Investigation of the Annexin A5 M2 haplotype in 500 white European recurrent miscarriage couples

Annexin A5 is a placental anti-coagulant protein that contains four nucleotide substitutions (M2 haplotype) in its promoter. Studies have shown that this haplotype is a risk factor for recurrent miscarriage (RM). Our aim was to investigate the influence of the M2 haplotype in the gestational timing of miscarriages, assessing the paternal risk and investigate for relationships with known risk factors. Five hundred white European couples with three or more consecutive miscarriages and two fertile control groups were selected for this study. The allele frequency of M2 was found to be significantly higher among early RM patients than among controls (P=0.002) and there was no difference between controls and patients with late miscarriages. Moreover, there was no difference between RM patients who had a live birth or no live births or between patients who were positive or negative for known risk factors. Male and female partners in each group had similar allele frequencies of M2. In conclusion, the M2 haplotype is a risk factor for early miscarriages, before the 12 th week of gestation and confers about the same relative risk to carriers of both sexes. Having one or more M2 allele(s) in combination with other risk factors further increases the RM risk.