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.

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.

Usability, accuracy, and cost-effectiveness of a medical software for early pregnancies: a retrospective study.

STUDY QUESTION: Can early pregnancies be accurately and cost-effectively diagnosed and managed using a new medical computerized tool? SUMMARY ANSWER: Compared to the standard clinical approach, retrospective implementation of the new medical software in a gynaecological emergency unit was correlated with more accurate diagnosis and more cost-effective management. WHAT IS KNOWN ALREADY: Early pregnancy complications are responsible for a large percentage of consultations, mostly in emergency units, with guidelines becoming complex and poorly known/misunderstood by practitioners. STUDY DESIGN, SIZE, DURATION: A total of 780 gynaecological emergency consultations (446 patients), recorded between November 2018 and June 2019 in a tertiary university hospital, were retrospectively encoded in a new medical computerized tool. The inclusion criteria were a positive hCG test result, ultrasonographical visualization of gestational sac, and/or embryo corresponding to a gestational age of 14 weeks or less. Diagnosis and management suggested by the new computerized tool are named eDiagnoses, while those provided by a gynaecologist member of the emergency department staff are called medDiagnoses. PARTICIPANTS/MATERIALS, SETTING, METHODS: Usability was the primary endpoint, with accuracy and cost reduction, respectively, as secondary and tertiary endpoints. Identical eDiagnoses/medDiagnoses were considered as accurate. During follow-up visits, if the updated eDiagnoses and medDiagnoses became both identical to a previously discrepant eDiagnosis or medDiagnosis, this previous eDiagnosis or medDiagnosis was also considered as correct. Four double-blinded experts reviewed persistent discrepancies, determining the accurate diagnoses. eDiagnoses/medDiagnoses accuracies were compared using McNemar's Chi square test, sensitivity, specificity, and predictive values. MAIN RESULTS AND THE ROLE OF CHANCE: Only 1 (0.1%) from 780 registered medical records lacked data for full encoding. Out of the 779 remaining consultations, 675 eDiagnoses were identical to the medDiagnoses (86.6%) and 104 were discrepant (13.4%). From these 104, 60 reached an agreement during follow-up consultations, with 59 medDiagnoses ultimately changing into the initial eDiagnoses (98%) and only one discrepant eDiagnosis turning later into the initial medDiagnosis (2%). Finally, 24 remained discrepant at all subsequent checks and 20 were not re-evaluated. Out of these 44, the majority of experts agreed on 38 eDiagnoses (86%) and 5 medDiagnoses (11%, including four twin pregnancies whose twinness was the only discrepancy). No majority was reached for one discrepant eDiagnosis/medDiagnosis (2%). In total, the accuracy of eDiagnoses was 99.1% (675 + 59 + 38 = 772 eDiagnoses out of 779), versus 87.4% (675 + 1 + 5 = 681) for medDiagnoses (P < 0.0001). Calculating all basic costs of extra consultations, extra-medications, extra-surgeries, and extra-hospitalizations induced by incorrect medDiagnoses versus eDiagnoses, the new medical computerized tool would have saved 3623.75 Euros per month. Retrospectively, the medical computerized tool was usable in almost all the recorded cases (99.9%), globally more accurate (99.1% versus 87.4%), and for all diagnoses except twinning reports, and it was more cost-effective than the standard clinical approach. LIMITATIONS, REASONS FOR CAUTION: The retrospective study design is a limitation. Some observed improvements with the medical software could derive from the encoding by a rested and/or more experienced physician who had a better ultrasound interpretation. This software cannot replace clinical and ultrasonographical skills but may improve the compliance to published guidelines. WIDER IMPLICATIONS OF THE FINDINGS: This medical computerized tool is improving. A new version considers diagnosis and management of multiple pregnancies with their specificities (potentially multiple locations, chorioamnionicity). Prospective evaluations will be required. Further developmental steps are planned, including software incorporation into ultrasound devices and integration of previously published predictive/prognostic factors (e.g. serum progesterone, corpus luteum scoring). STUDY FUNDING/COMPETING INTEREST(S): No external funding was obtained for this study. F.B. and D.G. created the new medical software. TRIAL REGISTRATION NUMBER: NCT03993015.

Low-dose HCG may improve pregnancy rates and lower OHSS in antagonist cycles: a meta-analysis.

Human chorionic gonadotrophin (HCG) may substitute FSH to complete follicular growth in IVF cycles. This may be useful in the prevention of ovarian hyperstimulation syndrome. Relevant studies were identified on Medline. To evaluate outcomes, a meta-analysis of low-dose HCG-supplemented IVF cycles versus non-supplemented ones was performed with data from 435 patients undergoing IVF who were administered low-dose HCG in various agonist and antagonist protocols and from 597 conservatively treated patients who served, as control subjects. Using these published data, a decision analysis evaluated four different management strategies. Effectiveness and economic outcomes were assessed by FSH consumption, clinical pregnancy and incremental cost-effectiveness ratios. Clinical pregnancy and ovarian hyperstimulation were the main outcome measures. Nine trials published in 2002-2007 were included. From the prospective studies, in the gonadotrophin-releasing hormone antagonist group, a trend for significance in clinical pregnancy rate was evident (odds ratio [OR], 1.54; 95% confidence interval [CI], 0.98-2.42). Ovarian hyperstimulation was less significant in the antagonist low-dose HCG protocol compared with the non-supplemented agonist protocol (OR 0.30; 95% CI 0.09-0.96). Less FSH was consumed in the low-dose HCG group but this difference was not statistically significant. Low-dose HCG supplementation may improve pregnancy rates in antagonist protocols. Overall, low-dose HCG-supplemented protocols are a cost-effective strategy.