Orzack S.H.,Fresh Pond Research Institute |
Stubblefield J.W.,Fresh Pond Research Institute |
Akmaev V.R.,Genzyme |
Akmaev V.R.,Berg Inc |
And 6 more authors.
Proceedings of the National Academy of Sciences of the United States of America | Year: 2015
We describe the trajectory of the human sex ratio from conception to birth by analyzing data from (i) 3- to 6-d-old embryos, (ii) induced abortions, (iii) chorionic villus sampling, (iv) amniocentesis, and (v) fetal deaths and live births. Our dataset is the most comprehensive and largest ever assembled to estimate the sex ratio at conception and the sex ratio trajectory and is the first, to our knowledge, to include all of these types of data. Our estimate of the sex ratio at conception is 0.5 (proportion male), which contradicts the common claim that the sex ratio at conception is malebiased. The sex ratio among abnormal embryos is male-biased, and the sex ratio among normal embryos is female-biased. These biases are associated with the abnormal/normal state of the sex chromosomes and of chromosomes 15 and 17. The sex ratio may decrease in the first week or so after conception (due to excess male mortality); it then increases for at least 10-15 wk (due to excess female mortality), levels off after ∼20 wk, and declines slowly from 28 to 35 wk (due to excess malemortality). Total female mortality during pregnancy exceeds total male mortality. The unbiased sex ratio at conception, the increase in the sex ratio during the first trimester, and total mortality during pregnancy being greater for females are fundamental insights into early human development. © 2015, National Academy of Sciences. All rights reserved.
Templado C.,Autonomous University of Barcelona |
Uroz L.,Center Internacional Of Reproduccio Humana Assistida Of Barcelona |
Molecular Human Reproduction | Year: 2013
In humans, the mostcommon chromosomal abnormality is aneuploidy. Because the majority of aneuploid conceptuses die during the early stages of embryonic development, an accurate estimate of the frequency of aneuploidy at conception can only be assessed by directly studying the gametes. The vast majority of aneuploidies arise de novo as a result of sporadic chromosome missegregation in paternal or maternal meiosis. In this review, we present the basic current knowledge about the incidence of aneuploidy in human spermatozoa in the general population and in patient populations where elevated levels of sperm aneuploidy are observed. These include infertile patients, patients with abnormal somatic karyotypes, and individuals exposed to certain environmental/lifestyle hazards. The clinical impact of increased levels of aneuploidy is discussed. We then focus on the non-disjunction mechanisms that cause aneuploidy during spermatogenesis and the factors that predispose to non-disjunction in male germ cells followed by an analysis of the sex differences in the incidence of gamete aneuploidy. Recent meiotic studies using multiplex-FISH on three fertile men have revealed that the frequency of conservative aneuploidy of metaphase II spermatocytes is similar to that observed in non-inseminated oocytes of young women. These findings suggest that the differences in the incidence of aneuploidy between spermatozoa and oocytes are not due to differences in chromosome segregation errors but rather to more effective checkpoint mechanisms in spermatogenesis than in oogenesis. © The Author 2013. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved.
News Article | November 7, 2016
PLEASANTON, Calif., Nov. 06, 2016 (GLOBE NEWSWIRE) -- The Cooper Companies, Inc. (NYSE:COO) today announced that CooperSurgical has acquired Wallace, the in-vitro fertilization (IVF) segment of Smiths Medical, a division of Smiths Group plc, for a purchase price of approximately $168 million subject to customary closing adjustments. Wallace reported sales of approximately $29 million in the last twelve months. Excluding non-recurring items and deal-related amortization, the transaction is expected to be approximately $0.10 accretive to earnings per share in fiscal 2017. Commenting on the transaction, Robert S. Weiss, Cooper's president and chief executive officer said, “This acquisition is a great strategic fit with our existing IVF portfolio as Wallace brings the gold standard of embryo transfer catheters along with several other premier products such as oocyte retrieval needles. The addition of these products further strengthens our IVF portfolio which is sold into fertility clinics worldwide.” The Cooper Companies, Inc. ("Cooper") is a global medical device company publicly traded on the NYSE (NYSE:COO). Cooper is dedicated to being A Quality of Life Company™ with a focus on delivering shareholder value. Cooper operates through two business units, CooperVision and CooperSurgical. CooperVision brings a refreshing perspective on vision care with a commitment to developing a wide range of high-quality products for contact lens wearers and providing focused practitioner support. CooperSurgical is committed to advancing the health of families with its diversified portfolio of products and services focusing on women’s health, fertility and diagnostics. Headquartered in Pleasanton, CA, Cooper has approximately 10,000 employees with products sold in over 100 countries. For more information, please visit www.coopercos.com. For more than 25 years, CooperSurgical has been a leader in manufacturing and marketing a wide range of trusted and innovative brands that have assisted clinicians in advancing the standard of health care for women worldwide. Through an aggressive growth and diversification strategy, CooperSurgical has evolved its portfolio to include key products and services for women’s health, fertility and genetic testing. Our global in-vitro fertilization (IVF) segment, ORIGIO, and our groundbreaking offering from the pioneers of genetic testing, Recombine/Reprogenetics/Genesis Genetics, complement our dynamic women’s health care offering. CooperSurgical, Inc. is a wholly owned subsidiary of The Cooper Companies (NYSE:COO) and is headquartered in Trumbull, CT. Through the delivery of insightful technologies and products to health care providers, we envision a world with healthier babies, individuals, and families. More information can be found at www.coopersurgical.com. This news release contains "forward-looking statements" as defined by the Private Securities Litigation Reform Act of 1995. Statements relating to guidance, plans, prospects, goals, strategies, future actions, events or performance and other statements which are other than statements of historical fact, including our 2016 Guidance and all statements regarding the acquisition of Smiths Medical’s Wallace including Wallace’s financial position, market position, product development and business strategy, expected cost synergies, expected timing and benefits of the transaction, difficulties in integrating entities or operations, as well as estimates of our and Wallace’s future expenses, sales and earnings per share are forward looking. In addition, all statements regarding anticipated growth in our revenue, anticipated effects of any product recalls, anticipated market conditions, planned product launches and expected results of operations and integration of any acquisition are forward-looking. To identify these statements look for words like "believes," "expects," "may," "will," "should," "could," "seeks," "intends," "plans," "estimates" or "anticipates" and similar words or phrases. Forward-looking statements necessarily depend on assumptions, data or methods that may be incorrect or imprecise and are subject to risks and uncertainties. Among the factors that could cause our actual results and future actions to differ materially from those described in forward-looking statements are: adverse changes in the global or regional general business, political and economic conditions, including the impact of continuing uncertainty and instability of certain countries that could adversely affect our global markets, including the adverse economic impact and related uncertainty caused by the United Kindom’s election to withdraw from the European Union; foreign currency exchange rate and interest rate fluctuations including the risk of fluctuations in the value of foreign currencies that would decrease our revenues and earnings; acquisition-related adverse effects including the failure to successfully obtain the anticipated revenues, margins and earnings benefits of the Wallace acquisition or other acquisitions, integration delays or costs and the requirement to record significant adjustments to the preliminary fair value of assets acquired and liabilities assumed within the measurement period, required regulatory approvals for an acquisition not being obtained or being delayed or subject to conditions that are not anticipated, adverse impacts of changes to accounting controls and reporting procedures, contingent liabilities or indemnification obligations, increased leverage and lack of access to available financing (including financing for the acquisition or refinancing of debt owed by us on a timely basis and on reasonable terms); Our indebtedness could adversely affect our financial health, prevent us from fulfilling our debt obligations or limit our ability to borrow additional funds; a major disruption in the operations of our manufacturing, research and development or distribution facilities, due to technological problems, including any related to our information systems maintenance, enhancements, or new system deployments and integrations, integration of acquisitions, natural disasters, excess or constrained manufacturing capacity, or other causes; disruptions in supplies of raw materials, particularly components used to manufacture our silicone hydrogel lenses; new U.S. and foreign government laws and regulations, and changes in existing tax laws, regulations and enforcement guidance, which affect the medical device and healthcare industries generally; compliance costs and potential liability in connection with U.S. and foreign healthcare regulations and federal and state laws pertaining to privacy and security of health information, including product recalls, warning letters, and data security breaches; legal costs, insurance expenses, settlement costs and the risk of an adverse decision, prohibitive injunction or settlement related to product liability, patent infringement or other litigation; changes in tax laws or their interpretation and changes in statutory tax rates; limitations on sales following product introductions due to poor market acceptance; new competitors, product innovations or technologies; reduced sales, loss of customers and costs and expenses related to recalls; failure to receive, or delays in receiving, U.S. or foreign regulatory approvals for products; failure of our customers and end users to obtain adequate coverage and reimbursement from third party payors for our products and services; the requirement to provide for a significant liability or to write off, or accelerate depreciation on, a significant asset, including goodwill; the success of our research and development activities and other start-up projects; dilution to earnings per share from acquisitions or issuing stock; changes in accounting principles or estimates; environmental risks; and other events described in our Securities and Exchange Commission filings, including the “Business” and “Risk Factors” sections in the Company’s Annual Report on Form 10-K for the fiscal year ended October 31, 2015, as such Risk Factors may be updated in quarterly filings. We caution investors that forward-looking statements reflect our analysis only on their stated date. We disclaim any intent to update them except as required by law.
News Article | December 9, 2016
Many more three-parent babies will soon be on their way. A clinic in Mexico is planning to use the technique in 20 pregnancies in the first half of 2017, according to its medical director Alejandro Chavez-Badiola. The first baby to be born using such a technique to prevent passing on genetic disease was born this year. Test results yet to be published have revealed that the baby boy is perfectly healthy, New Scientist has been exclusively told. The idea is that the technique, called mitochondrial replacement, avoids harmful mitochondrial mutations passing from the mother to her children. It works by removing the nucleus from a mother’s egg and inserting it into a donor egg, which has its own nucleus removed. The egg is then fertilised with the father’s sperm. In this way, an embryo gets chromosomes from its mother and father, but the DNA in the mitochondria comes from the donor. The hope is this should enable children not to inherit harmful mitochondrial mutations from their mothers, but will mean that they have genetic material from three people – the father and two women. The baby born this year is now 8 months old. To create him, Chavez-Badiola and colleagues at the New Hope Fertility Center Mexico manipulated and implanted the embryo in 2015. All the tests done so far suggest the treatment has worked and the boy is perfectly healthy. “Based on this mutation load, I don’t think he will have any problems,” says Taosheng Huang of Cincinnati Children’s Hospital Medical Center, who has been doing the genetic analysis for the team. Full details are due to be published in coming weeks, he says. Since news of the birth was first reported, the team has been contacted by many would-be parents whose children risk inheriting the same kind of disorder. “There’s so many desperate families looking for help,” says Huang. But should clinics hold off until we have more information about whether the technique is safe? “I think they should treat more patients,” says Jacques Cohen of fertility company Reprogenetics, whose team created the first three-parent babies in the 1990s as a result of an experimental fertility treatment. “But how many patients do you treat and how long do you wait until you do more? I don’t have the answers.” The parents of the boy born this year sought the team’s help after having two children who died from Leigh syndrome, which is caused by mutations in mitochondria. About 50 to 60 per cent of the mitochondria in each cell have to carry these harmful mutations for children to develop the syndrome. It is not yet clear how effective mitochondrial replacement is. When the nucleus is transferred from the mother to the donor egg, it carries with it some of the mother’s mitochondria. Lab studies suggest that in around 1 in 20 cases, children could still end up with a high enough proportion of their mother’s mitochondria to cause disease. But Huang has confirmed that most of the boy’s mitochondria come from the donor. His team has tested cells from many different parts of his body: hair follicles, saliva, cheek swabs, blood, umbilical cord, urine and foreskin. In some tissues, no mutant mitochondria were detected at all. Most had 3 to 4 per cent mutant mitochondria, while the highest level was 9 per cent. That is far below the level that causes Leigh syndrome, and the mother has seen no signs of the problems that her other children had. “I am very happy to see the outcome,” says Huang. The clinic is now working with other would-be parents, Chavez-Badiola told New Scientist, although Huang says the final decision to proceed with further treatments has not yet been taken. It is likely that none of the parents will be from Mexico, although Chavez-Badiola says he would like to treat local patients as well. Mexico has no specific regulations governing mitochondrial replacement or assisted reproduction. But Chavez-Badiola dismisses the suggestion that the procedure is being done in Mexico to avoid regulations elsewhere. “It is wrong to say there are no rules in Mexico,” he says. The procedure to produce the boy was approved by an ethical committee, and the clinic is overseen by a regulatory agency. “I am meeting with the government next week,” he says. Huang says the team has also been in discussions with the US regulator, the Food and Drug Administration, about allowing the procedure to be done there, but progress has been “very minimal” so far. In 2015, the UK became the first country in the world to specifically make mitochondrial replacement legal. The UK’s regulator will decide whether it is safe enough to proceed on 15 December. If they decide to let it go ahead, the country’s first three-parent babies are likely to be conceived in 2017. In the Ukraine, three-parent baby methods are being used as a fertility treatment, rather than to prevent disease. A recent scientific report concluded that there is no evidence to suggest such techniques improve women’s chances of having children. Cohen does not support its use for fertility either. IVF success rates are much better now than in the 1990s, he says, so there is much less justification for trying experimental techniques. Read more: Everything you wanted to know about ‘3-parent’ babies; Should fertility clinics offer experimental unproven treatments?
Templado C.,Unitat de Biologia Cellular i Genetica Medica |
Templado C.,Autonomous University of Barcelona |
Vidal F.,Autonomous University of Barcelona |
Cytogenetic and Genome Research | Year: 2011
We reviewed the frequency and distribution of disomy in spermatozoa obtained by multicolor-FISH analysis on decondensed sperm nuclei in (a) healthy men, (b) fathers of aneuploid offspring of paternal origin and (c) individuals with Klinefelter syndrome and XYY males. In series of healthy men, disomy per autosome is approximately 0.1% but may range from 0.03 (chromosome 8) to 0.47 (chromosome 22). The great majority of authors find that chromosome 21 (0.18%) and the sex chromosomes (0.27%) have significantly elevated frequencies of disomy although these findings are not universal. The total disomy in FISH studies is 2.26% and the estimated aneuploidy (2× disomy) is 4.5%, more than double that seen in sperm karyotypes (1.8%). Increased disomy levels of low orders of magnitude have been reported in spermatozoa of some normal men (stable variants) and in men who have fathered children with Down, Turner and Klinefelter syndromes. These findings suggest that men with a moderately elevated aneuploidy rate may be at a higher risk of fathering paternally derived aneuploid pregnancies. Among lifestyle factors, smoking, alcohol and caffeine have been studied extensively but the compounding effects of the 3 are difficult to separate because they are common lifestyle behaviors. Increases in sex chromosome abnormalities, some autosomal disomies, and in the number of diploid spermatozoa are general features in 47,XXY and 47,XYY males. Aneuploidy of the sex chromosomes is more frequent than aneuploidy of any of the autosomes not only in normal control individuals, but also in patients with sex chromosome abnormalities and fathers of paternally derived Klinefelter, Turner and Down syndromes. Copyright © 2011 S. Karger AG, Basel.
Chavez S.L.,Stanford University |
Loewke K.E.,Auxogyn Inc. |
Han J.,Stanford University |
Moussavi F.,Auxogyn Inc. |
And 4 more authors.
Nature Communications | Year: 2012
Previous studies have demonstrated that aneuploidy in human embryos is surprisingly frequent with 50-80% of cleavage-stage human embryos carrying an abnormal chromosome number. Here we combine non-invasive time-lapse imaging with karyotypic reconstruction of all blastomeres in four-cell human embryos to address the hypothesis that blastomere behaviour may reflect ploidy during the first two cleavage divisions. We demonstrate that precise cell cycle parameter timing is observed in all euploid embryos to the four-cell stage, whereas only 30% of aneuploid embryos exhibit parameter values within normal timing windows. Further, we observe that the generation of human embryonic aneuploidy is complex with contribution from chromosome-containing fragments/micronuclei that frequently emerge and may persist or become reabsorbed during interphase. These findings suggest that cell cycle and fragmentation parameters of individual blastomeres are diagnostic of ploidy, amenable to automated tracking algorithms, and likely of clinical relevance in reducing transfer of embryos prone to miscarriage. © 2012 Macmillan Publishers Limited. All rights reserved.
Current Genomics | Year: 2012
At least 50% of human embryos are abnormal, and that increases to 80% in women 40 years or older. These abnormalities result in low implantation rates in embryos transferred during in vitro fertilization procedures, from 30% in women <35 years to 6% in women 40 years or older. Thus selecting normal embryos for transfer should improve pregnancy results. The genetic analysis of embryos is called Preimplantation Genetic Diagnosis (PGD) and for chromosome analysis it was first performed using FISH with up to 12 probes analyzed simultaneously on single cells. However, suboptimal utilization of the technique and the complexity of fixing single cells produced conflicting results. PGD has been invigorated by the introduction of microarray testing which allows for the analysis of all 24 chromosome types in one test, without the need of cell fixation, and with staggering redundancy, making the test much more robust and reliable. Recent data published and presented at scientific meetings has been suggestive of increased implantation rates and pregnancy rates following microarray testing, improvements in outcome that have been predicted for quite some time. By using markers that cover most of the genome, not only aneuploidy can be detected in single cells but also translocations. Our validation results indicate that array CGH has a 6Mb resolution in single cells, and thus the majority of translocations can be analyzed since this is also the limit of karyotyping. Even for translocations with smaller exchanged fragments, provided that three out of the four fragments are above 6Mb, the translocation can be detected. © 2012 Bentham Science Publishers.
Alfarawati S.,University of Oxford |
Alfarawati S.,Institute of Reproductive science |
Fragouli E.,University of Oxford |
Fragouli E.,Institute of Reproductive science |
And 3 more authors.
PLoS Genetics | Year: 2012
Balanced chromosomal rearrangements represent one of the most common forms of genetic abnormality affecting approximately 1 in every 500 (0.2%) individuals. Difficulties processing the abnormal chromosomes during meiosis lead to an elevated risk of chromosomally abnormal gametes, resulting in high rates of miscarriage and/or children with congenital abnormalities. It has also been suggested that the presence of chromosome rearrangements may also cause an increase in aneuploidy affecting structurally normal chromosomes, due to disruption of chromosome alignment on the spindle or disturbance of other factors related to meiotic chromosome segregation. The existence of such a phenomenon (an inter-chromosomal effect-ICE) remains controversial, with different studies presenting contradictory data. The current investigation aimed to demonstrate conclusively whether an ICE truly exists. For this purpose a comprehensive chromosome screening technique, optimized for analysis of minute amounts of tissue, was applied to a unique collection of samples consisting of 283 oocytes and early embryos derived from 44 patients carrying chromosome rearrangements. A further 5,078 oocytes and embryos, derived from chromosomally normal individuals of identical age, provided a robust control group for comparative analysis. A highly significant (P = 0.0002) increase in the rate of malsegregation affecting structurally normal chromosomes was observed in association with Robertsonian translocations. Surprisingly, the ICE was clearly detected in early embryos from female carriers, but not in oocytes, indicating the possibility of mitotic rather than the previously suggested meiotic origin. These findings have implications for our understanding of genetic stability during preimplantation development and are of clinical relevance for patients carrying a Robertsonian translocation. The results are also pertinent to other situations when cellular mechanisms for maintaining genetic fidelity are relaxed and chromosome rearrangements are present (e.g. in tumors displaying chromosomal instability). © 2012 Alfarawati et al.
Harton G.L.,Reprogenetics |
Tempest H.G.,Florida International University
Asian Journal of Andrology | Year: 2012
Infertility in humans is surprisingly common occurring in approximately 15% of the population wishing to start a family. Despite this, the molecular and genetic factors underlying the cause of infertility remain largely undiscovered. Nevertheless, more and more genetic factors associated with infertility are being identified. This review will focus on our current understanding of the chromosomal basis of male infertility specifically: chromosomal aneuploidy, structural and numerical karyotype abnormalities and Y chromosomal microdeletions. Chromosomal aneuploidy is the leading cause of pregnancy loss and developmental disabilities in humans. Aneuploidy is predominantly maternal in origin, but concerns have been raised regarding the safety of intracytoplasmic sperm injection as infertile men have significantly higher levels of sperm aneuploidy compared to their fertile counterparts. Males with numerical or structural karyotype abnormalities are also at an increased risk of producing aneuploid sperm. Our current understanding of how sperm aneuploidy translates to embryo aneuploidy will be reviewed, as well as the application of preimplantation genetic diagnosis (PGD) in such cases. Clinical recommendations where possible will be made, as well as discussion of the use of emerging array technology in PGD and its potential applications in male infertility. © 2012 AJA, SIMM &SJTU. All rights reserved.
Munne S.,Reprogenetics |
Wells D.,Reprogenetics UK Ltd. |
Wells D.,University of Oxford |
Fertility and Sterility | Year: 2010
Preimplantation genetic diagnosis has been proposed as a method to improve assisted reproduction technology outcomes, but different techniques have produced conflicting results. The use of appropriate techniques may provide positive outcomes. © 2010 American Society for Reproductive Medicine.