Showing papers by "Carlo Alviggi published in 2022"

Second stimulation in the same ovarian cycle: an option to fully-personalize the treatment in poor prognosis patients undergoing PGT-A

Abstract: Our primary objective was to assess whether immediately undergoing a second stimulation in the same ovarian cycle (DuoStim) for advanced-maternal-age and/or poor-ovarian-reserve (AMA/POR) patients obtaining ≤ 3 blastocysts for preimplantation-genetic-testing-for-aneuploidies (PGT-A) is more efficient than the conventional-approach. All AMA/POR patients obtaining ≤ 3 blastocysts after conventional-stimulation between 2017 and 2019 were proposed DuoStim, and 143 couples accepted (DuoStim-group) and were matched for the main confounders to 143 couples who did not accept (conventional-group). GnRH-antagonist protocol with recombinant-gonadotrophins and agonist trigger, intra-cytoplasmatic-sperm-injection (ICSI) with ejaculated sperm, PGT-A and vitrified-warmed euploid single-blastocyst-transfer(s) were performed. The primary outcome was the cumulative-live-birth-delivery-rate per intention-to-treat (CLBdR per ITT) within 1 year. If not delivering, the conventional-group had 1 year to undergo another conventional-stimulation. A cost-effectiveness analysis was also conducted. The CLBdR was 10.5% in the conventional-group after the first attempt. Only 12 of the 128 non-pregnant patients returned (165 ± 95 days later; drop-out = 116/128,90.6%), and 3 delivered. Thus, the 1-year CLBdR was 12.6% (N = 18/143). In the DuoStim-group, the CLBdR was 24.5% (N = 35/143; p = 0.01), 2 women delivered twice and 13 patients have other euploid blastocysts after a LB (0 and 2 in the conventional-group). DuoStim resulted in an incremental-cost-effectiveness-ratio of 23,303€. DuoStim was costlier and more effective in 98.7% of the 1000 pseudo-replicates generated through bootstrapping, and the cost-effectiveness acceptability curves unveiled that DuoStim would be more cost-effective than the conventional-approach at a willingness-to-pay threshold of 23,100€. During PGT-A treatments in AMA/POR women, DuoStim can be suggested in progress to rescue poor blastocyst yields after conventional-stimulation. It might indeed prevent drop-out or further aging between attempts.

Effect of Genetic Variants of Gonadotropins and Their Receptors on Ovarian Stimulation Outcomes: A Delphi Consensus

Abstract: Background A Delphi consensus was conducted to evaluate the influence of single nucleotide polymorphisms (SNPs) in genes encoding gonadotropin and gonadotropin receptors on clinical ovarian stimulation outcomes following assisted reproductive technology (ART) treatment. Methods Nine experts plus two Scientific Coordinators discussed and amended statements plus supporting references proposed by the Scientific Coordinators. The statements were distributed via an online survey to 36 experts, who voted on their level of agreement or disagreement with each statement. Consensus was reached if the proportion of participants agreeing or disagreeing with a statement was >66%. Results Eleven statements were developed, of which two statements were merged. Overall, eight statements achieved consensus and two statements did not achieve consensus. The statements reaching consensus are summarized here. (1) SNP in the follicle stimulating hormone receptor (FSHR), rs6166 (c.2039A>G, p.Asn680Ser) (N=5 statements): Ser/Ser carriers have higher basal FSH levels than Asn/Asn carriers. Ser/Ser carriers require higher amounts of gonadotropin during ovarian stimulation than Asn/Asn carriers. Ser/Ser carriers produce fewer oocytes during ovarian stimulation than Asn/Asn or Asn/Ser carriers. There is mixed evidence supporting an association between this variant and ovarian hyperstimulation syndrome. (2) SNP of FSHR, rs6165 (c.919G>A, p.Thr307Ala) (N=1 statement): Few studies suggest Thr/Thr carriers require a shorter duration of gonadotropin stimulation than Thr/Ala or Ala/Ala carriers. (3) SNP of FSHR, rs1394205 (−29G>A) (N=1 statement): Limited data in specific ethnic groups suggest that A/A allele carriers may require higher amounts of gonadotropin during ovarian stimulation and produce fewer oocytes than G/G carriers. (4) SNP of FSH β-chain (FSHB), rs10835638 (−211G>T) (N=1 statement): There is contradictory evidence supporting an association between this variant and basal FSH levels or oocyte number. (5) SNPs of luteinizing hormone β-chain (LHB) and LH/choriogonadotropin receptor (LHCGR) genes (N=1 statement): these may influence ovarian stimulation outcomes and could represent potential future targets for pharmacogenomic research in ART, although data are still very limited. Conclusions This Delphi consensus provides clinical perspectives from a diverse international group of experts. The consensus supports a link between some variants in gonadotropin/gonadotropin receptor genes and ovarian stimulation outcomes; however, further research is needed to clarify these findings.

Exposure to artificial light at night: A common link for obesity and cancer?

Abstract: Exposure to artificial light at night (ALAN) has been associated with disruption of the circadian system, which has been pointed out to have detrimental effects on health. Exposure to outdoor ALAN is very frequent in industrialised countries due to nocturnal light pollution and the relevant involvement of the total workforce in shift work and night work. Ecological and epidemiologic studies highlight the association between exposure to ALAN and several diseases, mainly obesity and cancer. More recently, also indoor ALAN exposure has been investigated. Among several multifactorial mechanisms linking ALAN exposure and health risks, suppression of melatonin secretion plays a pivotal role leading to alterations in circadian rhythm patterns, that are detrimental in terms of appetite regulation, and dysfunctions in metabolic signalling and cell growth in cancer. In addition, gut dysbiosis, inflammation, hypovitaminosis D, imbalance in cytokine secretion and levels are responsible for the multiple relationship linking circadian dysregulation due to ALAN exposure and obesity, and cancer. Therefore, the current manuscript summarises human and basic studies pointing out the impact of ALAN exposure on health, mostly focusing on obesity and cancer. Based on extant evidence, prevention strategies for obesity and cancer should be prompted, targeting exposure to ALAN.

The effect of extended cryo-storage following vitrification on embryo competence: a systematic review and meta-analysis

Abstract: Few studies explored whether prolonged cryo-storage after vitrification affects embryo competence and perinatal outcomes. This systematic review and meta-analysis aims at highlighting any putative impact of cryo-storage duration on cryo-survival, miscarriage, live birth and major malformations. A systematic review was performed using MEDLINE (PubMed), ISI Web of Knowledge, Scopus and Embase databases up to June 2021. Data were combined to obtain a pooled OR, and meta-analysis was conducted using a random effects model. Out of 1,389 screened abstracts, 22 papers were assessed for eligibility, and 5 studies were included (N = 18,047 embryos). Prolonged cryo-storage was defined as > 12 months (N = 3389 embryos). Subgroup analysis was performed for untested vitrified cleavage stage embryos (N = 1739 embryos) and for untested and euploid vitrified blastocysts (N = 13,596 and 2712 embryos, respectively). Survival rate, miscarriage, live birth and major malformation rates were all similar in the two groups. These data further support the safety of long-term cryo-storage of human embryos beyond 12 months. This is reassuring for good prognosis patients with surplus embryos, couples seeking a second child from supernumerary embryos and women postponing the transfer for clinical or personal reasons.

The effect of polymorphisms in FSHR gene on late follicular phase progesterone and estradiol serum levels in predicted normoresponders.

Abstract: STUDY QUESTION Does the presence of FSHR single-nucleotide polymorphisms (SNPs) affect late follicular phase progesterone and estradiol serum levels in predicted normoresponders treated with rFSH? SUMMARY ANSWER The presence of FSHR SNPs (rs6165, rs6166, rs1394205) had no clinically significant impact on late follicular phase serum progesterone and estradiol levels in predicted normoresponders undergoing a GnRH antagonist protocol with a fixed daily dose of 150 IU rFSH. WHAT IS KNOWN ALREADY Previous studies have shown that late follicular phase serum progesterone and estradiol levels are significantly correlated with the magnitude of ovarian response. Several authors have proposed that individual variability in the response to ovarian stimulation (OS) could be explained by variants in FSHR. However, so far, the literature is scarce on the influence of this genetic variability on late follicular phase steroidogenic response. Our aim is to determine whether genetic variants in the FSHR gene could modulate late follicular phase serum progesterone and estradiol levels. STUDY DESIGN, SIZE, DURATION In this multicenter multinational prospective study conducted from November 2016 to June 2019, 366 patients from Vietnam, Belgium and Spain (166 from Europe and 200 from Asia) underwent OS followed by oocyte retrieval in a GnRH antagonist protocol with a fixed daily dose of 150 IU rFSH. All patients were genotyped for 3 FSHR SNPs (rs6165, rs6166, rs1394205) and had a serum progesterone and estradiol measurement on the day of trigger. PARTICIPANTS/MATERIALS, SETTING, METHODS Included patients were predicted normal responder women <38 years old undergoing their first or second OS cycle. The prevalence of late follicular phase progesterone elevation (PE), as well as mean serum progesterone and estradiol levels on the day of trigger were compared between the different FSHR SNPs genotypes. PE was defined as >1.50 ng/ml. MAIN RESULTS AND THE ROLE OF CHANCE The overall prevalence of PE was 15.8% (n = 58). No significant difference was found in the prevalence of PE in Caucasian and Asian patients (17.5% versus 14.5%). Estradiol levels on the day of trigger and the number of retrieved oocytes were significantly higher in patients with PE (4779 ± 6236.2 versus 3261 ± 3974.5 pg/ml, P = 0.003, and 16.1 ± 8.02 versus 13.5 ± 6.66, P = 0.011, respectively). Genetic model analysis, adjusted for patient age, body mass index, number of retrieved oocytes and continent (Asia versus Europe), revealed a similar prevalence of PE in co-dominant, dominant and recessive models for variants FSHR rs6166, rs6165 and rs1394205. No statistically significant difference was observed in the mean late follicular phase progesterone serum levels according to the genotypes of FSHR rs6166 (P = 0.941), rs6165 (P = 0.637) and rs1394205 (P = 0.114) in the bivariate analysis. Also, no difference was found in the genetic model analysis regarding mean late follicular phase progesterone levels across the different genotypes. Genetic model analysis has also revealed no statistically significant difference regarding mean estradiol levels on the day of trigger in co-dominant, dominant and recessive models for variants FSHR rs6166, rs6165 and rs1394205. Haplotype analysis revealed a statistically significant lower estradiol level on the day of trigger for rs6166/rs6165 haplotypes GA, AA and GG when compared to AG (respectively, estimated mean difference (EMD) -441.46 pg/ml (95% CI -442.47; -440.45), EMD -673.46 pg/ml (95% CI -674.26; -672.67) and EMD -582.10 pg/ml (95% CI -584.92; -579.28)). No statistically significant differences were found regarding the prevalence of PE nor late follicular phase progesterone levels according to rs6166/rs6165 haplotypes. LIMITATIONS, REASONS FOR CAUTION Results refer to a population of predicted normal responders treated with a normal/low fixed dose of 150 IU rFSH throughout the whole OS. Consequently, caution is needed before generalizing our results to all patient categories. WIDER IMPLICATIONS OF THE FINDINGS Based on our results, FSHR SNPs rs6165, rs6166 and rs1394205 do not have any clinically significant impact neither on late follicular phase serum progesterone nor on estradiol levels in predicted normal responders. These findings add to the controversy in the literature regarding the impact of individual genetic susceptibility in response to OS in this population. STUDY FUNDING/COMPETING INTEREST(S) This study was supported by an unrestricted grant by Merck Sharp & Dohme (MSD, IISP56222). N.P.P. reports grants and/or personal fees from MSD, Merck Serono, Roche Diagnostics, Ferring International, Besins Healthcare, Gedeon Richter, Organon, Theramex and Institut Biochimique SA (IBSA). C.A. reports conference fees from Merck Serono, Medea and Event Planet. A.R.N., C.B., C.S., P.Q.M.M., H.T., C.B., N.L.V., M.T.H. and S.G. report no conflict of interests related to the content of this article. TRIAL REGISTRATION NUMBER NCT03007043.

POSEIDON groups and their distinct reproductive outcomes: Effectiveness and cost-effectiveness insights from real-world data research.

Abstract: The Patient-Oriented Strategies Encompassing IndividualizeDOocyte Number (POSEIDON) criteria identify and classify the so-called 'low-prognosis' patients undergoing assisted reproductive technology (ART). Recent large-scale studies using real-world data (RWD) have shown that patients classified under this system have distinct reproductive outcomes. Moreover, these studies also confirm that POSEIDON patients are commonly found in fertility centers. RWD has substantiated the validity of the POSEIDON biomarkers' thresholds (antral follicle count [AFC] and/or anti-Müllerian hormone [AMH]) for patient classification. Lastly, a predictive model has been developed and validated to estimate the POSEIDON metric of success (i.e., number of oocytes needed to achieve at least one euploid blastocyst). Although more evidence is needed in this area, current insights from RWD research indicate that infertility patients can be counseled and managed more effectively under the POSEIDON scope, with potential gains for all parties involved.

Severe impact of late diagnosis of congenital adrenal hyperplasia on gender identity, sexual orientation and function: case report and review of the literature

Abstract: Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21-OHD) represents the most frequent form of CAH and of 46, XX disorder of sex development in female newborns. In the majority of cases, particularly in developed countries, female patients suffering from the classic forms of CAH reach the diagnosis at birth or in the early childhood, allowing a prompt treatment with a correct gender assignment. The current manuscript describes an unusual case of an Italian 46-year-old woman, homeborn in the 60s, receiving an extraordinarily late diagnosis of simple virilising classic form of CAH due to 21-OHD, determining a relevant impairment of both physical and psychosexual development. The patient presented primary amenorrhea, height under target, overweight with visceral adiposity, hypercholesterolemia and insulin resistance, hirsutism with a typical male-pattern hair growth, external genital ambiguity, and a severe impairment in the entire series of psychological dimensions, particularly severe depressive symptoms, together with gender dysphoria relative to the female gender assigned at birth, cross-gender behaviours, and body image discomfort, which were associated with homosexual orientation, and sexual dysfunction. Following diagnosis and glucocorticoid (GC) replacement therapy, the hyperandrogenism control and familial and socio-cultural factors changes, particularly, living alone and the interruption of social isolation, were accompanied by menarche appearance, improvement in hirsutism and metabolic profile, and a resolution in all psychological dimensions, depressive symptoms, and gender dysphoria. The patient began to perceive homosexual orientation without discomfort, and ameliorating sexual function. Few cases of female patients with CAH due to 21-OHD receiving an extremely delayed diagnosis have been published. However, to the best of our knowledge, this is the first case including a complete psychosexual assessment at diagnosis with a detailed re-evaluation after 5 years of disease treatment.

Effectiveness of progesterone supplementation in women presenting low progesterone levels on the day of frozen embryo transfer: a randomised controlled trial

Abstract: Introduction Progesterone is an essential hormone involved in the process of implantation and pregnancy maintenance. Evidence from recent studies has supported the importance of serum progesterone level around the time of embryo transfer in hormonal replacement therapy frozen embryo transfer cycles and recommended the need for individualised luteal support. Low progesterone around the time of embryo transfer is found to be associated with decreased rate of pregnancy after frozen embryo transfer. This single-centre, longitudinal, randomised, interventional controlled study aims to compare the rate of ongoing pregnancy between two groups of women with progesterone level below 10 ng/mL on the day of frozen embryo transfer: the study group using 800 mg vaginal micronised progesterone supplemented with 50 mg intramuscular progesterone per day and the control group using only 800 mg vaginal micronised progesterone. Methods and analysis We enrol patients who are undergoing frozen embryo transfers with blastocyst-stage or cleavage-stage embryos and who satisfy the inclusion and exclusion criteria. After signing the informed consent, participants are randomised into two groups: the study group using vaginal micronised progesterone supplemented with progesterone intramuscular 50 mg per day and the control group using only vaginal micronised progesterone. Randomisation will be performed using R software at a 1:1 allocation ratio. Sequentially numbered, opaque sealed envelopes are used for allocation. The primary outcome is the rate of ongoing pregnancy. To demonstrate a difference of 10% with regard to rate of ongoing pregnancy, at least 370 participants per arm are required (type I error α=0.05, power=0.8). Assuming a dropout rate of 10%, a total of 824 patients (412 per group) will be invited. Ethics and dissemination This study was approved by the Ethics Committee of Tu Du Hospital on 17 May 2021 (reference number: 1251/QĐ-BVTD). All participants provide informed consent before being enrolled in the study. The results of our study will be submitted to reproductive medicine conferences and journals. Trial registration number NCT04897269.

Does Intrauterine Injection of hCG Improve IVF Outcome? A Systematic Review and a Meta-Analysis

Abstract: Various interventions have been proposed to improve embryo implantation in IVF. Among these, intrauterine injections of human chorionic gonadotropin seem to have promising results. Consequently, we conducted a review and meta-analysis to assess IVF outcomes by comparing couples who underwent intrauterine hCG injection transfer versus those who underwent embryo transfer with intrauterine injection of placebo, or without any additional intervention. The primary outcome was the clinical pregnancy rate. Secondary outcomes were the implantation rate, miscarriage rate, and live birth rate. A meta-analysis was conducted using the random effects model, while bias within studies was detected using the Cochrane risk of bias tool. Ectopic pregnancies and stillbirths were also assessed. The clinical pregnancy (RR 1.38, 95% CI 1.17–1.62, p < 0.0001) and implantation rate (RR 1.40, 95% CI 1.12–1.75, p = 0.003) were significantly higher in women who underwent hCG injection than in the control group. These significant effects persisted only in women who underwent cleavage-stage embryo transfer. No significant differences between groups were observed in the other secondary outcomes. In conclusion, our systematic review and meta-analysis demonstrate that intrauterine injection of hCG could be a valuable approach in women who undergo cleavage-stage embryo transfer. Given the lack of data about the live birth rate, caution should be exercised in interpreting these data.

Neither rationale nor scientific evidence exist to support that double stimulation is potentially unsafe.

Abstract: Sir, We have carefully read the opinion paper published by Dr Angelo Tocci about the hypothetical mechanism explaining the effectiveness of double stimulation in the same ovarian cycle (DuoStim) (Tocci, 2022). Tocci (2022) suggests that the higher oocyte number generally collected after the second stimulation is imputable to differentiation of two FSH-responsive stem cell populations, i.e. very small embryonic-like and human ovarian stem cells (OSCs), presumably present in the ovarian surface epithelium (OSE). The opinion viewpoint is that the first stimulation may trigger the commitment of oocyte progenitors to differentiate into mature oocytes. We certainly recognize the author’s efforts in explaining how anovulatory waves of follicle growth may result in oocytes like those collected after the first stimulation per embryological, clinical and perinatal outcomes (Vaiarelli et al., 2020). On the contrary, strong concerns arose about the misleading inference that a second stimulation is ‘potentially unsafe’....

Cryopreservation of ovarian tissue: the biggest challenge of oncofertility.

Abstract: Survival rates after cancer diagnosis and treatment have been raising through the last decades. Nowadays, oncofertility represents a useful strategy for young women affected by cancer to preserve their ovarian function and their family planning opportunity. Apart from more diffused techniques as cryopreservation of mature oocytes after controlled ovarian stimulation and gonadal downregulation with GnRH agonist depots, the cryopreservation of the cortical region of the ovarian tissue, which contains 90% of the follicular reserve, and later autologous transplant represent a possible and intriguing strategy. Nonetheless, the safety of the procedure is still a matter of debate and is a topic of great interest in both oncologic and reproductive fields. Especially, in order to improve the efficacy of the strategy the open questions are 1) how to search for malignant cells, 2) slow freezing vs. vitrification, 3) state of the art on the "artificial ovary". The aim of this review is to summarize the recent advances in ovarian tissue cryopreservation and present future perspectives.

Pharmacogenomic Approach in Controlled Ovarian Stimulation: Time to Take the Plunge?

Abstract: none.

P-660 Polymorphisms in FSHR gene do not affect late follicular phase steroidogenic response in predicted normoresponders. Secondary analysis of a prospective multicenter cohort study

Abstract: Does the presence of FSHR SNPs influence late follicular phase progesterone and estradiol serum levels in predicted normoresponders treated with rFSH? The presence of FSHR SNPs (rs6165, rs6166, rs1394205) had no statistically significant impact on late follicular phase serum progesterone and estradiol levels. Previous studies have shown that late follicular phase serum progesterone and estradiol levels are significantly correlated with the magnitude of ovarian response. Several authors have proposed that individual variability in the response to ovarian stimulation could be explained by variants in FSHR. So far, the literature is scarce on the influence of this genetic variability on late follicular phase steroidogenic response. Our aim is to determine whether genetic variants in the FSHR gene could modulate late follicular phase serum progesterone and estradiol levels. We performed a secondary analysis of a multicenter multinational prospective study including 366 patients from Vietnam, Belgium and Spain (166 from Europe and 200 from Asia), conducted from 11/2016-06/2019. All patients underwent ovarian stimulation followed by oocyte retrieval in an antagonist protocol with a fixed daily dose of 150IU rFSH. All patients had a serum progesterone and estradiol measurement on the day of trigger and were genotyped for 3 FSHR SNPs (rs6165, rs6166, rs1394205). Patients included were predicted normal responder women <38 years old undergoing their first or second ovarian stimulation cycle. The prevalence of late follicular phase elevated serum progesterone (EP), as well as mean serum progesterone and estradiol levels on the day of trigger were compared between the different FSHR SNPs genotypes. EP was defined as > 1.5 ng/ml. The overall prevalence of EP was 15.8% (n = 58). No significant difference was found in the prevalence of EP in Caucasian and Asian patients (17.5% vs. 14.5%). Genetic model analysis revealed a similar prevalence of EP in co-dominant, dominant and recessive models for variants FSHR rs6166, rs6165 and rs1394205. Also, no statistically significant difference was found in the mean serum progesterone levels in the three genetic models. Likewise, FSHR SNPs genotypes had no statistically significant impact in the mean late follicular phase serum estradiol levels This study is a post-hoc analysis of a multicenter multinational prospective cohort study. The results must be interpreted with caution considering the sample size of the EP group. The fact that a fixed daily dose of 150 IU rFSH was used in this population precludes the generalization of the results. Based on our results, FSHR SNPs rs6165, rs6166, rs1394205 do not influence late follicular phase serum progesterone nor estradiol levels in predicted normal responders. These findings add to the controversy in the literature regarding the impact of individual genetic susceptibility in response to ovarian stimulation in this population. not-applicable

P-621 Different gonadotrophins adopted for controlled ovarian stimulation do not affect metaphase-II oocyte competence. A matched case-control study on 351 patients and 2258 oocytes

Abstract: Do different gonadotrophins for controlled-ovarian-stimulation (COS) affect metaphase-II (MII) oocyte competence? Euploid blastocyst rate (EBR) per cohort of MII-oocytes, live-birth-rate (LBR) per first vitrified-warmed euploid single-embryo-transfer (SET) and cumulative-LBR are independent from the gonadotrophins used. Controlled-ovarian-stimulation (COS) is a cornerstone of IVF. Its purpose is maximizing ovarian reserve exploitation and obtaining ≥1 euploid blastocyst to transfer. Indeed, ovarian reserve decreases and blastocyst aneuploidy rates increase with increasing maternal age, making this task quite complicated in advanced maternal age. Old-fashioned studies suggested an association between COS and embryonic aneuploidy rates. Conversely, recent studies excluded an impact of COS dosage, duration, ovarian response, and ovulation trigger, on blastocyst aneuploidy rate. An aspect, though, needs more clarity: do different gonadotropins impact oocyte competence after COS, comprehensively defined as EBR per cohort of MII-oocytes? Out of 3169 PGT cycles with ³1 MII oocyte conducted between 2014-2018, we excluded (i)PGT-M/-SR, (ii)women<35yr, (iii)severe-male-factor, (iv)DuoStim or long-active FSH, (v)culture with sequential-media, and (v)multiple cycles. Among the 784 cycles left, a propensity-score-matching (PSM) based on the number of inseminated MII-oocytes was adopted to match patients using recFSH [without (N = 57; 337 MII-oocytes)/with recLH (N = 55; 374 MII-oocytes)] and Human-Menopausal-Gonadotrophin (HMG; N = 127; 835 MII-oocytes). The patients using recFSH+HMG were all included (N = 112; 712 MII-oocytes). Only GnRH-antagonist COS, ICSI with fresh MII-oocytes, single culture in continuous-media, trophectoderm biopsy without assisted-hatching, comprehensive-chromosome-testing to assess full-chromosome non-mosaic aneuploidies and vitrified-warmed euploid SET were conducted. Oocyte competence was comprehensively defined as EBR per cohort of MII-oocytes with all intermediate outcomes (fertilization, blastulation and euploidy). LBR per first vitrified-warmed euploid SET and cumulative-LBR per retrieval were also assessed. Generalized-linear-models and multivariate regressions were adopted to adjust the results for confounders. All cycles were concluded. Patients using recFSH+recLH and recFSH+HMG (40.7 yr) were older than patients using recFSH-only or HMG-only (40 yr; ANOVA<0.01). No other difference was reported in the 4 patient populations. The overall gonadotrophins dosage (2615±977, 3601±1889, 3818±946 and 2892±911 IU in the recFSH-only, recFSH+recLH, recFSH+HMG and HMG-only groups, respectively) and duration of COS (9.7±1.9, 9.4±1.5, 9.9±1.8 and 10.2±1.8 days) were different (Kruskal-Wallis tests=0.02). The number of cumulus-oocyte-complexes (9.2±6.5) and MII-oocytes collected (6.4±4.4) were instead well-matched across the groups. The EBR per cohort of inseminated MII-oocytes was different in the four groups (20.7±27.1%, 9.6±12.9%, 12.4±18.5% and 16.9±21.8%, respectively), but, when adjusted for maternal age in a generalized-linear-model, the gonadotrophin used for COS did not show any significant association with this outcome (partial-eta2=0.02, p = 0.1, power=0.6). All intermediate embryological outcomes were also similar. The LBR per first vitrified-warmed euploid SET was comparable in the four groups [N = 14/33 (42%), N = 9/22 (41%), N = 26/62 (45%), N = 24/55 (44%), respectively], as confirmed by the logistic regression adjusted for blastocyst quality (multivariate-OR: 0.97, 95%CI 0.73-1.31, adjusted-p=0.9). Lastly, the cumulative-LBRs per retrieval were equivalent [N = 17/57 (30%), N = 14/55 (26%), N = 34/127 (27%), and N = 33/112 (30%), respectively], as confirmed by the logistic regression adjusted for maternal age (multivariate-OR: 1.01, 95%CI 0.8-1.3, adjusted-p=0.9). The gonadotrophins were chosen based on patient compliance to their administration route and gynecologist judgement, and only qualitative outcomes were assessed. Therefore, randomized-controlled-trials and cost-effectiveness analysis investigating the efficiency in oocyte recruitment and cumulative-LBR per intention-to-treat are needed. Different gonadotrophins might not affect MII-oocyte competence. This information is key since, in view of the optimization of follicle recruitment through personalized-COS, it allows more flexibility in the choice of the most suitable protocol. Therefore, gynecologists might ponder also features like patient reproductive history and compliance to different administration routes. none

Ovarian Hyperstimulation Syndrome after GnRH Agonist Triggering and Freeze-All Protocol? Never Not, Hardly Ever: A Systematic Review of Case Reports

Abstract: Introduction: Ovarian hyperstimulation syndrome (OHSS) is a severe complication associated with controlled ovarian stimulation (COS). GnRH agonist (GnRH-a) triggering is considered an efficient strategy to prevent OHSS in the high-risk patient. Methods: We performed a review of 11 cases of early and severe OHSS following GnRH-a triggering and freeze-all protocol. Electronic databases were searched from inception of each database until October 2021, to identify case reports and case series that reported OHSS after GnRH-a triggering and freeze-all approach describing patient demographics, COS protocol, and patient outcomes. Results: From the literature review, it is possible to suggest that (1) following GnRH-a triggering, the risk of early and severe OHSS is not totally cancelled; (2) despite it is not possible to predict the event, polycystic ovary syndrome is the most common risk factor; (3) the use of GnRH antagonist starting from the day of PU may represent a valid strategy for preventing OHSS in women with high-risk profile; (4) following the unexpected onset of OHSS, measuring serum levels of human chorionic gonadotropin (hCG) is helpful to exclude an inadvertent exogenous administration or a pregnancy. Conclusion: The statement that OHSS risk is eliminated when GnRH-a triggering, a freeze-all strategy, and no hCG in the luteal phase may generate the idea that this event cannot occur. Although rare, these cases have been observed in a relatively short period of time.