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Purpose: The present systematic review aimed to assess the fecundity of women with congenital uterine anomalies (CUAs) undergoing assisted reproductive technology (ART)., Methods: The present systematic review of the literature was reported according to the PRISMA guidelines. We systematically searched PubMed, MEDLINE, Embase and Scopus, from database inception to 17th October 2023. Studies were deemed eligible only if they included women with CUAs clearly fitting into one of the categories of the ASRM Müllerian anomalies classification 2021., Results: Data relevant to the reproductive outcomes of women with CUAs who underwent ART were extracted from 55 studies. Regarding Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome, studies on gestational surrogacy reported a live birth rate (LBR) ranging from 37 to 54%. Uterus transplant, although still experimental, showed promising results. Most studies reported a negative impact of unicornuate uterus and partial or complete septate uterus on both the miscarriage rate (MR) and the live birth rate (LBR). The reproductive prognosis of women with unicornuate uterus was shown to be particularly poor in case of twin pregnancy. Uterus didelphys, bicornuate and arcuate uterus seem not to negatively impact the ART reproductive outcomes. Uterus didelphys was associated with an increased risk of preterm birth (PTB), cesarean section and low birth weight (LBW)., Conclusion: Women with CUAs should be informed regarding the impact (if any) of their congenital anomaly on both the chances of success of ART and on pregnancy-related complications. Elective single embryo transfer (eSET) should always be the first choice in patients with an increased baseline obstetric risk., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: The management of Non-Obstructive (NOA) Azoospermia or Obstructive Azoospermia (OA) patients relies on testicular sperm extraction (TESE) followed by intracytoplasmic sperm injection (ICSI). In NOA patients the sperm recovery is successful in only 50% of cases and therefore the ability to predict those patients with a high probability of achieving a successful sperm retrieval would be a great value in counselling the patient and his partner. Several studies tried to suggest predictors of a positive TESE (e.g. FSH concentration), but most concluded that diagnostic testicular biopsy (histology) is best., Methods: This is a retrospective analysis of 526 TESE patients. After the extraction of the testis, the resulting sample was immediately given to the embryologist, who examined the tubules for sperm cryopreservation. During the same procedure, a different specimen was destined to the histological analysis. The comparison between the two methodological approaches was carried out through a score., Results: Concordance between TESE and testicular histology outcomes was found in 70,7% of patients; discordance was found in 29,3% of patients. Among the discordance outcomes, in approximately 95% we found at least 1 sperm in the TESE retrieval, while the histology report did not find any spermatozoa or found not enough compared to our evaluation; in only 5% of cases we did not find any spermatozoa or found not enough compared to what was detected in the testicular histology., Conclusion: Based on our experience, to increase diagnostic accuracy, a larger biopsy should be sent to the histopathology laboratory; another option may be to use TESE cell suspension (the same embryologists employ for cryopreservation) for cytological evaluation of spermatogenesis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Castellano, Tondo, Bulbul, Aprea, Monti, Carnesi, Levi Setti and Albani.)

Objective: The objectives of the study were to correlate live birth rate with the initial level of β-hCG in all patients undergoing embryo transfer and develop a predictive model of live birth based on patients' and assisted reproductive technology (ART) characteristics., Study Design: Single-center retrospective cohort study, including a total of 7587 positive first serum β-hCG from women who performed fresh and frozen embryo transfer. Twenty-one variables related to patient characteristics and treatment modalities were analyzed by step-wise univariate analysis followed by multivariate analysis. The study included women between 18 and 45 years with a positive (>20 IU/L) serum β-hCG between January 2011 and December 2020 while it excluded cycles from donation of gametes, PGT and >3 embryos transferred simultaneously., Main Results and the Role of Chance: Among the positive serum β-hCG measurements 5085 (67.0 %) resulted in live births. β-hCG was higher in the live birth group (691 IU/L) compared to the failed pregnancies group (304 IU/L) (p500 IU/mL provided a positive predictive value for live birth of 85.3 % (95 %CI 84.0-86.4). Failed pregnancies were more common among older maternal and paternal age. Previous abortions were more common in the failed pregnancies group (25.0 %) compared to the live birth group (19.4 %). The most common indication to treatment was male infertility, accounting for a larger portion in the live birth group (41.7 %). At multivariate analysis, the factors independently associated with live birth were: first serum β-hCG (OR 1.35, 95 %CI 1.32-1.37), maternal age (OR 0.93, 95 %CI 0.91-0.95), previous abortions (OR 0.77, 95 % CI 0.68-0.88). The number of embryos transferred showed a positive correlation below a maternal age of 39 (<35 years old OR 1.60, CI 95 % 1.32-1.94; <39 years old OR 1.27 CI 95 % 1.09-1.47). The prediction model incorporating these four variables resulted in a sensitivity and specificity with an area under the ROC curve of 0.798., Conclusion: The study confirms the importance of the first value of β-hCG and proposes a predictive model that takes into account maternal age, number of embryos transferred, and obstetric history, thereby aiding in couples' counseling and ultimately improve patients' care., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objective: To evaluate in vitro fertilization (IVF) and perinatal outcomes of donor egg and autologous cycles in patients with advanced reproductive age after undergoing single frozen euploid embryo transfer., Design: A multicenter, retrospective, cohort study., Setting: University-affiliated and private IVF centers., Patient(s): Patients aged 39-46 years who underwent IVF with intracytoplasmic sperm injection and preimplantation genetic testing for aneuploidy using whole-chromosome sequencing with donor (n = 278) or autologous (n = 278) oocytes between October 2017 and October 2021., Intervention(s): Single frozen euploid embryo transfer with donor or autologous euploid embryo., Main Outcome Measure(s): The main outcome measure was the live birth rate (LBR) after the first embryo transfer, calculated per embryo transfer. The secondary outcomes included the implantation rate, ectopic pregnancy rate, miscarriage rate, and gestational age and birth weight at the time of delivery., Result(s): Patients using donor or autologous oocytes had a similar likelihood of implantation (57.91% [51.87-63.78] vs. 57.19% [51.15-63.09]) and LBR (41.01% [95% confidence interval {CI}, 35.17-47.04] vs. 42.45% [95% CI, 36.56-48.49]). Furthermore, there were no significant differences in the ectopic pregnancy rate (0.72% [0.09-2.57] vs. 0.36% [0.01-1.99]), miscarriage rate (16.19% [12.06-21.05] vs. 14.39% [95% CI, 10.48-19.08]), gestational age (38.50 [38.08-38.92] vs. 39.16 [38.25-40.07] weeks), or birth weight of infants (2,982.25 [2,606.69-3,357.81] vs. 3,128.24 [2,962.30-3,294.17] kg). The univariate analysis showed no association between advanced maternal age and the LBR (relative risk, 1.03 [95% CI, 0.84-1.25]). Multivariate analysis using putative confounders for embryo competency found no associations with LBR (adjusted relative risk, 1.22 [95% CI, 0.75-1.98])., Conclusion(s): Patients with euploid blastocysts derived from donor or autologous oocytes did not reveal statistically significant differences in the LBR, implantation rate, ectopic pregnancy rate, miscarriage rate, duration of gestation, or infant birth weight. These findings suggest that age-related reproductive decline and/or poor IVF outcomes associated with women with advanced reproductive age undergoing IVF are heavily driven by embryonic aneuploidy., Competing Interests: Declaration of Interests M.C. has nothing to disclose. A.C. has nothing to disclose. J.A.G.-V. has nothing to disclose. A.P. has nothing to disclose. A.V. has nothing to disclose. D.G. has nothing to disclose. D.C. has nothing to disclose. F.M.U. has nothing to disclose. V.P. has nothing to disclose. P.E.L.-S. has nothing to disclose., (Copyright © 2024 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Background: Women with endometriosis may constitute a group at a particularly increased risk of pregnancy-related complications. Furthermore, women selected for assisted reproductive technology (ART) are exposed to additional endocrinological and embryological factors that have been associated with adverse pregnancy outcomes., Objective and Rationale: This study aimed to investigate the independent effect of endometriosis, adenomyosis, and various ART-related factors on adverse maternal, placental, fetal, and neonatal outcomes., Search Methods: Published randomized controlled trials, cohort studies, and case-control studies were considered eligible. PubMed, MEDLINE, ClinicalTrials.gov, Embase, and Scopus were systematically searched up to 1 March 2024. This systematic review and meta-analysis was performed in line with the PRISMA and the MOOSE reporting guidelines. To thoroughly investigate the association between endometriosis/adenomyosis and adverse pregnancy outcomes, sub-analyses were conducted, whenever possible, according to: the method of conception (i.e. ART and non-ART conception), the endometriosis stage/phenotype, the coexistence of endometriosis and adenomyosis, any pre-pregnancy surgical treatment of endometriosis, and the form of adenomyosis. The odds ratio (OR) with 95% CI was used as effect measure. The quality of evidence was assessed using the GRADE approach., Outcomes: We showed a higher risk of placenta previa in women with endometriosis compared to controls (34 studies, OR 2.84; 95% CI: 2.47, 3.26; I2 = 83%, moderate quality). The association was observed regardless of the method of conception and was particularly strong in the most severe forms of endometriosis (i.e. rASRM stage III-IV endometriosis and deep endometriosis (DE)) (OR 6.61; 95% CI: 2.08, 20.98; I2 = 66% and OR 14.54; 95% CI: 3.67, 57.67; I2 = 54%, respectively). We also showed an association, regardless of the method of conception, between endometriosis and: (i) preterm birth (PTB) (43 studies, OR 1.43; 95% CI: 1.32, 1.56; I2 = 89%, low quality) and (ii) cesarean section (29 studies, OR 1.52; 95% CI: 1.41, 1.63; I2 = 93%, low quality). The most severe forms of endometriosis were strongly associated with PTB. Two outcomes were associated with adenomyosis both in the main analysis and in the sub-analysis that included only ART pregnancies: (i) miscarriage (14 studies, OR 1.83; 95% CI: 1.53, 2.18; I2 = 72%, low quality) and (ii) pre-eclampsia (7 studies, OR 1.70; 95% CI: 1.16, 2.48; I2 = 77%, low quality). Regarding ART-related factors, the following associations were observed in the main analysis and confirmed in all sub-analyses conducted by pooling only risk estimates adjusted for covariates: (i) blastocyst stage embryo transfer (ET) and monozygotic twinning (28 studies, OR 2.05; 95% CI, 1.72, 2.45; I2 = 72%, low quality), (ii) frozen embryo transfer (FET) and (reduced risk of) small for gestational age (21 studies, OR 0.59; 95% CI, 0.57, 0.61; P < 0.00001; I2 = 17%, very low quality) and (increased risk of) large for gestational age (16 studies, OR 1.70; 95% CI, 1.60, 1.80; P < 0.00001; I2 = 55%, very low quality), (iii) artificial cycle (AC)-FET and pre-eclampsia (12 studies, OR 2.14; 95% CI: 1.91-2.39; I2 = 9%, low quality), PTB (21 studies, OR 1.24; 95% CI 1.15, 1.34; P < 0.0001; I2 = 50%, low quality), cesarean section (15 studies, OR 1.59; 95% CI 1.49, 1.70; P < 0.00001; I2 = 67%, very low quality) and post-partum hemorrhage (6 studies, OR 2.43; 95% CI 2.11, 2.81; P < 0.00001; I2 = 15%, very low quality)., Wider Implications: Severe endometriosis (i.e. rASRM stage III-IV endometriosis, DE) constitutes a considerable risk factor for placenta previa and PTB. Herein, we recommend against superimposing on this condition other exposure factors that have a strong association with the same obstetric adverse outcome or with different outcomes which, if coexisting, could determine the onset of an ominous obstetric syndrome. Specifically, we strongly discourage the use of AC regimens for FET in ovulatory women with rASRM stage III-IV endometriosis or DE. We also recommend single ET at the blastocyst stage in this high-risk population., Registration Number: CRD42023401428., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Follitropin delta is a novel recombinant follicle stimulating hormone preparation uniquely expressed in a human fetal retinal cell line by recombinant DNA technology. To date, no systematic review was available about the safety and the efficacy of the follitropin delta. The objective of this study was systematically reviewing the available literature and to provide updated evidence regarding the efficacy-safety profile of follitropin delta when compared to other gonadotropin formulations for ovarian stimulation in in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) cycles., Methods: An extensive search was performed to identify phase 1, phase 2 and phase 3 RCTs in humans focused on follitropin delta use for ovarian stimulation in IVF/ICSI cycles. The risk of bias and the overall quality of the evidence was analyzed. All data were extracted and analyzed using the intention-to-treat principle and expressed per woman randomized., Results: A total of 7 RCTs (1 phase 1 RCT, 2 phase 2 RCTs and 4 phase 3 RCTs) were included in the qualitative analysis, whereas data of three phase 3 RCTs were meta-analyzed. All trials compared personalized recombinant follitropin delta treatment versus conventional recombinant follitropin alfa/beta administration in potentially normo-responder patients who receive ovarian stimulation in GnRH antagonist IVF/ICSI cycles. No difference between two regimens was detected for clinical pregnancy rate [odds ratio (OR) 1.06; 95% confidence intervals (CI): 0.90, 1.24; P = 0.49; I 2  = 26%], ongoing pregnancy rate (OR 1.15; 95%CI: 0.90, 1.46; P = 0.27; I 2  = 40%), and live birth rate (OR 1.18; 95%CI: 0.89, 1.55; P = 0.25; I 2  = 55%). No data were available regarding cumulative success rates. The rate of adoption of strategies to prevent ovarian hyperstimulation syndrome (OHSS) development (OR 0.45; 95%CI: 0.30, 0.66; P < 0.0001; I 2  = 0%), and the rate of both early OHSS (OR 0.62; 95%CI: 0.43, 0.88; P = 0.008; I 2  = 0%) and all forms of OHSS (OR 0.61; 95%CI: 0.44, 0.84; P = 0.003; I 2  = 0%) were significantly lower in the group of patients treated with personalized follitropin delta treatment compared to those treated with conventional follitropin alfa/beta administration., Conclusion: Personalized follitropin delta treatment is associated with a lower risk of OHSS compared to conventional follitropin alfa/beta administration in potentially normo-responder patients who receive ovarian stimulation in GnRH antagonist IVF/ICSI cycles. The absence of cumulative data does not allow definitive conclusions to be drawn regarding the comparison of the effectiveness of the two treatments., Protocol Study Registration: CRD42023470352 (available at http://www.crd.york.ac.uk/PROSPERO )., (© 2024. The Author(s).)

Purpose: Comparison of intracytoplasmic sperm injection cycles with testicular sperm extraction in obstructive azoospermia and non-obstructive azoospermia are limited, and few studies have addressed obstetric and neonatal outcomes., Design: This study analyzed couples who underwent testicular sperm extraction-intracytoplasmic sperm injection cycles for obstructive azoospermia and non-obstructive azoospermia to determine whether impaired spermatogenesis in non-obstructive azoospermia patients would lead to worse reproductive outcomes and higher rates of pregnancy complications and fetal anomalies. This study is a retrospective, single-center analysis of all testicular sperm cycles performed between January 1, 2001 and December 31, 2020., Results: A total of 392 couples were considered in the study, leading to 1066 induction cycles, 620 (58.2%) from patients with obstructive azoospermia and 446 (41.8%) from non-obstructive azoospermia. The cumulative delivery rate did not significantly differ between the two groups (34% vs. 31%; p = 0.326). The miscarriage rate was similar between obstructive azoospermia and non-obstructive azoospermia patients. Fertilization rate instead showed a statistically significant difference (obstructive azoospermia: 66.1 ± 25.7 vs. non-obstructive azoospermia: 56.1 ± 27.0; p < 0.001). The overall maternal complication rate in the non-obstructive azoospermia group was higher (10.7% vs. 18.4%; p = 0.035), but there was no statistical significance for each pathology. There was no statistical difference in gestational age between the two groups for both single and twin pregnancies. Seven cases of congenital defects occurred in the obstructive azoospermia group, while two cases occurred in the non-obstructive azoospermia group., Conclusions: Despite impaired spermatogenesis in non-obstructive azoospermia patients, there were no substantial differences in reproductive outcomes compared to patients with obstructive azoospermia, even in terms of obstetric safety and neonatal well-being., (© 2023 American Society of Andrology and European Academy of Andrology.)

Purpose: To assess whether embryo transfer (ET) technique can influence the clinical pregnancy rate (CPR) and its correlation with the embryo transfer difficulty., Design: This single center retrospective cohort analysis of fresh and frozen single blastocyst transfers performed between January 2016 and December 2021 included fresh and frozen single blastocyst transfers performed during the study timeframe. Direct technique was the only one used from January 2016 to September 2017. From September 2017 to March 2019, the choice between the two techniques was given by randomization, due to a clinical trial recruitment. From April 2019, only the afterload technique was used. Preimplantation genetic testing cycles and gamete donation procedures and cycles performed with external gametes or embryos were excluded. CPR was the primary outcome, while difficult transfer rate the secondary one. Univariate and multivariate logistic regressions were performed., Results: During the period, 8,189 transfers were performed. CPR of the afterload group resulted significantly higher compared to the direct group (44.69% versus 41.65%, OR 1.13, 95% CI 1.02-1.25, p = 0.017) and the rate of difficult transfers two-thirds lower (9.06% versus 26.85%, OR 0.27, 95% CI 0.24-0.31, p < 0.001)., Conclusion: Our study demonstrated that CPR is significantly affected by the ET technique. In particular, with the afterload protocol, both CPR and easy transfer rates increased., Trial Registration: http://clinicaltrials.gov registration number: NCT05364528, retrospectively registered on 3rd of May 2022., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: The limited evidence available on the cost-effectiveness (CE) of expanded carrier screening (ECS) prevents its widespread use in most countries, including Italy. Herein, we aimed to estimate the CE of 3 ECS panels (ie, American College of Medical Genetics and Genomics [ACMG] Tier 1 screening, "Focused Screening," testing 15 severe, highly penetrant conditions, and ACMG Tier 3 screening) compared with no screening, the health care model currently adopted in Italy., Methods: The reference population consisted of Italian couples seeking pregnancy with no increased personal/familial genetic risk. The CE model was developed from the perspective of the Italian universal health care system and was based on the following assumptions: 100% sensitivity of investigated screening strategies, 77% intervention rate of at-risk couples (ARCs), and no risk to conceive an affected child by risk-averse couples opting for medical interventions., Results: The incremental CE ratios generated by comparing each genetic screening panel with no screening were: -14,875 ± 1,208 €/life years gained (LYG) for ACMG1S, -106,863 ± 2,379 €/LYG for Focused Screening, and -47,277 ± 1,430 €/LYG for ACMG3S. ACMG1S and Focused Screening were dominated by ACMG3S. The parameter uncertainty did not significantly affect the outcome of the analyses., Conclusion: From a universal health care system perspective, all the 3 ECS panels considered in the study would be more cost-effective than no screening., Competing Interests: Conflict of Interest Antonio Capalbo, Maurizio Poli, Matteo Figliuzzi, and Silvia Caroselli are full-time employees of Juno Genetics. All other authors declare no conflicts of interest., (Copyright © 2023 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)

To date, infertility affects 10% to 15% of couples worldwide. A male factor is estimated to account for up to 50% of cases. Oral supplementation with antioxidants could be helpful to improve sperm quality by reducing oxidative damage. At the same time, there is a growing interest in the literature on the use of testicular sperm in patients with high DNA fragmentation index (DFI). This narrative review aims to evaluate the effectiveness of supplementation of oral antioxidants in infertile men with high DFI compared to testicular sperm retrieval. The current evidence is non-conclusive because of serious risk of bias due to small sample sizes and statistical methods. Further large well-designed randomised placebo-controlled trials are still required to clarify the exact role of these to different therapeutic approaches., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Romano, Cirillo, Spadaro, Busnelli, Castellano, Albani and Levi-Setti.)

The purpose was to determine any difference in outcomes, primarily in terms of number of retrieved oocytes per procedure, between two different needles used for oocytes retrieval procedure in Assisted Reproductive Technologies: the single-lumen needle (SLN) versus the double-lumen needle (DLN) with follicle flushing after aspiration. This randomized controlled trial included oocyte retrieval (OR) cycles for IVF and ICSI performed in 18 to 42-year-old women between March 2019 and January 2021 at a tertiary-care Fertility Center. A total of 200 ORs were randomized, 100 in each group. The mean number of retrieved oocytes was not different between groups (10.2 ± 6.5 for DLNs vs. 10.7 ± 7.0 for SLNs, p = 0.810). No significant differences were observed also in terms of number of retrieved oocytes/punctured follicles (83.0% ± 27.0% vs. 81.0% ± 22.0%, p = 0.916), number of retrieved oocytes/follicles at trigger (78.0% ± 29.0% vs. 78.0% ± 27.0%, p = 0.881), number of mature oocytes (7.6 ± 5.3 vs. 8.0 ± 5.1, p = 0.519), and pregnancy rate (27% vs. 23%, p = 0.514). However, the time required to retrieve each oocyte was longer using the DLN (1.5 ± 1.3 vs. 1.1 ± 0.9 minutes, p = 0.002). The present study confirmed the new perspectives on the sole use of SLNs in terms of saving time, without affecting the number of retrieved oocytes. Trial registration number and date of registration NCT03611907; July 26, 2018., (© 2023. The Author(s), under exclusive licence to Society for Reproductive Investigation.)

Objective: To test the hypothesis claiming an association between human papilloma virus (HPV) sperm infection and idiopathic recurrent pregnancy loss (RPL)., Design: Multicenter retrospective case-control study., Setting: Three university hospitals., Patient(s): Cases included men belonging to couples affected by first trimester idiopathic RPL. Controls included men belonging to couples with proven fertility and no history of pregnancy loss; RPL was defined as the previous loss of 2 or more pregnancies. Couples were defined as "fertile" if they achieved a full-term pregnancy within the year before enrollment in the study. All participants conceived without assistance., Main Outcome Measure(s): The association between HPV DNA sperm infection, as identified using polymerase chain reaction, and RPL., Results: The HPV DNA sperm infection was detected in 23 of 117 cases (20%; 95% confidence interval [CI]: 13%, 28%) and in 3 of 84 controls (4%; 95% CI; 1%, 10%) (P<.001). A comparison across baseline characteristics and multiple regression analysis did not identify any potentially confounding factors. Multivariate regression models showed a significant association between HPV DNA sperm infection and RPL (adjusted odds ratio, 7.44; 95% CI: 2.08, 26.58; P=.002 [Model 1]; adjusted odds ratio, 8.96; 95% CI: 2.41, 33.44; P=.001 [Model 2])., Conclusions: The prevalence of HPV sperm infection was significantly higher in couples affected by RPL than in their fertile counterparts. Notably, the semen sample was infected by HPV in approximately 1 out of 5 patients., (Copyright © 2022 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Introduction: Oocyte cryopreservation is a valid option for female cancer patients to preserve fertility. The number of patients undergoing fertility preservation (FP) cycles has increased over the past years. Nevertheless, the rates of patients returning to use their cryopreserved material have shown to be considerably low, ranging from 5-8%, but significant data regarding the reasons of such low return rates are scarce., Methods: This study is a single-center follow-up retrospective study evaluating the return rate of oncological women who underwent FP at a tertiary care Fertility Center and assessing the reasons influencing the patients who did not return. Data about patients who returned to attempt pregnancy were retrieved from internal registries. Non-returned patients were assessed with a standardized phone survey investigating health condition, marital status and family projects, spontaneous conceptions, and the reasons why they had not returned to use their gametes. A univariate analysis between returned and non-returned patients was performed., Results: Of the 397 patients who received counseling about FP, 171 (43.1%) underwent oocyte cryopreservation between 2001 and 2017. Nine (5%) died, and 17 (10%) were lost at follow-up. A total of 20 patients (11.7%) returned and 125 did not. In the non-returned group, 37 (29.6%) did not have a partner, 10 (8%) had a previous spontaneous conception, and 15 (12%) had recurrent malignancy at the time of follow-up. In the univariate analysis, younger age at freezing (31.8±6.2 vs. 35.2±4.7; p 0.018), lack of a partner (p 0.002), type of cancer (other than breast cancer; p 0.024) were the significant factors in the non-returned group. As for the personal reason for not coming back, patients mainly answered as follows: lack of a partner (29, 23.2%), the desire for spontaneous motherhood (24, 19.2%), previous spontaneous pregnancies after FP procedures (16, 12.8%), and still ongoing hormonal therapy for breast cancer (13, 10.4%). All patients confirmed their will to keep the storage of their oocytes., Discussion: The impact of a cancer diagnosis on a woman's maternal desire, sentimental status and life priorities should be studied more thoroughly. Studies investigating hormonal therapy suppression in breast cancer patients seeking pregnancy should be encouraged., Clinical Trial Registration: https://clinicaltrials.gov, identifier NCT05223764., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Immediata, Cirillo, Baggiani, Zanagnolo, Ronchetti, Morenghi, Cesana, Specchia and Levi-Setti.)

The present retrospective study included both intrauterine insemination and in vitro assisted reproductive technologies (ART) procedures performed from January 2009 to December 2018 at a tertiary-care Fertility Centre. The purpose was to assess the incidence of ectopic pregnancy (EP) in infertile population who undergoes ART and to identify any risk factor impacting the occurrence of EP after ART. Among 27,376 cycles, 7352 pregnancies were achieved, of which 132 were EPs, the 1.80% (95% CI 1.5-2.1) of all pregnancies. In fresh embryo transfer cycles, a history of prior pelvic adhesions showed the greatest impact on the incidence of EP (aOR 2.49 95% CI 1.53-4.07 p < 0.001). Other factors associated with EP incidence were also identified, such as female age, basal FSH, the transfer of blastocyst embryos and difficulties during the embryo transfer procedure. In frozen embryo transfer cycles, the only factor influencing the incidence of EP was anti Müllerian hormone (AMH) serum concentration (aOR 0.81 95% CI 0.65-1.00, p = 0.048). To conclude, the incidence of EP observed was comparable to that reported after natural conception. On the other hand, pre-existing risk factors, traditionally more common in infertile population, appeared to influence the incidence of EP and should thus be modified if possible., (© 2022. The Author(s).)

Purpose: The risk of monozygotic twins (MZTs) is increased in couples undergoing assisted reproductive technology (ART) treatments. Several systematic reviews have investigated the possible determinants linked to ART, but results obtained have not been conclusive. The study aims to investigate whether the incidence of MZT differed among ART centers., Methods: This is a multicenter retrospective cohort study using the Italian ART National Registry database and involving the centers reporting data from individual ART cycles from 2015 to 2019. To investigate the incidence of MZT, only single embryo transfer cycles were considered. Women who had sex-discordant deliveries were excluded. MZT rate was calculated as the number of multiple pregnancies (more than one gestational sac at first ultrasound) out of the total number of clinical pregnancies. A binomial distribution model was used to determine the 95% CI of the frequency of MZT., Results: Eighteen centers were included, and they provided data on 10,433 pregnancies. The total number of MZT was 162, corresponding to an incidence of 1.5% (95% CI: 1.3-1.8%). The rate of MZT among centers varied between 0% (95% CI: 0.0-25.9%) and 3.2% (95% CI: 1.3-8.1%). All the 95% CIs included 1.5%, rejecting the hypothesis that the MZT rate may significantly differ among centers., Conclusions: The rate of MZT did not significantly vary among ART centers. Local factors are unlikely to explain the increased rate of MZT in ART pregnancies., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Research Question: Does the embryologist performing the embryo transfer impact the cycle outcome, in terms of ongoing pregnancy rate (OPR)?, Design: This single-centre retrospective study analysed the results, corrected for main confounders, from 28 embryologists and 32 physicians who performed respectively 24,992 and 24,669 fresh embryo transfers (either at cleavage or blastocyst stage) during a 20-year period from January 2000 to December 2019, in a university-affiliated tertiary care assisted reproductive technology (ART) centre. Primary outcome was OPR, defined as the number of viable pregnancies that had completed at least 12 weeks of gestation on the total number of embryo transfers performed. The study also assessed whether the embryologist's experience, measured in terms of number of embryo transfers performed prior to the day of the procedure, had an impact on their performance. The secondary aim was to assess which variable, between the embryologist and physician, more significantly impacted OPR., Results: The overall unadjusted OPR was 22.54%. The embryologist performing the embryo transfer was found to significantly affect the OPR (P < 0.0001), corrected for potential confounders. However, the physician factor made a slightly greater contribution to the model (likelihood ratio 21.86, P < 0.001 versus likelihood ratio 17.20, P < 0.0001). No significant association was found between the experience of the embryologist and OPR (P = 0.067)., Conclusions: These results show how the 'human factor' influences the chances of a positive outcome in the final step of a high-tech procedure and underline the importance of implementing an operator quality performance programme (both for physicians and embryologists) to ensure the maintenance of benchmark results and eventually retrain underperforming operators., (Copyright © 2022 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

Purpose: Since the end of February 2020, SARS-CoV-2 dramatically spread in Italy. To ensure that most of National Health System (NHS) resources were employed to control the pandemic, non-urgent medical procedures (including IVF) were suspended in March 2020. Here, we aimed at assessing the impact of the restrictive measures on Italian IVF activity., Methods: In May 2020, the Italian ART Register launched an online survey (multiple choices and open answers) across ART centers (89.0% response rate; N = 170/191) to investigate how they were facing the emergency and estimate the reduction in their activity. In February 2022, the official data of the whole 2020 were published and retrospectively analyzed. The ART cycles conducted in Italy in 2020 (67,928 by 57,423 patients) were then compared to those conducted in 2019 (82,476 by 67,633 patients). The estimates formulated through the survey were compared to the actual reduction., Results: In 2020, 14,548 less IVF cycles were conducted with respect to 2019 (- 17.6% reduction). This led to 2539 fewer live births (- 19.8%) than 2019. If the reduction unveiled by the survey launched in May 2020 (i.e., - 35%) would have persisted throughout 2020, a significantly larger impact was expected (4200 less newborns). Instead, the activity was gradually recovered, and it compensated the months of greatest emergency, thus fulfilling the most optimistic scenario., Conclusions: Italy suffers from the lowest birth rate in Europe, and COVID-19 impact on IVF-derived live births testified how key ART is for Italian demographics. The government should support access to these treatments with dedicated actions., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Thyroid autoimmunity (TAI) has a high prevalence among women of reproductive age. Investigating its possible impact on ovarian function and fertility is, thus, of utmost relevance. The aim of this systematic review and meta-analysis was to elucidate the effect of TAI on both assisted reproductive technology (ART) outcomes and ovarian reserve. Methods: This systematic review and meta-analysis was restricted to two groups of research articles investigating the association between TAI and: (1) autologous ART outcomes (i.e., fertilization rate [FR], implantation rate, clinical pregnancy rate [CPR], miscarriage rate, and live birth rate), (2) markers of ovarian reserve (i.e., anti-Müllerian hormone, basal follicle stimulating hormone, antral follicle count, and number of oocytes retrieved). Studies including women affected by overt hypo/hyperthyroidism were excluded. Relevant studies were identified by a systematic search in PubMed, MEDLINE, ClinicalTrials.gov, Embase, and Scopus, from database inception to May 1, 2022. Results: From a total of 432 identified publications, 22 studies were included in Group 1 and 26 studies in Group 2. The presence of TAI was associated with a higher risk of miscarriage (7606 participants, odds ratio [OR] 1.52, confidence interval [CI 1.14-2.01], p  = 0.004, I 2  = 53%), lower chance of embryo implantation (7118 participants, OR 0.72, [CI 0.59-0.88], p  = 0.001, I 2  = 36%), and live birth (11417 participants, OR 0.73, [CI 0.56-0.94], p  = 0.02, I 2  = 71%). These associations were no longer observed in a subgroup analysis of patients who exclusively underwent intracytoplasmic sperm injection (ICSI). The FR and CPR as well as the mean values of surrogate markers of oocyte quantity appeared not to be affected by TAI. Conclusions: This data synthesis suggest a higher risk of adverse ART outcomes in women with positive TAI. However, the reliability of these findings is hampered by the relatively low quality of the evidence and significant heterogeneity in many of the meta-analyses. The possible protective effect of ICSI is promising but should be confirmed in controlled prospective clinical trials. PROSPERO Registration ID : CRD42021236529.

The management of infertile women affected by hypogonadotropic hypogonadism (HH) or conditions mimicking it is particularly challenging. In the present narrative review, we aimed to synthesize the available evidence on the benefit (if any) of exogenous luteinizing hormone (LH) supplementation in this group of patients. Available data support LH supplementation in women with organic or functional HH. On the contrary, the benefit of exogenous LH on reproductive outcomes both in advanced maternal age patients and in cases of depletion of FSH and LH levels induced by GnRH analogues has not been demonstrated. unfortunately, the inhomogeneous study populations as well as the methodological heterogeneity between studies focused on women affected by conditions mimicking HH do not allow reliable conclusions to be drawn., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Di Segni, Busnelli, Secchi, Cirillo and Levi-Setti.)

Basic scientific research on human reproduction and oxidative damage has been extensively performed; however, a more clinical view is still lacking. As a result, exhaustive data on the influence of oxidative stress on human ovarian response and, consequently, on fertility are still lacking. This narrative review aims at summarizing the role of oxidative stress in different conditions associated to female infertility and to list some of the main antioxidant agents. A systematic literature search was performed in May 2022 to retrieve studies regarding the oxidative stress and the human ovarian response from somatic ovarian cells to oocytes damage. Only human studies were included and the authors focused their review, in particular, on clinical implications in order to define a new research perspective on the assessment of any eventual strategy to preserve women's fertility. Thereby, the authors evaluated the contribution of DNA repair pathways in improving women's fertility by reducing the DNA damage associated with aging or diseases, such as endometriosis or polycystic ovary syndrome, and eventually, in prolonging the reproductive lifespan after cancer treatment.

Background: Nowadays, pathogenesis of preeclampsia (PE) is still unknown. Among the different etiological hypotheses, some authors proposed that it might be because of an abnormal immunologic response to a foreign fetal antigen derived from the father's spermatozoa. Indeed, the fetus is considered a semi-allograft, being one half paternally derived in its antigenicity, and the first pathogenic insult of PE may be an abnormal maternal immune response toward this semi-allogenic implant. In the context of artificial reproductive techniques, it has been shown that the use of donor and surgically retrieved spermatozoa (e.g., testicular sperm extraction [TESE]) increases the risk of PE, confirming the protective effect of sperm exposure on maternal complications., Objective: Determining whether the lack of exposure to sperm antigens is associated with worse maternal and neonatal outcomes in pregnancies obtained through intracytoplasmic sperm injection after TESE (ICSI-TESE) for obstructive azoospermia (OA)., Materials and Methods: This is a single-center case-control retrospective study, focusing on all first pregnancies obtained through ICSI-TESE for OA at Humanitas Fertility Center between January 1, 2010 and December 31, 2019. Controls included patients that achieved their first pregnancy with ICSI and ejaculated spermatozoa, for a diagnosis other than azoospermia, in the same time period. Cases were matched with controls in a 1:2 ratio, considering female age, female BMI, and year of controlled ovarian stimulation. The primary outcome measure was the delivery rate, defined as the number of deliveries divided by the total number of clinical pregnancies. Secondary outcome measures focused on maternal and neonatal complications, such as miscarriage rate, rate of main obstetric complications, prematurity rate, and rate of congenital malformations., Results: By analyzing overall 113 pregnancies among cases and 214 pregnancies among controls, this study showed that the delivery rate was higher in controls with respect to cases (92.06% vs. 84.07%, p = 0.026); among deliveries, live births were 98.95% and 100%, respectively, whereas only one stillbirth occurred in cases. The first trimester miscarriage rate was higher in the cases than controls (13.27% vs. 6.07%, p = 0.027), whereas no difference was found among the rate of second trimester miscarriages, therapeutic abortions, and ectopic pregnancies. There was no difference regarding the rate of maternal complications, including gestational hypertension, PE, HELLP syndrome, gestational diabetes, placenta previa, placental abruption, and premature rupture of the membranes. Considering neonatal complications, it was shown that twins belonging to controls had a higher prematurity rate with respect to cases (65.79% vs. 50.00%) but without a statistical relevance. Lastly, the rate of congenital malformations did not differ among the two groups., Discussion: This study showed that, once couples diagnosed with OA achieve a pregnancy, they have a much higher risk of miscarriage in the first trimester in respect to non-azoospermic patients. Moreover, controls had a higher delivery rate in respect to cases; however, when the fetal status at birth was compared, no difference was found between live births and stillbirths., Conclusions: Differently from the findings in the literature, no association with PE was found. This might be related to a collider bias/left truncation bias: As azoospermic patients are at higher risk of early termination of pregnancy, it results that they do not have the possibility to develop PE and other adverse outcomes., (© 2022 American Society of Andrology and European Academy of Andrology.)

Study Question: Is there an association between the different endometrial preparation protocols for frozen embryo transfer (FET) and obstetric and perinatal outcomes?, Summary Answer: Programmed FET protocols were associated with a significantly higher risk of hypertensive disorders of pregnancy (HDP), pre-eclampsia (PE), post-partum hemorrhage (PPH) and cesarean section (CS) when compared with natural FET protocols., What Is Known Already: An important and growing source of concern regarding the use of FET on a wide spectrum of women, is represented by its association with obstetric and perinatal complications. However, reasons behind these increased risks are still unknown and understudied., Study Design, Size, Duration: Systematic review with meta-analysis. We systematically searched PubMed, MEDLINE, Embase and Scopus, from database inception to 1 November 2021. Published randomized controlled trials, cohort and case control studies were all eligible for inclusion. The risk of bias was assessed using the Newcastle-Ottawa Quality Assessment Scale. The quality of evidence was also evaluated using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach., Participants/materials, Setting, Methods: Studies were included only if investigators reported obstetric and/or perinatal outcomes for at least two of the following endometrial preparation protocols: programmed FET cycle (PC-FET) (i.e. treatment with hormone replacement therapy (HRT)); total natural FET cycle (tNC-FET); modified natural FET cycle (mNC-FET); stimulated FET cycle (SC-FET)., Main Results and the Role of Chance: Pooled results showed a higher risk of HDP (12 studies, odds ratio (OR) 1.90; 95% CI 1.64-2.20; P < 0.00001; I2 = 50%) (very low quality), pregnancy-induced hypertension (5 studies, OR 1.46; 95% CI 1.03-2.07; P = 0.03; I2 = 0%) (very low quality), PE (8 studies, OR 2.11; 95% CI 1.87-2.39; P < 0.00001; I2 = 29%) (low quality), placenta previa (10 studies, OR 1.27; 95% CI 1.05-1.54; P = 0.01; I2 = 8%) (very low quality), PPH (6 studies, OR 2.53; 95% CI 2.19-2.93; P < 0.00001; I2 = 0%) (low quality), CS (12 studies, OR 1.62; 95% CI 1.53-1.71; P < 0.00001; I2 = 48%) (very low quality), preterm birth (15 studies, OR 1.19; 95% CI 1.09-1.29; P < 0.0001; I2 = 47%) (very low quality), very preterm birth (7 studies, OR 1.63; 95% CI 1.23-2.15; P = 0.0006; I2 = 21%) (very low quality), placenta accreta (2 studies, OR 6.29; 95% CI 2.75-14.40; P < 0.0001; I2 = 0%) (very low quality), preterm premature rupture of membranes (3 studies, OR 1.84; 95% CI 0.82-4.11; P = 0.14; I2 = 61%) (very low quality), post-term birth (OR 1.90; 95% CI 1.25-2.90; P = 0.003; I2 = 73%) (very low quality), macrosomia (10 studies, OR 1.18; 95% CI 1.05-1.32; P = 0.007; I2 = 45%) (very low quality) and large for gestational age (LGA) (14 studies, OR 1.08; 95% CI 1.01-1.16; P = 0.02; I2 = 50%) (very low quality), in PC-FET pregnancies when compared with NC (tNC + mNC)-FET pregnancies. However, after pooling of ORs adjusted for the possible confounding variables, the endometrial preparation by HRT maintained a significant association in all sub-analyses exclusively with HDP, PE, PPH (low quality) and CS (very low quality)., Limitations, Reasons for Caution: The principal limitation concerns the heterogeneity across studies in: (i) timing and dosage of HRT; (ii) embryo stage at transfer; and (iii) inclusion of preimplantation genetic testing cycles. To address it, we undertook subgroup analyses by pooling only ORs adjusted for a specific possible confounding factor., Wider Implications of the Findings: Endometrial preparation protocols with HRT were associated with worse obstetric and perinatal outcomes. However, because of the methodological weaknesses, recommendations for clinical practice cannot be made. Well conducted prospective studies are thus warranted to establish a safe endometrial preparation strategy for FET cycles aimed at limiting superimposed risks in women with an 'a priori' high-risk profile for obstetric and perinatal complications., Study Funding/competing Interest(s): None., Registration Number: CRD42021249927., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Despite the fact that knowledge on obstetrical management of Inflammatory Bowel Diseases (IBDs) has greatly improved over the years, many patients still actively avoid pregnancy for fear of adverse maternal or neonatal outcomes, of adverse effects of pregnancy on the disease activity, of eventual IBD inheritance, or of an increased risk of congenital malformations. Indeed, though data prove that fertility is hardly affected by the disease, a reduced birth rate is nevertheless observed in patients with IBD. Misconceptions on the safety of drugs during gestation and breastfeeding may influence patient choice and negatively affect their serenity during pregnancy or lactation. Moreover, physicians often showed concerns about starting IBD medications before and during pregnancy and did not feel adequately trained on the safety of IBD therapies. IBD-expert gastroenterologists and gynecologists should discuss pregnancy and breastfeeding issues with patients when starting or changing medications in order to provide appropriate information; therefore, pre-conception counselling on an individualized basis should be mandatory for all patients of reproductive age to reassure them that maintaining disease remission and balancing the eventual obstetrical risks is possible.

The aim of this retrospective cohort study is to establish whether strategies favoring frozen-thawed embryo transfer (FET) have an impact on differences in cumulative live birth rate (CLBR), weighted mean cost per live birth, and multiple pregnancy rate (MPR) between fertility clinics. Data were extracted from the Assisted Reproductive Technology (ART) Italian National Registry and refer to classical IVF or intracytoplasmic sperm injection (ICSI) cycles performed in 2018 in public funded Lombardy region fertility clinics. Propensity to FET cycles was expressed with the so-called freezing tendency index (FTI): [(No. of FETs + No. of transfers of embryos obtained from frozen-thawed oocytes) / (No. of fresh ETs + No. of canceled IVF cycles + Numerator)] × 100. Fertility clinics were divided according to their FTI: group A (FTI: 0-20%); group B (FTI: 20-40%); and group C (FTI: 40-60%). Groups A, B, and C included 6, 8, and 8 fertility clinics, respectively. The CLBR (95% CI) per started COH cycle was 13.1% (11.8-14.5%) in group A, 19.6% (18.6-20.7%) in group B, and 27.8% (26.8-28.9%) in group C (p < 0.0001). The weighted mean live birth cost was 32,770 ± 10,662 € in group A, 25,863 ± 11,510 € in group B, and 20,426 ± 3788 € in group C (p < 0.0001). The MPR (95% CI) was 15.4% (12.1-19.4%) in group A, 10.2% (8.7-12.1%) in group B (p = 0.0065), and 6.3% (5.2-7.6%) in group C (p = 0.0001). In conclusion, our results suggest that strategies favoring FET cycles are associated with an increased CLBR, a decreased weighted mean cost per live birth, and a decreased MPR., (© 2021. Society for Reproductive Investigation.)

Purpose: To assess whether live birth rates (LBR) and maternal/neonatal complications differed following single fresh and frozen-warmed blastocyst transfer., Methods: The present retrospective observational study analyzed 4,613 single embryo transfers (SET) (646 fresh and 3,967 frozen) from January 1, 2014, to December 31, 2018. Fresh embryo transfer at blastocyst stage was considered according to the age of the patient and her prognosis. In case of the risk of ovarian hyperstimulation syndrome, premature progesterone rise, non-optimal endometrial growth, or supernumerary embryos, cryopreservation with subsequent frozen embryo transfer (FET) was indicated., Results: No differences in LBR were recorded. Fresh embryo transfers yielded an increase both in neonatal complications OR 2.15 (95% CI 1.20-3.86, p 0.010), with a higher prevalence of singletons weighting below the 5th percentile (p 0.013) and of intrauterine growth retardation (p 0.015), as well as maternal complications, with a higher placenta previa occurrence OR 3.58 (95% CI 1.54-8.28, p 0.003), compared to FET., Conclusion: LBR appears not to be affected by the transfer procedure preferred. Fresh embryo transfer is associated with higher risk of neonatal complications (specifically a higher prevalence of singletons weighting below the 5th percentile and of intrauterine growth retardation) and placenta previa. Reflecting on the increased practice of ART procedures, it is imperative to understand whether a transfer procedure yields less complications than the other and if it is time to switch to a "freeze-all" procedure as standard practice., Trial Registration: Clinical Trial Registration Number: NCT04310761. Date of registration: March 17, 2020, retrospectively registered., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Chromosome imbalance (aneuploidy) is the major cause of pregnancy loss and congenital disorders in humans. Analyses of small biopsies from human embryos suggest that aneuploidy commonly originates during early divisions, resulting in mosaicism. However, the developmental potential of mosaic embryos remains unclear. We followed the distribution of aneuploid chromosomes across 73 unselected preimplantation embryos and 365 biopsies, sampled from four multifocal trophectoderm (TE) samples and the inner cell mass (ICM). When mosaicism impacted fewer than 50% of cells in one TE biopsy (low-medium mosaicism), only 1% of aneuploidies affected other portions of the embryo. A double-blinded prospective non-selection trial (NCT03673592) showed equivalent live-birth rates and miscarriage rates across 484 euploid, 282 low-grade mosaic, and 131 medium-grade mosaic embryos. No instances of mosaicism or uniparental disomy were detected in the ensuing pregnancies or newborns, and obstetrical and neonatal outcomes were similar between the study groups. Thus, low-medium mosaicism in the trophectoderm mostly arises after TE and ICM differentiation, and such embryos have equivalent developmental potential as fully euploid ones., Competing Interests: Declaration of interests A.C., M.P., L.G., C.P., M.F., M.F., J.C., and C.R. are full-time employees of Igenomix. L.R. is the Scientific Director of GeneraLife IVF. She is editor of reproductive biomedicine online and has been associate editor of human reproduction update. She has been the principal investigator of a study sponsored by Merck KGaA. She has received honoraria and consultation fees from Merck, MSD, Ferring, Ibsa, Cooper Surgical, Cook, Nterilizer, Fujifilm-Irvine Scientific, Medea, and Universal Clinics. She is a partner and shareholder of Global Investment Clinics, Genera Health Care, and Nterilizer and has been affiliated with Flam. D.C. is a full-time employee of GeneraLife IVF, where he is the science and research manager. He received paid lectures from Fujifilm-Irvine Scientific. He received paid consultations from Merck. F.B. reports personal fees from Fujifilm-Irvine Scientific, outside the submitted work. A.V. reports personal fees from Gedeon Richter, personal fees from Merck, and personal fees from MSD, outside the submitted work. E.H. and I.V. are supported by an ERC consolidator grant (724718-ReCAP), the Novo Nordisk Foundation Young Investigator Award (NNF15OC0016662), ReproUnion, and the Danish National Research Foundation (center grant 6110-00344B). The views expressed in this article are those of the authors and not necessarily those of the sponsors. The funders of the study had no role in study design, data collection, data analysis, data interpretation, or writing of this article. The corresponding authors had full access to all the data in the study and had final responsibility for the decision to submit for publication. E.H. is the executive board member and chair of the scientific advisory board of ReproUnion, which is co-funded by Ferring Pharmaceuticals. F.M.U. is the scientific director of GeneraLife IVF. He is the president of the Italian Society of Fertility and Sterility (SIFES). He has been the principal investigator of a study sponsored by Merck and by S&R Farmaceutici. He has received honoraria and consultation fees from Merck, Merck Sharp and Dohnme Corporation, Ferring, Institut Biochimique, Cooper Surgical, Cook, Nterilizer, Fujifilm-Irvine Scientific, Medea, and Universal Clinics. He is partner/shareholder of Global Investment Clinics, Genera Health Care, and Nterilizer, and has been of Flam. C.S. is the head of the scientific advisory board of Igenomix. The other authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Ovarian hyperstimulation syndrome (OHSS) is a severe complication of controlled ovarian stimulation (COS). Pathogenesis of the disease is based on massive transudation of protein-rich fluid from the vascular compartment into the peritoneal, pleural and pericardial spaces, with a variable picture of clinical manifestations depending on its severity. Nowadays OHSS can easily be avoided by several prevention methods, ranging from identification of high-risk patients, choice of a correct protocol stimulation, trigger with gonadotropin-releasing hormone (GnRH) agonists or, finally, the freeze-all strategy. When OHSS occurs, it can usually be managed as outpatient care. Only if severe/critical cases are diagnosed hospitalization is necessary for appropriate rehydration, monitoring of fluid balance and eventual drainage of ascitic fluid. One of the most dangerous complications of OHSS is venous thromboembolism (VTE). Thromboprophylaxis has shown to be cost effective and widely used, while there are controversies regarding the usage of low dose aspirin (LDA) as a preventive measure., Competing Interests: Disclosure The authors report no conflicts of interest in this work., (Thieme. All rights reserved.)

Background: Anti-Müllerian hormone (AMH) serum concentration and antral follicle count (AFC), as measured by transvaginal ultrasonography, accurately reflect the antral follicle pool. However, AMH and AFC association with fertility surrogates (i.e. age at menopause, probability of conceiving naturally and ART success rate) is questioned. Miscarriage is often considered an alternative measure of reproductive capacity. Nonetheless, the impact of diminished ovarian reserve (DOR) on miscarriage incidence remains an understudied and unresolved issue., Objective and Rationale: The aim of this systematic review and meta-analysis was to elucidate associations between DOR and miscarriage risk, both in women who conceived naturally and in those who achieved pregnancy through ART., Search Methods: Relevant studies were identified by a systematic search in PubMed, MEDLINE, Embase and Scopus, from database inception to 1 March 2021. Studies were included only if all the following conditions were met: DOR was defined using serum AMH concentration or AFC; miscarriage rate was reported separately for different groups of women categorized according to the AMH and/or AFC level; authors reported either the rate of intrauterine pregnancy loss before 22 weeks of gestation or enough data were available to calculate it., Outcomes: From a total of 347 publications initially identified, 16 studies were included. Pooled results from 13 retrospective studies focusing on ART pregnancies showed a significantly higher rate of miscarriage in women with a low AMH, as compared to women with a medium or high serum AMH concentration (12 042 women, random effects model, odds ratio (OR) 1.35; 95% CI, 1.10-1.66; P = 0.004; I2=50%). The only prospective study on ART pregnancies failed to show any association (61 women, risk ratio (RR) 2.95; 95% CI, 0.66-3.18; P = 0.16). Data from two prospective studies, which included naturally conceived pregnancies, showed a significantly increased miscarriage risk for women with low serum AMH. However, these data could not undergo meta-analysis owing to differing study designs. Using three retrospective studies, we observed an association between low AFC and miscarriage incidence (three retrospective studies on ART pregnancies, random effects model, OR 1.81; 95% CI, 1.02-3.21; P = 0.04; I2=64%)., Wider Implications: Our meta-analysis findings suggest that within the DOR patient subgroup, serum AMH and AFC biomarker levels may correlate with both the quantitative and qualitative aspects of ovarian reserve. However, owing to study limitations, the aetiology of this effect remains unclear and we are unable to define a causal relationship between DOR and increased miscarriage or to provide clinical recommendations based on this information. However, if confirmed by future well-designed studies, these findings would be profoundly informative for guiding women in family planning decisions., (© The Author(s) 2021. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: To appraise the fertilization rate as a predictive factor for cumulative live birth rate (CLBR)., Design: Multicenter retrospective cohort study., Setting: Ten in vitro fertilization clinics, whose data were collected and processed by the assisted reproductive technology (ART) Italian National Registry., Patient(s): 7,968 couples undergoing 9,394 complete intracytoplasmic sperm injection cycles., Intervention(s): None., Main Outcome Measure(s): The primary outcome measure was the CLBR in association with the fertilization rate intervals (<65%-group 1; 65%-80%-group 2; and >80%-group 3). Further data stratification was performed on the basis of maternal age (<34, 35-38, and 39-42 years) and number of retrieved oocytes (5-7, 8-10, and > 10 oocytes)., Result(s): The CLBR was progressively higher in relation to the fertilization rate in groups 1, 2, and 3 (20.1%, 34.7%, and 41.3%, respectively). The number of recovered oocytes, embryo number per cycle, and cumulative pregnancy rate followed the same trend. The decrease in CLBR with increasing maternal age was significantly correlated with the fertilization rate and CLBR in all 3 maternal age groups. Multivariate logistic regression analysis showed fertilization rate as a factor independently associated with CLBR., Conclusion(s): The present data indicated a positive association between the fertilization rate and the CLBR, suggesting the predictive clinical relevance of this parameter and its adoption as a key performance indicator., (Copyright © 2021 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Study Question: What are the differences in ease of use between two different embryo transfer (ET) techniques: the preload direct approach and the afterload approach., Summary Answer: The afterload technique seems to reduce the rate of difficult ETs., What Is Known Already: Numerous published trials now document that the ET procedure has an impact on pregnancy and delivery rates after IVF. Difficult transfers should be avoided, as they reduce implantation and pregnancy rates. Preload direct ETs with soft catheters under ultrasound guidance is currently considered the best procedure. However, when using soft catheters, it is not known which technique is preferable or which one should be implemented to reduce the operator factor., Study Design, Size, Duration: This prospective randomised unblinded controlled clinical trial, included 352 ultrasound-guided ETs assigned to either direct ET or afterload ET, between September 2017 and March 2019. The sample size was calculated based on the historical rate of difficult ETs encountered between 2014 and 2015 with a direct ET procedure., Participants/materials, Setting, Methods: The inclusion criteria were women 18-38 years old, with BMI between 18 and 28, receiving a single-thawed blastocyst transfer. The exclusion criteria were use of testicular sperm and preimplantation genetic testing (PGT) cycles. The primary outcome was the rate of difficult or suboptimal transfers defined as: advancement of the outer sheath (specific for the direct transfer), multiple attempts, use of force, required manipulation, use of a stylet or tenaculum, dilatation, or use of a different catheter. The secondary outcome was clinical pregnancy rate., Main Results and the Role of Chance: A total of 352 frozen ETs were randomised, with 176 patients in each group. The two arms were homogeneous for female and male age, female BMI, duration of infertility, secondary infertility, previous deliveries or miscarriages, myomas, previous surgery to the uterine cavity, cycle day at ovulation trigger, freeze all cycles, first transfers, indication for treatment, endometrial preparation protocol and duration, endometrial thickness, and blastocyst grade at vitrification. Across the entire population, 85 (24.1%) ETs were defined as difficult. The rate of difficult transfers was significantly higher in the direct ET group than in the afterload group: 68 (38.6%) versus 17 (9.7%), respectively (OR 0.17, 95% CI 0.09-0.30, P < 0.001). The mean percentage in the rate of difficult transfers per operator was 22.5% (SD ± 14.5%), of which 36.1% (SD ± 23.4%) were in the direct group compared with 8.6% (± 8.2%) in the afterload group (P < 0.001). The difficult transfer rate among operators varied from 0 to 43.8% (0-77.8% in the direct group and 0 to 25.0% in the afterload group). The clinical pregnancy rates (42.0% vs 48.3%, P = 0.239 in the direct and afterload groups, respectively) were not significantly different between the groups., Limitations, Reasons for Caution: There were 18 experienced operators who participated in the trial. Conclusions about the pregnancy rate should not be generalised, since the sample analysis was not performed on this outcome and, although clinically relevant, the difference was not significantly different., Wider Implications of the Findings: The rate of difficult transfers was significantly higher in the direct ET group compared with the afterload ET group, although a wide variation was observed among operators. Further studies regarding the association between transfer technique and ART outcomes are required., Study Funding/competing Interest(s): No specific funding was sought and there are no competing interests., Trial Registration Number: NCT03161119., Trial Registration Date: 5 April 2017., Date of First Patient's Enrolment: 26 September 2017., (© The Author(s) 2021. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: The aim of the present study was to analyze the IVF success rates and the economic cost per delivery in all the public funded IVF Units in Lombardy in the 2017-2018 period and to assess any significant difference in ART outcomes among the enrolled centers. Methods: Analysis of costs for the 2017 and 2018 fresh transfer delivery rate (DR) and Cumulative delivery rate (CDR) considering both fresh and frozen cycles were extracted from the ART Italian Registry on oocytes retrievals, fresh and frozen embryos and oocytes embryo transfer performed in 22 Lombardy IVF Units. Results: In 2017, 29,718 procedures were performed, resulting in 4,543 pregnancies and 3,253 deliveries. In 2018, there were 29,708 procedures, 4,665 pregnancies and 3,348 deliveries. Pregnancies lost to follow up were 5.0% with a (range of 0-67.68%) in 2017 and 3.4% (range of 0-45.1%) in 2018. The cost reimbursement for the cycles were €2,232 ($2,611) for oocyte retrieval and €2,194 ($2,567) for embryo transfer, excluding ovarian stimulation therapy and luteal phase support. 19.33 (5.80). The DR was 13.23 ± 5.69% (range 2.86-29.11%) in 2017 and 19.33 ± 5.80% in 2018 (range 11.82-34.98 %) and the CDR was 19.86 ± 9.38% (range 4.43-37.88%) in 2017 and 21.32 ± 8.84% (range 4.24-37.11%). The mean multiple pregnancy delivery rate (MDR) was 11.08 ± 5.55% (range 0.00-22.73%) in 2017 and 10.41 ± 4.99% (range 1.33-22.22%) in 2018. The mean CDR cost in euros was 26,227 ± 14,737 in 2017 and 25,018 ± 16,039 in 2018. The mean CDR cost among centers was 12,480 to 76,725 in 2017 and 12,973 to 86,203 in 2018. Conclusions: Our findings show impressive differences in the DR and CDR among centers and the importance of cryopreservation in patients' safety and economic cost reduction suggesting the formulation of specific KPI's (Key performance indexes) and minimal performance indexes (PI) as a basis for the allocation of public or insurance resources. In particular, the reduction of multiple pregnancy rates costs, may lead to a more widespread use of ART even in lower resources countries., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Levi-Setti, Busnelli, Bodina, De Luca and Scaravelli.)

Objective: To investigate the impact of controlled ovarian hyperstimulation (COH) for in vitro fertilization (IVF) on thyroid function., Design: Systematic review and meta-analysis., Setting: Not applicable., Patient(s): Infertile women undergoing conventional IVF or intracytoplasmic sperm injection., Intervention(s): Systematic search of PubMed, MEDLINE, Embase, Scopus, and Web of Science from inception until November 2020. Studies could be included only if they met the following criteria: subjects were classified as euthyroid or hypothyroid; serum thyroid-stimulating hormone (TSH) and/or free thyroxine (FT4) levels were evaluated before COH; and the same thyroid function test was reassessed after COH (i.e., at the time of trigger for final follicle maturation and/or at pregnancy test)., Main Outcome Measure(s): Mean difference (MD) between the serum TSH or FT4 levels assessed after COH and before COH., Result(s): In euthyroid women, the serum TSH levels assessed at the time of trigger and at the time of pregnancy test were significantly higher than those at baseline (MD: 0.69 mIU/L, 95% confidence interval [CI]: 0.30-1.08, I 2 = 93% and MD: 0.67, 95% CI: 0.49-0.85, I 2 = 72%, respectively). The serum FT4 levels did not undergo significant changes. Subanalysis confirmed an increase in the TSH level after restricting the analysis to women treated with gonadotropin-releasing hormone agonist protocols and to those who achieved pregnancy. A pronounced increase in the TSH level was observed in women treated for hypothyroidism (MD: 1.50 mIU/L, 95% CI: 1.10-1.89, I 2 = 0%)., Conclusion(s): Pooling of the results showed a significant increase in serum TSH level in women undergoing COH for IVF. This change was particularly pronounced in women treated for hypothyroidism. New thyroid function screening strategies for women undergoing COH are warranted., (Copyright © 2021 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

The aim of the present systematic review and meta-analysis was to assess the effect of the different therapeutic options for repeated embryo implantation failure (RIF) on a subsequent IVF cycle outcome. Twenty-two RCTs and nineteen observational studies were included. Pooling of results showed a beneficial effect of intrauterine PBMC infusion on both CPR (RR 2.18; 95% CI 1.58-3.00; p < 0.00001; OR 2.03; 95% CI 1.22-3.36; p = 0.006) and LBR (RR 2.41; 95% CI 1.40-4.16; p = 0.002; OR 3.73; 95% CI 1.13-12.29; p = 0.03), of subcutaneous G-CSF administration on CPR (RR 2.29; 95% CI 1.58-3.31; p < 0.0001) and of intrauterine PRP infusion on CPR (RR 2.45; 95% CI 1.55-3.86; p = 0.0001). Observational studies also demonstrated a positive effect of IVIG and intrauterine hCG infusion on both CPR and LBR and of atosiban on CPR. Studies investigating intrauterine G-CSF infusion, LMWH, intravenous intralipid, hysteroscopy, blastocyst-stage ET, ZIFT, PGT-A and AH failed to observe an impact on IVF outcome. The quality of the evidence that emerged from RCTs focused on intrauterine PBMC infusion and subcutaneous G-CSF administration was moderate. For all other therapies/interventions it varied from low to very low. In conclusion, intrauterine PBMC infusion and subcutaneous G-CSF administration are the most promising therapeutic options for RIF. However, further well conducted RCTs are necessary before their introduction into clinical practice.

The reduction of female fertility over time is considered as a natural consequence of ovarian aging. The exact mechanism underlying this process is not fully elucidated. However, it is becoming increasingly evident that qualitative and quantitative mitochondrial genome alterations might play a relevant role. The former include mitochondrial DNA (mtDNA) damage caused by oxidative stress, the accumulation of acquired mtDNA mutations, the effects of inherited mtDNA mutations, and alterations in the mitochondrial stress response mechanism. The latter refer to alterations in the oocytes, granuolosa cells, and embryonic cells mtDNA content. The present review aims to investigate the evidence about: (1) the effect of qualitative and quantitative mtDNA alterations on female fertility, paying particular attention to those with a pathophysiology characterized by a relevant role of oxidative stress; (2) the use of oocytes, granulosa cells (GCs), embryonic cells, and peripheral blood cells mtDNA copy number as a female fertility surrogate biomarker; (3) experimental therapies tested to try to subvert the ovarian aging process with particular reference to antioxidant treatments.

The pandemic caused by Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) has led to several concerns on male fertility. Nowadays, there are numerous unanswered questions, for example: is the virus present or not in the seminal fluid of infected subjects? Could the seminal fluid represent a way of sexual transmission for the virus? Why do men appear to be more susceptible than women? Several studies have been carried out to ascertain the presence of SARS-CoV-2 in the seminal fluid, with contrasting results; the expression of angiotensin-converting enzyme-2 (ACE2) and transmembrane serine protease 2 (TMPRSS2) in the testes and in the male genital tract led to speculation about the possible presence of the virus in the seminal fluid. However, it was found that ACE2 and TMPRSS2, used by the virus to enter host cells, are expressed differently in certain testicle cells (stem germ cells, Leydig and Sertoli cells), yet the testicle cells in which ACE2 and TMPRSS2 molecules are simultaneously expressed are rare. This fact would suggest that the virus is not able to enter testicular cells, that it is not present in the seminal fluid and that it cannot infect male germ cells. However, the direct influence of SARS-CoV-2 on the testes is still to be evaluated, and recent results are very controversial. SARS-CoV-2 could enter the testicle using alternative paths and lead to alterations in testicular functionality. Another plausible consideration is that the COVID-19 disease could also indirectly cause alterations to testicular activity, since the fever and the cytokinic storm generated by the immune system can lead to damage of the testicular activity, consequently compromising male fertility. Although the literature provides controversial evidence, the purpose of this review is to lend a general overview about the state of the art. Despite the lack of studies, it would represent a starting point for further investigation about the effect of this coronavirus on male fertility., (Copyright © 2020 Navarra, Albani, Castellano, Arruzzolo and Levi-Setti.)

Objective: To assess the association between serum ovulation trigger progesterone (P) levels and the outcome of in vitro fertilization cycles. Design Setting: Real world single-center retrospective cohort study. Patient Intervention(s): All fresh cleavage and blastocyst-stage embryo transfers (ETs) performed from January 2012 to December 2016. Main outcome Measure(s): The impact of premature high serum P levels cycles in terms of clinical pregnancy rates (CPRs) and live birth rates (LBRs). Results: 8,034 ETs were performed: 7,597 cleavage-stage transfers and 437 blastocyst transfers. Serum P levels demonstrated to be inversely related to CPR (OR 0.72, p < 0.001) and LBR (OR 0.73, p < 0.001). The progressive decrease of LBR and CPR started when P levels were >1 ng/ml in a good prognosis cleavage ET subgroup, whereas in patients with worse prognosis only for P ≥ 1.75 ng/ml. In the blastocyst ET subgroup, the negative effect of P elevation was reported only if P was >1.75 ng/ml. CPR (OR 0.71 (0.62-0.80), p < 0.001) and LBR (OR 0.73 (0.63-0.84), p < 0.001) in thawed cycles resulted statistically significantly higher than in fresh cycles in the cleavage-stage subgroup. In the blastocyst group, no significant difference resulted between thawed and fresh cycles, independently of P levels [CPR OR 0. 37 (0.49-1.09), p = 0.123; LBR OR 0.71 (0.46-1.10), p = 0.126]. Conclusion: High P levels decrease CPR as well as LBR in both cleavage and blastocyst ET. In the cleavage group, for P levels below 1.75 ng/ml, our data suggest the possibility to wait until day 5 for ET, and if P level is ≥1.75 ng/ml, it should be considered to freeze all embryos and postpone the ET. Clinical Trial Registration: ClinicalTrials.gov, ID: NCT04253470., (Copyright © 2020 De Cesare, Morenghi, Cirillo, Ronchetti, Canevisio, Persico, Baggiani, Sandri and Levi-Setti.)

The COVID-19 pandemic is an unprecedented global situation. As assisted reproductive technology (ART) specialists, we should be cautious, carefully monitoring the situation while contributing by sharing novel evidence to counsel our patients, both pregnant women and would-be mothers. Time to egg collection and drop-out rates are critical parameters for scheduling treatments once the curve of infections has peaked and plateaued in each country. In order to reduce the values for these two parameters, infertile patients now require even more support from their IVF team: urgent oocyte collection for oncology patients must be guaranteed, and oocyte retrievals for women of advanced maternal age and/or reduced ovarian reserve cannot be postponed indefinitely. This document represents the position of the Italian Society of Fertility and Sterility and Reproductive Medicine (SIFES-MR) in outlining ART priorities during and after this emergency., (Copyright © 2020 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)