Erminia Alviggi

Bio: Erminia Alviggi is an academic researcher from University of Naples Federico II. The author has contributed to research in topics: Embryo transfer & Follicular phase. The author has an hindex of 10, co-authored 14 publications receiving 424 citations.

High outcome predictability after IVF using a combined score for zygote and embryo morphology and growth rate

Abstract: BACKGROUND: A scoring system has been developed to determine preimplantation embryo quality, and used to select embryos for transfer into the uterus of patients. METHODS AND RESULTS: The system was used to study early embryo development and to test whether these scores alone can accurately predict IVF outcome. Following zygote and embryo scores through early development, the data showed that a top quality zygote does not necessarily indicate that the resulting embryo will be top quality after in-vitro culture. The embryo quality score can change dramatically when embryos are cultured to day 2 or 3 post-fertilization. Pregnancy rates and implantation rates were compared with the cumulative and separated zygote and embryo scores. Analysis of the predictability of scoring systems suggested that morphological scores alone are relatively unpredictive of IVF outcome. When weighted for in-vitro growth rate, scores were highly predictive, more so than the rate of development alone. CONCLUSIONS: These data suggested that a combination of in-vitro growth rate and morphological analysis both of zygotes and embryos was highly indicative of outcome after IVF. The results can be adopted to the single embryo transfer approach to IVF.

Effects of recombinant LH (rLH) supplementation during controlled ovarian hyperstimulation (COH) in normogonadotrophic women with an initial inadequate response to recombinant FSH (rFSH) after pituitary downregulation.

Abstract: Summary background This study was aimed to evaluate the effect of different recombinant LH (rLH) doses on the ovarian outcome of normogonadotrophic women with an initial inadequate response to recombinant FSH (rFSH) after pituitary downregulation. methods Only women undergoing a ‘long protocol’ with a GnRH-agonist followed by rFSH administration were enrolled. On the eighth day of stimulation, 46 patients with serum E2 levels 10 mm were randomized in two groups to receive a supplementation with a daily rLH dose of 75 (group A) or 150 IU (group B), respectively. Forty-six normal responders continuing their monotherapy with rFSH formed the control group (C). results The mean number of oocytes retrieved and the percentage of mature oocytes in the group B (9·65 ± 2·16, 79·0%) were comparable with those observed in the group C (10·65 ± 2·8, 82·5%) and significantly higher when compared with the group A (6·39 ± 1·53, 65·7%). The mean number of ampoules of rLH was significantly higher in the group B (14·4 ± 2·0 vs. 9·65 ± 1·1), whereas these patients received a significantly lower mean number of rFSH ampoules (44·6 ± 7·4 vs. 36·1 ± 3·8). Seven (30·4%), 9 (39·1%) and 22 (47·8%) pregnancies were achieved in the groups A, B and C, respectively. conclusions These results suggest that patients with initial inadequate responses to rFSH after pituitary downregulation benefit from the addition of a daily dose of 150 IU of rLH, starting from the eighth day of stimulation.

Luteal phase anovulatory follicles result in the production of competent oocytes: intra-patient paired case-control study comparing follicular versus luteal phase stimulations in the same ovarian cycle.

Abstract: STUDY QUESTION Are the mean numbers of blastocysts obtained from sibling cohorts of oocytes recruited after follicular phase and luteal phase stimulations (FPS and LPS) in the same ovarian cycle similar? SUMMARY ANSWER The cohorts of oocytes obtained after LPS are larger than their paired-FPS-derived cohorts and show a comparable competence, thus resulting in a larger mean number of blastocysts. WHAT IS KNOWN ALREADY Three theories of follicle recruitment have been postulated to date: (i) the 'continuous recruitment' theory, (ii) the 'single recruitment episode' theory and (iii) the 'wave' theory. Yet, a clear characterization of this crucial biological process for human reproduction is missing. Recent advances implemented in in vitro fertilization (IVF), such as blastocyst culture, aneuploidy testing and vitrification, have encouraged clinicians to maximize the exploitation of the ovarian reserve through tailored stimulation protocols, which is crucial especially for poor prognosis patients aiming to conceive after IVF. LPS has been already successfully adopted to treat poor prognosis or oncological patients through Duostim, LPS-only or random-start ovarian stimulation approaches. Nevertheless, little, and mainly retrospective, evidence has been produced to support the safety of LPS in general. Feasibility of the LPS approach would severely question the classic 'single recruitment episode' theory of follicular development. STUDY DESIGN, SIZE, DURATION This case-control study was conducted with paired follicular phase- and luteal phase-derived cohorts of oocytes collected after stimulations in the same ovarian cycle (DuoStim) at two private IVF clinics between October 2015 and December 2017. PARTICIPANTS/MATERIALS, SETTING, METHODS The study included 188 poor prognosis patients undergoing DuoStim with preimplantation genetic testing for aneuploidies (PGT-A). FPS and LPS were performed with the same daily dose of recombinant-gonadotrophins in an antagonist protocol. Blastocyst culture, trophectoderm biopsy, vitrification and frozen-warmed euploid single blastocyst transfers were performed. The primary outcome was the mean number of blastocysts obtained per oocyte retrieval from paired-FPS- and LPS-derived cohorts (required sample size = 165 patients; power = 90%). Mean blastulation and euploidy rates were monitored, along with the number of oocytes, euploid blastocysts and clinical outcomes. MAIN RESULTS AND THE ROLE OF CHANCE Significantly fewer blastocysts were obtained after FPS than LPS (1.2 ± 1.1 vs. 1.6 ± 1.6, P 22 weeks) between FPS- and LPS-derived euploid blastocysts, that need to be extended in the future, to populations other than poor prognosis patients and using approaches other than DuoStim together with a constant monitoring of the related peri-natal and post-natal outcomes. WIDER IMPLICATIONS OF THE FINDINGS These data, from a paired study design, highlight that LPS-derived oocytes are as competent as FPS-derived oocytes, thereby adding some evidence to support the use of LPS for poor prognosis and oncological patients and to question the 'single recruitment episode' theory of follicle recruitment. These findings also encourage additional studies of the basics of folliculogenesis, with direct clinical implications for the management of ovarian stimulation in IVF. TRIAL REGISTRATION None. STUDY FUNDING/COMPETING INTEREST(S) No external funds were used for this study and there are no conflicts of interest.

Intra-follicular leptin concentration as a predictive factor for in vitro oocyte fertilization in assisted reproductive techniques

Abstract: Background: Granulosa-cells are able to produce and store leptin, suggesting that this hormone is locally involved in the regulation of follicular growth. In this study, the role of follicular fluid (FF) leptin concentration in predicting oocyte fertilization and embryo quality was evaluated in 35 normogonadotrophic women undergoing controlled ovarian stimulation (COS) for assisted reproductive techniques. Materials and Methods: Leptin concentration was measured in 47 consecutively collected FF in which a mature oocyte had been found during the ovum pick-up. Embryos deriving from fertilized oocytes were submitted to quality scoring systems. Results: Mean leptin concentration was significantly higher in FF whose oocytes showed 2 pronuclei (no. 25) when compared with those with no evidence of fertilization (no. 22) at the 16–18 h check (26.0±6.1 vs 15.3±10.6 ng/ml, respectively, p<0.01). Follicular mean diameters were similar in the two groups (21.4±3.4 and 21.0±5.1 mm, respectively). Logistic regression analysis identified FF leptin levels as the best predictive parameter for oocyte fertilization (p<0.001). When receiving operating characteristics curve was employed, a FF leptin concentration of 20.25 ng/ml was the most reliable cut-off in predicting fertilization of oocytes. FF with leptin concentrations higher than this value (no. 27) had an oocyte fertilization rate of 85.7%. In contrast, FF levels ≤20.25 ng/ml (no. 20) were associated with a rate of 16.7% (p<0.05). No correlation emerged between FF leptin and the score attributed to 15 valuable embryos at the zygote stage (r=−0.01) and at 48 h after insemination (r=0.1). Conclusions: FF leptin levels are a better predictor of oocyte fertilization success rates than follicular diameter. These results underline the relevance of FF variables in developing methods for oocyte selection.

Cleavage stage versus blastocyst stage embryo transfer in assisted reproductive technology

Abstract: Background Advances in cell culture media have led to a shift in in vitro fertilisation (IVF) practice from cleavage stage embryo transfer to blastocyst stage transfer. The rationale for blastocyst transfer is to improve both uterine and embryonic synchronicity and enable self selection of viable embryos, thus resulting in better live birth rates. Objectives To determine whether blastocyst stage (day 5 to 6) embryo transfers improve the live birth rate, and other associated outcomes, compared with cleavage stage (day 2 to 3) embryo transfers. Search methods We searched the Cochrane Gynaecology and Fertility Group Specialised Register of controlled trials, Cochrane Central Register of Controlled Trials (CENTRAL; the Cochrane Library; 2016, Issue 4), MEDLINE, EMBASE, PsycINFO, CINAHL, and Bio extracts from inception to 4th April 2016. We also searched registers of ongoing trials and the reference lists of studies retrieved. Selection criteria We included randomised controlled trials (RCTs) which compared the effectiveness of blastocyst versus cleavage stage transfers. Data collection and analysis We used standard methodological procedures recommended by Cochrane. Our primary outcomes were live birth and cumulative clinical pregnancy rates. Secondary outcomes were clinical pregnancy, multiple pregnancy, high order pregnancy, miscarriage, failure to transfer embryos, and embryo freezing. We assessed the overall quality of the evidence for the main comparisons using GRADE methods. Main results We included 27 RCTs (4031 couples or women). The live birth rate following fresh transfer was higher in the blastocyst transfer group (odds ratio (OR) 1.48, 95% confidence interval (CI) 1.20 to 1.82; 13 RCTs, 1630 women, I2 = 45%, low quality evidence) following fresh transfer. This suggests that if 29% of women achieve live birth after fresh cleavage stage transfer, between 32% and 42% would do so after fresh blastocyst stage transfer. There was no evidence of a difference between the groups in rates per couple of cumulative pregnancy following fresh and frozen-thawed transfer after one oocyte retrieval (OR 0.89, 95% CI 0.64 to 1.22; 5 RCTs, 632 women, I2 = 71%, very low quality evidence). The clinical pregnancy rate was also higher in the blastocyst transfer group, following fresh transfer (OR 1.30, 95% CI 1.14 to 1.47; 27 RCTs, 4031 women, I2 = 56%, moderate quality evidence). This suggests that if 36% of women achieve clinical pregnancy after fresh cleavage stage transfer, between 39% and 46% would do so after fresh blastocyst stage transfer. There was no evidence of a difference between the groups in rates of multiple pregnancy (OR 1.05, 95% CI 0.83 to 1.33; 19 RCTs, 3019 women, I2 = 30%, low quality evidence), or miscarriage (OR 1.15, 95% CI 0.88 to 1.50; 18 RCTs, 2917 women, I2 = 0%, low quality evidence). These data are incomplete as under 70% of studies reported these outcomes. Embryo freezing rates were lower in the blastocyst transfer group (OR 0.48, 95% CI 0.40 to 0.57; 14 RCTs, 2292 women, I2 = 84%, low quality evidence). This suggests that if 60% of women have embryos frozen after cleavage stage transfer, between 37% and 46% would do so after blastocyst stage transfer. Failure to transfer any embryos was higher in the blastocyst transfer group (OR 2.50, 95% CI 1.76 to 3.55; 17 RCTs, 2577 women, I2 = 36%, moderate quality evidence). This suggests that if 1% of women have no embryos transferred in (planned) fresh cleavage stage transfer, between 2% and 4% will have no embryos transferred in (planned) fresh blastocyst stage transfer. The evidence was of low quality for most outcomes. The main limitation was serious risk of bias, associated with failure to describe acceptable methods of randomisation, and unclear or high risk of attrition bias. Authors' conclusions There is low quality evidence for live birth and moderate quality evidence for clinical pregnancy that fresh blastocyst stage transfer is associated with higher rates than fresh cleavage stage transfer. There was no evidence of a difference between the groups in cumulative pregnancy rates derived from fresh and frozen-thawed cycles following a single oocyte retrieval, but the evidence for this outcome was very low quality. Thus, although there is a benefit favouring blastocyst transfer in fresh cycles, it remains unclear whether the day of transfer impacts on cumulative live birth and pregnancy rates. Future RCTs should report rates of live birth, cumulative live birth, and miscarriage to enable couples or women undergoing assisted reproductive technology (ART) and service providers to make well informed decisions on the best treatment option available.

Follicular fluid content and oocyte quality: from single biochemical markers to metabolomics.

Abstract: The assessment of oocyte quality in human in vitro fertilization (IVF) is getting increasing attention from embryologists. Oocyte selection and the identification of the best oocytes, in fact, would help to limit embryo overproduction and to improve the results of oocyte cryostorage programs. Follicular fluid (FF) is easily available during oocyte pick-up and theorically represents an optimal source on non-invasive biochemical predictors of oocyte quality. Unfortunately, however, the studies aiming to find a good molecular predictor of oocyte quality in FF were not able to identify substances that could be used as reliable markers of oocyte competence to fertilization, embryo development and pregnancy. In the last years, a well definite trend toward passing from the research of single molecular markers to more complex techniques that study all metabolites of FF has been observed. The metabolomic approach is a powerful tool to study biochemical predictors of oocyte quality in FF, but its application in this area is still at the beginning. This review provides an overview of the current knowledge about the biochemical predictors of oocyte quality in FF, describing both the results coming from studies on single biochemical markers and those deriving from the most recent studies of metabolomics

Extra- and intra-ovarian factors in polycystic ovary syndrome: impact on oocyte maturation and embryo developmental competence

Abstract: BACKGROUND Polycystic ovary syndrome (PCOS) is a common metabolic dysfunction and heterogeneous endocrine disorder in women of reproductive age. Although patients with PCOS are typically characterized by increased numbers of oocytes retrieved during IVF, they are often of poor quality, leading to lower fertilization, cleavage and implantation rates, and a higher miscarriage rate. METHODS For this review, we searched the database MEDLINE (1950 to January 2010) and Google for all full texts and/or abstract articles published in English with content related to oocyte maturation and embryo developmental competence. RESULTS The search showed that alteration of many factors may directly or indirectly impair the competence of maturating oocytes through endocrine and local paracrine/autocrine actions, resulting in a lower pregnancy rate in patients with PCOS. The extra-ovarian factors identified included gonadotrophins, hyperandrogenemia and hyperinsulinemia, although intra-ovarian factors included members of the epidermal, fibroblast, insulin-like and neurotrophin families of growth factors, as well as the cytokines. CONCLUSIONS Any abnormality in the extra- and/or intra-ovarian factors may negatively affect the granulosa cell-oocyte interaction, oocyte maturation and potential embryonic developmental competence, contributing to unsuccessful outcomes for patients with PCOS who are undergoing assisted reproduction.

Interventions for 'poor responders' to controlled ovarian hyper stimulation (COH) in in-vitro fertilisation (IVF).

Abstract: Background The success of in-vitro fertilisation (IVF) treatment depends on adequate follicle recruitment by using controlled ovarian stimulation with gonadotrophins. Failure to recruit adequate follicles is called 'poor response'. Various treatment protocols have been proposed that are targeted at this cohort of women, aiming to increase their ovarian response. Objectives To compare the effectiveness of different treatment interventions in women who have poor response to controlled ovarian hyperstimulation (are poor responders) in the context of in vitro fertilisation. Search strategy We searched the Cochrane Menstrual Disorders and Subfertility Group Specialised Register of controlled trials (MDSG), the Cochrane Central Register of Controlled trials (CENTRAL) (The Cochrane Library 2003, Issue 1), MEDLINE (1966 to August 2006), EMBASE (1980 to August 2006) and The National Research Register (NRR). The citation lists of relevant publications, review articles, abstracts of scientific meetings and included studies were also searched. The authors were contacted to identify or clarify data that were unclear from the trial reports. Selection criteria Only randomised controlled trials (RCTs) comparing one type of intervention versus another for controlled ovarian stimulation of poor responders to a previous IVF treatment, using a standard long protocol were included. Data collection and analysis Two review authors independently scanned the abstracts, identified relevant papers, assessed inclusion and trial quality and extracted relevant data. Validity was assessed in terms of method of randomisation, completeness of treatment cycle and co-intervention. Where possible, data were pooled for analysis. Main results Nine trials involving six different comparison groups have been included in this review. Only one trial reported live birth rates. Four groups compared the long protocol with another intervention. Only one comparison group (bromocryptine versus long protocol) reported a higher clinical pregnancy rate per cycle, in the bromocryptine arm (OR 5.60, 95% CI 1.40 to 22.47). Two comparison groups showed a lower number of oocytes in the long protocol group (versus stop and gonadotrophin releasing hormone (GnRH) antagonist protocols). However, two comparison groups also showed lower cancellation rates in the long protocol treatment group (versus stop and GnRHa flare-up protocols). None reported any evident difference in the adverse effects. Authors' conclusions There is insufficient evidence to support the routine use of any particular intervention either for pituitary downregulation, ovarian stimulation or adjuvant therapy in the management of poor responders to controlled ovarian stimulation in IVF. More robust data from good quality RCTs with relevant outcomes are needed.

Impact of Maternal Age on Oocyte and Embryo Competence

Abstract: The overall success of human reproduction, either spontaneously or after IVF, is highly dependent upon maternal age. The main reasons for age-related infertility include reduced ovarian reserve and decreased oocyte/embryo competence due to aging insults, especially concerning an increased incidence of aneuploidies and possibly decreased mitochondrial activity. Age-related chromosomal abnormalities mainly arise because of meiotic impairments during oogenesis, following flawed chromosome segregation patterns such as non-disjunction, premature separation of sister chromatids, or the recent reverse segregation. In this review, we briefly discuss the main mechanisms putatively impaired by aging in the oocytes and the deriving embryos. We also report the main strategies proposed to improve the management of advanced maternal age women in IVF: fertility preservation through oocyte cryopreservation to prevent aging; optimization of the ovarian stimulation and enhancement of embryo selection to limit its effects; and oocyte donation to circumvent its consequences.