Anticoagulant drugs for the prevention of recurrent miscarriage in women with antiphospholipid antibodies

We set out to determine if antithrombotic drugs improve pregnancy outcomes for women with persistent antiphospholipid antibody levels who have had a number of miscarriages.

What is the issue?

Phospholipid molecules help form the cell membranes and are critical to a cell's ability to function. The immune system can develop antibodies that are directed against proteins attached to the phospholipids. Different types of antiphospholipid antibodies exist. Presence of these antibodies can lead to the development of blood clots in either veins or arteries, but also repeated pregnancy losses.

Why is this important?

Antiphospholipid antibodies are associated with a higher risk of pregnancy complications, including the risk of pregnancy loss. Use of antithrombotic drugs during pregnancy may help prevent pregnancy loss for women who have had recurrent miscarriages. Aspirin is an anti-inflammatory drug that reduces platelet aggregation and blood clotting. Heparin is a potent anticoagulant that prevents blood clot formation. Aspirin and heparin may reduce the risk of miscarriage associated with antiphospholipid antibodies. Low-molecular-weight heparin is easier to use and causes less side effects for the mother than undivided or unfractionated heparin.

What evidence did we find?

We searched the medical literature for evidence from randomised controlled trials up to June 2019. We identified 11 studies involving 1672 women who had previously experienced at least two pregnancy losses and had persistent antiphospholipid antibodies in their blood. Most studies started eligible women on aspirin before conception with women randomly assigned to receive additional heparin, or not, once pregnancy was confirmed. The dose and type of heparin varied among studies, as did timing for when treatment was started and the length of time women were treated.

The evidence we identified is low certainty due to the small numbers of women in the studies and to the risk of bias in the studies.

Compared to placebo, we are very uncertain if aspirin has any effect on live birth, pre-eclampsia, pregnancy loss, preterm delivery of a live infant, intrauterine growth restriction or adverse events in the child or in the mother. Venous thromboembolism and arterial thromboembolism were not reported in the studies investigating aspirin compared with placebo.

Heparin plus aspirin may increase the number of live births and may reduce the risk of pregnancy loss.

Compared with aspirin alone, we are uncertain if heparin plus aspirin has any effect on the risk of pre-eclampsia, preterm delivery of a live infant, intrauterine growth restriction, or bleeding in the mother.

No women in either the heparin plus aspirin group or the aspirin alone group had heparin-induced thrombocytopenia, allergic reactions, or venous or arterial thromboembolism. Similarly, no infants had congenital malformations.

What does this mean?

The combination of heparin with aspirin during the course of pregnancy for women with persistent antiphospholipid antibodies may lead to a higher number of live births than treatment with aspirin alone. We are uncertain about the safety of heparin and aspirin for mothers and infants because of the lack of reporting of adverse events. Future trials should recruit adequate numbers of women and to fully evaluate the risks and benefits of this treatment strategy.

Authors' conclusions: 

The combination of heparin (UFH or LMWH) plus aspirin during the course of pregnancy may increase live birth rate in women with persistent aPL when compared with aspirin treatment alone. The observed beneficial effect of heparin was driven by one large study in which LMWH plus aspirin was compared with aspirin alone. Adverse events were frequently not, or not uniformly, reported in the included studies. More research is needed in this area in order to further evaluate potential risks and benefits of this treatment strategy, especially among women with aPL and recurrent pregnancy loss, to gain consensus on the ideal prevention for recurrent pregnancy loss, based on a risk profile.

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Background: 

Aspirin and heparin are widely used as preventive strategy to reduce the high risk of recurrent pregnancy loss in women with antiphospholipid antibodies (aPL).

This review supersedes a previous, out-of-date review that evaluated all potential therapies for preventing recurrent pregnancy loss in women with aPL. The current review focusses on a narrower scope because current clinical practice is restricted to using aspirin or heparins, or both for women with aPL in an attempt to reduce pregnancy complications.

Objectives: 

To assess the effects of aspirin or heparin, or both for improving pregnancy outcomes in women with persistent (on two separate occasions) aPL, either lupus anticoagulant (LAC), anticardiolipin (aCL) or aβ2-glycoprotein-I antibodies (aβ2GPI) or a combination, and recurrent pregnancy loss (two or more, which do not have to be consecutive).

Search strategy: 

We searched Cochrane Pregnancy and Childbirth’s Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (3 June 2019), and reference lists of retrieved studies. Where necessary, we attempted to contact trial authors.

Selection criteria: 

Randomised, cluster-randomised and quasi-randomised controlled trials that assess the effects of aspirin, heparin (either low-molecular-weight heparin (LMWH) or unfractionated heparin (UFH]), or a combination of aspirin and heparin compared with no treatment, placebo or another, on pregnancy outcomes in women with persistent aPL and recurrent pregnancy loss were eligible. All treatment regimens were considered.

Data collection and analysis: 

Two review authors independently assessed trials for inclusion criteria and risk of bias. Two review authors independently extracted data and checked them for accuracy and the certainty of the evidence was assessed using the GRADE approach.

Main results: 

Eleven studies (1672 women) met the inclusion criteria; nine randomised controlled trials and two quasi-RCTs. The studies were conducted in the USA, Canada, UK, China, New Zealand, Iraq and Egypt. One included trial involved 1015 women, all other included trials had considerably lower numbers of participants (i.e. 141 women or fewer).

Some studies had high risk of selection and attrition bias, and many did not include sufficient information to judge the risk of reporting bias. Overall, the certainty of evidence is low to very low due to the small numbers of women in the studies and to the risk of bias.

The dose and type of heparin and aspirin varied among studies. One study compared aspirin alone with placebo; no studies compared heparin alone with placebo and there were no trials that had a no treatment comparator arm during pregnancy; five studies explored the efficacy of heparin (either UFH or LMWH) combined with aspirin compared with aspirin alone; one trial compared LMWH with aspirin; two trials compared the combination of LMWH plus aspirin with the combination of UFH plus aspirin; two studies evaluated the combination of different doses of heparin combined with aspirin. All trials used aspirin at a low dose.

Aspirin versus placebo

We are very uncertain if aspirin has any effect on live birth compared to placebo (risk ratio (RR) 0.94, 95% confidence interval (CI) 0.71 to 1.25, 1 trial, 40 women, very low-certainty evidence).

We are very uncertain if aspirin has any effect on the risk of pre-eclampsia, pregnancy loss, preterm delivery of a live infant, intrauterine growth restriction or adverse events in the child, compared to placebo. We are very uncertain if aspirin has any effect on adverse events (bleeding) in the mother compared with placebo (RR 1.29, 95% CI 0.60 to 2.77, 1 study, 40 women). The certainty of evidence for these outcomes is very low because of imprecision, due to the low numbers of women involved and the wide 95% CIs, and also because of risk of bias.

Venous thromboembolism and arterial thromboembolism were not reported in the included studies.

Heparin plus aspirin versus aspirin alone

Heparin plus aspirin may increase the number of live births (RR 1.27, 95% CI 1.09 to 1.49, 5 studies, 1295 women, low-certainty evidence).

We are uncertain if heparin plus aspirin has any effect on the risk of pre-eclampsia, preterm delivery of a live infant, or intrauterine growth restriction, compared with aspirin alone because of risk of bias and imprecision due to the low numbers of women involved and the wide 95% CIs. We are very uncertain if heparin plus aspirin has any effect on adverse events (bleeding) in the mother compared with aspirin alone (RR 1.65, 95% CI 0.19 to 14.03, 1 study, 31 women).

No women in either the heparin plus aspirin group or the aspirin alone group had heparin-induced thrombocytopenia, allergic reactions, or venous or arterial thromboembolism. Similarly, no infants had congenital malformations.

Heparin plus aspirin may reduce the risk of pregnancy loss (RR 0.48, 95% CI 0.32 to 0.71, 5 studies, 1295 women, low-certainty evidence).

When comparing LMWH plus aspirin versus aspirin alone the pooled RR for live birth was 1.20 (95% CI 1.04 to 1.38, 3 trials, 1155 women). In the comparison of UFH plus aspirin versus aspirin alone, the RR for live birth was 1.74 (95% CI 1.28 to 2.35, 2 trials, 140 women).

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