ESHRE guideline: recurrent pregnancy loss: an update in 2022.

STUDY QUESTION: What are the updates for the recommended management of women with recurrent pregnancy loss (RPL) based on the best available evidence in the literature from 2017 to 2022? SUMMARY ANSWER: The guideline development group (GDG) updated 11 existing recommendations on investigations and treatments for RPL, and how care should be organized, and added one new recommendation on adenomyosis investigation in women with RPL. WHAT IS KNOWN ALREADY: A previous ESHRE guideline on RPL was published in 2017 and needs to be updated. STUDY DESIGN SIZE DURATION: The guideline was developed and updated according to the structured methodology for development and update of ESHRE guidelines. The literature searches were updated, and assessments of relevant new evidence were performed. Relevant papers published between 31 March 2017 and 28 February 2022 and written in English were included. Cumulative live birth rate, live birth rate, and pregnancy loss rate (or miscarriage rate) were considered the critical outcomes. PARTICIPANTS/MATERIALS SETTING METHODS: Based on the collected evidence, recommendations were updated and discussed until consensus was reached within the GDG. A stakeholder review was organized after the updated draft was finalized. The final version was approved by the GDG and the ESHRE Executive Committee. MAIN RESULTS AND THE ROLE OF CHANCE: The new version of the guideline provides 39 recommendations on risk factors, prevention, and investigation in couples with RPL, and 38 recommendations on treatments. These includes 62 evidence-based recommendations-of which 33 were formulated as strong recommendations and 29 as conditional-and 15 good practice points. Of the evidence-based recommendations, 12 (19.4%) were supported by moderate-quality evidence. The remaining recommendations were supported by low (34 recommendations; 54.8%), or very low-quality evidence (16 recommendations; 25.8%). Owing to the lack of evidence-based investigations and treatments in RPL care, the guideline also clearly mentions those investigations and treatments that should not be used for couples with RPL. LIMITATIONS REASONS FOR CAUTION: The guidelines have been updated; however, several investigations and treatments currently offered to couples with RPL have not been well studied; for most of these investigations and treatments, a recommendation against using the intervention or treatment was formulated based on insufficient evidence. Future studies may require these recommendations to be revised. WIDER IMPLICATIONS OF THE FINDINGS: The guideline provides clinicians with clear advice on best practice in RPL, based on the best and most recent evidence available. In addition, a list of research recommendations is provided to stimulate further studies in RPL. Still, the absence of a unified definition of RPL is one of the most critical consequences of the limited scientific evidence in the field. STUDY FUNDING/COMPETING INTERESTS: The guideline was developed and funded by ESHRE, covering expenses associated with the guideline meetings, with the literature searches and with the dissemination of the guideline. The guideline group members did not receive payment.O.B.C. reports being a member of the executive board of the European Society for Reproductive Immunology and has received payment for honoraria for giving lectures about RPL in Australia in 2020. M.G. reports unconditional research and educational grant received by the Centre for Reproductive Medicine, Amsterdam UMC from Guerbet, Merck and Ferring, not related to the presented work. S.L. reports position funding from EXAMENLAB Ltd. and ownership interest by stock or partnership of EXAMENLAB Ltd (CEO). S.Q. reports being a deputy director of Tommy's National centre for miscarriage research, with payment received by the institution for research, staff time, and consumables for research. H.S.N. reports grants with payment to institution from Freya Biosciences ApS, Ferring Pharmaceuticals, BioInnovation Institute, the Danish ministry of Education, Novo Nordic Foundation, Augustinus Fonden, Oda og Hans Svenningsens Fond, Demant Fonden, Ole Kirks Fond, and Independent Research Fund Denmark and speakers' fees for lectures from Ferring Pharmaceuticals, Merck A/S, Astra Zeneca, IBSA Nordic and Cook Medical. She also reports to be an unpaid founder and chairman of a maternity foundation. M.-L.v.d.H. received small honoraria for lectures on RPL care. The other authors have no conflicts of interest to declare. DISCLAIMER: This guideline represents the views of ESHRE, which were achieved after careful consideration of the scientific evidence available at the time of preparation. In the absence of scientific evidence on certain aspects, a consensus between the relevant ESHRE stakeholders has been obtained.Adherence to these clinical practice guidelines does not guarantee a successful or specific outcome, nor does it establish a standard of care. Clinical practice guidelines do not replace the need for application of clinical judgment to each individual presentation, nor variations based on locality and facility type.ESHRE makes no warranty, express or implied, regarding the clinical practice guidelines and specifically excludes any warranties of merchantability and fitness for a particular use or purpose. (Full disclaimer available at www.eshre.eu/guidelines.).

HLA class I associations with the severity of COVID-19 disease in the United Arab Emirates.

SARS-CoV-2 appears to induce diverse innate and adaptive immune responses, resulting in different clinical manifestations of COVID-19. Due to their function in presenting viral peptides and initiating the adaptive immune response, certain Human Leucocyte Antigen (HLA) alleles may influence the susceptibility to severe SARS-CoV-2 infection. In this study, 92 COVID-19 patients from 15 different nationalities, with mild (n = 30), moderate (n = 35), and severe (n = 27) SARS-CoV-2 infection, living in the United Arab Emirates (UAE) were genotyped for the Class I HLA -A, -C, and -B alleles using next-generation sequencing (NGS) between the period of May 2020 to June 2020. Alleles and inferred haplotype frequencies in the hospitalized patient group (those with moderate to severe disease, n = 62) were compared to non-hospitalized patients (mild or asymptomatic, n = 30). An interesting trend was noted between the severity of COVID-19 and the HLA-C*04 (P = 0.0077) as well as HLA-B*35 (P = 0.0051) alleles. The class I haplotype HLA-C*04-B*35 was also significantly associated (P = 0.0049). The involvement of inflammation, HLA-C*04, and HLA-B*35 in COVID-19 severity highlights the potential roles of both the adaptive and innate immune responses against SARS-CoV-2. Both alleles have been linked to several respiratory diseases, including pulmonary arterial hypertension along with infections caused by the coronavirus and influenza. This study, therefore, supports the potential use of HLA testing in prioritizing public healthcare interventions for patients at risk of COVID-19 infection and disease progression, in addition to providing personalized immunotherapeutic targets.

Semen Quality is Associated with Sperm Aneuploidy and DNA Fragmentation in the United Arab Emirates Population.

Background: Sperm chromosome aneuploidy and the extent of sperm DNA fragmentation (SDF) are contributing factors to male infertility. Their extent can be measured using platforms such as sperm chromatin dispersion (SCD) and sperm fluorescence in situ hybridization (sFISH). Additional studies, however, are needed to understand the clinical applicability of these in vitro tests based on statistically validated thresholds. Aim: The primary objective of this study was to report the incidence of SDF and chromosomal aneuploidy with respect to sperm quality in the United Arab Emirates (UAE) population. In addition, we wished to establish clinically useful SDF and aneuploidy cutoff values. Materials and Methods: A total of 302 subjects were enrolled in this study. The control group consisted of n = 100 (33.11%) reproductively-proven fertile men, and the case group consisted of n = 202 (66.89%) infertile men. The sperm quality of the cases was further subclassified as normospermia ("Normo," n = 88; 43.56%); teratozoospermia ("T," n = 40; 19.80%); oligoasthenoteratozoospermia ("OAT," n = 37; 18.32%); asthenoteratozoospermia ("AT," n = 19; 9.41%); or oligoteratozoospermia ("OT," n = 18; 8.91%). The assessments of SDF were done using SCD tests. Chromosomal aneuploidy (Chr 13, 18, 21, X, and Y) was investigated using sFISH. Furthermore, based on the fragmentation index, cases were divided into subfertile groups defined as low, medium, high, and severe. The Mann-Whitney test was used to set the upper threshold value for sFISH, and the odds ratio was used for SDF assessment. Results: Cases having sperm quality "AT," "OAT," and "OT" together with the moderate, high, and severe subfertile groups had the highest DNA fragmentation indices: 31.58%, 27.03%, and 22.22%, respectively. In the sFISH analyses, groups with sperm quality "OAT," "T," and "OT" exhibited high degrees of abnormalities: 86.49%, 52.50%, and 50%, respectively. The most common chromosomal abnormalities found were "sex chromosome hyperploidy (XY18)" and "diploid (Chr 13, 21)." The incidences of sperm quality with respect to SDF and sFISH are also reported in detail. Conclusions: This is the first study in the UAE which shows SDF and sFISH incidences together with sperm quality. This study also establishes SDF and sFISH cutoff values for the UAE population.

Introducing the first whole genomes of nationals from the United Arab Emirates.

Whole Genome Sequencing (WGS) provides an in depth description of genome variation. In the era of large-scale population genome projects, the assembly of ethnic-specific genomes combined with mapping human reference genomes of underrepresented populations has improved the understanding of human diversity and disease associations. In this study, for the first time, whole genome sequences of two nationals of the United Arab Emirates (UAE) at >27X coverage are reported. The two Emirati individuals were predominantly of Central/South Asian ancestry. An in-house customized pipeline using BWA, Picard followed by the GATK tools to map the raw data from whole genome sequences of both individuals was used. A total of 3,994,521 variants (3,350,574 Single Nucleotide Polymorphisms (SNPs) and 643,947 indels) were identified for the first individual, the UAE S001 sample. A similar number of variants, 4,031,580 (3,373,501 SNPs and 658,079 indels), were identified for UAE S002. Variants that are associated with diabetes, hypertension, increased cholesterol levels, and obesity were also identified in these individuals. These Whole Genome Sequences has provided a starting point for constructing a UAE reference panel which will lead to improvements in the delivery of precision medicine, quality of life for affected individuals and a reduction in healthcare costs. The information compiled will likely lead to the identification of target genes that could potentially lead to the development of novel therapeutic modalities.

ESHRE guideline: recurrent pregnancy loss.

STUDY QUESTION: What is the recommended management of women with recurrent pregnancy loss (RPL) based on the best available evidence in the literature? SUMMARY ANSWER: The guideline development group formulated 77 recommendations answering 18 key questions on investigations and treatments for RPL, and on how care should be organized. WHAT IS KNOWN ALREADY: A previous guideline for the investigation and medical treatment of recurrent miscarriage was published in 2006 and is in need of an update. STUDY DESIGN SIZE DURATION: The guideline was developed according to the structured methodology for development of ESHRE guidelines. After formulation of key questions by a group of experts, literature searches and assessments were performed. Papers published up to 31 March 2017 and written in English were included. Cumulative live birth rate, live birth rate and pregnancy loss rate (or miscarriage rate) were considered the critical outcomes. PARTICIPANTS/MATERIALS SETTING METHODS: Based on the collected evidence, recommendations were formulated and discussed until consensus was reached within the guideline group. A stakeholder review was organized after finalization of the draft. The final version was approved by the guideline group and the ESHRE Executive Committee. MAIN RESULTS AND THE ROLE OF CHANCE: The guideline provides 38 recommendations on risk factors, prevention and investigations in couples with RPL, and 39 recommendations on treatments. These include 60 evidence-based recommendations - of which 31 were formulated as strong recommendations and 29 as conditional - and 17 good practice points. The evidence supporting investigations and treatment of couples with RPL is limited and of moderate quality. Of the evidence-based recommendations, only 10 (16.3%) were supported by moderate quality evidence. The remaining recommendations were supported by low (35 recommendations: 57.4%), or very low quality evidence (16 recommendations: 26.2%). There were no recommendations based on high quality evidence. Owing to the lack of evidence-based investigations and treatments in RPL care, the guideline also clearly mentions investigations and treatments that should not be used for couples with RPL. LIMITATIONS REASONS FOR CAUTION: Several investigations and treatments are offered to couples with RPL, but most of them are not well studied. For most of these investigations and treatments, a recommendation against the intervention or treatment was formulated based on insufficient evidence. Future studies may require these recommendations to be revised. WIDER IMPLICATIONS OF THE FINDINGS: The guideline provides clinicians with clear advice on best practice in RPL, based on the best evidence available. In addition, a list of research recommendations is provided to stimulate further studies in RPL. One of the most important consequences of the limited evidence is the absence of evidence for a definition of RPL. STUDY FUNDING/COMPETING INTERESTS: The guideline was developed and funded by ESHRE, covering expenses associated with the guideline meetings, with the literature searches and with the dissemination of the guideline. The guideline group members did not receive payment. J.E. reports position funding from CARE Fertility. S.L. reports position funding from SpermComet Ltd. S.M. reports research grants, consulting and speaker's fees from GSK, BMS/Pfizer, Sanquin, Aspen, Bayer and Daiichi Sankyo. S.Q. reports speaker's fees from Ferring. The other authors report no conflicts of interest.ESHRE Pages are not externally peer reviewed. This article has been approved by the Executive Committee of ESHRE.

Low Gonadotropin Dosage Reduces Aneuploidy in Human Preimplantation Embryos: First Clinical Study in a UAE Population.

TYPE OF STUDY: Retrospective analysis of embryo aneuploidy in patients undergoing in vitro fertilization (IVF) cycles. AIM: To evaluate factors that might affect the incidence of embryo aneuploidy during IVF cycles. METHODS: Three hundred twelve IVF cases were included in the present study. Preimplantation genetic testing for aneuploidy (PGT-A) was performed for all the subjects involved. Subject stratification was done based on maternal age, gonadotropin drug dosage, and IVF outcomes data. Maternal age <35 years were placed in the "Young" age group and age ≥35 years were placed in the "Advanced Maternal Age" group. Similarly, IVF drug administered <200 International units (IU) was considered "low dosage," group and ≥200 IU were considered "high dosage" group. Patients were stratified into four groups-group 1: age <35 years and administered <200 IU; group 2: age <35 years and administered ≥200 IU; group 3: age ≥35 years and administered at <200 IU; and group 4: age ≥35 years and administered ≥200 IU. PGT-A results were attained using a next-generation sequencing-based protocol. Embryo transfer was guided by transabdominal ultrasound. Statistical significance was calculated with the use of chi-square test. RESULTS: One thousand fifty blastocyst trophectoderm biopsies from 312 IVF cases were retrieved. The IVF outcome of a total of 105 normal cases resulted in 65.71% pregnancies. Stratifying for maternal age and IVF drug stimulation with PGT-A analyses we found the euploid embryo percentages equal to 37.59% in Group 1; 16.18% in Group 2; 22.44% in Group 3; and 2.59% in Group 4. Similarly the aneuploid embryo (percentage)s were 62.40% for Group 1; 83.81% for Group 2; 77.55% for Group 3; and 87.40% for Group 4. CONCLUSION: This is the first clinical study reporting that gonadotropin dosage may act as a contributing factor in increasing aneuploidy incidences for the patients undergoing IVF cycles in the UAE population. This study shows that in all patient age groups, lower drug stimulation leads to an increasing trend in embryo euploidy.

Validation of Next-Generation Sequencer for 24-Chromosome Aneuploidy Screening in Human Embryos.

BACKGROUND: Next-Generation Sequencing (NGS) is the latest approach for preimplantation genetic diagnoses (PGD). AIM: The purpose of this study was to standardize and validate an NGS method for comprehensive chromosome screening and to investigate its applicability to PGD. METHODS: Embryo biopsy, whole-genome amplification, array comparative genomic hybridization (aCGH), and semiconductor sequencing were employed. RESULTS: A total of 204 whole-genome-amplified products were tested with an NGS-based protocol, from which 100 samples were used for standardization and to evaluate the quality of the results produced by this new technique. The remaining 104 samples tested by NGS were previously analyzed by using the aCGH protocol to determine the sensitivity and specificity of this new technique. In total, 4896 chromosomes were assessed, out of which 196 carried a copy number imbalance. NGS sensitivity and specificity for calling aneuploidy was 100%. CONCLUSION: This is the first study reporting preclinical validation and accuracy assessment of the Ion Torrent Personal Genome Machine (PGM) NGS-based comprehensive chromosome screening method using blastomeres and blastocysts. The NGS proved to be a robust methodology and is ready for clinical application in reproductive medicine, with the major advantage of low cost and enhanced precision when compared with other technologies used for comprehensive chromosome screening.