Reply of the Authors

Abstract

We do not deny that ANXA5 single-nucleotide polymorphisms (SNPs) were risk alleles. Variations with the ANXA5 gene upstream region, especially SNP5, were confirmed to be risk factors for recurrent pregnancy loss (RPL) but not recurrent miscarriage in our cross-sectional study (1Hayashi Y. Sasaki H. Suzuki S. Nishiyama T. Kitaori T. Mizutani E. et al.Genotyping analyses for polymorphisms of ANXA5 gene in patients with recurrent pregnancy loss.Fertil Steril. 2013; 100: 1018-1024Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar). The reason why the significant difference in the other SNPs except SNP5 could not be obtained in our study might be because the mean number of previous pregnancy losses was less than that in the Miyamura study (2Miyamura H. Nishizawa H. Ota S. Suzuki M. Inagaki A. Egusa H. et al.Polymorphisms in the annexin A5 gene promoter in Japanese women with recurrent pregnancy loss.Mol Humanit Rep. 2011; 17: 447-452Crossref PubMed Scopus (45) Google Scholar). The abnormal rate of embryonic (fetal) karyotype depends on the women's age and the number of previous miscarriages. Over half of the abnormalities were found in fewer than four miscarriages (3Ogasawara M. Aoki K. Okada S. Suzumori K. Embryonic karyotype of abortuses in relation to the number of previous miscarriages.Fertil Steril. 2000; 73: 300-304Abstract Full Text Full Text PDF PubMed Scopus (379) Google Scholar). The presence or absence of the ANXA5 risk allele did not have any predictive effect for subsequent pregnancy outcome in unselected patients with RPL. Our patients with a history of two or more RPLs were not selected from the patients who visited our hospital for examination. Recently, we found that an abnormal embryonic (fetal) karyotype was the most frequent cause of RPL, accounting for as many as 41% of the cases (4Sugiura-Ogasawara M. Ozaki Y. Katano K. Suzumori N. Kitaori T. Mizutani E. Abnormal embryonic karyotype is the most frequent cause of recurrent miscarriage.Hum Reprod. 2012; 27: 2297-2303Crossref PubMed Scopus (112) Google Scholar). The prevalence of truly unexplained causes, with normal karyotype, was only 25%. Thus, the predictive value of ANXA5 SNPs for subsequent pregnancy outcome might be shown if the study were conducted in patients with five or more miscarriages or only miscarriages with normal embryonic (fetal) karyotype. However, such patients are rare. Furthermore, our controls had a history of live birth and no history of miscarriage, which is different from the general population. In the general population, 15% and 10% to 15% of women experience miscarriage and infertility, respectively. Our control women were more appropriate for controls against RPL. Risk alleles showed a relatively small odds ratio around 2.0 in the previous study (2Miyamura H. Nishizawa H. Ota S. Suzuki M. Inagaki A. Egusa H. et al.Polymorphisms in the annexin A5 gene promoter in Japanese women with recurrent pregnancy loss.Mol Humanit Rep. 2011; 17: 447-452Crossref PubMed Scopus (45) Google Scholar). Our cohort study suggested that risk alleles with a small odds ratio had little influence on subsequent live birth. The subsequent live-birth rate was 84.0% and 84.3% in patients with and without the risk allele of SNP5, respectively, after the exclusion of cases with an abnormal embryonic (fetal) karyotype. The combination of many kinds of risk alleles might cause the susceptibility to RPL. In fact, some patients received anticoagulant treatment because of the risk alleles of ANXA5 in Japan, though the randomized controlled trial concluded that there was no effect of combined heparin and aspirin treatment for unexplained recurrent miscarriage (5Kaandrop S.P. Goddijn M. van der Post J.A. Hutten B.A. Verhoeve H.R. Hamulyak K. et al.Aspirin plus heparin or aspirin alone in women with recurrent miscarriage.N Engl J Med. 2010; 362: 1586-1596Crossref PubMed Scopus (344) Google Scholar). Our study was very important for clinicians and patients because it proved that patients with a risk allele could give live birth without medication. Haplotypes and polymorphisms of the ANXA5 nontranslated region in Japanese and European women with recurrent miscarriage and in controlsFertility and SterilityVol. 101Issue 1PreviewYuko Hayashi and coauthors (1) confirmed that the single-nucleotide polymorphism (SNP) rs1050606 (SNP5) of the nontranslated region of the ANXA5 gene is a risk factor for recurrent pregnancy loss (RPL) in Japanese patients. They also concluded that this risk allele had no influence on pregnancy outcome in 79 spontaneous abortions at Nagoya City University Hospital that occurred from November 2012 to February 2013 in a group of 264 Japanese women with RPL history. Almost two-thirds of the 79 spontaneously aborted fetuses, or approximately 64%, had abnormal karyotypes, which left only 17 cases that were possibly influenced by thrombophilia through carriage of common ANXA5 SNPs/haplotypes, among other factors. Full-Text PDF