ALIFE2 Study Call for participation Paulien de Jong Dr. Mariëtte Goddijn Prof. dr. Saskia Middeldorp

Disclosures Paulien de Jong Research contracts: - Consulting: Employment in industry: Stockholder of a healthcare company: Owner of a healthcare company: Other:

Rationale for the study Inherited thrombophilia is associated with pregnancy loss1,2 recurrent early loss: OR 1.9 – 2.72 Thrombosis of (micro-)vasculature of placenta Inhibition of throphoblast differentiation and subsequent placentation3 Possible therapy for pregnancy loss: anticoagulants ? 1. Rey, Lancet, 2003 2. Robertson, Br. J. of Haematology 2006 3. Quenby, Fertility and Sterility, 2005

ALIFE study 364 women Randomized 123 aspirin and nadroparin 121 placebo Live birth: 69% Live birth: 62% Live birth: 67% RR 1.03 RR 0.92 Reference RR 1.31 RR 1.22 Reference Inherited thrombophilia Kaandorp NEJM 2010

ALIFE2 study Objective: to evaluate the efficacy of LMWH in women with recurrent miscarriage and inherited thrombophilia Primary outcome: live birth Secondary outcomes: adverse pregnancy outcomes & safety Design: Multicenter, investigator-initiated study Open label

In-/exclusion criteria Inclusion criteria: ≥2 miscarriages and / or IUFDs Age 18-42 Confirmed inherited thrombophilia: Factor V Leiden mutation, prothrombin gene mutation, protein C deficiency, protein S deficiency, antithrombin deficiency Exclusion criteria: Pregnancy duration ≥ 7 weeks Indication for anticoagulant treatment during pregnancy (for instance prosthetic heart valves, a history of venous thromboembolism or antiphospholipid syndrome) Contraindications to LMWH (previous heparin induced thrombocytopenia, active bleeds or renal insufficiency with creatinine clearance of less than 30ml/min) Known allergy to at least 3 different LMWH preparations Previous inclusion in the ALIFE2 study (for another pregnancy)

In-/exclusion criteria Inclusion criteria: ≥2 miscarriages and / or IUFDs Age 18-42 Confirmed inherited thrombophilia: Factor V Leiden mutation, prothrombin gene mutation, protein C deficiency, protein S deficiency, antithrombin deficiency Exclusion criteria: Pregancy duration ≥7 weeks Indication for anticoagulant treatment during pregnancy (for instance prosthetic heart valves, a history of venous thromboembolism or antiphospholipid syndrome) Contraindications to LMWH (previous heparin induced thrombocytopenia, active bleeds or renal insufficiency with creatinine clearance of less than 30ml/min) Known allergy to at least 3 different LMWH preparations Previous inclusion in the ALIFE2 study (for another pregnancy)

® Primary efficacy outcome: Live birth M M Confirmed Inherited thrombophilia LMWH + standard pregnancy surveillance ® Recruitment delivery Follow-up M M Positive urine pregnancy test ≥ 2 miscarriages and/or IUFDs Standard pregnancy surveillance 6 weeks

Participating centers - AMC - Amphia - UMCG - Jeroen Bosch Ziekenhuis - VUMC - Isala Klinieken - MUMC - OLVG - UMCN - Maxima MC - UMCU Foreign centers: Brussels USA/UK/Canada/Australia…..

Inclusions n=399 Sample size Inclusions n=15

We are looking for you! Think of ALIFE2 in case of Recurrent miscarriage and/or IUFD Women with inherited thrombophilia Refer study candidates Contact us for questions regarding eligibility

www.ALIFE2study.org p.g.dejong@amc.uva.nl s.middeldorp@amc.uva.nl