A comparative study of oxytocin, carboprost, methylergometrine and misoprostol in prevention of postpartum haemorrhage a prospective study

Background: Post partumhemorrhage (PPH) is an important cause of maternal mortality accounting for nearly 15-20% of maternal deaths in India. Oxytocic drugs like oxytocin, ergot alkaloids, and various prostaglandins are being used for active management of third stage of labour. Materials and Methods: A prospective study was conducted in the Department of Obstetrics and Gynaecology of Al Ameen Medical College, Vijayapur, in 400 women. Patients were randomized into four groups of 100 each and were given oxytocic within 60 seconds of delivery anterior shoulder of the baby. Oxytocics used were 10 IU intramuscular oxytocin,125 μg intramuscular carboprost, 0.2 mg intravenous methylergometrine, and 800 μg tablet misoprostol per rectally in groups A, B, C and D respectively. Results: Duration of third stage of labor recorded was minimum with carboprost with mean duration of 3.84+/-0.99 minutes and was maximum with methylergometrine with mean duration of 5.04+/-1.02 minutes. Amount of blood loss observed was minimum with carboprost (mean 131 +/-72.037 ml) and maximum with Methylergometrine (mean 435+/-147.578 ml). Hemoglobin drop was also seen more with Methylergometrine with mean drop of 0.872+/-0.458 gm% and minimally with carboprost with mean drop of 0.236 +/-0.221 gm%. Conclusion: It is concluded from this study that carboprost is the uterotonic of choice followed by oxytocin for active management of third stage of labor.


Introduction
The third stage of labour is the most crucial stage, begins with expulsion of baby and ends with expulsion of placenta and membranes. Its average duration is 15 min in both primigravida and multigravida [1]. Postpartum hemorrhage is one of the dreaded complications of third stage of labour. In India every 4 minutes a woman dies during childbirth [2]. Maternal mortality rate in India is 212 per 100000 live births. Among them 30% of deaths are due to postpartum hemorrhage (PPH) [3].
Reducing likelihood of postpartum haemorrhage by routine active management of third stage of labour could play an important role in reducing maternal mortality and morbidity in modern obstetrics. The decrease in the problems associated with third stage of labour has been attributed to judicious use of different oxytocic preparations administered at time of delivery of anterior shoulder and a transition from expectant to active intervention [4][5]. Drugs conventionally used for prophylaxis against PPH includes oxytocin, methylergometrine, misoprostol and 15 methyl PGF2α(Carboprost) [6]. Recent studies have shown that there are still wide variations in practice around the world in the management of third stage of labour [7][8].
Prophylactic use of oxytocic agents after delivery of the infant has been shown to reduce the incidence of PPH by 40%. But it is associated with side effects ranging from nausea, vomiting, and hypertension to postpartum eclampsia, intracerebral haemorrhage, myocardial infarction, cardiac arrest and pulmonary oedema [2]. Carboprost tromethamine is a PGF2 α analogue. It is

Original Research Article
Obsgyne Review: Journal of Obstetrics and Gynecology Available online at: www.medresearch.in 100 |P a g e given as a single intramuscular injection. It is free from side effects such as hypertension [9]. Postpartum haemorrhage is defined as any amount of bleeding following delivery which can lead to deterioration in the condition of woman.
It is difficult to delineate the risk factors for postpartum haemorrhage. So, all woman are considered at risk. Active management of third stage of labor has been universally recommended as not an option but a rule.
This includes administration of uterotonics, controlled cord traction and fundal massage the placenta will be delivered safely after the delivery of fetus and can prevent postpartum haemorrhage and maternal deaths.

Aims and Objectives
1. To evaluate and compare the efficacy of oxytocin, carboprost, methylergometrine and misoprostol in the active management of third stage of labor and thereby prevention of PPH.
2. To compare the amount of blood loss in third stage.
3. To compare the duration of third stage.

Methods
The present prospective study was conducted in the Department of Obstetrics and Gynaecology, Al Ameen Medical College, Vijayapur, over the period from 2017 to 2018 after taking approval from Institutional Ethical Committee. Four hundred patients were enrolled and these patients were distributed in four different groups randomly.
Informed consent and counselling of the patients was done. A detailed history of all the patients was taken including name, age, parity, socioeconomic status, and menstrual history, period of gestation (in weeks), obstetrical history including postpartum hemorrhage and history of any medical disorder. Complete general and systemic examination was done. Detailed systemic and obstetrical examination was done. Pelvic examination was done.
After detailed history and examination, patients were randomized into four groups of 100 each as follows: Group A-Patients received 10 IU intramuscular oxytocin.
Placebo control is not possible in this study because we can't deny a uterotonic to a patient after delivery.
Inclusion Criteria: Women with singleton pregnancy, Term gestation, without any high risk factors.
3. Maternal complications: PIH, Multiple pregnancy, Grand multipara, APH, malpresentations, patient with known blood coagulation disorder, patient with known allergy to prostaglandins, history of medical disorderscardiac disease/renal disease, anemia (Hb<7gm%) Active management of third stage of labor was done within one minute after the birth of the baby using one of the four oxytocic drugs as per the group of the patient.
Within a minute of delivery of baby, Brass-V drapes were immediately applied to measure the amount of blood loss. Placenta was delivered by controlled cord traction as soon as signs of placental separation appeared. Inspection of vulva for perineal tears and per speculum examination for cervical tear was carried out and if present patients were not taken into series. Repeat haemoglobin estimation was done on second postpartum day.
Type of study: Prospective study. However 6 patients in group C had postpartum hemorrhage (statistically significant with p-value of 0.004) ( Table 2).
Two patients out of six who had postpartum haemorrhage necessitating additional oxytocics and blood transfusion which is statistically significant with a p-value of 0.111 (Table 2).
Nausea and vomiting were found to be the commonest side effects in all groups followed by shivering and fever.

Discussion
Postpartum hemorrhage is one of the most important cause for maternal deaths throughout the world. Active management of third stage of labor and the use of prophylactic oxytocics has reduced its incidence in many countries. The primary aim in the management of postpartum hemorrhage should be its prevention. The active management of the third stage with routine prophylactic administration of oxytocics at the time of delivery of the anterior shoulder of the fetus has been shown to reduce the risk of postpartum hemorrhage by about 40% [5,10].
Recent studies show that there are still wide variations in practice around the world in the management of third stage of labour. Methyl ergometrine is a conventional oxytocic used extensively but is associated with unpleasant side effects like hypertension. Intramuscular oxytocin used alone has been found effective in preventing postpartum hemorrhage with fewer side effects and is recommended by world health organization but most of the times additional uterotonics are required [8,11]. Various drugs and routes of administration have been tested with varying success. Oxytocin is probably the most commonly used oxytocic and has been well known in midwifery for a long time. Though commonly used it is not the potent drug and many a times requires additional drugs and blood loss is more compared with other drugs [11].
The production of PGF2α in the decidual tissue was found to be more when obtained during labour indicating the increase in the synthesis and release of PGF2α into the circulation. PGF 2α is a powerful uterotonic agent with a physiological role in human parturition both in the delivery of the foetus and control of post partum bleeding. The discovery of prostaglandins and its analogues as an oxytocics has improved prospect in modern era in control of PPH due to its significant influence on uterine tone resulting in minimizing blood loss which outweighs its cost. The side effects are also subtle [12][13]. Hence this study was conducted at Al Ameen medical college to evaluate the four uterotonic drugs. This study has shown that that carboprost is the uterotonic of choice followed by oxytocin for active management of third stage of labor. There are few studies where carboprost has been compared with methyl ergometrine and found that the mean duration of third of labour with carboprost was comparable to our study [14,15]. As compared to other studies and in accordance with it, the present study showed decrease in mean duration of third stage of labor incarboprost group was 3.84 minutes compared to oxytocin 4.72 minutes. Therefore carboprost can be effective in reducing the duration of third stage of labour.

Original Research Article
Obsgyne Review: Journal of Obstetrics and Gynecology Available online at: www.medresearch.in 103 |P a g e Various studies have shown that the mean blood loss with carboprost 125μg was less compared to methyl ergometrine.
Few studies compared carboprost with syntometrine, which did not show any difference in mean blood loss in both the group [14]. In the present study mean blood loss in third stage in carboprost was 131.8 ml and oxytocin was 223.2 ml.
(p value of 0.0001) which was highly significant [11]. None of them developed PPH in carboprost group but 6 women had PPH in methylergometrine group. This was comparable with other studies as shown in the table. Hence carboprost is effective in reducing blood loss and carboprost has sustained impact on tone of uterus. Hemoglobin was 0.3 in oxytocin and 0.23 carboprost, 0.87gm% in methylergometrine group, 0.44gm% in misoprostol group which was statistically significant (p value of 0.0001). Two required blood transfusion in methylergometrine group and none in other 3 groups.
In group A, minor side effects in the form of shivering, vomiting and headache were observed. Our findings are not consistent with that of Gohil J et al (2011) as the incidence of these minor side effects was much lowerintheir study [21].
In group B Diarrhea and vomiting were most commonly observed inalong with chills in only 12%. This is comparable to the study of Chua S et al (1995) where they found a significant increase in the incidence of diarrhea with prostidin [24].
In group C in addition to shivering and nausea, side effects like hypertension was also observed in 24% of patients, study being consistent with that of Gohil J et al (2011) as patients exhibited hypertension in their study also [21].
In group D, minor side effects, like shivering and fever, were present in 48% and 56% of patients. Our study is consistent with the study of El Refaey et al ( in which their patients also exhibited fever and shivering [22,23,25].
The only Drawback in using carboprost is its storage in cold chain at 2-4 celsius while oxytocin can be stored at room temperature.

Conclusion
Carboprost when used prophylactically results in minimal blood loss with fewer side effects. This small dose 125μg is well tolerated by the patients. An added advantage is it can be used in patients with hypertension and cardiovascular disease. In India where anemia highly prevalent, the risk of PPH is very high.
Intramuscular carboprost, a potent uterotonic is a desirable drug as it is well tolerated in small doses and significantly reduces the risk of PPH by limiting duration of 3 rd stage of labour & by reducing the blood loss Our study emphasizes that carboprost is better alternative to intramuscular oxytocin in active management of third stage of labour.
Acknowledgements-All my regards to my patients without whom the study was not possible and the ethical committee of Al Ameen medical college and my team in department of OBG.

Contribution by Co-Authors:
Our corresponding author and second author are senior professor and experienced in this field, hence their guidance helped us in selecting the type of study in various discussions of cases and getting maximum number of study material and patients.
What this study adds to existing knowledge: 1. Our study proves that carboprost is most effective and well tolerated uterotonic in prevention of PPH. 2. Lesser requirement of additional uterotonics and blood transfusion.