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

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.

Aspirin plus heparin or aspirin alone in women with recurrent miscarriage.

BACKGROUND: Aspirin and low-molecular-weight heparin are prescribed for women with unexplained recurrent miscarriage, with the goal of improving the rate of live births, but limited data from randomized, controlled trials are available to support the use of these drugs. METHODS: In this randomized trial, we enrolled 364 women between the ages of 18 and 42 years who had a history of unexplained recurrent miscarriage and were attempting to conceive or were less than 6 weeks pregnant. We then randomly assigned them to receive daily 80 mg of aspirin plus open-label subcutaneous nadroparin (at a dose of 2850 IU, starting as soon as a viable pregnancy was demonstrated), 80 mg of aspirin alone, or placebo. The primary outcome measure was the live-birth rate. Secondary outcomes included rates of miscarriage, obstetrical complications, and maternal and fetal adverse events. RESULTS: Live-birth rates did not differ significantly among the three study groups. The proportions of women who gave birth to a live infant were 54.5% in the group receiving aspirin plus nadroparin (combination-therapy group), 50.8% in the aspirin-only group, and 57.0% in the placebo group (absolute difference in live-birth rate: combination therapy vs. placebo, -2.6 percentage points; 95% confidence interval [CI], -15.0 to 9.9; aspirin only vs. placebo, -6.2 percentage points; 95% CI, -18.8 to 6.4). Among 299 women who became pregnant, the live-birth rates were 69.1% in the combination-therapy group, 61.6% in the aspirin-only group, and 67.0% in the placebo group (absolute difference in live-birth rate: combination therapy vs. placebo, 2.1 percentage points; 95% CI, -10.8 to 15.0; aspirin alone vs. placebo -5.4 percentage points; 95% CI, -18.6 to 7.8). An increased tendency to bruise and swelling or itching at the injection site occurred significantly more frequently in the combination-therapy group than in the other two study groups. CONCLUSIONS: Neither aspirin combined with nadroparin nor aspirin alone improved the live-birth rate, as compared with placebo, among women with unexplained recurrent miscarriage. (Current Controlled Trials number, ISRCTN58496168.)

Aspirin or anticoagulants for treating recurrent miscarriage in women without antiphospholipid syndrome.

BACKGROUND: Since hypercoagulability might result in recurrent miscarriage, anticoagulant agents could potentially increase the live-birth rate in subsequent pregnancies in women with either inherited thrombophilia or unexplained recurrent miscarriage. OBJECTIVES: To evaluate the efficacy and safety of anticoagulant agents, such as aspirin and heparin, in women with a history of at least two miscarriages without apparent causes other than inherited thrombophilia. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (April 2008), the Cochrane Central Register of Controlled Trials (The Cochrane Library 2007, Issue 1), MEDLINE (January 1966 to March 2007), and EMBASE (1980 to March 2007). We 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 the live-birth rate in women with a history of at least two miscarriages (up to 20 weeks of amenorrhoea) without apparent causes other than inherited thrombophilia were eligible. Interventions included aspirin, unfractionated heparin, and low molecular weight heparin for the prevention of miscarriage. One treatment could be compared with another or with placebo. DATA COLLECTION AND ANALYSIS: Two authors assessed the trials for inclusion in the review and extracted the data. We double checked the data. MAIN RESULTS: Two studies (189 participants) were included in the review. In one study, 54 pregnant women with recurrent miscarriage (RM) but no detectable anticardiolipin antibodies were randomised to low-dose aspirin or placebo. RM was defined as three or more consecutive miscarriages (occurring before 22 weeks' gestational age (based on last menstrual period)). Similar live-birth rates were observed with aspirin and placebo, both 81% (risk ratio (RR) 1.00, 95% confidence interval (CI) 0.78 to 1.29). In the other study, 107 women with consecutive recurrent miscarriage without any apparent cause and no hereditary thrombophilia were randomised between enoxaparin and aspirin. Here RM was stated as three or more consecutive first trimester miscarriages or at least two consecutive second trimester miscarriages. Similar live birth rates were observed with enoxaparin and aspirin, respectively 82% and 84% (RR 0.97, 95% CI 0.81 to 1.16). AUTHORS' CONCLUSIONS: There is a paucity in studies on the efficacy and safety of aspirin and heparin in women with a history of at least two miscarriages without apparent causes other than inherited thrombophilia. The two reviewed trials studied different treatments and only one study was placebo-controlled. Neither of the studies showed a benefit of one treatment over the other. Therefore, the use of anticoagulants in this setting is not recommended. However, large randomised placebo-controlled trials are still urgently needed.

Inherited thrombophilias.

Many inherited thrombophilias have been detected and the pathophysiologic insight has increased tremendously during the last decades. Despite, however, the overwhelming observational evidence on the association between inherited thrombophilia and several women's health issues, including VTE, thus far the implications for clinical practice are uncertain. Although there is firm epidemiologic evidence that is helpful in counseling women who have inherited thrombophilia to prevent a first or recurrent VTE, the uncertainty is particularly present for women who have other pregnancy complications, such as recurrent pregnancy loss and pre-eclampsia. For this group, well-designed placebo-controlled trials to assess the harm-benefit ratio are urgently needed.