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Concept: Embryo transfer

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BACKGROUNDGenetic testing of preimplantation embryos has been used for preimplantation genetic diagnosis (PGD) and preimplantation genetic screening (PGS). Microarray technology is being introduced in both these contexts, and whole genome sequencing of blastomeres is also expeted to become possible soon. The amount of extra information such tests will yield may prove to be beneficial for embryo selection, will also raise various ethical issues. We present an overview of the developments and an agenda-setting exploration of the ethical issues.METHODSThe paper is a joint endeavour by the presenters at an explorative ‘campus meeting’ organized by the European Society of Human Reproduction and Embryology in cooperation with the department of Health, Ethics & Society of the Maastricht University (The Netherlands).RESULTSThe increasing amount and detail of information that new screening techniques such as microarrays and whole genome sequencing offer does not automatically coincide with an increasing understanding of the prospects of an embryo. From a technical point of view, the future of comprehensive embryo testing may go together with developments in preconception carrier screening. From an ethical point of view, the increasing complexity and amount of information yielded by comprehensive testing techniques will lead to challenges to the principle of reproductive autonomy and the right of the child to an open future, and may imply a possible larger responsibility of the clinician towards the welfare of the future child. Combinations of preconception carrier testing and embryo testing may solve some of these ethical questions but could introduce others.CONCLUSIONSAs comprehensive testing techniques are entering the IVF clinic, there is a need for a thorough rethinking of traditional ethical paradigms regarding medically assisted reproduction.

Concepts: In vitro fertilisation, Ethics, Assisted reproductive technology, Preimplantation genetic diagnosis, Prenatal diagnosis, Medical genetics, Embryo transfer, Gattaca

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Follicle flushing has been proved to be ineffective in polyfollicular in-vitro fertilization. To analyse the effect of flushing in monofollicular in-vitro fertilisation we aspirated and then flushed the follicles in 164 cycles. Total oocyte yield/aspiration was 44.5% in the aspirate, 20.7% in the 1(st) flush, 10.4% in the 2(nd) flush and 4.3% in the 3(rd) flush. By flushing, the total oocyte yield increased (p<0.01) by 80.9% from 44.5% to 80.5%. The total transfer rate increased (p<0.01) by 91.0% from 20.1% to 38.4%. The results indicate that the oocyte yield and the number of transferable embryos can be significantly increased by flushing. © 2012 The Authors Acta Obstetricia et Gynecologica Scandinavica © 2012 Nordic Federation of Societies of Obstetrics and Gynecology.

Concepts: Pregnancy, Obstetrics, In vitro fertilisation, Gynecology, Flushing, Fertilisation, Obstetrics and gynaecology, Embryo transfer

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To preclude transfer of aneuploid embryos, current preimplantation genetic screening (PGS) usually involves one trophectoderm biopsy at blastocyst stage, assumed to represent embryo ploidy. Whether one such biopsy can correctly assess embryo ploidy has recently, however, been questioned.

Concepts: Cell, Embryo, Endometrium, Zygote, Preimplantation genetic diagnosis, Blastocyst, Prenatal diagnosis, Embryo transfer

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Embryo donation (also known as embryo adoption) is the compassionate gifting of residual cryopreserved embryos by consenting parents to infertile recipients. At present, only a limited number of such transactions occur. In 2010, the last year for which U.S. data were available, fewer than 1000 embryo donations were recorded. These acts of giving, unencumbered by federal law, are being guided by a limited number of state laws. Moreover, the practice is sanctioned by professional societies, such as the American Society for Reproductive Medicine, subject to the provision that “the selling of embryos per se is ethically unacceptable.”(1) As such, the . . .

Concepts: Pregnancy, Embryo, United States, Law of the United States, Embryo transfer, Giving, Donation, Embryo donation

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Preimplantation genetic diagnosis (PGD) aims to test the embryo for specific conditions before implantation in couples at risk of transmitting genetic abnormality to their offspring. The couple must undergo IVF procedures to generate embryos in vitro. The embryos can be biopsied at either the zygote, cleavage or blastocyst stage. Preimplantation genetic screening uses the same technology to screen for chromosome abnormalities in embryos from patients undergoing IVF procedures as a method of embryo selection. Fluorescence in-situ hybridization was originally used for chromosome analysis, but has now been replaced by array comparative genomic hybridization or next generation sequencing. For the diagnosis of single gene defects, polymerase chain reaction is used and has become highly developed; however, single nucleotide polymorphism arrays for karyomapping have recently been introduced. A partnership between IVF laboratories and diagnostic centres is required to carry out PGD and preimplantation genetic screening. Accreditation of PGD diagnostic laboratories is important. Accreditation gives IVF centres an assurance that the diagnostic tests conform to specified standards. ISO 15189 is an international laboratory standard specific for medical laboratories. A requirement for accreditation is to participate in external quality assessment schemes.

Concepts: DNA, Molecular biology, In vitro fertilisation, Assisted reproductive technology, Preimplantation genetic diagnosis, Comparative genomic hybridization, Prenatal diagnosis, Embryo transfer

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Despite excellent published results, the lack of well-designed, multicentre, randomized clinical trials results in an absence of general consensus on the efficacy of autologous endometrial cells coculture (AECC) in Assisted Reproductive Technology (ART). An open, multicentre, prospective, randomized controlled trial was designed to compare the pregnancy rate (PR) after the transfer of one blastocyst on day 5 after AECC to the transfer of one embryo on day 3 (control group). Patients were women aged 18 to 36, undergoing an ART cycle with no more than 1 embryo transfer failure. Sample size was calculated at 720 for a superiority trial involving an intermediate analysis at 300 patients. We present the results of the intermediate analysis that resulted in the study ending considering the observed difference. Three hundred thirty nine patients were randomized: 170 in the AECC group and 169 in the control group. The clinical PR per transfer was 53.4% with AECC and 37.3% in the control group (p=0.025). The quality of embryos was improved with AECC. These results suggest that implementation of the AECC technique to a large number of In-Vitro Fertilization (IVF) centres could lead to a substantial improvement in the proportion of successful assisted reproduction. The study was supported by the Laboratoires Genévrier, France.

Concepts: Pregnancy, Reproduction, Embryo, Randomized controlled trial, In vitro fertilisation, Preimplantation genetic diagnosis, Artificial insemination, Embryo transfer

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Background The transfer of fresh embryos is generally preferred over the transfer of frozen embryos for in vitro fertilization (IVF), but some evidence suggests that frozen-embryo transfer may improve the live-birth rate and lower the rates of the ovarian hyperstimulation syndrome and pregnancy complications in women with the polycystic ovary syndrome. Methods In this multicenter trial, we randomly assigned 1508 infertile women with the polycystic ovary syndrome who were undergoing their first IVF cycle to undergo either fresh-embryo transfer or embryo cryopreservation followed by frozen-embryo transfer. After 3 days of embryo development, women underwent the transfer of up to two fresh or frozen embryos. The primary outcome was a live birth after the first embryo transfer. Results Frozen-embryo transfer resulted in a higher frequency of live birth after the first transfer than did fresh-embryo transfer (49.3% vs. 42.0%), for a rate ratio of 1.17 (95% confidence interval [CI], 1.05 to 1.31; P=0.004). Women who underwent frozen-embryo transfer also had a lower frequency of pregnancy loss (22.0% vs. 32.7%), for a rate ratio of 0.67 (95% CI, 0.54 to 0.83; P<0.001), and of the ovarian hyperstimulation syndrome (1.3% vs. 7.1%), for a rate ratio of 0.19 (95% CI, 0.10 to 0.37; P<0.001), but a higher frequency of preeclampsia (4.4% vs. 1.4%), for a rate ratio of 3.12 (95% CI, 1.26 to 7.73; P=0.009). There were no significant between-group differences in rates of other pregnancy and neonatal complications. There were five neonatal deaths in the frozen-embryo group and none in the fresh-embryo group (P=0.06). Conclusions Among infertile women with the polycystic ovary syndrome, frozen-embryo transfer was associated with a higher rate of live birth, a lower risk of the ovarian hyperstimulation syndrome, and a higher risk of preeclampsia after the first transfer than was fresh-embryo transfer. (Funded by the National Basic Research Program of China and others; ClinicalTrials.gov number, NCT01841528 .).

Concepts: Pregnancy, Obstetrics, In vitro fertilisation, Gynecology, Assisted reproductive technology, Anovulation, Fertility medicine, Embryo transfer

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Background Elective frozen-embryo transfer has been shown to result in a higher live-birth rate than fresh-embryo transfer among anovulatory women with the polycystic ovary syndrome. It is uncertain whether frozen-embryo transfer increases live-birth rates among ovulatory women with infertility. Methods In this multicenter, randomized trial, we randomly assigned 2157 women who were undergoing their first in vitro fertilization cycle to undergo either fresh-embryo transfer or embryo cryopreservation followed by frozen-embryo transfer. Up to two cleavage-stage embryos were transferred in each participant. The primary outcome was a live birth after the first embryo transfer. Results The live-birth rate did not differ significantly between the frozen-embryo group and the fresh-embryo group (48.7% and 50.2%, respectively; relative risk, 0.97; 95% confidence interval [CI], 0.89 to 1.06; P=0.50). There were also no significant between-group differences in the rates of implantation, clinical pregnancy, overall pregnancy loss, and ongoing pregnancy. Frozen-embryo transfer resulted in a significantly lower risk of the ovarian hyperstimulation syndrome than fresh-embryo transfer (0.6% vs. 2.0%; relative risk, 0.32; 95% CI, 0.14 to 0.74; P=0.005). The risks of obstetrical and neonatal complications and other adverse outcomes did not differ significantly between the two groups. Conclusions The live-birth rate did not differ significantly between fresh-embryo transfer and frozen-embryo transfer among ovulatory women with infertility, but frozen-embryo transfer resulted in a lower risk of the ovarian hyperstimulation syndrome. (Funded by the National Key Research and Development Program of China and the National Natural Science Foundation of China; Chinese Clinical Trial Registry number, ChiCTR-IOR-14005406 .).

Concepts: Pregnancy, In vitro fertilisation, Menstrual cycle, Implantation, Polycystic ovary syndrome, Anovulation, Fertility medicine, Embryo transfer

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IMPORTANCE Between 1978 and 2010, approximately 5 million infants were born after in vitro fertilization (IVF) treatments. Yet limited information on neurodevelopment after IVF exists, especially after the first year of life. OBJECTIVE To examine the association between use of any IVF and different IVF procedures and the risk of autistic disorder and mental retardation in the offspring. DESIGN, SETTING, AND PARTICIPANTS A population-based, prospective cohort study using Swedish national health registers. Offspring born between 1982 and 2007 were followed up for a clinical diagnosis of autistic disorder or mental retardation until December 31, 2009. The exposure of interest was IVF, categorized according to whether intracytoplasmic sperm injection (ICSI) for male infertility was used and whether embryos were fresh or frozen. For ICSI, whether sperm were ejaculated or surgically extracted was also considered. MAIN OUTCOMES AND MEASURES Relative risks (RRs) for autistic disorder and mental retardation and rates per 100 000 person-years, comparing spontaneously conceived offspring with those born after an IVF procedure and comparing 5 IVF procedures used in Sweden vs IVF without ICSI with fresh embryo transfer, the most common treatment. We also analyzed the subgroup restricted to singletons. RESULTS Of the more than 2.5 million infants born, 30 959 (1.2%) were conceived by IVF and were followed up for a mean 10 (SD, 6) years. Overall, 103 of 6959 children (1.5%) with autistic disorder and 180 of 15 830 (1.1%) with mental retardation were conceived by IVF. The RR for autistic disorder after any procedure compared with spontaneous conception was 1.14 (95% CI, 0.94-1.39; 19.0 vs 15.6 per 100 000 person-years). The RR for mental retardation was 1.18 (95% CI, 1.01-1.36; 46.3 vs 39.8 per 100 000 person-years). For both outcomes, there was no statistically significant association when restricting analysis to singletons. Compared with IVF without ICSI with fresh embryo transfer, there were statistically significantly increased risks of autistic disorder following ICSI using surgically extracted sperm and fresh embryos (RR, 4.60 [95% CI, 2.14-9.88]; 135.7 vs 29.3 per 100 000 person-years); for mental retardation following ICSI using surgically extracted sperm and fresh embryos (RR, 2.35 [95% CI, 1.01-5.45]; 144.1 vs 60.8 per 100 000 person-years); and following ICSI using ejaculated sperm and fresh embryos (RR, 1.47 [95% CI, 1.03-2.09]; 90.6 vs 60.8 per 100 000 person-years). When restricting the analysis to singletons, the risks of autistic disorder associated with ICSI using surgically extracted sperm were not statistically significant, but the risks associated with ICSI using frozen embryos were significant for mental retardation (with frozen embryos, RR, 2.36 [95% CI, 1.04-5.36], 118.4 vs 50.6 per 100 000 person-years]; with fresh embryos, RR, 1.60 [95% CI, 1.00-2.57], 80.0 vs 50.6 per 100 000 person-years). CONCLUSIONS AND RELEVANCE Compared with spontaneous conception, IVF treatment overall was not associated with autistic disorder but was associated with a small but statistically significantly increased risk of mental retardation. For specific procedures, IVF with ICSI for paternal infertility was associated with a small increase in the RR for autistic disorder and mental retardation compared with IVF without ICSI. The prevalence of these disorders was low, and the increase in absolute risk associated with IVF was small.

Concepts: Pregnancy, Relative risk, Autism, Fertility, In vitro fertilisation, Fertility medicine, Embryo transfer, Embryo donation

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A plethora of assisted reproductive technologies (ARTs) have come into routine use over the past half century. Some of these procedures were used much earlier experimentally. For example, Spallanzani performed artificial insemination in the dog in the late 1700s, and Heap did successful embryo transfer in the rabbit in 1890. Truly revolutionary tools and concepts important for ART occur at approximately half-decade intervals, for example, recombinant DNA procedures, transgenic technology, somatic cell nuclear transplantation, the polymerase chain reaction, and microRNAs. Similarly, obvious technologies sometimes take decades to come into practical use, such as sexing sperm and in vitro fertilization. I have categorized ARTs into five somewhat arbitrary categories in terms of perceived difficulty and feasibility: (a) when the seemingly possible turns out to be (essentially) impossible, e.g., homozygous, uniparental females; (b) when the seemingly impossible becomes possible, e.g., cryopreservation of embryos and transgenesis; © when the seemingly difficult turns out to be relatively easy, e.g., cryopreservation of sperm; (d) when the seemingly easy turns out to be difficult in key species, e.g., in vitro fertilization; and (e) when the seemingly difficult remains difficult, e.g., making true embryonic stem cells. The adage that “it is easy when you know how” applies repeatedly. The boundaries between what appears impossible/possible and difficult/easy change constantly owing to new tools and insights, one of the more important lessons learned. ARTs frequently are synergistic with each other. For example, somatic cell nuclear transplantation has made many kinds of experiments feasible that otherwise were impractical. Another example is that sexing sperm is useless for application without artificial insemination or in vitro fertilization. ARTs frequently are perceived as neat tricks and stimulate further thinking. This is useful for both teaching and research. Expected final online publication date for the Annual Review of Animal Biosciences Volume 3 is February 15, 2015. Please see http://www.annualreviews.org/catalog/pubdates.aspx for revised estimates.

Concepts: DNA, Reproduction, Embryonic stem cell, In vitro fertilisation, Assisted reproductive technology, Artificial insemination, Fertility medicine, Embryo transfer