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

Abstract

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.

Association between ANXA5 haplotypes and the risk of recurrent pregnancy loss

“…Luciferase reporter assays have shown that HeLa and BeWo cells have a lower expression level of c.-467G>A SNP than that of the M1 allele. Reduced ANXA5 mRNA expression has been detected in patients carrying the M2 haplotype 14 and this change is specific for haplotypes. 5 , 9 Additionally, reduced ANXA5 protein levels have been detected in patients with pre-eclampsia carrying the M2 allele.…”

Paternal thrombophilia and recurrent implantation failure: an exploratory case-control study

“…Successful implantation requires the coordination between a healthy embryo and a functionally competent and receptive endometrium. Failure of implantation due to embryonic causes is associated with either genetic abnormalities or inherited thrombophilia that impair the embryo to develop in utero, and implant (Rogenhofer et al, 2021). As half of the fetal genes are inherited from the father, it has been hypothesized that paternal thrombophilic alleles play a role in adverse assisted reproductive technology (ART) outcomes (Simon & Laufer, 2012).…”

Immunologic Factors and Genomic Considerations in Recurrent Pregnancy Loss: A Review

“…Remarkably, the paternal ANXA5 M2 haplotype has been found to have a similar effect on the risk of RPL as the maternal mutation [29]. New findings indicate that embryos carrying the M2/ANXA5 haplotype inherited from both parents are susceptible to recurrent implantation failure (RIF) [28].…”

“…Besides RPL, studies have also proved the association of this haplotype to various obstetric pathologies, including gestational hypertension, preeclampsia, fetal growth restriction, preterm birth, and antiphospholipid syndrome [28].…”