The role of endometrial scratching prior to in vitro fertilization: an updated systematic review and meta-analysis.

RESEARCH QUESTION: To evaluate the role of endometrial scratching performed prior to an embryo transfer cycle on the probability of pregnancy compared to placebo/sham or no intervention. DESIGN: A computerized literature (using a specific search strategy) search was performed across the databases MEDLINE, EMBASE, COCHRANE CENTRAL, SCOPUS and WEB OF SCIENCE up to June 2023 in order to identify randomized controlled trials (RCTs) evaluating the effect of endometrial scratching prior to an embryo transfer cycle on the probability of pregnancy, expressed either as live birth, ongoing pregnancy or clinical pregnancy (in order of significance) compared to placebo/sham or no intervention. Data were pooled using random-effects or fixed-effects model, depending on the presence or not of heterogeneity. Heterogeneity was assessed using the I2 statistic. Subgroup analyses were performed based on the population studied in each RCT, as well as on the timing and method of endometrial biopsy. Certainty of evidence was assessed using the GRADEPro tool. RESULTS: The probability of live birth was significantly higher in embryo transfer cycles after endometrial scratching as compared to placebo/sham or no intervention (relative risk-RR: 1.12, 95% CI: 1.05-1.20; heterogeneity: I2=46.30%, p<0.001, 28 studies; low certainty). The probability of ongoing pregnancy was not significantly difference between the two groups (RR: 1.07, 95% CI: 0.98-1.18; heterogeneity: I2=27.44%, p=0.15, 11 studies; low certainty). The probability of clinical pregnancy was significantly higher in embryo transfer cycles after endometrial scratching as compared to placebo/sham or no intervention (RR: 1.12, 95% CI: 1.06-1.18; heterogeneity: I2=47.48%, p<0.001, 37 studies; low certainty). A subgroup analysis was performed based on the time that endometrial scratching was carried out. When endometrial scratching was performed during the menstrual cycle prior to the embryo transfer cycle a significantly higher probability of live birth was present (RR: 1.18, 95% CI:1.09-1.27; heterogeneity: I2=39.72%, p<0.001, 21 studies; moderate certainty). On the contrary, no effect on the probability of live birth was present when endometrial injury was performed during the embryo transfer cycle (RR: 0.87, 95% CI: 0.67-1.15; heterogeneity: I2=65.18%, p=0.33, 5 studies; low certainty). In addition, a higher probability of live birth was only present in women with previous IVF failures (RR: 1.35, 95% CI: 1.20-1.53; heterogeneity: I2=0%, p<0.001, 13 studies; moderate certainty) with evidence suggesting that the more IVF failures the more likely endometrial scratching to be beneficial (p=0.004). The number of times endometrial scratching was performed, as well as the type of instrument used did not appear to affect the probability of live birth. CONCLUSIONS: Endometrial scratching during the menstrual cycle prior to an embryo transfer cycle can lead to a higher probability of live birth in patients with previous IVF failures. PROSPERO REGISTRATION: PROSPERO CRD42023433538 (18 Jun 2023).

Methotrexate treatment of very high ß-HCG ectopic pregnancy on previous cesarean scar: A case report.

Ectopic pregnancy in a previous caesarean scar is a rare, potentially life-threatening situation that can cause massive bleeding and uterine rupture. Clinical symptoms can range from vaginal bleeding with or without pain, to uterine rupture with hypovolemic shock. Early diagnosis is possible by ultrasound examination, and it is very important because it leads to prompt management, improving maternal morbidity and mortality as well as future fertility. The current case report refers to a G3P2 woman with a history of 2 previous caesarean deliveries, who was diagnosed with an ectopic pregnancy on the caesarean scar using ultrasonography. The patient was treated with methotrexate both systemic and into the sac, as well as with injection into the sac of 5mEq potassium chloride. The woman was followed up until measurements of serum ß-Human Chorionic Gonadotropin were within nonpregnant levels. There is no clear-cut best way to handle cesarean scar pregnancy. Pregnancy with a cesarean scar should be identified and treated as soon as possible in order to avoid serious problems and preserve fertility. However, even more advanced cesarean scar pregnancies can be managed conservatively at first, when a highly expertized team in a tertiary hospital is available.

The Impact of Coronavirus Disease 2019 Pandemic on Female Patients Seeking or Undergoing Fertility Treatment in a Single In vitro Fertilisation Clinic in Greece: An International, Cross-sectional Study.

Background: The temporary delay in fertility treatments due to the coronavirus disease 2019 (COVID-19) pandemic, in combination with the imposed lockdowns, has created psychological distress and anxiety amongst infertile patients. Aims: The aim of this study was to evaluate how the pandemic has influenced assisted reproduction technology (ART) patients in Greece, during the second wave of the pandemic. An additional aim was to examine the effects of the pandemic on cross-border patients in particular, compared to national ones. Settings and Design: This study was a cross-sectional, questionnaire-based study, distributed to 409 patients of a single in vitro fertilisation (IVF) clinic in Greece, during the period between January until the end of April 2021. Materials and Methods: The survey was conducted online via E-mail and was distributed to national and international female patients of a single IVF clinic in Greece, who were undergoing ART treatment during the second wave of the COVID-19 pandemic. Patient participation was anonymous, and participants provided informed consent for collection and publication of data. Statistical Analysis Used: The mean values of baseline characteristics, along with answer percentages per questionnaire item, were calculated. Collected data were cross-tabulated, and the Chi-square test was used as a measurement of the differences between national and cross-border patients. A P value lower than 0.05 was considered statistically significant. All analyses were conducted using the SPSS Statistics software. Results: From 409 initial candidates, 106 women, with a mean age of 41.2 years, completed the questionnaire (26% response rate). The majority of national patients did not experience any delays in their fertility plans (62%), while cross-border patients experienced over 6 months of delays (54.7%). The main reason for fertility postponement was travel restrictions due to COVID-19 for cross-border patients (62.5%), while national patients cited additional reasons. The majority of patients experienced a degree of stress (65.2%) due to the delays, however were not fearful of COVID-19 infection (54.7%). Most patients were aware of the protective measures taken by IVF clinics (80.2%), and this was a determinant factor (71.7%) for their decision to restart their fertility treatment. Conclusion: The COVID-19 pandemic lockdowns had a significant emotional impact on patient receiving or undergoing ART treatment in Greece. This impact was more pronounced on cross-border patients. This highlights the need for continuation of ART care, with the appropriate protective measures, during the pandemic, as well as during similar times of crisis in the future.

The importance of follicular flushing in optimizing oocyte retrieval.

PURPOSE OF REVIEW: To critically evaluate the use of follicular flushing during oocyte retrieval. RECENT FINDINGS: The latest meta-analysis evaluating follicular flushing does not favour its use over single aspiration. The randomized controlled trials (RCTs) included, however, are characterized by significant heterogeneity regarding the population analysed, the needle type and lumen used, the aspiration pressure applied and the number of flushing attempts performed. More importantly, information regarding the flow rate used for aspiration is scarce. The only RCT employing a constant flow rate between single aspiration and follicular flushing in women with monofollicular development, suggests that a higher number of oocytes is retrieved after follicular flushing. SUMMARY: In order to eliminate clinical heterogeneity that might obscure the detection of the true effect of follicular flushing, randomization to single aspiration and follicular flushing should occur within the same patient. This can be achieved by randomly allocating each patient's ovary to either single aspiration or follicular flushing, maintaining similar flow rates between the groups compared.Given the importance of maximizing the number of oocytes retrieved from a given number of follicles developed, the conduction of properly designed RCTs evaluating follicular flushing is certainly required.

Oxytocin preprotein and oxytocin receptor mRNA expression is altered in semen samples with abnormal semen parameters.

RESEARCH QUESTION: Are oxytocin preprotein and the oxytocin receptor expressed in human spermatozoa and is their mRNA expression different between normal semen samples and samples with at least one abnormal parameter? DESIGN: An in-vitro prospective study of 175 semen samples from Greek men, according to World Health Organization criteria, 2010. mRNA expression levels were compared between different categories of semen samples, classified according to their concentration, total number, motility and morphology. Immunohistochemistry was used to detect oxytocin preprotein and its receptor on spermatozoa smears. RESULTS: Compared with normal samples (normal motility and normal concentration), samples with at least one abnormal sperm parameter had statistically significantly lower oxytocin preprotein mRNA expression (P = 0.019) and higher oxytocin receptor mRNA expression levels (P < 0.001). Oligozoospermic samples had statistically significantly higher oxytocin preprotein mRNA expression levels (P = 0.002) and lower oxytocin receptor mRNA expression levels (P = 0.047). Asthenozoospermic samples had statistically significantly lower oxytocin preprotein mRNA expression levels (P < 0.001). Teratozoospermic samples had statistically significantly lower oxytocin preprotein mRNA expression levels (P = 0.049) and higher oxytocin receptor mRNA expression levels (P < 0.001). Oxytocin preprotein mRNA expression was positively associated with total progressive motility (P < 0.001) and negatively associated with the percentage of immotile spermatozoa (P = 0.001). Oxytocin receptor mRNA expression was negatively associated with the percentage of normal forms (P < 0.001). CONCLUSION: Oxytocin preprotein and oxytocin receptor mRNA expression in spermatozoa could be used as a novel and unbiased diagnostic tool for male infertility.

Higher live birth rate following transdermal testosterone pretreatment in poor responders: a systematic review and meta-analysis.

A systematic review and meta-analysis was performed aiming to identify good-quality randomized controlled trials (RCT) evaluating testosterone pretreatment in poor responders. Eight RCTs were analysed, evaluating 797 women. Transdermal testosterone gel was used in all studies, with a dose ranging from 10 to 12.5 mg/day for 10-56 days. The main outcome measure was achievement of pregnancy, expressed as clinical pregnancy or live birth. Testosterone pretreatment was associated with a significantly higher live birth (risk ratio [RR] 2.07, 95% confidence interval [CI] 1.09-3.92) and clinical pregnancy rate (RR 2.25, 95% CI 1.54-3.30), as well as a significant increase in the number of cumulus-oocyte complexes retrieved. Significantly fewer days to complete ovarian stimulation, a lower total dose of gonadotrophins, a lower cancellation rate due to poor ovarian response and a thicker endometrium on the day of triggering of final oocyte maturation were observed. No significant differences were observed in oestradiol concentration, the numbers of follicles ≥17 mm, metaphase II oocytes, two-pronuclear oocytes and embryos transferred, and the proportion of patients with embryo transfer. The current study suggests that the probability of pregnancy is increased in poor responders pretreated with transdermal testosterone who are undergoing ovarian stimulation for IVF.

The human embryo following biopsy on day 5 versus day 3: viability, ultrastructure and spindle/chromosome configurations.

RESEARCH QUESTION: Are there any differences in viability, spindle abnormalities and mitochondrial and other organelle structures amongst embryos biopsied on day 3 versus day 5 before and after vitrification? DESIGN: A total of 240 day 3 biopsied embryos that developed to blastocysts but were rejected for transfer following preimplantation genetic testing for monogenic/single gene defects (PGT-M) (n = 115) or for aneuploidies (PGT-A) (n = 125) were divided into two groups: (i) 120 blastocysts treated for viability, spindle/chromosome configuration (SCC) analysis and transmission electron microscopy (TEM) analysis (fresh n = 20, n = 20, n = 20 and following vitrification/warming n = 20, n = 20, n = 20); (ii) 120 embryos were re-biopsied at the blastocyst stage and treated for viability, SCC and TEM analysis (fresh n = 20, n = 20, n = 20 and following vitrification/warming n = 20, n = 20, n = 20). Also, 60 vitrified blastocysts biopsied only on day 5 that were rejected for transfer following PGT-M (n = 6) or PGT-A (n = 54) were treated following warming for viability (n = 20), SCC (n = 20) and TEM analysis (n = 20). RESULTS: No differences were observed in SCC and ultrastructure between embryos biopsied on day 5 and day 3 but following vitrification higher numbers of abnormal spindles, distension of mitochondria, multivesicular bodies, lipofuscin droplets, altered cell junctions and occasionally excessive accumulation of glycogen granules were evident. The fresh day 3 biopsied group also had a lower incidence of damaged (propidium iodide-stained) cells compared with the fresh day 3+5 (P = 0.02) and the vitrified day 5 (P = 0.001) biopsied groups. CONCLUSIONS: Biopsies on day 5 and day 3 do not adversely affect embryo viability, SCC or ultrastructure, although following vitrification minimal embryo quality-dependent increases in spindle abnormalities and cell damage are observed.

Is Hysteroscopy Prior to IVF Associated with an Increased Probability of Live Births in Patients with Normal Transvaginal Scan Findings after Their First Failed IVF Trial?

(1) Background: Nowadays, pregnancy can be achieved by in vitro fertilisation (IVF) or by intracytoplasmic sperm injection (ICSI) for many infertile couples. However, implantation failure still remains a significant problem and it can be stressful for both patients and doctors. One of the key players for pregnancy achievement is the uterine environment. Hysteroscopy is the most reliable method to evaluate the uterine cavity and to identify any intauterine pathology. The aim of this retrospective study was to compare live birth ranges in between women who after a first failed IVF/ICSI attempt underwent a hysteroscopy and those who were evaluated by a transvaginal scan. (2) The retrospective study took place at the Assisted Reproductive Unit of the University Hospital of Ioannina, Greece, from 2017 to 2020. It included 334 women with normal findings in a repeat ultrasound scan after a failed IVF/ICSI trial, 137 of whom underwent in turn diagnostic hysteroscopy before the next IVF/ICSI. (3) Results: Live birth rates were higher in the study group (58/137 vs. 52/197 p = 0.0025). Abnormal endometrial findings were identified in 30% of the patients of the study group. (4) Conclusions: The addition of hysteroscopy as an additional investigation to those patients with a first failed IVF/ICSI could improve the rates of live births. A properly conducted RCT could lead to a robust answer.

Effects of Different Drug Therapies and COVID-19 mRNA Vaccination on Semen Quality in a Man with Ankylosing Spondylitis: A Case Report.

Background and Objectives: Ankylosing spondylitis (AS) is a condition that affects 0.1% to 0.5% of the adult population. The aim of this case report was to investigate the possible effects of the drugs taken for treatment of AS as well as mRNA vaccination for COVID-19 on semen quality by performing a highly detailed analysis. Materials and Methods: Sperm characteristics were examined by light microscopy, DNA fragmentation (DFI) was analysed by flow cytometry and morphology was evaluated by transmission electron microscopy (TEM). Results: Semen analysis under therapy with (1) celecoxib and sulphasalazine showed: concentration 47 million/mL, 53% progressive motility, 7% normal morphology and 9.6% DFI, (2) Golimumab and before mRNA Vaccination showed: concentration 108 million/mL, 82% progressive motility, 1% normal morphology and 7.6% DFI, and (3) Golimumab and after 3 doses of mRNA Vaccination showed: concentration 142 million/mL, 85% progressive motility, 1% normal morphology and 6.8% DFI. TEM revealed head, neck and tail abnormalities, as well as the presence of cells with incomplete spermiogenesis white cells and phagocytes in the sample under therapy with celecoxib and sulphasalazine. Golimumab treatment lead to an increased incidence of elongated heads but in general reduced inflammation as no white cells were evident in TEM. Conclusion: The anti-inflamatory drugs celecoxib and sulphasalazine had no adverse effect on sperm quality as all parameters were within normal limits and the patient achieved under that treatment 2 pregnancies following natural conception that lead to the birth of a healthy boy and girl respectively. Anti-TNFa treatment with Golimumab exerted a negative effect on morphology but not on concentration, motility and DFI. After 3 doses of mRNA Vaccination, sperm concentration increased while motility, morphology and DFI remained similar to the values before vaccination suggesting no negative effect of the mRNA vaccine for COVID-19 on sperm quality.

The Maribor consensus: report of an expert meeting on the development of performance indicators for clinical practice in ART.

STUDY QUESTION: Is it possible to define a set of performance indicators (PIs) for clinical work in ART, which can create competency profiles for clinicians and for specific clinical process steps? SUMMARY ANSWER: The current paper recommends six PIs to be used for monitoring clinical work in ovarian stimulation for ART, embryo transfer, and pregnancy achievement: cycle cancellation rate (before oocyte pick-up (OPU)) (%CCR), rate of cycles with moderate/severe ovarian hyperstimulation syndrome (OHSS) (%mosOHSS), the proportion of mature (MII) oocytes at ICSI (%MII), complication rate after OPU (%CoOPU), clinical pregnancy rate (%CPR), and multiple pregnancy rate (%MPR). WHAT IS KNOWN ALREADY: PIs are objective measures for evaluating critical healthcare domains. In 2017, ART laboratory key PIs (KPIs) were defined. STUDY DESIGN SIZE DURATION: A list of possible indicators was defined by a working group. The value and limitations of each indicator were confirmed through assessing published data and acceptability was evaluated through an online survey among members of ESHRE, mostly clinicians, of the special interest group Reproductive Endocrinology. PARTICIPANTS/MATERIALS SETTING METHODS: The online survey was open for 5 weeks and 222 replies were received. Statements (indicators, indicator definitions, or general statements) were considered accepted when ≥70% of the responders agreed (agreed or strongly agreed). There was only one round to seek levels of agreement between the stakeholders.Indicators that were accepted by the survey responders were included in the final list of indicators. Statements reaching less than 70% were not included in the final list but were discussed in the paper. MAIN RESULTS AND THE ROLE OF CHANCE: Cycle cancellation rate (before OPU) and the rate of cycles with moderate/severe OHSS, calculated on the number of started cycles, were defined as relevant PIs for monitoring ovarian stimulation. For monitoring ovarian response, trigger and OPU, the proportion of MII oocytes at ICSI and complication rate after OPU were listed as PIs: the latter PI was defined as the number of complications (any) that require an (additional) medical intervention or hospital admission (apart from OHSS) over the number of OPUs performed. Finally, clinical pregnancy rate and multiple pregnancy rate were considered relevant PIs for embryo transfer and pregnancy. The defined PIs should be calculated every 6 months or per 100 cycles, whichever comes first. Clinical pregnancy rate and multiple pregnancy rate should be monitored more frequently (every 3 months or per 50 cycles). Live birth rate (LBR) is a generally accepted and an important parameter for measuring ART success. However, LBR is affected by many factors, even apart from ART, and it cannot be adequately used to monitor clinical practice. In addition to monitoring performance in general, PIs are essential for managing the performance of staff over time, and more specifically the gap between expected performance and actual performance measured. Individual clinics should determine which indicators are key to the success in their organisation based on their patient population, protocols, and procedures, and as such, which are their KPIs. LIMITATIONS REASONS FOR CAUTION: The consensus values are based on data found in the literature and suggestions of experts. When calculated and compared to the competence/benchmark limits, prudent interpretation is necessary taking into account the specific clinical practice of each individual centre. WIDER IMPLICATIONS OF THE FINDINGS: The defined PIs complement the earlier defined indicators for the ART laboratory. Together, both sets of indicators aim to enhance the overall quality of the ART practice and are an essential part of the total quality management. PIs are important for education and can be applied during clinical subspecialty. STUDY FUNDING/COMPETING INTERESTS: This paper was developed and funded by ESHRE, covering expenses associated with meetings, literature searches, and dissemination. The writing group members did not receive payment.Dr G.G. reports personal fees from Merck, MSD, Ferring, Theramex, Finox, Gedeon-Richter, Abbott, Biosilu, ReprodWissen, Obseva, PregLem, and Guerbet, outside the submitted work. Dr A.D. reports personal fees from Cook, outside the submitted work; Dr S.A. reports starting a new employment in May 2020 at Vitrolife. Previously, she has been part of the Nordic Embryology Academic Team, with meetings were sponsored by Gedeon Richter. The other authors have no conflicts of interest to declare. DISCLAIMER: This document represents the views of ESHRE, which are the result of consensus between the relevant ESHRE stakeholders and where relevant based on the scientific evidence available at the time of preparation.The recommendations should be used for informational and educational purposes. They should not be interpreted as setting a standard of care, or be deemed inclusive of all proper methods of care nor exclusive of other methods of care reasonably directed to obtaining the same results. They do not replace the need for application of clinical judgment to each individual presentation, nor variations based on locality and facility type.Furthermore, ESHREs recommendations do not constitute or imply the endorsement, recommendation, or favouring of any of the included technologies by ESHRE.

Higher ovulation rate with letrozole as compared with clomiphene citrate in infertile women with polycystic ovary syndrome: a systematic review and meta-analysis.

BACKGROUND: Polycystic ovary syndrome (PCOS) is a common cause of anovulatory infertility. According to the latest guidelines, letrozole should be considered as the first-line pharmacological treatment for women with WHO Group II anovulation or PCOS. However, the use of letrozole as an ovulation induction agent is not FDA or EMA approved, and its use is "off-label." The main concern with respect to letrozole regards its potential teratogenic effect on the fetus. PURPOSE: To determine whether the probability of ovulation is higher with letrozole as compared to clomiphene citrate (CC) in anovulatory women with PCOS. METHODS: Randomized controlled trials (RCTs) comparing letrozole versus CC used for ovulation induction in infertile women with PCOS followed by timed intercourse (TI) or intrauterine insemination (IUI) were included in this meta-analysis. Primary outcome was ovulation. Secondary outcomes were live birth, clinical pregnancy, miscarriage, multiple pregnancy, and congenital anomalies. Subgroup analysis included patients who received letrozole or CC as first-line treatment, and patients with PCOS diagnosed according to the Rotterdam criteria. RESULTS: Twenty-six RCTs published between 2006 and 2019, involving 4168 patients who underwent 8310 cycles of ovulation induction, were included. The probability of ovulation was significantly higher in letrozole as compared to CC cycles (RR: 1.148, 95% CI: 1.077 to 1.223, 3017 women, 19 trials, I2: 47.7%, low-quality evidence). CONCLUSION: A higher probability of ovulation is expected in infertile patients with PCOS treated with letrozole as compared to CC. The higher ovulation rate might have contributed to the higher clinical pregnancy and live birth rate. This finding is also true for patients who were administered letrozole as first-line treatment. TRIAL REGISTRATION: CRD42019125166.

Decline in anti-Müllerian hormone concentrations following radioactive iodine treatment in women with differentiated thyroid cancer: A systematic review and meta-analysis.

AIM: Radioactive iodine (RAI) is frequently used as adjuvant therapy in patients with differentiated thyroid cancer (DTC). However, its effect on ovarian reserve has not been fully elucidated, with studies yielding inconsistent results. The aim of this study was to systematically review and meta-analyze the best available evidence regarding the effect of RAI on ovarian reserve in premenopausal women with DTC. METHODS: A comprehensive literature search was conducted in PubMed, Cochrane and Scopus, through to December 6th, 2020. Data were expressed as weighted mean difference (WMD) with a 95% confidence interval (CI). The I2 index was used to assess heterogeneity. RESULTS: Four prospective studies were included in the qualitative and quantitative analysis. Anti-Müllerian hormone (AMH) concentrations decreased at three (WMD -1.66 ng/ml, 95% CI -2.42 to -0.91, p<0.0001; I2 0%), six (WMD -1.58, 95% CI -2.63 to -0.52, p=0.003; I2 54.7%) and 12 months (WMD -1.62 ng/ml, 95% CI -2.02 to -1.22, p<0.0001; I2 15.5%) following a single RAI dose compared with baseline (three studies; n=104). With respect to follicle-stimulating hormone (FSH) concentrations, no difference was observed at six (WMD +3.29 IU/l, 95% CI -1.12 to 7.70, p=0.14; I2 96.8%) and 12 months (WMD +0.13 IU/l, 95% CI -1.06 to 1.32, p=0.83; I2 55.2%) post-RAI compared with baseline (two studies; n=83). No data were available for antral follicle count. CONCLUSIONS: AMH concentrations are decreased at three months and remain low at 6 and 12 months following RAI treatment in women with DTC. No difference in FSH concentrations post-RAI is observed.

How frequent is severe ovarian hyperstimulation syndrome after GnRH agonist triggering in high-risk women? A systematic review and meta-analysis.

The aim of the present systematic review and meta-analysis was to assess the incidence of severe ovarian hyperstimulation syndrome (OHSS) after triggering of final oocyte maturation with gonadotrophin releasing hormone agonist (GnRHa) in high-risk women. The pooled incidence of severe OHSS in high-risk women who did not receive any form of luteal phase support was 0% (95% CI 0.0 to 0.0, I2 = 0%, random-effects model, 14 data sets, 983 women). The pooled incidence of severe OHSS in high-risk women in whom HCG was added to standard luteal phase support was 1% (95% CI 0.0 to 2.0, I2 = 27.02%, random-effects model, 10 data sets, 707 women). The incidence of severe OHSS in high-risk women triggered by a combination of GnRHa and HCG (dual triggering), who received standard luteal phase support, was 1% (95% CI 0.0 to 3.0, one study, 182 women). The incidence of severe OHSS in high-risk women, is not eliminated when HCG is administered either concomitantly with GnRHa (dual triggering), during the luteal phase after GnRHa triggering, or both. On the contrary, it is eliminated when no luteal support is administered.

Is there an optimal number of oocytes retrieved at which live birth rates or cumulative live birth rates per aspiration are maximized after ART? A systematic review.

The association between the number of oocytes retrieved and fresh live birth rate (LBR) or cumulative LBR (CLBR), and whether an optimal number of oocytes are retrieved when LBR or CLBR are maximized, are highly relevant clinical questions; however published results are conflicting. A systematic review of all eligible studies (n = 16) published until January 2020 on MEDLINE, Embase, Scopus, CINAHL and Web of Science was conducted. Five studies evaluated only LBR from fresh cycles, five studies evaluated only CLBR from stimulated cycles and six evaluated both. A marked difference was observed between the oocyte yields at which LBR and CLBR were reportedly maximized in the individual studies. On the basis of nine studies, the optimal number of oocytes at which fresh LBR seems to be maximized is proposed to be between 12 and 18 oocytes (15 oocytes was the most common suggestion). On the other hand, CLBR continues to increase with the number of oocytes retrieved. This is the first systematic review on the topic, and it suggests that the retrieval of 12-18 oocytes is associated with maximal fresh LBR, whereas a continuing positive association is present between the number of oocytes retrieved and CLBR.

Expression of genes that regulate follicle development and maturation during ovarian stimulation in poor responders.

RESEARCH QUESTION: Sex hormone-binding globulin (SHBG), androgen receptor (AR), LH beta polypeptide (LHB), progesterone receptor membrane component 1 (PGRMC1) and progesterone receptor membrane component 2 (PGRMC2) regulate follicle development and maturation. Their mRNA expression was assessed in peripheral blood mononuclear cells (PBMC) of normal and poor responders, during ovarian stimulation. DESIGN: Fifty-two normal responders and 15 poor responders according to the Bologna criteria were enrolled for IVF and intracytoplasmic sperm injection and stimulated with 200 IU of follitrophin alpha and gonadotrophin-releasing hormone antagonist. HCG was administered for final oocyte maturation. On days 1, 6 and 10 of stimulation, blood samples were obtained, serum hormone levels were measured, RNA was extracted from PBMC and real-time polymerase chain reaction was carried out to identify the mRNA levels. Relative mRNA expression of each gene was calculated by the comparative 2-DDCt method. RESULTS: Differences between mRNA levels of each gene on the same time point between the two groups were not significant. PGRMC1 and PGRMC2 mRNA levels were downregulated, adjusted for ovarian response and age. Positive correlations between PGRMC1 and AR (standardized beta = 0.890, P < 0.001) from day 1 to 6 and PGRMC1 and LHB (standardized beta = 0.806, P < 0.001) from day 1 to 10 were found in poor responders. PGRMC1 and PGRMC2 were positively correlated on days 6 and 10 in normal responders. CONCLUSIONS: PGRMC1 and PGRMC2 mRNA are significantly decreased during ovarian stimulation, with some potential differences between normal and poor responders.

Female Infertility and Cardiovascular Risk - A Hype or an Underestimated Reality?

Infertility may be an early indicator of later-life health risk development, such as cardiovascular disease (CVD), the leading cause of death globally. Various infertility-associated factors such as female age, polycystic ovarian syndrome, endometriosis and metabolic syndrome are also risk factors for CVD. Whether there is a real association between female infertility and CVD, given that common pathways lead to both entities, or since both female infertility and CVD share a common basis, needs to be further investigated. If such an association is confirmed, infertile women might benefit from the initiation of preventive strategies aiming to control CVD risk factors. Thus, female infertility may represent an early indicator of future CVD and concomitantly a unique opportunity to identify women at increased risk for developing CVD. It is therefore imperative that large population- based studies are performed to elucidate this issue further and promote public awareness, if necessary.

Risk of gestational diabetes mellitus in women achieving singleton pregnancy spontaneously or after ART: a systematic review and meta-analysis.

BACKGROUND: Women who achieve pregnancy by ART show an increased risk of obstetric and perinatal complications compared with those with spontaneous conception (SC). OBJECTIVE AND RATIONALE: The purpose of this systematic review and meta-analysis was to synthesize the best available evidence regarding the association between ART and gestational diabetes mellitus (GDM) in women with singleton pregnancies. The research question asked was whether the risk of GDM is higher in women achieving singleton pregnancy by ART compared with those achieving singleton pregnancy spontaneously. SEARCH METHODS: A literature search, in MEDLINE, Scopus and Cochrane databases, covering the period 1978-2019, was performed aiming to identify studies comparing the risk of GDM in singleton pregnancies after ART versus after SC. Both matched and unmatched studies were considered eligible. Meta-analysis of weighted data was performed using the random effects model. Results were reported as risk ratio (RR) with 95% CI. Heterogeneity was quantified with the I2 index. OUTCOMES: The study reports on 63 760 women who achieved a singleton pregnancy after ART (GDM was present in 4776) and 1 870 734 women who achieved a singleton pregnancy spontaneously (GDM in 158 526). Women with singleton pregnancy achieved by ART showed a higher risk of GDM compared with those with singleton pregnancy achieved spontaneously (RR 1.53, 95% CI 1.39-1.69; I2 78.6%, n = 37, 1 893 599 women). The direction or the magnitude of the effect observed did not change in subgroup analysis based on whether the study was matched (n = 17) or unmatched (n = 20) (matched: RR 1.42, 95% CI 1.17-1.72; I2 61.5%-unmatched: RR 1.58, 95% CI 1.40-1.78; I2 84.1%) or whether it was prospective (n = 12) or retrospective (n = 25) (prospective studies: RR 1.52, 95% CI 1.27-1.83, I2 62.2%-retrospective studies: RR 1.53, 95% CI 1.36-1.72, I2 82.5%). Regarding the method of fertilization, a higher risk of GDM after ART versus SC was observed after IVF (n = 7), but not after ICSI (n = 6), (IVF: RR 1.95, 95% CI 1.56-2.44, I2 43.1%-ICSI: RR 1.42, 95% CI 0.94-2.15, I2 73.5%). Moreover, regarding the type of embryo transfer (ET), a higher risk of GDM after ART versus SC was observed after fresh (n = 14) but not after frozen (n = 3) ET (fresh ET: RR 1.38, 95% CI 1.03-1.85, I2 75.4%-frozen ET: RR 0.46, 95% CI 0.10-2.19; I2 73.1%). A higher risk of GDM was observed after ART regardless of whether the eligible studies included patients with polycystic ovary syndrome (RR 1.49, 95% CI 1.33-1.66, I2 75.0%) or not (RR 4.12, 95% CI 2.63-6.45, I2 0%), or whether this information was unclear (RR 1.46, 95% CI 1.22-1.75, I2 77.7%). WIDER IMPLICATIONS: The present systematic review and meta-analysis, by analysing 1 893 599 women, showed a higher risk of GDM in women achieving singleton pregnancy by ART compared with those achieving singleton pregnancy spontaneously. This finding highlights the importance of early detection of GDM in women treated by ART that could lead to timely and effective interventions, prior to ART as well as during early pregnancy.

Association between vitamin D and endometriosis: a systematic review.

BACKGROUND: Endometriosis is one of the most common gynecological diseases of reproductive age, with a prevalence of 5-10% and grave consequences for quality of life and fertility. Vitamin D (vit D), a classic regulator of plasma calcium concentration and skeleton mineralization, is also an effective modulator of the immune system. Several studies suggest that immunologic properties attributed to vit D along with vit D receptor (VDR) expression in reproductive tissues may be involved in the pathogenesis of endometriosis. OBJECTIVE: To systematically review the literature for the association between components of vit D metabolism and endometriosis. MATERIALS AND METHODS: A systematic review of the literature published in the Medline and Cochrane Central databases was conducted for original research articles on humans, published in any language. RESULTS: Twenty-one studies were included in the systematic review. Among them, 12 examined the relationship of endometriosis with vit D metabolites, eight with vit D-binding protein (VDBP), three with VDR polymorphisms, and two with vit D regulatory enzymes. There are discrepancies between the outcomes of the available literature publications. CONCLUSIONS: This is a systematic attempt to collect, evaluate, and present the known data on the association between vit D and endometriosis. Given the heterogeneity and the diversity of the present studies, more research is required to elucidate the association between vit D and endometriosis.

Association between body mass index and oocyte maturation in patients triggered with GnRH agonist who are at high risk for severe ovarian hyperstimulation syndrome: an observational cohort study.

RESEARCH QUESTION: Is body-mass index (BMI) associated with oocyte maturation in women at high risk for developing severe ovarian hyperstimulation syndrome (OHSS) who are triggered with gonadotrophin releasing hormone (GnRH) agonist? DESIGN: Prospective observational cohort study. A total of 113 patients at high risk for severe OHSS (presence of at least 19 follicles ≥11 mm) pre-treated with gonadotrophin releasing hormone (GnRH) antagonists and recombinant FSH were administered 0.2 mg triptorelin to trigger final oocyte maturation. Patients were classified in two groups depending on their BMI: ΒΜΙ less than 25 kg/m2 (n = 72) and ΒΜΙ 25 kg/m2 or over (n = 41). Baseline, ovarian stimulation and embryological characteristics, as well as luteal-phase hormone profiles, were compared in patients classified into the two BMI groups. The main outcome measure was the number of mature oocytes. RESULTS: A significantly higher number of mature (metaphase II) oocytes (19 [18-21] versus 16 [13-20], P = 0.029) was present in women with BMI less than 25 kg/m2 compared with those with BMI 25 kg/m2 or greater. The number of retrieved oocytes, the number of fertilized oocytes, oocyte retrieval, maturation and fertilization rates were similar in the two groups. A significantly higher dose of recombinant FSH was required for patients with BMI 25 kg/m2 or greater compared with patients with BMI less than 25 kg/m2 (1875 [1650-2150] IU versus 1650 [1600-1750] IU, P = 0.003) and the two groups displayed different luteal phase hormonal profiles. CONCLUSIONS: Among women at high risk for developing severe OHSS who are triggered with a standard dose (0.2 mg) of the GnRH agonist triptorelin, women with BMI 25 kg/m2 or greater had significantly fewer mature oocytes, required a higher total dose of recombinant FSH compared with women with BMI less than 25 kg/m2.