title: Lessons From the EThIGII Trial: Proper Putative Benefit Assessment of Low-Molecular-Weight Heparin Treatment in M2/ANXA5 Haplotype Carriers.
abstract: This study presents sample size considerations derived from the Efficacy of Thromboprophylaxis as an Intervention during Gravidity (EThIGII) trial (ClinicalTrials.gov: NCT00400387) to address the question of low-molecular-weight heparin (LMWH) treatment in women with recurrent pregnancy loss (RPL) depending on the M2/ANXA5 haplotype. To evaluate the possible influence of such treatment on miscarriage rates of trial participants, a post hoc analysis of ANXA5 promoter genotypes in the light of M2/ANXA5 (RPRGL3) distribution was performed using logistic models. DNA for genotyping was available from 129 LMWH and 95 control patients, 44 (19.6%) of whom were M2/ANXA5 carriers. Miscarriages occurred in 1 (4.0%) of 25 M2/ANXA5 carriers from the LMWH group compared to 4 (21.1%) of 19 in the control group, resulting in an odds ratio (95% confidence interval) for miscarriage of 0.16 (0.016-1.5) for women treated with LMWH. In noncarriers, miscarriage rates were 6 (5.8%) of 104 versus 7 (9.2%) of 76 for the LMWH and the control groups, respectively, corresponding to an odds ratio for miscarriage of 0.60 (0.19-1.9). The apparent beneficial effects of miscarriage rate reduction in M2/ANXA5 carriers with RPL concur with biological considerations about improvement in reduced ANXA5 function through LMWH treatment in an adequate murine model. The data obtained were instrumental to design proper assessment of the existence and magnitude of this effect.
authors.affiliation: Division of Gynecological Endocrinology and Reproductive Medicine, Department of Gynecology and Obstetrics, Klinikum der Ludwig-Maximilians-Universität, Munich, Germany.
authors.forename: Nina
authors.initials: N
authors.lastname: Rogenhofer
authors.affiliation: Insititute of Human Genetics, UKM and WWU Muenster, Muenster, Germany markoff@uni-muenster.de.
authors.forename: Arseni
authors.initials: A
authors.lastname: Markoff
authors.affiliation: Center for Human Genetics and Laboratory Diagnostics, Dr Klein, Dr Rost and Colleagues, Martinsried, Germany.
authors.forename: Annett
authors.initials: A
authors.lastname: Wagner
authors.affiliation: Center for Human Genetics and Laboratory Diagnostics, Dr Klein, Dr Rost and Colleagues, Martinsried, Germany.
authors.forename: Hanns-Georg
authors.initials: HG
authors.lastname: Klein
authors.affiliation: Clinical Trial Centre, University of Leipzig, Leipzig, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Petroff
authors.forename: Ekkehard
authors.initials: E
authors.lastname: Schleussner
authors.affiliation: Division of Gynecological Endocrinology and Reproductive Medicine, Department of Gynecology and Obstetrics, Klinikum der Ludwig-Maximilians-Universität, Munich, Germany.
authors.forename: Christian J
authors.initials: CJ
authors.lastname: Thaler
mesh_terms: D000026:Abortion, Habitual / Q000628:therapy*; D005260:Female; D005838:Genotype; D006239:Haplotypes; D006495:Heparin, Low-Molecular-Weight / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D012307:Risk Factors
chemical_list: D006495:Heparin, Low-Molecular-Weight
keywords: 
  	  M2/ANXA5
  	; annexin A5; low-molecular-weight heparin (LWMH); miscarriage; recurrent pregnancy loss (RPL)