Effect of a Combination of Myo-Inositol, Alpha-Lipoic Acid, and Folic Acid on Oocyte Morphology and Embryo Morphokinetics in non-PCOS Overweight/Obese Patients Undergoing IVF: A Pilot, Prospective, Randomized Study.

Herein we aimed at assessing whether Myo-Inositol (MI), Alpha-Lipoic acid (ALA), and Folic acid (FA) could improve oocyte quality and embryo development in non-PCOS overweight/obese women undergoing IVF. Three hundred and twenty-four mature oocytes were obtained from non-PCOS overweight/obese patients, randomized to receive either MI, ALA, and FA (MI + ALA + FA group, n = 155 oocytes) or FA alone (FA-only group, n = 169 oocytes). Oocytes were examined using Polarized Light Microscopy to assess morphological features of zona pellucida (ZP) and meiotic spindle (MS). One hundred and seventy-six embryos (n = 84 in the MI + ALA + FA group, n = 92 in the FA-only group) were assessed by conventional morphology on days 2 and 5, as well as using the Time-Lapse System morphokinetic analysis. A significantly higher ZP retardance, area, and thickness (p < 0.05), and a shorter MS axis (p < 0.05) were observed in the MI + ALA + FA group, suggesting a positive effect on oocyte quality. Conventional morphology evaluation on day 2 showed a higher mean embryo score in the MI + ALA + FA group, whereas embryo morphokinetic was comparable in the two groups. Overall, our data show a possible beneficial effect of the combination of MI, ALA, and FA on oocyte and embryo morphology, encouraging testing of this combination in adequately powered randomized trials to assess their impact of clinical IVF results.

Controlled ovarian stimulation and progesterone supplementation affect vaginal and endometrial microbiota in IVF cycles: a pilot study.

PURPOSE: Does controlled ovarian stimulation (COS) and progesterone (P) luteal supplementation modify the vaginal and endometrial microbiota of women undergoing in vitro fertilization? METHODS: Fifteen women underwent microbiota analysis at two time points: during a mock transfer performed in the luteal phase of the cycle preceding COS, and at the time of fresh embryo transfer (ET). A vaginal swab and the distal extremity of the ET catheter tip were analyzed using next-generation 16SrRNA gene sequencing. Heterogeneity of the bacterial microbiota was assessed according to both the Bray-Curtis similarity index and the Shannon diversity index. RESULTS: Lactobacillus was the most prevalent genus in the vaginal samples, although its relative proportion was reduced by COS plus P supplementation (71.5 ± 40.6% vs. 61.1 ± 44.2%). In the vagina, an increase in pathogenic species was observed, involving Prevotella (3.5 ± 8.9% vs. 12.0 ± 19.4%), and Escherichia coli-Shigella spp. (1.4 ± 5.6% vs. 2.0 ± 7.8%). In the endometrium, the proportion of Lactobacilli slightly decreased (27.4 ± 34.5% vs. 25.0 ± 29.9%); differently, both Prevotella and Atopobium increased (3.4 ± 9.5% vs. 4.7 ± 7.4% and 0.7 ± 1.5% vs. 5.8 ± 12.0%). In both sites, biodiversity was greater after COS (p < 0.05), particularly in the endometrial microbiota, as confirmed by Bray-Curtis analysis of the phylogenetic distance among bacteria genera. Bray-Curtis analysis confirmed significant differences also for the paired endometrium-vagina samples at each time point. CONCLUSIONS: Our findings suggest that COS and P supplementation significantly change the composition of vaginal and endometrial microbiota. The greater instability could affect both endometrial receptivity and placentation. If our findings are confirmed, they may provide a further reason to encourage the freeze-all strategy.

Human Recombinant FSH and Its Biosimilars: Clinical Efficacy, Safety, and Cost-Effectiveness in Controlled Ovarian Stimulation for In Vitro Fertilization.

Exogenous human follicle-stimulating hormone (hFSH), either derived from extraction and purification from the urine or obtained by recombinant technology in the form of follitropin α, ß and δ (rFSH), has been used for decades in the treatment of infertility. The main applications of FSH treatment in the woman have been, and still are, ovulation induction in oligo-anovulatory subjects, and stimulation of the development of a cohort of follicles in patients undergoing controlled ovarian stimulation (COS) for in vitro fertilization (IVF). In the last years, two biosimilars of follitropin alfa, rFSH compounds structurally and functionally similar to the originator, have been approved and marketed for clinical use in Europe. Moreover, some other rFSH biosimilars are currently under investigation. The objective of this article is to review the available evidences comparing the efficacy, safety, and cost-effectiveness of rFSH follitropin alpha originator with its biosimilars, discussing the clinical trials that allowed biosimilars to get registration and marketing authorization.

The Ovarian Sensitivity Index (OSI) Significantly Correlates with Ovarian Reserve Biomarkers, Is More Predictive of Clinical Pregnancy than the Total Number of Oocytes, and Is Consistent in Consecutive IVF Cycles.

BACKGROUND AND OBJECTIVES: Some biomarkers of ovarian responsiveness to gonadotropins and the total number of retrieved oocytes are known to affect the success rate after controlled ovarian stimulation (COS) and in vitro fertilization (IVF). The aim of this study was to study another putative marker, the Ovarian Sensitivity Index (OSI: (number of retrieved oocytes/total gonadotropin dose) × 1000), assessing whether (a) it correlates with ovarian responsiveness biomarkers, (b) it is an independent predictor of clinical pregnancy, (c) it predicts clinical pregnancy comparably to the number of retrieved oocytes, and (d) it is consistent in the repeated COS cycles of the same woman. DESIGN: retrospective analysis. SETTING: public IVF Unit in University Hospital. Cases and Measurements: 1612 patients submitted to 3353 IVF cycles were included, their OSI was calculated and it was correlated with the ovarian responsiveness biomarkers (age, BMI, anti-Mullerian hormone, antral follicle count). The OSI and the total number of oocytes were compared for their value in predicting clinical pregnancy. The inter-cycle consistency of the OSI was estimated in 209 patients who underwent two consecutive cycles in which the ovarian stimulation regimen was changed from the Gonadotropin-releasing Hormone (GnRH)-agonist long protocol to the GnRH-antagonist protocol or vice-versa. RESULTS: The OSI turned out to be significantly related to age and BMI (inversely), the anti-Mullerian hormone (AMH) and the antral follicle count (AFC) (directly), to be an independent predictor of clinical pregnancy, and to correlate with clinical pregnancy better than the total number of oocytes (p < 0.0001 vs. <0.002). In patients who underwent two consecutive COS cycles changing stimulation regimen, the OSI showed 82% consistency. CONCLUSION(S): The OSI significantly correlates to the currently used biomarkers of ovarian responsiveness; it is an independent predictor of clinical pregnancy; it is more predictive of clinical pregnancy than the total number of oocytes, and is highly consistent in repeated IVF cycles even when the COS protocol changes. These characteristics make the OSI quite suitable to be incorporated into more complex prediction models of IVF outcome.

Morphokinetic analysis of cleavage stage embryos and assessment of specific gene expression in cumulus cells independently predict human embryo development to expanded blastocyst: a preliminary study.

To assess whether morphokinetic features at the cleavage stage together with specific gene expression in cumulus cells (CCs) may be used to predict whether human embryos are able to achieve the expanded blastocyst stage on day 5. Eighty-one embryos were cultured using the Geri plus® time-lapse system. Twenty-seven embryos progressing to the expanded blastocyst stage (BL group) were compared with thirty-five embryos showing developmental arrest (AR group) and nineteen reaching the stage of early or not fully expanded blastocyst (nBL group). The analyzed morphokinetic variables were pronuclear appearance (tPNa), pronuclear fading (tPNf), and completion of cleavage to two, three, four, and eight cells (t2, t3, t4, and t8). CCs were analyzed by RT-qPCR for bone morphogenetic protein 15 (BMP15), cytochrome c oxidase subunit II (COXII), ATP synthase subunit 6 (MT-ATP6), connexin 43 (Cx43), and heme oxygenase-1 (HO-1). Embryos of BL group showed a significantly faster kinetic. BMP15, COXII, and MT-ATP6 mRNA expression was significantly higher in CCs of BL group embryos, whereas Cx43 and HO-1 mRNA levels were higher in AR group. Kinetic parameters and gene expression were not significantly different between either the BL and nBL groups or the AR and nBL groups. ROC curves showed that the most predictive cut-offs were t2 < 26.25 for morphokinetics and COXII > 0.3 for gene expression. Multivariable logistic regression analysis showed that morphokinetic variables and gene expression were both valuable, independent predictors of embryo development to expanded blastocyst. Our results suggest the possibility of developing integrated prediction models for early embryo selection at the cleavage stage.

Impact of the addition of Early Embryo Viability Assessment to morphological evaluation on the accuracy of embryo selection on day 3 or day 5: a retrospective analysis.

In this study we aimed at retrospectively assessing in a homogeneous group of IVF patients whether the addition of Early Embryo Viability Assessment (Eeva™) to standard morphology increases the accuracy of embryo selection in case of double embryo transfer (DET) on day 3 or single embryo transfer (SET) on day 5. Eeva™ is an algorhythm aimed at indicating on day 3, according to morphokinetic parameters observed in the first three days of embryo growth, which embryos are more likely to develop into viable blastocysts and implant. A total number of 328 patients were included in the study; IVF or ICSI were performed and 428 embryos were transferred, either with DET on day 5, or (when at least four top scored embryos were available on day 3) with SET of day 5. Four groups were considered: (a) patients receiving day 3 DET with embryos selected by standard morphology (DET-3 M, n = 106, receiving 212 embryos), (b) patients receiving day 3 DET with embryos selected by morphology plus Eeva™ (DET-3 ME group, n = 48, receiving 96 embryos), (c) patients receiving day 5 SET with a blastocyst selected by standard morphology (SET-5 M group, n = 126, receiving 126 embryos), and (d) patients receiving day 5 SET with a blastocyst selected by morphology plus Eeva™ (SET-5 ME group, n = 48, receiving 48 embryos). Overall, a clinical pregnancy rate of 49.1%, implantation rate of 40%, and ongoing pregnancy rate of 43.6% were observed. The implantation rate was significantly higher in DET-3 ME group than in DET-3 M group (44.8% vs. 30.2%, p < 0.02), whereas it was comparable in groups DET-3 ME, SET-5 M and SET-5 ME. Differently, the ultrasound-verified clinical pregnancy rate and the ongoing pregnancy rate at 12 weeks did not significantly differ in all four groups. Overall, our findings suggest that Eeva™ algorhythm can improve embryo selection accuracy of standard morphology when ET on day 3 is scheduled, leading to a higher implantation rate, but its impact on ongoing pregnancy and live birth needs to be further clarified.