Lemmers Marike, Verschoor Marianne Ac, Kim Bobae Veronica, Hickey Martha, Vazquez Juan C, Mol Ben Willem J, Neilson James P
Department of Obstetrics and Gynaecology, Academic Medical Center, Meibergdreef 9, Amsterdam, Netherlands, 1105 AZ.
Cochrane Database Syst Rev. 2019 Jun 17;6(6):CD002253. doi: 10.1002/14651858.CD002253.pub4.
In most pregnancies that miscarry, arrest of embryonic or fetal development occurs some time (often weeks) before the miscarriage occurs. Ultrasound examination can reveal abnormal findings during this phase by demonstrating anembryonic pregnancies or embryonic or fetal death. Treatment has traditionally been surgical but medical treatments may be effective, safe, and acceptable, as may be waiting for spontaneous miscarriage. This is an update of a review first published in 2006.
To assess, from clinical trials, the effectiveness and safety of different medical treatments for the termination of non-viable pregnancies.
For this update, we searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (24 October 2018) and reference lists of retrieved studies.
Randomised trials comparing medical treatment with another treatment (e.g. surgical evacuation), or placebo, or no treatment for early pregnancy failure. Quasi-randomised studies were excluded. Cluster-randomised trials were eligible for inclusion, as were studies reported in abstract form, if sufficient information was available to assess eligibility.
Two review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. We assessed the quality of the evidence using the GRADE approach.
Forty-three studies (4966 women) were included. The main interventions examined were vaginal, sublingual, oral and buccal misoprostol, mifepristone and vaginal gemeprost. These were compared with surgical management, expectant management, placebo, or different types of medical interventions were compared with each other. The review includes a wide variety of different interventions which have been analysed across 23 different comparisons. Many of the comparisons consist of single studies. We limited the grading of the quality of evidence to two main comparisons: vaginal misoprostol versus placebo and vaginal misoprostol versus surgical evacuation of the uterus. Risk of bias varied widely among the included trials. The quality of the evidence varied between the different comparisons, but was mainly found to be very-low or low quality.Vaginal misoprostol versus placeboVaginal misoprostol may hasten miscarriage when compared with placebo: e.g. complete miscarriage (5 trials, 305 women, risk ratio (RR) 4.23, 95% confidence interval (CI) 3.01 to 5.94; low-quality evidence). No trial reported on pelvic infection rate for this comparison. Vaginal misoprostol made little difference to rates of nausea (2 trials, 88 women, RR 1.38, 95% CI 0.43 to 4.40; low-quality evidence), diarrhoea (2 trials, 88 women, RR 2.21, 95% CI 0.35 to 14.06; low-quality evidence) or to whether women were satisfied with the acceptability of the method (1 trial, 32 women, RR 1.17, 95% CI 0.83 to 1.64; low-quality evidence). It is uncertain whether vaginal misoprostol reduces blood loss (haemoglobin difference > 10 g/L) (1 trial, 50 women, RR 1.25, 95% CI 0.38 to 4.12; very-low quality) or pain (opiate use) (1 trial, 84 women, RR 5.00, 95% CI 0.25 to 101.11; very-low quality), because the quality of the evidence for these outcomes was found to be very low.Vaginal misoprostol versus surgical evacuation Vaginal misoprostol may be less effective in accomplishing a complete miscarriage compared to surgical management (6 trials, 943 women, average RR 0.40, 95% CI 0.32 to 0.50; Heterogeneity: Tau² = 0.03, I² = 46%; low-quality evidence) and may be associated with more nausea (1 trial, 154 women, RR 21.85, 95% CI 1.31 to 364.37; low-quality evidence) and diarrhoea (1 trial, 154 women, RR 40.85, 95% CI 2.52 to 662.57; low-quality evidence). There may be little or no difference between vaginal misoprostol and surgical evacuation for pelvic infection (1 trial, 618 women, RR 0.73, 95% CI 0.39 to 1.37; low-quality evidence), blood loss (post-treatment haematocrit (%) (1 trial, 50 women, mean difference (MD) 1.40%, 95% CI -3.51 to 0.71; low-quality evidence), pain relief (1 trial, 154 women, RR 1.42, 95% CI 0.82 to 2.46; low-quality evidence) or women's satisfaction/acceptability of method (1 trial, 45 women, RR 0.67, 95% CI 0.40 to 1.11; low-quality evidence).Other comparisonsBased on findings from a single trial, vaginal misoprostol was more effective at accomplishing complete miscarriage than expectant management (614 women, RR 1.25, 95% CI 1.09 to 1.45). There was little difference between vaginal misoprostol and sublingual misoprostol (5 trials, 513 women, average RR 0.84, 95% CI 0.61 to 1.16; Heterogeneity: Tau² = 0.10, I² = 871%; or between oral and vaginal misoprostol in terms of complete miscarriage at less than 13 weeks (4 trials, 418 women), average RR 0.68, 95% CI 0.45 to 1.03; Heterogeneity: Tau² = 0.13, I² = 90%). However, there was less abdominal pain with vaginal misoprostol in comparison to sublingual (3 trials, 392 women, RR 0.58, 95% CI 0.46 to 0.74). A single study (46 women) found mifepristone to be more effective than placebo: miscarriage complete by day five after treatment (46 women, RR 9.50, 95% CI 2.49 to 36.19). However the quality of this evidence is very low: there is a very serious risk of bias with signs of incomplete data and no proper intention-to-treat analysis in the included study; and serious imprecision with wide confidence intervals. Mifepristone did not appear to further hasten miscarriage when added to a misoprostol regimen (3 trials, 447 women, RR 1.18, 95% CI 0.95 to 1.47).
AUTHORS' CONCLUSIONS: Available evidence from randomised trials suggests that medical treatment with vaginal misoprostol may be an acceptable alternative to surgical evacuation or expectant management. In general, side effects of medical treatment were minor, consisting mainly of nausea and diarrhoea. There were no major differences in effectiveness between different routes of administration. Treatment satisfaction was addressed in only a few studies, in which the majority of women were satisfied with the received intervention. Since the quality of evidence is low or very low for several comparisons, mainly because they included only one or two (small) trials; further research is necessary to assess the effectiveness, safety and side effects, optimal route of administration and dose of different medical treatments for early fetal death.
在大多数发生流产的妊娠中，胚胎或胎儿发育停止发生在流产前的一段时间（通常为数周）。超声检查可通过显示无胚胎妊娠或胚胎或胎儿死亡，在此阶段发现异常情况。传统的治疗方法是手术，但药物治疗可能有效、安全且可接受，等待自然流产也可能如此。这是2006年首次发表的一篇综述的更新。
从临床试验评估不同药物治疗终止不可行妊娠的有效性和安全性。
为进行此次更新，我们检索了Cochrane妊娠与分娩试验注册库、ClinicalTrials.gov、世界卫生组织国际临床试验注册平台（ICTRP）（2018年10月24日）以及检索到的研究的参考文献列表。
比较药物治疗与另一种治疗（如手术清宫）、安慰剂或不治疗早期妊娠失败的随机试验。排除半随机研究。整群随机试验符合纳入标准，以摘要形式报告的研究也符合纳入标准，前提是有足够信息评估其是否符合纳入条件。
两位综述作者独立评估试验是否符合纳入标准及偏倚风险，提取数据并检查其准确性。我们使用GRADE方法评估证据质量。
纳入了43项研究（4966名女性）。所研究的主要干预措施为阴道、舌下、口服和颊部米索前列醇、米非司酮和阴道吉美前列素。将这些与手术治疗、期待治疗、安慰剂进行比较，或比较不同类型的药物干预措施。该综述包括多种不同的干预措施，已在23种不同的比较中进行了分析。许多比较仅包含一项研究。我们将证据质量分级限制在两个主要比较：阴道米索前列醇与安慰剂，以及阴道米索前列醇与手术清宫。纳入试验中的偏倚风险差异很大。不同比较之间的证据质量各不相同，但主要发现为极低质量或低质量。
与安慰剂相比，阴道米索前列醇可能会加速流产：例如，完全流产（5项试验，305名女性，风险比（RR）4.23，95%置信区间（CI）3.01至5.94；低质量证据）。没有试验报告该比较的盆腔感染率。阴道米索前列醇对恶心发生率（2项试验，88名女性，RR 1.38，95%CI 0.43至4.40；低质量证据）、腹泻发生率（2项试验，88名女性，RR 2.21，95%CI 0.35至14.06；低质量证据）或女性对该方法可接受性是否满意（1项试验，32名女性，RR 1.17，95%CI 0.83至1.64；低质量证据）影响不大。不确定阴道米索前列醇是否会减少失血（血红蛋白差异>10g/L）（1项试验，50名女性，RR 1.25，95%CI 0.38至4.12；极低质量）或疼痛（使用阿片类药物）（1项试验，84名女性，RR 5.00，95%CI 0.25至$101.11；极低质量），因为这些结局的证据质量被发现非常低。
与手术治疗相比，阴道米索前列醇在实现完全流产方面可能效果较差（6项试验,943名女性，平均RR 0.40，95%CI 0.32至0.50；异质性：Tau² = 0.03，I² = 46%；低质量证据），且可能与更多恶心（1项试验，154名女性，RR 21.85，95%CI 1.31至364.37；低质量证据）和腹泻（1项试验，154名女性，RR 40.85，95%CI 2.52至662.57；低质量证据）相关。阴道米索前列醇与手术清宫在盆腔感染（1项试验,618名女性，RR 0.73，95%CI 0.39至1.37；低质量证据）、失血（治疗后血细胞比容（%））（1项试验，50名女性，平均差异（MD）1.40%，95%CI -3.51至0.71；低质量证据）、疼痛缓解（1项试验，154名女性，RR 1.42，95%CI 0.82至2.46；低质量证据）或女性对方法的满意度/可接受性（1项试验，45名女性，RR 0.67，95%CI 0.4至1.11；低质量证据）方面可能几乎没有差异。
基于一项试验的结果，阴道米索前列醇在实现完全流产方面比期待治疗更有效（614名女性，RR 1.25，95%CI 1.09至1.45）。阴道米索前列醇与舌下米索前列醇之间差异不大（5项试验，513名女性，平均RR值0.84，95%CI 0.61至1.16；异质性：Tau² = 0.10，I² = 871%），或者在小于13周时口服和阴道米索前列醇在完全流产方面差异不大（4项试验，418名女性），平均RR值0.68，95%CI 0.45至1.03；异质性：Tau² = 0.值13，I² = 90%）。然而，与舌下米索前列醇相比，阴道米索前列醇引起的腹痛较少（3项试验，392名女性，RR 0.58，95%CI 0.46至0.74）。一项研究（46名女性）发现米非司酮比安慰剂更有效：治疗后第5天流产完全（46名女性，RR 9.50，95%CI 2.49至36.19）。然而，该证据质量非常低：纳入研究存在严重的偏倚风险，存在数据不完整的迹象且未进行适当的意向性分析；并且存在严重的不精确性，置信区间很宽。米非司酮添加到米索前列醇方案中似乎并未进一步加速流产（3项试验，447名女性，RR 1.18，95%CI 0.95至1.47）。
随机试验的现有证据表明，阴道米索前列醇药物治疗可能是手术清宫或期待治疗的可接受替代方案。一般来说，药物治疗的副作用较小，主要包括恶心和腹泻。不同给药途径在有效性方面没有重大差异。只有少数研究涉及治疗满意度，其中大多数女性对所接受的干预措施满意。由于几项比较的证据质量低或非常低，主要是因为它们仅包括一两项（小型）试验；因此有必要进行进一步研究，以评估不同药物治疗早期胎儿死亡的有效性、安全性和副作用、最佳给药途径和剂量。
