Hofmeyr G Justus, Gülmezoglu A Metin, Novikova Natalia, Lawrie Theresa A
Department of Obstetrics and Gynaecology, East London Hospital Complex, University of the Witwatersrand, University of FortHare, Eastern Cape Department of Health, East London, South
Cochrane Database Syst Rev. 2013 Jul 15;2013(7):CD008982. doi: 10.1002/14651858.CD008982.pub2.
The primary objective of postpartum haemorrhage (PPH) prevention and treatment is to reduce maternal deaths. Misoprostol has the major public health advantage over injectable medication that it can more easily be distributed at community level. Because misoprostol might have adverse effects unrelated to blood loss which might impact on mortality or severe morbidity, it is important to continue surveillance of all relevant evidence from randomised trials. This is particularly important as misoprostol is being introduced on a large scale for PPH prevention in low-income countries, and is commonly used for PPH treatment in well-resourced settings as well.
To review maternal deaths and severe morbidity in all randomised trials of misoprostol for prevention or treatment of PPH.
We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (11 January 2013).
We included randomised trials including pregnant women who received misoprostol in the postpartum period, versus placebo/no treatment or other uterotonics for prevention or treatment of PPH, and reporting on maternal death, severe morbidity or pyrexia.We planned to include cluster- and quasi-randomised trials in the analysis, as a very large number of women will be needed to obtain robust estimates of maternal mortality but we did not identify any for this version of the review. In future updates of this review we will include trials reported only as abstracts if sufficient information is available from the abstract or from the authors.
Two review authors independently assessed trials for inclusion and extracted data.
We included 78 studies (59,216 women) and excluded 34 studies.There was no statistically significant difference in maternal mortality for misoprostol compared with control groups overall (31 studies; 11/19,715 versus 4/20,076 deaths; risk ratio (RR) 2.08, 95% confidence interval (CI) 0.82 to 5.28); or for the trials of misoprostol versus placebo: 10 studies, 6/4626 versus 1/4707 ; RR 2.70; 95% CI 0.72 to 10.11; or for misoprostol versus other uterotonics: 21 studies, 5/15,089 versus 3/15,369 (19/100,000); RR 1.54; 95% CI 0.40 to 5.92. All 11 deaths in the misoprostol arms occurred in studies of misoprostol ≥ 600 µg.There was a statistically significant difference in the composite outcome 'maternal death or severe morbidity' for the comparison of misoprostol versus placebo (12 studies; average RR 1.70, 95% CI 1.02 to 2.81; Tau² = 0.00, I² = 0%) but not for the comparison of misoprostol versus other uterotonics (17 studies; average RR 1.50, 95% CI 0.50 to 4.52; Tau² = 1.81, I² = 69%). When we excluded hyperpyrexia from the composite outcome in exploratory analyses, there was no significant difference in either of these comparisons.Pyrexia > 38°C was increased with misoprostol compared with controls (56 studies, 2776/25,647 (10.8%) versus 614/26,800 (2.3%); average RR 3.97, 95% CI 3.13 to 5.04; Tau² = 0.47, I² = 80%). The effect was greater for trials using misoprostol 600 µg or more (27 studies; 2197/17,864 (12.3%) versus 422/18,161 (2.3%); average RR 4.64; 95% CI 3.33 to 6.46; Tau² = 0.51, I² = 86%) than for those using misoprostol 400 µg or less (31 studies; 525/6751 (7.8%) versus 185/7668 (2.4%); average RR 3.07; 95% CI 2.25 to 4.18; Tau² = 0.29, I² = 58%).
AUTHORS' CONCLUSIONS: Misoprostol does not appear to increase or reduce severe morbidity (excluding hyperpyrexia) when used to prevent or treat PPH. Misoprostol did not increase or decrease maternal mortality. However, misoprostol is associated with an increased risk of pyrexia, particularly in dosages of 600 µg or more. Given that misoprostol is used prophylactically in very large numbers of healthy women, the greatest emphasis should be placed on limiting adverse effects. In this context, the findings of this review support the use of the lowest effective dose. As for any new medication being used on a large scale, continued vigilance for adverse effects is essential and there is a need for large randomised trials to further elucidate both the relative effectiveness and the risks of various dosages of misoprostol.
产后出血（PPH）防治的主要目标是降低孕产妇死亡。米索前列醇相较于注射用药物具有显著的公共卫生优势，即它能更便捷地在社区层面进行分发。鉴于米索前列醇可能存在与失血无关的不良反应，而这些反应可能影响死亡率或严重发病率，持续监测来自随机试验的所有相关证据至关重要。尤其重要的是，在低收入国家米索前列醇正被大规模用于预防PPH，在资源充足的环境中它也常用于PPH治疗。
回顾米索前列醇预防或治疗PPH的所有随机试验中的孕产妇死亡和严重发病率情况。
我们检索了Cochrane妊娠与分娩组试验注册库（2013年1月11日）。
我们纳入了随机试验，这些试验中的孕妇在产后接受了米索前列醇，与安慰剂/未治疗或其他宫缩剂进行对比，以预防或治疗PPH，并报告孕产妇死亡、严重发病率或发热情况。我们计划在分析中纳入整群随机试验和半随机试验，因为需要大量妇女才能对孕产妇死亡率进行可靠估计，但在本次综述版本中我们未识别出相关试验。在本综述的未来更新中，如果摘要或作者能提供足够信息，我们将纳入仅以摘要形式报告的试验。
两位综述作者独立评估试验是否纳入并提取数据。
我们纳入了78项研究（59216名妇女），排除了34项研究。总体而言，与对照组相比，米索前列醇组的孕产妇死亡率无统计学显著差异（31项研究；11/19715例死亡与4/20076例死亡；风险比（RR）2.08，95%置信区间（CI）0.82至5.28）；米索前列醇与安慰剂对比的试验中：10项研究，6/4626例死亡与1/4707例死亡；RR 2.70；95% CI 0.72至10.11；米索前列醇与其他宫缩剂对比的试验中：21项研究，5/15089例死亡与3/15369例死亡（19/100000）；RR 1.54；95% CI 0.40至5.92。米索前列醇组的所有11例死亡均发生在米索前列醇剂量≥600μg的研究中。在米索前列醇与安慰剂对比中，“孕产妇死亡或严重发病率”这一综合结局存在统计学显著差异（12项研究；平均RR 1.70，95% CI 1.02至2.81；Tau² = 0.00，I² = 0%），但在米索前列醇与其他宫缩剂对比中无差异（17项研究；平均RR 1.50，95% CI 0.50至4.52；Tau² = 1.81，I² = 69%）。在探索性分析中，当我们从综合结局中排除高热时，这两种对比均无显著差异。与对照组相比，米索前列醇组体温>38°C的情况增加（56项研究，2776/25647（10.8%）与614/26800（2.3%）；平均RR 3.97，95% CI 3.13至5.04；Tau² = 0.47，I² = 80%）。使用600μg及以上米索前列醇的试验中该效应更大（27项研究；2197/17864（12.3%）与422/18161（2.3%）；平均RR 4.64；95% CI 3.33至6.46；Tau² = 0.51，I² = 86%），高于使用400μg及以下米索前列醇的试验（31项研究；525/6751（7.8%）与185/7668（2.4%）；平均RR 3.07；95% CI 2.25至4.18；Tau² = 0.29，I² = 58%）。
米索前列醇用于预防或治疗PPH时，似乎不会增加或降低严重发病率（不包括高热）。米索前列醇既未增加也未降低孕产妇死亡率。然而，米索前列醇与发热风险增加相关，尤其是在剂量为600μg及以上时。鉴于大量健康妇女预防性使用米索前列醇，应最优先关注限制不良反应。在此背景下，本综述结果支持使用最低有效剂量。对于任何正在大规模使用的新药，持续警惕不良反应至关重要，并且需要进行大型随机试验以进一步阐明米索前列醇不同剂量的相对有效性和风险。
