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      Effect of women’s age on embryo morphology, cleavage rate and competence—A multicenter cohort study

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          Abstract

          This multicenter cohort study on embryo assessment and outcome data from 11,744 IVF/ICSI cycles with 104,830 oocytes and 42,074 embryos, presents the effect of women’s age on oocyte, zygote, embryo morphology and cleavage parameters, as well as cycle outcome measures corrected for confounding factors as center, partner’s age and referral diagnosis. Cycle outcome data confirmed the well-known effect of women’s age. Oocyte nuclear maturation and proportion of 2 pro-nuclear (2PN) zygotes were not affected by age, while a significant increase in 3PN zygotes was observed in both IVF and ICSI (p<0.0001) with increasing age. Maternal age had no effect on cleavage parameters or on the morphology of the embryo day 2 post insemination. Interestingly, initial hCG value after single embryo transfer followed by ongoing pregnancy was increased with age in both IVF (p = 0.007) and ICSI (p = 0.001) cycles. For the first time, we show that a woman’s age does impose a significant footprint on early embryo morphological development (3PN). In addition, the developmentally competent embryos were associated with increased initial hCG values as the age of the women increased. Further studies are needed to elucidate, if this increase in initial hCG value with advancing maternal age is connected to the embryo or the uterus.

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          Most cited references26

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          The Istanbul consensus workshop on embryo assessment: proceedings of an expert meeting.

          Many variations in oocyte and embryo grading make inter-laboratory comparisons extremely difficult. This paper reports the proceedings of an international consensus meeting on oocyte and embryo morphology assessment. Background presentations about current practice were given. The expert panel developed a set of consensus points to define the minimum criteria for oocyte and embryo morphology assessment. It is expected that the definition of common terminology and standardization of laboratory practice related to embryo morphology assessment will result in more effective comparisons of treatment outcomes. This document is intended to be referenced as a global consensus to allow standardized reporting of the minimum data set required for the accurate description of embryo development.
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            The nature of aneuploidy with increasing age of the female partner: a review of 15,169 consecutive trophectoderm biopsies evaluated with comprehensive chromosomal screening.

            To determine the relationship between the age of the female partner and the prevalence and nature of human embryonic aneuploidy. Retrospective. Academic. Trophectoderm biopsies. Comprehensive chromosomal screening performed on patients with blastocysts available for biopsy. Evaluation of the impact of maternal age on the prevalence of aneuploidy, the probability of having no euploid embryos within a cohort, the complexity of aneuploidy as gauged by the number of aneuploid chromosomes, and the trisomy/monosomy ratio. Aneuploidy increased predictably after 26 years of age. A slightly increased prevalence was noted at younger ages, with >40% aneuploidy in women 23 years and under. The no euploid embryo rate was lowest (2% to 6%) in women aged 26 to 37, was 33% at age 42, and was 53% at age 44. Among the biopsies with aneuploidy, 64% involved a single chromosome, 20% two chromosomes, and 16% three chromosomes, with the proportion of more complex aneuploidy increasing with age. Finally, the trisomy/monosomy ratio approximated 1 and increased minimally with age. The lowest risk for embryonic aneuploidy was between ages 26 and 30. Both younger and older age groups had higher rates of aneuploidy and an increased risk for more complex aneuploidies. The overall risk did not measurably change after age 43. Trisomies and monosomies are equally prevalent. Copyright © 2014 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.
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              Evidence that weakened centromere cohesion is a leading cause of age-related aneuploidy in oocytes.

              Aneuploidy arising early in development is the leading genetic cause of birth defects and developmental disabilities in humans. Most errors in chromosome number originate from the egg, and maternal age is well established as the key risk factor. Although the importance of this problem for reproductive health is widely recognized, the underlying molecular basis for age-related aneuploidy in female meiosis is unknown. Here we show that weakened chromosome cohesion is a leading cause of aneuploidy in oocytes in a natural aging mouse model. We find that sister kinetochores are farther apart at both metaphase I and II, indicating reduced centromere cohesion. Moreover, levels of the meiotic cohesin protein REC8 are severely reduced on chromosomes in oocytes from old mice. To test whether cohesion defects lead to the observed aneuploidies, we monitored chromosome segregation dynamics at anaphase I in live oocytes and counted chromosomes in the resulting metaphase II eggs. About 90% of age-related aneuploidies are best explained by weakened centromere cohesion. Together, these results demonstrate that the maternal age-associated increase in aneuploidy is often due to a failure to effectively replace cohesin proteins that are lost from chromosomes during aging. Copyright © 2010 Elsevier Ltd. All rights reserved.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                19 April 2017
                2017
                : 12
                : 4
                : e0172456
                Affiliations
                [1 ]Herlev Hospital, Fertility Clinic, Copenhagen University Hospital, Herlev, Denmark
                [2 ]Aarhus University Hospital, Fertility Clinic, Aarhus, Denmark
                [3 ]Brædstrup Fertility Clinic, Horsens, Denmark
                [4 ]Rigshospitalet, Fertility Clinic, Copenhagen University Hospital, Copenhagen, Denmark
                [5 ]Ballerup IVF, Copenhagen, Denmark
                [6 ]Hvidovre Hospital, Fertility Clinic, Copenhagen University Hospital, Hvidovre, Denmark
                [7 ]CellCura Solutions A/S, Copenhagen, Denmark
                [8 ]Hvidovre Hospital, Statistics, Clinical Research Center, Copenhagen University Hospital, Hvidovre, Denmark
                Hull York Medical School, UNITED KINGDOM
                Author notes

                Competing Interests: Two of the authors got salaries from commercial companies Cell Cura Solutions and Balleup IVF. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

                • Conceptualization: MLG JB IEA JGL USK PL.

                • Data curation: MR MLG.

                • Formal analysis: SL.

                • Funding acquisition: MLG.

                • Investigation: MLG.

                • Methodology: MLG SL.

                • Project administration: MLG.

                • Resources: MLG JB.

                • Writing – original draft: MLG SC SL.

                • Writing – review & editing: USK IEA PL JGL.

                Article
                PONE-D-16-08110
                10.1371/journal.pone.0172456
                5396884
                28422964
                97b14a75-ba09-4c88-b52a-32c59dd565ae
                © 2017 Grøndahl et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 25 February 2016
                : 6 February 2017
                Page count
                Figures: 1, Tables: 3, Pages: 12
                Funding
                The study was supported with an unrestricted grant from MSD, Denmark. Cell Cura Solutions and Balleup IVF provided support in the form of salaries for authors MRJ (Cell Cura Solutions) and PL (Balleup IVF), but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the 'author contributions' section.
                Categories
                Research Article
                Biology and Life Sciences
                Developmental Biology
                Embryology
                Embryos
                Biology and Life Sciences
                Cell Biology
                Cellular Types
                Animal Cells
                Germ Cells
                OVA
                Oocytes
                Biology and Life Sciences
                Cell Biology
                Cellular Types
                Animal Cells
                Germ Cells
                OVA
                Zygotes
                People and Places
                Population Groupings
                Age Groups
                Biology and Life Sciences
                Cell Biology
                Cellular Types
                Animal Cells
                Blastomeres
                Biology and Life Sciences
                Developmental Biology
                Embryology
                Blastomeres
                Medicine and Health Sciences
                Women's Health
                Maternal Health
                Pregnancy
                Medicine and Health Sciences
                Women's Health
                Obstetrics and Gynecology
                Pregnancy
                Biology and Life Sciences
                Developmental Biology
                Fertilization
                Insemination
                Medicine and Health Sciences
                Women's Health
                Maternal Health
                Pregnancy
                Embryo Transfer
                Medicine and Health Sciences
                Women's Health
                Obstetrics and Gynecology
                Pregnancy
                Embryo Transfer
                Custom metadata
                All relevant data are within the paper and its Supporting Information files.

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                Uncategorized

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