Association between M2/ANXA5 haplotype and repeated pregnancy loss: a meta-analysis

This meta-analysis ascertains the odds of M2/ANXA5 haplotype in repeated pregnancy loss (RPL), especially consecutive early idiopathic RPL. Hence, screening for the haplotype is recommended as a panel of laboratory investigations for RPL.

Volume 111, Issue 5, Pages 971–981.e2


Kai-Cheen Ang, Ph.D., Nadja Bogdanova, M.D., Ph.D., Arseni Markoff, Ph.D., Ewe Seng Ch'ng, M.D., M.Path., Thean Hock Tang, Ph.D.



To ascertain the magnitude and precision of the association between M2/ANXA5 haplotype and repeated pregnancy loss (RPL).


Meta-analysis of odds ratios.


Not applicable.


Subjects were women with RPL and their partners.


Not applicable.

Main Outcome Measure(s)

The association between M2/ANXA5 haplotype and RPL was evaluated in a meta-analysis of odds ratios. We further scrutinized this association according to [1] the sequence of miscarriages, [2] the number of consecutive losses, [3] the extent of excluding other pathologies of RPL, and [4] the timing of fetal loss.


Fourteen individual studies (n = 4,664 subjects) were included in this meta-analysis. The results show that women with the M2/ANXA5 haplotype have 1.54 times (95% confidence interval, 1.08–2.20) the odds of having associated RPL compared with women with the normal haplotype, regardless of consecutive or nonconsecutive pregnancy losses. Acknowledging the clinical heterogeneity among the studies, this significant association comes with a caveat that the lower bound of the confidence interval is close to unity. In couple populations (n = 2,449), M2/ANXA5 haplotype subjects have an odds ratio of 1.48 (95% confidence interval, 1.14–1.91) of experiencing RPL, which suggests contributions from paternal M2/ANXA5 carriers in RPL.


This meta-analysis ascertains that women with the M2/ANXA5 haplotype have a higher risk of experiencing RPL, especially consecutive early idiopathic RPL. Male partners with the M2/ANXA5 haplotype partly contribute to this risk. Hence, screening for the M2/ANXA5 haplotype as a panel of laboratory investigations for RPL is recommended.

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