Aspirin or heparin or both for improving pregnancy outcomes in women with persistent antiphospholipid antibodies and recurrent pregnancy loss

Eva N Hamulyák, Luuk Jj Scheres, Mauritia C Marijnen, Mariëtte Goddijn, Saskia Middeldorp, Eva N Hamulyák, Luuk Jj Scheres, Mauritia C Marijnen, Mariëtte Goddijn, Saskia Middeldorp

Abstract

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 This review supersedes a previous, out-of-date review that evaluated all potential therapies for preventing recurrent pregnancy loss in women with aPL.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 methods: 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).

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.

Trial registration: ClinicalTrials.gov NCT01051778 NCT00564174 NCT01661439 NCT00180778 NCT02144064 NCT00467363 NCT00959621 NCT02303171 NCT03100123.

Conflict of interest statement

Eva N Hamulyák: none known

Luuk JJ Scheres: is a PhD‐candidate of the CREW project (2013T083) funded by the Netherlands Heart Foundation

Mauritia C Marijnen: none known

Mariette Goddijn: has received travel expenses from European Society of Human Reproduction and Embryology regarding Executive Committee work (Amsterdam‐Brussels) until july 2019. She works at both locations of the Department of Reproductive Medicine of the Amsterdam UMC (Location AMC and location VUMC). Location VUMC has received several research and educational grants from Guerbet, Merck and Ferring, outside the scope of the submitted work.

Saskia Middeldorp has received a Netherlands Organisation for Scientific Research (NWO) personal Innovation VIDI grant (paid to her institution) on Thrombophilia and Reproduction from the Netherlands Organisation for Scientific Research (NWO). She has carried out paid consultancy (paid to her institution, and not in relation to this review) for Daiichi Sankyo (as a member of the Writing Committee of the Hokusai VTE study (published in 2013)); Daiichi Sankyo, Bayer, and Janssen (local investigator for various treatment and prophylaxis studies in VTE patients). She has received payment (to her institution) for lectures on VTE treatment from Bayer, BMS/Pfizer, Boehringer Ingelheim, Daiichi Sankyo, Sanofi, and for developing educational presentations for Bayer, Aspen, Daiichi Sankyo, BMS/Pfizer). Saskia also has grants/grants for investigator‐initiated studies from Aspen, Daiichi Sankyo and Bayer, all paid to her institution.