Maternal and paternal carriage of the annexin A5 M2 haplotype: a possible risk factor for recurrent implantation failure (RIF)

OBJECTIVE This study was carried out to determine the potential role of the M2/ANXA5 haplotype as a risk factor for recurrent implantation failure (RIF). Carriage of the M2/ANXA5 haplotype that induces prothrombotic changes has been implicated in failure of early pregnancies and placenta-mediated complications (preeclampsia, IUGR, preterm birth). MATERIAL AND METHODS In the present case control study, 63 couples (females and males) with RIF presenting for IVF/ICSI to the Fertility Center of masked were analyzed. RIF was defined as ≥ 4 consecutive failed ART-transfers of ≥ 4 blastocysts or ≥ 8 cleavage-stage embryos of optimal quality and maternal age ≤ 41. Fertile female controls (n = 90) were recruited from the same center. Population controls (n = 533) were drafted from the PopGen biobank, UKSH Kiel. RESULTS Couples carrying the M2/ANXA5 haplotype turned out to have a significantly increased relative risk (RR) for RIF. Compared with female fertile controls, RR was 1.81 with p = 0.037 (OR 2.1, 95{\%}CI 1.0-4.3) and RR was 1.70, with p = 0.004 (OR 2.0, 95{\%}CI 1.2-3.1) compared with population controls (15.4{\%} M2 carriers). Male partners were comparable with RIF females for M2/ANXA5 haplotypes (28.6{\%} vs. 23.8{\%}, p = 0.54). RIF females compared with population controls had a RR of 1.55 (p = 0.09) and RIF males compared with population controls had a RR of 1.9 (p = 0.01). Couples with ≥ 7 failed transfers showed a RR of 1.82 (p = 0.02) compared with population controls. CONCLUSION Our findings suggest that maternal as well as paternal M2/ANXA5 haplotype carriages are risk factors for RIF. These results allow new insights into the pathogenesis of RIF and might help to identify relevant risk groups