ESHRE guideline: number of embryos to transfer during IVF/ICSI†.

STUDY QUESTION: Which clinical and embryological factors should be considered to apply double embryo transfer (DET) instead of elective single embryo transfer (eSET)? SUMMARY ANSWER: No clinical or embryological factor per se justifies a recommendation of DET instead of eSET in IVF/ICSI. WHAT IS KNOWN ALREADY: DET is correlated with a higher rate of multiple pregnancy, leading to a subsequent increase in complications for both mother and babies. These complications include preterm birth, low birthweight, and other perinatal adverse outcomes. To mitigate the risks associated with multiple pregnancy, eSET is recommended by international and national professional organizations as the preferred approach in ART. STUDY DESIGN, SIZE, DURATION: The guideline was developed according to the structured methodology for development and update of ESHRE guidelines. Literature searches were performed in PUBMED/MEDLINE and Cochrane databases, and relevant papers published up to May 2023, written in English, were included. Live birth rate, cumulative live birth rate, and multiple pregnancy rate were considered as critical outcomes. PARTICIPANTS/MATERIALS, SETTING, METHODS: Based on the collected evidence, recommendations were discussed until a consensus was reached within the Guideline Development Group (GDG). A stakeholder review was organized after the guideline draft was finalized. The final version was approved by the GDG and the ESHRE Executive Committee. MAIN RESULTS AND THE ROLE OF CHANCE: The guideline provides 35 recommendations on the medical and non-medical risks associated with multiple pregnancies and on the clinical and embryological factors to be considered when deciding on the number of embryos to transfer. These recommendations include 25 evidence-based recommendations, of which 24 were formulated as strong recommendations and one as conditional, and 10 good practice points. Of the evidence-based recommendations, seven (28%) were supported by moderate-quality evidence. The remaining recommendations were supported by low (three recommendations; 12%), or very low-quality evidence (15 recommendations; 60%). Owing to the lack of evidence-based research, the guideline also clearly mentions recommendations for future studies. LIMITATIONS, REASONS FOR CAUTION: The guideline assessed different factors one by one based on existing evidence. However, in real life, clinicians' decisions are based on several prognostic factors related to each patient's case. Furthermore, the evidence from randomized controlled trials is too scarce to formulate high-quality evidence-based recommendations. WIDER IMPLICATIONS OF THE FINDINGS: The guideline provides health professionals with clear advice on best practice in the decision-making process during IVF/ICSI, based on the best evidence currently available, and recommendations on relevant information that should be communicated to patients. In addition, a list of research recommendations is provided to stimulate further studies in the field. STUDY FUNDING/COMPETING INTEREST(S): The guideline was developed and funded by ESHRE, covering expenses associated with the guideline meetings, the literature searches, and the dissemination of the guideline. The guideline group members did not receive payment. DPB declared receiving honoraria for lectures from Merck, Ferring, and Gedeon Richter. She is a member of ESHRE EXCO, and the Mediterranean Society for reproductive medicine and the president of the Croatian Society for Gynaecological Endocrinology and Reproductive Medicine. CDG is the past Chair of the ESHRE EIM Consortium and a paid deputy member of the Editorial board of Human Reproduction. IR declared receiving reimbursement from ESHRE and EDCD for attending meetings. She holds an unpaid leadership role in OBBCSSR, ECDC Sohonet, and AER. KAR-W declared receiving grants for clinical researchers and funding provision to the institution from the Swedish Cancer Society (200170F), the Senior Clinical Investigator Award, Radiumhemmets Forskningsfonder (Dnr: 201313), Stockholm County Council FoU (FoUI-953912) and Karolinska Institutet (Dnr 2020-01963), NovoNordisk, Merck and Ferring Pharmaceuticals. She received consulting fees from the Swedish Ministry of Health and Welfare. She received honoraria from Roche, Pfizer, and Organon for chairmanship and lectures. She received support from Organon for attending meetings. She participated in advisory boards for Merck, Nordic countries, and Ferring. She declared receiving time-lapse equipment and grants with payment to institution for pre-clinical research from Merck pharmaceuticals and from Ferring. SS-R received research funding from Roche Diagnostics, Organon/MSD, Theramex, and Gedeo-Richter. He received consulting fees from Organon/MSD, Ferring Pharmaceuticals, and Merck Serono. He declared receiving honoraria for lectures from Ferring Pharmaceuticals, Besins, Organon/MSD, Theramex, and Gedeon Richter. He received support for attending Gedeon Richter meetings and participated in the Data Safety Monitoring Board of the T-TRANSPORT trial. He is the Deputy of ESHRE SQART special interest group. He holds stock options in IVI Lisboa and received equipment and other services from Roche Diagnostics and Ferring Pharmaceuticals. KT declared receiving payment for honoraria for giving lectures from Merck Serono and Organon. She is member of the safety advisory board of EDQM. She holds a leadership role in the ICCBBA board of directors. ZV received reimbursement from ESHRE for attending meetings. She also received research grants from ESHRE and Juhani Aaltonen Foundation. She is the coordinator of EHSRE SQART special interest group. 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 judgement 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 https://www.eshre.eu/Guidelines-and-Legal).

Serum concentrations of neuropilin-1 in women with endometriosis.

Objective of this work is to investigate, for the first time, serum concentration of neuropilin-1 (NRP-1), aiming to evaluate its diagnostic performance in endometriosis and usability as a potential non-invasive serum marker of endometriosis. Two hundred women were treated laparoscopically. After laparoscopic surgery women were divided into two groups: 120 women diagnosed with endometriosis and 80 healthy women (control group). Blood samples were taken from all women undergoing laparoscopy half an hour before the induction of anesthesia, for the purpose of collection of serum. The level of NRP-1 in serum was assayed by a standardised sandwich enzyme-linked immunosorbent assay. Differences between endometriosis and healthy control group in NRP-1 levels were significant. All values were significantly and several times higher in patients group, p < .001. After receiver operating characteristic analysis, the area under curve was 0.97 (95% confidence interval: 0.941 to 0.989, p < .0001) at 11 µg/L cut-off level for NRP-1. Preliminary threshold values for NRP-1 in serum were assumed to serve as diagnostic parameters with sensitivity of 99.3% and specificity of 97.8%. Serum concentration of NRP-1 can be considered as a potentially good laboratory diagnostic, non-invasive marker for endometriosis.

Combined ovulation triggering with GnRH agonist and hCG in IVF patients.

The aim of the review is to analyse the combination of a gonadotrophin releasing hormone (GnRH) agonist with a human chorionic gonadotrophin (hCG) trigger, for final oocyte maturation in in vitro fertilisation (IVF) cycles. The concept being a ''dual trigger'' combines a single dose of the GnRH agonist with a reduced or standard dosage of hCG at the time of triggering. The use of a GnRH agonist with a reduced dose of hCG in high responders demonstrated luteal phase support with improved pregnancy rates, similar to those after conventional hCG and a low risk of ovarian hyperstimulation syndrome (OHSS). The administration of a GnRH agonist and a standard hCG in normal responders, demonstrated significantly improved live-birth rates and a higher number of embryos of excellent quality, or cryopreserved embryos. The concept of the ''double trigger" represents a combination of a GnRH agonist and a standard hCG, when used 40 and 34 h prior to ovum pick-up, respectively. The use of the ''double trigger" has been successfully offered in the treatment of empty follicle syndrome and in patients with a history of immature oocytes retrieved or with low/poor oocytes yield. Further prospective studies are required to confirm the aforementioned observations prior to clinical implementation.

[Hormone replacement therapy and venous thromboembolism]. / Hormonsko nadomjesno lijecenje I venske tromboembolije.

Venous thromboembolism (VTE) is the most important side effect of using hormone replacement therapy (HRT). Biological and epidemiological studies have shown that oral administration of estrogen is associated with an increased risk of VTE compared to transdermal route of administration. Addition of progestogen to estrogen further increases the risk of VTE. Different pharmacological classes of progestogens differently contribute to the risk of VTE. Observational studies observed that the application of micronized progesterone and didrogesteron are safer regarding the risk of VTE compared to other progestins. These results should be further confirmed in the randomized studies. A personal or family history of VTE, existence of hereditary thrombophilia or/and multiple risk factors for VTE represent a strong contraindication to oral HRT use. In such persons the application of transdermal estrogen can be considered after careful individual evaluation of the benefits and risks. Transdermal estrogen should be also the first choice in overweight/obese women requiring HRT.

[Diagnostic and therapeutic algorithm for the treatment of premenstrual dysphoric disorder]. / Dijagnosticke i terapijske smjernice za lijecenje predmenstruacijskog disforicnog poremecaja.

Many women experience psychological and physical symptoms associated with menstrual cycle. In 3% to 5% of women that meet the criteria for premenstrual dysphoric disorder, the symptoms are severe and impair their social and occupational functioning. Although the etiology of premenstrual dysphoric disorder is unknown, the symptoms of dysphoria, including depression and anxiety, have been associated with serotonergic dysregulation. Selective serotonin reuptake inhibitors, taken only during the symptomatic luteal phase, are considered as first-line therapy for premenstrual dysphoric disorder.

Questionnaire on the Midwives' Knowledge About Oral Emergency Contraception.

The aim of the study was to assess the level of knowledge of midwives working in different clinical settings about oral emergency contraception. The study included 225 midwives; during the period from December 2015 to February 2016, they completed a 16-item web-based survey using the SurveyMonkey software available on the Croatian Midwives Chamber site. In total 277 participants started to fill out the survey and 225 participants responded to all 16 questions. Demographic, educational and professional characteristics of the participants in this survey are provided. Distri-bution of participant responses to questions regarding basic reproductive endocrinology, unplanned pregnancies and emergency contraception clearly revealed important gaps in the group knowledge. There was evident gap in the knowledge about emergency contraception in the study group of Croa-tian midwives. Having in mind the study group grounds in gynecology and obstetrics, and their public health relevance, targeted educational activities both during midwife formal education and on-job are required to improve the group knowledge about emergency contraception. National guidelines on oral emergency contraception are an at hand learning tool and the most appropriate local source of information on emergency contraception. Various initiatives should be considered for this document to become an integral part of formal midwife education and regular part of their on-job trainings.

Hyperandrogenemia association with acne and hirsutism severity in Croatian women with polycystic ovary syndrome.

Clinical traits associated with androgen, acne and hirsutism, are important diagnostic features of polycystic ovary syndrome (PCOS). As androgens are necessary for the development of cutaneous signs of PCOS, patients with severe forms of clinical hyperandrogenism are expected to present with higher levels of plasma androgens. This relationship has not been well established and studies examining the relationship have produced inconsistent results. The aim of this study was to analyze the correlation between the severity of clinical traits caused by androgen, acne and hirsutism, with plasma levels of androgens in Croatian women diagnosed with PCOS. One hundred and forty-five women of reproductive age with isolated acne (n=61) or isolated hirsutism (n=84), oligo/amenorrhea and polycystic morphology of the ovaries were enrolled in the study. Acne grade, hirsutism grade, body mass index (BMI) and waist to hip ratio (WHR) were recorded. Hormonal profiles were measured and assessment of insulin resistance was performed. There were no significant associations between acne severity and BMI, WHR and examined hormonal and insulin resistance parameters. There was a significant correlation between sex-hormone binding globulin (SHBG) and free testosterone levels and the severity of hirsutism (ρ=-0.611, P<0.001 and ρ=0.337, P=0.002, respectively). No significant association was found between the hirsutism grade and other hormonal and metabolic parameters examined. In conclusion, acne severity in PCOS patients is not linearly associated with serum androgen levels; therefore, their levels should not be used to determine the dose of anti-androgen therapy. The observed negative correlation between serum SHBG levels and the degree of hirsutism suggests that hormonal contraception, which elevates SHBG, should be used as primary therapy in hirsute PCOS patients.