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

BackgroundPregnancy 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.MethodsCouples (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.FindingsThe 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).InterpretationPragmatic 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.

Live births after embryo selection using morphokinetics versus conventional morphology: a retrospective analysis

“…The advantage of the EmbryoScope morphokinetic data was evident too for recipients aged over 37 years, demonstrating that the transfer of a single blastocyst had the same chance of a live birth as two transferred after standard treatment without the risk of multiple pregnancy. Finally, it must always be recognized that such analyses cannot account for all factors affecting successful pregnancy outcome, particularly in the IVF population cohort; normal placental function (Fishel et al, 2016) and endometrial receptivity (Miravet-Valenciano et al, 2015;Nejat et al, 2014)…”

“…Pituitary suppression for ovarian stimulation was carried out either with gonadotrophin-releasing hormone agonist (Suprecur; 0.5 ml subcutaneously daily; Sanofi Aventis, UK) or antagonist (Cetrotide; 0.25 mg daily; Merck Serono, UK). Ovarian stimulation was achieved using human menopausal gonadotrophin (Menopur, Ferring, UK), recombinant FSH (Gonal-F; Merck Serono), or both (as previously described (Campbell et al, 2013b;Fishel et al, 2016). (continued on next page)…”

Assessment of M2/ANXA5 haplotype as a risk factor in couples with placenta-mediated pregnancy complications

“…In other words, maternal M2 carrier status might modulate the clinical presentation of the thrombophilia predisposition in pregnancy. The recently reported assisted conception trial with low-molecularweight heparin (LMWH) in M2 carrying couples may lend support to such notion [38]. According to their results, LMWH-treated couples in which only the male was an M2 carrier benefited significantly more regarding live births than those with only female M2 carriers.…”

Genetic analysis of the M2/ANXA5 haplotype as recurrent pregnancy loss predisposition in the Malay population

“…Male and female M2 carriers are subject to similar RPL predisposition with the highest exposure for early pregnancies, less than 15 weeks of gestation. Considering the relatively high pregnancy loss rates of Malay women and the estimated high general prevalence of the M2 haplotype, couples who have experienced primary and secondary RPL might be screened for M2 carrier status as a biomarker of possible successful anticoagulant treatment, as suggested by recent genetic evidence from the EThIGII and the CARE Fertility Group clinical trials [35,36]. Related to this, Malay RPL couples appear as a very suitable population model for a properly powered therapeutic randomized clinical trial.…”