Gonadotropins in the Management of Couple Infertility: Toward the Rational Use of an Empirical Therapy.

Although epidemiology shows that both men and woman can experience infertility, the female partner usually experiences most of the diagnostic and therapeutic burden. Thus, management of couple infertility is a unique example of gender inequality. The use of exogenous gonadotropins in assisted reproductive technology (ART) to induce multifollicular growth is well consolidated in women, but the same is not done with the same level of confidence and purpose in infertile men. Indeed, the treatment of idiopathic male infertility is based on an empirical approach that involves administration of the follicle-stimulating hormone (FSH) in dosages within the replacement therapy range. This treatment has so far been attempted when the endogenous FSH serum levels are within the reference ranges. According to the most recent evidence, a "substitutive" FSH administration may not be effective enough, while a stimulatory approach could boost spermatogenesis over its basal levels without adverse extragonadal effects. This article aims to describe the rationale behind the empirical application of gonadotropins in couple infertility, highlighting the need for a change in the therapeutic approach, especially for the male partner.

Risk factors for stillbirth at term: an Italian area-based, prospective cohort study.

BACKGROUND: Stillbirth at term has great emotional impact on both parents and professionals. In developed countries, efforts to identify risk factors are mandatory to plan area-specific prevention strategies. OBJECTIVE: The aim of the study was to identify independent risk factors that contribute to stillbirth at 37 weeks' gestation or later. STUDY DESIGN: This was an area-based, prospective cohort study on pregnancy at term with enrolled from 2014 to 2021 in Emilia-Romagna, a north Italian region. Data were retrieved from both birth certificates and the Stillbirth Surveillance system database. To identify independent risk factors, a multivariate analysis using logistic regression was performed. A descriptive analysis of the causes of stillbirth is also reported. RESULTS: In the observation period, 246,437 babies born at term (including 260 stillbirths, giving a rate of 1.06/1000) were considered. The risk factors independently associated with stillbirth were small for gestational age babies (odds ratio, 2.58; 95% confidence interval, 1.88-3.53), pregnancy achieved though fertility treatments (odds ratio, 2.01; 95% confidence interval, 1.15-3.51), and delayed access to pregnancy services (odds ratio, 1.56; 95% confidence interval, 1.10-2.22). In multipara, the presence of a previous stillbirth (odds ratio, 3.91; 95% confidence interval, 1.98-7.72) was also associated with an increased risk for recurrence. Early- rather than late-term was an additional risk factor. The most frequent causes of death were placental and cord disorders (61/260 and 56/260, respectively). However, 28.1% of cases remain unexplained. CONCLUSION: The risks for stillbirth at term are known early in pregnancy or could be identified through tailored antenatal management, allowing effective preventive strategies to reduce preventable cases.

Evidence for the expression of vasorin in the human female reproductive tissues.

Objective: To investigate the expression and localization of Vasorin (Vasn) in human female reproductive system. Methods: The presence of Vasorin was evaluated by RT-PCR and immunoblotting analyses in patient-derived endometrial, myometrial and granulosa cells (GCs) primary cultures. Immunostaining analyses were performed to detect Vasn localization in primary cultures and in ovarian and uterine tissues. Results: Vasn mRNA was detected in patient-derived endometrial, myometrial and GCs primary cultures without significant differences at the transcript level. Otherwise, immunoblotting analysis showed that Vasn protein levels were significantly higher in GCs than proliferative endometrial stromal cells (ESCs) and myometrial cells. Immunohistochemistry performed in ovarian tissues revealed that Vasn was expressed in the GCs of ovarian follicles at different stages of development with a higher immunostaining signal in mature ovarian follicles such as the antral follicle or on the surface of cumulus oophorus cells than in early-stage follicles. The immunostaining of uterine tissues showed that Vasn was expressed in the proliferative stroma endometrium while it was significantly less expressed in the secretory endometrium. Conversely, no protein immunoreactivity was revealed in health myometrial tissue. Conclusions: Our results revealed the presence of Vasn in the ovary and the endometrium. The pattern of Vasn expression and distribution suggests that this protein may have a role in the regulation of processes such as folliculogenesis, oocyte maturation, and endometrial proliferation.

Female BMI and Body Weight Is Not Associated with Oocyte Yield and Maturation in hCG, Agonist or Dual Trigger Cycles: A Large Observational Study including 5000 Cycles.

BACKGROUND: Triggering final oocyte maturation is a key step of ovarian stimulation. Although previous studies demonstrated a negative association between female BMI and serum hCG levels, little evidence is available regarding the association between oocyte yield and patients' BMI. The scope of the current study was to examine whether the efficiency of the r-hCG and triptorelin to trigger final oocyte maturation may be associated with patients' BMI or weight. METHODS: This is a retrospective observational study including 5190 ovarian stimulation cycles performed between January 2019 and September 2022 in the Reproductive Medicine Department of Dexeus University Hospital. Cycles were analyzed according to the type of trigger (triptorelin vs. r-hCG vs. dual). The primary outcome measures were oocyte maturation rate (MII/oocytes) and FOI (oocytes/AFC); secondary outcomes were oocyte and MII yield. RESULTS: Multivariable regression analysis, adjusting for confounding factors, demonstrated that BMI was not associated with oocyte maturation rate (OR: 1.00 [95%CI: 0.99; 1.01]), FOI (Beta 0.52 [95%CI: -0.49; 1.54]), number of oocytes (Beta 0.02 [95%CI: -0.08; 0.13]) or MIIs (Beta 0.01 [95%CI: -0.08; 0.10]) retrieved. Similarly, all analyses conducted considering patients' weight failed to reveal any association. CONCLUSION: Our study demonstrates that, independent of the type of trigger, patients' BMI and weight are not associated with oocyte yield, maturation, or FOI.

Corrigendum: The silent epidemic of diabetic ketoacidosis at diagnosis of type 1 diabetes in children and adolescents in italy during the covid-19 pandemic in 2020.

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The Silent Epidemic of Diabetic Ketoacidosis at Diagnosis of Type 1 Diabetes in Children and Adolescents in Italy During the COVID-19 Pandemic in 2020.

Aim/Hypothesis: To compare the frequency of diabetic ketoacidosis (DKA) at diagnosis of type 1 diabetes in Italy during the COVID-19 pandemic in 2020 with the frequency of DKA during 2017-2019. Methods: Forty-seven pediatric diabetes centers caring for >90% of young people with diabetes in Italy recruited 4,237 newly diagnosed children with type 1 diabetes between 2017 and 2020 in a longitudinal study. Four subperiods in 2020 were defined based on government-imposed containment measures for COVID-19, and the frequencies of DKA and severe DKA compared with the same periods in 2017-2019. Results: Overall, the frequency of DKA increased from 35.7% (95%CI, 33.5-36.9) in 2017-2019 to 39.6% (95%CI, 36.7-42.4) in 2020 (p=0.008), while the frequency of severe DKA increased from 10.4% in 2017-2019 (95%CI, 9.4-11.5) to 14.2% in 2020 (95%CI, 12.3-16.4, p<0.001). DKA and severe DKA increased during the early pandemic period by 10.4% (p=0.004) and 8% (p=0.002), respectively, and the increase continued throughout 2020. Immigrant background increased and high household income decreased the probability of presenting with DKA (OR: 1.55; 95%CI, 1.24-1.94; p<0.001 and OR: 0.60; 95 CI, 0.41-0.88; p=0.010, respectively). Conclusions/Interpretation: There was an increase in the frequency of DKA and severe DKA in children newly diagnosed with type 1 diabetes during the COVID-19 pandemic in 2020, with no apparent association with the severity of COVID-19 infection severity or containment measures. There has been a silent outbreak of DKA in children during the pandemic, and preventive action is required to prevent this phenomenon in the event of further generalized lockdowns or future outbreaks.

Which factors influence the success rate of egg donation programmes with imported vitrified oocytes?

RESEARCH QUESTION: Which factors influence the success rate of egg donation programmes with imported vitrified oocytes? DESIGN: Observational longitudinal cohort study of 431 oocyte donation cycles conducted between January 2015 and February 2019. A total of 398 couples underwent an IVF cycle with imported donated vitrified eggs. All consecutive oocyte donation cycles conducted at the Centre for Reproductive Medicine of the European Hospital in Rome, Italy, were included. RESULTS: A univariable analysis was conducted. Among the demographic characteristics studied, body mass index (BMI) was significantly able to influence outcome. In 49% of unsuccessful cycles, men were overweight, compared with 39.4% in cycles with a positive beta-HCG test (P = 0.03). The relationship between female or donor BMI and treatment outcome, however, was not statistically significant. The day on which the embryo is transferred affects the outcome of the cycle: transferring on day 2 versus day 5 reduces the probability of clinical pregnancy. The relationship between male BMI classes and semen parameters was studied: obese men have a significantly lower sperm concentration than normal-weight men (P = 0.006 after Bonferroni correction). No statistically significant differences were found in semen volume (P = 0.722), sperm morphology (P = 0.100) and motility (P = 0.179) in obese men compared with normal weight men. CONCLUSION: In addition to the number of oocytes available after warming, male BMI, semen characteristics and blastocyst transfer are critical parameters able to influence the reproductive outcomes of egg donation programmes with imported vitrified oocytes.

Stillbirth occurrence during COVID-19 pandemic: a population-based prospective study.

OBJECTIVES: Data collected worldwide on stillbirth (SB) rates during the Covid-19 pandemic are contradictory. Variations may be due to methodological differences or population characteristics. The aim of the study is to assess the changes in SB rate, risk factors, causes of death and quality of antenatal care during the pandemic compared to the control periods. METHODS: This prospective study is based on the information collected by the Emilia-Romagna Surveillance system database. We conducted a descriptive analysis of SB rate, risk factors, causes of death and quality of cares, comparing data of the pandemic (March 2020-June 2021) with the 16 months before. RESULTS: During the pandemic, the SB rate was 3.45/1,000 births, a value in line with the rates of previous control periods. Neonatal weight >90th centile was the only risk factor for SB that significantly changed during the pandemic (2.2% vs. 8.0%; p-value: 0.024). No significant differences were found in the distribution of the causes of death groups. Concerning quality of antenatal cares, cases evaluated with suboptimal care (5.2%) did not change significantly compared to the control period (12.0%), as well as the cases with less than recommended obstetric (12.6% vs. 14%) and ultrasound evaluations (0% vs. 2.7%). CONCLUSIONS: During the COVID-19 pandemic, no significant differences in SB rates were found in an area that maintained an adequate level of antenatal care. Thus, eventual associations between SB rate and the COVID-19 infection are explained by an indirect impact of the virus, rather than its direct effect.

Screening for Low-Tract Genital Infections in Women with Threatened Preterm Labor: Which Role?

OBJECTIVES: The aim of this study was to evaluate the possible relationship between cultural specimens and preterm birth in women admitted for threatened preterm labor. Preterm birth is the leading cause of neonatal mortality and antenatal hospitalization; several risk factors including intrauterine infections have been identified, but its real causes remain poorly understood. DESIGN: This is a retrospective, multicenter, cohort study including 250 women admitted for threatened preterm labor. Methods, Participants/Materials, Setting: All women admitted for threatened preterm labor, i.e., presenting with cervical changes and uterine activity before 37 weeks at the obstetrics unit of the hospitals of Modena, Monza, Carate, and Vimercate were included in the study. We excluded twin pregnancies and cases with preterm premature rupture of membranes at admission. Data about maternal history, pregnancy complications, cervical length, vaginal swabs, and urine culture at admission and gestational age at delivery were collected from clinical records in order to compare the incidence of preterm birth according to some known risk factors, cervical length, and microbiological test at admission. RESULTS: 250 women were included in the study; preterm birth at less than 37 weeks occurred in 44.4% women admitted for threatened preterm labor. The incidence of preterm birth was not different between those with a positive or a negative vaginal swab (48.3 vs. 38.4%, p = 0.22) or positive versus negative urine culture (31.8 vs. 42.1%, p = 0.23) at admission. A shorter cervical length at admission was found in women with subsequent preterm birth (17 vs. 19.5 mm, p = 0.03). Cervical length <15 mm (OR 1.82, 95% CI: 1.03-3.23, p = 0.039) predicted the risk of preterm birth. Furthermore, only the history of a previous preterm birth (p = 0.02) and a previous uterine curettage (p = 0.045) was associated with preterm birth. LIMITATIONS: The observational and retrospective nature of the study and its small sample size are important limitations of the study. Moreover, women were not systematically or randomly assigned to the screening for vaginal or urinary infections. CONCLUSIONS: There is no evidence that the search for vaginal or urinary infections in women admitted for threatened preterm labor is helpful to identify those at increased risk of preterm birth. Although several studies have explored the role of screening for bacterial vaginosis in asymptomatic women and some studies evaluated vaginal or urinary infections in women with preterm birth, none of them focused on the possible role of microbiological specimens as a predictive tool in women admitted for threatened PTL. No association was found in our study, but prospective randomized controlled trials are required to confirm the results of this observation.

COVID-19 - compliant - IVF: reorganized clinical practice taking into account the pandemic.

PURPOSE: The need for protective measures during the COVID-19 pandemic forced assisted reproduction centers to adopt new protocols in order to reduce the risk of infection for patients and staff. A COVID-19 Compliant IVF (in vitro fertilization) program based on the use of follitropin delta to induce ovarian stimulation and fixed protocol with GnRH (Gonadotropin-Releasing Hormone) antagonists was applied to demonstrate the efficacy of this program in reducing the necessity of patients to be present within the clinic while maintaining the expected success rate. METHODS: The program was applied to 100 patients (women aged between 20 and 40 years, at their first IVF cycle): pretreatment assessment was carried out via video conference and clinical documentations were sent by email. Ovarian stimulation was based on doses of Follitropin delta selected on the basis of body weight and serum AMH (Anti-Müllerian Hormone). The study population was then compared with historical controls to assess the percentage of patients receiving fresh embryo transfer. Finally, a questionnaire was proposed to assess patient satisfaction. RESULTS: The ovarian stimulation protocol with a fixed dose of follitropin delta led to an optimal ovarian response (8-14 oocytes) in 54% of the women included in the study. The rate of hyper response was 15% and was significantly lower that what reported in the control group (26.8%, p < .05). The good control of ovarian response to stimulation is the reason for the large percentage of cycles associated with fresh embryo transfer (84%, n 84/100). The rate of fresh embryo transfer was significantly higher that what reported for the control population (68.5%, p < .05). In 40 out of 84 patients, blastocysts were available for the fresh embryo transfer procedure. Eighty-five percent (89/100) of survey responders reported being extremely satisfied with the simplified approach to the IVF cycle because of reduced number of visits, easy management of working hours and reduction in travel costs. CONCLUSIONS: The use of follitropin delta and fixed protocol with GnRH antagonist in COVID-19 - Compliant IVF program is associated to a low percentage of patients developing excessive ovarian response compared to conventional strategy and a very good level of patient satisfaction. Beyond the pandemic, the new approach to ovarian stimulation, modern technologies and telemedicine could play a key role in bridging the gap between different geographic areas and could offer advantages such as increased accessibility, cost saving and patient satisfaction.

Impact of endocrine disorders on stillbirth: a prospective cohort study.

OBJECTIVE: Among risk factors for SB, maternal endocrine diseases (ED), such as thyroids dysfunction and gestational diabetes mellitus (GDM), are the most frequent. This study aimed to investigate the rate of ED in a population of SB cases collected prospectively, and the relationship between these and causes of death. METHODS: This is an area-based, prospective cohort study conducted in Emilia-Romagna, Italy between January 2014 and December 2020. Data included all cases of SB (>22 weeks). RESULTS: From 2014 to 2020, 766 SB occurred out of a total of 232.506 births (SB rate:0.3/1000). The ED were present in 197/766 cases of SB (25.7%), respectively, 104 thyroid disease (52.8%), 74 GDM (37.5%), and 19 cases of concomitant GDM and thyroid disease (9.6%). Women who had SB associated with ED presented significantly higher mean maternal age (p < 0.001), BMI (p < 0.001), obesity (p < 0.001) and lower smoking habit (p = 0.02) respect with control group. Neonatal and placental weight of stillborn women with ED was significantly higher (p < 0.001) in respect to stillborn of the control group. Women with ED as associated condition (ReCODE classification), present significantly higher cases of SB caused by placenta pathologies (p = 0.009) namely abruptio placentae (p = 0.001) respect than control group. CONCLUSIONS: ED was more frequent in older and obese women experiencing SB. The main cause of death was abruptio placentae. This information can be helpful when counseling mothers with ED and planning antenatal management to prevent SB.

Second trimester uterine arteries pulsatility index is a function of placental pathology and provides insights on stillbirth aetiology: A multicenter matched case-control study.

INTRODUCTION: The aim of this study was to investigate the relationships between maternal vascular malperfusions (MVM) and second trimester uterine arteries pulsatility index (UtA-PI) in cases of stillbirth (SB), compared to live-birth (LB) matched controls. METHODS: This was a multicentre, observational, matched case-control study performed at five referral maternity centres over a 4-year period including SB and LB control pregnancies at high-risk for preeclampsia (PE) and/or fetal growth restriction (FGR), matched and stratified for UtA-PI MoM quartiles values of the SB cases. Logistic regression was used to assess the rates of each MVM finding, within each increasing MoM quartile subcategory in SB and matched LB controls. RESULTS: 82 SB and 82 LB matched high-risk pregnancies were included. Placental hypoplasia, placental infarction, retroplacental hematoma, distal villous hypoplasia and accelerated villous maturation showed a significant correlation with UtA-PI. At univariable analysis, placental infarction and distal villous hypoplasia were more highly associated with the increasing quartile uterine Doppler measurements (odds ratio 2.24 and 2.23, respectively). Logistic regressions showed a significant positive and independent association between rates of retroplacental hematoma or distal villous hypoplasia and stillbirth within corresponding UtA-PI MoM quartiles (odds ratio 5.21 and 2.28, respectively). DISCUSSION: We are providing evidence for characterization of two major etiological stillbirth categories, characterized by a positive or absent association with UtA-PI impairment and specific histopathological placental MVM lesions. Our results support a strict third trimester follow-up of cases with increased second trimester UtA-PI, in order to improve the reproductive chances of these pregnant patients.

The predicted probability of live birth in In Vitro Fertilization varies during important stages throughout the treatment: analysis of 114,882 first cycles.

RESEARCH QUESTION: How much the variability in patients' response during in vitro fertilization (IVF) may add to the initial predicted prognosis based only on patients' basal characteristics? DESIGN: Anonymous data were obtained from the Human Fertilization and Embryology Authority (HFEA). Data involving 114,882 stimulated fresh IVF cycles were retrospectively analyzed. Logistic regression was used to develop the models. RESULTS: Prediction of live birth was feasible with moderate accuracy in all of the three models; discrimination of the model based only on basal patients' characteristics (AUROC 0.61) was markedly improved adding information of number of embryos (AUROC 0.65) and, mostly, number of oocytes (AUROC 0.66). CONCLUSIONS: The addition to prediction models of parameters such as the number of embryos obtained and especially the number of oocytes retrieved can statistically significantly improve the overall prediction of live birth probabilities when based on only basal patients' characteristics. This seems to be particularly true for women after the first IVF cycle. Since ovarian response affects the probability of live birth in IVF, it is highly recommended to add markers of ovarian response to models based on basal characteristics to increase their predictive ability.

The complex relationship between female age and embryo euploidy.

BACKGROUND: Female age is the strongest predictor of embryo chromosomal abnormalities and has a nonlinear relationship with the blastocyst euploidy rate: with advancing age there is an acceleration in the reduction of blastocyst euploidy. Aneuploidy was found to significantly increase with maternal age from 30% in embryos from young women to 70% in women older than 40 years old. The association seems mainly due to chromosomal abnormalities occurring in the oocyte. We aimed to elaborate a model for the blastocyst euploid rate for patients undergoing in-vitro fertilization/intra cytoplasmic sperm injection (IVF/ICSI) cycles using advanced machine learning techniques. METHODS: This was a retrospective analysis of IVF/ICSI cycles performed from 2014 to 2016. In total, data of 3879 blastocysts were collected for the analysis. Patients underwent PGT-Aneuploidy analysis (PGT-A) at the Center for Reproductive Medicine of European Hospital (Rome, Italy) have been included in the analysis. The method involved whole-genome amplification followed by array comparative genome hybridization. To model the rate of euploid blastocysts, the data were split into a train set (used to fit and calibrate the models) and a test set (used to assess models' predictive performance). Three different models were calibrated: a classical linear regression; a gradient boosted tree (GBT) machine learning model; a model belonging to the generalized additive models (GAM). RESULTS: The present study confirms that female age, which is the strongest predictor of embryo chromosomal abnormalities, and blastocyst euploidy rate have a nonlinear relationship, well depicted by the GBT and the GAM models. According to this model, the rate of reduction in the percentage of euploid blastocysts increases with age: the yearly relative variation is -10% at the age of 37 and -30% at the age of 45. Other factors including male age, female and male Body Mass Index, fertilization rate and ovarian reserve may only marginally impact on embryo euploidy rate. CONCLUSIONS: Female age is the strongest predictor of embryo chromosomal abnormalities and has a non-linear relationship with the blastocyst euploidy rate. Other factors related to both the male and female subjects may only minimally affect this outcome.

Testicular pain as an unusual presentation of COVID-19: a brief review of SARS-CoV-2 and the testis.

RESEARCH QUESTION: Can the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus induce testis damage and dysfunction? DESIGN: This is the description of the case of a young man presenting with heavy testicular pain as the first symptom of COVID-19 infection. A review of the literature is also presented. RESULTS: SARS-CoV-2 may enter into the host cell by binding to angiotensin-converting enzyme 2. This receptor seems to be widely expressed in different testicular cell types, making possible the occurrence of orchitis in male patients with COVID-19 infection. From a review of the literature, it seems that there is currently no evidence of sexual transmission of SARS-CoV-2; however, the possibility of virus-induced testis damage and dysfunction cannot be excluded. CONCLUSIONS: Further studies are necessary on the pathological effect of SARS-CoV-2 in the male reproductive system and to ensure a proper andrological follow-up for male patients.

Polycystic ovary syndrome, amenorrhea and the diagnostic role of anti-Müllerian hormone.

The differential diagnosis of anovulatory disorders is actually based on serum gonadotrophin and estradiol levels. However, several other markers have been proposed. The purpose of this review was to underline the role of anti-Müllerian hormone (AMH) as a possible marker in differential diagnosis of the anovulatory diseases and its use as a predictive marker of prognosis. In this article we discuss clinical and experimental evidences actually existing in literature and we suggest new potential clinical application of AMH.

Vitamin D levels at birth and risk of type 1 diabetes in childhood: a case-control study.

AIMS: To assess whether vitamin D levels at birth were associated with risk of having type 1 diabetes up to 10 years of age and the potential modifier effect of ethnic group. METHODS: The Piedmont Diabetes Registry and the Newborn Screening Regional data were linked to identify cases (n = 67 incident children aged ≤10 years at diabetes onset, 2002-2012) and up to five controls (n = 236) matched for birthday and ethnic group. Cards with neonatal blood spot were used and 25-hydroxyvitamin D(3) assessed with tandem mass spectroscopy. RESULTS: In conditional logistic regression, OR for unit increment of log vitamin D was 0.78 (95 % CI 0.56-1.10). Vitamin D was significantly lower in migrant than in Italian control newborn babies (p < 0.0001), and interaction between vitamin D and migrant status was statistically significant (p = 0.04). Compared to migrant newborns babies with vitamin D ≥ 2.14 ng/ml, migrants with lower levels had an OR of 14.02 (1.76-111.70), whereas no association was evident in Italians. CONCLUSIONS: Our case-control study within the Piedmont Diabetes Registry showed no association between vitamin D levels at birth and risk of having type 1 diabetes up to 10 years of age, apart from the subgroup of migrant babies, which might have clinical implications if confirmed.