Title: HYPATIA: A prospective randomised controlled trial of HYdroxychloroquine versus placebo during Pregnancy in women with AnTIphospholipid Antibodies
Funder: Department of Health and Social Care

Abstract: Background: Antiphospholipid syndrome (APS) is the association of persistent antiphospholipid antibodies (aPL) with arterial & venous thromboses and/or obstetric morbidity (Miyakis 2006). The obstetric morbidity includes recurrent first trimester pregnancy loss, and conditions associated with ischaemic placental dysfunction including stillbirth, intrauterine death, pre-eclampsia (PET), eclampsia, premature birth and fetal growth restriction (FGR). APS is often associated with systemic lupus erythematosus (SLE). Current treatment regimes to prevent obstetric morbidity include low-dose aspirin and low molecular weight heparin and have improved pregnancy outcome, but reduction in pregnancy loss remains sub-optimal (Bramham 2010). Our recent retrospective single centre study in women with aPL who were also taking hydroxychloroquine (HCQ) to treat SLE during pregnancy, suggested that HCQ had an antithrombotic effect and improved pregnancy outcome (Sciascia et al. submitted). Our results showed that HCQ treatment was associated with a higher rate of live births (67% in group A (HCQ treated) vs. 57% in group B, p=0.05) and a lower rate of pregnancy morbidity (47% in group A vs. 63% in group B, p=0.004). Pregnancy duration was longer in group A than B (27.6 weeks [6-40] vs. 21.5 [6-40], p=0.03). Fetal losses >10th week of gestation were less frequent in group A than B (2% vs. 11%, p=0.05). Ischemic placental mediated complications (pre-eclampsia, eclampsia and fetal growth restriction (FGR) were less prevalent in HCQ treated women than controls (2% vs 11%, p=0.05). The association of HCQ with the absence of any aPL-related complication in pregnancy was confirmed after multivariate analysis (OR 2.2; 95% CI 1.2-136.1; p=0.04). However this study was not ideal, because it was retrospective and the worse obstetric histories were present in group B. Therefore we propose the first RCT of HCQ versus placebo in pregnant women with aPL (this term encompasses isolated aPL and those with APS) . Objective: To undertake a randomise controlled trial (RCT) of HCQ 200mg once daily versus placebo in addition to usual medication in patients with aPL with the aim to assess pregnancy outcome. Methods and design: We propose a RCT of HCQ versus placebo in addition to usual medication in pregnant women with aPL. 328 pregnant with aPL women will be included. Eligible women will be recruited from participating centres across the UK & Europe if they are actively planning pregnancy and have peristent aPL according to international criteria. The power study is based on detecting a 16% improvement in pregnancy outcome of women with aPL Outcomes: The primary endpoint include all aPL-related adverse pregnancy outcomes. These include otherwise unexplained miscarriage (this includes miscarriage 10 weeks gestation), premature birth Summary: Pregnancies in women with aPL are 'high risk'. Current treatment regimes have improved pregnancy outcome to a live birth rate of > 70%, but this means 30% of women continue to have problems in pregnancy. Our recent retrospective study showed that HCQ improved pregnancy outcomes in women SLE and aPL. This proposed RCT will address the utility of HCQ in improving pregnancy outcome in women with aPL. This RCT will answer a necessary question as to the utility of HCQ in improving pregnancy outcome in women with aPL. If the results improve outcome then women with aPL within the NHS and centres worldwide may benefit.

Lay abstract: Antiphospholipid syndrome (APS) is the combination of persisting antiphospholipid antibodies (aPL) and a previous thrombosis and/or pregnancy problems. Antibodies are part of the immune system, and can sometimes be directed against part of our own cells, this is known as autoimmune disease, and APS is such a problem. aPL occur in about 1% of the population; so extrapolating this to a birth-rate of 800,000/year in the UK, this means 8,000 women with aPL are giving birth every year. Women with aPL (this term includes those with APS) are more likely to have pregnancy loss. During the first 12 weeks of pregnancy, aPL can inhibit the growth of the early fetal cells and later cause blood clots in the blood vessels of the placenta in the second and third trimester (14-36 weeks). This means that the placenta is unable to supply the fetus with enough nutrition, so the fetus may stop growing, grow slowly (intrauterine growth restriction) and in extreme cases may die. Some mothers in this situation also develop pre-eclampsia. Pregnant women with aPL are treated with aspirin, and sometimes heparin, depending on whether they had blood clots and/or obstetric problems before. This has improved the live-birth rate to >70%. We did a retrospective study of women with aPL who were taking hydroxychloroquine (HCQ), during pregnancy to treat their lupus, and found those taking HCQ had a better pregnancy outcome compared to women who do not take it, with fewer miscarriages & preterm births and a higher live birth rate. HCQ is safe in pregnancy, well-tolerated, and costs only &pound;0.10/tablet in the UK. To find out more about this observation, we are proposing the first randomised controlled trial , treating consenting women with aPL either with HCQ or placebo throughout pregnancy in addition to usual medications, and comparing the pregnancy outcomes.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH;INFLAMMATORY AND IMMUNE SYSTEM