What is the issue?
Miscarriage is the most common cause of pregnancy loss and one of the most common complications in early pregnancy. An estimated 15% of pregnancies will end in miscarriage, with 25% of women experiencing a miscarriage in their lifetime. Miscarriage can lead to serious complications, including haemorrhage and infection, and even death, particularly in low-income countries. Miscarriage is generally defined as the spontaneous loss of a pregnancy before 24 weeks’ gestation. Most miscarriages happen in the first 14 weeks, and are known as early miscarriages.
Why is this important?
Miscarriage can be managed expectantly (waiting for the pregnancy tissue to pass naturally), medically (tablets given to make the womb expel the pregnancy tissue) or surgically (removal of the pregnancy tissue during surgery). However, there is uncertainty about the effectiveness, safety, and side effects of the available methods for managing a miscarriage. The aim of this Cochrane Review is to find out which method is the most effective and safest with the least side effects. We collected and analysed all the relevant studies to answer this question.
What evidence did we find?
We searched for evidence in February 2021 and identified 78 studies involving 17,795 women. Most women were managed in hospitals. Women were diagnosed with missed (also called silent miscarriage where no pregnancy tissue has been expelled and there is no bleeding or pain) or incomplete miscarriage (already started to bleed or have pain and perhaps expelled some pregnancy tissue). We found evidence for six different methods of managing a miscarriage; three surgical methods (suction aspiration plus cervical preparation, dilatation and curettage, or suction aspiration), two medical methods (mifepristone plus misoprostol or misoprostol alone), and expectant management or placebo.
The analysis suggested that all three surgical methods and both medical methods may be more effective than expectant management or placebo for completing the process of miscarriage. Suction aspiration plus cervical preparation was the best method of miscarriage management followed by dilatation and curettage, and suction aspiration alone. The two medical methods of mifepristone combined with misoprostol, and misoprostol alone were ranked fourth and fifth best methods, respectively.
From the available data, we cannot learn much for the outcome of death or serious complications. No deaths were reported in the studies that contributed towards this outcome. Amongst the serious complications, the majority were women who required blood transfusions, some had womb perforations related to surgery or required further life-saving procedures. We could not know which method is best for this outcome due to limited data. However, expectant management or placebo was associated with more serious complications compared with the alternative treatment options.
We also looked separately at women suffering from an incomplete miscarriage compared to those suffering from a missed miscarriage. For both groups of women, all three surgical methods and both medical methods were found to be more effective than expectant management or placebo for providing a definitive treatment for a miscarriage. These analyses for incomplete and missed miscarriages agreed with the overall analysis in that surgical methods were better for providing a definitive treatment for a miscarriage than medical methods, which in turn were better than expectant management or placebo. However, the benefits for women with missed miscarriages undergoing any management method other than expectant management or placebo were far greater compared to women with incomplete miscarriages. This is probably because expectant management or placebo is more effective in women in whom the process of miscarriage has already started compared with women in whom the process is yet to start.
What does this mean?
All methods were generally more effective for managing a miscarriage compared with expectant management or placebo, but surgical methods were more effective than medical methods. Expectant management or placebo has the lowest chance of successfully treating a miscarriage and has the highest chance of serious complications and the need for unplanned or emergency surgery. In this review we found that the benefits for women with missed miscarriages undergoing any management method other than expectant management or placebo were far greater compared to women with incomplete miscarriages.
Based on relative effects from the network meta-analysis, all surgical and medical methods for managing a miscarriage may be more effective than expectant management or placebo. Surgical methods were ranked highest for managing a miscarriage, followed by medical methods, which in turn ranked above expectant management or placebo. Expectant management or placebo had the highest chance of serious complications, including the need for unplanned or emergency surgery. A subgroup analysis showed that surgical and medical methods may be more beneficial in women with missed miscarriage compared to women with incomplete miscarriage. Since type of miscarriage (missed and incomplete) appears to be a source of inconsistency and heterogeneity within these data, we acknowledge that the main network meta-analysis may be unreliable. However, we plan to explore this further in future updates and consider the primary analysis as separate networks for missed and incomplete miscarriage.
Miscarriage, defined as the spontaneous loss of a pregnancy before 24 weeks’ gestation, is common with approximately 25% of women experiencing a miscarriage in their lifetime. An estimated 15% of pregnancies end in miscarriage. Miscarriage can lead to serious morbidity, including haemorrhage, infection, and even death, particularly in settings without adequate healthcare provision. Early miscarriages occur during the first 14 weeks of pregnancy, and can be managed expectantly, medically or surgically. However, there is uncertainty about the relative effectiveness and risks of each option.
To estimate the relative effectiveness and safety profiles for the different management methods for early miscarriage, and to provide rankings of the available methods according to their effectiveness, safety, and side-effect profile using a network meta-analysis.
We searched the Cochrane Pregnancy and Childbirth’s Trials Register (9 February 2021), ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform (ICTRP) (12 February 2021), and reference lists of retrieved studies.
We included all randomised controlled trials assessing the effectiveness or safety of methods for miscarriage management. Early miscarriage was defined as less than or equal to 14 weeks of gestation, and included missed and incomplete miscarriage. Management of late miscarriages after 14 weeks of gestation (often referred to as intrauterine fetal deaths) was not eligible for inclusion in the review. Cluster- and quasi-randomised trials were eligible for inclusion. Randomised trials published only as abstracts were eligible if sufficient information could be retrieved. We excluded non-randomised trials.
At least three review authors independently assessed the trials for inclusion and risk of bias, extracted data and checked them for accuracy. We estimated the relative effects and rankings for the primary outcomes of complete miscarriage and composite outcome of death or serious complications. The certainty of evidence was assessed using GRADE. Relative effects for the primary outcomes are reported subgrouped by the type of miscarriage (incomplete and missed miscarriage). We also performed pairwise meta-analyses and network meta-analysis to determine the relative effects and rankings of all available methods.
Our network meta-analysis included 78 randomised trials involving 17,795 women from 37 countries. Most trials (71/78) were conducted in hospital settings and included women with missed or incomplete miscarriage. Across 158 trial arms, the following methods were used: 51 trial arms (33%) used misoprostol; 50 (32%) used suction aspiration; 26 (16%) used expectant management or placebo; 17 (11%) used dilatation and curettage; 11 (6%) used mifepristone plus misoprostol; and three (2%) used suction aspiration plus cervical preparation. Of these 78 studies, 71 (90%) contributed data in a usable form for meta-analysis.
Complete miscarriage
Based on the relative effects from the network meta-analysis of 59 trials (12,591 women), we found that five methods may be more effective than expectant management or placebo for achieving a complete miscarriage:
· suction aspiration after cervical preparation (risk ratio (RR) 2.12, 95% confidence interval (CI) 1.41 to 3.20, low-certainty evidence),
· dilatation and curettage (RR 1.49, 95% CI 1.26 to 1.75, low-certainty evidence),
· suction aspiration (RR 1.44, 95% CI 1.29 to 1.62, low-certainty evidence),
· mifepristone plus misoprostol (RR 1.42, 95% CI 1.22 to 1.66, moderate-certainty evidence),
· misoprostol (RR 1.30, 95% CI 1.16 to 1.46, low-certainty evidence).
The highest ranked surgical method was suction aspiration after cervical preparation. The highest ranked non-surgical treatment was mifepristone plus misoprostol. All surgical methods were ranked higher than medical methods, which in turn ranked above expectant management or placebo.
Composite outcome of death and serious complications
Based on the relative effects from the network meta-analysis of 35 trials (8161 women), we found that four methods with available data were compatible with a wide range of treatment effects compared with expectant management or placebo:
· dilatation and curettage (RR 0.43, 95% CI 0.17 to 1.06, low-certainty evidence),
· suction aspiration (RR 0.55, 95% CI 0.23 to 1.32, low-certainty evidence),
· misoprostol (RR 0.50, 95% CI 0.22 to 1.15, low-certainty evidence),
· mifepristone plus misoprostol (RR 0.76, 95% CI 0.31 to 1.84, low-certainty evidence).
Importantly, no deaths were reported in these studies, thus this composite outcome was entirely composed of serious complications, including blood transfusions, uterine perforations, hysterectomies, and intensive care unit admissions. Expectant management and placebo ranked the lowest when compared with alternative treatment interventions.
Subgroup analyses by type of miscarriage (missed or incomplete) agreed with the overall analysis in that surgical methods were the most effective treatment, followed by medical methods and then expectant management or placebo, but there are possible subgroup differences in the effectiveness of the available methods.