Ido Feferkorn

BACKGROUND: There has been an increase in the average age of patients seeking fertility treatments over the past decades, with a significantly higher rate of advanced maternal age (AMA) patients undergoing IVF. It is unclear if different treatment strategies in IVF improve outcomes in AMA patients. OBJECTIVE AND RATIONALE: The aim of this systematic review was to assess the efficacy of different interventions employed in IVF in patients of AMA. SEARCH METHODS: A comprehensive search in Embase, Medline, and the Cochrane Library was performed. The search strategy included keywords related to IVF and AMA. We included all original peer-reviewed articles published in English, from January 1985 to September 2024, primarily designed to assess the efficacy of different interventions in IVF on clinical outcomes in AMA patients. Meta-analyses were performed for interventions for which sufficient randomized controlled trials existed. OUTCOMES: A total of 151 studies were included in the review. AMA was not consistently defined in all studies reviewed, although common to all studies was an age above 35 years. For the majority of evidence, there appeared to be no clear advantage to any stimulation protocol in AMA patients. There also appeared to be no advantage to any specific FSH medication, while a meta-analysis performed for the addition of LH to follicular stimulating hormone in stimulation demonstrated similar clinical pregnancy and live birth rates. No good evidence was found to support the routine implementation of ICSI in AMA patients, while a meta-analysis performed for assisted hatching (AH) pointed to decreased live birth rates with its implementation. Low-quality evidence demonstrated an increase in live birth rates with multiple embryos transferred with an increase in multiple pregnancies delivered. Finally, a meta-analysis performed for preimplantation genetic testing for aneuploidy (PGT-A) pointed to similar live birth rates as for no testing. WIDER IMPLICATIONS: This review failed to find an advantage to the routine implementation of treatment strategies such as specific stimulation protocols and gonadotropins, ICSI, and PGT-A, and a potential harmful effect for AH. Future high-quality randomized controlled trials are needed to affirm the majority of this review’s conclusions. REGISTRATION NUMBER: PROSPERO ID: CRD42022335889.

The present study was conducted to compare embryo survival rate and treatment outcomes including pregnan-cy, miscarriage and live birth rates of IVF and ICSI vitrified-thawed embryo transfers. Authors suggested to compare treatment outcomes [clinical pregnancy, miscarriage, ectopic pregnancy, and live birth rates] after transfer of IVF versus ICSI vitrified-thawed embryos. Cohort retrospective study in the IVF unit at a university af-filiated Medical Center which included 845 frozen thawed embryo transfer cycles of vitrified embryos from treatment cycles between the years 2013-2019. Out of 845 FET cycles of vitrified thawed embryos, 223 clinical pregnancies were achieved [26.4%]. Of these 64 [28.4%] following IVF, 131 [25.6%] after ICSI and 28 [25.9%] in the sibling oocytes group [P =0.631]. Live birth rate did not differ between the three groups: 23.6%, 22.3% and 21.5% for groups IVF, ICSI and IVF+ICSI, respectively [p=0.899]. Sub analysis by age below 35 and above 35 years old revealed no statistical difference between IVF and ICSI cycles in terms of clinical pregnancy, miscarriage, ectopic pregnancy, and live birth rates between the groups. The present study suggests that the technique of insemina-tion has no adverse effect related to vitrification.

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.

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.