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Recurrent miscarriage is the spontaneous loss of three or more consecutive pregnancies with the same biological father in the first trimester, and affects 1-2% 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 April 2007 (BMJ 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 1-2% 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 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.
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 may not increase live birth rates in women with antiphospholipid syndrome, and increases the risk of adverse effects compared with placebo.
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 and first- and second-trimester recurrent miscarriages in women with APS.
Incidence/
Prevalence
In Western populations, recurrent miscarriage affects 1-2% 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 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 rate, miscarriage rate, adverse effects of treatment.
Methods
BMJ Clinical Evidence search and appraisal April 2007. The following databases were used to identify studies for this systematic review: Medline 1966 to April 2007, Embase 1980 to April 2007, and The Cochrane Database of Systematic Reviews and Cochrane Central Register of Controlled Clinical Trials 2007, Issue 1. Additional searches were carried out using these websites: NHS Centre for Reviews and Dissemination (CRD) — for Database of Abstracts of Reviews of Effects (DARE) and Health Technology Assessment (HTA), Turning Research into Practice (TRIP), and NICE. 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 author for additional assessment, using pre-determined criteria to identify relevant studies. Study-design criteria for evaluation in this review were: published systematic reviews and RCTs in any language and containing more than 20 individuals of whom more than 80% were followed up. The minimum length of follow-up required to include studies was 1 year or until end of pregnancy if the patient conceived. We included all studies described as "open", "open label", or not blinded. We also searched for observational studies on specific harms of interventions. In addition, we use a regular surveillance protocol to capture harms alerts from organisations such as the FDA and the UK Medicines and Healthcare products Regulatory Agency (MHRA), which are added to the reviews as required. We have included studies 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 studies were not explicit about the gestational age at miscarriage, which can be difficult to determine clinically, or whether they were with same biological father. Where it was clear that a study has used a definition that varies from the usual definition of unexplained recurrent miscarriage, we have reported this. We have also included studies that descibed their population as women with recurrent miscarriage caused by antiphospholipid syndrome. We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table
).
Table.
GRADE evaluation of interventions for recurrent miscarriage
Important outcomes
Live births, miscarriage rates, adverse effects
Number of 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 v placebo
4
−3
0
−1
0
Very low
Quality points deducted for sparse data, uncertainty about randomisation, allocation, and methodological weaknesses. Directness point deducted for inclusion of women with 2 or more consecutive miscarriages
8 (303)
Live births
Intravenous immunoglobulin treatment v placebo/no treatment
4
0
0
0
0
High
1 (54)
Live births
Low-dose aspirin v placebo
4
−2
0
0
0
Low
Quality points deducted for sparse data and for methodological weaknesses
12 (641)
Live births
Paternal white cell immunisation v placebo
4
0
0
0
0
High
1 (93)
Miscarriage rates
Progesterone v placebo/no treatment
4
−3
0
0
0
Very low
Quality points deducted for sparse data, uncertainty about randomisation, allocation concealments, and methodological weaknesses
1 (37)
Live births
Trophoblastic membrane infusion v 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)
Live births
Low-dose aspirin v placebo or usual care
4
−1
0
0
0
Moderate
Quality point deducted for sparse data
3 (212)
Live births
Low-dose aspirin v low-dose aspirin plus unfractionated heparin
4
−1
0
0
0
Moderate
Quality point deducted for uncertainty about blinding or method of randomisation
1 (98)
Live births
Low-dose aspirin v 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)
Live births
Corticosteroids plus low-dose aspirin v placebo
4
−1
0
0
0
Moderate
Quality point deducted for sparse data
1 (39)
Miscarriage rates
Corticosteroids plus low-dose aspirin v low-dose aspirin alone
4
−3
0
0
0
Very low
Quality points deducted for sparse data, incomplete reporting of results, and for no-intention-to-treat analysis
1 (202)
Adverse effects
Corticosteroids plus low-dose aspirin v placebo/low-dose aspirin
4
0
0
0
0
High
2 (73)
Adverse effects
Corticosteroids plus low-dose aspirin v low-dose aspirin alone
Type of evidence: 4 = RCT; 2 = Observational; 1 = Non-analytical/expert opinion. Consistency: similarity of results across studies Directness: generalisability of population or outcomes Effect size: based on relative risk or odds 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.
Disclaimer
The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate a judgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit and harms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices. Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical research we strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, the categories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimately it is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients.To the fullest extent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to any person or property (including under contract, by negligence, products liability or otherwise) whether they be direct or indirect, special, incidental or consequential, resulting from the application of the information in this publication.
Contributor Information
Kirsten Duckitt, John Radcliffe Hospital, Oxford, UK.
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We found no direct information about early scanning in subsequent pregnancies in women with unexplained recurrent miscarriage.
Benefits
We found no systematic review or RCTs of early scanning in subsequent pregnancies in women with unexplained recurrent miscarriage.
Harms
We found no RCTs.
Comment
Early scanning in subsequent pregnancies may reduce anxiety in women with recurrent miscarriage. It has been hypothesised that reducing anxiety may reduce immunological factors that may be detrimental in early intrauterine development.
MISCARRIAGE RATES Compared with placebo: Human chorionic gonadotrophin may be more effective at reducing miscarriages in women with unexplained recurrent miscarriage ( very low-quality evidence ).
Benefits
We found one systematic review (search date 1998, 4 RCTs, 180 women; see comment below) comparing human chorionic gonadotrophin (HCG) versus placebo in women with unexplained recurrent miscarriage. It found that HCG significantly reduced miscarriage compared with placebo (AR: 13/95 [14%] with HCG v 34/85 [40%] with placebo; RR 0.35, 95% CI 0.20 to 0.63; see comment below). However, the results may be unreliable owing to methodological weaknesses of the included RCTs (see comment below).
Harms
This review did not present data on harms.
Comment
The review included studies in women with two or more consecutive unexplained miscarriages. Three of the four included RCTs did not provide any data on randomisation or allocation methods, one study had missing data, and another had several exclusions after randomisation. The authors of the review state that the reduction in miscarriage should be interpreted with caution because it is largely reliant on two older and methodologically weaker studies.
LIVE BIRTHS Compared with placebo/no treatment: Intravenous immunoglobulin treatment is no more effective at increasing live birth rates in women with unexplained recurrent miscarriage ( high-quality evidence ).
Benefits
We found one systematic review (search date 2004, 8 RCTs, 303 women) comparing intravenous immunoglobulin treatment versus placebo or no treatment (control) in women with unexplained recurrent miscarriage. The review found no significant difference in live births between intravenous immunoglobulin treatment and control (AR: 92/159 [58%] with immunoglobulin v 85/144 [59%] with control; RR 0.99, 95% CI 0.83 to 1.19).
Harms
The review did not report on harms. One non-systematic review reported that mild adverse events such as fever, headache, nausea, blood pressure changes, and mild tachycardia occur in between 1% and 15% of people receiving intravenous immunoglobulin treatment. It reported that rare severe adverse effects may include anaphylactic reactions, haemolytic anaemia, viral infection (due to contamination of immunoglobulin), renal failure, and thrombotic events. Most severe adverse reactions tended to occur in people with anti-IgA antibodies.
Comment
None.
Substantive changes
Intravenous immunoglobulin treatment in unexplained miscarriage One already-included systematic review updated;no new evidence added, categorisation unchanged (Unlikely to be beneficial).
We found no direct information about lifestyle adaptation (smoking cessation, reduced alcohol consumption, losing weight) in women with unexplained recurrent miscarriage.
Benefits
We found no systematic review or RCTs of lifestyle adaptation (smoking cessation, reduced alcohol consumption, losing weight) in women with unexplained recurrent miscarriages.
LIVE BIRTHS Compared with placebo: We don't know whether low-dose aspirin is more effective at increasing live birth rates in women with unexplained recurrent miscarriage ( low-quality evidence ).
Benefits
Low-dose aspirin versus placebo:
We found one systematic review (search date 2004), which identified one RCT. The RCT found no significant difference in the live birth rate between low-dose aspirin (50 mg/day) and placebo (54 women with recurrent miscarriage without antiphospholipid syndrome; AR for live birth: 22/27 [81%] with low-dose aspirin v 22/27 [81%] with placebo; RR 1.00, 95% CI 0.78 to 1.29).
Low-dose aspirin plus corticosteroids versus either drug alone:
We found no systematic review or RCTs.
Low-dose aspirin plus heparin versus aspirin alone:
We found no systematic review or RCTs.
Harms
Low-dose aspirin versus placebo:
The review reported that no data on preterm delivery, obstetric complications, or bleeding rate could be obtained from the included RCT. We found another systematic review of RCTs of aspirin (search date 2000; aspirin 20–150 mg/day) in any pregnant women, not specifically those with unexplained recurrent miscarriage. It found no significant difference in perinatal mortality between aspirin and placebo (20 RCTs, 28,208 women; AR for perinatal mortality: 2.9% with aspirin v 3.1% with placebo; RR 0.92, 95% CI 0.81 to 1.05). Analysis of RCTs using aspirin at doses of 75 mg daily or less found also found no significant difference in perinatal mortality between aspirin and placebo (13 RCTs, number of women not stated; RR 0.92, 95% CI 0.78 to 1.09). The review found no significant difference in neonatal bleeding between aspirin (any dose) and placebo (12 RCTs, 26,058 women; 1.8% with aspirin v 1.8% with placebo; RR 1.03, 95% CI 0.86 to 1.25).
Low-dose aspirin plus corticosteroids versus either drug alone:
We found no RCts
Comment
The RCT in women with unexplained recurrent miscarriage included in the systematic review had small sample size, important methodological limitations, and questionable external validity.
We found no direct information about oestrogen supplementation in women with unexplained recurrent miscarriage. Exposure to diethylstilbestrol in utero may increase primary infertility and vaginal adenosis or cervical polyps among female offspring, and increase testicular abnormalities in male offspring.
Benefits
We found no systematic review or RCTs of oestrogen supplementation in women with unexplained recurrent miscarriage.
Harms
We found no RCTs of oestrogen supplementation specifically in women with unexplained recurrent miscarriage. We found one systematic review (search date 2002, 7 RCTs) comparing oestrogen (mainly diethylstilbestrol) versus placebo for the prevention of miscarriage, not specifically in women with unexplained recurrent miscarriage. It found that, compared with placebo, diethylstilbestrol increased the risk of miscarriage (5 RCTs; AR 117/1220 [10%] with diethylstilbestrol v 69/1159 [6%] with placebo; RR 1.37, 95% CI 1.08 to 1.74), increased the risk of preterm birth before 38 weeks (3 RCTs; AR 161/1100 [15%] with diethylstilbestrol v 100/1073 [9%] with placebo; RR 1.61, 95% CI 1.28 to 2.02), and increased the risk of delivering a baby weighing less than 2500 g (2 RCTs; AR 94/988 [10%] with diethylstilbestrol v 64/978 [7%] with placebo; RR 1.48, 95% CI 1.09 to 2.00). It found that female offspring exposed to diethylstilbestrol in utero were at increased risk of vaginal adenosis or cervical polyps (1 RCT; AR 153/229 [67%] with diethylstilbestrol v 5/136 [4%] with placebo; RR 18.17, 95% CI 7.65 to 43.17), and at increased risk of primary infertility (1 RCT; AR 69/408 [17%] with diethylstilbestrol v 28/388 [7%] with placebo; RR 2.34, 95% CI 1.55 to 3.55). Female offspring exposed to diethylstilbestrol had a greater incidence of cancer of the genital tract, but this increase did not reach significance (1 RCT; AR 14/693 [2.0%] with diethylstilbestrol v 9/668 [1.3%] with placebo; RR 1.50, 95% CI 0.65 to 3.44). Testicular abnormalities (not defined further) were significantly increased in male offspring exposed to diethylstilbestrol in utero (2 RCTs; AR 119/434 [27%] with diethylstilbestrol v 53/445 [12%] with placebo; RR 2.32, 95% CI 1.71 to 3.13).
LIVE BIRTHS Compared with placebo: Paternal white cell immunisation is no more effective at improving live birth rates in women with unexplained recurrent miscarriage ( high-quality evidence ). NOTE White cell immunisation may be associated with allergic reactions such as soreness and redness at the injection site, fever, maternal platelet alloimmunisation, blood group sensitisation, and cutaneous graft versus host reaction.
Benefits
We found one systematic review (search date 2004, 12 RCTs, 641 women) comparing paternal white cell immunisation versus placebo in women with unexplained recurrent miscarriage. It found no significant difference in live birth rates between paternal white cell immunisation and placebo (AR 205/316 [65%] with immunisation v 195/325 [60%] with placebo; RR 1.08, 95% CI 0.96 to 1.22).
Harms
The review did not report on harms.Immunisation with blood products, such as mononuclear cells, carries risk of transmitting infections such as hepatitis B and HIV. Non-systematic reviews have suggested that white cell immunisation may be associated with allergic reactions such as soreness and redness at the injection site, fever, maternal platelet alloimmunisation, blood group sensitisation, and cutaneous graft versus host reaction.
Comment
None.
Substantive changes
Paternal white cell immunisation in unexplained miscarriage One already-included systematic review updated; benefits and harms data enhanced, categorisation unchanged (Unlikely to be beneficial).
MISCARRIAGE RATES Compared with placebo/no treatment: Progesterone may be more effective at reducing miscarriage in women with unexplained recurrent miscarriage ( very low-quality evidence ).
Benefits
We found one systematic review (search date 2003) comparing progesterone versus placebo or no treatment (control) for preventing miscarriage.The review identified three RCTs that presented results specifically in women with three or more consecutive miscarriages (93 women). It found that progesterone significantly reduced miscarriage compared with control in women with recurrent miscarriage (AR 12/48 [25%] with progesterone v 21/45 [47%] with control; RR 0.53, 95% CI 0.29 to 0.95).
Harms
The review did not report on harms specifically in women with unexplained recurrent miscarriage. Overall, the review found no significant difference in neonatal death between progesterone and placebo (2 RCTs; AR 2/79 [2.5%] with progesterone v 0/72 [0%] with placebo; RR 2.8, 95% CI 0.3 to 26.2) or genital tract abnormalities (2 RCTs; AR 2/12 [16.7%] with progesterone v 0/8 [0%] with placebo; RR 2.45, 95% CI 0.34 to 17.71). One retrospective observational study in women who had received infertility treatment (1016 pregnancies in 913 women) found no significant difference in the incidence of congenital abnormalities in infants of women who had received medroxyprogesterone acetate and those who had not (AR 4.1% with medroxyprogesterone acetate v 3.5% with control; P reported as not significant).
Comment
The RCTs in women with unexplained recurrent miscarriage included in the review had methodological weaknesses. They either did not provide details of randomisation, or they used quasi-randomisation methods. Allocation concealment was inadequate or unclear. One RCT excluded a large number of people after randomisation (26/56 [46%] women) and the other RCTs did not describe withdrawal.
We found no direct information about corticosteroids (either alone or combined with heparin or low-dose aspirin) in women with unexplained recurrent miscarriage.
Benefits
We found no systematic review or RCTs of corticosteroids (either alone or combined with heparin or low-dose aspirin) in women with unexplained recurrent miscarriage.
LIVE BIRTHS Compared with placebo: Trophoblastic membrane infusion is no more effective at increasing live birth rates in women with recurrent miscarriage ( moderate-quality evidence ).
Benefits
We found one systematic review (search date 2004), which identified one small RCT (37 women) comparing trophoblastic membrane infusion versus placebo in women with recurrent miscarriages. The review found no significant difference in live birth rate between trophoblastic membrane infusion and placebo, but it may have lacked power to detect differences between groups (AR 8/17 [47%] with trophoblastic membrane infusion v 14/20 [70%] with placebo; RR 0.67, 95% CI 0.38 to 1.20).
Harms
The review did not report on harms.
Comment
None.
Substantive changes
Trophoblastic membrane infusion in unexplained miscarriage One already-included systematic review updated;no new evidence added, categorisation unchanged (Unknown effectiveness).
We found no direct information about vitamin supplementation in women with unexplained recurrent miscarriage.
Benefits
We found no systematic review or RCTs of vitamin supplementation in women with unexplained recurrent miscarriage.
Harms
We found no RCTs.
Comment
We found one systematic review (search date 2003) that addressed vitamin supplementation before 20 weeks' gestation in pregnant women, but not specifically in women with recurrent miscarriage or at particular risk for miscarriage. There was no significant difference in total fetal loss (10 RCTs, 31,167 women; RR 1.05, 95% CI 0.95 to 1.15) or early or late miscarriage (7 RCTs, 8490 women; RR 1.08, 95% CI 0.95 to 1.24) between vitamin supplementation compared with no vitamins or minimal vitamins. Most RCTs included in the review did not clearly present data about previous miscarriages, and meaningful subgroup analyses could therefore not be performed in such groups. It is not clear whether the findings of this review are generalisable to women with unexplained recurrent miscarriage.
LIVE BIRTHS Compared with placebo/usual care: Low-dose aspirin is no more effective at reducing pregnancy loss ( moderate-quality evidence ). Compared with low-dose aspirin plus unfractionated heparin: Low-dose aspirin is less effective at reducing pregnancy loss (moderate-quality evidence). Compared with low-dose aspirin plus low molecular weight heparin: We don't know whether low-dose aspirin is more effective at reducing pregnancy loss ( low-quality evidence ). MISCARRIAGE RATES Compared with low-dose aspirin plus corticosteroids: Low-dose aspirin alone may be as effective as prednisolone plus low-dose aspirin at reducing miscarriage rates ( very low-quality evidence ). ADVERSE EFFECTS Compared with low-dose aspirin plus corticosteroids: Low-dose aspirin plus prednisolone is more likely to increase the risk of preterm birth and is associated with low-birthweight neonates (moderate-quality evidence).
Benefits
Low-dose aspirin versus placebo or usual care:
We found one systematic review (search date 2003) that compared aspirin versus placebo or usual care. It found no significant difference in pregnancy loss between aspirin and control (aspirin dose 50–81 mg/day: 3 RCTs, 71 women; AR 10/37 [27%] with aspirin v 8/34 [24%] with control; RR 1.05, 95% CI 0.66 to 1.68).
Low-dose aspirin alone versus low-dose aspirin plus unfractionated heparin:
We found one systematic review and one subsequent small RCT. The review found that low-dose aspirin alone significantly increased pregnancy loss compared with low-dose aspirin plus unfractionated heparin (aspirin dose 75–81 mg/day, unfractionated heparin 5000 U twice daily: 2 RCTs, 140 women; AR 40/70 [57%] with aspirin alone v 18/70 [26%] with aspirin plus unfractionated heparin; RR 2.17, 95% CI 1.41 to 3.45). The subsequent small RCT (72 women) found a significantly lower proportion of women with live births with low-dose aspirin alone compared with low-dose aspirin plus unfractionated heparin (aspirin dose 80 mg/day, unfractionated heparin 5000 U twice daily: live births, AR 24/39 [62%] with aspirin alone v 28/33 [85%] with aspirin plus unfractionated heparin; P = 0.04).The study reported that it was randomised, but the method of randomisation was not described. The level of blinding was not reported.
Low-dose aspirin alone versus low-dose aspirin plus low molecular weight heparin (LMWH):
We found one systematic review. It found no significant difference in pregnancy loss between low-dose aspirin and low-dose aspirin plus LMWH (aspirin dose 75 mg/day: 1 RCT, 98 women; 13/47 [28%] with aspirin alone v 11/51 [22%] for aspirin plus LMWH; RR 1.28, 95% CI 0.64 to 2.56).
Low-dose aspirin alone versus corticosteroids plus low-dose aspirin:
See benefits of corticosteroids.
Harms
Low-dose aspirin versus placebo or usual care:
The review found no significant difference between low-dose aspirin and control in premature birth (1 RCT, 40 women; 2/20 [10%] with aspirin v 0/20 [0%] with control; RR 5.0, 95% CI 0.3 to 98.0) or fetal growth restriction (3 RCTs, 125 women; 4/64 [6.3%] with aspirin v 8/61 [13.1%] with control; RR 0.6, 95% CI 0.2 to 1.7). However, these analyses were likely to have been underpowered to detect differences between groups. Higher doses of aspirin (such as 300–600 mg every 6–8 hours) are associated with bronchospasm, gastrointestinal haemorrhage, and hypersensitive skin reactions. However, the adverse profile of lower-dose aspirin may differ. See also harms of low-dose aspirin in treatment of women with unexplained recurrent miscarriage.
Low-dose aspirin alone versus low-dose aspirin plus unfractionated heparin or LMWH:
The review found no significant difference between low-dose aspirin alone and low-dose aspirin plus unfractionated heparin in premature birth (2 RCTs; AR 5/70 [7.1%] with aspirin alone v 11/70 [15.7%] with aspirin plus unfractionated heparin; RR 0.5, 95% CI 0.2 to 1.3) or in fetal growth restriction (2 RCTs; AR 2/70 [2.9%] with aspirin alone v 6/70 [8.6%] with aspirin plus unfractionated heparin; RR 0.3, 95% CI 0.1 to 1.6). Similarly, there was no significant difference in premature delivery between low-dose aspirin alone and low-dose aspirin plus LMWH (1 RCT; 4/47 [8.5%] with aspirin alone v 2/51 [3.9%] with aspirin plus LMWH; RR 2.2, 95% CI 0.4 to 11.1). However, these analyses were likely to have been underpowered to detect differences between groups. One of the RCTs included in the review (90 women) found that unfractionated heparin plus aspirin reduced maternal lumbar spine bone mineral density (median change –5.4%, range –8.6% to +1.7%), but there were no vertebral fractures (figures not reported for aspirin-alone group; see comment below). This decrease is similar to that normally seen with 6 months of lactation. The subsequent RCT reported that minor epistaxis was encountered in three women with aspirin plus unfractionated heparin, and that occasional bruises were seen at the injection site in those given subcutaneous heparin (no further details reported).
Low-dose aspirin alone versus corticosteroids plus low-dose aspirin:
See harms of corticosteroids.
Comment
Low-dose aspirin alone versus low-dose aspirin plus LMWH:
The RCTs included in the review comparing low-dose aspirin versus low-dose aspirin plus LMWH may have underestimated fetal loss rate because women were enrolled up until week 12 of gestation (mean 6.7 weeks, range 4.0–12.0 weeks), by which time some antiphospholipid-related pregnancy losses would already have taken place. Further RCTs are needed to explore the potential differences between unfractionated heparin and LMWH. The reduction in bone mineral density seen with unfractionated heparin may be reversible to some extent once heparin is discontinued, and may be less marked with LMWH.
Substantive changes
Aspirin (low dose) in antiphospholipid syndrome One RCT comparing low-dose aspirin alone versus low-dose aspirin plus unfractionated heparin added;benefits and harms data enhanced, categorisation unchanged (Unknown effectiveness)
LIVE BIRTHS Low-dose aspirin plus unfractionated heparin compared with low-dose aspirin alone: Low-dose aspirin plus unfractionated heparin is more effective at reducing pregnancy loss ( moderate-quality evidence ). Low-dose aspirin plus low molecular weight heparin compared with low-dose aspirin alone: We don't know whether low-dose aspirin plus low molecular weight heparin is more effective at reducing pregnancy loss ( low-quality evidence ). NOTE We found no direct information about whether low-dose aspirin plus heparin is better than no active treatment in women with recurrent miscarriage caused by antiphospholipid syndrome.
Benefits
Low-dose aspirin plus unfractionated or low molecular weight heparin versus placebo:
We found one systematic review (search date 2004), which found no RCTs, and we found no subsequent RCTs.
Low-dose aspirin plus unfractionated heparin versus low-dose aspirin alone:
See benefits of low-dose aspirin.
Low-dose aspirin plus low molecular weight heparin versus low-dose aspirin alone:
See benefits of low-dose aspirin.
Harms
One case series (150 pregnant women with antiphospholipid syndrome) found that heparin plus low-dose aspirin was associated with a median reduction in lumbar spine bone mineral density of +3.4% (range –11.7% to +9.0%). One cohort study (123 pregnant women with antiphospholipid syndrome receiving low-dose aspirin plus heparin) found no significant difference in bone mineral density loss between women receiving unfractionated heparin and those receiving low molecular weight heparin (lumbar spine loss: 0.044 g/cm2 with low molecular weight heparin v 0.049 g/cm2 with unfractionated heparin; P = 0.6).
Low-dose aspirin plus heparin versus placebo:
We found no RCTs.
Low-dose aspirin plus unfractionated or low molecular weight heparin versus low-dose aspirin alone:
See harms of low-dose aspirin.
Comment
See comment on low-dose aspirin.
Substantive changes
Aspirin (low dose) plus heparin (in antiphospholipid syndrome) One RCT comparing low-dose aspirin plus unfractionated heparin versus low-dose aspirin alone added;benefits and harms data enhanced, categorisation unchanged (Unknown effectiveness).
LIVE BIRTH Corticosteroids plus low-dose aspirin compared with placebo: Prednisolone plus low-dose aspirin is no more effective at reducing pregnancy loss ( moderate-quality evidence ). MISCARRIAGE RATES Corticosteroids plus low-dose aspirin compared with low-dose aspirin alone: Corticosteroids plus low-dose aspirin may be no more effective at reducing miscarriages ( very low-quality evidence ). ADVERSE EFFECTS Corticosteroids plus low-dose aspirin compared with placebo: Prednisolone plus low-dose aspirin increases the risk of hypertension, preterm birth, and admission to neonatal intensive care ( high-quality evidence ). Corticosteroids plus low-dose aspirin compared with low-dose aspirin alone: Prednisolone plus low-dose aspirin increases the risk of preterm birth and is associated with low-birthweight neonates (moderate-quality evidence). NOTE We found no direct information about corticosteroids alone in women with recurrent miscarriage caused by antiphospholipid syndrome.
Benefits
Corticosteroids alone:
We found one systematic review (search date 2003), which found no RCTs of corticosteroids alone in women with recurrent miscarriage caused by antiphospholipid syndrome. We found no subsequent RCTs.
Corticosteroids plus low-dose aspirin versus placebo:
We found one systematic review, which identified one RCT. The RCT found no significant difference between prednisolone plus low-dose aspirin (100 mg/day) and placebo in pregnancy loss (88 women; AR 17/42 [40%] with prednisolone plus aspirin v 22/46 [48%] with placebo; RR 0.85, 95% CI 0.53 to 1.36).
Corticosteroids plus low-dose aspirin versus low-dose aspirin alone:
We found one systematic review, which identified one RCT comparing prednisolone plus low-dose aspirin versus aspirin alone. There were no miscarriages in either group (1 RCT, 39 women randomised; 0/12 with prednisolone plus aspirin v 0/22 in aspirin-alone group; analysis not by intention to treat).
Harms
Corticosteroids alone:
We found no RCTs.
Corticosteroids plus low-dose aspirin versus placebo:
The RCT identified by the systematic review found that prednisolone plus aspirin significantly increased the risk of hypertension (AR 13% with prednisolone plus aspirin v 5% with placebo; P = 0.05) and gestational diabetes (202 women, including 88 women with antiphospholipid syndrome; AR 15/101 [15%] with prednisolone plus aspirin v 5/101 [5%] with placebo; RR 3.0, 95% CI 1.1 to 7.9) compared with placebo. Prednisolone plus aspirin significantly increased the risk of preterm birth (AR 41/101 [41%] with prednisolone plus low-dose aspirin v 7/101 [7%] with placebo; RR 5.9, 95% CI 2.8 to 12.4) and admission to neonatal intensive care (AR for admission to neonatal intensive care: 18/101 [18%] with prednisolone plus aspirin v 2/101 [2%] with placebo; RR 9.0, 95% CI 2.1 to 37.8) compared with placebo.
Corticosteroids plus low-dose aspirin versus low-dose aspirin alone:
The review found that prednisolone plus aspirin significantly increased the risk of preterm birth compared with aspirin alone (1 RCT, 39 women randomised; 8/12 [67%] with prednisolone plus low-dose aspirin v 3/22 [14%] with aspirin alone; RR 4.9, 95% CI 1.6 to 15.1). Prednisolone plus aspirin was associated with significantly lower birthweight of neonates compared with aspirin alone (34 neonates; mean birthweight: 2800 g with prednisolone plus aspirin v 3352 g with aspirin alone; mean weight reduction 552 g, 95% CI 1064 g to 39 g). However, no infants in either group were growth retarded (below 10th percentile) at birth. There were no perinatal deaths or significant haemorrhage in mother or neonate.
Comment
The review identified one RCT comparing prednisolone plus low-dose aspirin versus heparin plus low-dose aspirin. Although the review reported that the RCT included 45 women, the original paper reported that only 20 of these women had been randomised to their treatment group, with only eight women randomised to prednisolone plus aspirin. This RCT therefore did not meet BMJ Clinical Evidence inclusion criteria, which require at least 10 randomised people in each treatment group.
