Retained placenta: diagnosis, definition and the burden of disease
The diagnosis 'retained placenta' (RP) is established when the placenta is not expelled after a certain time period following the delivery of the infant[1, 2]. The time period in the definition of RP varies among countries. In our study location Tanzania, like most English speaking countries, RP is defined as lack of expulsion of the placenta 30 minutes after delivery of the infant [3], while in other countries the diagnosis RP is only made after 60 minutes postpartum [4]. Complications of RP are postpartum haemorrhage and infection[5], which may both lead to maternal morbidity and mortality. The need to improve maternal mortality has been recognized at a global level by including it in the Millennium Development Goals [6].
Tanzania is a low resource country with a high maternal mortality rate. It is estimated that 578 women per 100,000 live-births die as a result of pregnancy-related complications [7]. A retrospective study in Tanzania showed that RP contributed by 13% to the maternal deaths [8]. The morbidity due to RP is mainly caused by infections and anaemia. A study by Tandberg et al found a significant fall in haemoglobin level postpartum compared to antepartum by a mean of 3.4 g/dl (2.1 mmol/l) in the RP group as compared to no significant change in the controls; blood transfusion was required in 10% of the RP group versus 0.5% in the control group [9].
Retained Placenta: incidence
The incidence of RP is approximately 1-2% of all deliveries worldwide, the exact data for Tanzania is not known. The reported incidence of RP is affected by the following four factors: definition of the time interval [4], gestational age, an obstetrical history of previous RP or not, and the presence or absence of active management of the third stage of labour (AMTSL).
The incidence of RP in an unselected group of nulliparous women in The Netherlands was 6.3% at 30 minutes and 1.8% at 60 minutes after delivery of the newborn [4]. The incidence of RP, 30 minutes after delivery of the newborn has been reported as 8% in preterm and 1.1% in term deliveries [10]. The recurrence risks of RP reported in two studies of parous women were 16% and 23% [9, 11]. A randomized controlled trial (RCT) showed that AMTSL reduced the incidence of RP (after 30 minutes) to 1.6% as compared to 4.6% in the control group [12].
Retained placenta: how can we prevent maternal mortality?
Blood loss associated with RP can be acute life-threatening and requires emergency interventions like administration of uterotonics, correction of hypovolaemia by administration of intravenous fluids, manual removal of the placenta (MRP) under anaesthesia and blood transfusions[13]. All these interventions need skilled personnel and equipment. In many low-resource countries women deliver at home, and the nearest health care facility often lacks drugs and equipment to perform MRP or to give blood transfusion, leaving the midwife empty-handed. Transport to health care facilities with comprehensive emergency obstetrical care requires time and money, both are limited commodities in those circumstances [6, 8]. Medical treatment of RP with an easy-to-administer drug could save the life of patients under those circumstances.
Retained placenta: medical treatment with prostaglandin analogues
Medical treatment of RP includes the administration of oxytocin in the umbilical vein, which was reported to be effective in one out of eight women (relative risk 0.79, 95% CI 0.69-0.91) [14]. The disadvantage of this method in low resource settings is that it requires skilled medical personnel and equipment.
A RCT in The Netherlands showed that administration of 250 microgram prostaglandin E2 (sulprostone) intravenously 60 minutes after delivery of the infant effectively expelled 49% of RP versus 11% in the placebo group [15] within 60 minutes after administration. Blood loss was 388 ml lower in the sulprostone group (average blood loss 1062 ml) as compared to controls (average blood loss 1450 mls). Unfortunately, treatment with sulprostone is not applicable in low resources settings because the drug is relatively expensive and needs to be stored refrigerated.
The prostaglandin E1 analogue misoprostol is inexpensive and does not need to be stored refrigerated. Therefore, it is of potential use in low-resource countries. In a recent study in which 54 patients with RP were randomised to misoprostol, oxytocin and placebo, administered through the umbilical cord [16], a significant reduction of MRP was reported for the misoprostol (43% MRP) compared to the oxytocin (80% MRP) and placebo (54% MRP) groups. When misoprostol was administered rectally in a group of 10 patients [17], it was reported to avoid MRP in 7 patients and to reduce blood loss. Oral or sublingual administration of misoprostol, though potentially the fastest acting [18] and most practical, has not been studied in an effort to reduce MRP.
Misoprostol
Misoprostol is an prostaglandin E1-analogue with uterotonic properties that can be administered orally, sublingually, vaginally and rectally [19]. Sublingual administration of misoprostol achieves the highest serum peak concentration and takes the shortest time to reach the peak level, in comparison with other routes of administration [18]. Misoprostol is cheap and stable at room temperature. Originally, misoprostol was introduced as treatment for peptic ulcers. It soon became obvious that it stimulates uterine contractions [20]. Misoprostol has been used to treat various obstetrical problems, including uterine atony, postpartum haemorrhage [21], induction of labour, and induction of abortion [19, 20]. Misoprostol when given postpartum is known to cause only mild side effects (shivering and pyrexia) [19, 22–24]. Misoprostol is a sustainable drug for use in developing countries for the treatment of various obstetrical complications [20] like postpartum haemorrhage, induction of labour and induction of abortion. It is registered in Tanzania for the prevention and treatment of postpartum haemorrhage.
Study justification
Women in rural areas in resource-poor settings who deliver at home or in a village health care facility, and in whom the delivery is complicated by RP, have difficulty to reach appropriate medical help in time and have a considerable chance to die because from post partum hemorrhage. Because preliminary evidence suggests that prostaglandins like misoprostol may expel the placenta and reduce blood loss in women with RP, a RCT is designed to compare sublingually administered misoprostol with placebo to tests its effectiveness to reduce the need of MRP and blood transfusion in a low-resource setting.
Aims of the trial
The aims of this randomised, double blind, placebo-controlled trial is to assess if sublingual misoprostol reduces the need of Manual Removal of Placenta (MRP) and the amount of blood loss in women with RP in a low resource setting. The primary outcome variable is reduction in the incidence of MRP and the secondary outcome variable is the reduction in the number of units of packed cells administered.
The primary hypothesis of this randomised trial is that the administration of misoprostol to women with RP reduces the number of women who need MRP. The secondary hypothesis is that misoprostol reduces the amount of blood loss in women with RP, especially in those in whom the placenta is expelled by the intervention. Since measurement of blood loss during delivery is not always very reliable, we choose as secondary outcome variable both the measured amount of blood loss and the number of administered packed cells.
