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

Abstract

Objective: To ascertain the magnitude and precision of the association between M2/ANXA5 haplotype and repeated pregnancy loss (RPL). Design: Meta-analysis of odds ratios. Setting: Not applicable. Patient(s): Subjects were women with RPL and their partners. Intervention(s): 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. Result(s): Fourteen individual studies (n ¼ 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 ¼ 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. Conclusion(s):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. (Fertil Steril Ò 2019;111: 971-81. Ó2019 by American Society for Reproductive Medicine.) El resumen está disponible en Español al final del artículo.

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

“…Since 2007, much work has been accumulated on a newly identified hereditary thrombophilic genetic factor, the 'M2 haplotype' of the annexin A5 (ANXA5) gene. Indeed, we and others identified the M2 haplotype associated with obstetric pathologies such as gestational hypertension, preeclampsia [23][24][25][26][27], fetal growth restriction, preterm birth [26,[28][29][30], antiphospholipid syndrome [31], and most incriminatory recurrent pregnancy losses (RPL) [32]. Moreover, in our previous studies, we confirmed risks of maternal M2/ANXA5 haplotype and identified the paternal carrier status as an equal risk factor for RPL and obstetric complications [23,33].…”

Development of cost-effective and accurate allele-specific PCR for determination of M2/ANXA5 haplotype in recurrent pregnancy loss

“…A recent meta-analysis demonstrates that a M2/ANXA5 woman carrier has 1.54 times the odds to experience RPL. Male partners with M2/ANXA5 haplotype are also implied to carry similar risk for RPL (Ang et al, 2019). Recent studies have also proposed that low-molecularweight heparin Fishel et al, 2016;Rogenhofer et al, 2017) and micromolar zinc intake (Danisik et al, 2019) could be the precision anticoagulant interventions for M2/ANXA5 haplotype-associated RPL.…”

“…Recent studies have also proposed that low-molecularweight heparin Fishel et al, 2016;Rogenhofer et al, 2017) and micromolar zinc intake (Danisik et al, 2019) could be the precision anticoagulant interventions for M2/ANXA5 haplotype-associated RPL. Therefore, screening for M2/ANXA5 haplotype for patients afflicted by RPL is recommended as a panel of laboratory investigations (Ang et al, 2019). Although there are several methods reported over the years to determine M2/ANXA5 haplotype, namely direct sequencing of PCR products, probe-based qPCR and PCR-RE, these methods have their inherent strength and drawback.…”

“…M2/ANXA5 haplotype will result in reduced ANXA5 mRNAs (Chinni et al, 2009;Markoff et al, 2010) and its protein levels (Ota et al, 2013) in placentas; this would cause insufficient coverage of PS and trigger thrombotic events leading to RPL (Bogdanova et al, 2012). A recent meta-analysis across different geographic areas ascertains the association between M2/ANXA5 haplotype and RPL, with the odds of 1.54 (95% CI: 1.08 to 2.20) (Ang et al, 2019). Therefore, M2/ANXA5 haplotype screening test is highly recommended for idiopathic RPL (Ang et al, 2019).…”

“…A recent meta-analysis across different geographic areas ascertains the association between M2/ANXA5 haplotype and RPL, with the odds of 1.54 (95% CI: 1.08 to 2.20) (Ang et al, 2019). Therefore, M2/ANXA5 haplotype screening test is highly recommended for idiopathic RPL (Ang et al, 2019).…”