Too many embryos: a critical perspective on a global challenge.

Over the past decade, significant endeavors have been directed toward establishing an optimal oocyte number to maximize the chances for successful in vitro fertilization outcomes. The effectiveness of assisted reproductive technologies has greatly improved, and more good-quality embryos are being created in each cycle. However, many of these embryos remain unused. Notably, in Europe, approximately one-third of couples did not use their surplus cryopreserved embryos. Surplus embryos pose a challenge for patients and clinics. Embryo disposal practices are not the same all over the continent, with embryo donation and embryo discharge not allowed in several countries. In this scenario, limiting the number of surplus embryos by reducing the number of inseminated oocytes, according to couple clinical history, could be a strategy.

Delphi Initiative for Early-Onset Colorectal Cancer (DIRECt) International Management Guidelines.

BACKGROUND & AIMS: Patients with early-onset colorectal cancer (eoCRC) are managed according to guidelines that are not age-specific. A multidisciplinary international group (DIRECt), composed of 69 experts, was convened to develop the first evidence-based consensus recommendations for eoCRC. METHODS: After reviewing the published literature, a Delphi methodology was used to draft and respond to clinically relevant questions. Each statement underwent 3 rounds of voting and reached a consensus level of agreement of ≥80%. RESULTS: The DIRECt group produced 31 statements in 7 areas of interest: diagnosis, risk factors, genetics, pathology-oncology, endoscopy, therapy, and supportive care. There was strong consensus that all individuals younger than 50 should undergo CRC risk stratification and prompt symptom assessment. All newly diagnosed eoCRC patients should receive germline genetic testing, ideally before surgery. On the basis of current evidence, endoscopic, surgical, and oncologic treatment of eoCRC should not differ from later-onset CRC, except for individuals with pathogenic or likely pathogenic germline variants. The evidence on chemotherapy is not sufficient to recommend changes to established therapeutic protocols. Fertility preservation and sexual health are important to address in eoCRC survivors. The DIRECt group highlighted areas with knowledge gaps that should be prioritized in future research efforts, including age at first screening for the general population, use of fecal immunochemical tests, chemotherapy, endoscopic therapy, and post-treatment surveillance for eoCRC patients. CONCLUSIONS: The DIRECt group produced the first consensus recommendations on eoCRC. All statements should be considered together with the accompanying comments and literature reviews. We highlighted areas where research should be prioritized. These guidelines represent a useful tool for clinicians caring for patients with eoCRC.

The first mitotic division: a perilous bridge connecting the zygote and the early embryo.

Human embryos are very frequently affected by maternally inherited aneuploidies, which in the vast majority of cases determine developmental failure at pre- or post-implantation stages. However, recent evidence, generated by the alliance between diverse technologies now routinely employed in the IVF laboratory, has revealed a broader, more complex scenario. Aberrant patterns occurring at the cellular or molecular level can impact at multiple stages of the trajectory of development to blastocyst. In this context, fertilization is an extremely delicate phase, as it marks the transition between gametic and embryonic life. Centrosomes, essential for mitosis, are assembled ex novo from components of both parents. Very large and initially distant nuclei (the pronuclei) are brought together and positioned centrally. The overall cell arrangement is converted from being asymmetric to symmetric. The maternal and paternal chromosome sets, initially separate and scattered within their respective pronuclei, become clustered where the pronuclei juxtapose, to facilitate their assembly in the mitotic spindle. The meiotic spindle is replaced by a segregation machinery that may form as a transient or persistent dual mitotic spindle. Maternal proteins assist the decay of maternal mRNAs to allow the translation of newly synthesized zygotic transcripts. The diversity and complexity of these events, regulated in a precise temporal order and occurring in narrow time windows, make fertilization a highly error-prone process. As a consequence, at the first mitotic division, cellular or genomic integrity may be lost, with fatal consequences for embryonic development.

Fertility specialists' views, behavior, and attitudes towards the use of endometrial scratching in Italy.

BACKGROUND: Endometrial scratching (ES) or injury is intentional damage to the endometrium performed to improve reproductive outcomes for infertile women desiring pregnancy. Moreover, recent systematic reviews with meta-analyses and randomized controlled trials demonstrated that ES is not effective, data on the safety are limited, and it should not be recommended in clinical practice. The aim of the current study was to assess the view and behavior towards ES among fertility specialists throughout infertility centers in Italy, and the relationship between these views and the attitudes towards the use of ES as an add-on in their commercial setting. METHODS: Online survey among infertility centers, affiliated to Italian Society of Human Reproduction (SIRU), was performed using a detailed questionnaire including 45 questions with the possibility to give "closed" multi-choice answers for 41 items and "open" answers for 4 items. Online data from the websites of the infertility centers resulting in affiliation with the specialists were also recorded and analyzed. The quality of information about ES given on infertility centers websites was assessed using a scoring matrix including 10 specific questions (scored from 0 to 2 points), and the possible scores ranged from 0 to 13 points ('excellent' if the score was 9 points or more, 'moderate' if the score was between 5 and 8, and 'poor' if it was 4 points or less). RESULTS: The response rate was of 60.6% (43 questionnaires / 71 infertility SIRU-affiliated centers). All included questionnaires were completed in their entirety. Most physicians (~ 70%) reported to offer ES to less than 10% of their patients. The procedure is mainly performed in the secretory phase (69.2%) using pipelle (61.5%), and usually in medical ambulatory (56.4%) before IVF cycles to improve implantation (71.8%) without drugs administration (e.g., pain drugs, antibiotics, anti-hemorrhagics, or others) before (76.8%) or after (64.1%) the procedure. Only a little proportion of infertility centers included in the analysis proposes formally the ES as an add-on procedure (9.3%), even if, when proposed, the full description of the indications, efficacy, safety, and costs is never addressed. However, the overall information quality of the websites was generally "poor" ranging from 3 to 8 and having a low total score (4.7 ± 1.6; mean ± standard deviation). CONCLUSIONS: In Italy, ES is a procedure still performed among fertility specialists for improving the implantation rate in IVF patients. Moreover, they have a poor attitude in proposing ES as an add-on in the commercial setting.

Delayed blastocyst development is influenced by the level of progesterone on the day of trigger.

PURPOSE: To evaluate the association between progesterone (P) level on the day of trigger and time to blastulation in IVF cycles. METHODS: This was a retrospective cohort study with autologous IVF cycles performed at our Institution from January 2019 to December 2021. A total of 1109 IVF cycles were included. The primary outcome was to compare time to blastulation in terms of percentage of expanded (grade 3) blastocysts on day 5 according to progesterone level at trigger. RESULTS: A total of 3517 blastocysts were analyzed. After dividing progesterone level in quartiles (Q1, P < 0.50 ng/ml; Q2 0.50 ng/ml ≤ P ≤ 0.78 ng/ml; Q3, 0.79 ng/ml ≤ P ≤ 1.15 ng/ml; Q4, P > 1.15 ng/ml), we observed a delay in blastocyst development according to the increasing level of progesterone at trigger (analysis by rank, P-value = 0.01). After adjusting for confounding factors at the multivariate analysis, the percentage of day 5 blastocysts was reduced for Q3 (- 13.8%, 95% CI from - 20.5 to - 7.0%, p < 0.001) and Q4 (- 7.7%, 95% CI from - 15.5 to 0.0%, p = 0.05) compared to Q1 (reference). CONCLUSIONS: Progesterone levels on day of trigger correlate to the percentage of expanded (grade 3) blastocysts on day 5 and a delayed blastocyst development day 5 is expected for high progesterone levels.

Progesterone levels during ovarian stimulation in segmented ART cycles inversely correlate with normalized birthweight of neonates conceived through subsequent frozen-thawed embryo transfer.

PURPOSE: To evaluate the association between serum progesterone (P) at the day of ovulation trigger and neonatal birthweight in singletons born after frozen-thawed embryo transfer in segmented ART cycles. METHODS: A retrospective multicenter cohort study involving data from patients who achieved uncomplicated pregnancy and term delivery of ART-conceived singleton babies following a segmented GnRH antagonist cycle. The main outcome was birthweight's z-score of the neonate. Univariate and multivariate linear logistic regression analyses were made to investigate the relation of z-score with variables inherent to the patient and to the ovarian stimulation. The variable P per oocyte was created by dividing the value of progesterone at ovulation trigger by the number of oocytes retrieved at oocyte retrieval. RESULTS: A total of 368 patients were included in the analysis. At univariate linear regression, the birthweight z-score of the neonate appeared to be inversely related to both P levels at the ovulation trigger (- 0.101, p = 0.015) and P levels per oocyte at trigger (- 1.417, p = 0.001), while it was directly related to the height of the mother (0.026, p = 0.002) and to the number of previous live births (0.291, p = 0.016). In multivariate analysis, both serum P (- 0.1; p = 0.015) and P per oocyte (- 1.347, p = 0.002) maintained the significant inverse association with birthweight z-score after adjusting for height and parity. CONCLUSIONS: Serum progesterone level on the day of ovulation trigger inversely correlates with normalized birthweight of neonates in segmented GnRH antagonist ART cycles.

The effect of vitrified-warmed blastocyst transfer on postnatal growth: a 1-year follow-up questionnaire study.

RESEARCH QUESTION: Is postnatal growth of singletons aged 12 months born after vitrified-warmed blastocyst transfer (frozen embryo transfer [FET]) different from children born after fresh blastocyst transfer? DESIGN: A retrospective cohort study conducted at a single university-affiliated obstetrics and fertility centre between 2014 and 2016. Women who underwent fresh transfer or FET at blastocyst stage and obtained a singleton live birth were included. Propensity score inverse probability weighting was used to balance baseline maternal characteristics between fresh and FET cycles. RESULTS: Of the 382 women with singleton live births, 124 underwent a fresh blastocyst transfer and 258 underwent a FET. Significantly higher birth weight and length z-scores were observed after FET (P = 0.01 and P = 0.002, respectively) compared with the fresh transfer group. At 12 months of age, the fresh and FET groups showed no significant effect on the weight z-score, but the FET was associated with a higher height z-score (P = 0.001) compared with fresh blastocyst transfer. The comparison between males and females from the same study group showed higher birth weight z-score for males in the FET group (P < 0.001). During the first 12 months, however, males in the FET group showed a slower growth trajectory in terms of weight (P = 0.007). CONCLUSIONS: At 12 months of postnatal life, an increased height and sex-dependent differences in growth trajectories were observed in singletons born after FET compared with those born after fresh embryo transfer.

Anti-Müllerian hormone concentration as an indicator of female general health status: a cross-sectional study.

RESEARCH QUESTION: To evaluate the correlation between clinical and hormonal parameters and comorbidity burden in Caucasian women presenting for fertility treatment. DESIGN: Monocentric cross-sectional study including a cohort of 3163 Caucasian women seeking medical care for fertility treatment. All patients underwent centralized laboratory testing for hormonal assessment. Complete clinical and laboratory data from the entire cohort were retrospectively analysed. Comorbidity burden score was assessed by the Charlson Comorbidity Index (CCI; categorized as 0 versus 1 versus ≥2). RESULTS: Descriptive statistics and regression models tested the associations between clinical and laboratory parameters and CCI. Among the entire cohort of patients, a CCI = 0 was found in 2977 women (94.1%), and CCI = 1 and CCI ≥2 were found in 113 (3.6%) and 73 (2.3%) patients, respectively. Age (P = 0.009), gravidity (P = 0.001), anti-Müllerian hormone (AMH, P < 0.001) and TSH (P = 0.003) values were significantly different among CCI groups. In regression models, age at presentation and AMH emerged as independent indicators of CCI ≥ 1. Age at presentation <36 years (odds ratio [OR] 1.742, 95% confidence interval [CI] 1.284-2.364) and an AMH concentration ≤2.3 ng/ml (OR 1.864, 95% CI 1.29-2.69) were the most informative cut-off values for CCI ≥ 1 in the study population. CONCLUSIONS: A younger age at presentation and lower AMH concentrations are significant independent indicators of decreased general health in women requiring clinical evaluation for fertility treatment. As observed for sperm parameters in men, AMH might serve as a proxy of women's general health status.

Ovarian failure risk in post-pubertal patients with cancer: a prognostic model.

Aim: To develop a predictive model for ovarian failure (OF) after chemotherapy in young post-pubertal women with cancer. Methods: Retrospective, monocentric cohort study including 348 patients referring to the Oncofertility Unit of San Raffaele Hospital (Milan, Italy) from August 2011 to January 2020. A predictive model was constructed by multivariate logistic regression and receiver operating characteristic analysis. Results: Data about menstrual function resumption were available for 184 patients. The best predictive model for OF was identified by the combination of age; number of chemotherapy lines; vincristine, adriamycin, ifosphamide/adriamycin, ifosphamide; capecitabine; adriamycin, bleomycine, vinblastine, doxorubicin (area under the curve = 0.906; CI 95% 0.858-0.954; p = 0.0001). Conclusions: The model predicts the probability of loss of ovarian function at cancer diagnosis and with every change of treatment.

Chemotherapy can reduce fertility in young women surviving cancer. The effects of chemotherapy on ovarian function range from no damage to several degrees of reduced fertility. In some cases, premature menopause can occur. This variability depends on many different individual and treatment-related factors. In this study, we analyzed the outcomes in terms of menses regularity and fertility of 348 oncological patients receiving counseling on fertility at our unit from August 2011 to January 2020. We developed a predictive model to estimate the risk of premature menopause of each patient, to be used at diagnosis and every time a new treatment must be started. This model includes a combination of patient's age, number of lines of chemotherapeutic treatment, and three chemotherapy schedules commonly used in young patients with cancer. It allows an improved counseling on fertility, and it can aid decision making regarding fertility preservation strategies for each patient.

A prospective, observational study of chemotherapy-induced ovarian damage on follicular reserve and maturation.

BACKGROUND: Chemotherapy negatively affects gonadal function, often resulting in premature ovarian failure (POF) due to ovarian reserve depletion. Mechanisms of gonadotoxicity, such as primordial follicle overactivation and "burnout", remain to be established. Ovarian tissue cryopreservation (OTC) before treatment plays an important role in safeguarding fertility. METHODS: This is a prospective observational study that aims to evaluate the feasibility of OTC after chemotherapeutic treatment initiation. Patients were divided into 2 groups depending on whether they received chemotherapy before the harvesting procedure (Group 1) or not (Group 2). The main outcomes of this study are serum anti-Mullerian hormone (AMH) levels and histological follicular counts on ovarian tissue biopsies. RESULTS: Between 2012 and 2020, 79 patients underwent OTC at our Hospital. Follicular counts from the ovarian biopsies of 30 post-pubertal patients and respective serum AMH levels were included in the analysis. AMH levels did not significantly differ between the 2 groups (P = 0.70) as well as the number of primordial follicles (P = 0.73). Ovarian biopsies of patients from Group 1 showed a higher number of primary follicles (P = 0.04) and atretic follicles (P = 0.05) with respect to Group 2. CONCLUSIONS: In conclusion, OTC appears to be feasible even after the start of chemotherapeutic treatment, since in treated patients, the main ovarian reserve indicators (number of primordial follicles and serum AMH levels) were not significantly reduced compared to untreated patients. The "burnout" theory of chemotherapeutic damage to the ovary seems to be supported by the higher number of primary follicles found in the ovaries of patients who received chemotherapy before OTC.

Clinical outcomes of potential high responders after individualized FSH dosing based on anti-Müllerian hormone and body weight.

RESEARCH QUESTION: How does the efficacy and safety of individualized follitropin delta dosing compare with conventional dosing for ovarian stimulation in potential high responders? DESIGN: Retrospective analysis of 153 potential high responders identified on the basis of baseline serum anti-Müllerian hormone (AMH) levels above 35 pmol/l, who were originally randomized to an individualized fixed dose of follitropin delta based on AMH and body weight (n = 78) or to a daily starting dose of 150 IU follitropin alfa (n = 75). RESULTS: At the end of stimulation, patients treated with individualized follitropin delta or conventional follitropin alfa had 12.1 ± 7.0 and 18.3 ± 7.0 (P < 0.001) follicles measuring 12 mm or wider, and 27.3% and 62.7% had serum progesterone levels higher than 3.18 nmol/l (P < 0.001), respectively. Overall number of oocytes in these two respective arms was 9.3 ± 6.7 and 17.9 ± 8.7 (P < 0.001), and the ongoing pregnancy rate per started cycle after fresh blastocyst transfer was 28.2% and 24.0%. The risk of ovarian hyperstimulation syndrome (OHSS) for all cases was three times higher in the conventional follitropin alfa arm at 16.0% versus 5.1% with individualized follitropin delta treatment (P = 0.025) and 26.7% versus 7.7% (P = 0.001) for early moderate or severe OHSS, preventive interventions for early OHSS, or both. CONCLUSIONS: Treatment with individualized follitropin delta provides an improved efficacy-safety balance in women with high ovarian reserve, as it normalizes the ovarian response and decreases the risk of OHSS without compromising the chance of pregnancy.

Levonorgestrel-releasing intrauterine system versus oral medroxyprogesterone acetate in infertile women with endometrial hyperplasia without atypia.

RESEARCH QUESTION: How does use of a levonorgestrel-releasing intrauterine system (LNG-IUS) in infertile women with endometrial hyperplasia without atypia affect endometrial hyperplasia regression and pregnancy rates compared with oral medroxyprogesterone acetate (MPA)? DESIGN: This prospective cohort study included 215 infertile women with an indication for assisted reproductive technology (ART) and a diagnosis of endometrial hyperplasia without atypia. Endometrial hyperplasia was diagnosed by hysteroscopic endometrial biopsy. At the time of first- and second-line treatment, patients were offered therapy with either oral MPA 10 mg daily or LNG-IUS. Follow-up biopsies were scheduled after 90 days' treatment. After endometrial hyperplasia regression, patients were admitted to IVF/intracytoplasmic sperm injection (ICSI) cycles. RESULTS: Baseline characteristics and confounders including age at diagnosis, body mass index and duration of infertility did not differ between LNG-IUS users and control participants and were accounted for using propensity score weighting. Endometrial hyperplasia regression rate at first follow-up was higher in the LNG-IUS group than the oral progestins group (28/28, 100% and 110/187, 58.8%; P < 0.001), while that after second-line treatment was comparable between the two groups (89/91, 97.8% and 122/124, 98.4%; P = 0.22). Clinical pregnancy rate, miscarriage rate and cumulative live birth rate following ART in patients ever receiving LNG-IUS were similar to those of patients receiving only MPA (34% versus 39.5%, 22.6% versus 34.7% and 26.4% versus 25.8%). CONCLUSION: Endometrial hyperplasia regression is greater in women receiving LNG-IUS compared with oral MPA, while live birth rates following ART are comparable between the two groups. The use of LNG-IUS does not jeopardize the chances of pregnancy in women seeking fertility treatment.

Single oral dose of vitamin D3 supplementation prior to in vitro fertilization and embryo transfer in normal weight women: the SUNDRO randomized controlled trial.

BACKGROUND: Improving in vitro fertilization success is an unmet need. Observational studies have suggested that women with deficient or insufficient vitamin D have lower chances of in vitro fertilization success, but whether supplementation improves clinical pregnancy rate remains unclear. OBJECTIVE: This study aimed to determine whether oral vitamin D3 supplementation improves clinical pregnancy in women undergoing an in vitro fertilization cycle. STUDY DESIGN: The "supplementation of vitamin D and reproductive outcome" trial is a 2-center randomized superiority double-blind placebo-controlled trial. Subjects were recruited between October 2016 and January 2019. Participants were women aged 18 to 39 years with low vitamin D (peripheral 25-hydroxyvitamin D of <30 ng/mL), serum calcium of ≥10.6 mg/dL, body mass index of 18 to 25 kg/m2, and antimüllerian hormone levels of >0.5 ng/mL and starting their first, second, or third treatment cycle of conventional in vitro fertilization or intracytoplasmic sperm injection. The primary outcome was the cumulative clinical pregnancy rate per cycle. Pregnancies obtained with both fresh or frozen embryo transfers were included. Clinical pregnancy was defined as an intrauterine gestational sac with a viable fetus. The primary analysis was performed according to the intention-to-treat principle and could also include natural conceptions. Secondary outcomes included total dose of gonadotropins used, embryologic variables (number of oocytes retrieved, number of suitable oocytes retrieved, fertilization rate, and rate of top-quality embryos), and clinical outcomes (miscarriage rate and live birth rate). RESULTS: Overall, 630 women were randomized 2 to 12 weeks before the initiation of the in vitro fertilization cycle to receive either a single dose of 600,000 IU of vitamin D3 (n=308) or placebo (n=322). Interestingly, 113 (37%) and 130 (40%) women achieved a clinical pregnancy in the treatment and placebo groups, respectively (P=.37). The risk ratio of clinical pregnancy in women receiving vitamin D3 was 0.91 (95% confidence interval, 0.75-1.11). Compared with the placebo, vitamin D3 supplementation did not improve the rate of clinical pregnancy. Exploratory subgroup analyses for body mass index, age, indication to in vitro fertilization, ovarian reserve, interval between drug administration and initiation of the cycle, and basal levels of 25-hydroxyvitamin D failed to highlight any clinical situation that could benefit from the supplementation. CONCLUSION: In women with normal weight with preserved ovarian reserve and low vitamin D levels undergoing in vitro fertilization cycles, a single oral dose of 600,000 IU of vitamin D3 did not improve the rate of clinical pregnancy. Although the findings do not support the use of vitamin D3 supplementation to improve in vitro fertilization success rates, further studies are required to rule out milder but potentially interesting benefits and explore the effectiveness of alternative modalities of supplementation.

Normal sperm parameters per se do not reliably account for fertility: A case-control study in the real-life setting.

A proportion of men are infertile despite having normal medical history/physical examination and normal semen analysis. We aimed to assess whether normal sperm parameters per se account for male factor fertility. 1,957 infertile men were compared with 103 age-comparable fertile controls. Semen analysis was based on 2010 World Health Organization reference criteria. Of all, 12.1% of infertile men and 40.8% of fertile men presented with normal sperm parameters. Among fertile men, 36.9% had isolated sperm abnormalities and 22.3% men showed two or more concomitant sperm abnormalities. Serum total testosterone was higher in infertile men with normal sperm parameters compared to those with ≥2 sperm abnormalities or azoospermia, but similar to those with isolated sperm abnormalities (p ≤ .001). Circulating hormones were similar among sperm parameters groups in fertile men. At multivariable analyses, testicular volume (OR 1.12, p ≤ .001) and FSH (OR 0.8, p ≤ .001) were associated with normal sperm parameters. Overall, the longer the infertility period, the greater the number of sperm parameters abnormalities (p < .01). In conclusion, we found that 12% of infertile men and only 41% of fertile men present with normal sperm parameters. Normal sperm parameters per se do not reliably account for fertility in the real-life setting.

Shooting STAR: reinterpreting the data from the 'Single Embryo TrAnsfeR of Euploid Embryo' randomized clinical trial.

Preimplantation genetic testing for aneuploidy (PGT-A) still remains controversial in clinical practice. Recently, the randomized controlled trial, 'Single Embryo TrAnsfeR of Euploid Embryo' (STAR) by Munné and coworkers showed a similar live birth rate per intention to treat in the two study groups (PGT-A and controls). A wrong diagnosis and/or biopsy-related damage to the embryo might underlie these results. To assess the impact of these factors on the efficiency of PGT-A, the live birth rate of 'euploid' embryos transferred in the PGT-A group was compared with its ideal value, namely the live birth rate of embryos with the potential to implant and to give rise to a baby in the control group. This estimate has been derived using the results of the genetic testing reported in the STAR trial. According to this model, the STAR trial has demonstrated that transferring only blastocysts classified as 'euploid' after PGT-A leads to a reduction from 82.2% to 50.0% of the live birth rate for competent embryos, thus supporting the idea that PGT-A is associated with some embryo wastage.

Oocyte Retrieval during Laparoscopic Vaginoplasty to Reduce Invasiveness in the Treatment of Mayer-Rokitansky-Küster-Hauser Syndrome.

STUDY OBJECTIVE: To evaluate the treatment of patients with Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome with a combination of oocyte retrieval and surgical vaginoplasty in a single laparoscopic procedure. DESIGN: A case series. SETTING: The study was conducted at 2 tertiary referral facilities for MRKH syndrome in Milan, Italy, between July 2017 and September 2018. PATIENTS: Eleven patients presented with MRKH and required surgical vaginoplasty while expressing a desire for future fertility. INTERVENTIONS: Two experienced surgeons and an expert in assisted reproductive technology performed concomitant vaginoplasty according to the modified technique of Davydov and laparoscopic oocyte retrieval for gamete cryopreservation. MEASUREMENTS AND MAIN RESULTS: Before the procedure, patients underwent extensive counseling and gave written consent. At the start of surgery, 10.4 ± 4.4 (mean ± standard deviation [SD]) oocytes were retrieved laparoscopically, and 8.8 ± 3.1 (SD) mean mature oocytes were cryopreserved. After oocyte retrieval, the steps of the modified Davydov technique were followed. The total operative time was 116 ± 16 minutes (mean ± SD), and no intraoperative/postoperative complications were observed. CONCLUSION: This is the first report of combined oocyte retrieval and vaginoplasty for patients with MRKH syndrome. The approach was found to be feasible in patients with a desire for future fertility. It is our belief that physicians treating patients with MRKH should refer patients to centers with expertise in both vaginoplasty and assisted reproductive technology.

Assessment of pre-implantation genetic testing for embryo aneuploidies: A SWOT analysis.

The recently re-named pre-implantation genetic testing for determining embryo aneuploidies (PGT-A) is presently very popular although its acceptance by the scientific community is controversial. This approach still encounters drawbacks. This paper uses a SWOT (strengths, weaknesses, opportunities and threats) analysis to discuss salient points to be considered when examining the pre-implantation genetic testing (PGT-A) strategy to gather information from a range of perspectives. One of the strengths associated with the procedure is represented by an increase in implantation rate although data from the highest level of evidence do not support an increase in cumulative pregnancy rates. The current difficulty in the management of mosaicisms represents a weakness of PGT-A. The application of the strategy represents an opportunity to favor the single embryo transfer while other advantages, such as reduction of time to pregnancy and emotional distress are controversial. Potential important threats, at present still undefined, are represented by the biopsy-related damage to the blastocyst and the impact on neonatal and long-term outcomes.

Effect of vitamin D supplementation on assisted reproduction technology (ART) outcomes and underlying biological mechanisms: protocol of a randomized clinical controlled trial. The "supplementation of vitamin D and reproductive outcome" (SUNDRO) study.

BACKGROUND: Vitamin D plays an important role in human physiology and pathology. The receptor for vitamin D regulates 0.5-5% of the human genome. Accordingly, vitamin D insufficiency has been shown to increase the risk of several diseases. In recent years, based on growing evidence, on a role of vitamin D has been also postulated in reproductive health both in animals and humans, especially in female fertility female fertility. In vitro fertilization success was shown to be higher in women with appropriate reserves of vitamin D. However a causal relation has not been demonstrated and randomized controlled trials testing the effectiveness of vitamin D supplementation in IVF are warranted. METHODS: This is a multicenter randomized double blinded placebo controlled study aimed at determining the benefits of vitamin D [25(OH)D] supplementation in improving clinical pregnancy rate in women undergoing IVF. Eligible women with a serum level of 25-hydroxyvitamin D [25(OH)D] < 30 ng/ml will be randomized. Recruited women will be given the drug (either 600,000 IU of 25(OH) D or placebo in a single oral administration) at the time of randomization. Two centres will participate and the sample size (700 women) is foreseen to be equally distributed between the two. Patients will be treated according to standard IVF protocols. DISCUSSION: The primary aim of the study is the cumulative clinical pregnancy rate per oocyte retrieval. Clinical pregnancy is defined as the presence of at least one intrauterine gestational sac with viable foetus at first ultrasound assessment (3 weeks after a positive human chorionic gonadotropin [hCG] assessment). Secondary outcomes include: 1) clinical and embryological variables; 2) oocyte and endometrium quality at a molecular level. To investigate this latter aspect, samples of cumulus cells, follicular and endometrial fluids will be obtained from a subgroup of 50 age-matched good-prognosis cases and controls. TRIAL REGISTRATION: The protocol was included in EudraCT on 22nd September 2015 with the registration number assigned ' 2015-004233-27 '; it was submitted through the database of the Italian "Osservatorio Nazionale della Sperimentazione Clinica (OsSC)" - (National Monitoring Centre of Clinical Trials) to the National Competent Authority on 8th March 2016 and approved on 23rd June 2016.

Uterine artery Doppler pulsatility index at 11-38 weeks in ICSI pregnancies with egg donation.

BACKGROUND: Uterine artery Doppler pulsatility index (UtA-PI) may be different in pregnancies with egg donation (ICSI-ED) as compared to conceptions with autologous intra-cytoplasmatic sperm injection (autologous ICSI) and to spontaneous conceptions (SC). METHODS: One hundred and ninety-four pregnant women with different modes of conception (MC) were prospectively evaluated: 53 ICSI-ED, 36 autologous ICSI and 105 SC. To evaluate the effects of different MC on PI, multivariable linear regression (MLR) models predicting UtA-PI were fitted after adjustment for maternal age, body mass index, race, parity, smoking status and gestational age. RESULTS: In the first trimester, at MLR, autologous ICSI was not associated with a significantly different UtA-PI [estimate (EST) 0.01; 95% confidence interval (CI) -0.19, 0.2; P=0.9] when compared to SC. Conversely, MC by ICSI-ED was associated with lower first trimester UtA-PI (EST -0.32; CI -0.55, -0.08; P=0.01) when compared to SC. At MLR, MC by autologous ICSI and by ICSI-ED were not associated with significant differences in the second and third trimester UtA-PI when compared to SC. CONCLUSION: ICSI-ED conception presented lower UtA-PI when compared to SC at 11+0-13+6 weeks but not at later assessments. Correction of UtA-PI measurement specifying the origin of oocyte may be useful in first trimester screening.

Abnormal sperm concentration and motility as well as advanced paternal age compromise early embryonic development but not pregnancy outcomes: a retrospective study of 1266 ICSI cycles.

PURPOSE: To investigate the effect of sperm concentration, motility and advanced paternal age on reproductive outcomes. METHODS: A retrospective analysis of 1266 intracytoplasmic sperm injection (ICSI) cycles between 2013 and 2017. The cohort was divided into four groups according to semen concentration based on the WHO criteria (2010): group A (conc. <1 M/ml), group B (1 ≤ conc. <5 M/ml), group C (5 ≤ conc. < 15 M/ml) and the control group D (conc. ≥15 M/ml). The primary outcome investigated was the blastulation rate. Secondary outcomes were fertilization rate, top quality blastocyst formation rate and ongoing pregnancy rate. RESULTS: After adjustment for maternal age and number of oocytes recovered, a significant difference was observed between group A and group D on the rate of fertilized oocytes [66.7 (40.0-80.0) vs 75.0 (57.1-90.2), adjusted p < 0.001] and the blastocyst formation rate [50.0 (33.3-66.3) vs 55.6 (40.0-75.0), adjusted p < 0.05]. However, the male factor did not affect the top quality blastocyst formation rate nor the ongoing pregnancy rate. Considering the age of the male partner as confounding factor, at the increase of each year of age, a reduction of 0.3% on the fertilization rate was observed but no other outcome was impacted. A negative correlation was also observed between sperm motility and fertilization rate in the group with a motility <5%. CONCLUSION: Male factor infertility and advanced paternal age may compromise fertilization and blastulation rates but not top quality blastocyst formation rate or the establishment of pregnancy in ICSI cycles.