bluuebunny/crossref_metadata_2025 huggingface dataset:
O-147 Genomic analyses in 101,127 UK women show that previously reported monogenic genes are not common causes of premature ovarian insufficiency
Authors: Shekari S , Stankovic S , Ruth K. S , Prague J , Perry J , Murray A
Published: June 2022

Study question

What is the penetrance of variants in previously reported genes for premature ovarian insufficiency (POI) in the general population?

Summary answer

Heterozygous genetic variants in previously reported monogenic genes are not a common, highly penetrant cause of POI.

What is known already

Premature ovarian insufficiency (POI), defined as menopause before 40, has been associated with variants in over 70 genes. However, the evidence to support the causality of individual genetic variants varies between studies. As genomic data becomes more accessible, it is essential to ascertain the penetrance of variants in the absence of family history information. We identified 75 genes associated with POI from the literature, including family segregation studies, consanguineous pedigrees and cohort analyses of whole-exome/targeted sequencing data. Functional evaluation was also available for many of the genes.

Study design, size, duration

We used data from 101,127 females of European ancestry in the UK Biobank, to study the role of previously reported monogenic causal genes on ovarian function. We tested the association of 301 previously reported variants with POI and ANM, plus more than 2.5 million rare variants which were annotated and had not been implicated in POI previously. Genomic variants were tested individually and also combined into a gene burden test.

Participants/materials, setting, methods

Age at natural menopause (ANM) was derived from self-reported questionnaire data from the age at last menstrual period, excluding those with surgical menopause or taking hormone replacement therapy. POI cases were classified as women with ANM under 40 years (N = 2,213). Linked primary care records were used to identify a clinical cohort of POI cases, including primary amenorrhea (N = 113).

Main results and the role of chance

All of the previously reported individual variants we identified in our POI cases were also detected in the control group. Moreover, the gene burden tests were not associated with POI or ANM as a quantitative trait. Our results indicate that autosomal dominant causes of POI are rare; a single predicted loss-of-function (LOF) or non-synonymous genetic variant in one of the previously reported genes is generally not pathogenic.

Limitations, reasons for caution

The penetrance of monogenic disease-causing variants is likely to be lower in population-based cohorts such as UK Biobank than in clinically-ascertained cohorts.

Wider implications of the findings

Heterozygous LOF or non-synonymous variants in previously reported POI genes should be interpreted with caution and are unlikely to cause POI. The findings have implications for clinicians diagnosing causes of POI.

Trial registration number

Not applicable
O-153 Unravelling the causes of male infertility: the role of genetics
Authors: Tüttelmann F
Published: June 2022

Infertility is a common multifactorial disease and global health problem affecting 10-15% of couples. It can often be overcome by medically assisted reproduction (MAR), offering couples that fail to conceive naturally the chance for parenthood. In half of the couples, the infertility is due to male-factors. Despite advances in the past decade, in the majority of infertile men, the underlying genetic, molecular, cellular, and/or organ defect(s) still remain ill-defined or unknown altogether. Thereby, evidence-based treatment decisions for testicular sperm extraction (TESE) and MAR, estimating and counselling as to risks for both the men and their offspring, and potential preventive measures are largely precluded.

However, in recent years, the number of male infertility cases “solved” by genetic analyses, most importantly exome sequencing, increases continuously. We and others have contributed significantly to 1) identifying novel genes and causal variants (mutations), 2) functionally scrutinising them, and 3) translating findings into the clinic. Most attention is currently focussed on azoospermia, supposedly affecting up to 1% of the male population, and specific sperm defects clinically detected as morphological aberrations or decreased/completely lacking motility.

Crypto- and azoospermia (very few/no sperm in the semen) are main contributors to male factor infertility. Genetic causes for spermatogenic failure (SPGF) include Klinefelter syndrome (47,XXY) and Y-chromosomal AZF microdeletions, and CFTR mutations for obstructive azoospermia (OA). However, the majority of cases remain unexplained because monogenic causes are not analysed. The clinical distinction between azoospermia due to SPGF (non-obstructive azoospermia, NOA) and obstructive azoospermia (OA) is challenging but critical for counselling patients prior to surgical sperm retrieval procedures: men with OA have high success rates for TESE and subsequent intracytoplasmic sperm injection (ICSI), while rates for NOA patients range from virtually zero up to ∼50% depending on the genotype.

One focus of the talk will be the recent results of our four years prospective exome sequencing study in crypto-/azoospermic men and the impact for predicting TESE and MAR success based on identified mutations. Another focus will be the genetic makeup of morphologically abnormal sperm and the consequences for MAR/ICSI. Lastly, a previously underestimated cause for infertility and IVF failure will be reviewed.
O-155 What strategies help patients cope with endometriosis in everyday life: a doctor's perspective
Authors: Seeber B
Published: June 2022

Endometriosis is an enigmatic disease characterized by chronic pain and infertility and associated with a diminished quality of life.  While surgery, pain medications and hormonal treatments are the mainstays of treating endometriosis, patients are increasing seeking complementary therapies to help them cope with their symptoms in everyday life.  Too often, clinicians caring for women with endometriosis are at a loss when it comes to discussing or recommending such alternative therapies, as they are not part of typical western medical training.  

This lecture will review the evidence behind –or lack thereof—for many commonly sought therapies for endometriosis to enable physicians and clinicians to better counsel their patients.  Topics to be addressed include: is there any benefit to special diets for endometriosis and endometriosis-associated pain? ; is there a role for physical activity or specific exercises in improving symptoms?;  are yoga and meditation effective in helping women cope with endometriosis? ; are there specific phytotherapies that improve symptoms? ; has acupuncture been shown to help women cope with endometriosis symptoms? ; are there complementary therapies that improve fertility?

In addition, based on clinical experience in treating with women with endometriosis, the importance of setting shared goals and expectations for treatment and supporting patients in their plans for attempting pregnancy and fulfilling the wish for a child will be discussed.
O-164 Contraceptive and endocrine treatment for endometriosis
Authors: Thomas M.A.
Published: June 2022

Endometriosis-associated pain can be incapacitating for many patients who suffer with this condition. Contraceptive agents and endocrine preparations have been proven to be a better choice for pain relief in these individuals compared to analgesics alone. In this lecture, we will discuss evidence-based recommendations for the hormonal options that are available to treat endometriosis-associated pain.
O-165 Impact of endometriosis on the oocyte
Authors: Racowsky C
Published: June 2022

Available evidence indicates that women with endometriosis tend to have lower implantation rates following IVF than those without endometriosis.  Whether this reduction in implantation rate is due to compromised endometrial receptivity or reduced embryo quality remains controversial.  However, studies with the oocyte donor model in which reciprocal transfers are performed involving oocytes/embryos from women with or without endometriosis support the conclusion that oocyte quality is the main factor compromising implantation rate.  This conclusion is consistent with documented elevations of inflammatory cytokines, reactive oxygen species and growth- and angiogenic factors in follicular fluid and peritoneal fluid of women diagnosed with endometriosis.

In this lecture, we will review evidence in support of negative effects of endometriosis on oocyte quality.  We will discuss the results of studies directly assessing oocyte quality through gross morphological analyses and transmission electron microscopy assessments on human oocytes.  Given the paucity of human oocytes available for research, we will then consider studies on animal oocytes matured in vitro in medium supplemented with either follicular fluid or peritoneal fluid from women with endometriosis.  We will then proceed to reviewing the clinical IVF literature assessing the relationship between endometriosis and embryo quality, as the latter is predominantly driven by oocyte quality.  We will specifically appraise studies investigating any association between endometriosis and 1) the proportion of good quality embryos and blastocyst formation rate, as categorized by conventional morphology assessment; and 2) risks of aneuploidy, and aberrations in embryo morphokinetics identified by time-lapse imaging.  We will close by a brief discussion of the challenges that prevail in untangling negative effects of endometriosis on oocyte quality.
O-306 LINZAGOLIX FOR ENDOMETRIOSIS-ASSOCIATED PAIN: SAFETY RESULTS FROM EDELWEISS 3, A PHASE 3, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL
Authors: Donnez J , Taylor H , Gemzell-Danielsson K , Catherino W , Bestel E , Gotteland J.P , Humberstone A , Moore L , Garner E
Published: June 2022

Study question

Is once-daily linzagolix treatment for women with moderate to severe endometriosis-associated pain (EAP) safe for use for up to 6 months of treatment?

Summary answer

Both doses of linzagolix were well-tolerated with minimal BMD decrease and few TEAEs >5% in either linzagolix arm.

What is known already

Linzagolix (LGX) is an investigational once-daily oral GnRH receptor antagonist that reduces serum estradiol in a dose-dependent manner and is being developed in two dosages for the treatment of endometriosis-associated pain (EAP): 75 mg, and 200 mg dose with hormonal add-back therapy (ABT). 

Study design, size, duration

EDELWEISS 3 is a randomized, double-blind, placebo-controlled, multicenter Phase 3 trial of linzagolix in women with moderate to severe EAP. The trial includes 3 treatment arms: 75 mg LGX, 200 mg LGX with ABT (E2 1 mg/ NETA 0.5 mg), or placebo. Here we present safety results up to 6 months (24 weeks) of treatment.

Participants/materials, setting, methods

Eligible reproductive-aged women with moderate-to-severe EAP were randomized and treated (n = 484) for 6 months with 75 mg LGX, 200 mg LGX with ABT (E2 1 mg/ NETA 0.5 mg), or placebo. Safety and tolerability objectives reported here include 6-month results for treatment emergent adverse events (TEAEs), assessment of mean percent change from baseline (CfB) in lumbar spine (LS) bone mineral density (BMD) and Z-scores.

The safety analysis set included 484 subjects across the 3 treatment groups.

Main results and the role of chance

The overall incidence of TEAEs was similar between the placebo and LGX 75 mg group (46.9%) and slightly higher (56.8%) in the LGX 200 mg + ABT group. There were few (3) serious TEAEs, and none were related to LGX. TEAEs that occurred in over 5% of patients in either active treatment arm included headache (10.5%, 8.1%, and 8.0%), hot flush (6.8%, 7.5%, and 2.5%), and fatigue (6.8%, 3.8%, and 2.5%) for the 200 mg LGX with ABT, 75 mg LGX, and placebo groups, respectively. Mean percent CfB (95% CI) in LS BMD was -0.79% (-1.15,  -0.43%), -0.89% (-1.31, -0.47%), and +0.78% (0.41, 1.15%) for the 200 mg LGX with ABT, 75 mg LGX, and placebo groups, respectively. Z-scores at 6 months remained within the same range as baseline in all groups.

Limitations, reasons for caution

Additional efficacy and safety results from the trial's 24 weeks (6 mo) extension phase are pending. (Edelweiss 6 protocol: NCT04335591)

Wider implications of the findings

These results support further development of ABT and non-ABT doses of linzagolix that have potential to provide flexibility and choice for women seeking treatment for EAP. A non-ABT option is important for women who have a contraindication to, are at increased risk for complications, or prefer not to use ABT.

Trial registration number

ClinicalTrials.gov: NCT02778399
O-225 Endometrioma and fertility preservation: how can we save the oocytes?
Authors: Donnez J
Published: June 2022

Endometriosis is a benign estrogen-dependent disease

In the ovary, endometrioma formation may cause local inflammation, giving rise to structural alterations to the ovarian cortexwhich manifest as massive fibrosis and loss of cortex-specific stroma that maintains follicular nests.

Subsequent dysregulation of folliculogenesis results in “burn out” of the stockpile of dormant follicles. Moreover, endometriomas contain much higher concentrations of free iron, reactive oxygen species (ROS) and proteolytic enzymzes which could reach adjacent ovarian tissue and lead to follicular loss and intraovarian vascular injury.

Fertility preservation is a major challenge when therapeutic approaches of ovarian endometrioma are contemplated.

Surgery is often proposed in cases of endometrioma more than 3 cm in size but there are two main risks associated with the surgical treatmant of endometrioma :

1. the risk of excessive surgery (removal or destruction of normal ovarian cortex together with the endometrioma pseudocapsula).Close the ovarian hilus, ovarian tissue removed with the endometrioma wall contained follicles in more than 60% of cases in a study of Muzii and some meta-analyses have revealed significant decreases in AMH after excision.

2. The risk of incomplete surgery with subsequent early recurrence.

A correct surgical approach is therefore the first step to preserve oocytes and several techniques are discussed.

How to preserve fertility in women at risk of premature ovatian insufficiency (POI) due to severe and/or recurrent ovarian endometriosis?

Two main options are currently available :

1. COS,ovum pick-up and vitrification of oocytes is an important fertility preservation approach. Cobo et all published several series and reported high cumulative live birth rates in women less than 35 years, suggesting that patients with endometrioma should be encouraged to freeze oocytes at a younger age.

2. In some circonstances, orthotopic autotransplantation of cryopreserved ovarian cortex (which has led to more than 200 live births ) could be proposed to maintain the follicular pool.
O-228 How to introduce time-lapse technology in the IVF lab
Authors: Ebner T
Published: June 2022

Although there is conflicting evidence on the actual clinical relevance of time-lapse technique (TLT) it is an add on technique that does come along with several advantages that would justify its use. However, once the decison has been made to go with TLT it has to be brought to mind that the European Tissues and Cells Directive dictates that new equipment is qualified accordingly before used routinely. This process is usually done according to GMP standards, e.g. a proper design qualification (DQ) would identify the most superior equipment which then undergoes further qualification steps such as installation (IQ), operational (OQ) and performance qualifications (PQ). The latter should involve a comparison with generally accepted laboratory KPIs, a process which would allow to establish levels of competence and aspirational benchmark. Upon proper qualification and clearance TLT can be an important tool in an existing quality management system, e.g. for evaluation of inter- and intraobserver variation, implementation of new consumables, and for testing the safety and efficacy of new lab methods.
O-231 Is there a role for medical management of fibroids in infertile patients?
Authors: Palshetkar N
Published: June 2022

Uterine Fibroids are one of the most common benign uterine tumors. 33% of women with fibroids will be symptomatic. Surgical treatment has usually been the treatment of choice. However, the medical management of fibroids is a less explored territory. Evidence suggests that progesterone pathways play a crucial role in the path physiology of uterine fibroids. Selective progesterone receptor modulators (SPRMs) such as ulipristal acetate (UPA) may be used. There have been many RCTs suggesting the use of UPA. Medical management can reduce the morbidity of surgery and also help preserve fertility as well. Therefore having a new tool in every gynecologist's bag opens up novel strategies for the management of uterine fibroids.

Trial registration number
O-278 Prenatal outcomes of mosaic embryo transfer and neonatal assessment
Authors: Viotti M
Published: June 2022

Ever-improving PGT-A methodologies now make it feasible to routinely detect chromosomal mosaicism. What is the appropriate clinical management of those embryos? What is the impact on pregnancies and births when such embryos are transferred? Mosaicism is the consequence of chromosome-segregation errors at mitosis, resulting in a mix of cells with different chromosomal content. The transfer of embryos with evidence of diploid-aneuploid mosaicism in their PGT-A results has become relatively common practice, and numerous clinics have published their experiences with such transfers. On average, ‘mosaic’ embryos have decreased potential to establish a pregnancy and higher risk for miscarriage compared to ‘euploid’ embryos, but pregnancies reaching term seem to produce apparently healthy babies. These findings favor an expansion of the binary ‘normal vs abnormal’ classification system of PGT-A to include ‘mosaicism’ as a third category. Further data suggest that features of mosaicism detected with PGT-A associate with different clinical outcomes, namely the mosaic level (percent aneuploid cells) and the mosaic type (nature of aneuploidy). ‘Low level’ mosaicism is preferable to ‘high level’ mosaicism, and segmental abnormalities are preferable to aneuploidies affecting whole chromosomes. Therefore, the ‘mosaic’ category can be further refined for optimal ranking purposes in the clinic. While many mosaic embryo transfers have resulted in babies, systematic and detailed follow-up studies on pregnancies from such embryos are urgently needed. The present talk will give an update on the ongoing data collection effort by an international, multicenter consortium containing 1700+ ‘mosaic’ embryo transfers, neonate information from 500+ babies born from those transfers, and 380+ associated prenatal test results. Analysis of the data reveals that late-term pregnancies and babies from ‘mosaic’ and ‘euploid’ embryos have largely equivalent health, with a few notable exceptions.
P-099 The effect of sperm DNA quality on blastocyst and euploid rates
Authors: Exeter H , Odia R , Cawood S , Haddock L , Lewis S , Srividya S , Serhal P , Saab W
Published: June 2022

Study question

Do sperm DNA quality measurements influence the blastocyst rate and/or euploid rates?

Summary answer

Sperm DNA fragmentation has a negative influence on the rate of blastulation. It does not impact on euploidy rates assessed by pre-implantation genetic testing (PGT-A).

What is known already

Some studies show that sperm DNA has no influence on embryo development and that its negative influence begins following implantation. Other studies show that every step of the fertility process from fertilization onwards is impacted by the male gamete as well as the female gamete. To date, data has been confounded by different sperm DNA tests and different clinical practices and parameters measured.

Study design, size, duration

This was a retrospective study using the sensitive Comet assay to analyse whether it’s three sperm DNA fragmentation scores influence embryo development or euploidy.

Participants/materials, setting, methods

Data from 110 cycles of intracytoplasmic sperm injection (ICSI) where the blastocyst rate (number of blastocysts/number of mature oocytes injected) was obtained from the patient database of a UK single centre. Inclusion criteria: Only outcomes from the first assisted reproductive cycle after a Comet assay had been performed were included. Included cycles were within one year of the test.

Main results and the role of chance

Blastocysts were ranked in 4 groups- 0.25-0.49, 0.5-0.74, 0.75-1.00. Three Comet scores were analysed: Average Comet Score (damage across the semen sample; ACS), Low Comet Score (proportion of sperm with good DNA; LCS) and High Comet Score ( proportion of sperm with high DNA damage; HCS). Clinical thresholds were calculated by comparison with fertile donor sperm. High ACS and LCS and low HCS were all associated with higher blastocyst rates (ANOVA, p = 0.013; Kruskal Wallis, p = 0.027, Post Hoc pairwise comparisons between blastocyst groups (p = 0.016-0.024). No relationship was found between euploid rate (number of euploid embryos/total embryo number) and sperm DNA damage p = 0.761).

Limitations, reasons for caution

Retrospective design requiring more data to clarify these associations coupled with the lack of randomisation and low power analysis.

Wider implications of the findings

This study reports the negative impact of sperm DNA fragmentation on blastocyst formation rates. Male partner diagnostic assessments such as sperm DNA quality testing are useful adjuncts to semen analysis. Further research to determine if there is a relationship between sperm DNA damage and euploid embryo outcomes is ongoing.

Trial registration number

IRB-001C06-01-22
P-194 Healthy babies after intrauterine transfer of mosaic blastocysts
Authors: Fernandez Sanguino A , Oviedo O , De pablo J.L , Belmonte M , Diez Alcantara J , Martin Garcia B , Pilar L , Collazos R
Published: June 2022

Study question

Can mosaic blastocysts be considered a valid alternative to patients undergoing IVF with no euploid embryos?

Summary answer

We believe that mosaic embryos can be a valid alternative when no euploid embryos are obtaines, particularly in diminished ovarian reserve and advance maternal age

What is known already

Preimplantational genetic screening is used to identify chromosomal euploid embryos and select them for intrauterine transfer in order to improve clinical IVF outcome.Chromosomal mosaicism is defined as two or more distinct chromosomical cells within an embryo and is a relatively common finding in human embryos. Mosaicism arises from mitotic errors occurring after fertilization or meiotic failures in gametes. The variables for the risk stratification of mosaic embryos have been defined as the percentage of mosaicism, specific chromosomes involved, monosomy versus trisomy and inclusion of complete or segmental chromosome mosaicism. High risk mosaic embryos may decrease implantation potential and increase miscarriages.

Study design, size, duration

A retrospective observational review of our results. During the period of 2017 - 2021 we performed 532 PGT-a studies. Embryos underwent blastocyst-stage preimplantation genetic testing for aneuploidy by next-generation sequencing. We obtained 39 low risk mosaic blastocysts, and from those we transferred 8 mosaic blastocysts.

Participants/materials, setting, methods

Patients in our clinic undergoing IVF treatment with PGT-a screening.

Main results and the role of chance

Our success pregnancy rate when transferring mosaic blastocysts was 62,5 %. From 10 mosaic embryos, 1 patient was lost in the study, 3 transferred embryos gave negative bHCG results and we obtained 5 ongoing pregnancies which resulted in 5 healthy babies. An amniocentesis was performed during the pregnancies to correlate the karyotype of the babies. The pregnancies were controlled with no pathological findings in detailed ultrasonography and the fetuses showed normal fetal growth. All pregnancies were delivered at term.

Limitations, reasons for caution

The main limitation of the study is the number of patients. A bigger size is needed in order to have full data which can support future decisions on whether to transfer mosaic embryos.

Wider implications of the findings

Our study shows that mosaic embryos can develop into healthy babies.

Our study is small, but we have achieved a high pregnancy rate. Further studies should be performed in order to be able to counsel women who undergo PGAT-a screening in IVF cycles with only mosaic embryos.

Trial registration number

not aplicable
P-323 Should We Measure Oxidative Stress Biomarkers In Follicular Fluid Of Women With Endometriosis Undergoing IVF?
Authors: Gupta P , Malhotra N , Dada R
Published: June 2022

Study question

Do levels of Oxidative stress (OS) biomarkers differ in the follicular fluid of women with endometriosis compared to tubal factor infertility?

Summary answer

8-Isoprostane is a promising biomarker in diagnosing oxidative stress in women with endometriosis opening a window of opportunity for improving outcomes.

What is known already

A delicate balance between oxidants and antioxidants is required for oocyte development and maturation. Any perturbation in the oocyte microenvironment which is the follicular fluid results in hampered oocyte quality and further affects the embryo development. As endometriosis causes destruction of the oocyte milieu, various OS biomarkers have been explored with inconclusive results. The present study aimed to compare these biomarkers in follicular fluid of women with endometriosis and tubal factor infertility undergoing in-vitro fertilization and correlate with ART outcomes.

Study design, size, duration

In a cross sectional study conducted at the assisted conception unit at a tertiary care hospital from 2017-2018 women undergoing their first IVF cycles for endometriosis and tubal factor infertility were recruited in the study. The study included a total of 107 patients with 50 in the endometriosis group (Group1) and 57 in the tubal group (Group 2).

Participants/materials, setting, methods

Follicular fluid from women undergoing IVF in both the groups was collected and evaluated for Oxidative stress biomarkers including Reactive Oxygen species (ROS), Total Antioxidant Capacity (TAC), 8-Isoprostane (8-IP) levels. ROS levels were detected by chemiluminescence and TAC and 8-IP using enzyme immunoassays.

Main results and the role of chance

Levels of ROS {(39.6 cpm vs 54.8 cpm) (p = 0.2)}were comparable in both the groups. Levels of 8-IP were significantly higher in group 1 as compared to the group 2 {(85.2  pg/ul vs 39.2  pg/ul) (p = 0.01)}. TAC levels were higher in endometriosis group compared to the tubal group {(5.4 mM of Trolox vs 4.1 mM of Trolox) (p = 0.005)} which could explain comparable ongoing clinical pregnancy rate in both groups (24.0% vs 24.5%, p = 0.34). There was no correlation of OS biomarkers with ART outcomes in tubal factor. Follicular fluid in Group 1 revealed a negative correlation of ROS with cleavage rate (r = - 0.42, p = 0.002) and positive correlation of TAC with fertilization rate (r = 0.44, p = 0.001) and Good grade embryos (r = 0.4, p = 0.001).

Limitations, reasons for caution

The main limitation is the inability to assess the dietary intake and blood oxidative stress biomarkers in both the groups.

Wider implications of the findings

OS biomarkers especially 8-IP could be useful in prognosticating IVF outcomes in women with endometriosis with a potential role of addition of antioxidants in culture media during IVF in these women.

Trial registration number

Not Applicable
P-336 Progesterone receptor is not downregulated in the endometrial epithelial compartment of women without embryo implantation during frozen thawed embryo transfer cycles
Authors: Palomino W , Rivas M.P , Godoy A , Villarroel C , Sequeira K , Salinas A , Savaris R
Published: June 2022

Study question

Is the mean endometrial progesterone receptor (PGR) expression in the endometrial epithelial compartment different between women with and without embryo implantation failure?

Summary answer

PGR expression is higher in epithelial endometrial compartment of women with embryo implantation failure, during mock hormonal endometrial preparation preceding frozen thawed embryo transfer cycles.

What is known already

PGR downregulation is critical for embryo implantation. Downregulation takes place during the window of implantation in the EEC, while, in stromal cells, it is highly expressed. Embryos are unable to attach to the maternal surface when PGR expression remains expressed in epithelial endometrial compartment (EEC). Limited information is available whether PGR is downregulated during hormonal endometrial preparation for frozen thawed embryo transfer cycles.

Study design, size, duration

In this cohort study, 47 endometrial biopsies were obtained between 2016-2017

Participants/materials, setting, methods

Infertile women (n = 47) submitted to frozen thawed embryo transfer (FET) cycles had an endometrial biopsy after 5 days of intravaginal progesterone supplementation during mock hormonal endometrial preparation (HEP) preceding FET and prospectively followed until confirmation of an intrauterine pregnancy. PGR immunostaining was performed using standard immunohistochemical technique (clone BSB2 - BS2126, BIO SB). PRG expression was quantified using the histologic score (HScore, range from 0 - 4). Ethical approval was obtained from local ethical committee.

Main results and the role of chance

Age, body mass index, endometrial thickness, and the number of embryos transferred were not significantly different between women who became or not pregnant. PGR Hscore (mean ± SD) in EEC was significantly lower in pregnant women (1.2 ± 0.8; n = 14 ) compared to women without pregnancy (2.8 ± 0.6; n = 33 ) Student t-test p < 0.0001. The AUC was 0.90 ± 0.05 (95% CI: 0.7-1) p < 0.0001 displaying 94.2 % sensitivity and 80.4% specificity for a 1.65 PGR cut-off value.

Limitations, reasons for caution

This is an observational study to determine if a difference in PGR expression was identified in these cases

Wider implications of the findings

The mean PGR expression is abnormally higher in EEC of women with embryo implantation failure using HEP for FET cycles. The 1.65 cut-off may be used in future studies to investigate whether high PGR expression is a risk factor for failure of blastocyst implantation in HEP for FET.

Trial registration number

not applicable
P-415 Study of the incidence of herpes viruses in the endometrium of women with evidence of chronic endometritis and reproductive problems
Authors: Blazheva S
Published: June 2022

Study question

What is the prevalence of herpes viruses in endometrial mucosa in women with chronic endometritis and without bacterial causative agents and reproductive problems.

Summary answer

In our study in 12.5% were found to be positive for herpes viruses in endometrial sample.

What is known already

Herpes viruses affect the genital tract and can lead to chronic inflammation of the genital system. They are represented by over 100 different species, 8 of which affect humans. After the initial infection, they usually enter a latent stage as integrated DNA or as an extrachromosomal form. There are various causes that lead to reactivation of herpes viruses in the genital tract, such as decreased immune reactivity, cyclic hormonal changes associated with the menstrual cycle, hypothermia or hyperthermia, infections, invasive gynecological interventions, disturbed psychoemotional status. This can lead to the development of persistent chronic infections in the endometrial lining.

Study design, size, duration

Prospective cohort study at a Medical Center Institute for Reproductive Medicine, Pleven, Bulgaria. Data collection took place between June 2020 to January 2022.

Participants/materials, setting, methods

Of all the patients who underwent the Medical Center “Institute of Reproductive Medicine”, we found that in 24 of them (mean age 35.56±3.86 years) there was no evidence of pathogenic microorganisms in the endometrial biopsy. The results of flow cytometric analysis showed a high percentage of CD138+ plasma cells. These were included for further investigation of herpesviruses by Multiplex Real-Time PCR. The endometrial biopsy study was performed mandatorily after negative microbiological result of vaginal swab.

Main results and the role of chance

The results of this study indicate that 12.5% of women with reproductive problems have herpes virus found in the endometrial mucosa. Demonstration of herpes viruses in endometrial biopsy in women with reproductive problems directs the assisted reproduction specialist to the possible cause of pregnancy loss and helps to prepare and adopt the right strategy for subsequent pregnancies. Endometrial biopsy testing may facilitate the choice of antibacterial or antiviral therapy, which helps to limit the antibiotic effect on the balance of microorganisms forming the genital microbiome.

Limitations, reasons for caution

The insufficient number of patients.

Wider implications of the findings

Developing a diagnostic and treatment plan for patients with evidence of chronic endometritis.

Trial registration number

1
P-435 Diagnosing ectopic pregnancy using the Bayes theorem, a classic that is good as new: a retrospective cohort study
Authors: Savaris R , Maissiat J , Mol B.W , Barnhart K.T , Link C.A
Published: June 2022

Study question

What is the accuracy of an algorithm using Bayes' theorem for diagnosing ectopic pregnancy (EP) having hCG, ultrasound, and clinical data in a real cohort?

Summary answer

The accuracy of the algorithm is 98.9% (95%CI=98.4% to 99.3%)

What is known already

The Bayes' theorem describes the probability of an event after the input of prior knowledge of conditions that might be related to the event. Ectopic pregnancy has been diagnosed using clinical aspects, transvaginal ultrasound (TVUS) and serial measurement of hCGs

Study design, size, duration

The Bayes' theorem describes the probability of an event after the input of prior knowledge of conditions that might be related to the event. Ectopic pregnancy has been diagnosed using clinical aspects, transvaginal ultrasound (TVUS) and serial measurement of hCGs.

Participants/materials, setting, methods

First-trimester patients who attended the Gynaecologic Emergency Unit were included. Clinical signs and symptoms, the presence of risk factors for ectopic pregnancy (EP), ultrsound findings and hCG levels were independent variables. Pre-test probability, based on clinical presentation and risk factors, likelihood ratio (LR) of variable were calculated, yielding a post-test probability (PTP). EP was the main outcome. EP was excluded with PTP <1%, while a PTP ≥ 95% warranted a treatment.

Main results and the role of chance

The incidence of ectopic pregnancy was 8.5% (212/2495;95%CI=7.4% to 9.6%); 310 patients were excluded because they were submitted to surgery with decision thresholds <95%. The algorithm was applied in 2185 patients. Just one case remained inconclusive after 3 consultations, and it was considered as an error in prediction. The sensitivity, specificity, and accuracy values (95%CI) of the algorithm were 98.9% (96.1% to 99.8%), 98.9% (98.3% to 99.2%), and 98.9% (98.3% to 99.2%), respectively.

Limitations, reasons for caution

These results were based on a single centre, and β-hCG were measured using the 4th International Standard in Cobas HCG+ β Elecsys 2010 Modular Analytics E170 machine

Wider implications of the findings

An online and customizable algorithm was developed to be used by different centers

Trial registration number

not applicable
P-515 An Exploration of Young Women’s Process of Adjustment in Spontaneous Premature Ovarian Insufficiency: A Grounded Theory Study
Authors: Banat S
Published: June 2022

Study question

How do young women process their condition?

Summary answer

Throughout the women's adolescence and early twenties, they continually reconceptualised their menopausal body, until they achieved a sense of being developmentally ‘fully grown’.

What is known already

Premature Ovarian Insufficiency (POI) is the decline of ovarian function before the age of 40 (Cooper et al., 2011) Prevalence rates of POI can reach 3-6% of women aged between 12 and 40 and for the majority of cases no known cause will be found. This is referred to as spontaneous or idiopathic POI and can be a life changing diagnosis with profound physical and psychological consequences (Webber., 2017). However, little is known about younger women's experiences of receiving a diagnosis, treatment and overall experiential nature of the condition by women of their age.

Study design, size, duration

Women that received a diagnosis between the ages of 12 to 20 years old (adolescence) were interviewed.

Participants/materials, setting, methods

Semi-structed interviews were conducted over Zoom, with twelve women that had experienced a diagnosis of POI/POF during their adolescence (now aged 21 to 35 years old). The interviews were transcribed and analysed following constructivist Grounded Theory methods.

Main results and the role of chance

The gradual awareness of physical developmental differences from their peers evoked a strong desire to recreate naturally occurring ‘womanly' milestones, such as the development of hips and breasts, menstruating, and future family planning. The young women described an all consuming compulsion to ‘keep up' with their peers following their diagnosis, during their teenage years and into their twenties, falling a sense of "falling behind". This required the young women to continually reconceptualize their menopausal body, how they perceived its purpose and its appearance, allowing them to eventually maturate their self-perception of their body. Viewing themselves as ‘fully grown' women and no longer developmentally different to other women.

Limitations, reasons for caution

The research findings are limited to the confines of qualitative research and therefore larger studies are suggested, moving forward.

Wider implications of the findings

The research suggests that psychological support aimed at supporting the menopausal transition at this early age would be greatly beneficial to young women that have received a diagnosis. This may protect against the later development of body dysmorphic presentations and depression related conditions.

Trial registration number

N/A
P-523 rs2277698 Single nucleotides polymorphisms in tissue inhibitors of metalloproteinases 2 (TIMP2) affected clinical outcomes of women undergoing in vitro fertilization
Authors: Lee C.I , Lee Y.J , Cheng E.H , Tsao H.M , Huang C.C , Lee T.H , Lin P.Y , Chen C.I , Yang S.F , Lee M.S
Published: June 2022

Study question

Is there any association between clinical outcomes of women undergoing in vitro fertilization (IVF) and the polymorphic variants of matrix metalloproteinases (MMPs) or tissue inhibitors of metalloproteinases (TIMPs)?

Summary answer

Our findings suggested that clinical outcomes of women undergoing IVF were associated with rs2277698 SNPs in TIMP2.

What is known already

The extracellular matrix proteolytic machinery is one of the most important mechanisms for regulating trophoblast invasion. Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs), which are involved in the extracellular matrix proteolysis process, have the ability to regulate the degradation of the extracellular matrix and play a critical role in trophoblast invasion.

Study design, size, duration

A prospective study was composed of 1014 women undergoing their first fresh IVF cycle with non-donor from January 2014 to December 2015.

Participants/materials, setting, methods

The present study was carried out in Lee Women’s Hospital, Taiwan. DNA was extracted from the peripheral blood of all participants, and the SNPs were genotyped by real-time polymerase chain reaction. The effects of the following three single nucleotide polymorphisms (SNPs) on IVF outcomes were explored: TIMP1 (rs4898 C/T), TIMP2 (rs2277698 C/T) and MMP2 (rs243865 C/T). The SNP genotype, correlation with clinical pregnancy, embryo implantation, abortion and live birth rates of IVF were analyzed.

Main results and the role of chance

In the analysis of 1014 patients attempting their first cycle of IVF, the genotypes frequencies of the study population showed a statistically significant association between TIMP2 (rs2277698 C/T) and clinical outcome. For TIMP2 polymorphisms, women with wild genotype (CC) hadhigher clinical pregnancy rate (34.8% v.s 28.0%; p = 0.032), embryo implantation rate (19.4% v.s 15.4%; p = 0.009), live birth rate (29.8% v.s 22.1%; p = 0.006), and lower abortion rate (7.0% v.s 17.1%; p = 0.005) compared women with CT/TT genotype. On the other hand, the clinical outcomes in different TIMP1 or MMP2 gene polymorphisms groups were no statistically significant difference.

Limitations, reasons for caution

The size number of the study samples.

Wider implications of the findings

This study showed that the TIMP2 SNP polymorphisms CT/TT was associated with low trend of clinical outcomes. The mechanism of TIMP2 gene T allele affected the outcomes of IVF remains to be determined. Further studies should focus on the mechanism of these associations in a larger, more heterogeneous cohort.

Trial registration number

CS13194
P-560 Diagnostic value of whole exome sequencing (WES) in case of recurrent pregnancy losses
Authors: Avdeichik S
Published: June 2022

Study question

Is it justified during genetic counseling to inform families with recurrent pregnancy losses about the possibility of testing abortion material using the WES method?

Summary answer

Informed families have the opportunity to find the monogenic cause of recurrent pregnancy losses with subsequent PGT-M analysis of embryos to prevent it.

What is known already

Despite WES is not recommended for recurrent pregnancy losses as a routine procedure, there are more and more data in favor of the practice.

Study design, size, duration

This is a retrospective study from 2019 to 2021 including 21 cases that were negative in case of routine karyotyping or aCGH. Three of them (14,3%) were found the cause of diseases by using WES. The study is ongoing.

Participants/materials, setting, methods

Whole exome sequencing of abortion material, chorionic villi specimens.

Main results and the role of chance

Family 1 has a history of euploid fetuses losses during the pregnancy. An autosomal recessive disease, Smith-Lemli-Opitz syndrome type II with early lethality (MIM 270400) was revealed by WES Trio at the 6th pregnancy loss case (mutations detected: c.964-1G>C and c.651C>A in DHCR7 gene in compound heterozygote state). The parents are Ashkenazi Jews and heterozygous carriers of a mutation in the same gene. The risk of pregnancy loss or stillbirth is 25%, and pregnancy planning by IVF with PGT-M is recommended.

Family 2 has recurrent pregnancy losses, happening up to 11 weeks. A child was born with cardioencephalomyopathy, fatal infantile, due to cytochrome C oxidase deficiency 1 (MIM 604377). Mutation: c.418G>A in SCO2 gene in a homozygous state. The mutation was previously described as the cause of missed abortion.

For family 3 was performed WES of abortus with congenital pathology. Mutation c.8263delC in Ciliary dyskinesia, primary, 40 (MIM 618300) gene DNAH9 in homo/heterozygous state. The mutation can result in malformations and stops in pregnancy development. The family is suggested to perform IVF with PGT-M.

Limitations, reasons for caution

The low detection frequency of monogenic causes of pregnancy losses and the high cost of the testing does not allow the use of WES of abortion material as a screening method.

Wider implications of the findings

Performing the WES helps to identify the high risks of monogenic pathology in the families. Changing reproductive tactics and pregnancy planning by IVF with PGT-M is recommended for early prevention of severe congenital pathology, stillbirth, malformations during pregnancy, recurrent pregnancy losses and reduction of the time to achieve healthy childbearing.

Trial registration number

not applicable
P-625 In vitro maturation of oocytes: a breakthrough for treating infertility in inactivating mutation of the luteinizing hormone/choriogonadotropin receptor
Authors: Labrosse J , Sifer C , Cedrin I , Peigne M , Grynberg M
Published: June 2022

Study question

How can pregnancy and live birth be achieved in patients with inactivating homozygous luteinizing hormone/choriogonadotropin receptor (LHCGR) mutation?

Summary answer

We report the first live birth after in vitro maturation (IVM) in a patient with a novel homozygous inactivating LHCGR mutation (exon 6, c.470 A>G).

What is known already

LH plays a fundamental role in female reproductive physiology and is responsible for steroidogenesis, oocyte maturation, ovulation and subsequent progesterone production by the corpus luteum. LH binds to the LHCGR located on the membrane of theca cells and mature granulosa cells. Inactivating mutations of the LHCGR lead to the impossibility to obtain final oocyte maturation both during natural cycles and after ovarian stimulation for in vitro fertilization purposes. Therefore, egg donation represents the only option for treating their infertility.

Study design, size, duration

A case report.

Participants/materials, setting, methods

A 35 year-old nulliparous patient referred to our university hospital for primary infertility.

Main results and the role of chance

The 35-year-old nulliparous patient presented with primary spaniomenorrhea but timely and spontaneous onset of secondary sexual characteristics. Serum LH levels were high (ranging from 15 to 30 IU/L) and to a lesser extent so were FSH levels. The ovarian reserve was normal for age, as assessed by serum AMH levels and ultrasound. There was no argument for polycystic ovarian syndrome, 21-hydroxylase deficiency, Cushing’s syndrome or hyperprolactinemia. Two previous attempts of controlled ovarian stimulation with gonadotropins and ovulation trigger with hCG and GnRH-agonist trigger had failed, resulting in low estradiol levels despite correct follicular growth on ultrasound and absence of ovulation after trigger. However, genetic analysis identified a novel homozygous inactivating LHCGR mutation (exon 6, c.470A>G) which had never been described previously. IVM was performed. A total of 7 oocytes were obtained after IVM, resulting in 4 Day 3 embryos. All embryos were frozen. Subsequently, 2 Day 3 embryos were replaced after endometrial preparation by hormone replacement therapy. The patient became pregnant and gave birth to a healthy baby. Two Day 3 embryos remain.

Limitations, reasons for caution

By definition, a case-report requires further studies to confirm our findings.

Wider implications of the findings

We describe a novel inactivating LHCGR mutation with subsequent live birth after IVM. As a growing number of gonadotropin receptor mutations are identified, this successfully achieved live birth places IVM as the only reliable option for these patients to conceive with their own eggs.

Trial registration number

Not applicable.