This study aimed to determine whether the use of vaginal Endometrin plus intramuscular progesterone on every third day (VIM) in programmed frozen embryo transfer (FET) is associated with lower pregnancy and live birth rates compared to daily intramuscular progesterone (IM). FET data from a single program were collected between November 2018 and December 2021. A total of 903 FETs were analyzed, including 504 FETs in the IM group, and 399 FETs in the VIM group. Inclusion criteria were women undergoing FETs with either 50 mg daily IM progesterone only (control) or 200 mg Endometrin twice daily plus 50 mg IM progesterone on every third day, with the transfer of a single day 5 or 6 frozen embryo. There were no significant differences in patient age at time of FETs, BMI, endometrial thickness, blastocyst quality, or infertility diagnosis between the groups. The VIM had significantly lower positive hCG and clinical pregnancy rates compared to the IM (60.2% vs 72.0% and 40.6% vs 56.7%, respectively, P = 0.0002 and P < 0.0001). The live birth rate was 36.1% in the VIM, compared to 49.4% in the IM (P < 0.0001). These findings also remained significant when excluding FETs with donor egg (35.9% vs 50.1%, P < 0.0001). This study demonstrated that VIM in FET cycles yields significantly lower pregnancy and live birth rates compared to IM along. IM progesterone alone may be preferable to combined Endometrin and IM progesterone in patients undergoing programmed frozen embryo transfers.

OBJECTIVE: Despite advances in IVF techniques, determining the prognostic factors influencing cumulative live birth rate (CLBR) remains crucial for optimizing outcomes. Among the various key performance indicators in the lab, blastulation rate, and more specifically Total Blastocyst Usable Rate (TBUR), has gained particular interest. In this study we aimed at determining if TBUR was significantly associated with CLBR.
METHODS: This monocentric retrospective case-control study was conducted in 317 consecutive IVF/ICSI cycles in 2014-2020 and leading to the formation of 3 usable blastocysts, including freeze all cycles. TBUR (usable blastocysts / 2PNs) was calculated and CLBR after 2-year follow up was recorded, including both fresh and frozen embyro transfers. CLBR was then compared between 2 groups according to TBUR (group 1: TBUR ≥50 % vs group 2: TBUR ≤30 %).
RESULTS: CLBR was significantly higher in group 1 than in group 2 (57 vs. 41 %, p = 0.02). Adjusted logistic regression showed a statistically significant relationship between CLBR and TBUR, with a significantly lower chance of achieving a live birth in group 2 than in group 1 (OR = 0.408 [0.17-0.96]; p = 0.04).
CONCLUSIONS: Although the monocentric design and the arbitrary choice of thresholds for TBUR and number of blastocysts call for caution when generalizing the findings and advocates for external validation, our results illustrate that TBUR is a valuable prognostic factor of CLBR in IVF cycles which might serve as a tool for lab monitoring, cycle analysis by medical staff and patients\' counselling. These results fit well within the P4 medicine concept (Predictive, Preventive, Personalized, and Participatory), and advocate for further research in order to improve embryo culture conditions.

UNASSIGNED: To investigate the effects of β-cell dysfunction on IVF outcomes in women with PCOS.
UNASSIGNED: This retrospective cohort study includes 1,212 women with PCOS undergoing their first IVF cycle between September 2010 and December 2019. Beta-cell dysfunction was measured by homeostasis model assessment of β-cell function (HOMA-β) index.
UNASSIGNED: In quartiles of HOMA-β, the incidence of miscarriage dramatically increased from 10.2% (Q1) to 31.1% (Q4) (P for trend <0.001). Likewise, the incidence of miscarriage in quartiles of HOMA-β also showed a similar trend (P for trend <0.001). After adjusting for confounding factors, logistic regression analyses showed that high HOMA-IR values were independently associated with a high risk of miscarriage, with the odds ratios (OR) and 95% confidence intervals for quartiles 2-4 versus quartile 1 were 1.30 (0.69-2.46), 1.82 (0.97-3.43), and 3.57 (1.86-6.85), respectively (P for trend <0.001). When analyzed jointly, women in the highest HOMA-IR and highest HOMA-β group exhibited the highest risk for miscarriage compared with all other groups. Furthermore, higher HOMA-IR values were associated with higher risks of miscarriage among PCOS women regardless of HOMA-β values.
UNASSIGNED: β-cell dysfunction is independently associated with increased miscarriage rate and decreased live birth rate in women with PCOS. It also plays a synergistic role with IR in terms of the reproductive outcomes, while the influence of IR overweighs that of β-cell dysfunction.

OBJECTIVE: The introduction of the time-lapse monitoring system (TMS) and the development of predictive algorithms could contribute to the optimal embryos selection for transfer. Therefore, the present study aims at investigating the efficiency of KIDScore and iDAScore systems for blastocyst stage embryos in predicting live birth events.
METHODS: The present retrospective study was conducted in a private IVF Unit setting throughout a 10-month period from October 2021 to July 2022, and included the analysis of 429 embryos deriving from 91 IVF/ICSI cycles conducted due to infertility of various etiologies. Embryos incubated at the Embryoscope+ timelapse incubator were analyzed through the established scoring systems: KIDScore and iDAScore®. The main outcome measure was the comparison of the two scoring systems in terms of live birth prediction. Embryos with the higher scores at day 5 (KID5 score/iDA5 score) were transferred or cryopreserved for later use.
RESULTS: Embryos with high KID5 and iDA5 scores positively correlated with the probability of successful live birth, with KID5 score yielding a higher efficiency in predicting a successful reproductive outcome compared to a proportionally high iDA5 score. KID5 demonstrated conservative performance in successfully predicting live birth compared to iDA5 score, indicating that an efficient prediction can be either provided by a relatively lower KID5 score or a relatively higher iDA5 score.
CONCLUSIONS: The developed artificial intelligence tools should be implemented in clinical practice in conjunction with the conventional morphological assessment for the conduction of optimized embryo transfer in terms of a successful live birth.

OBJECTIVE: What is the effect of SARS Cov-2 on IVF outcome?
CONCLUSIONS: Mild or asymptomatic Covid-19 infection does not appear to affect clinical or ongoing pregnancy rate after IVF.
BACKGROUND: Covid-19 has been shown to affect female and male fertility and reproductive function. Studies have shown variable results regarding impact of Covid-19 on IVF outcome with few reporting impaired ovarian reserve, oocyte and embryo quality, semen parameters, clinical pregnancy rate (CPR) and live birth rate (LBR) while others reported no effect on IVF outcome.
METHODS: An electronic database search of PubMed, EMBASE, SCOPUS, WHO Covid-19 database, Clinical trials.gov and Cochrane Central was performed for articles published in English language between 1st January 2020 and 15th October 2022 by two independent reviewers using predefined eligibility criteria We have included observational studies both prospective and retrospective, cohort studies, and case control studies and excluded narrative reviews, case studies, cost-effectiveness studies or diagnostic studies. Risk of bias was assessed using NOS and quality of evidence was graded by GRADE pro.
UNASSIGNED: Studies comparing women undergoing IVF and comparing Covid-19 affected with those unaffected by Covid-19 were included. Also, studies comparing immune group (infected or vaccinated) in the study group and unaffected as controls (historical controls, IVF cycles done prior to Covid-19 outbreak but matched with study group) were included. Those with no comparison group or published in language other than English language or duplicate studies were excluded.
RESULTS: We identified 5046 records and after full text screening of 82 studies, 12 studies were selected for final review. For the clinical pregnancy rate, there was no difference in the CPR in covid recovered or control patients (OR 0.90, 95 % CI = 0.67 to1.21; I2 = 29 %). Similarly, there was no significant effect on implantation rate (RR 0.92, 95 % CI = 0.68 to1.23; I2 = 31 %) and ongoing pregnancy rate (RR 0.96, 95 % CI = 0.79 to 1.15;I2 = 21 %). The mean number of the oocyte retrieved per patient was not significantly different in both the groups (mean difference 0.52, 95 % CI = -1.45 to 2.49; I2 = 75 %). The certainty of the evidence was low.
CONCLUSIONS: The meta-analysis is based on observational studies each involving small number of participants. Few studies reported outcomes as per patient while others reported as per cycle, for uniformity we have reported outcomes as per cycle. Sample size in most of studies was small.
CONCLUSIONS: This systematic review has not shown any significant effect on the outcome of IVF cycles in patients post Covid-19 recovery compared to controls. But given the sample size, the findings should be considered with caution.
BACKGROUND: The review protocol has been registered on PROSPERO (registration number CRD42022314515).

Dysregulation of the stress-regulatory hormone cortisol is associated with anxiety, but its potential impact on infertile women and in vitro fertilization (IVF) treatment remains unclear. This prospective cross-sectional study aimed at evaluating the dysregulation of cortisol and its correlation to anxiety in infertile women. The influence of stress on IVF outcomes was also investigated.
A point-of-care test was used for the measurement of morning serum cortisol in 110 infertile women and 112 age-matching healthy individuals. A Self-Rating Anxiety Scale (SAS) was used for the anxiety assessment of infertile women, and 109 of them underwent IVF treatment starting with the GnRH-antagonist protocol. If clinical pregnancy was not achieved, more IVF cycles were conducted with adjusted protocols until the patients got pregnant or gave up.
Higher morning serum cortisol level was identified for infertile patients, especially for the elder. Women with no anxiety showed significant differences in cortisol levels, monthly income, and BMI compared with those with severe anxiety. A strong correlation was found between the morning cortisol level and the SAS score. When the cutoff value is 22.25 μg/dL, cortisol concentration could predict the onset of anxiety with high accuracy (95.45%) among infertile women. After IVF treatments, women with high SAS scores (>50) or cortisol levels (>22.25 μg/dL) demonstrated a lower rate of pregnancy (8.0%-10.3%) and more IVF cycles, although the impact of anxiety was not affirmative.
Hypersecretion of cortisol related to anxiety was prevalent among infertile women, but the influence of anxiety on multi-cycle IVF treatment was not affirmative due to the complicated treatment procedures. This study suggested that the assessment of psychological disorders and stress hormone dysregulation should not be overlooked. An anxiety questionnaire and rapid cortisol test might be included in the treatment protocol to provide better medical care.

Pre-conception counselling and management of expectations about chance of success of IVF/ICSI treatments is an integral part of fertility care. Registry data are usually used to inform patients about expected success rates of IVF/ICSI treatment, as these data should best represent real-world populations and clinical practice. In registries, the success rate of IVF/ICSI treatments is conventionally reported per treatment cycle or per embryo transfer and estimated from data for which several treatment attempts per subject have been pooled (e.g. repetitive IVF/ICSI attempts or repetitive attempts of cryotransfer). This, however, may underestimate the true mean chance of success per treatment attempt, because treatment attempts of women with a poor prognosis will usually be over-represented in a pool of treatment cycle data compared to treatment events of women with a good prognosis. Of note, this phenomenon is also a source of potential bias when comparing outcomes between fresh transfers and cryotransfers, since women can undergo a maximum of only one fresh transfer after each IVF/ICSI treatment, but potentially several cryotransfers. Herein, we use a trial dataset from 619 women, who underwent one cycle of ovarian stimulation and ICSI, a Day 5 fresh transfer and/or subsequent cryotransfers (follow-up of all cryotransfers up to 1 year after the start of stimulation), to exemplify the underestimation of the live birth rate, when not accounting for repeated transfers in the same woman. Using mixed-effect logistic regression modelling, we show that the mean live birth rate per transfer per woman in cryocycles is underestimated by the factor 0.69 (e.g. live birth rate per cryotransfer of 36% after adjustment versus 25% unadjusted). We conclude that the average chance of success of treatment cycles of women of a given age, treated in a given centre, etc., when conventionally calculated per cycle or per embryo transfer from a pool of treatment events, do not apply to an individual woman. We suggest that patients are, especially at the outset of treatment, systematically confronted with mean estimates of success per attempt that are too low. Live birth rates per transfer from datasets encompassing multiple transfers from single individuals could be more accurately reported using statistical models accounting for the correlation between cycle outcomes within women.

OBJECTIVE: To investigate differences in reproductive outcomes among IVF patients with lean compared to obese polycystic ovarian syndrome (PCOS) phenotypes.
METHODS: A retrospective cohort study of patients with PCOS who underwent IVF in a single, academically affiliated infertility center in the USA between December 2014 and July 2020. The diagnosis of PCOS was assigned based on Rotterdam criteria. Patients were designated as lean (< 25) or overweight/obese (≥ 25) PCOS phenotype based on BMI (kg/m2) at cycle start. Baseline clinical and endocrinologic laboratory panel, cycle characteristics, and reproductive outcomes were analyzed. The cumulative live birth rate included up to 6 consecutives cycles. A Cox proportional hazards model and Kaplan-Meier curve for estimating live birth rates were used to compare the two phenotypes.
RESULTS: A total of 1395 patients who underwent 2348 IVF cycles were included. The mean (SD) BMI was 22.7 (2.4) in the lean and 33.8 (6.0) in the obese group (p < 0.001). A number of endocrinological parameters were similar between lean and obese phenotypes: total testosterone 30.8 ng/dl (19.5) vs 34.1 (21.9), p > 0.02 and pre-cycle hemoglobin A1C 5.33% (0.38) vs 5.51% (0.51) p > 0.001, respectively. The CLBR was higher in those with a lean PCOS phenotype: 61.7% (373/604) vs 54.0% (764/1414) respectively. Miscarriage rates were significantly higher for O-PCOS patients (19.7% (214/1084) vs 14.5% (82/563) p < 0.001) and the rate of aneuploids was similar (43.5%, 43.8%, p = 0.8). A Kaplan-Meier curve estimating the proportion of patients with a live birth was higher in the lean group (log-rank test p = 0.013). After adjusting for potential confounders, the lean phenotype was associated with an increased hazard ratio for live birth: HR = 1.38 p < 0.001.
CONCLUSIONS: Lean PCOS phenotype is associated with a significantly higher CLBR compared to their obese counterparts. Miscarriage rates were significantly higher among obese patients, despite comparable pre-cycle HBA1C and similar aneuploidy rates in patients who underwent PGT-A.

Several strategies have been proposed for ovarian stimulation in older women, such as using an increased daily dose of gonadotropins (300-450 IU per day) with GnRH agonist (long or micro dose flare protocols), or using GnRH antagonist protocols. The objective of this study is to compare the efficacy of flexible GnRH antagonist protocol and GnRH agonist flare - pituitary block protocols for ovarian stimulation in women above 40 years old undergoing IVF.
This study was performed between January 2016 and February 2019. One hundred and fourteen women aged between 40 and 42 years who underwent IVF were divided into two groups; group I were treated by Flexible GnRH antagonist protocol (Antagonist group, n=68); and group II were treated by Flare GnRH agonist protocol (Flare group, n=46).
Patients treated with the antagonist protocol had a significantly lower cancellation rate when compared with patients treated with flare agonist protocol (10.3% vs. 21.7%, p value 0.049). The other parameters evaluated did not show statistically significant differences.
Our finding showed that both Flexible antagonist and Flare agonist protocols had comparable outcomes, with lower cycle cancellation rates for older patients treated with the antagonist protocol.

BACKGROUND: Several studies showed that human papillomavirus (HPV) affects male fertility, but its impact on female fertility and in vitro fertilization (IVF) outcome is not yet clear.
METHODS: Objective of this observational, prospective, cohort study was to evaluate the prevalence of HPV infection in women candidate to IVF, and the effects of HPV infection on the kinetic of embryonic development and on IVF outcome. A total number of 457 women candidate to IVF were submitted to HR-HPV test; among them, 326 underwent their first IVF cycle and were included in the analysis on IVF results.
RESULTS: 8.9% of women candidate to IVF were HPV-positive, HPV16 being the most prevalent genotype. Among the infertility causes, endometriosis was significantly more frequent in HPV-positive than in negative women (31.6% vs. 10.1%; p < 0.01). Granulosa and endometrial cells resulted HPV-positive in 61% and 48% of the women having HPV-positive cervical swab, respectively. Comparing HPV-positive and negative women at their first IVF cycle, no significant difference was observed in the responsiveness to controlled ovarian stimulation (COS) in terms of number and maturity of retrieved oocytes, and of fertilization rate. The mean morphological embryo score was comparable in the two groups; embryos of HPV-positive women showed a quicker development in the early stages, with a significantly shorter interval between the appearance of pronuclei and their fusion. In the following days, embryo kinetic was comparable in the two groups until the early blastocyst stage, when embryos of HPV-positive women became significantly slower than those of HPV-negative women. Overall, these differences did not affect live birth rate/started cycle, that was comparable in HPV-positive and negative women (22.2 and 28.1%, respectively).
CONCLUSIONS: (a) the prevalence of HPV infection in women candidate to IVF is similar to that observed in the general female population of the same age range; (b) HPV infection migrates along the female genital apparatus, involving also the endometrium and the ovary, and perhaps participates in the genesis of pelvic endometriosis; (c) HPV slightly affects the developmental kinetic of in vitro-produced embryos, but does not exert an effect on live birth rate.