Luteinizing hormone profiles during ovarian stimulation in assisted reproductive treatment.

Introduction: Few data is available on the natural course of luteinizing hormone (LH) during ovarian stimulation, but it has been suggested that 'oversuppressed' LH could decrease fertility outcomes. Our aim with this study is to evaluate the changes in LH depending on the used stimulation protocol to better define LH oversuppressioin.

Methods: Patients undergoing oocyte retrieval in a tertiary fertility center between 01-01-2015 and 30-09-2020 after stimulation with a short-agonist (SA) or antagonist (A) protocol were included.

The Impact of Chronic Endometritis on Infertility: Prevalence, Reproductive Outcomes, and the Role of Hysteroscopy as a Screening Tool.

Objectives: The objective of this study was to examine the prevalence of chronic endometritis (CE) in infertile women, its impact on reproductive outcomes, and the accuracy of hysteroscopy as a screening tool for CE.

Design: This was a prospective observational study.

Participants: Participants involved in this study were 514 asymptomatic patients with infertility.

Preclinical workup using long-read amplicon sequencing provides families with de novo pathogenic variants access to universal preimplantation genetic testing.

Study Question: Can long-read amplicon sequencing be beneficial for preclinical preimplantation genetic testing (PGT) workup in couples with a de novo pathogenic variant in one of the prospective parents?

Summary Answer: Long-read amplicon sequencing represents a simple, rapid and cost-effective preclinical PGT workup strategy that provides couples with de novo pathogenic variants access to universal genome-wide haplotyping-based PGT programs.

What Is Known Already: Universal PGT combines genome-wide haplotyping and copy number profiling to select embryos devoid of both familial pathogenic variants and aneuploidies. However, it cannot be directly applied in couples with a de novo pathogenic variant in one of the partners due to the absence of affected family members required for phasing the disease-associated haplotype.

Parental genomes segregate into distinct blastomeres during multipolar zygotic divisions leading to mixoploid and chimeric blastocysts.

Background: During normal zygotic division, two haploid parental genomes replicate, unite and segregate into two biparental diploid blastomeres.

Results: Contrary to this fundamental biological tenet, we demonstrate here that parental genomes can segregate to distinct blastomeres during the zygotic division resulting in haploid or uniparental diploid and polyploid cells, a phenomenon coined heterogoneic division. By mapping the genomic landscape of 82 blastomeres from 25 bovine zygotes, we show that multipolar zygotic division is a tell-tale of whole-genome segregation errors.

Single-cell genome-wide concurrent haplotyping and copy-number profiling through genotyping-by-sequencing.

Single-cell whole-genome haplotyping allows simultaneous detection of haplotypes associated with monogenic diseases, chromosome copy-numbering and subsequently, has revealed mosaicism in embryos and embryonic stem cells. Methods, such as karyomapping and haplarithmisis, were deployed as a generic and genome-wide approach for preimplantation genetic testing (PGT) and are replacing traditional PGT methods. While current methods primarily rely on single-nucleotide polymorphism (SNP) array, we envision sequencing-based methods to become more accessible and cost-efficient.

Haplotyping-based preimplantation genetic testing reveals parent-of-origin specific mechanisms of aneuploidy formation.

Chromosome instability is inherent to human IVF embryos, but the full spectrum and developmental fate of chromosome anomalies remain uncharacterized. Using haplotyping-based preimplantation genetic testing for monogenic diseases (PGT-M), we mapped the parental and mechanistic origin of common and rare genomic abnormalities in 2300 cleavage stage and 361 trophectoderm biopsies. We show that while single whole chromosome aneuploidy arises due to chromosome-specific meiotic errors in the oocyte, segmental imbalances predominantly affect paternal chromosomes, implicating sperm DNA damage in segmental aneuploidy formation.

Identity-by-state-based haplotyping expands the application of comprehensive preimplantation genetic testing.

Study Question: Is it possible to haplotype parents using parental siblings to leverage preimplantation genetic testing (PGT) for monogenic diseases and aneuploidy (comprehensive PGT) by genome-wide haplotyping?

Summary Answer: We imputed identity-by-state (IBS) sharing of parental siblings to phase parental genotypes.

What Is Known Already: Genome-wide haplotyping of preimplantation embryos is being implemented as a generic approach for genetic diagnosis of inherited single-gene disorders. To enable the phasing of genotypes into haplotypes, genotyping the direct family members of the prospective parent carrying the mutation is required.

Multi-centre evaluation of a comprehensive preimplantation genetic test through haplotyping-by-sequencing.

Study Question: Can reduced representation genome sequencing offer an alternative to single nucleotide polymorphism (SNP) arrays as a generic and genome-wide approach for comprehensive preimplantation genetic testing for monogenic disorders (PGT-M), aneuploidy (PGT-A) and structural rearrangements (PGT-SR) in human embryo biopsy samples?

Summary Answer: Reduced representation genome sequencing, with OnePGT, offers a generic, next-generation sequencing-based approach for automated haplotyping and copy-number assessment, both combined or independently, in human single blastomere and trophectoderm samples.

What Is Known Already: Genome-wide haplotyping strategies, such as karyomapping and haplarithmisis, have paved the way for comprehensive PGT, i.e.

Genome-wide haplotyping embryos developing from 0PN and 1PN zygotes increases transferrable embryos in PGT-M.

Study Question: Can genome-wide haplotyping increase success following preimplantation genetic testing for a monogenic disorder (PGT-M) by including zygotes with absence of pronuclei (0PN) or the presence of only one pronucleus (1PN)?

Summary Answer: Genome-wide haplotyping 0PNs and 1PNs increases the number of PGT-M cycles reaching embryo transfer (ET) by 81% and the live-birth rate by 75%.

What Is Known Already: Although a significant subset of 0PN and 1PN zygotes can develop into balanced, diploid and developmentally competent embryos, they are usually discarded because parental diploidy detection is not part of the routine work-up of PGT-M.

Study Design, Size, Duration: This prospective cohort study evaluated the pronuclear number in 2229 zygotes from 2337 injected metaphase II (MII) oocytes in 268 cycles.

Cost-effectiveness of ovarian stimulation with gonadotrophin and clomiphene citrate in an intrauterine insemination programme for subfertile couples.

Ovarian stimulation with low-dose human menopausal gonadotrophin (HMG) is superior to clomiphene citrate in intrauterine insemination (IUI) cycles with respect to clinical pregnancy rate, but it is unclear whether HMG is also the more cost-effective option. The aim of this study was to compare the cost-effectiveness of ovarian stimulation with low-dose subcutaneously administred HMG (37.5-75 IU per day) to orally administred clomiphene citrate (50 mg/day from day 3-7) in an IUI programme for subfertile couples.

Effect of day 3 embryo morphometrics and morphokinetics on survival and implantation after slow freezing-thawing and after vitrification-warming: a retrospective cohort study.

Background: Morphometric and morphokinetic evaluation of in vitro cultured human embryos allows evaluation without time restriction and reduces intra- and inter-observer variability. Even though these technologies have been reported to improve the quality of cleavage stage embryo evaluation during fresh culture, possible advantages in the evaluation of cryopreserved embryos have been scarcely explored. This study aims to compare morphometric and morphokinetic parameters between slow frozen and vitrified embryos and to determine their relationship to embryo survival and implantation rate (IR) after thawing/warming.

A 50% reduction in multiple live birth rate is associated with a 13% cost saving: a real-life retrospective cost analysis.

Belgian legislation limiting the number of embryos for transfer has been shown to result in a 50% reduction of the multiple live birth rate (MLBR) per cycle without having a negative impact on the cumulative delivery rate per patient within six cycles or 36 months. The objective of the current study was to evaluate the cost saving associated with a 50% reduction in MLBR. A retrospective cost analysis was performed of 213 couples, who became pregnant and had a live birth after one or more assisted reproductive technology treatment cycles, and their 254 children.

Human embryo research in Belgium: an overview.

Objective: To present an overview of the numbers and types of human embryos used in research projects in Belgium from 2007 to 2015.

Design: Analysis of all research proposals approved by the Federal Commission for Medical and Scientific Research on Embryos In Vitro.

Setting: Not applicable.

Principles guiding embryo selection following genome-wide haplotyping of preimplantation embryos.

Study Question: How to select and prioritize embryos during PGD following genome-wide haplotyping?

Summary Answer: In addition to genetic disease-specific information, the embryo selected for transfer is based on ranking criteria including the existence of mitotic and/or meiotic aneuploidies, but not carriership of mutations causing recessive disorders.

What Is Known Already: Embryo selection for monogenic diseases has been mainly performed using targeted disease-specific assays. Recently, these targeted approaches are being complemented by generic genome-wide genetic analysis methods such as karyomapping or haplarithmisis, which are based on genomic haplotype reconstruction of cell(s) biopsied from embryos.

Effect of embryo morphology and morphometrics on implantation of vitrified day 3 embryos after warming: a retrospective cohort study.

Background: Characteristics routinely used to evaluate embryo quality after thawing include number of blastomeres survived and presence of mitosis resumption after overnight culture. It is unknown to which extent symmetry and fragmentation affect implantation after warming and whether application of stricter criteria either before vitrification or after warming would improve implantation rate (IR) of vitrified/warmed embryos. This study aimed to find new parameters to improve selection criteria for vitrification and for transfer after warming.

Selecting the embryo with the highest implantation potential using a data mining based prediction model.

Background: Embryo selection has been based on developmental and morphological characteristics. However, the presence of an important intra-and inter-observer variability of standard scoring system (SSS) has been reported. A computer-assisted scoring system (CASS) has the potential to overcome most of these disadvantages associated with the SSS.

Revised guidelines for good practice in IVF laboratories (2015).

Study Question: Which recommendations can be provided by the European Society of Human Reproduction and Embryology Special Interest Group (ESHRE SIG) Embryology to support laboratory specialists in the organization and management of IVF laboratories and the optimization of IVF patient care?

Summary Answer: Structured in 13 sections, the guideline development group formulated recommendations for good practice in the organization and management of IVF laboratories, and for good practice of the specific procedures performed within the IVF laboratory.

What Is Known Already: NA.

Study Design, Size, Duration: The guideline was produced by a group of 10 embryologists representing different European countries, settings and levels of expertise.

Frozen-thawed embryo transfer in a natural or mildly hormonally stimulated cycle in women with regular ovulatory cycles: a RCT.

Study Question: Can ovarian stimulation with low dose hMG improve the implantation rate (IR) per frozen-thawed embryo transferred (FET) when compared with natural cycle in an FET programme in women with a regular ovulatory cycle?

Summary Answer: Both IR and live birth rate (LBR) per FET were similar in the group with mild ovarian stimulation and the natural cycle group.

What Is Known Already: Different cycle regimens for endometrial preparation are used prior to FET: spontaneous ovulatory cycles, cycles with artificial endometrial preparation using estrogen and progesterone hormones, and cycles stimulated with gonadotrophins or clomiphene citrate. At present, it is not clear which regimen results in the highest IR or LBR.

Is There a Correlation between the Number of Follicular Flushings, Oocyte/Embryo Quality and Pregnancy Rate in Assisted Reproductive Technology Cycles? Results from a Prospective Study.

Objective: To determine the mean number of follicular flushings needed to retrieve the maximal number of oocytes and to investigate the correlation between the number of flushings and oocyte/embryo quality as well as reproductive outcome.

Methods: This prospective study included 154 oocyte retrieval cycles in 138 patients undergoing assisted reproductive technology treatment. During oocyte retrieval, aspirate and flushes were collected in four separate collections (A, F1, F2, F3) and inspected for the presence of an oocyte-cumulus complex (OCC).

Concurrent whole-genome haplotyping and copy-number profiling of single cells.

Methods for haplotyping and DNA copy-number typing of single cells are paramount for studying genomic heterogeneity and enabling genetic diagnosis. Before analyzing the DNA of a single cell by microarray or next-generation sequencing, a whole-genome amplification (WGA) process is required, but it substantially distorts the frequency and composition of the cell's alleles. As a consequence, haplotyping methods suffer from error-prone discrete SNP genotypes (AA, AB, BB) and DNA copy-number profiling remains difficult because true DNA copy-number aberrations have to be discriminated from WGA artifacts.

Low-dose human menopausal gonadotrophin versus clomiphene citrate in subfertile couples treated with intrauterine insemination: a randomized controlled trial.

Study Question: Can controlled ovarian stimulation with low-dose human menopausal gonadotrophin (hMG) improve the clinical pregnancy rate when compared with ovarian stimulation with clomiphene citrate (CC) in an intrauterine insemination (IUI) programme for subfertile couples?

Summary Answer: Ovarian stimulation with low-dose hMG is superior to CC in IUI cycles with respect to clinical pregnancy rate.

What Is Known Already: IUI after ovarian stimulation is an effective treatment for mild male subfertility, unexplained subfertility and minimal-mild endometriosis, but it is unclear which medication for ovarian stimulation is more effective.

Study Design, Size, Duration: A total of 330 women scheduled for IUI during 657 cycles (September 2004-December 2011) were enrolled in an open-label randomized clinical trial to ovarian stimulation with low-dose hMG subcutaneous (n = 334, 37.

The spatial arrangement of blastomeres at the 4-cell stage and IVF outcome.

This study compared the developmental and implantation potential of tetrahedrally arranged versus non-tetrahedrally arranged 4-cell-stage embryos. If the cleavage planes of a 4-cell-stage embryo were perpendicularly orientated, blastomeres were defined as tetrahedrally arranged, while embryos with parallel-orientated cleavage axes were considered as non-tetrahedral embryos. The 4-cell-stage embryos (n=862) examined in this study were obtained from 299 patients aged <36 years.

Is there a link between blastomere contact surfaces of day 3 embryos and live birth rate?

Background: Cell-cell communication and adhesion are essential for the compaction process of early stage embryos. The aim of this study was to develop a non-invasive objective calculation system of embryo compaction in order to test the hypothesis that embryos with a larger mean contact surface result in a higher live birth rate compared to embryos with a lower mean contact surface.

Methods: Multilevel images of 474 embryos transferred on day 3 were evaluated by the Cellify software.

Triple touch sperm immobilization vs. single touch sperm immobilization in ICSI - a randomised trial.

Background: Although different techniques for sperm immobilization have been described, their value has not been assessed in an adequately powered randomized study. The aim of this study was to compare two types of sperm immobilization methods prior to ICSI and to test the hypothesis that triple touch immobilization (TTIm) would lead to a higher (5% -65% up to 70%) fertilization rate (FR) than single touch immobilization (STIm).

Methods: A total of 3056 metaphase II (MII) oocytes, from 290 patients, were randomly assigned to the STIm group (n = 1528 oocytes; 145 cycles) or to the TTIm group (n = 1528 oocytes; 138 cycles).