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A randomized trial of sublingual misoprostol to augment routine third-stage management among women at risk of postpartum hemorrhage
IJG-08500; No of Pages 5 International Journal of Gynecology and Obstetrics xxx (2015) xxx–xxx
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International Journal of Gynecology and Obstetrics journal homepage: www.elsevier.com/locate/ijgo
CLINICAL ARTICLE
A randomized trial of sublingual misoprostol to augment routine third-stage management among women at risk of postpartum hemorrhage Picklu Chaudhuri ⁎, Arindam Majumdar Department of Obstetrics and Gynecology, Nilratan Sircar Medical College, West Bengal University Of Health Sciences, Kolkata, India
a r t i c l e
i n f o
Article history: Received 15 March 2015 Received in revised form 18 June 2015 Accepted 20 October 2015 Keywords: Adjunct Blood loss Misoprostol Oxytocin Postpartum hemorrhage
a b s t r a c t Objective: To assess whether a combination of misoprostol and oxytocin is more beneficial than oxytocin alone in reducing blood loss after vaginal delivery among women with known risk factors for postpartum hemorrhage (PPH). Methods: A randomized, double-blind trial was conducted in a medical college in eastern India among women aged at least 18 years who had known high-risk factors for PPH. Using a computer-generated random number sequence (block size 6–8), participants were randomly assigned to receive 400 μg misoprostol or matched placebo tablets sublingually, in addition to 10 units of oxytocin, after vaginal delivery. The primary outcomes were postpartum blood loss at 1 hour and frequency of PPH. Analyses were by intention to treat. Results: Both groups contained 144 participants. Postpartum blood loss at 1 hour after delivery was significantly lower among women who received misoprostol than among those who received placebo (225.8 ± 156.7 mL vs 302.4 ± 230.3 mL; P b 0.001). The frequency of moderate PPH (500–999 mL) was significantly lower in the group receiving misoprostol than in the placebo group (5 [3.5%] vs 15 [10.4%] participants; P = 0.03). Conclusion: As compared with oxytocin alone, misoprostol with oxytocin more effectively reduced blood loss after vaginal delivery among women at risk of PPH. Clinical Trial Registry India: CTRI/2014/03/004491 © 2015 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.
1. Introduction Postpartum hemorrhage (PPH) is the single major cause of maternal mortality and serious maternal morbidity in low-income countries [1]. Most cases of PPH (almost 80%) occur because the uterus fails to contract [2], and might be avoided by anticipation of risk factors, active management of the third stage of labor (AMTSL), and prompt intervention. Multiple pregnancy, polyhydramnios, grand multiparity, severe pre-eclampsia, prepartum hemorrhage, prolonged and obstructed labor, augmented labor, obesity, anemia, and known previous PPH are some of the risk factors for atonic PPH [3]. The use of uterotonic drugs in the form of oxytocin (10 IU intramuscularly) within 1 minute of delivery of the newborn has been recommended by WHO as an essential component of AMTSL for all deliveries [4]. Misoprostol (600 μg orally), a prostaglandin E1 derivative, has been recommended as the alternative uterotonic drug in settings where oxytocin is unavailable [5]. However, a meta-analysis [6] found that PPH still occurs even after administration of the “gold standard
⁎ Corresponding author at: Department of Obstetrics and Gynecology, Nilratan Sircar Medical College, 138 AJC Bose Road, Sealdah, Kolkata, 700014, West Bengal, India. Tel.: +91 9432277443; fax: +91 03322658179. E-mail address: [email protected] (P. Chaudhuri).
first line oxytocic”. This finding could be important for women with one or more of the risk factors for PPH. Although oxytocin has a rapid onset of action (within 3–7 minutes of intramuscular injection), its clinical effect lasts for only approximately 1 hour owing to its short half-life of 4–7 minutes [7]. Misoprostol, which has beneficial properties (e.g. stability at room temperature, low cost, long shelf-life, and non-parenteral routes of administration), has been widely evaluated as an alternative to oxytocin for prophylaxis and treatment of PPH [8]. Its onset of action after sublingual administration—the quickest of all routes—is about 30 minutes and its duration of action is not less than 6 hours [9,10]. Oxytocin and misoprostol act through oxytocin and prostanoid receptors, respectively, in the myometrium. Poor response to one uterotonic could be due to individual variation in the receptor population. Although a synergistic action between oxytocin and misoprostol has not been reported so far, a combined uterotonic regime could be beneficial by enabling maximum utilization of the available receptors. The dose and the dose-related adverse effects of an individual uterotonic might also be reduced with a combined approach. The combination of misoprostol and oxytocin has been compared with oxytocin alone for PPH prophylaxis among women undergoing both cesarean delivery [11–14] and vaginal delivery [15–19]. Although women at high risk of PPH are more likely to benefit from the combined uterotonics, only one of the previous studies included exclusively high-
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Please cite this article as: Chaudhuri P, Majumdar A, A randomized trial of sublingual misoprostol to augment routine third-stage management among women at risk of postpartum hemorrhage, Int J Gynecol Obstet (2015), http://dx.doi.org/10.1016/j.ijgo.2015.06.064
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P. Chaudhuri, A. Majumdar / International Journal of Gynecology and Obstetrics xxx (2015) xxx–xxx
risk women [17]. Evidence is therefore lacking with respect to requirement of uterotonics for the subset of women with known risk factors for PPH. Any intervention that would lessen the risk of blood loss for these women would be beneficial from the global point of view by averting not only maternal death but also morbidity in terms of additional surgical intervention, blood transfusion, and postpartum anemia. Against this background, the aim of the present study was to evaluate whether augmentation of routine third-stage management with sublingual misoprostol would be beneficial for women at risk of PPH. 2. Materials and methods The present prospective, randomized, double-blind study was conducted in the Department of Obstetrics and Gynaecology, Nilratan Sircar Medical College and Hospital, Kolkata, India, a tertiary-care teaching hospital in eastern India. The study included women aged 18 years or older who delivered vaginally between October 1, 2012, and May 31, 2014, and who had one or more of the following known risk factors for PPH: multiple pregnancy; polyhydramnios; induced and augmented labor; prolonged labor, defined in accordance with standard guidelines via a partogram; obesity, defined as a body mass index (BMI, calculated as weight in kilograms divided by the square of height in meters) above 30; grand multiparty (≥4); severe pre-eclampsia or eclampsia; anemia, defined as a hemoglobin level less than 80 g/L; and known previous PPH. The study excluded women who had cesarean delivery or instrumental vaginal delivery; known hypersensitivity to misoprostol and/ or oxytocin; major cardiovascular, hepatic, or hematologic disorders; or intrauterine fetal death or stillbirth. The protocol was approved by the Institutional Ethical Committee and was registered with Clinical Trial Registry India (Registration No. CTRI/2014/03/004491). All participants in the study provided written informed consent. On admission to the labor ward, women were screened for eligibility by interview, clinical examination, and review of recent investigations. Those who fulfilled the selection criteria were approached for participation during the first stage of labor and consent was obtained. Labor was monitored by partogram, and women who needed augmentation of labor or had prolonged labor were also enrolled on providing consent. When delivery was imminent with crowning of the presenting fetal part, each participant was randomized by computer-generated random number sequence and block randomization (blocks of 6–8) to receive either two 200-μg tablets of misoprostol (Zitotec; Sun Pharmaceutical Industries Ltd, Mumbai, India) or two tablets of placebo (with the same color, size, and shape) using sealed, opaque, and sequentially numbered packets. Randomization and maintenance of confidential records were done by residents who were not involved in the trial. Preparation of the sealed packets, allocation, and administration of the drugs were done by the labor room midwife. Participants, investigators, and data analysts were masked to group assignment. All deliveries were conducted by residents. The packets were opened and misoprostol/placebo was administered sublingually within 1 minute of delivery of the newborn (or second newborn in the case of twins) by the labor room midwife. Simultaneously, each participant received 10 IU of intramuscular oxytocin (Syntocinon; Novartis India Ltd, Mumbai, India). Additional oxytocic drugs were administered on the basis of clinical judgement by the senior resident. Blood transfusions were given to women who were hemodynamically unstable and/or had a postpartum hemoglobin concentration of less than 60 g/L, in line with the hospital protocol. Linens soaked with amniotic fluid were removed soon after delivery of the newborn, and a pre-weighed thick cotton pad with plastic lining was placed under the buttocks. All blood clots were removed from the vagina and kept in a plastic bag. The pad was replaced if completely soaked during the 1-hour observation period. Episiotomies were repaired immediately after complete delivery of the placenta, and cotton swabs used during this procedure were not included in the blood loss assessment. The difference in weight between the soaked and dry pad was
added to the weight of blood clots to calculate the total blood loss (1 mL was considered equal to 1 g given the specific gravity of blood of 1.08). Vital signs were recorded every 15 minutes. Hemoglobin was measured before delivery and 24 hours after delivery. The primary outcomes were the measured postpartum blood loss (from delivery of the newborn to 1 hour after delivery) and the incidence of PPH. The secondary outcomes were postpartum drop in hemoglobin (24 hours after delivery), requirement of additional oxytocic (1 hour), need for blood transfusion (before discharge), additional surgical intervention for PPH (24 hours), maternal complications (before discharge), and adverse effects related to the uterotonic (1 hour). A power calculation was used to determine the sample size. In a previous study, mean postpartum blood loss among women with high-risk factors receiving oxytocin after vaginal delivery was 386 ± 298 mL [17]. Under the assumption that administration of misoprostol would reduce blood loss by 100 mL, 140 women would be required in each group to have a 80% chance of detecting a significant difference at the 5% level. Under the further assumption of approximately 5% loss during followup, participants were enrolled until there were a few more than 140 in each group. Analysis was done by intention to treat. Excel version 7 (Microsoft, Redmond, WA, USA) and MedCalc version 11 (MedCalc Software, Ostend, Belgium) were used for statistical analyses. Results were reported as mean ± SD, number (percentage), and median (range). Student t, Mann–Whitney U, χ2, and Fisher exact tests were performed to compare variables. Mean and median differences with 95% confidence intervals (CIs) and relative risks with 95% CIs were calculated for outcome parameters as appropriate. P b 0.05 was considered statistically significant.
3. Results During the study period, 750 women admitted to the labor ward were screened for eligibility. In total, 364 had one or more risk factors for PPH and were enrolled in the study. A further 78 women, who were initially screened and found to be ineligible because of a lack of risk factor, were subsequently enrolled because they needed augmentation of labor or showed evidence of prolonged labor. After exclusion of 154 women, 288 women underwent randomization and received the assigned drug (Fig. 1). The two groups had similar baseline demographic and obstetric characteristics (Table 1). The various risk factors for PPH were observed in similar proportions in the two groups (Table 2). Mean postpartum blood loss at 1 hour after delivery was significantly lower among women who received adjunct misoprostol with oxytocin than among those who received oxytocin alone (P b 0.001) (Table 3). The amount of blood loss was initially divided into three categories (b500 mL, 500–999 mL, and ≥ 1000 mL). However, blood loss was less than 500 mL for most women in both groups; as the result, the first category was subdivided into two (b 150 mL and 150–499 mL). A significantly greater proportion of women on adjunct misoprostol lost less than 150 mL of blood as compared with women on oxytocin alone (P b 0.001) (Table 3). The incidence of moderate PPH (500–999 mL) was also significantly lower in the group receiving adjunct misoprostol than in the group receiving placebo (P = 0.03) (Table 3). However, there was no significant difference in the incidence of severe PPH (≥1000 mL) between the two groups (Table 3). The mean postpartum drop in hemoglobin was significantly lower among women who received adjunct misoprostol with oxytocin than among those who received oxytocin alone (P = 0.004) (Table 4). It was also observed that more women in the combined uterotonic group had a postpartum drop in hemoglobin of less than 5 g/L (P b 0.001) (Table 4). Additional uterotonic drugs and blood transfusion were required slightly less frequently for women who received adjunct misoprostol than for those who received placebo, although the differences were not significant (Table 4).
Please cite this article as: Chaudhuri P, Majumdar A, A randomized trial of sublingual misoprostol to augment routine third-stage management among women at risk of postpartum hemorrhage, Int J Gynecol Obstet (2015), http://dx.doi.org/10.1016/j.ijgo.2015.06.064
P. Chaudhuri, A. Majumdar / International Journal of Gynecology and Obstetrics xxx (2015) xxx–xxx
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Patients assessed for eligibility (n=750) Excluded (n=386) 1 risk factor for PPH (n=364) Needed augmentation of labor or had prolonged labor (n=78)
Eligible for inclusion (n=442) Excluded (n=154) Coagulopathy (n=4) HELLP syndrome (n=6) Cesarean delivery (n=108) Instrumental delivery (n=26) Declined to participate (n=10)
Randomization (n=288)
Allocated to and received misoprostol (n=144)
Allocated to and received placebo (n=144)
Fig. 1. Flow of participants through the study. Abbreviations: PPH, postpartum hemorrhage; HELLP, hemolysis, elevated liver enzymes, low platelet count.
One woman in each group required surgical intervention for intractable PPH. Manual removal of placenta was needed for two women who received oxytocin alone. No maternal death occurred. Shivering was the most common adverse effect, and it occurred significantly more often among women given adjunct misoprostol (P b 0.001) (Table 5). Although pyrexia was more frequent in the adjunct misoprostol group in than in the placebo group, the difference was not significant (P = 0.1) (Table 5).
4. Discussion Among the present cohort of women with known risk factors for PPH, administration of misoprostol plus oxytocin reduced postpartum blood loss during a 1-hour observation period and decreased the incidence of moderate PPH as compared with oxytocin alone. No significant
difference was observed in the incidence severe PPH (≥1000 mL) or the requirement for additional uterotonic drugs and blood transfusion. Of five randomized trials that previously compared oxytocin plus misoprostol with oxytocin alone for prevention of PPH after vaginal delivery, two were similar to the present study in terms of the dose and route of misoprostol [18,19], whereas two studies in Turkey [15,16] and one in Nigeria [17] differed in dose and route of administration, as well as in the drug administered in the control group. In agreement with the present findings, a trend toward a reduction in blood loss with combined use of misoprostol and routine oxytocic as compared with oxytocic alone was observed by Hofmeyr et al. [18] (189 mL vs 199 mL; mean difference −9.58 mL, 95% CI, −22.3 to 3.1) and Fawole et al. [19] (211.8 mL vs 217.5 mL; mean difference − 5.7 mL, 95% CI − 16.0 to 27.4). However, the reduction was small and insignificant in both studies. The discrepancy between the present study and the previous investigations in terms of the size of the reduction in blood loss could be due to the following factors: first, the
Table 1 Demographic and obstetric characteristics of the study patients.a Characteristic
Misoprostol group (n = 144)
Placebo group (n = 144)
P value
Age, y Parity Primipara Grand multipara (≥4) Length of pregnancy, wk BMI Birth weight, kg Preoperative hemoglobin, g/L 1 risk factor ≥2 risk factors Episiotomy/perineal tear
24.7 ± 4.1 0 (0–5) 77 (53.5) 8 (5.6) 37.8 ± 0.9 25.3 ± 4.5 2.7 ± 0.4 111.9 ± 17.9 125 (86.8) 19 (13.2) 87 (60.4)
25.3 ± 4.2 1 (0–5) 64 (44.4) 5 (3.5) 37.5 ± 1.4 24.7 ± 4.1 2.8 ± 0.4 113.3 ± 15.1 118 (81.9) 26 (18.1) 94 (65.2)
0.2b 0.5b 0.2c 0.6d 0.1b 0.2b 0.2b 0.5b 0.3c 0.3c 0.5c
Abbreviation: BMI, body mass index (calculated as weight in kilograms divided by the square of height in meters). a Values are given as mean ± SD, median (range), or number (percentage), unless indicated otherwise. b By t test. c By χ2 test. d By Fisher exact test.
Table 2 Risk factors.a,b Risk factor
Misoprostol group (n = 144)
Placebo group (n = 144)
P value
Multiple pregnancy Polyhydramnios Severe pre-eclampsia or eclampsia Anemia (hemoglobin b80 g/L) Prolonged labor Labor augmented by oxytocin Obesity (BMI N30) Grandmultiparity (≥4) Known previous PPH
23 (16.0) 6 (4.2) 40 (27.8) 11 (7.6) 18 (12.5) 43 (29.9) 13 (9.0) 8 (5.6) 5 (3.5)
27 (18.8) 09 (6.3) 46 (32.0) 9 (6.3) 12 (8.3) 49 (34.0) 10 (7.0) 5 (3.5) 9 (6.3)
0.6c 0.6c 0.5c 0.8c 0.3c 0.5c 0.7c 0.6d 0.4d
Abbreviations: BMI, body mass index (calculated as weight in kilograms divided by the square of height in meters); PPH, postpartum hemorrhage. a Values are given as number (percentage) unless indicated otherwise. b The total number of risk factors in each group was more than the total number of women in each group because some women had more than one risk factor. c By χ2 test. d By Fisher exact test.
Please cite this article as: Chaudhuri P, Majumdar A, A randomized trial of sublingual misoprostol to augment routine third-stage management among women at risk of postpartum hemorrhage, Int J Gynecol Obstet (2015), http://dx.doi.org/10.1016/j.ijgo.2015.06.064
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Table 3 Primary outcomes.a Outcome
Table 5 Adverse effects.a Misoprostol group (n = 144)
Postpartum blood loss, mL Mean ± SD 225.8 ± 156.7 Median (range) 200 (120–1250) Blood loss, mL b150 25 (17.4) 150–499 112 (77.8) 500–999 5 (3.5) ≥1000 2 (1.4)
Placebo group (n = 144)
Difference or RR (95% CI)
P value
302.4 ± 230.3 76.6 (30.9–122.3) b0.001b 220 (145–1500) 20.0 (2.3–37.7) 1 (0.7) 124 (86.1) 15 (10.4) 4 (2.8)
25.0 (3.4–182.1) 0.9 (0.8–1.0) 0.3 (0.1–0.9) 0.5 (0.1–2.7)
b0.001c 0.09c 0.03d 0.7d
Abbreviations: RR, relative risk; CI, confidence interval. a Values are given as number (percentage) unless indicated otherwise. b By Mann–Whitney U test. c By χ2 test. d By Fisher exact test.
previous two studies included low-risk multiparous women; and second, the sample size in the previous studies was larger than the present cohort. It is possible that adding misoprostol to routine oxytocin might benefit women with high-risk factors for PPH to a greater extent, as observed in the present study. Although they included women with high-risk factors for PPH, Badejoko et al. [17] did not show any reduction in blood loss with the use of additional misoprostol (387.28 ± 203.09 mL vs 386.73 ± 298.51 mL, P = 0.07). Their finding might be a result of the fact that additional misoprostol was compared with additional intravenous oxytocin infusion, by contrast with the present study, which was placebo-controlled. The present observation of a significantly lower incidence of PPH (500–999 mL) among women given adjunct misoprostol was consistent with the results of a meta-analysis [18] of four previous trials (4013 women; relative risk 0.75, 95% CI 0.58–0.96). The present study, along with most previous investigations [15,16,18,19], observed no significant difference between the groups in the incidence of severe PPH (≥1000 mL) or the requirement for additional oxytocic drugs and blood transfusion. The combination of misoprostol and oxytocin was also found to be effective in reducing blood loss in the range 500–999 mL without affecting the incidence of major PPH (≥1000 mL) in a similar trial of women undergoing cesarean delivery [11]. Despite the high-risk population, the mean and median blood losses recorded in both groups of the present study were low in comparison with a previous study of high-risk women [17]. This difference might have arisen by chance, being dependent on a specific population sampled over a fixed period of time.
Adverse effect
Misoprostol group (n = 144)
Placebo group (n = 144)
Relative risk (95% CI)
P value
Shivering Pyrexia (N38 °C) Nausea/vomiting Diarrhea
39 (27.1) 8 (5.6) 2 (1.4) 2 (1.4)
6 (4.2) 2 (1.4) 0 0
6.5 (2.8–14.9) 4.0 (0.9–18.5) 5.0 (0.2–103.2) 5.0 (0.2–103.2)
b0.001b 0.1c 0.5c 0.5c
Abbreviation: CI, confidence interval. a Values are given as number (percentage) unless indicated otherwise. b By χ2 test. c By Fisher exact test.
A significantly smaller postpartum drop in hemoglobin concentration in the group that received adjunct misoprostol was evident in present study, consistent with the results of the Nigerian study [17]. The Turkish trials, however, failed to show any significant difference in the postpartum drop in hemoglobin [15,16]. Use of additional oxytocic and blood transfusion are the two factors that affect the drop in hemoglobin. Variability in the criteria for administering additional uterotonics and blood transfusion might have resulted in these conflicting findings related to the drop in hemoglobin. In the present study, a significantly higher number of women in the adjunct misoprostol group recorded a drop in hemoglobin of less than 5 g/L as compared with women given oxytocin alone. This indicates that there is a possible beneficial effect of the combined regime in preventing postpartum anemia. At present, however, there are no comparative data available and this observation should be verified in further studies. Maternal death or major morbidity was not observed in either group in the present study, consistent with previous observations [15–19]. Shivering and pyrexia were the two most common adverse effects after the administration of misoprostol, again in accordance with similar previous studies [15–19]. These adverse effects were, however, self-limiting. The strength of the present study lies in the exclusive inclusion of women at high risk of PPH. A limitation was the application of the gravimetric method of blood loss assessment, which is less accurate than other methods. In conclusion, adding 400 μg of sublingual misoprostol to the standard regime of 10 IU of intramuscular oxytocin for routine third-stage management of women with known high-risk factors for PPH seems to be more effective than does oxytocin alone in reducing both postpartum blood loss and the incidence of moderate PPH (500–999 mL). Future research with larger cohorts is required in this area. Conflict of interest The authors have no conflicts of interest. References
Table 4 Secondary outcomes.a Outcome
Drop in hemoglobin, g/L Mean ± SD Median (range) b5 N20 Additional uterotonic Blood transfusion needed
Misoprostol group (n = 144)
Placebo group (n = 144)
Difference or RR (95% CI)
P value
7±4 6 (4–30) 16 (11.1) 2 (1.4) 12 (8.3) 5 (3.5)
9±5 7 (4–30) 1 (0.7) 8 (5.6) 22 (15.3) 12 (8.3)
2 (0.9–3.1) 1 (0.5–1.5) 16.0 (2.2–119.1) 0.3 (0.1–1.2) 0.5 (0.3–1.1) 2.4 (0.39–6.6)
0.004b – b0.001b 0.1c 0.1b 0.1d
Abbreviations: RR, relative risk; CI, confidence interval. a Values are given as number (percentage) unless indicated otherwise. b By t test. c By χ2 test. d By Fisher exact test.
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Please cite this article as: Chaudhuri P, Majumdar A, A randomized trial of sublingual misoprostol to augment routine third-stage management among women at risk of postpartum hemorrhage, Int J Gynecol Obstet (2015), http://dx.doi.org/10.1016/j.ijgo.2015.06.064
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CLINICAL ARTICLE
A randomized trial of sublingual misoprostol to augment routine third-stage management among women at risk of postpartum hemorrhage Picklu Chaudhuri ⁎, Arindam Majumdar Department of Obstetrics and Gynecology, Nilratan Sircar Medical College, West Bengal University Of Health Sciences, Kolkata, India
a r t i c l e
i n f o
Article history: Received 15 March 2015 Received in revised form 18 June 2015 Accepted 20 October 2015 Keywords: Adjunct Blood loss Misoprostol Oxytocin Postpartum hemorrhage
a b s t r a c t Objective: To assess whether a combination of misoprostol and oxytocin is more beneficial than oxytocin alone in reducing blood loss after vaginal delivery among women with known risk factors for postpartum hemorrhage (PPH). Methods: A randomized, double-blind trial was conducted in a medical college in eastern India among women aged at least 18 years who had known high-risk factors for PPH. Using a computer-generated random number sequence (block size 6–8), participants were randomly assigned to receive 400 μg misoprostol or matched placebo tablets sublingually, in addition to 10 units of oxytocin, after vaginal delivery. The primary outcomes were postpartum blood loss at 1 hour and frequency of PPH. Analyses were by intention to treat. Results: Both groups contained 144 participants. Postpartum blood loss at 1 hour after delivery was significantly lower among women who received misoprostol than among those who received placebo (225.8 ± 156.7 mL vs 302.4 ± 230.3 mL; P b 0.001). The frequency of moderate PPH (500–999 mL) was significantly lower in the group receiving misoprostol than in the placebo group (5 [3.5%] vs 15 [10.4%] participants; P = 0.03). Conclusion: As compared with oxytocin alone, misoprostol with oxytocin more effectively reduced blood loss after vaginal delivery among women at risk of PPH. Clinical Trial Registry India: CTRI/2014/03/004491 © 2015 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.
1. Introduction Postpartum hemorrhage (PPH) is the single major cause of maternal mortality and serious maternal morbidity in low-income countries [1]. Most cases of PPH (almost 80%) occur because the uterus fails to contract [2], and might be avoided by anticipation of risk factors, active management of the third stage of labor (AMTSL), and prompt intervention. Multiple pregnancy, polyhydramnios, grand multiparity, severe pre-eclampsia, prepartum hemorrhage, prolonged and obstructed labor, augmented labor, obesity, anemia, and known previous PPH are some of the risk factors for atonic PPH [3]. The use of uterotonic drugs in the form of oxytocin (10 IU intramuscularly) within 1 minute of delivery of the newborn has been recommended by WHO as an essential component of AMTSL for all deliveries [4]. Misoprostol (600 μg orally), a prostaglandin E1 derivative, has been recommended as the alternative uterotonic drug in settings where oxytocin is unavailable [5]. However, a meta-analysis [6] found that PPH still occurs even after administration of the “gold standard
⁎ Corresponding author at: Department of Obstetrics and Gynecology, Nilratan Sircar Medical College, 138 AJC Bose Road, Sealdah, Kolkata, 700014, West Bengal, India. Tel.: +91 9432277443; fax: +91 03322658179. E-mail address: [email protected] (P. Chaudhuri).
first line oxytocic”. This finding could be important for women with one or more of the risk factors for PPH. Although oxytocin has a rapid onset of action (within 3–7 minutes of intramuscular injection), its clinical effect lasts for only approximately 1 hour owing to its short half-life of 4–7 minutes [7]. Misoprostol, which has beneficial properties (e.g. stability at room temperature, low cost, long shelf-life, and non-parenteral routes of administration), has been widely evaluated as an alternative to oxytocin for prophylaxis and treatment of PPH [8]. Its onset of action after sublingual administration—the quickest of all routes—is about 30 minutes and its duration of action is not less than 6 hours [9,10]. Oxytocin and misoprostol act through oxytocin and prostanoid receptors, respectively, in the myometrium. Poor response to one uterotonic could be due to individual variation in the receptor population. Although a synergistic action between oxytocin and misoprostol has not been reported so far, a combined uterotonic regime could be beneficial by enabling maximum utilization of the available receptors. The dose and the dose-related adverse effects of an individual uterotonic might also be reduced with a combined approach. The combination of misoprostol and oxytocin has been compared with oxytocin alone for PPH prophylaxis among women undergoing both cesarean delivery [11–14] and vaginal delivery [15–19]. Although women at high risk of PPH are more likely to benefit from the combined uterotonics, only one of the previous studies included exclusively high-
http://dx.doi.org/10.1016/j.ijgo.2015.06.064 0020-7292/© 2015 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.
Please cite this article as: Chaudhuri P, Majumdar A, A randomized trial of sublingual misoprostol to augment routine third-stage management among women at risk of postpartum hemorrhage, Int J Gynecol Obstet (2015), http://dx.doi.org/10.1016/j.ijgo.2015.06.064
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P. Chaudhuri, A. Majumdar / International Journal of Gynecology and Obstetrics xxx (2015) xxx–xxx
risk women [17]. Evidence is therefore lacking with respect to requirement of uterotonics for the subset of women with known risk factors for PPH. Any intervention that would lessen the risk of blood loss for these women would be beneficial from the global point of view by averting not only maternal death but also morbidity in terms of additional surgical intervention, blood transfusion, and postpartum anemia. Against this background, the aim of the present study was to evaluate whether augmentation of routine third-stage management with sublingual misoprostol would be beneficial for women at risk of PPH. 2. Materials and methods The present prospective, randomized, double-blind study was conducted in the Department of Obstetrics and Gynaecology, Nilratan Sircar Medical College and Hospital, Kolkata, India, a tertiary-care teaching hospital in eastern India. The study included women aged 18 years or older who delivered vaginally between October 1, 2012, and May 31, 2014, and who had one or more of the following known risk factors for PPH: multiple pregnancy; polyhydramnios; induced and augmented labor; prolonged labor, defined in accordance with standard guidelines via a partogram; obesity, defined as a body mass index (BMI, calculated as weight in kilograms divided by the square of height in meters) above 30; grand multiparty (≥4); severe pre-eclampsia or eclampsia; anemia, defined as a hemoglobin level less than 80 g/L; and known previous PPH. The study excluded women who had cesarean delivery or instrumental vaginal delivery; known hypersensitivity to misoprostol and/ or oxytocin; major cardiovascular, hepatic, or hematologic disorders; or intrauterine fetal death or stillbirth. The protocol was approved by the Institutional Ethical Committee and was registered with Clinical Trial Registry India (Registration No. CTRI/2014/03/004491). All participants in the study provided written informed consent. On admission to the labor ward, women were screened for eligibility by interview, clinical examination, and review of recent investigations. Those who fulfilled the selection criteria were approached for participation during the first stage of labor and consent was obtained. Labor was monitored by partogram, and women who needed augmentation of labor or had prolonged labor were also enrolled on providing consent. When delivery was imminent with crowning of the presenting fetal part, each participant was randomized by computer-generated random number sequence and block randomization (blocks of 6–8) to receive either two 200-μg tablets of misoprostol (Zitotec; Sun Pharmaceutical Industries Ltd, Mumbai, India) or two tablets of placebo (with the same color, size, and shape) using sealed, opaque, and sequentially numbered packets. Randomization and maintenance of confidential records were done by residents who were not involved in the trial. Preparation of the sealed packets, allocation, and administration of the drugs were done by the labor room midwife. Participants, investigators, and data analysts were masked to group assignment. All deliveries were conducted by residents. The packets were opened and misoprostol/placebo was administered sublingually within 1 minute of delivery of the newborn (or second newborn in the case of twins) by the labor room midwife. Simultaneously, each participant received 10 IU of intramuscular oxytocin (Syntocinon; Novartis India Ltd, Mumbai, India). Additional oxytocic drugs were administered on the basis of clinical judgement by the senior resident. Blood transfusions were given to women who were hemodynamically unstable and/or had a postpartum hemoglobin concentration of less than 60 g/L, in line with the hospital protocol. Linens soaked with amniotic fluid were removed soon after delivery of the newborn, and a pre-weighed thick cotton pad with plastic lining was placed under the buttocks. All blood clots were removed from the vagina and kept in a plastic bag. The pad was replaced if completely soaked during the 1-hour observation period. Episiotomies were repaired immediately after complete delivery of the placenta, and cotton swabs used during this procedure were not included in the blood loss assessment. The difference in weight between the soaked and dry pad was
added to the weight of blood clots to calculate the total blood loss (1 mL was considered equal to 1 g given the specific gravity of blood of 1.08). Vital signs were recorded every 15 minutes. Hemoglobin was measured before delivery and 24 hours after delivery. The primary outcomes were the measured postpartum blood loss (from delivery of the newborn to 1 hour after delivery) and the incidence of PPH. The secondary outcomes were postpartum drop in hemoglobin (24 hours after delivery), requirement of additional oxytocic (1 hour), need for blood transfusion (before discharge), additional surgical intervention for PPH (24 hours), maternal complications (before discharge), and adverse effects related to the uterotonic (1 hour). A power calculation was used to determine the sample size. In a previous study, mean postpartum blood loss among women with high-risk factors receiving oxytocin after vaginal delivery was 386 ± 298 mL [17]. Under the assumption that administration of misoprostol would reduce blood loss by 100 mL, 140 women would be required in each group to have a 80% chance of detecting a significant difference at the 5% level. Under the further assumption of approximately 5% loss during followup, participants were enrolled until there were a few more than 140 in each group. Analysis was done by intention to treat. Excel version 7 (Microsoft, Redmond, WA, USA) and MedCalc version 11 (MedCalc Software, Ostend, Belgium) were used for statistical analyses. Results were reported as mean ± SD, number (percentage), and median (range). Student t, Mann–Whitney U, χ2, and Fisher exact tests were performed to compare variables. Mean and median differences with 95% confidence intervals (CIs) and relative risks with 95% CIs were calculated for outcome parameters as appropriate. P b 0.05 was considered statistically significant.
3. Results During the study period, 750 women admitted to the labor ward were screened for eligibility. In total, 364 had one or more risk factors for PPH and were enrolled in the study. A further 78 women, who were initially screened and found to be ineligible because of a lack of risk factor, were subsequently enrolled because they needed augmentation of labor or showed evidence of prolonged labor. After exclusion of 154 women, 288 women underwent randomization and received the assigned drug (Fig. 1). The two groups had similar baseline demographic and obstetric characteristics (Table 1). The various risk factors for PPH were observed in similar proportions in the two groups (Table 2). Mean postpartum blood loss at 1 hour after delivery was significantly lower among women who received adjunct misoprostol with oxytocin than among those who received oxytocin alone (P b 0.001) (Table 3). The amount of blood loss was initially divided into three categories (b500 mL, 500–999 mL, and ≥ 1000 mL). However, blood loss was less than 500 mL for most women in both groups; as the result, the first category was subdivided into two (b 150 mL and 150–499 mL). A significantly greater proportion of women on adjunct misoprostol lost less than 150 mL of blood as compared with women on oxytocin alone (P b 0.001) (Table 3). The incidence of moderate PPH (500–999 mL) was also significantly lower in the group receiving adjunct misoprostol than in the group receiving placebo (P = 0.03) (Table 3). However, there was no significant difference in the incidence of severe PPH (≥1000 mL) between the two groups (Table 3). The mean postpartum drop in hemoglobin was significantly lower among women who received adjunct misoprostol with oxytocin than among those who received oxytocin alone (P = 0.004) (Table 4). It was also observed that more women in the combined uterotonic group had a postpartum drop in hemoglobin of less than 5 g/L (P b 0.001) (Table 4). Additional uterotonic drugs and blood transfusion were required slightly less frequently for women who received adjunct misoprostol than for those who received placebo, although the differences were not significant (Table 4).
Please cite this article as: Chaudhuri P, Majumdar A, A randomized trial of sublingual misoprostol to augment routine third-stage management among women at risk of postpartum hemorrhage, Int J Gynecol Obstet (2015), http://dx.doi.org/10.1016/j.ijgo.2015.06.064
P. Chaudhuri, A. Majumdar / International Journal of Gynecology and Obstetrics xxx (2015) xxx–xxx
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Patients assessed for eligibility (n=750) Excluded (n=386) 1 risk factor for PPH (n=364) Needed augmentation of labor or had prolonged labor (n=78)
Eligible for inclusion (n=442) Excluded (n=154) Coagulopathy (n=4) HELLP syndrome (n=6) Cesarean delivery (n=108) Instrumental delivery (n=26) Declined to participate (n=10)
Randomization (n=288)
Allocated to and received misoprostol (n=144)
Allocated to and received placebo (n=144)
Fig. 1. Flow of participants through the study. Abbreviations: PPH, postpartum hemorrhage; HELLP, hemolysis, elevated liver enzymes, low platelet count.
One woman in each group required surgical intervention for intractable PPH. Manual removal of placenta was needed for two women who received oxytocin alone. No maternal death occurred. Shivering was the most common adverse effect, and it occurred significantly more often among women given adjunct misoprostol (P b 0.001) (Table 5). Although pyrexia was more frequent in the adjunct misoprostol group in than in the placebo group, the difference was not significant (P = 0.1) (Table 5).
4. Discussion Among the present cohort of women with known risk factors for PPH, administration of misoprostol plus oxytocin reduced postpartum blood loss during a 1-hour observation period and decreased the incidence of moderate PPH as compared with oxytocin alone. No significant
difference was observed in the incidence severe PPH (≥1000 mL) or the requirement for additional uterotonic drugs and blood transfusion. Of five randomized trials that previously compared oxytocin plus misoprostol with oxytocin alone for prevention of PPH after vaginal delivery, two were similar to the present study in terms of the dose and route of misoprostol [18,19], whereas two studies in Turkey [15,16] and one in Nigeria [17] differed in dose and route of administration, as well as in the drug administered in the control group. In agreement with the present findings, a trend toward a reduction in blood loss with combined use of misoprostol and routine oxytocic as compared with oxytocic alone was observed by Hofmeyr et al. [18] (189 mL vs 199 mL; mean difference −9.58 mL, 95% CI, −22.3 to 3.1) and Fawole et al. [19] (211.8 mL vs 217.5 mL; mean difference − 5.7 mL, 95% CI − 16.0 to 27.4). However, the reduction was small and insignificant in both studies. The discrepancy between the present study and the previous investigations in terms of the size of the reduction in blood loss could be due to the following factors: first, the
Table 1 Demographic and obstetric characteristics of the study patients.a Characteristic
Misoprostol group (n = 144)
Placebo group (n = 144)
P value
Age, y Parity Primipara Grand multipara (≥4) Length of pregnancy, wk BMI Birth weight, kg Preoperative hemoglobin, g/L 1 risk factor ≥2 risk factors Episiotomy/perineal tear
24.7 ± 4.1 0 (0–5) 77 (53.5) 8 (5.6) 37.8 ± 0.9 25.3 ± 4.5 2.7 ± 0.4 111.9 ± 17.9 125 (86.8) 19 (13.2) 87 (60.4)
25.3 ± 4.2 1 (0–5) 64 (44.4) 5 (3.5) 37.5 ± 1.4 24.7 ± 4.1 2.8 ± 0.4 113.3 ± 15.1 118 (81.9) 26 (18.1) 94 (65.2)
0.2b 0.5b 0.2c 0.6d 0.1b 0.2b 0.2b 0.5b 0.3c 0.3c 0.5c
Abbreviation: BMI, body mass index (calculated as weight in kilograms divided by the square of height in meters). a Values are given as mean ± SD, median (range), or number (percentage), unless indicated otherwise. b By t test. c By χ2 test. d By Fisher exact test.
Table 2 Risk factors.a,b Risk factor
Misoprostol group (n = 144)
Placebo group (n = 144)
P value
Multiple pregnancy Polyhydramnios Severe pre-eclampsia or eclampsia Anemia (hemoglobin b80 g/L) Prolonged labor Labor augmented by oxytocin Obesity (BMI N30) Grandmultiparity (≥4) Known previous PPH
23 (16.0) 6 (4.2) 40 (27.8) 11 (7.6) 18 (12.5) 43 (29.9) 13 (9.0) 8 (5.6) 5 (3.5)
27 (18.8) 09 (6.3) 46 (32.0) 9 (6.3) 12 (8.3) 49 (34.0) 10 (7.0) 5 (3.5) 9 (6.3)
0.6c 0.6c 0.5c 0.8c 0.3c 0.5c 0.7c 0.6d 0.4d
Abbreviations: BMI, body mass index (calculated as weight in kilograms divided by the square of height in meters); PPH, postpartum hemorrhage. a Values are given as number (percentage) unless indicated otherwise. b The total number of risk factors in each group was more than the total number of women in each group because some women had more than one risk factor. c By χ2 test. d By Fisher exact test.
Please cite this article as: Chaudhuri P, Majumdar A, A randomized trial of sublingual misoprostol to augment routine third-stage management among women at risk of postpartum hemorrhage, Int J Gynecol Obstet (2015), http://dx.doi.org/10.1016/j.ijgo.2015.06.064
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P. Chaudhuri, A. Majumdar / International Journal of Gynecology and Obstetrics xxx (2015) xxx–xxx
Table 3 Primary outcomes.a Outcome
Table 5 Adverse effects.a Misoprostol group (n = 144)
Postpartum blood loss, mL Mean ± SD 225.8 ± 156.7 Median (range) 200 (120–1250) Blood loss, mL b150 25 (17.4) 150–499 112 (77.8) 500–999 5 (3.5) ≥1000 2 (1.4)
Placebo group (n = 144)
Difference or RR (95% CI)
P value
302.4 ± 230.3 76.6 (30.9–122.3) b0.001b 220 (145–1500) 20.0 (2.3–37.7) 1 (0.7) 124 (86.1) 15 (10.4) 4 (2.8)
25.0 (3.4–182.1) 0.9 (0.8–1.0) 0.3 (0.1–0.9) 0.5 (0.1–2.7)
b0.001c 0.09c 0.03d 0.7d
Abbreviations: RR, relative risk; CI, confidence interval. a Values are given as number (percentage) unless indicated otherwise. b By Mann–Whitney U test. c By χ2 test. d By Fisher exact test.
previous two studies included low-risk multiparous women; and second, the sample size in the previous studies was larger than the present cohort. It is possible that adding misoprostol to routine oxytocin might benefit women with high-risk factors for PPH to a greater extent, as observed in the present study. Although they included women with high-risk factors for PPH, Badejoko et al. [17] did not show any reduction in blood loss with the use of additional misoprostol (387.28 ± 203.09 mL vs 386.73 ± 298.51 mL, P = 0.07). Their finding might be a result of the fact that additional misoprostol was compared with additional intravenous oxytocin infusion, by contrast with the present study, which was placebo-controlled. The present observation of a significantly lower incidence of PPH (500–999 mL) among women given adjunct misoprostol was consistent with the results of a meta-analysis [18] of four previous trials (4013 women; relative risk 0.75, 95% CI 0.58–0.96). The present study, along with most previous investigations [15,16,18,19], observed no significant difference between the groups in the incidence of severe PPH (≥1000 mL) or the requirement for additional oxytocic drugs and blood transfusion. The combination of misoprostol and oxytocin was also found to be effective in reducing blood loss in the range 500–999 mL without affecting the incidence of major PPH (≥1000 mL) in a similar trial of women undergoing cesarean delivery [11]. Despite the high-risk population, the mean and median blood losses recorded in both groups of the present study were low in comparison with a previous study of high-risk women [17]. This difference might have arisen by chance, being dependent on a specific population sampled over a fixed period of time.
Adverse effect
Misoprostol group (n = 144)
Placebo group (n = 144)
Relative risk (95% CI)
P value
Shivering Pyrexia (N38 °C) Nausea/vomiting Diarrhea
39 (27.1) 8 (5.6) 2 (1.4) 2 (1.4)
6 (4.2) 2 (1.4) 0 0
6.5 (2.8–14.9) 4.0 (0.9–18.5) 5.0 (0.2–103.2) 5.0 (0.2–103.2)
b0.001b 0.1c 0.5c 0.5c
Abbreviation: CI, confidence interval. a Values are given as number (percentage) unless indicated otherwise. b By χ2 test. c By Fisher exact test.
A significantly smaller postpartum drop in hemoglobin concentration in the group that received adjunct misoprostol was evident in present study, consistent with the results of the Nigerian study [17]. The Turkish trials, however, failed to show any significant difference in the postpartum drop in hemoglobin [15,16]. Use of additional oxytocic and blood transfusion are the two factors that affect the drop in hemoglobin. Variability in the criteria for administering additional uterotonics and blood transfusion might have resulted in these conflicting findings related to the drop in hemoglobin. In the present study, a significantly higher number of women in the adjunct misoprostol group recorded a drop in hemoglobin of less than 5 g/L as compared with women given oxytocin alone. This indicates that there is a possible beneficial effect of the combined regime in preventing postpartum anemia. At present, however, there are no comparative data available and this observation should be verified in further studies. Maternal death or major morbidity was not observed in either group in the present study, consistent with previous observations [15–19]. Shivering and pyrexia were the two most common adverse effects after the administration of misoprostol, again in accordance with similar previous studies [15–19]. These adverse effects were, however, self-limiting. The strength of the present study lies in the exclusive inclusion of women at high risk of PPH. A limitation was the application of the gravimetric method of blood loss assessment, which is less accurate than other methods. In conclusion, adding 400 μg of sublingual misoprostol to the standard regime of 10 IU of intramuscular oxytocin for routine third-stage management of women with known high-risk factors for PPH seems to be more effective than does oxytocin alone in reducing both postpartum blood loss and the incidence of moderate PPH (500–999 mL). Future research with larger cohorts is required in this area. Conflict of interest The authors have no conflicts of interest. References
Table 4 Secondary outcomes.a Outcome
Drop in hemoglobin, g/L Mean ± SD Median (range) b5 N20 Additional uterotonic Blood transfusion needed
Misoprostol group (n = 144)
Placebo group (n = 144)
Difference or RR (95% CI)
P value
7±4 6 (4–30) 16 (11.1) 2 (1.4) 12 (8.3) 5 (3.5)
9±5 7 (4–30) 1 (0.7) 8 (5.6) 22 (15.3) 12 (8.3)
2 (0.9–3.1) 1 (0.5–1.5) 16.0 (2.2–119.1) 0.3 (0.1–1.2) 0.5 (0.3–1.1) 2.4 (0.39–6.6)
0.004b – b0.001b 0.1c 0.1b 0.1d
Abbreviations: RR, relative risk; CI, confidence interval. a Values are given as number (percentage) unless indicated otherwise. b By t test. c By χ2 test. d By Fisher exact test.
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Please cite this article as: Chaudhuri P, Majumdar A, A randomized trial of sublingual misoprostol to augment routine third-stage management among women at risk of postpartum hemorrhage, Int J Gynecol Obstet (2015), http://dx.doi.org/10.1016/j.ijgo.2015.06.064