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Kushnir V.A.,The New School | Darmon S.K.,The Center for Human Reproduction | Albertini D.F.,University of Kansas Medical Center | Barad D.H.,Foundation Medicine | Gleicher N.,New York University
Fertility and Sterility | Year: 2016

Objective: To assess effectiveness of preimplantation genetic screening (PGS) in fresh IVF cycles. Design: Reanalysis of retrospective US national data. Setting: Not applicable. Patient(s): A total of 5,471 fresh autologous IVF cycles with PGS and 97,069 cycles without PGS, reported in 2011-2012 to the Centers for Disease Control and Prevention. Intervention(s): Not applicable. Main Outcome Measure(s): Cycles that reached ET, miscarriage rates, live birth rates per cycle and per transfer. Result(s): More PGS than non-PGS cycles reached ET (64.2% vs. 62.3%), suggesting favorable patient selection bias for patients using PGS. Nevertheless, live births rates per cycle start (25.2% vs. 28.8%) and per ET (39.3% vs. 46.2%) were significantly better in non-PGS cycles, whereas miscarriage rates were similar (13.7% vs. 13.9%). With a maternal age >37 years significantly more cycles in the PGS group reached ET (53.1% vs. 41.9%), suggesting a significant selection bias for more favorable patients in the PGS population. This bias rather than the PGS procedure may partially explain the observed improved live birth rate per cycle (17.7% vs. 12.7%) and lower miscarriage rate (16.8% vs. 26.0%) in the older PGS group. Conclusion(s): Overall, PGS decreased chances of live birth in association with IVF. National improvements in live birth and miscarriage rates reported with PGS in older women are likely the consequence of favorable patient selection biases. © 2016 American Society for Reproductive Medicine.

Gleicher N.,The Center for Human Reproduction | Gleicher N.,Foundation Medicine | Kim A.,The Center for Human Reproduction | Weghofer A.,The Center for Human Reproduction | And 3 more authors.
Reproductive Biology and Endocrinology | Year: 2012

Background: Ovarian aging patterns differ between races, and appear to affect fertility treatment outcomes. What causes these differences is, however, unknown. Variations in ovarian aging patterns have recently been associated with specific ovarian genotypes and sub-genotypes of the FMR1 gene. We, therefore, attempted to determine differences in how functional ovarian reserve (FOR) changes with advancing age between races, and whether changes are associated with differences in distribution of ovarian genotypes and sub-genotypes of the FMR1 gene.Methods: We determined in association with in vitro fertilization (IVF) FOR in 62 young Caucasian, African and Asian oocyte donors and 536 older infertility patients of all three races, based on follicle stimulating hormone (FSH), anti-Müllerian hormone (AMH) and oocyte yields, and investigated whether differences between races are associated with differences in distribution of FMR1 genotypes and sub-genotypes.Results: Changes in distribution of mean FSH, AMH and oocyte yields between young donors and older infertility patients were significant (all P < 0.001). Donors did not demonstrate significant differences between races in AMH and FSH but demonstrated significant differences in oocyte yields [F(2,59) = 4.22, P = 0.019]: Specifically, African donors demonstrated larger oocyte yields than Caucasians (P = 0.008) and Asians (P = 0.022). In patients, AMH levels differed significantly between races [F (2,533) = 4.25, P = 0.015]. Holm-Sidak post-hoc comparisons demonstrated that Caucasians demonstrated lower AMH in comparison to Asians (P = 0.007). Percentages of FMR1 genotypes and sub-genotypes in patients varied significantly between races, with Asians demonstrating fewer het-norm/low sub-genotypes than Caucasians and Africans (P = 0.012).Conclusion: FOR changes in different races at different rates, and appears to parallel ovarian FMR1 genotypes and sub-genotype distributions. Differences in ovarian aging between races may, therefore, be FMR1-associated. © 2012 Gleicher et al.; licensee BioMed Central Ltd.

Gleicher N.,The Center for Human Reproduction | Gleicher N.,Foundation Medicine | Gleicher N.,Yale University | Weghofer A.,The Center for Human Reproduction | And 4 more authors.
Journal of Autoimmunity | Year: 2012

There, likely, is no more controversial issue in reproductive medicine than the effects of autoimmunity on female reproductive success. Published studies are, therefore, often biased. We performed PubMed, Google Scholar and Medline searches for the years 2000-2010 under various key words and phrases, referring to effects of autoimmunity/autoimmune diseases on pregnancy/pregnancy outcomes/pregnancy rates/reproduction/reproductive outcomes/fertility/infertility/fertility treatments/infertility treatments, and a number of similar terms. Reference lists of selected manuscripts were evaluated for additional, potential references. All selected manuscripts were reviewed by at least one author (N.G.). Opinions were reached based on preferential review of only selected studies, which offered data, primarily developed in pursuit of unrelated scientific questions. Data from various medical fields point, surprisingly effectively, toward significant impacts of autoimmunity on female reproductive success. Autoimmunity not only increases miscarriage risks but also reduces female fecundity and infertility treatment success. A, likely, reason why differences of opinion have persisted is that effects are primarily observed in genetically predisposed women, with specific fragile X mental retardation 1 (FMR1) genotypes. This discovery coincides with recently increasing appreciation of the importance of the long arm of the X chromosome (Xq) in control of functional ovarian reserve (reflective of female fertility) and autoimmunity, with FMR1at Xq27.3, located at cross roads of both. Autoimmune effects on female reproductive success deserve recognition. Further investigations must not ignore patient stratification, based on ovarian FMR1 genotypes. Genetic definition of high-risk patients should lead to development of successful therapeutic interventions. © 2011 Elsevier Ltd.

Gleicher N.,The Center for Human Reproduction | Gleicher N.,Foundation Medicine | Kushnir V.A.,The Center for Human Reproduction | Barad D.H.,The Center for Human Reproduction | Barad D.H.,Foundation Medicine
Reproductive Biology and Endocrinology | Year: 2015

Background: Approximately 10% of women suffer from premature ovarian senescence (POS), ca. 9% as occult primary ovarian insufficiency (OPOI, also called premature ovarian aging, POA) and ca. 1% as primary ovarian insufficiency (POI, also called premature ovarian failure, POF). In a large majority of cases POS is currently only diagnosed at advanced clinical stages when women present with clinical infertility. Methods: We here, based on published evidence, suggest a new diagnostic paradigm, which is based on identifying young women at increased risk for POS at much earlier stages. Results: Risk factors for POS are known from the literature, and can be used to identify a sub-group of young women at increased risk, who then are followed sequentially with serial assessments of functional ovarian reserve (FOR) until a diagnosis of POS is either reached or refuted. At approximately 25% prevalence in general U.S. populations (and somewhat different prevalence rates in more homogenous Asian and African populations), so-called low (CGGn<26) mutations of the fragile X mental retardation 1 (FMR1) gene, likely, represents the most common known risk factor, including history-based risk factors from medical, genetic and family histories. Conclusions: Women so affirmatively diagnosed with POS at relative young ages, then have the opportunity to reconsider their reproductive planning and/or choose fertility preservation via oocyte or ovarian tissue cryopreservation at ages when such procedures are clinically much more effective and, therefore, also more cost-effective. Appropriate validation studies will have to precede widespread utilization of this paradigm. © Gleicher et al.; licensee BioMed Central.

Weghofer A.,The Center for Human Reproduction | Weghofer A.,Medical University of Vienna | Tea M.-K.,Medical University of Vienna | Barad D.H.,The Center for Human Reproduction | And 6 more authors.
PLoS ONE | Year: 2012

BRCA1/2 mutations and recently described constitutional FMR1 genotypes have, independently, been associated with prematurely diminished ovarian reserve. Whether they interrelate in distribution, and whether observed effects of BRCA1/2 and FMR1 on ovaries are independent of each other, is unknown. In a prospective comparative cohort study, we, therefore, investigated the distribution of constitutional FMR1 genotypes, normal (norm), heterozygous (het) and homozygous (hom), and of their respective sub-genotypes (high/low), in 99 BRCA1/2 mutation-positive women and 410 female controls to determine whether distribution patterns differed between study and control patients. In contrast to controls, BRCA1/2 carriers demonstrated almost complete absence of all constitutional FMR1 genotypes except for sub-genotypes with low (CGG n<26) alleles. Cross tabulation between BRCA1/2-positive patients and controls confirmed significant group membership, related to FMR1 distribution (P<0.0001). These results offer as most likely explanation the conclusion that BRCA1/2 mutations are embryo-lethal, unless rescued by low (CGG n<26) FMR1 sub-genotypes, present in approximately one quarter of all women. Women with low FMR1 sub-genotypes, therefore, should reflect increased BRCA1/2-associated cancer risks, while the remaining approximately 75 percent should face almost no such risks. If confirmed, this observation offers opportunities for more efficient and less costly BRCA1/2 cancer screening. The study also suggests that previously reported risk towards prematurely diminished ovarian reserve in association with BRCA mutations is FMR1-mediated, and offers a possible explanation for the so-called "BRCA paradox" by raising the possibility that the widely perceived BRCA1/2-associated tumor risk is actually FMR1-mediated. © 2012 Weghofer et al.

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