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Meta-Analysis
. 2014 Jul 4;2014(7):CD004734.
doi: 10.1002/14651858.CD004734.pub4.

Aspirin and/or heparin for women with unexplained recurrent miscarriage with or without inherited thrombophilia

Paulien G de Jong  1 , Stef Kaandorp, Marcello Di Nisio, Mariëtte Goddijn, Saskia Middeldorp
Affiliations
Meta-Analysis

Aspirin and/or heparin for women with unexplained recurrent miscarriage with or without inherited thrombophilia

Paulien G de Jong et al. Cochrane Database Syst Rev. .

Abstract

Background: Since hypercoagulability might result in recurrent miscarriage, anticoagulant agents could potentially increase the chance of live birth in subsequent pregnancies in women with unexplained recurrent miscarriage, with or without inherited thrombophilia.

Objectives: To evaluate the efficacy and safety of anticoagulant agents, such as aspirin and heparin, in women with a history of at least two unexplained miscarriages with or without inherited thrombophilia.

Search methods: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (1 October 2013) and scanned bibliographies of all located articles for any unidentified articles.

Selection criteria: Randomised and quasi-randomised controlled trials that assessed the effect of anticoagulant treatment on live birth in women with a history of at least two unexplained miscarriages with or without inherited thrombophilia were eligible. Interventions included aspirin, unfractionated heparin (UFH), and low molecular weight heparin (LMWH) for the prevention of miscarriage. One treatment could be compared with another or with no-treatment (or placebo).

Data collection and analysis: Two review authors (PJ and SK) assessed the studies for inclusion in the review and extracted the data. If necessary they contacted study authors for more information. We double checked the data.

Main results: Nine studies, including data of 1228 women, were included in the review evaluating the effect of either LMWH (enoxaparin or nadroparin in varying doses) or aspirin or a combination of both, on the chance of live birth in women with recurrent miscarriage, with or without inherited thrombophilia. Studies were heterogeneous with regard to study design and treatment regimen and three studies were considered to be at high risk of bias. Two of these three studies at high risk of bias showed a benefit of one treatment over the other, but in sensitivity analyses (in which studies at high risk of bias were excluded) anticoagulants did not have a beneficial effect on live birth, regardless of which anticoagulant was evaluated (risk ratio (RR) for live birth in women who received aspirin compared to placebo 0.94, (95% confidence interval (CI) 0.80 to 1.11, n = 256), in women who received LMWH compared to aspirin RR 1.08 (95% CI 0.93 to 1.26, n = 239), and in women who received LMWH and aspirin compared to no-treatment RR 1.01 (95% CI 0.87 to 1.16) n = 322).Obstetric complications such as preterm delivery, pre-eclampsia, intrauterine growth restriction and congenital malformations were not significantly affected by any treatment regimen. In included studies, aspirin did not increase the risk of bleeding, but treatment with LWMH and aspirin increased the risk of bleeding significantly in one study. Local skin reactions (pain, itching, swelling) to injection of LMWH were reported in almost 40% of patients in the same study.

Authors' conclusions: There is a limited number of studies on the efficacy and safety of aspirin and heparin in women with a history of at least two unexplained miscarriages with or without inherited thrombophilia. Of the nine reviewed studies quality varied, different treatments were studied and of the studies at low risk of bias only one was placebo-controlled. No beneficial effect of anticoagulants in studies at low risk of bias was found. Therefore, this review does not support the use of anticoagulants in women with unexplained recurrent miscarriage. The effect of anticoagulants in women with unexplained recurrent miscarriage and inherited thrombophilia needs to be assessed in further randomised controlled trials; at present there is no evidence of a beneficial effect.

PubMed Disclaimer

Conflict of interest statement

Dr Kaandorp, Dr Goddijn, and Dr Middeldorp were investigators of the randomised controlled trial ALIFE study (Kaandorp 2010). Dr Middeldorp has also been and is involved in phase 2 and phase 3 trials that assess the efficacy and safety of anticoagulant drugs for the indication of venous thrombosis or superficial thrombophlebitis. These trials were, or are being, sponsored by various pharmaceutical companies.

Figures

1
1
'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.
1.1
1.1. Analysis
Comparison 1 Aspirin versus no treatment, Outcome 1 Live birth.
1.2
1.2. Analysis
Comparison 1 Aspirin versus no treatment, Outcome 2 Preterm delivery < 37 weeks.
1.3
1.3. Analysis
Comparison 1 Aspirin versus no treatment, Outcome 3 Preterm delivery 24‐28 weeks.
1.4
1.4. Analysis
Comparison 1 Aspirin versus no treatment, Outcome 4 Preterm delivery 28‐32 weeks.
1.5
1.5. Analysis
Comparison 1 Aspirin versus no treatment, Outcome 5 Preterm delivery 32‐37 weeks.
1.6
1.6. Analysis
Comparison 1 Aspirin versus no treatment, Outcome 6 Obstetric complications; pre‐eclampsia.
1.7
1.7. Analysis
Comparison 1 Aspirin versus no treatment, Outcome 7 Obstetric complications; IUGR.
1.8
1.8. Analysis
Comparison 1 Aspirin versus no treatment, Outcome 8 Congenital malformations.
1.9
1.9. Analysis
Comparison 1 Aspirin versus no treatment, Outcome 9 Side effects; any bleeding.
1.10
1.10. Analysis
Comparison 1 Aspirin versus no treatment, Outcome 10 HIT/thrombocytopenia.
2.1
2.1. Analysis
Comparison 2 LMWH versus aspirin, Outcome 1 Live birth.
2.2
2.2. Analysis
Comparison 2 LMWH versus aspirin, Outcome 2 Preterm delivery < 37 weeks.
2.3
2.3. Analysis
Comparison 2 LMWH versus aspirin, Outcome 3 Preterm delivery 24‐28 weeks.
2.4
2.4. Analysis
Comparison 2 LMWH versus aspirin, Outcome 4 Preterm delivery 28‐32 weeks.
2.5
2.5. Analysis
Comparison 2 LMWH versus aspirin, Outcome 5 Preterm delivery 32‐37 weeks.
2.6
2.6. Analysis
Comparison 2 LMWH versus aspirin, Outcome 6 Obstetric complications; pre‐eclampsia.
2.7
2.7. Analysis
Comparison 2 LMWH versus aspirin, Outcome 7 Obstetric complications; IUGR.
2.8
2.8. Analysis
Comparison 2 LMWH versus aspirin, Outcome 8 Obstetric complications; congenital malformations.
2.9
2.9. Analysis
Comparison 2 LMWH versus aspirin, Outcome 9 Side effects; any bleeding.
3.1
3.1. Analysis
Comparison 3 LMWH versus aspirin including studies at high risk of bias, Outcome 1 Live birth.
4.1
4.1. Analysis
Comparison 4 LMWH versus no treatment, Outcome 1 Live birth.
5.1
5.1. Analysis
Comparison 5 LMWH versus no treatment including studies at high risk of bias, Outcome 1 Live birth.
5.2
5.2. Analysis
Comparison 5 LMWH versus no treatment including studies at high risk of bias, Outcome 2 Preterm delivery < 37 weeks.
5.3
5.3. Analysis
Comparison 5 LMWH versus no treatment including studies at high risk of bias, Outcome 3 Obstetric complications; pre‐eclampsia.
5.4
5.4. Analysis
Comparison 5 LMWH versus no treatment including studies at high risk of bias, Outcome 4 Obstetric complications; IUGR.
5.5
5.5. Analysis
Comparison 5 LMWH versus no treatment including studies at high risk of bias, Outcome 5 Obstetric complications; congenital malformations.
5.6
5.6. Analysis
Comparison 5 LMWH versus no treatment including studies at high risk of bias, Outcome 6 Side effects; any bleeding.
5.7
5.7. Analysis
Comparison 5 LMWH versus no treatment including studies at high risk of bias, Outcome 7 Thromboembolic complications.
6.1
6.1. Analysis
Comparison 6 LMWH and aspirin versus no treatment, Outcome 1 Live birth.
6.2
6.2. Analysis
Comparison 6 LMWH and aspirin versus no treatment, Outcome 2 Preterm delivery < 37 weeks.
6.3
6.3. Analysis
Comparison 6 LMWH and aspirin versus no treatment, Outcome 3 Preterm delivery 24‐28 weeks.
6.4
6.4. Analysis
Comparison 6 LMWH and aspirin versus no treatment, Outcome 4 Preterm delivery 28‐32 weeks.
6.5
6.5. Analysis
Comparison 6 LMWH and aspirin versus no treatment, Outcome 5 Preterm delivery 32‐37 weeks.
6.6
6.6. Analysis
Comparison 6 LMWH and aspirin versus no treatment, Outcome 6 Obstetric complications; pre‐eclampsia.
6.7
6.7. Analysis
Comparison 6 LMWH and aspirin versus no treatment, Outcome 7 Obstetric complications; IUGR.
6.8
6.8. Analysis
Comparison 6 LMWH and aspirin versus no treatment, Outcome 8 Congenital Malformations.
6.9
6.9. Analysis
Comparison 6 LMWH and aspirin versus no treatment, Outcome 9 Side effects; any bleeding.
6.10
6.10. Analysis
Comparison 6 LMWH and aspirin versus no treatment, Outcome 10 Side effects; pain/itching/swelling at injection site.
7.1
7.1. Analysis
Comparison 7 LMWH and aspirin versus aspirin, Outcome 1 Live birth.
7.2
7.2. Analysis
Comparison 7 LMWH and aspirin versus aspirin, Outcome 2 Preterm delivery < 37 weeks.
7.3
7.3. Analysis
Comparison 7 LMWH and aspirin versus aspirin, Outcome 3 Preterm delivery 24‐28 weeks.
7.4
7.4. Analysis
Comparison 7 LMWH and aspirin versus aspirin, Outcome 4 Preterm delivery; 28‐32 weeks.
7.5
7.5. Analysis
Comparison 7 LMWH and aspirin versus aspirin, Outcome 5 Preterm delivery; 32‐37 weeks.
7.6
7.6. Analysis
Comparison 7 LMWH and aspirin versus aspirin, Outcome 6 Obstetric complications; pre‐eclampsia.
7.7
7.7. Analysis
Comparison 7 LMWH and aspirin versus aspirin, Outcome 7 Obstetric complications; IUGR.
7.8
7.8. Analysis
Comparison 7 LMWH and aspirin versus aspirin, Outcome 8 Congenital malformations.
7.9
7.9. Analysis
Comparison 7 LMWH and aspirin versus aspirin, Outcome 9 Side effects; any bleeding.
7.10
7.10. Analysis
Comparison 7 LMWH and aspirin versus aspirin, Outcome 10 Side effects; pain/itching/swelling at injection site.
7.11
7.11. Analysis
Comparison 7 LMWH and aspirin versus aspirin, Outcome 11 HIT/thrombocytopenia.
8.1
8.1. Analysis
Comparison 8 LMWH and aspirin versus LMWH, Outcome 1 Live birth.
8.2
8.2. Analysis
Comparison 8 LMWH and aspirin versus LMWH, Outcome 2 Preterm delivery < 37 weeks.
8.3
8.3. Analysis
Comparison 8 LMWH and aspirin versus LMWH, Outcome 3 Obstetric complications; pre‐eclampsia.
8.4
8.4. Analysis
Comparison 8 LMWH and aspirin versus LMWH, Outcome 4 Obstetric complications; IUGR.
8.5
8.5. Analysis
Comparison 8 LMWH and aspirin versus LMWH, Outcome 5 Congenital malformations.
8.6
8.6. Analysis
Comparison 8 LMWH and aspirin versus LMWH, Outcome 6 Side effects; any bleeding.
9.1
9.1. Analysis
Comparison 9 LMWH with or without aspirin vs no treatment including studies at high risk of bias, Outcome 1 Live birth.
10.1
10.1. Analysis
Comparison 10 LMWH with or without aspirin vs no treatment, Outcome 1 Live birth.
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