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Background

In all clinically recognised pregnancies, a single spontaneous miscarriage occurs in 14-19% of patients, and 1-5% of women experience two or more miscarriages (recurrent miscarriage, RM). In over 50% of cases of miscarriage the cause remains unexplained. Many studies have confirmed a relationship between inherited thrombophilia and miscarriage and other pregnancy complications. The role of thrombophilia in RM can be explained partially by the concept of thrombosis of the (microvasculature of the) placenta, and partially because of inhibition of extravillous trophoblast differentiation. Therefore, anticoagulants are considered a possible therapy for women with RM and inherited thrombophilia.

Hypothesis

In the previous ALIFE study, treatment with LMWH was administered in combination with aspirin and compared to aspirin alone and to no-treatment (placebo for aspirin) in women with recurrent miscarriage of unknown cause.8 The effect of aspirin in women with RM with or without inherited thrombophilia is unclear. In the current ALIFE2 study we are choosing to use LMWH as the intervention, without aspirin as additional intervention, to exclude a possible confounding effect of aspirin.

Trial summary

ALIFE 2 is a multi-centre randomised trial to compare LMWH with standard pregnancy surveillance in women with inherited thrombophilia and a history of recurrent miscarriage.

Women with a history of RM (2 or more not necessarily consecutive miscarriages or intra-uterine foetal deaths), confirmed inherited thrombophilia and who are attempting to conceive or are less than 7 weeks pregnant (based on first day of last menstruation) will be registered onto the study. As soon as a urine pregnancy test is positive (and confirmed in hospital), they will be randomised.

Participants in group 1 will inject LMWH once daily, starting immediately after randomisation. LMWH will be discontinued at the beginning of labour (to avoid peripartum haemorrhage) or end of pregnancy.

Participants in group 2 will receive no intervention in addition to standard pregnancy surveillance.

For the purposes of the ALIFE2 trial recurrent miscarriage will be defined as 2 or more consecutive or non-consecutive miscarriages

Inclusion criteria (at Registration)

  • Provision of written informed consent
  • Women with recurrent miscarriage and/or intra-uterine foetal deaths (i.e. ≥ 2 consecutive or non-consecutive miscarriages or intra-uterine foetal deaths, irrespective of gestational age)
  • Inherited thrombophilia; confirmed by factor V Leiden mutation, prothrombin gene mutation (G20210A), protein S deficiency, protein C deficiency or antithrombin deficiency or a combination hereof. (Protein S, protein C and antithrombin deficiencies need to be confirmed by two tests, performed on two separate occasions and not during anticoagulant therapy. Protein S tests should not be performed during pregnancy or in the 6-week post-partum period since spuriously low levels may then be observed).
  • Age 18 - 42 years*

*participants that are registered at age 42 must also be aged 42 at the time pregnancy is confirmed and they are randomised onto the trial. Registered participants that turn 43 prior to becoming pregnant should be informed they will not be eligible to be randomised on to the ALIFE2 trial.

Inclusion Criteria (at randomisation)

  • Pregnancy confirmed by urine pregnancy test in hospital (<7 weeks gestation – based on first day of last menstruation or confirmed via ultrasound scan).
  • Age 18 - 42 years

Exclusion criteria (for registration)

  • Duration of current pregnancy ≥ 7 weeks, based on first day of last menstruation or confirmed via ultrasound scan.
  • Weight = <50kg
  • 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, osteoporosis, hyperaldosteronism)
  • Known allergy to at least 3 different LMWH preparations
  • Previous inclusion in the ALIFE2 study (for another pregnancy)
  • Participation in a clinical trial of an investigational medicinal product in the last 90 days.

Primary objective

To evaluate the efficacy of LMWH in women with inherited thrombophilia and RM and/or intra-uterine foetal death (≥ 2).

Primary efficacy outcome

Live birth (defined as birth of a living child)

Secondary objectives

Efficacy:

To evaluate other possible effects of LMWH on adverse pregnancy outcome other than miscarriage (e.g. preeclampsia, intra-uterine growth restriction, HELLP syndrome, placental abruption, premature delivery, congenital malformations)

Safety:

To evaluate the safety of LMWH in women with RM with inherited thrombophilia by registering complications such as bleeding, thrombocytopenia and (allergic) skin reactions.

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Enquiries:

Tel: 02476 150589
Email: alife2@warwick.ac.uk