Evidence-based guideline: unexplained infertility†.

STUDY QUESTION: What is the recommended management for couples presenting with unexplained infertility (UI), based on the best available evidence in the literature? SUMMARY ANSWER: The evidence-based guideline on UI makes 52 recommendations on the definition, diagnosis, and treatment of UI. WHAT IS KNOWN ALREADY: UI is diagnosed in the absence of any abnormalities of the female and male reproductive systems after 'standard' investigations. However, a consensual standardization of the diagnostic work-up is still lacking. The management of UI is traditionally empirical. The efficacy, safety, costs, and risks of treatment options have not been subjected to robust evaluation. STUDY DESIGN, SIZE, DURATION: The guideline was developed according to the structured methodology for ESHRE guidelines. Following formulation of key questions by a group of experts, literature searches, and assessments were undertaken. Papers written in English and published up to 24 October 2022 were evaluated. PARTICIPANTS/MATERIALS, SETTING, METHODS: Based on the available evidence, recommendations were formulated and discussed until consensus was reached within the guideline development group (GDG). Following stakeholder review of an initial draft, the final version was approved by the GDG and the ESHRE Executive Committee. MAIN RESULTS AND THE ROLE OF CHANCE: This guideline aims to help clinicians provide the best care for couples with UI. As UI is a diagnosis of exclusion, the guideline outlined the basic diagnostic procedures that couples should/could undergo during an infertility work-up, and explored the need for additional tests. The first-line treatment for couples with UI was deemed to be IUI in combination with ovarian stimulation. The place of additional and alternative options for treatment of UI was also evaluated. The GDG made 52 recommendations on diagnosis and treatment for couples with UI. The GDG formulated 40 evidence-based recommendations-of which 29 were formulated as strong recommendations and 11 as weak-10 good practice points and two research only recommendations. Of the evidence-based recommendations, none were supported by high-quality evidence, one by moderate-quality evidence, nine by low-quality evidence, and 31 by very low-quality evidence. To support future research in UI, a list of research recommendations was provided. LIMITATIONS, REASONS FOR CAUTION: Most additional diagnostic tests and interventions in couples with UI have not been subjected to robust evaluation. For a large proportion of these tests and treatments, evidence was very limited and of very low quality. More evidence is required, and the results of future studies may result in the current recommendations being revised. WIDER IMPLICATIONS OF THE FINDINGS: The guideline provides clinicians with clear advice on best practice in the care of couples with UI, based on the best evidence currently available. In addition, a list of research recommendations is provided to stimulate further studies in the field. The full guideline and a patient leaflet are available in www.eshre.eu/guideline/UI. STUDY FUNDING/COMPETING INTEREST(S): The guideline was developed by ESHRE, who funded the guideline meetings, literature searches, and dissemination of the guideline in collaboration with the Monash University led Australian NHMRC Centre of Research Excellence in Women's Health in Reproductive Life (CREWHIRL). The guideline group members did not receive any financial incentives; all work was provided voluntarily. D.R. reports honoraria from IBSA and Novo Nordisk. B.A. reports speakers' fees from Merck, Gedeon Richter, Organon and Intas Pharma; is part of the advisory board for Organon Turkey and president of the Turkish Society of Reproductive Medicine. S.B. reports speakers' fees from Merck, Organon, Ferring, the Ostetric and Gynaecological Society of Singapore and the Taiwanese Society for Reproductive Medicine; editor and contributing author, Reproductive Medicine for the MRCOG, Cambridge University Press; is part of the METAFOR and CAPE trials data monitoring committee. E.B. reports research grants from Roche diagnostics, Gedeon Richter and IBSA; speaker's fees from Merck, Ferring, MSD, Roche Diagnostics, Gedeon Richter, IBSA; E.B. is also a part of an Advisory Board of Ferring Pharmaceuticals, MSD, Roche Diagnostics, IBSA, Merck, Abbott and Gedeon Richter. M.M. reports consulting fees from Mojo Fertility Ltd. R.J.N. reports research grant from Australian National Health and Medical Research Council (NHMRC); consulting fees from Flinders Fertility Adelaide, VinMec Hospital Hanoi Vietnam; speaker's fees from Merck Australia, Cadilla Pharma India, Ferring Australia; chair clinical advisory committee Westmead Fertility and research institute MyDuc Hospital Vietnam. T.P. is a part of the Research Council of Finland and reports research grants from Roche Diagnostics, Novo Nordics and Sigrid Juselius foundation; consulting fees from Roche Diagnostics and organon; speaker's fees from Gedeon Richter, Roche, Exeltis, Organon, Ferring and Korento patient organization; is a part of NFOG, AE-PCOS society and several Finnish associations. S.S.R. reports research grants from Roche Diagnostics, Organon, Theramex; consulting fees from Ferring Pharmaceuticals, MSD and Organon; speaker's fees from Ferring Pharmaceuticals, MSD/Organon, Besins, Theramex, Gedeon Richter; travel support from Gedeon Richter; S.S.R. is part of the Data Safety Monitoring Board of TTRANSPORT and deputy of the ESHRE Special Interest Group on Safety and Quality in ART; stock or stock options from IVI Lisboa, Clínica de Reprodução assistida Lda; equipment/medical writing/gifts from Roche Diagnostics and Ferring Pharmaceuticals. S.K.S. reports speakers' fees from Merck, Ferring, MSD, Pharmasure. HRV reports consulting and travel fees from Ferring Pharmaceuticals. The other authors have nothing to disclose. 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.).

The HERA (Hyper-response Risk Assessment) Delphi consensus definition of hyper-responders for in-vitro fertilization.

PURPOSE: To provide an agreed upon definition of hyper-response for women undergoing ovarian stimulation (OS)? METHODS: A literature search was performed regarding hyper-response to ovarian stimulation for assisted reproductive technology. A scientific committee consisting of 5 experts discussed, amended, and selected the final statements in the questionnaire for the first round of the Delphi consensus. The questionnaire was distributed to 31 experts, 22 of whom responded (with representation selected for global coverage), each anonymous to the others. A priori, it was decided that consensus would be reached when ≥ 66% of the participants agreed and ≤ 3 rounds would be used to obtain this consensus. RESULTS: 17/18 statements reached consensus. The most relevant are summarized here. (I) Definition of a hyper-response: Collection of ≥ 15 oocytes is characterized as a hyper-response (72.7% agreement). OHSS is not relevant for the definition of hyper-response if the number of collected oocytes is above a threshold (≥ 15) (77.3% agreement). The most important factor in defining a hyper-response during stimulation is the number of follicles ≥ 10 mm in mean diameter (86.4% agreement). (II) Risk factors for hyper-response: AMH values (95.5% agreement), AFC (95.5% agreement), patient's age (77.3% agreement) but not ovarian volume (72.7% agreement). In a patient without previous ovarian stimulation, the most important risk factor for a hyper-response is the antral follicular count (AFC) (68.2% agreement). In a patient without previous ovarian stimulation, when AMH and AFC are discordant, one suggesting a hyper-response and the other not, AFC is the more reliable marker (68.2% agreement). The lowest serum AMH value that would place one at risk for a hyper-response is ≥ 2 ng/ml (14.3 pmol/L) (72.7% agreement). The lowest AFC that would place one at risk for a hyper-response is ≥ 18 (81.8% agreement). Women with polycystic ovarian syndrome (PCOS) as per Rotterdam criteria are at a higher risk of hyper-response than women without PCOS with equivalent follicle counts and gonadotropin doses during ovarian stimulation for IVF (86.4% agreement). No consensus was reached regarding the number of growing follicles ≥ 10 mm that would define a hyper-response. CONCLUSION: The definition of hyper-response and its risk factors can be useful for harmonizing research, improving understanding of the subject, and tailoring patient care.

The HERA (Hyper-response Risk Assessment) Delphi consensus for the management of hyper-responders in in vitro fertilization.

PURPOSE: To provide agreed-upon guidelines on the management of a hyper-responsive patient undergoing ovarian stimulation (OS) METHODS: A literature search was performed regarding the management of hyper-response to OS for assisted reproductive technology. A scientific committee consisting of 4 experts discussed, amended, and selected the final statements. A priori, it was decided that consensus would be reached when ≥66% of the participants agreed, and ≤3 rounds would be used to obtain this consensus. A total of 28/31 experts responded (selected for global coverage), anonymous to each other. RESULTS: A total of 26/28 statements reached consensus. The most relevant are summarized here. The target number of oocytes to be collected in a stimulation cycle for IVF in an anticipated hyper-responder is 15-19 (89.3% consensus). For a potential hyper-responder, it is preferable to achieve a hyper-response and freeze all than aim for a fresh transfer (71.4% consensus). GnRH agonists should be avoided for pituitary suppression in anticipated hyper-responders performing IVF (96.4% consensus). The preferred starting dose in the first IVF stimulation cycle of an anticipated hyper-responder of average weight is 150 IU/day (82.1% consensus). ICoasting in order to decrease the risk of OHSS should not be used (89.7% consensus). Metformin should be added before/during ovarian stimulation to anticipated hyper-responders only if the patient has PCOS and is insulin resistant (82.1% consensus). In the case of a hyper-response, a dopaminergic agent should be used only if hCG will be used as a trigger (including dual/double trigger) with or without a fresh transfer (67.9% consensus). After using a GnRH agonist trigger due to a perceived risk of OHSS, luteal phase rescue with hCG and an attempt of a fresh transfer is discouraged regardless of the number of oocytes collected (72.4% consensus). The choice of the FET protocol is not influenced by the fact that the patient is a hyper-responder (82.8% consensus). In the cases of freeze all due to OHSS risk, a FET cycle can be performed in the immediate first menstrual cycle (92.9% consensus). CONCLUSION: These guidelines for the management of hyper-response can be useful for tailoring patient care and for harmonizing future research.

Zygotic splitting following embryo biopsy: a cohort study of 207 697 single-embryo transfers following IVF treatment.

OBJECTIVE: To evaluate the risk of monozygotic splitting with embryo biopsy during in vitro fertilisation (IVF). DESIGN: A cohort study. SETTING: Anonymised assisted reproductive technology national data from the Human Fertilisation and Embryology Authority, UK. POPULATION: Women undergoing single-embryo transfer (SET) following either pre-implantation genetic testing (PGT) involving embryo biopsy or IVF without PGT. METHODS: Data on women undergoing SET either following PGT and non-PGT IVF treatment in 2000-2016 were analysed to compare the risk of zygotic splitting and monozygotic twining. Logistic regression analysis was performed adjusting for potential confounders. MAIN OUTCOMES: Monozygotic spitting, monozygotic twin birth. RESULTS: Data comprising a total of 207 697 SET cycles (4544 following PGT and 203 153 following non-PGT IVF) were analysed. The live birth rate per embryo transfer was 31.9% (95% confidence interval [CI] 30.5-33.2%) following PGT and 26.9% (95% CI 26.7-27.1%) following non-PGT IVF. The incidence of zygotic splitting following PGT was 2.4% (95% CI 1.7-3.3%) versus 1.5% (95% CI 1.4-1.6%) following non-PGT IVF. There was a significantly higher risk of zygotic splitting with PGT versus non-PGT IVF cycles (odds ratio [OR] 1.64, 95% CI 1.19-2.27). The higher risk of zygotic splitting with PGT cycles remained significant after adjusting for potential confounders (adjusted OR 1.51, 95% CI 1.06-2.15). CONCLUSIONS: The present study demonstrated an increased risk of monozygotic splitting with embryo biopsy. Given the current sparse literature, it is important to accumulate further evidence to validate the findings. TWEETABLE ABSTRACT: A likely increased risk of monozygotic splitting following embryo biopsy.

Sub-optimal responders following controlled ovarian stimulation: an overlooked group?

Individualization of IVF treatment and tailored stimulation based on predicted ovarian response may maximize treatment success and minimize the risks following IVF. Whilst there has been a consensus in defining poor ovarian response and an attempt to elucidate the threshold for excessive ovarian response based on the number of oocytes retrieved following ovarian stimulation, no systematic effort has been made in order to refine the oocyte yield thresholds for a normal responder. In this opinion article we discuss the evidence behind the oocyte number thresholds for the ovarian response categories and present the rationale and merits in recognizing a new, overlooked, ovarian response group: The sub-optimal ovarian responders.

Effect of heparin on the outcome of IVF treatment: a systematic review and meta-analysis.

The effect of heparin on IVF outcome has been widely debated in the literature. A systematic review and meta-analysis of the published literature was conducted to evaluate the effect of heparin treatment on IVF outcome. Searches were conducted on MEDLINE, EMBASE, Cochrane Library and Web of Science and identified 10 relevant studies (five observational and five randomized) comprising 1217 and 732 IVF cycles, respectively. The randomized studies included small numbers of women and exhibited high methodological heterogeneity. Meta-analysis of the randomized studies showed no difference in the clinical pregnancy rate (RR 1.23, 95% CI 0.97-1.57), live birth rate (RR 1.27, 95% CI 0.89-1.81) implantation rate (RR 1.39, 95% CI 0.96-2.01) and miscarriage rate (RR 0.77, 95% CI 0.24-2.42) in women receiving heparin compared with placebo during IVF treatment. However, meta-analysis of the observational studies showed a significant increase in the clinical pregnancy rate (RR 1.83, 95% CI 1.04-3.23, P=0.04) and live birth rate (RR 2.64, 95% CI 1.84-3.80, P<0.0001). The role of heparin as an adjuvant therapy during IVF treatment requires further evaluation in adequately powered high-quality randomized studies. The effect of heparin on IVF outcome is widely debated. Despite the results of published studies being conflicting, it has been suggested that the use of heparin results in increased pregnancy rates following IVF treatment. We conducted a systematic and comprehensive of the published literature to evaluate the effect of heparin treatment on IVF outcome. Searches were conducted on MEDLINE, EMBASE, Cochrane Library and Web of Science. We identified 10 studies from the literature and extracted the relevant data from the studies. Analyses of the data from randomized trials showed no improvement in the clinical pregnancy rate or the live birth rate in the group that received heparin. However, the studies included had small numbers of women and high methodological heterogeneity. The role of heparin in this context requires further evaluation in adequately powered randomized studies.

Adenomyosis and female fertility: a critical review of the evidence.

Adenomyosis is frequent during the evaluation of infertile women. Present evidence suggests that adenomyosis has a negative impact on female fertility. Limited data from uncontrolled studies suggest that treatment of adenomyosis may improve fertility. This review critically appraises the existing evidence to determine the relationship between adenomyosis and female fertility. There is need for large epidemiological studies to substantiate the association between adenomyosis and infertility. Furthermore, if adenomyosis has a harmful impact on fertility there is a need to determine if its treatment improves fertility and the various treatment modalities reported need to be assessed for their effectiveness in randomised trials.

A systematic review and meta-analysis of acupuncture in in vitro fertilisation.

BACKGROUND: Numerous randomised studies have reported pregnancy outcome in women who received acupuncture during their in vitro fertilisation (IVF) treatment cycle. OBJECTIVE: The objective of this study was to conduct a systematic review with meta-analysis of the trials of acupuncture during IVF treatment on the outcomes of clinical pregnancy and live birth rates. SEARCH STRATEGY: Searches were conducted in MEDLINE, EMBASE, Cochrane Library, ISI Proceedings and SCISEARCH. SELECTION CRITERIA: All randomised controlled trials that evaluated the effects of acupuncture compared with no treatment or sham acupuncture in women undergoing IVF-intracytoplasmic sperm injection treatment were included. DATA COLLECTION AND ANALYSIS: Study selection, quality appraisal and data extraction were performed independently and in duplicate. A sensitivity analysis was conducted where the meta-analysis was restricted to trials in which sham acupuncture was used in the control group. Meta-regression analysis was used to explore the association between study characteristics and pregnancy rates. MAIN RESULTS: Thirteen relevant trials, including a total of 2500 women randomised to either acupuncture or control group, were identified. No evidence of publication bias was found (Begg's test, P = 0.50). Five trials (n = 877) evaluated IVF outcome when acupuncture was performed around the time of transvaginal oocyte retrieval, while eight trials (n = 1623) reported IVF outcome when acupuncture was performed around the time of embryo transfer (ET). Meta-analysis of the five studies of acupuncture around the time of egg collection did not show a significant difference in clinical pregnancy (relative risks [RR] = 1.06, 95% CI 0.82-1.37, P = 0.65). Meta-analysis of the eight studies of acupuncture around the time of ET showed no difference in the clinical pregnancy rate (RR = 1.23, 95% CI 0.96-1.58, P = 0.1). Live birth data were available from five of the eight studies of acupuncture around the time of ET. Meta-analysis of these studies did not show a significant increase in live birth rate with acupuncture (RR = 1.34, 95% CI 0.85-2.11). Using meta-regression, no significant association between any of the studied covariates and clinical pregnancy rate was found (P > 0.05 for all covariates). CONCLUSION: Currently available literature does not provide sufficient evidence that adjuvant acupuncture improves IVF clinical pregnancy rate.

Validity of the in vitro fertilisation league tables: influence of patients' characteristics.

We tested the hypothesis that restricting comparison of the live birth rate following in vitro fertilisation (IVF) treatment in those couples having their first IVF cycle in whom the female is under 35 years of age and has a normal follicle-stimulating hormone level would improve the validity of comparing IVF clinics' success rates. We analysed all cycles performed over a 2-year period in patients who fulfilled these criteria and divided the study population according to the referring primary care trusts: group A (n = 90) were referred from Lambeth, Southwark and Lewisham and group B (n = 134) were referred from Brent and Harrow. There was no significant difference between the two groups with regard to their IVF cycle characteristics. The two groups differed in their ethnicity, cause of infertility, prevalence of uterine fibroids and smoking and alcohol consumption habits. Group A had a significantly lower live birth rate (OR = 0.45, 95% CI 0.21-0.95, P = 0.02) compared with group B. This study confirms the impact of the non-IVF-related patient characteristics on treatment outcome and the poor validity of comparing IVF clinics' success rates based on the sparse data published by national IVF registries.

Micro-Computed tomography (CT) based assessment of dental regenerative therapy in the canine mandible model.

High-resolution 3D bone-tissue structure measurements may provide information critical to the understanding of the bone regeneration processes and to the bone strength assessment. Tissue engineering studies rely on such nondestructive measurements to monitor bone graft regeneration area. In this study, we measured bone yield, fractal dimension and trabecular thickness through micro-CT slices for different grafts and controls. Eight canines underwent surgery to remove a bone volume (defect) in the canine's jaw at a total of 44 different locations. We kept 11 defects empty for control and filled the remaining ones with three regenerative materials; NanoGen (NG), a FDA-approved material (n=11), a novel NanoCalcium Sulfate (NCS) material (n=11) and NCS alginate (NCS+alg) material (n=11). After a minimum of four and eight weeks, the canines were sacrificed and the jaw samples were extracted. We used a custom-built micro-CT system to acquire the data volume and developed software to measure the bone yield, fractal dimension and trabecular thickness. The software used a segmentation algorithm based on histograms derived from volumes of interest indicated by the operator. Using bone yield and fractal dimension as indices we are able to differentiate between the control and regenerative material (p<0.005). Regenerative material NCS showed an average 63.15% bone yield improvement over the control sample, NCS+alg showed 55.55% and NanoGen showed 37.5%. The bone regeneration process and quality of bone were dependent upon the position of defect and time period of healing. This study presents one of the first quantitative comparisons using non-destructive Micro-CT analysis for bone regenerative material in a large animal with a critical defect model. Our results indicate that Micro-CT measurement could be used to monitor in-vivo bone regeneration studies for greater regenerative process understanding.