Low Molecular Weight Heparin in Recurrent Miscarriage With Negative Antiphospholipid Antibodies
Condition: Recurrent Miscarriage
MeSH terms: Abortion, Spontaneous; Abortion, Habitual; Recurrence
Study type: Interventional
Phase: Phase 4

Summary: 
      Recurrent miscarriage (RM) is traditionally defined as three or more consecutive miscarriages
      occurring before 20 weeks post-menstruation. It is one of the most common clinical problems
      in reproduction, yet a definite cause can be established in only 50 percent of cases (ACOG
      practice bulletin, 2002). Many etiological factors have been proposed but none of them has
      been fully substantiated. RM has been directly associated with maternal thrombophilic
      disorders, parental chromosomal anomalies, and structural uterine anomalies and indirectly
      with maternal immune dysfunction and endocrine abnormalities.

      The association between pregnancy loss and antiphospholipid antibodies (aPL) was first
      noticed in the latter third of the last century. The antiphospholipid syndrome (APS) is
      characterized by the presence of antiphospholipid antibodies (APLA), associated with venous
      and/or arterial thrombosis, and/or pregnancy loss. The adverse pregnancy outcomes associated
      with the presence of APLAs include: recurrent fetal loss, intrauterine growth restriction
      (IUGR), and severe pre-eclampsia especially of early onset.

      Testing the effect of Heparin in treatment of cases with RA but negative for APA has bee done
      in few animal and clinical studies. Animal studies showed that the subset of cases with
      disorders suspicious for APS but who had negative test results for LAC and aCL is carrying
      antibodies pathogenic to murine pregnancy. Testing other immunoglobulin G may provide
      additional means to identify cases with an yet uncharacterized immune condition. Moreover,
      the clinical relevance of low levels of APLA in these women remains unproved.

      Randomized prospective study was done to assess the efficacy of early thromboprophylaxis of
      Low molecular weight heparin (LMWH) (Enoxaparin sodium 20 mg, once daily subcutaneously) in
      women with a history of recurrent miscarriages without identifiable causes versus no
      treatment. The results showed that, there is a significant reduction in the incidence of both
      early and late miscarriages (8.8% vs 4.1%) (2.3% versus 1.1%) with or without treatment,
      respectively.

      Cochrane Database systemic review (2005) shows randomized comparative studies for treating
      recurrent miscarriage in women without antiphospholipid syndrome. The first group treated by
      low dose aspirin alone and the second group treated by low dose aspirin + LMWH. The result of
      these studies shows that no significant differences between the two groups and identify the
      need of large randomized controlled trial to solve this problem.

      The above evidence suggests the probability of presence of untested LAC and aCL or very low
      levels of APLA by commonly used methods in women with recurrent miscarriage. These antibodies
      may explain recurrent miscarriage in cases with negative antiphospholipid antibodies. It
      remains to test the efficacy of heparin (proven effective treatment in those with positive
      antibodies) in the patients with negative antibodies. Finding a solution to this frustrating
      problem may open the way for an unsolved problem.

      The proposed study is an open labeled randomized controlled trial (RCT) To evaluate the
      effect of LMWH versus no heparin in treatment of recurrent miscarriage that is negative for
      antiphospholipid antibodies testing.
    


Intervention name(s): LMWH+Folic acid; Folic Acid
Intervention type(s): Drug; Drug
Intervention description(s): Patients will receive a fixed dose of 40 mg of enoxaparin subcutaneous daily. Treatment will start once positive pregnancy test and will be continued until abortion or delivery (if premature), or 37 weeks of pregnancy. Additionally, 500 micrograms Folic acid tablet once daily will be started once positive pregnancy test and continues until 13 weeks' of gestation.; Folic acid 500 micrograms daily once positive pregnancy test until the 13th week of pregnancy or abortion
Other intervention name(s): (Clexane, Sanofi Aventis, Paris, France)
Intervention MeSH terms: Folic Acid; Vitamin B Complex
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: LMWH; enoxaparin; recurrent miscarriage; continuing fetal viability beyond 20 weeks gestation