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Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References

Objective To evaluate the side effects of 600 μg misoprostol orally during the first 24 hours after administration in the third stage of labour.

Design Double blind randomised controlled trial.

Setting Tertiary care hospitals in Nigeria and Thailand.

Sample All women participating in the WHO Misoprostol trial in these two hospitals between January 1, 1999 and June 17, 1999.

Methods All women were followed up during the first 24 hours postpartum to evaluate the occurrence of shivering, nausea, vomiting, diarrhoea and other misoprostol-related side effects.

Main outcome measures Rates of shivering, nausea, vomiting, diarrhoea and pyrexia within 1 hour and in the intervals 2–6, 7–12, 13–18 and 19–24 hours after delivery.

Results A total of 1686 women were enrolled. Women who received misoprostol had higher incidence than the oxytocin group of ‘any’ shivering in the first hour (RR 6.4, 95% CI 3.9 to 10.4) and the period covering 2–6 hours following delivery (RR 4.7, 95% CI 1.9 to 11.2). Pyrexia was also more common in the misoprostol group in both the same time intervals (RR 2.8, 95% CI 1.4 to 5.3 and RR 6.3, 95% CI 3.7 to 10.8, respectively). Diarrhoea was not present in the first hour in either group but appeared in the second time period (2–6 hours) and third time period (7–12 hours) more frequently in the misoprostol group than with oxytocin.

Conclusion The increased incidence of shivering and pyrexia that occurs with postpartum use of misoprostol persists up to 6 hours following delivery. Approximately 5% of women experience diarrhoea that starts after 1 hour and subsides within 12 hours.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References

Postpartum haemorrhage is a leading cause of severe maternal morbidity and death, in both developing and industrialised countries. The use of uterotonic agents in the active management of the third stage of labour reduces the amount of bleeding and blood transfusion but is associated with side effects related to the ergot alkaloids1. Following earlier uncontrolled reports2,3 of misoprostol use during the third stage of labour, a large multicentre trial was conducted by WHO to evaluate the effectiveness of 600 μg misoprostol compared with 10 IU of oxytocin4.

This large randomised controlled trial and a systematic review of seven randomised controlled trials5 demonstrated that 10 IU of oxytocin (im or iv) is preferable to 600 μg misoprostol given orally in the active management of the third stage of labour in hospital settings where active management is the norm. Earlier studies on misoprostol use in the third stage of labour reported the side effects within 1 hour after delivery, which were mainly shivering and raised body temperature6. As part of the large WHO trial, data were collected on the side effects for 24 hours in two centres.

The side effects of oral 600 μg of misoprostol and 10 IU oxytocin used in the active management of the third stage of labour within 24 hours following their use are reported here.

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References

The original trial was a multicentre, double blind, randomised controlled trial conducted in hospitals in Argentina, China, Egypt, Ireland, Nigeria, South Africa, Switzerland, Thailand and Vietnam. A detailed description of the trial and results can be found elsewhere4. Each woman received either misoprostol 600 μg (3 × 200 μg tablets), or 10 IU oxytocin plus the corresponding placebo immediately after the baby was delivered and the cord was clamped and cut. The third stage of labour was managed actively, as routinely practised in the participating hospitals. The active management consisted of the use of a uterotonic, clamping and cutting of the umbilical cord immediately after delivery of the infant, and either fundal or suprapubic pressure with cord traction after signs of placental separation.

In Nigeria and Thailand, where all mothers stayed in the hospital more than 24 hours after delivery, all women recruited to the WHO trial between January 1, 1999 and June 17, 1999 had a special 24-hour follow up. Data were collected on the occurrence of shivering, nausea, vomiting, diarrhoea and other side effects in the intervals 2–6, 7–12, 13–18 and 19–24 hours and body temperature measurements at 6, 12, 18 and 24 hours after delivery. This information was recorded by postpartum ward nurses who were blinded to the allocation status of women in the trial.

Based on initial recruitment rates, the authors estimated that a total of approximately 1700 women should be recruited for this study, which would have more than 80% power to detect a difference in shivering of 10% with oxytocin and 15% with misoprostol in a two-sided 5% level test.

The outcomes were the occurrence of shivering, nausea, vomiting, diarrhoea and body temperature >38°C (pyrexia) within 1 hour and in the intervals 2–6, 7–12, 13–18 and 19–24 hours after delivery. Shivering, nausea, vomiting and diarrhoea were assessed by either direct observation or indirect questioning (i.e. “Do you have any complaints?”). If detected or reported, the woman was asked whether she would consider her experience as mild, moderate or severe. Any side effect necessitating treatment was marked as severe and a special form with details of the event was completed. Body temperature was assessed with the standard thermometres routinely used in each centre.

The characteristics of the women in the study were compared with those of women in the main trial as well as the total number of women recruited in these two hospitals. Percentages or means and standard deviations were computed as appropriate. The number and percentages of women with shivering, nausea, vomiting, diarrhoea and high body temperature within 1 hour and in the intervals 2–6, 7–12, 13–18 and 19–24 hours after delivery (at 6, 12, 18 and 24 hours in the case of high body temperature) were calculated with their 95% confidence intervals, using the exact binomial distribution. For the occurrence of each side effect, the mild and moderate categories were combined. The percentages and confidence intervals were plotted against the time interval by treatment group. Rate differences with corresponding 95% confidence intervals were computed at each time interval using the traditional method to compare independent proportions. Relative risks with corresponding 95% confidence intervals were also computed, using Taylor series approximation. A repeated measures analysis (giving results in the log odds ratio scale) was performed to test the difference between the time pattern of side effects between the two groups. The occurrence of a side effect was modelled as a function of centre and treatment group as between-subject factors, and time as the within-subject factor, using generalised estimating equations to account for the correlation between measures of the same subject7.

The trial was approved by the ethics committees of the participating hospitals and by the Scientific and Ethical Review Group of the UNDP/UNFPA/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction, Geneva, Switzerland.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References

There were 843 women in the misoprostol group and 843 women in the oxytocin group. These women represented about 50% of the total recruited from these two centres for the main trial.

The characteristics of women in the misoprostol and oxytocin groups in the follow up substudy were comparable with regard to baseline prognostic characteristics (Table 1). There were, overall, more nulliparous women (45.3%vs 32.9%) and a higher incidence of preterm delivery (19.6%vs 11.9%) in the follow up substudy when compared with the women in the whole study (data not shown). However, the characteristics of the women in the substudy were comparable to the remaining women who participated in the main trial in these two centres.

Table 1.  Baseline delivery characteristics of women from Nigeria and Thailand in the follow up substudy.
 Misoprostol (n= 843)Oxytocin (n= 843)
Events%Events%
  1. *n= 842.

Maternal age, mean (SD)*26.5 (5.1) 26.6 (5.1) 
Parity = 027532.628033.2
Parity ≥ 5313.7303.6
Gestational age, mean (SD)38.2 (1.9) 38.1 (1.9) 
Low birthweight (<2500 g)617.2718.4
Oxytocin or prostaglandin in labour31637.530335.9
Epidural analgesia20.270.8
Assisted vaginal delivery10212.19311.0
Perineal suturing51861.452762.5

Women in the misoprostol group had significantly higher incidence of ‘any’ shivering within 1 hour and in the interval 2–6 hours after delivery (rate differences 11.5%, 95% CI 9.0% to 14.0% and 2.6%, 95% CI 1.3% to 3.9%, respectively; RR 6.4, 95% CI 3.9 to 10.4 and RR 4.7, 95% CI 1.9 to 11.2, respectively). After 6 hours, the prevalence of shivering was very low and there were no clinically relevant differences (Table 2). There were no cases of severe shivering.

Table 2.  Incidence, rate difference and relative risk of ‘any’ shivering.
Time (hours)Misoprostol (n= 843)Oxytocin (n= 843)Rate differenceRelative risk
Events%Events%%95% CIRR95% CI
111513.6182.111.59.0 to 14.06.43.9 to 10.4
2–6283.360.72.61.3 to 3.94.71.9 to 11.2
7–1240.500.00.50.0 to 0.9
13–1820.210.10.1−0.3 to 0.52.00.2 to 22.0
19–2410.120.2−0.1−0.5 to 0.30.50.1 to 5.5

Nausea and vomiting were slightly more common in the misoprostol group but the incidences were extremely low and the differences between the groups were never statistically significant. There were no cases of severe nausea and vomiting.

Diarrhoea was not reported within 1 hour after delivery. However, it became apparent after the first hour and was significantly higher in the misoprostol group in the intervals 2–6 and 7–12 hours after delivery (rate differences 4.7%, 95% CI 3.2% to 6.3% and 2.4%, 95% CI 1.2% to 3.5%, respectively; RR 21.0, 95% CI 5.1 to 86.5 and RR 7.7, 95% CI 2.3 to 25.4, respectively). About 5% of women in the misoprostol group reported diarrhoea in the interval 2–6 hours (Table 3).

Table 3.  Incidence, rate difference and relative risk of diarrhoea.
Time (hours)Misoprostol (n= 843)Oxytocin (n= 843)Rate differenceRelative risk
Events%Events%%95% CIRR95% CI
100.000.00.0
2–6425.020.24.73.2 to 6.321.05.1 to 86.5
7–12232.730.42.41.2 to 3.57.72.3 to 25.4
13–1840.500.00.50.0 to 0.9
19–2410.120.2−0.1−0.5 to 0.30.50.1 to 5.5

Body temperature between 38°C and 40°C was also significantly more common in the misoprostol group within 1 hour and at 6 hours after delivery (rate differences 2.5%, 95% CI 1.0% to 4.0% and 9.5%, 95% CI 7.2% to 11.8%, respectively; RR 2.8, 95% CI 1.4 to 5.3 and RR 6.3, 95% CI 3.7 to 10.8, respectively). The magnitude of the difference was greater in the interval 2–6 hours with 11% of women in the misoprostol group having pyrexia but the incidence became lower and the difference was statistically non-significant at later intervals (Table 4).

Table 4.  Incidence, rate difference and relative risk of pyrexia.
Time (hours)Misoprostol (n= 843)Oxytocin (n= 843)Rate differenceRelative risk
Events%Events%%95% CIRR95% CI
1333.9121.42.51.0 to 4.02.81.4 to 5.3
2–69511.3151.89.57.2 to 11.86.33.7 to 10.8
7–12131.550.60.9−0.0 to 1.92.60.9 to 7.3
13–1820.210.10.1−0.3 to 0.52.00.2 to 22.0
19–2410.100.00.1−0.1 to 0.4

Figure 1 shows the time–trend comparison between misoprostol and oxytocin groups for the three most common side effects. Shivering peaked within 1 hour after delivery and continued into the interval 2–6 hours with misoprostol, while this was observed with oxytocin at much lower levels in both intervals (P= 0.44 for the group by time interaction from the repeated measures analysis). Diarrhoea and pyrexia peaked at 2–6 hours after delivery with misoprostol, while with oxytocin pyrexia was always less than 2% (P= 0.06 for the group by time interaction) and diarrhoea was practically absent (0.4% or less in all intervals). All side effects became negligible after 12 hours of delivery.

image

Figure 1. Time–trend comparison of shivering, pyrexia and diarrhoea in misoprostol and oxytocin groups (percentages with 95% confidence intervals).

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Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References

Women who received 600 μg oral misoprostol for the management of the third stage of labour experienced significantly more shivering, pyrexia and diarrhoea compared with women who received 10 IU oxytocin within 24 hours following delivery. Shivering was the most common side effect followed by pyrexia and diarrhoea. The incidence of shivering peaked within 1 hour and remained significantly higher for misoprostol in this and in the interval 2–6 hours. Diarrhoea peaked during the interval 2–6 hours when 5.0% of women reported its occurrence and was significantly higher than oxytocin even in the interval 7–12 hours after delivery. We have previously reported that the difference in shivering and pyrexia between women receiving misoprostol and those receiving oxytocin is independent of epidural analgesia although there is a positive interaction between misoprostol and epidural analgesia4.

The first report from a randomised placebo-controlled trial of 400 μg oral misoprostol among 500 women in South Africa indicated that shivering was the only significant side effect of misoprostol6. The observation period for the side effects was not specified. The Cochrane systematic review includes data from seven randomised controlled trials of which four used 600 μg, one used 500 μg and three used 400 μg misoprostol orally (one trial had three arms)5. Side effects were recorded in the immediate postpartum period within 1 hour in these trials with the exception of Surbek et al.8, who evaluated the side effects within 2 hours, and Cook et al.9, who did not give a timeframe for the recording of the side effects. The pilot, dose-finding, trial we conducted before initiation of the main trial indicated that shivering and pyrexia with misoprostol were dose related and were observed in 28% and 19% of women receiving 600 and 400 μg misoprostol orally, respectively, during the first hour after delivery10.

Diarrhoea has not been reported as a side effect of oral misoprostol for the management of the third stage of labour, although it is a well known prostaglandin-related effect. Our data indicate that diarrhoea started and peaked at 2–6 hours after delivery. Previous reports did not detect this side effect because they collected information only within 1 hour after delivery. Although diarrhoea remained significantly more common in the misoprostol group until 7–12 hours after delivery, all cases except one were reported as not severe.

Double blinding, including double placebos ensured that ascertainment bias in evaluating side effects was unlikely. Although the possibility to associate shivering and thus other side effects to misoprostol, partially unblinding the recording of side effects, cannot be ruled out, the side effect data were collected by staff who were not involved in the trial. We used the highest dose of misoprostol (600 μg) that was considered effective without an unacceptable level of side effects11. The possibility to collect the information on side effects during the 24-hour period after delivery in a large number of women gave us the opportunity to complete a comprehensive picture of the side effects of oral misoprostol when used in the management of the third stage of labour.

In conclusion, our study confirmed that the two most common side effects of 600 μg oral misoprostol for the management of the third stage of labour are shivering and pyrexia. We also observed that diarrhoea was also a significant side effect. These side effects remain significant up to 6–12 hours after delivery.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References
  • 1
    Prendiville WJ, Elbourne D, McDonald S. Active versus expectant management in the third stage of labour [Cochrane Review]. The Cochrane Library, Issue 2. Oxford : Update Software, 2001.
  • 2
    El-Refaey H, O'Brien P, Morafa W, Walder J, Rodeck C. Misoprostol for third stage of labour. Lancet 1996;347: 1257.
  • 3
    El-Refaey H, O'Brien P, Morafa W, Walder J, Rodeck C. Use of oral misoprostol in the prevention of postpartum haemorrhage. Br J Obstet Gynaecol 1997;104: 336339.
  • 4
    Gülmezoglu AM, Villar J, Ngoc NTN, et al. WHO multicentre double-blind randomized controlled trial to evaluate the use of misoprostol in the management of the third stage of labour. Lancet 2001;358: 689695.
  • 5
    Gülmezoglu AM, Forna F, Villar J, Hofmeyr GJ. Prostaglandins for prevention of postpartum haemorrhage [Cochrane Review]. The Cochrane Library, Issue 4. Oxford : Update Software, 2001.
  • 6
    Hofmeyr GJ, Nikodem C, de Jager M, Gelbare BR. A randomized placebo controlled trial of oral misoprostol in the third stage of labour. Br J Obstet Gynaecol 1998;105: 971975.
  • 7
    Liang KJ, Zeger SL. Longitudinal data analysis using generalized estimating models. Biometrika 1986;73: 1322.
  • 8
    Surbek DV, Fehr P, Hoesli I, Holzgreve W. Oral misoprostol for third stage of labor: a randomized placebo-controlled trial. Obstet Gynecol 1999;94: 255258.
  • 9
    Cook C, Spurrett B, Murray H. A randomized clinical trial comparing oral misoprostol with synthetic oxytocin or syntometrine in the third stage of labour. Aust N Z J Obstet Gynaecol 1999;39(4):414419.
  • 10
    Lumbiganon P, Hofmeyr GJ, Gülmezoglu AM, Pinol A, Villar J. Misoprostol dose-related shivering and pyrexia in the third stage of labour. WHO collaborative trial of misoprostol in the management of the third stage of labour. Br J Obstet Gynaecol 1999;106: 304308.
  • 11
    Song J. Use of misoprostol in obstetrics. Obstet Gynecol Surv 2000;55: 503510.