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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 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.

The etiology of recurrent pregnancy loss (RPL) is complex and multifactorial and in half of patients it remains unexplained (U-RPL). Recently, low-molecular-weight heparin (LMWH) has gained increasing relevance for its therapeutic potential. On this regard, the aim of this systematic review and meta-analysis is to analyze the efficacy of low molecular weight heparin (LMWH) from the beginning of pregnancy in terms of live birth rates (LBR) in U-RPL. Registered randomized controlled trials (RCTs) were included. We stratified findings based on relevant clinical factors including number of previous miscarriages, treatment type and control type. Intervention or exposure was defined as the administration of LMWH alone or in combination with low-dose aspirin (LDA). A total of 6 studies involving 1016 patients were included. The meta-analysis results showed that LMWH used in the treatment of U-RPL was not associated with an increase in LBR with a pooled OR of 1.01, a medium heterogeneity (26.42%) and no publication bias. Results of other sub-analyses according to country, treatment type, and control type showed no significant effect of LMWH on LBR in all subgroups, with a high heterogeneity. The results highlight a non-significant effect of LMWH in U-RPL on LBR based on moderate quality evidence. Registration number: PROSPERO: ( https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022326433 ).

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 ).

To evaluate whether telomere length (TL), mitochondrial-DNA (mt-DNA) or epigenetic age estimators based on DNA methylation (DNAm) pattern could be considered reliable predictors of in-vitro-fertilization (IVF) success in terms of live birth rate. Prospective cohort study. Infertility Unit of the Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico. 181 women aged 37-39 years who underwent IVF at a single-centre between January 2017 and December 2018. On the day of recruitment, blood samples were collected, and genomic DNA was isolated from white blood cells. TL, mt-DNA and DNAm assessment was performed using quantitative real-time polymerase chain reaction (qPCR). Biological age (DNAm age) was computed as the algorithm based on methylation pattern of five genes. Epigenetic age acceleration was estimated from the residuals of the linear model of epigenetic age regressed on chronological age. Long Interspersed Nuclear Elements (LINE)-1 methylation pattern was used as a surrogate for global DNA methylation. This study investigated whether peripheral TL, mt-DNA and DNAm could predict live birth in IVF cycles. TL, mt-DNA and LINE-1 methylation were not associated with IVF success. Conversely, DNAm age resulted significantly lower in women who had a live birth compared to women who did not (36.1 ± 4.2 and 37.3 ± 3.3 years, respectively, p = 0.04). For DNAm age, odds ratio (OR) for live birth per year of age was 0.90 (95%CI: 0.82-0.99, p = 0.036) after adjusting for FSH and antral follicle count (AFC) and 0.90 (95%CI: 0.82-0.99, p = 0.028) after adjusting also for number of oocytes retrieved. A significant association also emerged for epigenetic age acceleration after adjustments (OR = 0.91, 95%CI: 0.83-1.00, p = 0.048). DNAm age is associated with IVF success but the magnitude of this association is insufficient to claim a clinical use. However, our findings are promising and warrant further investigation. Assessment of biological age using different epigenetic clocks or focusing on different tissues may reveal new predictors of IVF success.

Background Models evaluating both costs and economic benefits of assisted reproductive technology (ART) implementation are lacking. This constitutes a major limitation in the decision-making process of resource allocation. Herein, we aimed to estimate the economic and social impact of female infertility in Italy and examine the benefits generated by investment in ART from a national perspective. Methods A retrospective cohort study was conducted using the Italian Hospital Discharge Records database to identify women aged 18–50 undergoing ART between 2014 and 2016 in Italy. Patients were followed for up to 36 months after the first ART complete cycle. Hospitalization costs were analyzed nationally, while outpatient care and drug consumption costs were assessed in a sub-analysis using administrative databases from LHU Umbria 2. A fiscal impact model was developed from a governmental perspective, projecting lifetime tax revenues and public expenditures associated with the ART birth cohort, including costs for healthcare, education, pensions, and social transfers. All future values were discounted at 3% in line with Italian economic evaluation guidelines. Results A total of 33,713 women met the inclusion criteria. During the follow-up, 48.4% achieved pregnancy resulting in childbirth. The average hospital care cost per patient was €5,853, with a projected national expenditure of €337 million for ART management. Younger women (18–33 years) had the highest success rates (61.8%). Assuming 16,300 live births, the model estimated net fiscal benefits of €3.3 billion over the lifetime of these individuals, equivalent to €203,856 per live birth. Conclusion This study highlights the economic and fiscal benefits of ART, emphasizing the need for policies promoting early access to treatment. ART investment represents a strategic approach to mitigate demographic decline, with each live birth substantially contributing to national fiscal stability. Key points • Investing in Assisted Reproductive Technology (ART) within national health systems can generate significant economic returns, substantially exceeding initial healthcare expenditures. • Public funding of ART contributes positively to national economies by increasing future tax revenues and addressing demographic challenges related to declining fertility.

A case report of a premenarcheal patient with ovarian torsion and mullerian agenesis is presented. A 12-year-old prepubertal girl is presented with severe right lower quadrant abdominal pain and mild rebound. Laparoscopy showed mullerian agenesis and twisted right adnexa. Detorsion and cystectomy of the right ovary were done, and the ovary was fixed to the pelvic sidewall. The postoperative course was uneventful. An association between the lax attachment of the adnexa and torsion may be a contributing factor in this condition.

The advent of random start protocols to shorten the time needed to store oocytes in women with malignancies has represented an important improvement in the field of fertility preservation. However, Randomized Controlled Trials are difficult to implement in this area and available evidence that supports this approach remains modest. To shed more light on this issue, we compared the follicular development between the ovary carrying the dominant follicle or the corpus luteum and the contralateral resting ovary in 90 women who underwent random start controlled ovarian stimulation (COS). In fact, ovarian response did not differ between the two ovaries. Subgroup analyses according to the phase of the cycle at the initiation of COS, the type of malignancy, the use of letrozole and the magnitude of the ovarian response did not allow to identify any condition showing a difference in the follicular response between the active and the resting ovaries. In conclusion, follicular growth does not seem to be perturbed by the presence of a dominant follicle or a corpus luteum.

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.

Here we present a case of severe post-partum pneumonia that we observed at the end of January 2020. Specimen of blood was cultured and revealed Klebsiella pneumoniae bacteremia. However, the course of infection was atypical and the recovery time particularly long. Subsequently emerged COVID-19 hallmarks suggested to re-evaluate the case. After a multidisciplinary consultation, we concluded that, considering the clinical and imaging characteristics, the most likely hypothesis was that the patient was affected by novel Coronavirus pneumonia. The present case supports the hypothesis that Coronavirus might have circulated in northern Italy for weeks before its official detection.