Recurrent miscarriage

Abstract

Introduction

Recurrent miscarriage is the spontaneous loss of three or more consecutive pregnancies with the same biological father in the first trimester, and affects 1% to 2% of women, half of whom have no identifiable cause. Overall, 75% of affected women will have a successful subsequent pregnancy, but this rate falls for older mothers and with increasing number of miscarriages.

Methods and outcomes

We conducted a systematic overview, aiming to answer the following clinical question: What are the effects of treatments for unexplained recurrent miscarriage? We searched Medline, Embase, The Cochrane Library, and other important databases up to June 2014 (BMJ Clinical Evidence overviews are updated periodically; please check our website for the most up-to-date version of this overview).

Results

At this update, searching of electronic databases retrieved 11 studies. After deduplication and removal of conference abstracts, 150 records were screened for inclusion in the review. Appraisal of titles and abstracts led to the exclusion of 137 studies and the further review of 13 full publications. Of the 13 full articles evaluated, two systematic reviews were updated, and one systematic review and one RCT were added at this update. One non-systematic review, two systematic reviews, and one RCT were added to the Comment sections. We performed a GRADE evaluation for five PICO combinations.

Conclusions

In this systematic overview we categorised the efficacy for five interventions, based on information about the effectiveness and safety of aspirin (low dose), corticosteroids, intravenous immunoglobulin treatment, lifestyle adaptation, and progesterone.

Key Points

Recurrent miscarriage is the spontaneous loss of three or more consecutive pregnancies with the same biological father in the first trimester; it affects 1% to 2% of women, in half of whom there is no identifiable cause.

• Overall, 75% of affected women will have a successful subsequent pregnancy, but this rate falls for older mothers and with increasing number of miscarriages.

• Recurrent miscarriage causes considerable distress and psychological morbidity.

• Antiphospholipid syndrome, with anticardiolipin or lupus anticoagulant antibodies, is present in 15% of women with recurrent first- and second-trimester miscarriage.

We examined evidence from RCTs and systematic reviews of RCTs in women with three or more unexplained recurrent miscarriages.

• For many of the interventions, we found few high-quality studies available.

• There is a need for further high-quality RCTs in this field to inform clinical practice.

We don't know whether lifestyle adaptation (to stop smoking, reduce alcohol consumption, and lose weight) or low-dose aspirin increase the likelihood of a successful pregnancy in women with unexplained recurrent miscarriage.

• We found no RCTs on the effects of lifestyle interventions.

• We only found one small RCT (54 women) with low-dose aspirin that met our inclusion criteria. Hence, it was difficult to draw any robust conclusions.

• We found one further larger RCT (364 women) on low-dose aspirin (in women with two or more recurrent miscarriages), which was outside our inclusion criteria for this BMJ Clinical Evidence overview.

We don't know whether progesterone supplementation or corticosteroids reduce miscarriage rates compared with placebo in women with unexplained recurrent miscarriage.

• The evidence on progesterone was difficult to interpret because of methodological weaknesses in the trials, such as quasi-randomisation, and because many of the trials were old.

• However, further RCTs are currently under way, which may clarify the position.

• We found one small pilot RCT on corticosteroids in a sub-group of women with unexplained recurrent miscarriage who had high levels of uterine natural killer (uNK) cells on screening. However, we found no RCTs in the general population of women with unexplained recurrent miscarriage.

Intravenous immunoglobulin treatment does not seem likely to improve live birth rates compared with placebo in women with unexplained recurrent miscarriage, and it may be associated with adverse effects.

Clinical context

General background

Recurrent miscarriage is the spontaneous loss of three or more consecutive pregnancies with the same biological father in the first trimester; it affects 1% to 2% of women, in half of whom there is no identifiable cause. It is a cause of considerable distress and psychological morbidity.

Focus of the review

Several factors may be involved in the aetiology of recurrent miscarriage. Antiphospholipid syndrome, with anticardiolipin or lupus anticoagulant antibodies, is present in 15% of women with recurrent first- and second-trimester miscarriage. Chromosomal, uterine, and endocrine abnormalities may also cause recurrent miscarriages. This overview focuses on women who do not have an obvious cause for their miscarriages. Their recurrent miscarriages are, therefore, unexplained.

Comments on evidence

We found no RCTs on the effects of lifestyle adaptation (smoking cessation, reducing alcohol consumption, and losing weight) and single, small RCTs on the effects of low-dose aspirin and corticosteroids. The latter RCT on corticosteroids was in a sub-group of women with high uterine natural killer (uNK) cells on screening. We found two systematic reviews that pooled data on intravenous immunoglobulins, one of which also produced a sub-group analysis on primary or secondary miscarriages, and whether treatment was before or after pregnancy. The regimens given varied widely between trials. The overall methodological quality on studies examining the effects of progesterone was weak, which made it difficult to draw reliable conclusions. The intervention used, and route of administration, differed in each trial.

Search and appraisal summary

The update literature search for this overview was carried out from the date of the last search, January 2010, to June 2014. For more information on the electronic databases searched and criteria applied during assessment of studies for potential relevance to the overview, please see the Methods section. Searching of electronic databases retrieved 398 studies. After deduplication and removal of conference abstracts, 150 records were screened for inclusion in the overview. Appraisal of titles and abstracts led to the exclusion of 137 studies and the further review of 13 full publications. Of the 13 full articles evaluated, two systematic reviews were updated, and one systematic review and one RCT were added at this update. Two systematic reviews, one non-systematic review, and one RCT were added to the Comment section.

About this condition

Definition

Recurrent miscarriage is usually defined as three or more consecutive, spontaneous miscarriages occurring in the first trimester, with the same biological father. They may or may not follow a successful birth. About half of recurrent miscarriages are unexplained. It is a cause of considerable distress and psychological morbidity. This overview covers unexplained recurrent miscarriages. We have included RCTs that described their population as women with unexplained recurrent miscarriage, which is usually defined as three or more consecutive, spontaneous miscarriages occurring in the first trimester with the same biological father. Most trials were not explicit about the gestational age at miscarriage, which can be difficult to determine clinically, or whether recurrent miscarriages occurred with the same biological father. Where it was clear that a trial had used a definition that varies from the usual definition of unexplained recurrent miscarriage, we have reported this. We have excluded RCTs undertaken solely in women with antiphospholipid syndrome (APS) from this review.

Incidence/ Prevalence

In Western populations, recurrent miscarriage affects 1% to 2% of women of childbearing age, and about half of these are unexplained. Antiphospholipid antibodies are present in 15% of women with recurrent miscarriage.

Aetiology/ Risk factors

Increasing maternal age and number of previous miscarriages increase the risk of further miscarriages.

Prognosis

On average, the live birth rate for women with unexplained recurrent miscarriage is 75% in a subsequent pregnancy, with a miscarriage rate of 20% up to 9 weeks, and a 5% miscarriage rate after this period. However, prognosis varies depending on maternal age and number of previous miscarriages. The chance of a successful subsequent pregnancy after three previous unexplained miscarriages varies from about 90% in a 20-year-old woman to about 54% in a 45-year-old woman. A 30-year-old woman with two previous unexplained miscarriages has about an 84% chance of a successful subsequent pregnancy; whereas for a woman of the same age with five previous unexplained miscarriages, the success rate drops to about 71%.

Aims of intervention

To prevent miscarriage and achieve live birth, with minimal adverse effects of treatment.

Outcomes

Live birth rates; miscarriage rates; adverse effects in both mother and infant, including perinatal mortality, preterm delivery, or low birth weight.

Methods

Search strategy BMJ Clinical Evidence search and appraisal June 2014. Databases used to identify studies for this systematic overview include: Medline 1966 to June 2014, Embase 1980 to June 2014, The Cochrane Database of Systematic Reviews 2014, issue 6 (1966 to date of issue), the Database of Abstracts of Reviews of Effects (DARE), and the Health Technology Assessment (HTA) database. Includion criteria Study design criteria for inclusion in this review were systematic reviews and RCTs published in English, containing 20 or more individuals (10 in each arm), of whom more than 80% were followed up. The minimum length of follow-up required to include RCTs was 1 year or until the end of pregnancy if the woman conceived. We included studies with any level of blinding including those described as 'open', 'open label', or not blinded. BMJ Clinical Evidence does not necessarily report every study found (e.g., every systematic review). Rather, we report the most recent, relevant and comprehensive studies identified through an agreed process involving our evidence team, editorial team, and expert contributors. Evidence evaluation A systematic literature search was conducted by our evidence team, who then assessed titles and abstracts, and finally selected articles for full text appraisal against inclusion and exclusion criteria agreed a priori with our expert contributors. In consultation with the expert contributors, studies were selected for inclusion and all data relevant to this overview extracted into the benefits and harms section of the review. In addition, information that did not meet our predefined criteria for inclusion in the benefits and harms section, may have been reported in the 'Further information on studies' or 'Comment' section. Adverse effects All serious adverse effects, or those adverse effects reported as statistically significant, were included in the harms section of the overview. Pre-specified adverse effects identified as being clinically important were also reported, even if the results were not statistically significant. Although BMJ Clinical Evidence presents data on selected adverse effects reported in included studies, it is not meant to be, and cannot be, a comprehensive list of all adverse effects, contraindications, or interactions of included drugs or interventions. A reliable national or local drug database must be consulted for this information. Comment and Clinical guide sections In the Comment section of each intervention, our expert contributors may have provided additional comment and analysis of the evidence, which may include additional studies (over and above those identified via our systematic search) by way of background data or supporting information. As BMJ Clinical Evidence does not systematically search for studies reported in the Comment section, we cannot guarantee the completeness of the studies listed there or the robustness of methods. Our expert contributors add clinical context and interpretation to the Clinical guide sections where appropriate. Data and quality To aid readability of the numerical data in our reviews, we round many percentages to the nearest whole number. Readers should be aware of this when relating percentages to summary statistics such as relative risks (RRs) and odds ratios (ORs). BMJ Clinical Evidence does not report all methodological details of included studies. Rather, it reports by exception any methodological issue or more general issue which may affect the weight a reader may put on an individual study, or the generalisability of the result. These issues may be reflected in the overall GRADE analysis. We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table). The categorisation of the quality of the evidence (high, moderate, low, or very low) reflects the quality of evidence available for our chosen outcomes in our defined populations of interest. These categorisations are not necessarily a reflection of the overall methodological quality of any individual study, because the Clinical Evidence population and outcome of choice may represent only a small subset of the total outcomes reported, and population included, in any individual trial. For further details of how we perform the GRADE evaluation and the scoring system we use, please see our website (www.clinicalevidence.com).

Table.

GRADE Evaluation of interventions for Recurrent miscarriage.

Important outcomes	Live birth rates, Miscarriage rates
Studies (Participants)	Outcome	Comparison	Type of evidence	Quality	Consistency	Directness	Effect size	GRADE	Comment
What are the effects of selected treatments for unexplained recurrent miscarriage?
9 (at least 303)	Live birth rates	Intravenous immunoglobulin versus placebo	4	–1	0	0	0	Moderate	Quality point deducted for weak methods (studies stopped prematurely, no ITT analysis, unclear if same partner in some RCTs)
1 (54)	Live birth rates	Low-dose aspirin versus placebo	4	–2	0	0	0	Low	Quality points deducted for sparse data and for weak methods (randomisation not stated, allocation concealment not clear)
4 (223)	Miscarriage rates	Progesterone versus placebo	4	–3	0	0	0	Very low	Quality points deducted for quasi-randomisation, unclear blinding, high risk of attrition bias in 1 RCT, no treatment rather than placebo in 2 RCTs
1 (40)	Miscarriage rates	Corticosteroids versus placebo	4	–3	0	0	0	Very low	Quality points deducted for sparse data, restricted population (high uNK), and weak methods (inconsistency in start of trial medication, which may have affected outcomes)
1 (40)	Live birth rates	Corticosteroids versus placebo	4	–3	0	0	0	Very low	Quality points deducted for sparse data, restricted population (high uNK), and weak methods (inconsistency in start of trial medication, which may have affected outcomes)

We initially allocate 4 points to evidence from RCTs, and 2 points to evidence from observational studies. To attain the final GRADE score for a given comparison, points are deducted or added from this initial score based on preset criteria relating to the categories of quality, directness, consistency, and effect size. Quality: based on issues affecting methodological rigour (e.g., incomplete reporting of results, quasi-randomisation, sparse data [<200 people in the analysis]). Consistency: based on similarity of results across studies. Directness: based on generalisability of population or outcomes. Effect size: based on magnitude of effect as measured by statistics such as relative risk, odds ratio, or hazard ratio.

Glossary

Low-quality evidence

Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.

Moderate-quality evidence

Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.

Very low-quality evidence

Any estimate of effect is very uncertain.

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