The purpose of this trial was to explore whether 600 mcg sublingual misoprostol offers any additional benefit when added simultaneously to conventional methods for the treatment of primary postpartum bleeding. Although the study findings reported here are consistent with the two placebo-controlled trials on adjunct use of misoprostol [4, 5], we were unable to measure statistical significance in our primary endpoints due to a much lower rate of PPH than expected. Our findings suggest a trend in reduced postpartum blood loss, smaller drop in postpartum hemoglobin, and fewer additional interventions among women treated with misoprostol in addition to standard oxytocics.
The use of misoprostol was not associated with a significant reduction in any of the pre-specified primary outcome measures in this study. However, the relative risk reduction of 41% of blood loss ≥ 500 ml after treatment (RR 0.59 95% CI [0.12, 2.99]) is similar to the two hospital-based placebo-controlled trials conducted in South Africa (RR 0.56 95% CI [0.21, 1.46]) and the Gambia (RR 0.58, 95% CI [0.32, 1.06]) [6]. Indeed, a combined analysis of results from this trial and the two placebo-controlled trials on adjunct use of misoprostol [4, 5] confirms that misoprostol use is associated with a significant reduction of blood loss of ≥ 500 ml following treatment (RR 0.58, 95% CI [0.35, 0.95], p = .029). This confers with results from other recent meta-analyses [2, 6, 7].
Our study findings on measured postpartum blood loss also highlight the clinical importance of a reduction of blood loss following PPH treatment. Women who bled less overall had a significantly smaller drop in hemoglobin and did not require additional interventions, such as blood transfusion, balloon tamponade, or uterine packing, to manage their postpartum bleeding. In contrast, women who had a significantly higher total blood loss were more likely to be given additional interventions and experience a larger drop in postpartum hemoglobin. A reduction in blood loss reduces need for more invasive procedures, results in a smaller change in postpartum hemoglobin, and as a result, may prevent more severe maternal morbidity experienced by recently delivered mothers. Based on the trends in blood loss we see among women in our study given misoprostol in addition to standard oxytocics for their PPH treatment, the adjunct use of misoprostol shows great potential in improving women's health outcomes after experiencing this obstetrical complication.
As found in previous studies on misoprostol, use of the drug was significantly associated with fever and shivering. These effects, however, were described as transient and did not result in any additional complication to the women. Within the literature on misoprostol as adjunct treatment, a total of three cases of high fever ≥ 40.0°C (≥ 104.0°F) have been reported following a 1000 mcg dose of misoprostol (400 mcg sublingually + 400 mcg rectally + 200 mcg orally) [4]. This study had one case of temperature over 40.0°C in the misoprostol group. Delivery ward staff should be trained to recognize and manage cases of severe shivering and high fever to ensure proper care of the patient.
Great efforts were taken to standardize PPH care within and across the participating hospitals. Representatives from the hospitals reviewed their PPH management policies and developed a document to guide their treatment practices over the course of the study and thereafter. Despite efforts to standardize PPH care, there still existed variation in the pharmacological agents/regimens used, especially in the administration of second- or third-line therapies. For instance, six patients were given an additional dose of misoprostol beyond initial treatments. Although the hospitals in this study had policies cautioning against the use of prostaglandins due to lack of evidence, providers still relied on their use as a therapy options.
Irrespective of the variability in PPH practices, a low rate of PPH < 2% across the four participating hospitals was demonstrated in this study. This rate of PPH was validated using an objective measurement protocol with marked bedpan in over 5,000 normal vaginal deliveries. Studies on postpartum hemorrhage often find that the incidence of PPH is underreported in settings prior to objective measurement of postpartum blood loss [19–22], however this study shows just the opposite with a measured PPH rate of 1.2%. According to the 2000 Cochrane Review, the rate of PPH ≥ 500 ml is roughly 5% for women receiving prophylactic uterotonics and 12% for those not receiving uterotonics prophylactically [23]. Importantly, only two of the four studies included in the review specified the use of an objective blood measurement technique. In general, there is wide variability in reported PPH rates in the literature. As Soriano and colleagues note, PPH incidence ≥ 500 ml has been reported at 1.0%, 5.0%, 7.2%, and 14.5% in studies comparing oxytocin-ergometrine and oxytocin alone in the third stage of labor [24]. This study, using objective measurement of postpartum blood loss, confirms that a very low rate of PPH can be achieved in hospital settings following the routine practice of active management of the third stage of labor. At the same time, the low rate of PPH in this study demonstrates the difficulty in conducting hospital-based studies on relatively rare, but clinically important obstetrical complications.
The objective assessment of postpartum bleeding provided a valuable, initially unexpected, insight into the diagnosis and management of PPH in the four Karachi hospitals. Individual exit interviews with study staff revealed that they believed the use of the bedpan had corrected their "over"-estimation of postpartum blood loss. Both doctors and nurses explained that previously they had overestimated postpartum blood loss, resulting in misdiagnosis of PPH, unnecessary treatments, and prolonged hospitalization. During the study, staff was trained to diagnose PPH at 500 ml using the bedpan for objective assessment. However, PPH was diagnosed, on average, after losing nearly 650 ml, which suggests that the use of the bedpan did not lead to more prompt diagnosis at 500 ml. The timing of diagnosis, which commonly occurred around 30 minutes after delivery, also provided valuable insight on the duration of close-monitoring necessary during the postpartum period for all recently delivered mothers. Objective measures using the bedpan and Hemocue apparatus also verified that those women with greater postpartum bleeding and larger decline in postpartum hemoglobin were commonly provided with additional interventions beyond standard uterotonic treatments to control their bleeding. The use of the bedpan proved to be a valuable tool for educating delivery ward staff over the course of the study on the diagnosis and management of postpartum hemorrhage, but the value of its continued use outside a clinical trial is not yet apparent.