Lessons From the EThIGII Trial

Rogenhofer, Nina; Markoff, Arseni; Wagner, Annett; Klein, Hanns‐Georg; Petroff, David; Schleußner, E; Thaler, Christian J.

doi:10.1177/1076029616658117

Cited by 13 publications

(10 citation statements)

References 38 publications

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“…As such, a sensitivity analysis was conducted focusing on consecutive RPL. The pooled data from 12 studies (seven individual studies [3,11,12,[15][16][17]31] and one group study [1,4,28,32,33] with a sample size of 3,410 subjects showed that women with the M2/ANXA5 haplotype (heterozygous or homozygous) had a significantly higher OR of 1.63 (95% CI, 1.01-2.62, P ¼ .045) compared with women with normal haplotype to have consecutive RPLs (Fig. 2).…”

Section: Association Of the M2/anxa5 Haplotype And Female Rpl Subjectsmentioning

confidence: 99%

“…Among these 14 studies (Table 1), we observed that five studies used the same parous control group (1,4,16,32,33), but women with RPL were recruited at different times across these studies. We grouped these five studies (justifications for grouping are summarized in Supplemental Table 1) with a total of 183 M2/ANXA5 haplotype carriers; 142 out of them experienced RPL (Fig.…”

Section: Characterization Of Studiesmentioning

confidence: 99%

“…To ascertain the association between the M2/ANXA5 haplotype and RPL in female subjects, a meta-analysis was performed on a pooled sample size of 4,664 subjects from the 14 recruited studies (nine individual studies [3,11,17,31] and one group study [1,4,[32][33][34]). Figure 2 shows that the M2/ANXA5 haplotype (heterozygous or homozygous) female subjects have a significantly higher OR of 1.54 (95% CI, 1.08-2.2; P ¼ .019) of having RPL as compared with the normal haplotype.…”

Section: Association Of the M2/anxa5 Haplotype And Female Rpl Subjectsmentioning

confidence: 99%

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

Ang

Bogdanova²,

Markoff³

et al. 2019

Fertility and Sterility

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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.

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Section: Association Of the M2/anxa5 Haplotype And Female Rpl Subjectsmentioning

confidence: 99%

Section: Characterization Of Studiesmentioning

confidence: 99%

Section: Association Of the M2/anxa5 Haplotype And Female Rpl Subjectsmentioning

confidence: 99%

See 1 more Smart Citation

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

Ang

Bogdanova²,

Markoff³

et al. 2019

Fertility and Sterility

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“…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. Therefore, screening for M2/ANXA5 haplotype for patients afflicted by RPL is recommended as a panel of laboratory investigations (Ang et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

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

Ang

Rozhdestvensky

Markoff³

et al. 2021

APJMBB

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Repeated Pregnancy Loss (RPL) affects approximately 1 out of 20 pregnant women globally; it is traumatic for parents seeking parenthood with ensuing anxieties for the next pregnancy. M2/ANXA5 haplotype is a hereditary predisposition gene for thrombophilia-associated RPL; the association between M2/ANXA5 haplotype and RPL is further ascertained in a recent meta-analysis. Precision treatments have been proposed for RPL women with M2/ANXA5 haplotype. Therefore, screening for M2/ANXA5 haplotype is highly recommended as a panel of laboratory investigations for idiopathic RPL. To date, direct sequencing of PCR products is the most common method for the determination of M2/ANXA5 haplotype; this method is however tedious, expensive and time- consuming. Hereby, we demonstrate a simple and robust allele-specific PCR (AS-PCR) that detects two inherent SNPs in a single tube, which could serve as a routine genotyping tool for M2/ANXA5 haplotype. This test is rapid, only taking maximum 4 working hours to complete the analysis. Validation of the assay by 105 clinical DNA samples yields 100% concordance rate with the DNA sequencing results.

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“…Patient groups were genotyped by using genomic DNA extracted from peripheral blood and employing Sanger sequencing of the relevant amplicon in line with established protocols [4,19]. The accuracy of the genotyping was verified by a random blinded inclusion of 2% repeated measures.…”

Section: Genotyping Of Anxa5 Proximal Promoter Regionmentioning

confidence: 99%

The relevance of ANXA5 genetic variants on male fertility

Lavorato

Markoff

Altholz

et al. 2019

J Assist Reprod Genet

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Purpose To investigate the effect of the anticoagulation factor annexin A5 on male fertility and to provide perspective on the influence of members of the coagulation cascade on fertility. Methods Patients with normozoospermia and with unexplained severe oligozoospermia were retrospectively selected and their genomic DNA sequenced for the promoter region of ANXA5. The genotypes proportions and the odds ratio for carriership of the haplotype M2 were compared between the groups and population control. The clinical data used were gathered from parameters determined during routine clinical assessment and were compared between carriers and non-carriers within the patient groups. Results The carrier rates for the haplotype M2/ANXA5 were of 25.73%, 20.81%, and 15.3% in the severe oligozoospermic, the normozoospermic, and the general population control groups, respectively. The OR between patients groups was of 1.31 (95% CI 0.88 to 1.96 p = 0.176). Oligozoospermic and normozoospermic patients compared with the control group had an OR of 1.9 (95% CI 1.33 to 2.73 p < 0.001) and 1.45 (95% CI 0.99 to 2.10 p = 0.054) respectively. The clinical parameters that differed between the carriers and non-carriers of the haplotype M2/ANXA5 were prolactin, α-glucosidase, and fructose. The differences were only statistically significant in the normozoospermic group. Conclusions Athough the infertile patient groups had a higher prevalence of promoter variants, we could not demonstrate any biologically relevant effect of lower levels of annexin A5 on most male fertility parameters. A deficiency in an anticoagulation factor does not seem to impact male fertility.

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Lessons From the EThIGII Trial

Cited by 13 publications

References 38 publications

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

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

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

The relevance of ANXA5 genetic variants on male fertility

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