Enoxaparin for Prevention of Unexplained Recurrent Miscarriage: A Multicenter Randomized Double-Blind Placebo-Controlled Trial

Kingsley Onokalah, PharmD candidate 2015, Mercer University College of Pharmacy

Recurrent miscarriage is defined as three pregnancy losses before twenty weeks gestation.1  It occurs in 10% to 15% of pregnancies and recurs in 5% of subsequent pregnancies.  Pasquier et al state that many experts extend the definition of recurrent miscarriage to two pregnancy losses since the recurrence rate is similar to that of three losses.2

Recurrent miscarriage may be attributed to numerous factors, including antiphospholipid syndrome, thrombophilias, hormonal or metabolic disorders, infection, genetics, and age.1  Per the Practice Committee of the American Society for Reproductive Medicine, most miscarriages occur intermittently and are thought to result from genetic causes that are mostly influenced by maternal age.3

According to a review of nine studies conducted by de Jong et al examining the use of anticoagulants in women with recurrent miscarriages with or without inherited thrombophilia, evidence does not support the use of anticoagulants with idiopathic recurrent pregnancies.4

Title: Enoxaparin for Prevention of Unexplained Recurrent Miscarriage: A Multicenter Randomized Double-Blind Placebo-Controlled Trial
Design Randomized, double-blind, placebo-controlled, multicenter trial; N= 258
Objective To investigate whether enoxaparin would improve the live-birth rate among non-thrombophilic women
Study Groups Enoxaparin (n= 138)

Placebo (n= 120)

Methods Eligible women were randomly assigned to receive enoxaparin 40 mg daily or placebo (saline solution). Treatment was administered subcutaneously daily, starting from the inclusion visit and continued by self-infection until 35 weeks’ gestation. Compliance was monitored at each visit by reviewing a “treatment adherence notebook” (daily time and injection site recorded by study participant). Folic acid supplementation was advised for all women.
Duration April 4, 2007 to October 31, 2012
Primary Outcome Measure Rate of live and viable births
Baseline Characteristics Enoxaparin: age 32.7 + 5.2, body mass index 23.9 + 4.4, >3 miscarriages (72.5%), daily smoking > 1 cigarette (15.9%)

Placebo: age 32.1 + 5.4, body mass index 23.9 + 5, >3 miscarriages (72.9%), daily smoking > 1 cigarette (22%)

Results Live-birth rate in intention-to-treat analysis (p= 0.34):

Enoxaparin: n= 92 (66.6%)

Placebo: n= 86 (72.9%)

Adverse Events Common Adverse Events:

Enoxaparin: bruising (7.9%), nosebleed (7.2%), bleeding gums (2.2%), minor vaginal bleeding (6.5%)

Serious Adverse Events:

Enoxaparin: congenital abnormality (5%), major bleeding (1.4%), severe skin reaction at injection site (0.7%), thrombocytopenia (2.9%)

Percentage that Discontinued due to Adverse Events: Not reported
Study Author Conclusions In this first reported randomized, double-blind, placebo-controlled trial, enoxaparin given at the daily dose of 40 mg did not improve the chance of a live birth in non-thrombophilic women with a history of unexplained recurrent miscarriage. Prophylactic doses of LMWH do not improve the chance of a live birth in non-thrombophilic women with unexplained recurrent miscarriage and should consequently no longer be routinely prescribed in this clinical setting.

This study does not support the use of enoxaparin alone to prevent unexplained recurrent miscarriage in pregnant women.  Future studies could investigate the possible role of enoxaparin in women with known inherited thrombophilias, as these are known to contribute to recurrent miscarriages as well.

References:

  1. Shahine L, Lathi R. Reccurent Pregnancy Loss: Evaluation and Treatment. Obstet Gynecol Clin North Am. March 2015;42(1):117-34. doi: 10.1016/j.ogc.2014.10.002.
  2. Pasquier E, de Saint Martin L, Buhec C, et al. Enoxaparin for prevention of unexplained recurrent miscarriage: a multicenter randomized double-blind placebo-controlled trial. Blood. April 2, 2015. 2015;125(14):2200-2205.
  3. Practice Committee of the American Society for Reproductive Medicine. Evaluation and treatment of recurrent pregnancy loss: a committee opinion. Fertil Steril. 2012 Nov;98(5):1103-11. doi: 10.1016/j.fertnstert.2012.06.048.
  4. De Jong PG, Kaandorp S, Di Nisio M, et al. Aspirin and/or heparin for women with unexplained recurrent miscarriage with or without inherited thrombophilia. Cochrane Database Syst Rev. 2014 Jul 4;7:CD004734. doi: 10.1002/14651858.CD004734.pub4.
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