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The rapid progress of the technologies applied to laboratory diagnostics allows several diagnostic and screening options for the identification of genetic diseases and chromosomal alterations in the antenatal age. Couples at risk to have a child with a chromosomal or genetic illness (i.e., carriers of previously identified genetic alterations, a previous child with a genetic condition, and/or a positive family history) should receive personalized genetic counselling, preferably before the pregnancy. In this way, couples will be able to receive appropriate information about the best diagnostic option based on their personal and familial history. Taking into account that prenatal diagnostic options are rapidly changing with the emerging of more sensitive technologies and that, consequently, the offer for diagnostic tests in reproductive medicine is increased, in this review we discuss about the diagnostic indications for each test in antenatal age, such as preimplantation, invasive prenatal and non-invasive prenatal diagnosis (PND). In addition, sampling and the laboratory techniques are well represented. Rapid progress of modern high-throughput molecular technologies, largely based on next generation sequencing, has required clinical validation studies. The most representative studies were included in order to better characterize the technology used for each diagnostic test. Therefore, the combination of innovative diagnostic technologies with the increase in demand (also related to the increased age of both partners facing the first pregnancy) has contributed to the practice of antenatal diagnosis and non-invasive prenatal screening (NIPT).

BACKGROUND: We developed a model to estimate the female age-dependent decrease in blastocyst euploidy and the impact of blastocyst cohort size on the likelihood of having at least one euploid blastocyst for transfer.METHODS: Retrospective analysis of 1,296 trophectoderm biopsies by next-generation sequencing analysis from 436 infertile couples undergoing intracytoplasmic sperm injection and preimplantation genetic testing for aneuploidy. A logistic regression model was fit to the data. The dependent and independent variables were embryo genetic status and female age, respectively. The method of fitting was quadratic on age, and the model was validated with cross validation by a data splitting technique.RESULTS: The decrease in the probability of blastocyst euploidy follows an age- dependent binomial distribution, progressing with every year of female age, from 1.2% to 24.5% in 28-44 years-old women (PCONCLUSIONS: A novel prediction model estimates the probability of blastocyst euploidy and the number of blastocysts required to obtain at least one euploid embryo for transfer. This new resource based on female age and blastocyst cohort size will aid clinicians counsel and plan treatment of infertile couples undergoing IVF/ICSI.

This research carries out with the aim of evaluating the ethical challenges faced by the use of antenatal diagnosis in late-onset genetic diseases.In a first study, we analysed the decisions of Multidisciplinary Centres for Prenatal Diagnosis (MCPD) and, through real and specific situations, we identified the elements for discussion and more particularly the ones that could influence the decision-making process. Then, we conducted two questionnaire surveys that allowed to: 1) Explore the viewpoints of people directly affected by this type of pathology (responsible gene carriers - ill or asymptomatic individuals -, partners and/or parents of gene carriers); 2) Examinate the opinions of professionals, working in association with a CPDPN and who are decision-makers of the acceptability or not for an antenatal diagnosis request in this context.This work has therefore brought out questions on ethics, and views on the potential legal and social developments in this area., Ce travail de recherche vise à évaluer les enjeux éthiques posés par le recours au diagnostic anténatal dans le cadre des maladies génétiques à révélation tardive.Notre première étude a été d’analyser les décisions prises en réunions de Centres Pluridisciplinaires de Diagnostic Prénatal (CPDPN) et, à travers des situations réelles et singulières, relever les éléments de discussion et plus particulièrement ceux pouvant influencer la décision. Nous avons, ensuite réalisé deux enquêtes par questionnaires qui ont permis: 1) D’explorer le point de vue des personnes directement concernées par une telle pathologie (porteurs du gène responsable - malades ou asymptomatiques -, conjoints et/ou parents d’une personne porteuse du gène) ; 2) D’étudier la position des professionnels de la parentalité, travaillant en lien avec un CPDPN, et qui sont décideurs de la recevabilité ou non d’une demande de diagnostic anténatal dans ce contexte.Ce travail a ainsi contribué à faire émerger des questionnements pertinents sur le plan éthique et une réflexion sur de possibles évolutions législatives et sociétales dans ce domaine.

This research carries out with the aim of evaluating the ethical challenges faced by the use of antenatal diagnosis in late-onset genetic diseases.In a first study, we analysed the decisions of Multidisciplinary Centres for Prenatal Diagnosis (MCPD) and, through real and specific situations, we identified the elements for discussion and more particularly the ones that could influence the decision-making process. Then, we conducted two questionnaire surveys that allowed to: 1) Explore the viewpoints of people directly affected by this type of pathology (responsible gene carriers - ill or asymptomatic individuals -, partners and/or parents of gene carriers); 2) Examinate the opinions of professionals, working in association with a CPDPN and who are decision-makers of the acceptability or not for an antenatal diagnosis request in this context.This work has therefore brought out questions on ethics, and views on the potential legal and social developments in this area., Ce travail de recherche vise à évaluer les enjeux éthiques posés par le recours au diagnostic anténatal dans le cadre des maladies génétiques à révélation tardive.Notre première étude a été d’analyser les décisions prises en réunions de Centres Pluridisciplinaires de Diagnostic Prénatal (CPDPN) et, à travers des situations réelles et singulières, relever les éléments de discussion et plus particulièrement ceux pouvant influencer la décision. Nous avons, ensuite réalisé deux enquêtes par questionnaires qui ont permis: 1) D’explorer le point de vue des personnes directement concernées par une telle pathologie (porteurs du gène responsable - malades ou asymptomatiques -, conjoints et/ou parents d’une personne porteuse du gène) ; 2) D’étudier la position des professionnels de la parentalité, travaillant en lien avec un CPDPN, et qui sont décideurs de la recevabilité ou non d’une demande de diagnostic anténatal dans ce contexte.Ce travail a ainsi contribué à faire émerger des questionnements pertinents sur le plan éthique et une réflexion sur de possibles évolutions législatives et sociétales dans ce domaine.

Objective To evaluate the impact of the male factor on the outcomes of intracytoplasmic sperm injection (ICSI) cycles combined with preimplantation genetic testing for aneuploidies (PGT-A). Design Observational longitudinal cohort study. Setting Private in vitro fertilization (IVF) center. Patient(s) A total of 1,219 oocyte retrievals divided into five study groups according to sperm parameters: normozoospermia (N), moderate male factor (MMF), severe oligoasthenoteratozoospermia (OAT-S), obstructive azoospermia (OA), and nonobstructive azoospermia (NOA). Intervention(s) ICSI with ejaculated/surgically retrieved sperm, blastocyst culture, trophectoderm-based quantitative polymerase chain reaction PGT-A, and frozen-warmed euploid embryo transfer (ET). Main Outcomes Measure(s) The primary outcome measures were fertilization, blastocyst development, and euploidy rates; the secondary outcome measures were live birth and miscarriage rates. Perinatal and obstetrical outcomes were monitored as well. Result(s) A total of 9,042 metaphase II oocytes were inseminated. The fertilization rate was significantly reduced in MMF, OAT-S, OA, and NOA compared with N (74.8%, 68.7%, 67.3%, and 53.1% vs. 77.2%). The blastocyst rate per fertilized oocyte was significantly reduced in MMF and NOA compared with N (48.6% and 40.6% vs. 49.3%). The timing of blastocyst development also was affected in OA and NOA. Logistic regression analysis adjusted for confounders highlighted NOA as a negative predictor of obtaining an euploid blastocyst per OPU (odds ratio 0.5). When the analysis was performed per obtained blastocyst, however, no correlation between male factor and euploidy rate was observed. Embryo transfers also resulted in similar live birth and miscarriage rates. No impact of sperm factor on obstetrical/perinatal outcomes was observed. Conclusion(s) Severe male factor impairs early embryonic competence in terms of fertilization rate and developmental potential. However, the euploidy rate and implantation potential of the obtained blastocysts are independent from sperm quality.

Objective To apply preimplantation genetic diagnosis (PGD) for the treatment of patients with a history of failed IVF-ET or habitual aborters. Design Prospective clinical study. Setting Tertiary center for assisted reproduction. Patient(s) Ninety-four couples with failed IVF-ET after >2 IVF cycles and 64 couples with >2 spontaneous abortions. Intervention(s) Patients were prepared for oocyte retrieval using standard controlled ovarian hyperstimulation protocols after standard laboratory techniques. Blastomeres from 6- to 8-cell embryos were analysed using fluorescence in situ hybridization with commercial chromosomal probes, and normoploid embryos were transferred on day 3 after fertilization. Main outcome measure(s) Pregnancy and implantation rates and live births. Result(s) Both 3- and 5-probe PGD resulted in a significantly higher outcome than controls for failed IVF-ET. Five-probe PGD appeared to be more suitable for habitual aborters. Conclusion(s) This pilot study suggests that 3-probe PGD is a valid option for failed IVF-ET patients. The use of five or more probes is indicated for habitual aborters.

At present, there is no evidence to suggest thrombophilic screening for patients with repeated IVF. Thrombophilic screening is very expensive and it has many implications, such as antithrombotic therapy in positive women and management of women carriers of mutations of uncertain pathological significance.Therefore, the introduction of thrombophilic screening in clinical practice should be evidence-based.

The clinical application of preimplantation genetic diagnosis (PGD) for aneuploidy has confirmed the hypothesis that implantation failure and spontaneous abortions are frequently due to aneuploidy. Following PGD, a higher implantation rate and a lower incidence of spontaneous abortions are obtained in patient categories where aneuploidy is the main cause of reproductive failure: women in advanced reproductive age, patients with an altered karyotype due to translocations or gonosomal mosaicism, and patients with recurrent spontaneous abortions. In these cases, the transfer of euploid embryos overcomes the poor prognosis condition in these couples. As expected, aneuploidy increases proportionally with female age; however, not all the chromosomes studied show this trend, suggesting that segregation errors could occur at different rates for each chromosome in relation to maternal age. Furthermore, the retrospective analysis of the results obtained in patients who repeated at least twice a PGD cycle permitted to estimate their chances of reproducing the same pattern of chromosomal abnormalities and consequently evaluating their possibility of a pregnancy: when no euploid embryos are detected at the first attempt, the chance of on-term pregnancy is below 10%; however, this chance is approximately 30% for couples with at least two euploid embryos in the first cycle.