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

• Published in: EBioMedicine Vol. 10; no. C; pp. 298 - 304
• Main Authors: Fishel, Simon, Baker, Deborah, Elson, Janine, Ragunath, Maha, Atkinson, Glenn, Shaker, Adel, Omar, Ahmed, Kazem, Rahnuma, Beccles, Ashley, Greer, Ian A.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01-08-2016; Elsevier
• Subjects: Adult; Annexin A5 - genetics; ANXA5 M2; Biomarkers; Cohort Studies; Female; Fertilization in Vitro; Fibrinolytic Agents - therapeutic use; Haplotypes; Heparin, Low-Molecular-Weight - therapeutic use; Humans; IVF; Live birth; LMWH; Male; PMPC; Precision Medicine - methods; Pregnancy; Pregnancy Outcome; Reproductive Techniques, Assisted; Research Paper; Retrospective Studies; IVF; LMWH; Live birth; PMPC; ANXA5 M2
• ISSN: 2352-3964; 2352-3964
• DOI: 10.1016/j.ebiom.2016.06.024

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.
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.
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).
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.
•The ANXA5 M2 haplotype is associated with early recurrent pregnancy loss and PMPC and is common in IVF populations.•Screening couples and treating with LMWH after IVF achieved a similar live birth outcome to younger more fertile couples.•Outcome results indicate benefit of screening and treatment with LMWH, supporting further studies on the role of M2 in PMPC.
Pregnancy failure, miscarriage and placental complications affect over 25% of pregnancies. No biomarker exists for treatment with anticoagulants. A novel marker for risk of these has been identified with a reduction in the naturally occurring placental anticoagulant required for normal development of the placenta and pregnancy. It is transmitted equally by the male and female to the embryo. This IVF study of infertile couples has shown that by testing them and treating the female of positive couples with anticoagulant from time of embryo transfer the live birth outcome was similar to that of younger less infertile couples.