A multicentre randomized controlled trial of oral misoprostol and i.m. syntometrine in the management of the third stage of labour

P.S. Ng1, A.S.M. Chan2, W.K. Sin3, L.C.H. Tang2, K.B. Cheung3 and P.M. Yuen1,4

1 Department of Obstetrics and Gynaecology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, 2 Department of Obstetrics and Gynaecology, Kwong Wah Hospital, Kowloon, and 3 Department of Obstetrics and Gynaecology Tuen Mun Hospital, Tuen Mun, New Territories, Hong Kong


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Postpartum haemorrhage accounts for nearly 28% of maternal mortality in developing countries. Syntometrine is an effective and commonly used oxytocic in preventing postpartum haemorrhage, but it requires a controlled storage environment and i.m. administration. Misoprostol is an orally active uterotonic agent. A total of 2058 patients having a singleton pregnancy, low risk for postpartum haemorrhage and vaginal delivery were randomized to receive either 1 ml syntometrine or 600 µg misoprostol for the management of the third stage of labour. There were no significant differences between the two groups in the mean blood loss, the incidence of postpartum haemorrhage and the fall in haemoglobin concentration. The need for additional oxytocic injection was significantly higher in the misoprostol group [relative risk (RR) 1.62, 95% confidence interval (CI) 1.34–1.96], but that of manual removal of placenta was reduced (RR 0.29, 95% CI 0.09–0.87). Shivering and transient pyrexia were more common in the misoprostol group. Oral misoprostol might be used in the management of the third stage, especially in situations where the use of syntometrine is contraindicated and facilities for storage and parenteral administration of oxytocics are limited.

Key words: misoprostol/syntometrine/third stage of labour


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Postpartum haemorrhage is an important cause of maternal morbidity and mortality, especially in developing countries where up to 28% of maternal deaths are attributed to this cause (Walder, 1997Go). The prophylactic use of oxytocics in the third stage of labour has been shown to significantly reduce the risk of postpartum haemorrhage (Prendiville et al., 1989Go) and its use is generally advocated in the management of the third stage of labour.

Most of the oxytocics require parental administration and syntometrine is one of the most widely used oxytocics. However, the administration and storage of syntometrine may not always be possible in some hospitals or rural communities due to the non-availability of sterile needles, syringes or refrigeration equipment. The efficacy of syntometrine has been shown to be significantly reduced when it is stored in a suboptimal environment (Chua et al., 1993Go). Oral administration of ergometrine has been shown to be ineffective in reducing post-partum blood loss (de Groot et al., 1996Go). and the oral preparation is not stable under simulated tropical conditions (de Groot et al., 1995Go), making it unsuitable for use in tropical countries. Misoprostol is an orally active uterotonic agent. It is a prostaglandin E1 analogue and was first marketed as an anti-peptic ulcer drug. Recently, it has been found to be effective in medical evacuation of the uterus in spontaneous abortion, cervical ripening and induction of labour. After oral administration, it is absorbed rapidly into the blood stream and when taken in early pregnancy, it has been reported to cause an increase in uterine tonus within 7 min (Danielsson et al., 1999Go). It is stable at high temperatures and has a long shelf-life. It is cheaper than the other oral and parenteral prostaglandins. Its use in the management of the third stage of labour was first reported in a small observational study in 1996 (El-Refaey et al., 1996Go). Thereafter, there were a number of small studies suggesting that oral misoprostol is better than a placebo in reducing the risk of postpartum haemorrhage (El-Refaey et al., 1997Go; Hofmeyr et al., 1998Go; Surbek et al., 1999Go).

Therefore, a randomized controlled trial was conducted to compare the efficacy and safety of oral misoprostol with i.m. syntometrine in the management of the third stage of labour.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Study population
This was a prospective, multicentre, randomized, controlled trial performed from June 1998 to February 1999 in three tertiary training centres in Hong Kong. All patients having a singleton pregnancy and a vaginal delivery were randomly assigned to receive either 600 µg (three 200 µg tablets) of oral misoprostol or 1 ml of i.m. syntometrine (containing 5 units of oxytocin and 0.5 mg ergometrine). Written consent was obtained from the patient on admission to the labour ward. However, randomization was not carried out until vaginal delivery was imminent and that was done by opening of sealed consecutively numbered opaque envelopes. The randomization was based on a table of computer-generated blocks of random numbers. Each centre was given a set of identical envelopes, each of which contained the mode of randomization, either 600 µg of oral misoprostol or 1 ml i.m. syntometrine.

Exclusion criteria
Exclusion criteria included the presence of contraindications for the use of either misoprostol or syntometrine, such as pre-eclampsia, cardiac disease and asthma, and the presence of conditions requiring prophylactic oxytocin infusion after delivery such as grand multiparity (parity >=4) or presence of uterine fibroids. However, patients receiving oxytocin infusion during the first stage of labour were included.

Treatment administration
Misoprostol was administered orally immediately after delivery of the baby; syntometrine was given i.m. at delivery of the anterior shoulder of the baby. If an oxytocic infusion was used during labour, it was stopped at the end of the second stage. The third stage was managed by awaiting for signs of placental separation and the placenta was delivered by controlled cord traction. Irrespective of the allocation of the medication, an additional dose of syntometrine was given if the uterus was not well contracted or if there was excessive vaginal bleeding as assessed by the midwife or doctor attending the delivery. In all cases, the randomization, preparation and administration of the medication was carried out by a second midwife who was not involved in the management of the patient except for the drug administration.

Assessment
The primary outcome of the trial was the amount of blood loss during delivery and the occurrence of primary postpartum haemorrhage, which was defined as a blood loss of 500 ml or more. The amount of blood loss during delivery was assessed by clinical estimation. Any delayed haemorrhage within the first 24 h after delivery was also recorded. Maternal haemoglobin concentration was measured on admission to the labour ward and repeated 48 h after delivery. Maternal blood pressure, pulse and temperature were recorded immediately after delivery and repeated 30 and 60 min later. The duration of third stage, the incidence of prolonged third stage (duration longer than 30 min), the need for manual removal of placenta and the use of additional i.m. syntometrine were recorded. One hour after delivery, the patients were asked about the occurrence of side-effects, including nausea, vomiting, headache, chest pain, fever and shivering. The severity of shivering was also assessed using a visual analogue scale.

Sample size estimation
Syntometrine is the oxytocic used in all the three participating hospitals. The incidence of postpartum haemorrhage is similar among the three hospitals, with a mean of 4% in the year preceding the study. The incidence of postpartum haemorrhage associated with oral misoprostol was reported to be 6% (El-Refaey et al., 1996Go). Therefore the sample size in this study was based on 1000 subjects in each study group, in order to detect a 2% difference in the incidence of postpartum haemorrhage with 80% power at {alpha} = 0.05.

Ethics
The study protocol was approved by the Clinical Research Ethics Committee of the Faculty of Medicine of the Chinese University of Hong Kong. All patients were required to give their written consent at the time of enrolment.

Statistical analysis
Statistical analysis was performed using the Statistical Package for Social Science for Windows (SPSS, Inc., Chicago, IL, USA). Differences between the misoprostol and syntometrine groups were assessed using the {chi}2-test for categorical data and Student's t-test for continuous variables. Where appropriate, relative risk (RR) and 95% confidence intervals (CI) were calculated. P < 0.05 was considered as statistically significant.


    Results
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
There were 11367 deliveries during the study period and 9048 patients were eligible for this study. A total of 2058 patients was recruited into the study and randomized to either oral misoprostol or i.m. syntometrine. There was no significant difference between the two groups in terms of their demographic characteristics both within and among the three individual hospitals. The data from all hospitals was therefore combined for further statistical analysis (Table IGo).


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Table I. Demographic characteristics of the recruited study population
 
There was no significant difference in the amount of estimated blood loss and the incidence of postpartum haemorrhage (>=500 ml) or severe postpartum haemorrhage (>=1000 ml) in both groups. However, the need for an additional oxytocic injection was significantly higher (P < 0.05) in the misoprostol group with a RR of 1.62 (95% CI 1.34–1.96). A multiparous patient in the syntometrine group developed massive postpartum haemorrhage of 5 l after a normal vaginal delivery because of uterine atony and required an abdominal hysterectomy. There was no significant difference in the incidence of delayed haemorrhage within the first 24h. The incidence of prolonged third stage (>=30 min) was similar; however, the incidence of manual removal of placenta was significantly lower (P < 0.05) in the misoprostol group with a RR of 0.29 (95% CI 0.09–0.87) (Table IIGo). There was no difference in the mean fall in haemoglobin concentration after delivery. In both groups, haemoglobin concentration decreased by 10–20% in 32.7 and 32.9% of patients, and by >20% in 18.6 and 17.6% respectively. The incidence of blood transfusion was 1.5 and 1.6% respectively (Table IIIGo).


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Table II. Effect of misoprostol and syntometrine on postpartum blood loss and complications
 

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Table III. Effect of misoprostol and syntometrine on peripartum haemoglobin concentration
 
The incidence of nausea, vomiting, headache and chest pain was low and similar in both groups. The incidence of shivering was significantly higher (P < 0.05) in the misoprostol group with a RR of 3.06 (95% CI 2.49–3.76). Among those who shivered, the degree of shivering was greater in the misoprostol group than those in the syntometrine group with a mean score of 4.4 (SD 2.9) and 1.8 (SD 2.0) respectively. The incidence of pyrexia (>=38°C) was also significantly higher (P < 0.05) in the misoprostol group and the RR was 6.73 (95% CI 3.78–11.98). Twenty patients in the misoprostol group developed high fever (>=39°C), of whom four had a temperature >=40°C. This compared to only one patient who had a temperature of 38°C in the syntometrine group. All fevers subsided spontaneously within 8 h of delivery and no patients developed any complications (Table IVGo). The incidence of hypertension (defined as blood pressure >=140/90 mmHg) after delivery was significantly (P < 0.05) lowered in the misoprostol group with a RR of 0.62 (95% CI 0.39–0.96) and 0.55 (95% CI 0.33–0.92) at 30 and 60 min respectively (Table VGo).


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Table IV. Side-effects of misoprostol and syntometrine in the management of the third stage of labour
 

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Table V. Effect of misoprostol and syntometrine on the incidence of hypertension (blood pressure >=140/90 mmHg)
 

    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Misoprostol stimulates the myometrium of the pregnant uterus by selectively binding to prostaglandin E2-sensitive receptors EP2 and EP3 (Senior et al., 1993Go). Its uterotonic activity enables its use in medical evacuation for miscarriage in the first trimester of pregnancy and induction of labour at term. Recently, misoprostol was reported for use in the management of third stage of labour with no increase in the incidence of postpartum haemorrhage (El-Refaey et al., 1996Go). Since then, several randomized trials have been published (Hofmeyr et al., 1998Go; O'Brien et al., 1998Go; Amant et al., 1999Go; Surbek et al., 1999Go). However, these studies are small in sample size and most of them compared misoprostol against a placebo, instead of the commonly used oxytocic agents. Prophylactic use of oxytocics has been established to be effective in reducing postpartum blood loss and the risk of primary postpartum haemorrhage, and is generally recommended for the management of the third stage of labour. Misoprostol may be an appropriate oxytocic agent in the developing world because it is cheaper and more stable than other oxytocic agents, and does not require an injection (Keirse, 1998Go). It is therefore important to know whether misoprostol is as effective as, if not better than, commonly used oxytocics, but not whether misoprostol is better than a placebo, in preventing postpartum haemorrhage.

Similar to other reported studies, the current study showed that oral misoprostol is effective in reducing postpartum haemorrhage. However, it is probably less effective than i.m. syntometrine as misoprostol was associated with a 1.62-fold increase in the administration of an additional oxytocic agent. A similar result was recently reported in a double-blind randomized trial comparing oral misoprostol with i.v. methylergometrine (Amant et al., 1999Go). This may partly be related to the relatively late onset of action of oral misoprostol as compared to parental oxytocics (Danielsson et al., 1999Go). However, whilst the effect of misoprostol on the uterine activity in first trimester is well established, similar data are limited at more advanced gestation (Choo et al., 1998Go).

As previously reported, misoprostol carries a higher incidence of pyrexia and shivering. Although it would have been relevant to correlate shivering with epidural analgesia, the data for our patients was not collected. The pyrexia is a centrally mediated prostaglandin E1 effect. In other clinical studies, the increase in temperature after the administration of misoprostol is a relatively common finding (El-Refaey et al., 1994Go; Amant et al., 1999Go). However, the pyrexia was only transient and not associated with any serious complications. The incidence of shivering associated with misoprostol was 30% and is comparable with that reported in the literature (El-Refaey et al., 1997Go; Hofmeyr et al., 1998Go; Surbek et al., 1999Go). The degree of shivering is only mild to moderate as reflected by the low mean score from the visual analogue scale. Side-effects of misoprostol seem to be dose-related. In a recent study, misoprostol at a dose of 400 µg appears to be effective in reducing the incidence of postpartum haemorrhage but carries a lower incidence of side-effects when compared with a 600 µg dose (Lumbiganon et al., 1999Go). Further investigation is required to determine the optimal effective dosage of oral misoprostol in the management of the third stage of labour.

Similar to our previous report, the use of syntometrine in the third stage of labour was associated with a 1.4% incidence of manual removal of placenta (Yuen et al., 1995Go), which was significantly higher than that associated with misoprostol. This is probably related to their different uterotonic effects as ergometrine characteristically induces tonic uterine contractions whereas prostaglandins induce rhythmic uterine contractions.

The use of syntometrine is contraindicated in hypertensive patients as ergometrine stimulates vasoconstriction and causes hypertension. In pre-eclamptic patients, it may cause maternal headaches, convulsion and even death (Ballie, 1963Go). In the current study, it was found that misoprostol does not cause hypertension and is associated with a 55–60% reduction in the incidence of hypertension when compared with syntometrine. It has been shown that misoprostol decreases the mean arterial pressure and systemic vascular resistance and has a modest and transient antihypertensive effect in patients with essential hypertension (Kailasam et al., 1994Go). Misoprostol may be used as an oxytocic in hypertensive or pre-eclamptic women undergoing vaginal delivery.

Although the cost of a 600 µg dose of oral misoprostol is similar to that of an ampoule of syntometrine in our locality (US$ 0.8), the latter has to be administered i.m. and requires the use of sterile syringe and alcohol swab. Syntometrine is also unstable in tropical conditions and requires special storage facilities to maintain its efficacy. Misoprostol is devoid of these constraints and may therefore be the choice of oxytocics in developing countries where storage facilities and resources are limited.

There are two major limitations in the current study. First, this was not a double-blinded study; potential bias in assessment of blood loss and the use of additional oxytocics could not be eliminated. However, this was minimized by having an independent nursing staff in the preparation and administration of the medication. The consistent results among the three participating hospitals and a similar overall result compared with that reported in the literature suggested that the results are unlikely to be due to bias.

Second, the amount of postpartum blood loss was assessed by clinical estimation instead of using quantitative techniques in assessing the blood loss. Although clinical estimation of blood loss has been shown to underestimate the true blood loss (Duthie et al., 1991Go; Razvi et al., 1996Go), this is how postpartum haemorrhage is diagnosed and managed in actual day-to-day clinical practice. Moreover, the clinical estimation of blood loss is one of the main methods used in some of the large randomized controlled trials regarding the management of the third stage of labour (McDonald et al., 1993Go; Amant et al., 1999Go; Surbek et al., 1999Go). In the current study, the mean blood loss in both misoprostol and syntometrine groups was only 250–300 ml, and the incidence of postpartum haemorrhage was low. Yet, 15% of patients still had a 10–20% drop in haemoglobin concentration and 18% dropped by >20% in both groups. These findings were consistent in all three participating hospitals. On the other hand, the use of clinical parameters such as blood pressure and pulse is also not reliable. As a result of the expanded blood volume, pregnant women generally can tolerate a greater amount of blood loss than non-pregnant women before the development of hypovolaemic shock. Measurement of the change in haemoglobin concentration before and after delivery is a more objective method in assessing the amount of blood loss. It is also clinically more important and relevant as it aids the decision for blood transfusion or iron supplementation. In fact, it has already been suggested that postpartum haemorrhage be defined as a peripartum fall in haematocrit of at least 10% or haemorrhage requiring transfusion (American College of Obstetricians and Gynecologists, 1989Go). Future studies on the efficacy of uterotonic agents on postpartum haemorrhage should therefore be based on the peripartum haemoglobin change rather than on clinical estimation of blood loss.

In conclusion, misoprostol may be used as an alternative to i.m. syntometrine in the management of the third stage of labour, especially in situations where syntometrine is contraindicated or where storage and parenteral administration of oxytocics is a potential problem.


    Notes
 
4 To whom correspondence should be addressed at: Department of Obstetrics and Gynaecology, Prince of Wales Hospital, Shatin, New Territories, Hong Kong. E-mail: pmyuen{at}cuhk.edu.hk Back


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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
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Submitted on June 16, 2000; accepted on October 3, 2000.





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