Objective
To evaluate the efficacy and safety of prophylactic misoprostol use at cesarean delivery for reducing intraoperative and postoperative hemorrhage.
Study Design
Systematic review and metaanalysis of randomized controlled trials.
Results
Seventeen studies (3174 women) were included of which 7 evaluated misoprostol vs oxytocin and 8 evaluated misoprostol plus oxytocin vs oxytocin alone. Overall, there were no significant differences in intraoperative and postoperative hemorrhage between sublingual or oral misoprostol and oxytocin. Rectal misoprostol, compared with oxytocin, was associated with a significant reduction in intraoperative and postoperative hemorrhage. The combined use of sublingual misoprostol and oxytocin, compared with the use of oxytocin alone, was associated with a significant reduction in the mean decrease in hematocrit (mean difference, –2.1%; 95% confidence interval, –3.4 to –0.8) and use of additional uterotonic agents (relative risk, 0.33; 95% confidence interval, 0.18–0.62). Compared with oxytocin alone, buccal misoprostol plus oxytocin reduced the use of additional uterotonic agents; rectal misoprostol plus oxytocin decreased intraoperative and postoperative blood loss, mean fall in hematocrit, and use of additional uterotonic agents; and intrauterine misoprostol plus oxytocin reduced the mean fall in hemoglobin and hematocrit. Women receiving misoprostol, alone or combined with oxytocin, had a higher risk of shivering and pyrexia.
Conclusion
Misoprostol combined with oxytocin appears to be more effective than oxytocin alone in reducing intraoperative and postoperative hemorrhage during cesarean section. There were no significant differences in intraoperative and postoperative hemorrhage when misoprostol was compared to oxytocin. However, these findings were based on a few trials with methodological limitations.
Cesarean delivery is the most common major surgical procedure performed on women worldwide and its rates continue to rise steadily in both developed and developing countries. In 2007, the global cesarean delivery rate was estimated to be 15%. Postpartum hemorrhage is a major contributor to maternal mortality, mainly in developing countries. Recent studies from developed countries report an increase in the rate of postpartum hemorrhage, which has been attributed (at least in part) to a rise in the rate of cesarean delivery. Large population- and hospital-based cohort studies have attributed this to uterine atony after vaginal or cesarean deliveries. Cesarean delivery, often performed because of “dystocia,” may predispose a patient to uterine atony. This has been traditionally attributed to either myometrial fatigue or impaired contractility at the site of the uterine incision.
Postpartum hemorrhage following a cesarean delivery has been defined as blood loss >1000 mL, based on a study from the early 1960s. Recent studies have estimated that the prevalence of postpartum hemorrhage after cesarean delivery ranges from 0.6–6.4% (median, 3%), although the frequency depends on the criteria used to define this condition and the method used to calculate blood loss.
The efficacy of routine administration of uterotonic agents, mainly oxytocin, to reduce the frequency of postpartum hemorrhage after vaginal birth is well established. It has been assumed that the benefits of injectable uterotonic agents observed for vaginal births also apply to cesarean deliveries; yet, this has not been rigorously demonstrated. An updated guideline of the Royal College of Obstetricians and Gynecologists on cesarean delivery recommends a slow intravenous bolus dose of 5 IU of oxytocin after delivery of the neonate to ensure adequate uterine contractility, minimize delay in the delivery of the placenta, reduce intraoperative blood loss, and prevent postpartum hemorrhage. In contrast, in the United States, the practice is to use an oxytocin infusion instead of a bolus dose. Regardless of the mode of administration, oxytocin use in the setting of cesarean delivery may result in maternal adverse effects, such as hypotension and tachycardia.
Misoprostol, a prostaglandin E1 analogue with strong uterotonic properties, has been suggested as an alternative to injectable uterotonic agents for preventing postpartum hemorrhage following vaginal or cesarean deliveries. A recent Cochrane review found that oral misoprostol was associated with a higher risk of severe postpartum hemorrhage and use of additional uterotonics after vaginal birth when compared to conventional uterotonic agents. However, oral or sublingual misoprostol was found to be more effective than placebo in reducing severe postpartum hemorrhage and blood transfusion after vaginal birth. The use of misoprostol during cesarean delivery to prevent hemorrhage attributable to uterine atony has received less attention and its effectiveness has not been systematically evaluated.
We conducted a systematic review and metaanalysis of all available randomized controlled trials (RCTs) to assess the efficacy and safety of prophylactic misoprostol use at cesarean delivery for reducing intraoperative and postoperative hemorrhage.
Materials and Methods
The study was conducted using a prospectively prepared protocol, and is reported using the Preferred Reporting Items for Systematic Reviews and Metaanalyses (PRISMA) guidelines for metaanalyses of RCTs.
Data sources and searches
We searched Medline, Embase, Cinahl, and Lilacs (all from inception through March 31, 2013); the Cochrane Central Register of Controlled Trials ( http://www.mrw.interscience.wiley.com/cochrane/cochrane_clcentral_articles_fs.html ) (1960 through March 31, 2013); ISI Web of Science ( http://www.isiknowledge.com ) (1960 through March 31, 2013); research registers of ongoing trials ( http://www.clinicaltrials.gov , http://www.controlled-trials.com , http://www.centerwatch.com , http://www.anzctr.org.au , http://www.nihr.ac.uk , and http://www.umin.ac.jp/ctr ); and Google Scholar using a combination of key words and text words related to misoprostol , cesarean delivery , and hemorrhage . Congress proceedings of international society meetings of maternal-fetal and reproductive medicine and international meetings on postpartum hemorrhage or cesarean delivery, reference lists of identified studies, textbooks, previously published systematic reviews, and review articles were also searched. Experts in the field were contacted to identify further studies. No language restriction was applied.
Study selection
We included RCTs in which misoprostol (alone or in combination) was used to reduce perioperative hemorrhage in women undergoing cesarean delivery compared with either another uterotonic agent or placebo/no uterotonic agent. Studies were included irrespective of women’s risk status for postpartum hemorrhage, dose, and route of administration. Trials were excluded if they were quasirandomized or if they evaluated only the effect of misoprostol on intestinal motility after cesarean delivery. Published abstracts alone were excluded if additional information on methodological issues and results could not be obtained.
Two investigators (A.C-A. and A.N.) independently reviewed all potentially relevant articles for eligibility. Disagreements regarding trial eligibility were resolved by consensus.
Outcome measures
The prespecified primary outcome measures were the mean intraoperative and postoperative blood loss, and the mean decrease in hemoglobin and hematocrit (difference between preoperative and postoperative levels). In addition, we also chose the use of additional uterotonic agents as a primary outcome because obstetricians are likely to intervene (when uterine atony does not respond to therapy) by employing additional agents. Secondary outcome measures included blood loss >500 and >1000 mL, blood transfusion, mean postoperative hemoglobin and hematocrit, shivering, pyrexia (≥38°C), nausea, vomiting, diarrhea, abdominal pain, headache, any side effect, neonatal outcomes, and costs.
Assessment of risk of bias
We assessed the risk of bias using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions. Seven domains related to risk of bias were assessed in each trial since there is evidence that these issues are associated with biased estimates of treatment effect: (1) random sequence generation; (2) allocation concealment; (3) blinding of participants and personnel; (4) blinding of outcome assessment; (5) incomplete outcome data; (6) selective reporting; and (7) other bias. The assessments were classified as “low,” “high,” or “unclear” risk of bias. In addition, we evaluated the technique of assessment of blood loss used in each study and classified it as objective, subjective, unmeasured, or unreported. The risk of bias in each trial included was assessed individually by 2 reviewers (A.C-A. and A.N.). Any differences of opinion regarding assessment of risk of bias were resolved by discussion.
Data extraction
Two reviewers (A.C-A. and A.N.) independently extracted data from each eligible study using a standardized data abstraction form. There was no blinding of authorship. From each article, reviewers extracted data on participants (inclusion and exclusion criteria, number of women randomized, baseline characteristics, and country and date of recruitment); study characteristics (randomization procedure, concealment allocation method, blinding of clinicians, women and outcome assessors, completeness of outcome data for each outcome–including attrition and exclusions from analysis, intention-to-treat analysis, anesthesia used, and method of assessment of blood loss used); details of interventions (aim, loading and maintenance dose, route, duration of treatment, and use of alternative uterotonic agents); and outcomes (definitions used, number of outcome events/total number, and mean ± SD for each outcome). In an attempt to obtain additional data, we contacted 7 authors by e-mail of whom 2 responded. Disagreements in extracted data were resolved by discussion among reviewers.
Statistical analysis
All statistical analyses were performed according to the guidelines of the Cochrane Collaboration. We analyzed outcomes on an intention-to-treat basis. If this was not clear from the original article, we then carried out a reanalysis when possible. If we found no evidence of a substantial difference in study populations, interventions, or outcome measurements, we performed a metaanalysis. For dichotomous data, we calculated the summary relative risk (RR) with 95% confidence interval (CI). For continuous data, we used the mean difference if outcomes were measured in the same way among trials, or standardized mean difference if the same outcome was measured in a variety of ways, with 95% CI. Analyses were stratified by route of misoprostol administration, irrespective of dose used, as follows: sublingual, oral, buccal, rectal, and intrauterine. Further subgroup analyses were planned to assess primary outcomes according to risk status for intraoperative/postoperative hemorrhage, gestational age at cesarean delivery, type of anesthesia, whether the cesarean delivery was unplanned, method of assessment of blood loss, and dose of misoprostol but these analyses were not undertaken due to the small number of trials included in each comparison.
Heterogeneity of the results among studies was tested with the quantity I 2 , which describes the percentage of total variation across studies that is due to heterogeneity rather than chance. A value of 0% indicates no observed heterogeneity, whereas I 2 values of ≥50% indicate a substantial level of heterogeneity. A fixed effects model was used if substantial statistical heterogeneity was not detected. If there was substantial statistical heterogeneity, a random effects model was used to pool data across studies if causes of heterogeneity could not be determined and the average treatment effect was considered clinically meaningful. One of the most important sources of bias in the conduct of clinical trials evaluating the efficacy of misoprostol to reduce hemorrhage at cesarean delivery is the lack of blinding, which is likely to influence the measurement of intraoperative and postoperative blood loss and use of additional uterotonic agents. We performed a predefined sensitivity analysis to explore the impact of study quality on the effect size for the primary outcomes by including only trials with adequate concealment allocation that were double-masked.
The number needed to treat (NNT) for benefit or harm with 95% CI was calculated for the outcomes for which there was a statistically significant reduction or increase in risk difference based on control event rates in the included trials. We planned to assess publication and related biases, but this was not performed because of paucity of trials in each comparison. Analyses were performed with the Review Manager (RevMan), version 5.1.7 (Nordic Cochrane Centre, Copenhagen, Denmark).
Results
Study selection, details, and quality
The searches yielded 1899 citations, of which 26 were considered to be potentially eligible ( Figure 1 ). Nine studies were excluded. Three of these studies evaluated only the effect of misoprostol on intestinal motility after cesarean delivery, 3 provided very little information on the methodology, 2 were non-RCTs, and the remainder was available only in abstract form with insufficient information on methods and results. The list of studies excluded is available from the authors upon request. Seventeen studies, including 3174 women, fulfilled the inclusion criteria of which 7 evaluated misoprostol vs oxytocin (n = 700), one evaluated misoprostol vs ergometrine (n = 374), 8 evaluated misoprostol plus oxytocin vs oxytocin (n = 1918), and one 3-arm trial evaluated misoprostol vs oxytocin vs misoprostol plus oxytocin (n = 182).
The main characteristics of studies included in the review are shown in Table 1 . Thirteen trials were conducted in developing countries (3 in India, 2 in Egypt, and 1 each in China, Iran, Thailand, Pakistan, Nigeria, Tunisia, Mexico, and Ecuador), 2 in the United Kingdom, and 1 each in the United States and Switzerland. Seven studies included women undergoing elective cesarean delivery and 10 included women undergoing both elective and emergency cesarean delivery. Regional anesthesia was used in 15 studies and general anesthesia in 2 studies. Twelve studies excluded women with any risk factors associated with an increased risk of intraoperative or postoperative hemorrhage, 3 excluded women with some risk factors, and 4 did not report on exclusion criteria. The sample size ranged from 40–400 (median, 174). Of the 17 trials included in the review, 8 evaluated misoprostol using the sublingual route, 4 using the oral route, 3 using the rectal route, and 1 each used buccal and intrauterine routes in doses of 200 μg (2 studies), 400 μg (9 studies), 500 μg (1 study), 600 μg (1 study), and 800 μg (4 studies). The most common dose used in studies evaluating the sublingual route was 400 μg, and 800 μg in studies that evaluated the rectal and intrauterine routes. Misoprostol was used after delivery of the neonate in 12 studies and before delivery of the neonate in 5 studies (orally or rectally at the time of peritoneal incision, rectally just before onset of cesarean section or after urinary catheter placement, and sublingually after tracheal intubation ). It should be noted that in 7 studies that compared misoprostol with placebo, all women received an intravenous infusion of oxytocin in doses ranging from 5–20 IU. Overall, misoprostol was compared with oxytocin in 16 trials and with ergometrine in 1 trial. Nine trials used oxytocin 20 IU and 6 used 10 IU intravenously. The remaining study used oxytocin 20 IU intramyometrially. The main primary outcome measures were intraoperative blood loss (12 studies), difference between preoperative and postoperative hemoglobin and/or hematocrit levels (10 studies), postoperative blood loss (6 studies), use of additional uterotonic agents (5 studies), and drug-related adverse effects (2 studies).
| Study | Location | Inclusion/exclusion criteria | Sample size | Interventions | Primary outcome |
|---|---|---|---|---|---|
| Zhao et al, 1998 | China |
| 182 |
| Postoperative blood loss |
| Acharya et al, 2001 | United Kingdom |
| 60 |
| Intraoperative blood loss and difference between preoperative and postoperative hemoglobin and hematocrit |
| Lokugamage et al, 2001 | United Kingdom |
| 40 |
| Intraoperative blood loss, difference between preoperative and postoperative hemoglobin, and use of additional uterotonic agents |
| Hamm et al, 2005 | United States |
| 352 |
| Need for additional uterotonic agents |
| Vimala et al, 2006 | India |
| 100 |
| Intraoperative blood loss, difference between preoperative and postoperative hemoglobin, and need for additional uterotonic agents |
| Lapaire et al, 2006 | Switzerland |
| 56 |
| Intraoperative and postoperative blood loss, and drug-related adverse effects |
| Quiroga Diaz et al, 2009 | Mexico |
| 200 |
| Difference between preoperative and postoperative hemoglobin and hematocrit |
| Eftekhari et al, 2009 | Iran |
| 100 |
| Intraoperative blood loss and difference between preoperative and postoperative hemoglobin |
| Fekih et al, 2009 | Tunisia |
| 250 |
| Difference between preoperative and postoperative hematocrit |
| Chaudhuri et al, 2010 | India |
| 200 |
| Intraoperative and postoperative blood loss, and difference between preoperative and postoperative hemoglobin |
| Chalermpolprapa, 2010 | Thailand |
| 120 |
| Intraoperative blood loss |
| Owonikoko et al, 2011 | Nigeria |
| 100 |
| Intraoperative and postoperative blood loss, difference between preoperative and postoperative hemoglobin, need for additional uterotonic agents, and drug-related adverse effects |
| Sood and Singh, 2012 | India |
| 174 |
| Intraoperative blood loss, need for additional uterotonic agents, and difference between preoperative and postoperative hemoglobin |
| Ali and Hina, 2012 | Pakistan |
| 374 |
| Intraoperative blood loss >500 mL and postoperative hemoglobin |
| Elsedeek, 2012 | Egypt |
| 400 |
| Intraoperative and postoperative blood loss, and difference between preoperative and postoperative hematocrit |
| El Tahan et al, 2012 | Egypt |
| 366 |
| Postoperative blood loss |
| Gavilanes Sáenz et al, 2012 | Ecuador |
| 100 |
| Intraoperative blood loss |
Figure 2 shows methodological quality of studies included in the systematic review. Thirteen studies had adequate generation of allocation sequence and reported adequate concealment of allocation. Nine trials were double masked and placebo controlled, 13 had an adequate handling of incomplete outcome data, and 14 were free of suggestion of selective outcome reporting. Fifteen studies appeared to be free of other sources of bias. Seven trials met all 7 methodological criteria and were considered to be at low risk of bias. One study met 6 criteria, 4 met 5 criteria, and the remaining 5 met <5 criteria. Blood loss was measured using objective methods in 10 studies and clinical estimation in 5 studies, unmeasured in 1 study, and unreported in another.
Misoprostol vs oxytocin
Sublingual misoprostol vs oxytocin
Four trials at moderate/high risk of bias, with a total of 400 women, compared sublingual misoprostol to oxytocin ( Table 2 ). There was a trend toward a lower mean intraoperative blood loss among women who received sublingual misoprostol (mean difference, 55 mL) although it was not statistically significant (95% CI, –115 to 5; P = .07; I 2 = 58%). One study showed a significant reduction in the mean postoperative blood loss associated with the use of sublingual misoprostol (mean difference, –23 mL; 95% CI, –32 to –14; P < .00001). The rates of both shivering and any side effect were higher among women allocated to sublingual misoprostol than among women allocated to oxytocin (49% vs 3%; RR, 18.3; 95% CI, 6.8–48.8; I 2 = 20%; NNT for harm 2, 95% CI, 1–6, and 53% vs 29%; RR, 1.82; 95% CI, 1.07–3.08; I 2 = 52%; NNT for harm 4, 95% CI, 2–49, respectively). No statistically significant differences were found between sublingual misoprostol and oxytocin for other outcomes. One study reported that the mean cost of uterotonic agents was significantly lower in the misoprostol group than in the oxytocin group (US$2.0 ± 0.8 vs US$5.1 ± 0.9; mean difference, –3.1; 95% CI, –3.4 to –2.9; P < .00001). Sensitivity analysis could not be performed because none of the 3 trials was double masked.
| Outcome | No. of trials | No. of events/total no. or total no. | Relative risk or mean difference (95% CI) | P value | I 2 (%) | |
|---|---|---|---|---|---|---|
| Misoprostol | Oxytocin | |||||
| Primary Outcomes | ||||||
| Mean intraoperative blood loss, mL | ||||||
| Sublingual misoprostol | 4 | 200 | 200 | −55 (−115 to 5) | .07 | 58 |
| Oral misoprostol | 2 | 50 | 50 | 20 (–53 to 93) | .59 | 0 |
| Rectal misoprostol | 1 | 96 | 94 | −90 (−147 to –32) | .002 | NA |
| Mean postoperative blood loss, mL | ||||||
| Sublingual misoprostol | 1 | 50 | 50 | −23 (−32 to −14) | < .00001 | NA |
| Rectal misoprostol | 1 | 96 | 94 | −40 (−76 to −4) | .03 | NA |
| Mean fall in hemoglobin, g/dL | ||||||
| Sublingual misoprostol | 2 | 100 | 100 | 0.1 (–0.2 to 0.3) | .61 | 0 |
| Oral misoprostol | 2 | 50 | 50 | 0.1 (–0.2 to 0.4) | .54 | 0 |
| Rectal misoprostol | 1 | 96 | 94 | −0.2 (−0.4 to 0.0) | .07 | NA |
| Mean fall in hematocrit, % | ||||||
| Oral misoprostol | 1 | 30 | 30 | 0.6 (–0.7 to 1.9) | .38 | NA |
| Use of additional uterotonic agents | ||||||
| Sublingual misoprostol | 4 | 57/200 | 67/200 | 0.85 (0.64–1.14) | .27 | 33 |
| Oral misoprostol | 2 | 8/50 | 4/50 | 1.87 (0.21–16.53) | .57 | 63 |
| Rectal misoprostol | 1 | 11/96 | 14/94 | 0.77 (0.37–1.61) | .49 | NA |
| Secondary Outcomes | ||||||
| Blood loss >500 mL | ||||||
| Sublingual misoprostol | 1 | 47/50 | 46/50 | 1.02 (0.92–1.14) | .70 | NA |
| Oral misoprostol | 1 | 17/20 | 17/20 | 1.00 (0.77–1.30) | 1.00 | NA |
| Rectal misoprostol | 1 | 38/96 | 51/94 | 0.73 (0.54–0.99) | .05 | NA |
| Blood loss >1000 mL | ||||||
| Sublingual misoprostol | 2 | 17/100 | 22/100 | 0.77 (0.44–1.36) | .37 | 0 |
| Oral misoprostol | 2 | 4/50 | 4/50 | 1.00 (0.27–3.67) | 1.00 | 0 |
| Rectal misoprostol | 1 | 1/96 | 6/94 | 0.16 (0.02–1.33) | .09 | NA |
| Blood transfusion | ||||||
| Sublingual misoprostol | 1 | 1/50 | 0/50 | 3.00 (0.13–71.92) | .50 | NA |
| Oral misoprostol | 2 | 2/50 | 1/50 | 1.67 (0.23–12.18) | .61 | 0 |
| Rectal misoprostol | 1 | 0/96 | 3/94 | 0.14 (0.01–2.67) | .19 | NA |
| Postoperative hemoglobin, g/dL | ||||||
| Sublingual misoprostol | 2 | 100 | 100 | −0.4 (−0.9 to 0.0) | .06 | 66 |
| Rectal misoprostol | 1 | 96 | 94 | 0.4 (0.1–0.8) | .02 | NA |
| Shivering | ||||||
| Sublingual misoprostol | 3 | 73/150 | 4/150 | 18.25 (6.82–48.8) | < .00001 | 20 |
| Oral misoprostol | 2 | 15/50 | 10/50 | 1.50 (0.82–2.75) | .19 | 0 |
| Rectal misoprostol | 1 | 8/96 | 1/94 | 7.83 (1.00–61.42) | .05 | NA |
| Pyrexia | ||||||
| Sublingual misoprostol | 1 | 8/50 | 2/50 | 4.00 (0.89–17.91) | .07 | NA |
| Oral misoprostol | 2 | 0/50 | 0/50 | Not estimable | NA | NA |
| Rectal misoprostol | 1 | 2/96 | 4/94 | 0.49 (0.09–2.61) | .40 | NA |
| Nausea | ||||||
| Sublingual misoprostol | 2 | 2/100 | 9/100 | 0.26 (0.07–1.02) | .05 | 0 |
| Vomiting | ||||||
| Sublingual misoprostol | 3 | 9/150 | 9/150 | 1.00 (0.43–2.34) | 1.00 | 0 |
| Oral misoprostol | 1 | 2/30 | 3/30 | 0.67 (0.12–3.71) | .64 | NA |
| Rectal misoprostol | 1 | 2/96 | 3/94 | 0.65 (0.11–3.82) | .64 | NA |
| Headache | ||||||
| Sublingual misoprostol | 3 | 7/150 | 12/150 | 0.60 (0.25–1.41) | .24 | 0 |
| Any side effect | ||||||
| Sublingual misoprostol | 2 | 53/100 | 29/100 | 1.82 (1.07–3.08) | .03 | 52 |
Oral misoprostol vs oxytocin
Two trials with a moderate risk of bias, including 100 women, compared oral misoprostol with oxytocin ( Table 2 ). There were no significant differences between oral misoprostol and oxytocin for any of the outcomes evaluated.
Rectal misoprostol vs oxytocin
One trial at low risk of bias (n = 200 women) compared rectal misoprostol with oxytocin ( Table 2 ). Women who used rectal misoprostol, compared with those who received oxytocin, had a statistically significant reduction in mean intraoperative and postoperative blood loss (mean difference, –90 mL; 95% CI, –147 to –32; P = .002, and mean difference, –40 mL; 95% CI, –76 to –4; P = .03, respectively) and blood loss >500 mL (RR, 0.73; 95% CI, 0.54–0.99), and a significant increase in the mean postoperative hemoglobin (mean difference, 0.4 g/dL; 95% CI, 0.1–0.8; P = .02). Rectal misoprostol was associated with a marginally significant increase in the risk of shivering. No significant differences were seen in other outcomes.
Misoprostol plus oxytocin vs oxytocin alone
Sublingual misoprostol plus oxytocin vs oxytocin alone
Four trials, which included 910 women, evaluated this comparison ( Table 3 ). Three of these studies were double masked and had a low risk of bias. The combined use of sublingual misoprostol and oxytocin, compared with the use of oxytocin alone, was associated with a significant reduction in the mean decrease in hematocrit (mean difference, –2.1%; 95% CI, –3.4 to –0.8; P = .001; 3 trials, 736 women; I 2 = 91%) and use of additional uterotonic agents (11% vs 31%; RR, 0.33; 95% CI, 0.18–0.62; 3 trials, 660 women; I 2 = 61%; NNT for benefit 5, 95% CI, 4–9). In addition, there was a trend toward a decrease in both the mean intraoperative blood loss and the mean decrease in hemoglobin with the use of sublingual misoprostol plus oxytocin. One study reported a significant reduction in mean postoperative blood loss (mean difference, –265 mL; 95% CI, –282 to –248; P < .00001).
| Outcome | No. of trials | No. of events/total no. or total no. | Relative risk or mean difference (95% CI) | P value | I 2 (%) | |
|---|---|---|---|---|---|---|
| Misoprostol plus oxytocin | Oxytocin | |||||
| PRIMARY OUTCOMES | ||||||
| Mean intraoperative blood loss, mL | ||||||
| Sublingual misoprostol | 4 | 454 | 456 | −139 (−300 to 21) | .09 | 99 |
| Oral misoprostol | 1 | 28 | 25 | −29 (−159 to 101) | .66 | NA |
| Buccal misoprostol | 1 | 173 | 179 | 24 (–16 to 64) | .24 | NA |
| Rectal misoprostol | 1 | 200 | 200 | −191 (−252 to −130) | < .00001 | NA |
| Mean postoperative blood loss, mL | ||||||
| Sublingual misoprostol | 1 | 179 | 187 | −265 (−282 to −248) | < .00001 | NA |
| Oral misoprostol | 1 | 28 | 25 | 28 (–30 to 86) | .34 | NA |
| Rectal misoprostol | 1 | 200 | 200 | −139 (−166 to −112) | < .00001 | NA |
| Mean fall in hemoglobin, g/dL | ||||||
| Sublingual misoprostol | 3 | 275 | 269 | −0.2 (−0.5 to 0.1) | .13 | 66 |
| Intrauterine misoprostol | 1 | 100 | 100 | −0.6 (−0.9 to −0.3) | .0002 | NA |
| Mean fall in hematocrit, % | ||||||
| Sublingual misoprostol | 3 | 364 | 372 | −2.1 (−3.4 to −0.8) | .0001 | 91 |
| Buccal misoprostol | 1 | 173 | 179 | −0.2 (−0.5 to 0.1) | .11 | NA |
| Rectal misoprostol | 1 | 200 | 200 | −3.5 (−4.2 to −2.9) | < .00001 | NA |
| Intrauterine misoprostol | 1 | 100 | 100 | −1.8 (−2.8 to −0.7) | .001 | NA |
| Use of additional uterotonic agents | ||||||
| Sublingual misoprostol | 3 | 35/329 | 102/331 | 0.33 (0.18–0.62) | .0005 | 61 |
| Oral misoprostol | 1 | 0/28 | 0/25 | Not estimable | NA | NA |
| Buccal misoprostol | 1 | 45/173 | 76/179 | 0.61 (0.45–0.83) | .002 | NA |
| Rectal misoprostol | 1 | 14/200 | 36/200 | 0.39 (0.22–0.70) | .002 | NA |
| Intrauterine misoprostol | 1 | 3/100 | 6/100 | 0.50 (0.13–1.94) | .32 | NA |
| SECONDARY OUTCOMES | ||||||
| Blood loss >500 mL | ||||||
| Sublingual misoprostol | 1 | 73/90 | 77/84 | 0.88 (0.79–1.00) | .05 | NA |
| Blood loss >1000 mL | ||||||
| Sublingual misoprostol | 3 | 25/275 | 29/269 | 0.85 (0.52–1.39) | .53 | 0 |
| Buccal misoprostol | 1 | 24/173 | 22/179 | 1.13 (0.66–1.94) | .66 | NA |
| Blood transfusion | ||||||
| Sublingual misoprostol | 3 | 3/394 | 17/396 | 0.24 (0.02–2.60) | .24 | 65 |
| Oral misoprostol | 1 | 0/28 | 0/25 | Not estimable | NA | NA |
| Buccal misoprostol | 1 | 3/173 | 3/179 | 1.03 (0.21–5.06) | .97 | NA |
| Rectal misoprostol | 1 | 0/200 | 0/200 | Not estimable | NA | NA |
| Intrauterine misoprostol | 1 | 0/100 | 0/100 | Not estimable | NA | NA |
| Postoperative hemoglobin, g/dL | ||||||
| Sublingual misoprostol | 2 | 150 | 144 | 0.1 (–0.4 to 0.6) | .68 | 64 |
| Oral misoprostol | 1 | 28 | 25 | −0.5 (−1.3 to 0.3) | .20 | NA |
| Intrauterine misoprostol | 1 | 100 | 100 | 0.6 (0.3–0.9) | .0007 | NA |
| Postoperative hematocrit, % | ||||||
| Sublingual misoprostol | 2 | 239 | 247 | 1.4 (–2.2 to 5.0) | .44 | 95 |
| Intrauterine misoprostol | 1 | 100 | 100 | 1.6 (0.6–2.6) | .002 | NA |
| Shivering | ||||||
| Sublingual misoprostol | 4 | 87/454 | 43/456 | 2.01 (1.50–2.70) | < .00001 | 34 |
| Oral misoprostol | 1 | 10/28 | 2/25 | 4.46 (1.08–18.45) | .04 | NA |
| Pyrexia | ||||||
| Sublingual misoprostol | 4 | 44/454 | 17/456 | 2.58 (1.50–4.45) | .0006 | 8 |
| Rectal misoprostol | 1 | 11/200 | 13/200 | 0.85 (0.39–1.84) | .67 | NA |
| Intrauterine misoprostol | 1 | 8/100 | 4/100 | 2.00 (0.62–6.43) | .24 | NA |
| Nausea | ||||||
| Sublingual misoprostol | 3 | 52/394 | 26/396 | 1.90 (0.87–4.17) | .11 | 64 |
| Oral misoprostol | 1 | 0/28 | 1/25 | 0.30 (0.01–7.02) | .45 | NA |
| Vomiting | ||||||
| Sublingual misoprostol | 2 | 20/215 | 13/209 | 1.51 (0.78–2.95) | .22 | 0 |
| Intrauterine misoprostol | 1 | 3/100 | 3/100 | 1.00 (0.21–4.84) | 1.00 | NA |
| Diarrhea | ||||||
| Sublingual misoprostol | 1 | 2/179 | 0/187 | 5.22 (0.25–108.0) | .28 | NA |
| Intrauterine misoprostol | 1 | 0/100 | 0/100 | Not estimable | NA | NA |
| Abdominal pain | ||||||
| Sublingual misoprostol | 1 | 24/179 | 13/187 | 1.93 (1.01–3.67) | .04 | NA |
| Intrauterine misoprostol | 1 | 7/100 | 8/100 | 0.88 (0.33–2.32) | .79 | NA |
| Headache | ||||||
| Sublingual misoprostol | 1 | 4/125 | 2/125 | 2.00 (0.37–10.72) | .42 | NA |
| Oral misoprostol | 1 | 0/28 | 1/25 | 0.30 (0.01–7.02) | .45 | NA |
| Any side effect | ||||||
| Sublingual misoprostol | 1 | 48/125 | 19/125 | 2.53 (1.58–4.04) | .0001 | NA |
| Apgar score at 1 min | ||||||
| Rectal misoprostol | 1 | 200 | 200 | −0.3 (−0.6 to 0.0) | .08 | NA |
| Apgar score at 5 min | ||||||
| Rectal misoprostol | 1 | 200 | 200 | 0.2 (0.1–0.3) | .005 | NA |
| NICU admission | ||||||
| Rectal misoprostol | 1 | 6/200 | 9/200 | 0.66 (0.23–1.88) | .43 | NA |
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