The study was conducted at the East London Hospital Complex (Frere Maternity and Cecilia Makiwane Hospitals, Eastern Cape) and Tembisa and Chris Hani Baragwanath Hospitals, Gauteng, South Africa, between Jan 2002 and Dec 2003. All are busy referral hospitals.
Treatment packs were prepared independently, ordered in computer-generated random sequence and numbered consecutively. The packs contained either misoprostol 5 × 200 μg or inactive placebo.
The treatment sequence was kept sealed, and the code broken only after complete entry and checking of all trial data.
A confidential interim analysis, blind to which group was which, was performed by AMG after the first 100 enrolments. Evidence of clear benefit or harm for either group would have prompted stopping the trial, which was not the case.
Women in labour were given basic information about the trial in the form of notices in the labour rooms (Table 2 [see additional file 1]). Management of labour 3rd stage was routine active management with oxytocin 10 units or syntometrine one ampoule soon after the birth. Women aged 18 or more with bleeding judged by the clinician to be more than expected at least 10 minutes after delivery, and thought to be due to uterine atony and requiring additional uterotonic therapy, were given all the routine treatment for PPH (intravenous infusion, uterotonics, etc) from a special 'PPH Trolley' kept in the labour ward. The uterotonics used were oxytocin by intravenous infusion, and/or oxytocin/ergometrine, at the discretion of the attending clinician. Prostaglandin preparations such as sulprostone were not routinely available in the labour wards, and were not part of routine management of postpartum haemorrhage in the participating units.
Once all emergency treatment was instituted, and if the women were in a position to give fully informed consent, they were given detailed information about the trial and asked whether they wished to participate. Information about the trial was given verbally and in writing in English or Xhosa (Table 3 [see additional file 2]). Those who gave written consent were enrolled in the trial. Baseline data were documented. The next treatment pack containing either misoprostol 5 × 200 μg or inactive placebo was drawn and the number recorded. In addition to routine management, misoprostol or placebo (an inactive base) were given, 1 orally, 2 buccally/sublingually and 2 rectally, and the time recorded.
A low-profile plastic 'fracture bedpan' was placed under the woman's buttocks. In previous studies we have shown this to be an efficient method of collecting ongoing blood loss with very little spillage . Any small swabs soaked with blood were dropped into the bedpan. After 1 hour, the blood collected in the bedpan was measured in a graduated measuring jug, the temperature was measured sublingually with a mercury thermometer, and any shivering was subjectively recorded as 'mild' (not causing any distress), 'moderate' or 'severe'.
All other management was by hospital staff according to the hospital routine for the management of postpartum haemorrhage.
After 24 hours, blood was collected for haemoglobin estimation and the hospital records checked for use of additional uterotonics and any other complications such as blood transfusion.
The primary outcome measures were specified prior to commencing the study: (1) measured blood loss ≥500 ml in 1 hour after enrolment; (2) mean measured blood loss in 1 hour after enrolment; (3) haemoglobin level day 1 after birth <6 g/dl or blood transfusion; (4) Side-effects (pyrexia 38.5°C or more, moderate or severe shivering 1 hour after enrolment).
Secondary outcome measures were: (1) blood loss ≥1,000 ml in 1 hour after enrolment; (2) blood transfusion; (3) haemoglobin level 1 day after birth <8 g/dl or blood transfusion; (4) additional uterotonic given after enrolment; (5) manual removal of the placenta; (6) evacuation of retained products of conception; (7) hysterectomy; (8) maternal death.
Sample size calculation
In the WHO misoprostol trial control group (routine syntocinon), significant postpartum haemorrhage (blood loss >1000 ml) occurred in 2.8% of women. Of these 25% lost >1,500 ml. To reduce blood loss >500 ml after enrolment from 25% to 10%, would require 112 per group (α = 95%, β = 80%).
Data were collected on a data form, entered onto an excel spreadsheet, checked for accuracy, then analysed using Epi-info 2002 (United States Department of Health and Human Services, Centres for Diseases Control and Prevention, Epidemiology Program Office) and Review Manager (RevMan) [Computer program] version 4.2 for Windows. Oxford, England: The Cochrane Collaboration, 2003. Results were expressed as relative risks or mean difference with 95% confidence intervals. Analysis was by intention to treat.
All women enrolled in the trial received all the conventional management available for postpartum haemorrhage, in addition to the trial medication (misoprostol or placebo). Rapid conventional therapy was facilitated by the ready availability of the 'PPH trolley' with all the necessary materials. This trolley was also available for women not enrolled in the trial. Participation was limited to women who were in a position to give fully informed consent. Ethical approval was given by the Committee for Research on Human Subjects, University of the Witwatersrand, and the Ethics Committee, East London Hospital Complex. The trial complied with the Helsinki Declaration for research on human subjects.