevention of PPH after vaginal birth. The trial methods and results are described in detail elsewhere [11]. This ancillary study was conducted in one of the six participating sites in India, and it consisted of including the additional measurement of pre-and post-delivery hemoglobin to the WHO CHAMPION protocol. Design and procedures are the ones described in the main study [11].
After initial clinical assessment of women presenting for delivery to the KLES Dr Prabhakar Kore Charitable Hospital & Medical Research Center, Belgaum, a written informed consent was taken separately for the ancillary study along with the consent for the main trial.
Pre-delivery hemoglobin of each participant was recorded before she was randomized to the main trial. Estimation of hemoglobin was done using the HemoCue Hb 301 with the technology of absorbance measurement of whole blood at Hb/HbO 2 isobestic point with a cuvette. Under aseptic conditions, 0.5 ml of the capillary blood was collected after nger prick with a sterile lancet and placed on the cuvette. The time required by the hemoglobinometer for the hemoglobin estimation was approximately 10 seconds. Hemoglobin values were recorded on a form speci cally designed for this study.
During the second stage of labour when vaginal delivery was imminent, eligible women were randomized to receive either oxytocin 10 IU IM or HS carbetocin 100 µg IM based on the random allocation sequence generated centrally at WHO Headquarters (the CHAMPION trial coordination centre) using computer-generated random numbers. During the third stage of labour women received the randomly assigned treatment, and blood loss was measured for one hour or two hours if bleeding continued after the rst hour [17].
Post-delivery hemoglobin was measured using the same standard procedure used for estimation of pre-delivery hemoglobin between 48-72 hours postpartum.
The present study was approved by JNMC Institutional Ethics Committee for Human Subjects. The trial was registered with Clinical Trial Registry of India CTRI/2016/06/006996.

Statistical analyses
The main analysis was conducted with the modi ed intention-to-treat population (as de ned in Widmer et al 2018).
Descriptive statistics were calculated for characteristics of women and those of babies at birth. The number of participants, number of events and percentages in each category were calculated for the categorical variables. Number of participants, median and interquartile range (IQR) were calculated for the numeric variables.
Univariate analyses were conducted with the variables: pre-delivery hemoglobin, post-delivery haemoglobin, the drop from predelivery to post-delivery hemoglobin, and blood loss, to compare the treatments, using analysis of variance techniques. The statistical distribution of the variables was examined to decide whether a transformation was needed. The difference of means was used if the distribution was close to normal. In the case of blood loss, the distribution was asymmetric and the logarithmic transformation was used.
The primary outcome, post-delivery hemoglobin, was analysed using analysis of covariance to compare treatments, with predelivery hemoglobin as covariate to adjust the post-delivery hemoglobin for possible differences in baseline values (Model 1). Analysis of covariance is the preferred technique compared to the analysis of post-pre-difference [18]. Adjusted means of postdelivery hemoglobin were calculated, with 95% con dence intervals.
Regression analysis was used to assess the association of post-delivery hemoglobin and blood loss volume between the treatments (Model 2). This association was explored by including an interaction term of blood loss by arm in the model in order to allow the treatment regression lines to have different slopes (Model 3). The association between post-delivery hemoglobin and blood loss was quanti ed by the treatment-speci c regression coe cients The proportion of women with a drop in post-delivery hemoglobin of 2 g/dl or more from pre-delivery hemoglobin was calculated for each treatment and compared using relative risk (RR) with 95% con dence intervals and risk difference with 95% con dence intervals. Both unadjusted and adjusted analysis for pre-delivery hemoglobin were conducted.

Results
The Belgaum site participated in the main study-CHAMPION Trial and recruited 1799 women for this sub-study. The trial pro le is shown in Figure 1. After randomization, two women underwent caesarean section in each group. After excluding the missing values, the participants included in nal analysis were 890 in the HS carbetocin group and 889 in the oxytocin group.
Baseline characteristics of women at trial entry, characteristics of women at labour and characteristics of babies at birth were similar for the two treatment groups ( Table 1).
The mean pre-delivery haemoglobin and median post-partum blood loss as shown in Table 2 were similar across the treatment groups. For post-delivery hemoglobin unadjusted analysis the mean was slightly lower for carbetocin compared to oxytocin (0.128 g/dl lower, p-value=0.0432). The drop in hemoglobin between pre-delivery and post-delivery was slightly higher for carbetocin (p-value=0.0786). The results of the adjusted analyses for post-delivery haemoglobin (Model 1) are shown in Table 3. The adjustment for pre-delivery hemoglobin showed similar results to the unadjusted analysis (similar point estimate for the difference between treatments in post-delivery hemoglobin means and p-value=0.0334). Additionally, adjusting for blood loss (Model 2) did not change the results.
From the regression coe cients (Model 3, see Appendix) it can be derived that post-delivery hemoglobin, adjusted for pre-delivery hemoglobin, decreases on average 0.09 g/dL for each dL of blood lost for carbetocin, and 0.14 g/dL for each dL of blood lost for oxytocin group. However, the difference of these coe cients was not signi cant (p-value=0.2171 for the interaction blood loss by treatment group). Therefore, there is no evidence that the decrease in post-delivery hemoglobin with blood loss is different between the treatment groups as shown in Figure 2.
A drop of ≥ 2 g/dL in hemoglobin from pre-delivery to post-delivery after 48-72 hours of delivery was seen in 27.9% of women in carbetocin group compared to 24.1% in the oxytocin group as shown in Table 4. The relative risk of having this event among women receiving carbetocin, compared to women receiving oxytocin, was 1.16 (95% CI 0.99 to 1.36) in the unadjusted analysis, not attaining signi cance at 5% (p-value=0.0682). When adjusted for pre-delivery hemoglobin, the relative risk was 1.29 (95% CI 1.02 to 1.63), signi cant at 5% (p-value≥0.0337).

Discussion
In the present ancillary study, we were able to assess the effect of HS carbetocin compared to that of oxytocin on the postdelivery (48-72 hours) hemoglobin and on the drop in hemoglobin between pre-delivery and post-delivery hemoglobin. There was a drop in hemoglobin between pre-delivery and post-delivery of the order of 1 g/dL, and there was no evidence of difference in this drop between HS carbetocin (1.2 g/dL) and oxytocin (1.1 g/dL) (p-value=0.0786). Post-delivery hemoglobin, adjusted for predelivery hemoglobin and blood loss, was marginally lower for HS carbetocin compared to oxytocin (0.13 g/dL lower), statistically signi cant but not clinically relevant. Our study showed that the decrease in post-delivery hemoglobin for each dL of blood lost (0.09 g/dL for carbetocin and 0.14 g/dL for oxytocin on average), adjusted for pre-delivery hemoglobin was not signi cantly different between two groups. The overall negative association between post-delivery hemoglobin and blood loss was statistically signi cant (p<0.0001). The drop in post-delivery hemoglobin ≥ 2 g/dL after 48-72 hours of delivery adjusted for predelivery hemoglobin was higher for carbetocin (p value=0.0337) although it was not clinically relevant.
A study done by Larciprete et al comparing the use of carbetocin versus oxytocin in caesarean section with high risk of postpartum haemorrhage showed that the post-partum drop in hemoglobin after 2 hours and 24 hours was similar in both the groups.17Another study done by Mark Boucher showed similar results wherein no signi cant difference was seen in the drop in haemoglobin and haematocrit values between the two groups receiving carbetocin and oxytocin after vaginal delivery [19].
Despite the slightly higher, but clinically insigni cant, drop in post-delivery haemoglobin for HS carbetocin compared to oxytocin, the former offers advantage in being heat stable. Delayed diagnosis and treatment can lead to hypovolemic shock in women with severe postpartum haemorrhage. Hence, accurate measurement of blood loss and timely diagnosis and management can prevent avoidable morbidity and mortality associated with cases of severe post-partum haemorrhage [13]. The use of heat stable carbetocin would be a boon for prevention of post-partum haemorrhage in peripheral regions of low-and middle-income countries where constant maintenance of cold temperature for oxytocin is a di culty.