Role of genetic analysis of products of conception and PGT in managing early pregnancy loss.

This article considers the addition of comprehensive 24-chromosomal microarray (CMA) analysis of products of conception (POC) to a standard evaluation for recurrent pregnancy loss (RPL) to help direct treatment towards expectant management versus IVF with preimplantation genetic testing for aneuploidies (PGT-A). The review included retrospective data from 65,333 miscarriages, a prospective evaluation of 378 couples with RPL who had CMA testing of POC and the standard workup, and data from an additional 1020 couples who were evaluated for RPL but did not undergo CMA testing of POC. Aneuploidy in POC explained the pregnancy loss in 57.7% (218/378) of cases. In contrast, the full RPL evaluation recommended by the American Society for Reproductive Medicine identified a potential cause in only 42.9% (600/1398). Combining the data from the RPL evaluation and the results of genetic testing of POC provides a probable explanation for the loss in over 90% (347/378) of women. Couples with an unexplained loss after the standard evaluation with POC aneuploidy accounted for 41% of cases; PGT-A may be considered after expectant management. Conversely, PGT-A would have a limited role in those with a euploid loss and a possible explanation after the standard workup. Categorizing a pregnancy loss as an explained versus unexplained loss after the standard evaluation combined with the results of CMA testing of POC may help identify patients who would benefit from expectant management versus PGT-A.

The Effects of Long-Term Dienogest Therapy on In Vitro Fertilization Outcomes in Women with Endometriosis: A Systematic Review and Meta-Analysis.

OBJECTIVES: Assessing dienogest's efficacy in endometriosis patients undergoing in vitro fertilization (IVF). DATA SOURCES: Systematic search in databases (PubMed, MEDLINE, Embase, Web of Science, Cochrane CENTRAL, Google Scholar) until 1 October 2022. STUDY SELECTIONS: Randomized trials and observational studies comparing extended dienogest pre-treatment, no pre-treatment, or gonadotropin-releasing hormone (GnRH) agonist pre-treatment in endometriosis-linked IVF. OUTCOME MEASURES: live birth, clinical pregnancy rates, oocytes collected, miscarriage rate, gonadotropin consumption. DATA EXTRACTIONS AND SYNTHESES: Two authors independently assessed eligibility. Dichotomous variables were analyzed via a random-effect model and Mantel-Haenszel method to calculate weighted estimates and 95% confidence intervals (CI). I2 statistic gauged study heterogeneity; GRADE criteria evaluated evidence quality. CONCLUSIONS: Out of 191 publications, five studies with 723 participants were included. Uncertainty persists on whether prolonged dienogest affects live birth (RR 1.42, 95% CI 0.29 to 6.84; 3 studies, n = 289; I2 86%) and clinical pregnancy rates (RR 1.33, 95% CI 0.31 to 5.65; 3 studies, n = 289; I2 86%) compared to conventional IVF. Moreover, uncertainty remains regarding intervention impact on live birth (RR 1.46, 95% CI 0.63 to 3.37; 1 study, n = 34) and clinical pregnancy rates (RR 1.32, 95% CI 0.78 to 2.23; 3 studies, n = 288; I2 0%) versus long-term GnRH agonist therapy before IVF. Given limited data and very low evidence quality, doubts arise about the benefits of long-term dienogest pre-treatment before conventional IVF in endometriosis patients.

Prevention of multiple pregnancies in gonadotropin-insemination cycles.

PURPOSE OF REVIEW: Although elective single embryo transfer has significantly reduced, the rate of multiple pregnancy in IVF cycles, this rate is still relatively high in gonadotropin-insemination cycles. Patients who fail to ovulate or to conceive with oral agents and have constraints for IVF are usually candidates for gonadotropin injections. The current review article provides an up-to-date summation of the different strategies that can be adopted to reduce the risk of multiple pregnancies in gonadotropin-stimulated intrauterine insemination cycles. RECENT FINDINGS: Gonadotropin-insemination treatments should be used judiciously by experienced providers. One should always start with the lowest effective gonadotropin dose (∼37.5 IU), monitor closely the ovarian response, and consider cycle cancellation or conversion to IVF whenever a high response is encountered. Therefore, every infertility practice should define its own cancellation and 'rescue IVF' criteria depending on the number of mature ovarian follicles and the age of the female partner. SUMMARY: These preventive measures amongst others should mitigate the risk of multiple pregnancies that can arise from gonadotropin-insemination cycles.

Genetic testing of products of conception in recurrent pregnancy loss evaluation.

Genetic testing of products of conception (POC) has been proposed as a tool to be used in the evaluation of patients with recurrent pregnancy loss (RPL). Following a complete RPL evaluation, POC results may reveal an aneuploidy and provide an explanation for the miscarriage in more than 55% of cases. When the cytogenetic result of the pregnancy loss reveals a euploid pregnancy, management should be directed towards the identification of treatable abnormalities. Furthermore, the results of POC testing might better define a subgroup of patients with unexplained RPL who may benefit from expectant management versus preimplantation genetics (aneuploid unexplained RPL) or investigational therapy (euploid unexplained RPL).

Impact of blastocyst biopsy and comprehensive chromosome screening technology on preimplantation genetic screening: a systematic review of randomized controlled trials.

Embryonic aneuploidy is highly prevalent in IVF cycles and contributes to decreased implantation rates, IVF cycle failure and early pregnancy loss. Preimplantation genetic screening (PGS) selects the most competent (euploid) embryos for transfer, and has been proposed to improve IVF outcomes. Use of PGS with fluorescence-in-situ hybridization technology after day 3 embryo biopsy (PGS-v1) significantly lowers live birth rates and is not recommended for use. Comprehensive chromosome screening technology, which assesses the whole chromosome complement, can be achieved using different genetic platforms. Whether PGS using comprehensive chromosome screening after blastocyst biopsy (PGS-v2) improves IVF outcomes remains to be determined. A systematic review of randomized controlled trials was conducted on PGS-v2. Three trials met full inclusion criteria, comparing PGS-v2 and routine IVF care. PGS-v2 is associated with higher clinical implantation rates, and higher ongoing pregnancy rates when the same number of embryos is transferred in both PGS and control groups. Additionally, PGS-v2 improves embryo selection in eSET practice, maintaining the same ongoing pregnancy rates between PGS and control groups, while sharply decreasing multiple pregnancy rates. These results stem from good-prognosis patients undergoing IVF. Whether these findings can be extrapolated to poor-prognosis patients with decreased ovarian reserve remains to be determined.

RETIRED: Technical Update: Preimplantation Genetic Diagnosis and Screening

This document has been archived because it contains outdated information. It should not be consulted for clinical use, but for historical research only. Please visit the journal website for the most recent guidelines.

Ce document a été archivé, car il contient des informations périmées. Il ne devrait pas être consulté pour un usage clinique, mais uniquement pour des recherches historiques. Veuillez consulter le site web du journal pour les directives les plus récentes.

Is the flexible GnRH antagonist protocol better suited for fresh eSET cycles?

OBJECTIVE: This study was performed to evaluate the efficacy of the flexible GnRH antagonist protocol in comparison with the long GnRH agonist protocol in elective single embryo transfer (eSET) practice. It was conducted in a publicly funded in vitro fertilization program. METHODS: We performed a prospective cohort analysis of data from a private infertility clinic from August 2010 to August 2011. Three hundred fourteen women with normal ovarian reserve and undergoing fresh eSET cycles were included. Sixty-four women underwent follicular stimulation using a flexible GnRH antagonist protocol, and 250 underwent stimulation with a standard long mid-luteal GnRH agonist protocol. RESULTS: Implantation rates (35.9% in the GnRH antagonist group and 29.6% in the GnRH agonist group, P = 0.5) and ongoing pregnancy rates (32.8% in the GnRH antagonist group and 28.8% in the GnRH agonist group, P = 0.5) were equivalent in both groups. The duration of stimulation (9.8 ± 2 days vs. 10.7 ± 1.8 days, P < 0.001) and total FSH dose required (2044 vs. 2775 IU, P < 0.001) were lower in the GnRH antagonist group than in the GnRH agonist group. The number of mature oocytes (6.0 vs. 10.0, P < 0. 001) and number of embryos (5.0 vs. 7.0, P < 0.001) were also lower in GnRH antagonist group. However, the number of embryos cryopreserved was similar in both groups (median 2.0, P = 0.3). CONCLUSION: In women undergoing in vitro fertilization, the flexible GnRH antagonist protocol yields implantation and ongoing pregnancy rates that are similar to the long GnRH agonist protocol, and requires lower doses of gonadotropins and a shorter duration of treatment. The flexible GnRH antagonist protocol appears to be the protocol of choice for an eSET IVF program.

Objectif : La présente étude visait à évaluer l'efficacité d'un protocole flexible ayant recours à des antagonistes de la GnRH, par comparaison avec celle d'un protocole long ayant recours à des agonistes de la GnRH, relativement au transfert sélectif d'un seul embryon (TsSE). L'étude a été menée dans le cadre d'un programme de fécondation in vitro financé par l'État. Méthodes : Nous avons effectué une analyse de cohorte prospective au moyen de données issues d'une clinique de fertilité privée, pour ce qui est de la période d'août 2010 à août 2011. Trois cent quatorze femmes présentant une réserve ovarienne normale et se soumettant à des cycles de TsSE frais ont été admises à l'étude. Un protocole flexible ayant recours à des antagonistes de la GnRH a été utilisé chez 64 femmes, aux fins de la stimulation folliculaire, tandis qu'un protocole long en phase lutéale standard ayant recours à des agonistes de la GnRH a été utilisé chez 250 autres femmes. Résultats : Les taux d'implantation (35,9 % au sein du groupe « antagonistes de la GnRH ¼ et 29,6 % au sein du groupe « agonistes de la GnRH ¼, P = 0,5) et les taux de grossesse en cours (32,8 % au sein du groupe « antagonistes de la GnRH ¼ et 28,8 % au sein du groupe « agonistes de la GnRH ¼, P = 0,5) étaient équivalents dans les deux groupes. La durée de la stimulation (9,8 jours ± 2 jours vs 10,7 jours ± 1,8 jour, P < 0,001) et la dose totale de FSH requise (2 044 vs 2 775 UI, P < 0,001) étaient moins élevées au sein du groupe « antagonistes de la GnRH ¼, par comparaison avec le groupe « agonistes de la GnRH ¼. Le nombre d'ovocytes matures (6,0 vs 10,0, P < 0,001) et le nombre d'embryons (5,0 vs 7,0, P < 0,001) étaient également moins élevés au sein du groupe « antagonistes de la GnRH ¼. Cependant, le nombre d'embryons cryoconservés était similaire dans les deux groupes (médiane : 2,0, P = 0,3). Conclusion : Chez les femmes qui font appel à la fécondation in vitro, le protocole flexible ayant recours à des antagonistes de la GnRH donne des taux d'implantation et de grossesse en cours similaires à ceux que permet le protocole long standard ayant recours à des agonistes de la GnRH, tout en nécessitant des doses plus faibles de gonadotropines et un traitement de plus courte durée. Le protocole flexible ayant recours à des antagonistes de la GnRH semble être le protocole à privilégier dans le cadre d'un programme de FIV utilisant le TsSE.

Rescue in vitro fertilization using a GnRH antagonist in hyper-responders from gonadotropin intrauterine insemination (IUI) cycles.

OBJECTIVE: To evaluate the outcomes in the conversion of high-response gonadotropin intrauterine insemination (IUI) cycles to "rescue" in vitro fertilization (IVF) using a Gonadotropin-Releasing Hormone (GnRH) antagonist, with regards to implantation rates, pregnancy rates, cost, and ovarian hyperstimulation syndrome (OHSS) as compared to matched, hyper-responder, IVF controls. METHODS: This prospective cohort study was conducted between January 2007 and December 2009 at our institution. In order to decrease high-order multiple pregnancy, minimize the incidence of OHSS, and avoid cycle cancellation, high-response stimulated-IUI patients opted to convert to "rescue" IVF using the GnRH antagonist cetrorelix acetate. We then compared their clinical outcomes with matched patients from high-response IVF cycles of the standard long mid-luteal GnRH agonist protocol (14 or more collected oocytes). Only cases of conventional IVF without intra-cytoplasmic sperm injection (ICSI) were included in the control group. RESULTS: Out of 184 patients undergoing stimulated-IUI cycles with gonadotropins, 87 patients developed a hyper-response, and 20 opted to convert to "rescue" IVF. These patients were compared with 157 matched, hyper responder IVF controls from our registry. The implantation rate was 25.6 % in the "rescue" IVF group and 20.7 % in the control IVF group (p < 0.0047). The ongoing clinical pregnancy rate per embryo transfer was 45.0 % and 33.6 % in the "rescue" IVF and the control IVF groups, respectively (p < 0.0001). The mean duration of stimulation was comparable between cohorts (10.0 vs.10.4 days, p = 0.6324). The mean dose of gonadotropin used per cycle was higher in the control group, 2664 international units (IU) of follicle stimulation hormone (FSH) compared to 1450 IU of FSH in the "rescue" IVF group (p < 0.0001). The incidence of severe OHSS is also higher in the control group, 5.1 % versus no cases in the "rescue" IVF group (p < 0.0001). CONCLUSION: Our study demonstrates that conversion of high-response gonadotropin-IUI cycles to "rescue" IVF using a GnRH antagonist is a cost-effective strategy that produces better results than regular IVF with relatively minimal morbidity, and shorter duration to achieve pregnancy. Implantation and ongoing clinical pregnancy rates tend to be higher than those from hyper-responder regular IVF patients.

Update on preimplantation genetic testing for aneuploidy and outcomes of embryos with mosaic results.

Preimplantation genetic testing for aneuploidy (PGT-A) is used as a frequent add-on for in-vitro fertilization (IVF) to improve clinical outcomes. The purpose is to select a euploid embryo following chromosomal testing on embryo biopsies. The current practice includes comprehensive chromosome screening (CCS) technology applied on trophectoderm (TE) biopsies. Despite its widespread use, PGT-A remains a controversial topic mainly because all of the RCTs comprised only good prognosis patients with 2 or more blastocysts available; hence the results are not generalizable to all groups of patients. Furthermore, with the introduction of the highly-sensitive platforms into clinical practice (i.e. next-generation sequencing [NGS]), a result consistent with intermediate copy number surfaced and is termed "Mosaic," consistent with a mixture of euploid and aneuploid cells within the biopsy sample. The optimal disposition and management of embryos with mosaic results is still an open question, as many 'mosaics' generated healthy live births with no identifiable congenital anomalies. The present article provides a complete and comprehensive up-to-date review on PGT-A. It discusses in detail the findings of all the published RCTs on PGT-A with CCS, comments on the subject of "mosaicism" and its current management, and describes the latest technique of non-invasive PGT-A.

Successful treatment of ptyalism gravidarum with clonidine hydrochloride: A case report.

Ptyalism gravidarum is a disorder characterized by significant hypersalivation during pregnancy, which affects and interferes with quality of life. No published data has demonstrated an effective approach to treat this condition. This case study reports the use of clonidine hydrochloride, an alpha-2-adrenergic receptor agonist that is typically used as an anti-hypertensive agent, to treat the excessive sialorrhea typical of this disorder. The patient who was treated with this medication saw significant improvement in her symptoms and did not experience any subsequent adverse effects throughout her pregnancy. As a result, we believe that further investigation into this potential treatment for ptyalism gravidarum is necessary ahead of medical guideline incorporation and clinical implementation.

Preimplantation Genetic Testing for Aneuploidy: A Review of the Evidence.

Preimplantation genetic testing for aneuploidy was developed as an invasive embryo-selection technique and is extensively used in in vitro fertilization (IVF) cycles. Around 95,000 preimplantation genetic testing cycles were carried out in the United States between 2014 and 2016, the majority of which were performed for aneuploidy. The objective of preimplantation genetic testing for aneuploidy is to select for transfer a euploid embryo, after embryo biopsy and cytogenetic analysis. The current technique consists of applying comprehensive chromosome screening on trophectoderm cells after blastocyst-stage embryo biopsy. This article reviews all the published randomized controlled trials on preimplantation genetic testing for aneuploidy with comprehensive chromosome screening and comments on the subject of embryo mosaicism detected by this technique. Most of these trials have been criticized because they only included good prognosis patients having normal ovarian reserve producing a high number of embryos available for biopsy. Preimplantation genetic testing for aneuploidy does not improve ongoing pregnancy rates per cycle started when routinely applied on the general IVF population but seems to be a good tool of embryo selection for a selected category of patients with normal ovarian reserve, yet should be only practiced by experienced IVF clinics. If no euploid embryo is available after preimplantation genetic testing for aneuploidy, a low-level mosaic embryo can be considered and prioritized for transfer after appropriate genetic counseling.