title: Precision Medicine in Assisted Conception: A Multicenter Observational Treatment Cohort Study of the Annexin A5 M2 Haplotype as a Biomarker for Antithrombotic Treatment to Improve Pregnancy Outcome.
abstract: BACKGROUND
  Pregnancy failure and placenta mediated pregnancy complications affect >25% of pregnancies. Although there is biological plausibility for a procoagulant mechanism underlying some of these events, antithrombotic intervention trials demonstrate limited benefit, possibly through lack of stratification in heterogeneous patient groups. The ANXA5 M2 haplotype is a possible procoagulant biomarker and was tested pragmatically to determine whether this screening and LMWH treatment normalized the outcome for ANXA5 M2 positive couples. This was a pragmatic study that aimed to measure the effectiveness of a testing (for the M2 haplotype) and treatment (LMWH) pathway in routine clinical practice where there is variation between patients. Such a study in couples with fertility problems can inform choices between treatments; it is then the management protocol which is the subject of the investigation, not the individual treatments.
  
  
  METHODS
  Couples (N=77) with one or both partners ANXA5 M2 positive demonstrated association of this haplotype with adverse IVF outcome. A pragmatic, multicenter, prospective cohort study of ANXA5 M2 haplotype screening, and LWMH treatment following embryo transfer (ET) in 103 IVF couples positive for ANXA5 M2 was performed. They were compared with a group of 1000 contemporaneous randomly selected unscreened and untreated couples undergoing assisted conception, from which 103 matched control couples were derived. The primary outcome measure was live birth incidence. Secondary outcomes were results following embryo transfer (ET) and live birth outcome by gender and M2 carriage, and allelic dose influence.
  
  
  RESULTS
  The tested and treated cohort of ANXA5 M2 carriers achieved a similar live birth rate (37.9%) per ET cycle compared to both the more fertile comparison group (38.5%), and to the 103 matched controls (33.0%). Significantly more treated male carrier only couples had a live birth versus female M2 only (47.7% vs. 25.0% p=0.045).
  
  
  CONCLUSIONS
  Pragmatic ANXA5 M5 screening and treatment with LMWH in couples undergoing IVF is associated with similar outcome to couples with more favorable prognostic factors. The difference in live birth outcome for treated male only carrier couples may be consistent with an additional maternal thrombophilic factor that may adversely affect pregnancy, although other mechanisms are possible. This study suggests that LMWH treatment should be started prior to clinical pregnancy.
authors.affiliation: CARE Fertility Group, John Webster House, 6 Lawrence Drive, Nottingham NG8 6PZ, UK.
authors.forename: Simon
authors.initials: S
authors.lastname: Fishel
authors.affiliation: IHG Pharmaco Ltd, 20-22 Wenlock Road, London N1 7GU, UK. Electronic address: d.baker@ihgpharmaco.com.
authors.forename: Deborah
authors.initials: D
authors.lastname: Baker
authors.affiliation: CARE Fertility Group, John Webster House, 6 Lawrence Drive, Nottingham NG8 6PZ, UK.
authors.forename: Janine
authors.initials: J
authors.lastname: Elson
authors.affiliation: CARE Nottingham, John Webster House, 6 Lawrence Drive, Nottingham NG8 6PZ, UK.
authors.forename: Maha
authors.initials: M
authors.lastname: Ragunath
authors.affiliation: CARE Manchester, 108-112 Daisy Bank Road, Victoria Park, Manchester M14 5QH, UK.
authors.forename: Glenn
authors.initials: G
authors.lastname: Atkinson
authors.affiliation: CARE Sheffield, 24-26 Glen Road, Sheffield S7 1RA, UK.
authors.forename: Adel
authors.initials: A
authors.lastname: Shaker
authors.affiliation: Beacon CARE Fertility, Beacon Court, Bracken Road, Sandyford, Dublin 18, Ireland.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Omar
authors.affiliation: CARE Northampton, Cliftonville, The Avenue, Northampton NN1 5BT, UK.
authors.forename: Rahnuma
authors.initials: R
authors.lastname: Kazem
authors.affiliation: CARE Fertility Group, John Webster House, 6 Lawrence Drive, Nottingham NG8 6PZ, UK.
authors.forename: Ashley
authors.initials: A
authors.lastname: Beccles
authors.affiliation: Faculty of Medical & Human, Sciences, Core Technology, Facility, 46 Grafton, Street, The University of Manchester, Manchester M13 9NT, UK.
authors.forename: Ian A
authors.initials: IA
authors.lastname: Greer
mesh_terms: D000328:Adult; D017304:Annexin A5 / Q000235:genetics; D015415:Biomarkers; D015331:Cohort Studies; D005260:Female; D005307:Fertilization in Vitro; D005343:Fibrinolytic Agents / Q000627:therapeutic use; D006239:Haplotypes; D006495:Heparin, Low-Molecular-Weight / Q000627:therapeutic use; D006801:Humans; D008297:Male; D057285:Precision Medicine / Q000379:methods; D011247:Pregnancy; D011256:Pregnancy Outcome; D027724:Reproductive Techniques, Assisted; D012189:Retrospective Studies
chemical_list: D017304:Annexin A5; D015415:Biomarkers; D005343:Fibrinolytic Agents; D006495:Heparin, Low-Molecular-Weight
keywords: ANXA5 M2; IVF; LMWH; Live birth; PMPC