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

Methods and outcomes

We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of treatments for unexplained recurrent miscarriage? What are the effects of treatments for recurrent miscarriage caused by antiphospholipid syndrome? We searched: Medline, Embase, The Cochrane Library, and other important databases up to January 2010 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).

Results

We found 14 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.

Conclusions

In this systematic review we present information relating to the effectiveness and safety of the following interventions: aspirin (low dose), bed rest, corticosteroids, early scanning in subsequent pregnancies, heparin plus low-dose aspirin, human chorionic gonadotrophin, intravenous immunoglobulin treatment, lifestyle adaptation, oestrogen, paternal white cell immunisation, progesterone, trophoblastic membrane infusion, and vitamin supplementation.

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.

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

We don't know whether bed rest, early scanning, lifestyle adaptation (to stop smoking, reduce alcohol consumption, and lose weight), low-dose aspirin, human chorionic gonadotrophin, trophoblastic membrane infusion, or vitamin supplementation increase the likelihood of a successful pregnancy in women with unexplained recurrent miscarriage.

We also don't know whether oestrogen supplementation increases the live birth rate in women with unexplained recurrent miscarriage, but it may increase the miscarriage rate and cause abnormalities in the fetus.

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

Paternal white cell immunisation and intravenous immunoglobulin treatment do not seem likely to improve live birth rates compared with placebo in women with unexplained recurrent miscarriage.

We don't know whether low-dose aspirin, alone or combined with heparin, can increase the live birth rate compared with placebo in women with antiphospholipid syndrome.

• Prednisolone plus aspirin does not seem to increase live birth rates, compared with placebo or aspirin alone, in women with antiphospholipid syndrome, and it increases the risk of adverse effects including hypertension, preterm birth, low birth weight, and admission to neonatal intensive care.

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. Antiphospholipid syndrome (APS) is one of the known causes of first- and second-trimester recurrent miscarriage. APS is defined as the presence of anticardiolipin antibodies or lupus anticoagulant antibodies, in association with either three or more consecutive fetal losses before week 10 of gestation, one or more unexplained intrauterine deaths beyond 10 weeks of gestation, or one or more premature births before 34 weeks due to severe pre-eclampsia or impaired fetal growth. This review covers unexplained recurrent miscarriages and both first- and second-trimester recurrent miscarriages in women with APS.

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. No separate risk factors for APS are known.

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 54% in a 45-year-old woman to about 90% in a 20-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 5 previous unexplained miscarriages, the success rate drops to about 71%. Prospective studies of low-risk pregnancies have found that the presence of anticardiolipin antibodies carried a three to 9 times greater risk of fetal loss. Women with a history of at least three prior miscarriages and no abnormality other than the presence of antiphospholipid antibodies are highly likely to have a future miscarriage.

Aims of intervention

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

Outcomes

Live birth rates, miscarriage rates, adverse effects of treatment in both mother and infant, including perinatal mortality.

Methods

Clinical Evidence search and appraisal January 2010. The following databases were used to identify studies for this systematic review: Medline 1966 to January 2010, Embase 1980 to January 2010, and The Cochrane Database of Systematic Reviews 2009, Issue 4 (1966 to date of issue). An additional search within The Cochrane Library was carried out for the Database of Abstracts of Reviews of Effects (DARE) and the Health Technology Assessment (HTA) database. We also searched for retractions of studies included in the review. Abstracts of the studies retrieved from the initial search were assessed by an information specialist. Selected studies were then sent to the contributor for additional assessment, using predetermined criteria to identify relevant studies. Study design criteria for inclusion in this review were: published systematic reviews of RCTs and RCTs in any language. RCTs had to contain 20 or more individuals of whom more than 80% were followed up. We included blinded and open-label RCTs. 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 systematic reviews of RCTs and RCTs where harms of an included intervention were studied applying the same study design criteria for inclusion as we did for benefits. In addition we did an observational search for harms — searching for cohort studies (prospective or retrospective, with or without a control group, minimum 20 people), case-control studies (minimum 20 people), and case series (minimum 100 people). We also use a regular surveillance protocol to capture harms alerts from organisations such as the FDA and the MHRA, which are added to the reviews as required. We have included trials 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 also included trials that described their population as women with recurrent miscarriage caused by antiphospholipid syndrome. 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). 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 treatments for unexplained recurrent miscarriage?
4 (180)	Miscarriage rates	Human chorionic gonadotrophin versus placebo	4	–3	0	–1	0	Very low	Quality points deducted for sparse data, uncertainty about randomisation, and for allocation and methodological weaknesses. Directness point deducted for inclusion of women with 2 or more consecutive miscarriages
8 (303)	Live birth rates	Intravenous immunoglobulin versus placebo/no treatment	4	0	0	0	0	High
1 (54)	Live birth rates	Low-dose aspirin versus placebo	4	–2	0	0	0	Low	Quality points deducted for sparse data and for methodological weaknesses
12 (641)	Live birth rates	Paternal white cell immunisation versus placebo	4	0	0	0	0	High
4 (223)	Miscarriage rates	Progesterone versus placebo	4	–3	0	0	0	Very low	Quality points deducted for sparse data, uncertainty about randomisation, allocation concealments, and methodological weaknesses
1 (37)	Live birth rates	Trophoblastic membrane infusion versus placebo	4	–1	0	0	0	Moderate	Quality point deducted for sparse data
What are the effects of treatments for recurrent miscarriage caused by antiphospholipid syndrome?
3 (71)	Miscarriage rates	Low-dose aspirin versus placebo or usual care	4	–1	0	0	0	Moderate	Quality point deducted for sparse data
2 (140)	Miscarriage rates	Low-dose aspirin alone versus low-dose aspirin plus unfractionated heparin	4	–1	0	0	0	Moderate	Quality point deducted for sparse data
1 (72)	Live birth rates	Low-dose aspirin alone versus low-dose aspirin plus unfractionated heparin	4	–2	0	0	0	Low	Quality points deducted for sparse data, and uncertainty about blinding and method of randomisation
1 (98)	Miscarriage rates	Low-dose aspirin alone versus low-dose aspirin plus low molecular weight heparin	4	–2	0	0	0	Low	Quality points deducted for sparse data and for enrolling women up to later gestation periods
1 (88)	Miscarriage rates	Corticosteroids plus low-dose aspirin versus placebo	4	–1	0	0	0	Moderate	Quality point deducted for sparse data
1 (39)	Miscarriage rates	Corticosteroids plus low-dose aspirin versus low-dose aspirin alone	4	–3	0	0	0	Very low	Quality points deducted for sparse data, incomplete reporting of results, and no intention-to-treat analysis

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

High-quality evidence

Further research is very unlikely to change our confidence in the estimate of effect.

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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