Letters to the Editors
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Are Y chromosome microdeletions and recurrent pregnancy loss really associated? TO THE EDITORS: We read with great interest the article by Karaer et al,1 because Y chromosome microdeletions (YMD) and recurrent pregnancy loss (RPL) represent an interesting and poorly studied association. However, we found some weaknesses that need to be clarified: first, they used 4 sequence tagged sites (STS): 1 for the AZFb region (DYS220 [sY129]) and 3 for the AZFd region (DYS235 [sY150], DYS236 [sY152], DYS237 [sY153]). AZFd zone was proposed in 1999, but confirmed evidence shows absence of this fourth zone, and all STS referred to as AZFd used in this study correspond to AZFc zone.2-4 Moreover, the same mistake was mentioned2 in the Dewan et al article,3 the original publication that showed this association in 2006. Second, for YMD screening there are validated guidelines for laboratory diagnosis endorsed by the European Academy of Andrology/European Quality Network (EAA/EQN).4 With these guidelines STS can detect 95% of YMD, and these were not used by Karaer et al.1 Neither were the STS selected according to Dewan et al,3 because the latter use the STS: DYS262 (sY67), DYS220 (sY129), DYF85S1 (sY150), and DYF86S1 (sY152). Karaer et al1 reported microdeletions in 7/43 patients in DYS220 (sY129) and 2/43 in DYS237 (sY153), but these cannot be considered true microdeletions, because individual STS absence should be considered as polymorphisms or methodological mistakes.2,4 For real microdeletions in AZFb, 2 STS deletions are necessary: sY127 and sY134, according EAA/EMQN.4 The deletion in DYS237 (sY153) has been shown to be polymorphic; it is present in multiple copies and does not fit the full criteria for accurate diagnosis.2 Based on these factors, we think that the results in the Karaer et al1 study should be reevaluated in order to give a conclusion, because it seems that the biological and possible clinical validity of Karaer et al1 results are poor with the methodology used. Furthermore, another recently published article by Kaare et al,5 with 46 Finish couples and analyzing 32 STS, including EAA/EMQN recommendations4 and STS used by Dewan et al,3 showed absence of YMD in male partners. There are important differences between the prevalence of YMD and RPL (0%, 16%, and 82%).1,3,5 We exhort authors to analyze their patients with molecular testing according to EAA/ EQN guidelines,4 in order to generate confident data, with clinical validity and comparable results with actual Y chromosome literature. Such testing would give us a better understanding of these associations and the possible implications in f future recurrent pregnancy loss for couples’ work-up. Raul E. Piña-Aguilar, MD Instituto de Ciencias en Reproducción Humana VIDA León, Guanajuato, México Facultad de Medicina, Universidad Autónoma de Yucatán Mérida, Yucatán, México
[email protected]
Sandra G. Martínez-Garza, PhD Instituto de Ciencias en Reproducción Humana VIDA León, Guanajuato, México Antonio M. Gutiérrez-Gutiérrez, MD, PhD Instituto de Ciencias en Reproducción Humana VIDA León, Guanajuato, México REFERENCES 1. Karaer A, Karaer K, Ozaksit G, Ceylaner S, Percin EF. Y chromosome azoospermia factor region microdeletions and recurrent pregnancy loss. Am J Obstet Gynecol 2008;199:662.e1-5. 2. Noordam MJ, van der Veen F, Repping S. Techniques and reasons to remain interested in the Y chromosome. Fertil Steril 2006;86:1801-2. 3. Dewan S, Puscheck EE, Coulam CB, Wilcox AJ, Jeyendran RS. Ychromosome microdeletions and recurrent pregnancy loss. Fertil Steril 2006;85:441-5. 4. Simoni M, Bakker E, Krausz C. EAA/EMQN best practice guidelines for molecular diagnosis of Y-chromosomal microdeletions. State of the art 2004. Int J Androl 2004;27:240-9. 5. Kaare M, Painter JN, Ulander VM, Kaaja R, Aittomäki K. Sex chromosome characteristics and recurrent miscarriage. Fertil Steril 2008;90: 2328-33. © 2009 Mosby, Inc. All rights reserved. doi: 10.1016/j.ajog.2009.05.005
REPLY We have evaluated the valuable comments of R.E. Pıña-Aguılar, MD, S.G. Martínez-Garza, PhD, and A.M. GutıérrezGutıérrez, MD, PhD, about our article. Regions related with spermatogenesis in the q arm of Y chromosome are divided into 3 subregions from proximal to distal parts called AZFa, AZFb, AZFc. The proximal part of AZFc region was firstly named as AZFd subregion in 19991 and has been studied and recognized by commercial sectors till yet (Promega Version 2.0; Promega, Madison, WI). It is difficult to detect the relationship between the specific defects in spermatogenesis and specific Y chromosome microdeletions. Deletions consisting of multiple regions on Y chromosome or microdeletions in AZFa region result in serious testicular phenotype (sperm count and testicular histology) such as complete spermatogonia absence (sertoli cell only) or severe oligozoospermia (partial spermatogenic arrest).On the other hand, patients with microdeletions on AZFb and AZFc regions have a large phenotype spectrum from azospermia to oligozoospermia. Patients with microdeletion on AZFd region have the widest range as phenotype (from azospermia to normal sperm count). Oligozoospermia and azospermia are not expected in most partners of patients with recurrent pregnancy loss, as most of them (all the participants of our study) have normal sperm count. If there is microdeletion, possibility of microdeletion being in AZFd is theoretical higher than other regions. In the light of a previous study about this topic and our financial NOVEMBER 2009 American Journal of Obstetrics & Gynecology
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Letters to the Editors problems have restricted us with 1 AZFb [DYS220 (sY129)] and 3 AZFd [DYS235 (sY150), DYS236 (sY152), DYS237 (sY153)] regions. DYS262 (sY67) that was studied in the previous report has been excluded from our study since it is out of AZF region.2 Different from previous study, DYS237 has been studied. In our study, only DYS220 region has been found to be statistically significant. It is possible that the involvement of microdeletions in the etiology of RM differs between populations. Different populations have different Y chromosome haplogroups, and it has been shown that the susceptibility to Y chromosomal microdeletions varies between different haplogroups.3 Quality-control studies about Y microdeletions indicate that microdeletion diagnosis may be wrong because of false positive or false negative results.4 To minimize this disadvantage, in our study in all PCR reactions as a negative control distilled water instead of DNA, as a positive control healthy fertile man DNA that has no microdeletion in AZF region and as an internal control glucose 6-phosphate dehydrogenase (G6PD) housekeeping gene marker have been studied. All the samples are studied twice to increase the reliability. The proposed guidelines depend on the studies between male infertility and Y microdeletion and the guidelines is not exhort for studies to explain the relationship between Y chromosome microdeletions and recurrent pregnancy loss, because testicular phenotypical characteristic of 2 groups are not identical. The studies about this topic are very new and it is obvious
www.AJOG.org that we need more new studies to explain the relationship between Y chromosome microdeletions and recurrent pregnancy f loss. Abdullah Karaer, MD Dr Zekai Tahir Burak Woman Health Education and Research Hospital Department of Obstetrics and Gynecology Ankara, Turkey
[email protected] Kadri Karaer, MD Gazi University School of Medicine, Department of Medical Genetics, Ankara, Turkey REFERENCES 1. Kent-First M, Muallem A, Shultz J, et al. Defining regions of the Ychromosome responsible for male infertility and identification of a fourth AZF region (AZFd) by Y-chromosome microdelection detection. Mol Reprod Develop 1999;53:27-41. 2. Dewan S, Puscheck EE, Coulam CB, Wilcox AJ, Jeyendran RS. Ychromosome microdeletions and recurrent pregnancy loss. Fertil Steril 2006;85:441-5. 3. Arredi B, Ferlin A, Speltra E, et al. Y chromosome haplogroups and susceptibility to azospermia factor c microdeletion in an Italian population. J Med Genet 2007;44:205-8. 4. Simoni M. Molecular diagnosis of Y chromosome microdeletions in Europe: state-of-the-art and quality control. Hum Reprod 2001; 16:402-9. © 2009 Mosby, Inc. All rights reserved. doi: 10.1016/j.ajog.2009.05.006
The need for comprehensive psychiatric perinatal care— The University of North Carolina at Chapel Hill, Department of Psychiatry, Center for Women’s Mood Disorders launches the first dedicated inpatient program in the United States TO THE EDITORS: The recent article by Pearlstein et al1 highlights the importance of increased screening, diagnosis and treatment of postpartum depression (PPD), a serious disorder estimated to affect up to 15% of women. The article identifies the lack of availability of specialized perinatal psychiatric treatment as a significant obstacle to both screening and treatment for PPD. At the time of submission, the article cited the partial day hospitalization program at Brown as the only psychiatric mother-infant unit in the United States. We are pleased to announce that, since that time, the University of North Carolina (UNC) at Chapel Hill, Department of Psychiatry, Center for Women’s Mood Disorders has expanded its services to include a Perinatal Inpatient Psychiatry Program. Although perinatal psychiatric treatment has become more common in Western Europe, Australia, and New Zealand, until fairly recently, specialized treatment options have been lacking in the United States. Our 6-bed perinatal inpatient program—the first such dedicated inpatient program in the e10
American Journal of Obstetrics & Gynecology NOVEMBER 2009
United States—provides comprehensive psychiatric assessment and treatment, including medication stabilization, individual, and group counseling, for patients at any stage of pregnancy and up to 1-year postpartum. Although our program does not provide overnight rooming-in with infants, families are given extended daytime visiting hours to maximize positive mother-infant interaction. Specialized treatment includes supportive psychotherapy, psychoeducation for patients and spouses, biofeedback and relaxation sessions targeting anxiety symptoms, and expressive art therapy. Other comfort measures include protected sleep times, gliders for nursing, and the availability of lactation consultations and hospital-grade breast pumps. All care is provided in consultation with the UNC Department of Obstetrics and Gynecology. PPD can be debilitating to the women experiencing it and their families. Specialized treatment of maternal perinatal psychiatric disorders is crucial to prevent needless suffering. Com-
