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 N 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. Findings: 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). Interpretation: 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.

Association between M2/ANXA5 haplotype and repeated pregnancy loss: a meta-analysis

“…Nonetheless, we emphasize the need to screen for the M2/ANXA5 haplotype as a genetic predisposition factor for RPL in both genders. Although the effectiveness of low-molecular-weight heparin (LMWH) in RPL is still disputed (46,47), recently LMWH has been proposed as a precision anticoagulant intervention for RPL in M2/ANXA5 haplotype women (22,32,48). However, the magnitude of the LMWH effect is uncertain and is beyond the scope of this meta-analysis.…”

“…The remaining 23 studies were fully reviewed. Ten of them were excluded due to [1] improper outcome-(e.g., small for gestational age, venous thrombosis, IVF), seven studies (21)(22)(23)(24)(25)(26)(27); [2] incoherent case groups (recruitment of RPL with PCOS), one study (28); [3] insufficient data, one study (7); and [4] pilot studies, one study (29). Thirteen studies were included in the initial search.…”

A novel test for annexin A5 M2 haplotyping in in vitro fertilization patients and preimplantation embryos

“…With the use of M2 haplotype PGT, success rates of both treatment options can be compared. Carrier couples who underwent LMWH therapy may have improved pregnancy outcomes (13). However, there are currently no data involving the characterization of embryo carrier status in pregnancies of carrier couples.…”

“…In 44% of couples undergoing assisted reproductive technologies, one or both partners have been shown to carry the M2 haplotype (5). An intervention study using low molecular weight heparin (LMWH) has been conducted to counter the effects of the M2 haplotype, thus increasing the success rates from 16% to 42% (13). However, further evaluation is needed to determine the significant impact of LMWH treatment.…”

Big Data and Artificial Intelligence (AI) are Poised to Transform Infertility Healthcare

“…For example, variants in the STK11 gene were associated with a decreased chance of ovulation in PCOS women treated with metformin 57 . Other examples include the identification of M2 carrier pregnancies by screening both partners for the M2 haplotype, which can be used to stratify couples for treatment with low-molecular-weight heparin (LMWH) 58 .…”