Treatment of retained placenta with misoprostol: A randomised controlled trial in a low-resource setting (Tanzania)

  • BMC Pregnancy and Childbirth, Volume 9, Year 2009

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Study Justification:
– Retained placenta is a common cause of maternal mortality in developing countries with limited access to obstetrical care.
– Current treatment of retained placenta requires manual removal under anesthesia, which is only available in larger healthcare facilities.
– Medical treatment with misoprostol could be a cost-effective and easy-to-use option in low-resource settings.
– This study aims to assess the efficacy and safety of sublingually administered misoprostol in women with retained placenta in a low-resource setting.
Highlights:
– Multicentered randomised, double-blind, placebo-controlled trial conducted in 5 hospitals in Tanzania.
– Inclusion criteria: Women with retained placenta, gestational age of 28 weeks or more, and blood loss less than 750 ml, 30 minutes after delivery.
– Sample size: 117 women, with a 2:1 randomization of misoprostol to placebo.
– Primary outcome: Expulsion of the placenta without manual removal.
– Secondary outcome: Number of blood transfusions.
Recommendations:
– Medical treatment with misoprostol should be considered as a potential alternative to manual removal of the placenta in low-resource settings.
– Further research should be conducted to assess the long-term safety and effectiveness of misoprostol for the treatment of retained placenta.
– Healthcare facilities in low-resource settings should be equipped with the necessary resources and training to administer misoprostol for the treatment of retained placenta.
Key Role Players:
– Researchers and healthcare providers in Tanzania.
– National Institute of Medical Research (NIMR).
– Senate Research and Publication Committee of Muhimbili University of Health and Allied Sciences.
– Muhimbili National Hospital.
Cost Items for Planning Recommendations:
– Training and education for healthcare providers on the use of misoprostol.
– Procurement and distribution of misoprostol medication.
– Monitoring and evaluation of the implementation of misoprostol treatment.
– Data management and analysis.
– Potential costs for additional research and studies on the long-term safety and effectiveness of misoprostol.

The strength of evidence for this abstract is 8 out of 10.
The evidence in the abstract is strong because it describes a multicentered randomised, double-blind, placebo-controlled trial conducted in 5 hospitals in Tanzania. The study has obtained approval from relevant research committees and has a data management safety board. The inclusion criteria, randomization process, sample size, primary and secondary outcomes, and statistical analysis plan are clearly outlined. However, to improve the evidence, the abstract could provide more details on the methodology, such as the specific interventions, follow-up duration, and potential confounding variables. Additionally, it would be helpful to include information on the results and conclusions of the study.

Background: Retained placenta is one of the common causes of maternal mortality in developing countries where access to appropriate obstetrical care is limited. Current treatment of retained placenta is manual removal of the placenta under anaesthesia, which can only take place in larger health care facilities. Medical treatment of retained placenta with prostaglandins E1 (misoprostol) could be cost-effective and easy-to-use and could be a life-saving option in many low-resource settings. The aim of this study is to assess the efficacy and safety of sublingually administered misoprostol in women with retained placenta in a low resource setting. Methods: Design: Multicentered randomised, double-blind, placebo-controlled trial, to be conducted in 5 hospitals in Tanzania, Africa. Discussion: Inclusion criteria: Women with retained placenta, at a gestational age of 28 weeks or more and blood loss less than 750 ml, 30 minutes after delivery of the newborn despite active management of third stage of labour. Clinical Trial Registration: Trial Entry & Randomisation & Study Medication: After obtaining informed consent, eligible women will be allocated randomly to the treatment groups using numbered envelopes that will be randomized in variable blocks containing identical capsules with either 800 microgram of misoprostol or placebo. The drugs will be given sublingually. The women, maternal care providers and researchers will be blinded to treatment allocation. Sample Size: 117 women, to show a 40% reduction in manual removals of the placenta (p = 0.05, 80% power). The randomization will be misoprostol: placebo = 2:1. Primary Study Outcome: Expulsion of the placenta without manual removal. Secondary outcome is the number of blood transfusions. This is a protocol for a randomized trial in a low resource setting to assess if medical treatment of women with retained placenta with misoprostol reduces the incidence of manual removal of the placenta. Current Controlled Trials ISRCTN16104753. © 2009 van Beekhuizen et al; licensee BioMed Central Ltd.

Multicentered randomised, double-blind, placebo-controlled trial. The study will be conducted in four rural hospitals in Southern Tanzania (the regional hospitals of Lindi and Mtwara regions and Ndanda and Nyangao mission hospitals) and in the university teaching hospital in the capital Dar es Salaam. Approval for this study was obtained from the National Institute of Medical Research (NIMR), the Senate Research and Publication Committee of Muhimbili University of Health and Allied Sciences and the Muhimbili National Hospital in Tanzania. A data management safety board has been installed. All labouring women will receive AMTSL and are eligible if 30 minutes after delivery of the infant the placenta has not been expelled and were delivered of a baby of 1 kg or more or at a gestational age of 28 weeks or more. AMTSL is defined as administration of 5IU oxytocin and controlled cord traction (CCT). If the placenta is delivered the uterus will be massaged. Women with one of the following conditions will be excluded from entering the trial: • Haemoglobin concentration less than 100 g/l (6.2 mmol/l) • Blood loss more than 750 ml • Pulse rate more than 120 beats per minute • Diastolic blood pressure reduction after delivery more than 20 mmHg Eligible women will be identified in the labour ward at 20 minutes after delivery of the infant. The bladder will be catheterised, an intravenous canula will be inserted and normal saline solution will be started, CCT will be performed again and blood will be taken for cross-match and haemoglobin concentration. They will receive verbal and written information in Kiswahili about participation in the trial and will be asked to give their informed consent. The randomisation schedule uses balanced variable blocks; sealed envelopes containing both registration form and blinded study medication are present in the delivery room. Allocation will be in sequence of enrolment in each of the five labour wards. Each sealed envelop contains two identical capsules with either 800 microgram misoprostol or placebo. The patient, the maternal care providers and the researchers are all blinded to the allocation. Women will enter the study after giving their informed consent at 30 minutes following the delivery of the infant, at which time the envelope will be opened and the two capsules of study medication will be administered sublingually. Figure ​Figure11 depicts the flowchart for trial entry. Flowchart for trial entry. AMTSL = Active management of third stage of labour. RP = retained placenta. CCT = controlled cord traction. Hb = Haemoglobin. BP = Blood pressure. MRP = Manual removal of placenta. Hb = haemoglobine. After administration of the study medication, the doctor or midwife will perform CCT every ten minutes to check if the placenta has separated from the uterine wall. Vaginal blood loss will be measured by weighing self absorbable mattresses. Blood loss exceeding 1500 ml will be considered as indication for emergency MRP. If the placenta is not expelled 30 minutes after the administration of the study medication, the patient will undergo MRP. All women enrolled in the study are followed up for 12-24 hours. Blood pressure, pulse rate uterine contraction and vaginal blood loss are monitored, and the haemoglobin concentration prior to discharge is recorded. Women are receiving blood transfusion and and/or intravenous iron dextrane infusion, according to the hospitals guidelines, if needed. All women receive combined ferrofumerate and folic acid tablets according to the national guideline on care for post partum women. The primary study outcome is: • Manual removal of the placenta. The secondary outcomes are: • Measured post partum blood loss, • Number of units of blood administered, • Adverse outcome for the woman, including side-effects from the study medication and number of emergency MRP needed. The primary endpoint of the study is manual removal of the placenta. For eligible women (with RP 30 minutes after delivery of the infant) the best estimate of MRP is 44% at 60 minutes post partum. Using 2:1 misoprostol to placebo randomisation, a sample size of 117 women will be able to show a 40% reduction in MRP (5% level of significance, two-tailed alpha, 80% power). Thus, 39 patients will receive placebo and 78 will receive misoprostol. Baseline characteristics of all women enrolled in the study are documented and analysed in order to verify the absence of confounding differences in baseline variables between groups. Outcome comparisons for women will be analysed according to ‘intention to treat’. Relative risks and 95% confidence intervals will be reported for the primary and secondary outcomes, and the number needed to treat to prevent one MRP will be calculated. A data management safety board will check the data at regular intervals.

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One potential innovation to improve access to maternal health is the use of misoprostol for the treatment of retained placenta. This innovation involves a multicentered randomized, double-blind, placebo-controlled trial conducted in low-resource settings, specifically in Tanzania. The study aims to assess the efficacy and safety of sublingually administered misoprostol in women with retained placenta. The study protocol includes the random allocation of eligible women to treatment groups using numbered envelopes containing either misoprostol or placebo. The primary outcome of the study is the expulsion of the placenta without manual removal, and secondary outcomes include the number of blood transfusions and adverse outcomes for the women. The study has obtained approval from relevant research and medical institutions in Tanzania and has implemented measures for data management and safety.
AI Innovations Description
The recommendation to improve access to maternal health is to conduct a multicentered randomised, double-blind, placebo-controlled trial in low-resource settings, specifically in Tanzania. The trial aims to assess the efficacy and safety of using misoprostol, a prostaglandin E1, for the treatment of retained placenta. Retained placenta is a common cause of maternal mortality in developing countries with limited access to obstetrical care.

The trial will be conducted in five hospitals in Tanzania, including four rural hospitals in Southern Tanzania and a university teaching hospital in the capital, Dar es Salaam. Approval for the study has been obtained from the National Institute of Medical Research, the Senate Research and Publication Committee of Muhimbili University of Health and Allied Sciences, and the Muhimbili National Hospital.

The inclusion criteria for the trial are women with retained placenta, at a gestational age of 28 weeks or more, and blood loss less than 750 ml, 30 minutes after delivery of the newborn, despite active management of the third stage of labor. Women with certain conditions, such as low hemoglobin concentration, excessive blood loss, high pulse rate, or significant blood pressure reduction after delivery, will be excluded from the trial.

After obtaining informed consent, eligible women will be randomly allocated to treatment groups using numbered envelopes containing either 800 micrograms of misoprostol or placebo. The drugs will be administered sublingually. The trial will be double-blind, meaning that the women, maternal care providers, and researchers will be unaware of the treatment allocation.

The primary outcome of the trial is the expulsion of the placenta without manual removal. The secondary outcome is the number of blood transfusions required. The sample size for the trial is 117 women, with a randomization ratio of 2:1 (misoprostol:placebo). The trial aims to show a 40% reduction in manual removals of the placenta with a significance level of 5% and 80% power.

The trial will monitor women for 12-24 hours after enrollment, measuring blood pressure, pulse rate, uterine contraction, vaginal blood loss, and recording the hemoglobin concentration prior to discharge. Women will receive blood transfusion or intravenous iron dextran infusion if needed, according to hospital guidelines. All women will also receive combined ferrofumerate and folic acid tablets as per national guidelines for postpartum care.

The data collected from the trial will be analyzed using intention-to-treat analysis. Relative risks and 95% confidence intervals will be reported for the primary and secondary outcomes, and the number needed to treat to prevent one manual removal of the placenta will be calculated. A data management safety board will regularly review the data.

Overall, this recommendation suggests conducting a rigorous clinical trial to evaluate the use of misoprostol for the treatment of retained placenta in low-resource settings. The trial aims to provide evidence on the efficacy and safety of this medical treatment option, which could potentially improve access to maternal health care and reduce maternal mortality in developing countries.
AI Innovations Methodology
In order to improve access to maternal health, one potential innovation is the use of misoprostol for the treatment of retained placenta in low-resource settings. This innovation aims to provide a cost-effective and easy-to-use alternative to the current practice of manual removal of the placenta under anesthesia, which can only be done in larger healthcare facilities.

To simulate the impact of this recommendation on improving access to maternal health, a methodology could be developed as follows:

1. Study Design: Conduct a multicentered randomized controlled trial in low-resource settings, such as rural hospitals in Tanzania, Africa. The trial should be double-blind and placebo-controlled to ensure unbiased results.

2. Sample Size: Determine the required sample size based on the desired statistical power and significance level. In this case, the study aims to show a 40% reduction in manual removals of the placenta, with a power of 80% and a significance level of 0.05. The randomization should be set at a ratio of 2:1, with 78 women receiving misoprostol and 39 women receiving a placebo.

3. Inclusion and Exclusion Criteria: Clearly define the criteria for including women in the study. In this case, eligible women would be those with retained placenta, at a gestational age of 28 weeks or more, and blood loss less than 750 ml, 30 minutes after delivery of the newborn despite active management of the third stage of labor. Women with certain conditions, such as low hemoglobin concentration, excessive blood loss, high pulse rate, or significant blood pressure reduction after delivery, would be excluded from the trial.

4. Randomization and Blinding: Develop a randomization schedule using balanced variable blocks. Sealed envelopes containing registration forms and blinded study medication should be prepared and present in the delivery room. The allocation should be in sequence of enrollment in each of the participating hospitals. Both the patients and the healthcare providers should be blinded to the treatment allocation.

5. Treatment Administration: Administer the study medication, either 800 micrograms of misoprostol or a placebo, sublingually to the eligible women. Monitor the patients closely after administration to check if the placenta has separated from the uterine wall.

6. Outcome Measures: Define the primary and secondary outcome measures. In this case, the primary outcome is the expulsion of the placenta without manual removal, while the secondary outcome is the number of blood transfusions. Other adverse outcomes, such as side effects from the study medication and the need for emergency manual removal of the placenta, should also be recorded.

7. Data Collection and Analysis: Collect data on blood pressure, pulse rate, uterine contraction, vaginal blood loss, and hemoglobin concentration prior to discharge. Analyze the data using appropriate statistical methods, such as intention-to-treat analysis. Calculate relative risks, 95% confidence intervals, and the number needed to treat to prevent one manual removal of the placenta.

8. Safety Monitoring: Establish a data management safety board to regularly review and monitor the data collected during the trial. This board should ensure the safety of the participants and the integrity of the study.

By following this methodology, the impact of using misoprostol for the treatment of retained placenta in low-resource settings can be simulated and evaluated, providing valuable insights into its effectiveness and potential for improving access to maternal health.


Statistics:
Citations: 8
Identifiers:
DOI: 10.1186/1471-2393-9-48
Research Areas:
Disability, Health System and Policy, Maternal and Child Health, Noncommunicable Diseases, Quality of Care, Social Determinants
Study Countries:
Tanzania
Study Design:
Cohort Study, randomised-control-trial
Participants Gender:
Female
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