Further insights into the role of the annexin A5 M2 haplotype as recurrent pregnancy loss factor assessing timing of miscarriage and partner risk

M2/ANXA5 carriers show a trend of maximal recurrent pregnancy loss risk in the 10th to 15th week of gestation with a confirmed partner risk.

Frank Tüttelmann, M.D., Petar Ivanov, M.D., Ph.D., Charlotte Dietzel, Anna Sofroniou, Tsvetomira Tsvyatkovska, Regina Komsa-Penkova, Ph.D., Arseni Markoff, Ph.D., Peter Wieacker, M.D., Nadja Bogdanova, M.D., Ph.D.

Volume 100, Issue 5, Pages 1321-1325, November 2013


To study the influence of M2/ANXA5 for recurrent pregnancy loss (RPL), according to the timing of miscarriages and assess the male partner risk.

Genetic association study.

Academic research center.

Female patients from two academic centers in Germany and Bulgaria with two or more unexplained miscarriages were selected for this study. Male partners were available for a part of the German sample. Population controls were recruited from healthy individuals of respective populations.


Main Outcome Measure(s):
Incidence of M2 carriage and odds ratios were calculated between patient and control groups, and RPL risk was evaluated.

The M2 haplotype in ANXA5 was associated with greater overall RPL risk in German and in Bulgarian women, and a trend of higher prevalence was seen for male partners of German RPL patients. The highest relative risk of M2 carriage was observed in women of both populations with “early” fetal losses between the 10th and 15th gestational weeks, which was significant in the meta-analysis.

M2 carriage seems to have an RPL risk role mostly for early abortions, gestational weeks 10–15. In the first phase of pregnancy this correlates with vascular remodeling to accomplish the transition from high- to low-resistance blood vessels.

  • Arseni Markoff

    In our recently published study we confirmed the M2 association with recurrent pregnancy loss in two independent European populations, Bulgarians and Germans that was significant in the meta-analysis. The highest risk was observed in pregnancies terminating from 10th to 15th week of gestation, a time frame of embryonal development that correlates with vascular remodeling to accomplish the transition from high- to low-resistance blood vessels. This finding fits the well studied function of ANXA5 as natural anticoagulant, abundantly expressed on the surface of placental villi. Our results in partners of the recurrent pregnancy loss patients also confirm the risk of paternal carriage we noted in a previous pilot study and is in accordance with the parentally-independent reduced expression we observed in M2 chorion.
    To our knowledge M2 in the ANXA5 gene, with 15% carriage rate in Europeans is the first instance of thrombophilia mediated EARLY pregnancy loss factor with about equal risk rate in both sexes.
    In conclusion, we are very much obliged to the Fertility & Sterility journal for the professional handling and discussion of our findings that in contrast to other reproduction medicine journals does not allow dull comments from the type ‘men don’t get pregnant’.

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