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In Italy the fertility rate is very low, and an increasing number of patients are infertile and require treatments. The Italian Law concerning the safety of patient care, and the professional liability of health professionals, indicates that health professionals must comply with the recommendations set out in the guidelines developed by public and private bodies and institutions, as well as scientific societies and technical-scientific associations of the health professions, except for specific cases. Unfortunately, no guideline for the diagnosis and the management of infertility is currently available in Italy. In 2019, the Italian Society of Human Reproduction pointed out the need to produce Italian guidelines and subsequently approved the establishment of a multidisciplinary and multiprofessional working group (MMWG) to develop such a guideline. The MMWG was representative of 5 scientific societies, one national federation of professional orders, 3 citizens' and patients' associations, 5 professions (including lawyer, biologist, doctor, midwife, and psychologist), and 3 medical specialties (including medical genetics, obstetrics and gynecology, and urology). The MMWG chose to adapt a high-quality guideline to the Italian context instead of developing one from scratch. Using the Italian version of the Appraisal of Guidelines for Research and Evaluation II scoring system, the National Institute of Clinical Excellence guidelines were selected and adapted to the Italian context. The document was improved upon by incorporating comments and suggestions where needed. This study presents the process of adaptation and discusses the pros and cons of the often-neglected choice of adapting rather than developing new guidelines. [ABSTRACT FROM AUTHOR]

Background: Infertility affects 15% of couples in Italy and approximately 10%–12% of couples worldwide. Focusing on female fertility, there are multiple causes, among which diet has a great influence. Methods: We investigated whether the consumption of certain fatty acids affects four outcomes of the assisted reproduction techniques. From September 2014 to December 2016, women referring to our Italian fertility unit, eligible for assisted reproduction techniques, were invited to participate. Information on diet was recorded through a validated food frequency questionnaire. Results: Four hundred and ninety‐four women were included, of whom 95% achieved good quality oocytes, 87% achieved embryo transfer, 32.0% achieved clinical pregnancies and 24.5% achieved pregnancy at term. The fourth quartile of saturated fatty acids consumption, compared to the first one, showed an association with clinical pregnancy (adjusted relative risk 0.67, 95% confidence interval 0.45–1.00, p = 0.0491). Some associations emerge accounting for confounders. Age was associated with clinical pregnancy and pregnancy at term in the models considering all fatty intakes and food groups variables but was not associated with oocytes quality and embryo transfer. Physical activity was associated with clinical pregnancy. Conclusions: There is biological plausibility for the effect of omega‐3 and omega‐6 polyunsaturated fatty acids on oocyte development via synthesis of eicosanoids, even if only limited associations are shown in the present study. Future research should aim to measure the serum levels of fatty acids and investigate the outcomes of assisted reproduction techniques. Research highlights: There is biological plausibility for the effect of omega‐3 and omega‐6 polyunsaturated fatty acids on oocyte development via synthesis of eicosanoids.We investigated the relationship between fatty acids intake in a population of women undergoing assisted reproduction techniques (ART) and four outcomes: good quality oocytes, embryo transfer, clinical pregnancy and pregnancy at term.No associations emerged between fatty acids intake and ART outcomes, except for the fourth quartile of saturated fatty acids consumption. [ABSTRACT FROM AUTHOR]

Background: Recent studies have suggested that ovarian stimulation and assisted reproductive techniques (ART) may increase the frequency of monozygotic twins. In this article, we present the analysis of the estimated frequency of twin deliveries following in vitro fertilization (IVF) in Lombardy during the period 2010-2014 for a total of 450,949 pregnancies.Method: This is a population-based study using data from the regional data base of Lombardy, a northern Italian region with a population of about 10 million inhabitants. During the considered period, a total of 461,424 single or multiple births were registered in Lombardy. After exclusion of triplets or more pregnancies, the total number of twin deliveries, in separate strata of like and unlike sex pregnancies twin deliveries, were obtained and the rate of twin deliveries was computed according to spontaneous and non-spontaneous conception and type of ART. Further, estimates of dizygotic or monozygotic twin births were calculated using Weinberg's methods.Results: The frequency of twins deliveries was 1.24/100 deliveries after natural conception and 20.05 after assisted conception. The estimated rates of monozygotic twins was 0.45 and 0.72/100 (95% CI: 0.58-0.91) deliveries after natural and assisted conception, respectively. This difference was statistically significant (p < .05).Conclusion: the present population based study suggests that the risk of monozygotic twin is about 60% higher among assisted than after natural conception. [ABSTRACT FROM AUTHOR]

Objective: To assess the impact of Assisted Reproductive Techniques (ART) on the risk of preterm birth (PTB).Study Design: This retrospective population-based study used healthcare utilization databases of the Lombardy Region to select all the deliveries occurred between 2007 and 2020. Log-binomial regression models were fitted to estimate prevalence ratio (PR) and the corresponding 95% confidence interval (CI) of PTB among deliveries after ART. Estimates were adjusted for maternal sociodemographic features. Furthermore, the population attributable fraction was computed. All the analyses were performed for calendar period and were repeated excluding multiple births.Results: In our cohort, an increasing trend in the number of ART emerged, with an overall rate of 25.8 per 1,000 deliveries (N = 28,742). ART was positively related to PTB (aPR = 2.83, 95 % CI: 2.76-2.91) with a downward trend. Over the period study, multiple births after ART decreased (from 20.4 % to 8.4 %) and were constantly burdened by a higher number of PTB. Excluding multiple births, the association was substantially lower (aPR = 1.72, 95 % CI: 1.65-1.79) and did not describe any trend. Moreover, stratifying for type of pregnancy, the association was observed only among singletons. Finally, the proportion of PTB considered attributable to ART increased from about 2-3 % to 6 % till the 2016, then decreased.Conclusion: The investigation suggested that ART was related to PTB; this association may be partly justified by the high rate of multiple births among women who conceived non spontaneously. However, excluding multiple births, ART remained associated with PTB. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the relative impact of different strategies of medically assisted reproduction (MAR), i.e. first line treatment (ovarian stimulation with or without intrauterine insemination) and in vitro fertilization (IVF) procedures (conventional IVF or intracytoplasmic sperm injection), on the risk of multiple births., Study Design: We utilized the health care utilization databases of the Lombardy region to identify births resulting from MAR between 2007 and 2022. We gathered data on the total number of multiple births and calculated the prevalence rate by dividing the number of multiples by the total number of births. To examine the temporal trend in the proportion of multiple births after MAR over time, a linear regression model was employed separately for different types of techniques and in strata of maternal age., Results: A total of 30,900 births after MAR were included; 4485 (14.5 %) first line treatments and 26,415 (85.5 %) IVF techniques. Overall, 4823 (15.6 %) multiple births were identified. The frequency of multiple births over the study period decreased from 22.0 % in 2007 to 8.7 % in 2022 (p < 0.01). Multiple births from first line treatments were stable ranging from 13.5 % in 2007-2008 to 12.0 % in 2021-2022 (p = 0.29). Multiple births from IVF procedures decreased from 23.8 % in 2007-2008 to 8.4 % in 2021-2022 (p < 0.01). Stratifying for maternal age (i.e. < 35 and ≥ 35 years), the trends remained consistent., Conclusions: The reduction in multiple births has been influenced by changes in IVF strategy and procedures. The decline has been gradual but steady since 2009, when a law restricting embryo freezing was repealed in Italy. In contrast, the proportion of multiple births resulting from first line treatments has remained constant over time. Despite declining, multiple births from MAR remained about one order of magnitude higher than those from spontaneous pregnancies., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Edgardo Somigliana reports grants from Ferring, grants and personal fees from Merck-Serono, grants and personal fees from Theramex, personal fees from Gedeon-Richter, outside the submitted work. Giovanni Corrao received research support from the European Community (EC), the Italian Agency of Drugs (AIFA), and the Italian Ministry for University and Research (MIUR). He took part in a variety of projects that were funded by pharmaceutical companies (i.e. Novartis, GSK, Roche, AMGEN and BMS). He also received honoraria as a member of the advisory board to Roche. The other authors declare that they have no conflicts of interest to disclose., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: In the field of assisted reproductive technology (ART), family rate is a neglected but emerging issue. The aim of the study was to investigate the epidemiological impact of ART on the second birth during the period 2007-2020 in Lombardy, Northern Italy., Methods: We conducted a population-based study using administrative data from regional healthcare databases of Lombardy including first and second births occurred from 2007 to 2020. The proportion of deliveries after ART was calculated separately among first and second births. The probability of undergoing ART to achieve second birth compared to first one was estimated computing odds ratio (OR), crude and adjusted for maternal age, education, and nationality. We also assessed changes with age and calendar period., Results: We obtained a cohort including 553,190 first births and 317,976 second births. The proportion of ART babies among first and second births was 4.3% and 1.0% respectively (p < 0.001). The probability of undergoing ART to achieve second birth compared to first one, adjusted for age, education, and nationality, was 0.14 (95%CI: 0.13-0.15). The proportion of deliveries after ART increased with maternal age and along the calendar period but remained always markedly higher among first births rather than among second births., Conclusion: ART played a significantly lower role in the determinism of the conception of a second birth in comparison to the conception of a first one., Competing Interests: Declaration of Competing Interest Edgardo Somigliana reports grants from Ferring, grants and personal fees from Merck-Serono, grants and personal fees from Theramex, personal fees from Gedeon-Richter, outside the submitted work. Giovanni Corrao received research support from the European Community (EC), the Italian Agency of Drugs (AIFA), and the Italian Ministry for University and Research (MIUR). He took part in a variety of projects that were funded by pharmaceutical companies (i.e., Novartis, GSK, Roche, AMGEN and BMS). He also received honoraria as a member of the advisory board to Roche. The other authors declare that they have no conflicts of interest to disclose., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

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., (© 2023. The Author(s).)

Purpose: The incidence of birth defects is increased in children born after assisted reproductive technologies (ART). However, changes in ART over time could influence this incidence. To investigate this issue, we present the frequency and trends of birth defects in ART and natural pregnancies in Lombardy, Northern Italy, during the period 2014-2020., Methods: This is a population-based study using automated system of healthcare utilization (HCU) databases. ART pregnancies included only those obtained with conventional IVF or ICSI. After identifying the total number of deliveries, the rate of newborns with birth defects was compared between natural and ART pregnancies. A logistic regression model was used to calculate the adjusted odd ratio (OR). Analyses were repeated for every calendar year., Results: Overall, 508,421 deliveries were identified, of which 14,067 (2.8%) were achieved after IVF-ICSI. A decreasing trend in birth defects over time was highlighted. The adjusted OR dropped from 1.40 (95%CI: 1.03-1.91) in 2014 to 0.92 (95%CI: 0.69-1.22) in 2020. During the study period, a significant reduction in multiple pregnancy and in the ratio of ICSI to conventional IVF was also observed, explaining at least in part the positive trend observed for birth defects., Conclusion: The increased risk of birth defects in children born after IVF-ICSI is not steady over time. A decline of this risk emerged in our region. Policy changes in ART may explain this beneficial effect., (© 2023. The Author(s).)

Objective: To evaluate whether telomere length (TL), mitochondrial-DNA (mt-DNA) or epigenetic age estimators based on DNA methylation (DNAm) pattern could be considered reliable predictors of in-vitro-fertilization (IVF) success in terms of live birth rate., Design: Prospective cohort study., Setting: Infertility Unit of the Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico., Patients: 181 women aged 37-39 years who underwent IVF at a single-centre between January 2017 and December 2018., Interventions: On the day of recruitment, blood samples were collected, and genomic DNA was isolated from white blood cells. TL, mt-DNA and DNAm assessment was performed using quantitative real-time polymerase chain reaction (qPCR). Biological age (DNAm age) was computed as the algorithm based on methylation pattern of five genes. Epigenetic age acceleration was estimated from the residuals of the linear model of epigenetic age regressed on chronological age. Long Interspersed Nuclear Elements (LINE)-1 methylation pattern was used as a surrogate for global DNA methylation., Main Outcome Measures: This study investigated whether peripheral TL, mt-DNA and DNAm could predict live birth in IVF cycles., Results: TL, mt-DNA and LINE-1 methylation were not associated with IVF success. Conversely, DNAm age resulted significantly lower in women who had a live birth compared to women who did not (36.1 ± 4.2 and 37.3 ± 3.3 years, respectively, p = 0.04). For DNAm age, odds ratio (OR) for live birth per year of age was 0.90 (95%CI: 0.82-0.99, p = 0.036) after adjusting for FSH and antral follicle count (AFC) and 0.90 (95%CI: 0.82-0.99, p = 0.028) after adjusting also for number of oocytes retrieved. A significant association also emerged for epigenetic age acceleration after adjustments (OR = 0.91, 95%CI: 0.83-1.00, p = 0.048)., Conclusion: DNAm age is associated with IVF success but the magnitude of this association is insufficient to claim a clinical use. However, our findings are promising and warrant further investigation. Assessment of biological age using different epigenetic clocks or focusing on different tissues may reveal new predictors of IVF success., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: Dr. Somigliana reports grants from Ferring, grants and personal fees from Merck-Serono, grants and personal fees from Theramex, personal fees from Gedeon-Richter, outside the submitted work. This does not alter our adherence to PLOS ONE policies on sharing data and materials, as detailed online in your guide for authors. All the other authors have no competing interests in relation to this study.

Research Question: What effects did the early phase of the COVID-19 pandemic have on natural and assisted reproductive technology (ART)-mediated birth rates?, Design: Regional registries were consulted with permission from the Health Authorities of Lombardy Region, Northern Italy, an area particularly affected by the early phase of the epidemic. Deliveries occurring in the area between 1 January 2019 and 31 December 2020 from women beneficiaries of the National Health System and resident in Lombardy were identified. Comparisons mainly focused on December 2020, when women who conceived after 8 March (the start of the stringent lockdown imposed by the authorities) were expected to deliver., Results: When comparing the periods January to November in 2019 and 2020, a 5.1% reduction of monthly general birth rate (from 5732 in 2019 to 5438 in 2020) was observed. The contribution of ART births was similar in 2019 and 2020, being 4.4% and 4.5%, respectively. In December 2020, a notable drop in natural (-17.8%), ART-mediated (-86.6%) and overall (-21.0%) births was observed compared with December 2019. After adjusting for the expected 5.1% reduction, the inferred effect of the COVID-19 crisis corresponded to a 16.7% reduction in birth rate, of which 76% was related to natural (707 births) and 24% to ART (218 births) conceptions., Conclusions: This is the first study providing population-based evidence on the effects of COVID-19 and its related stringent restrictions on birth rates. The birth rate was dramatically reduced following the critical period, and the closure of ART centres played only a marginal role (24%) in the overall detrimental effect., (Copyright © 2021 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

Purpose: The risk of monozygotic (MZT) twinning is increased in pregnancies after assisted reproductive technologies (ART). However, determinants remain poorly understood. To shed more light on this issue, we analyzed the estimated frequency of MZT twins from ART in Lombardy, Northern Italy, during the period 2007-2017., Methods: This is a population-based study using regional healthcare databases of Lombardy Region. After having detected the total number of deliveries of sex-concordant and sex-discordant twins from ART, we calculated MZT rate using Weinberg's method. Standardized ratios (SRs) and corresponding 95% confidence intervals (CI) of MZT deliveries, adjusted for maternal age, were computed according to calendar period, parity, and type of ART., Results: On the whole, 19,130 deliveries from ART were identified, of which 3,446 were twins. The estimated rate of MZT births among ART pregnancies was higher but decreased over time (p-value = 0.03); the SRs being 1.33 (95% CI: 1.18-1.51), 0.96 (95% CI: 0.83-1.11), and 0.92 (95% CI: 0.79-1.07) for the periods 2007-2010, 2011-2014, and 2015-2017, respectively. The SRs of MZT among women undergoing first-level techniques, conventional in vitro fertilization (IVF), and intracytoplasmic sperm injection (ICSI) were 0.47 (95% CI: 0.38-0.57), 1.02 (95% CI: 0.88-1.17), and 1.43 (95% CI: 1.27-1.61) (p-value < 0.0001). The ratio of MZT births was significantly higher in women younger than 35 years (p-value < 0.0001) and slightly higher among nulliparae (p-value < 0.0001)., Conclusion: Despite a reduction of MZT rate from ART over the time, the risk remains higher among ART pregnancies rather than natural ones. Younger women and women undergoing ICSI showed the highest risk of all., (© 2021. The Author(s).)

Background: Evidence on the outcome of SARS-CoV-2 infection in pregnancy is generally reassuring but yet not definitive., Methods: To specifically assess the impact of SARS-CoV-2 infection in late pregnancy, we prospectively recruited 315 consecutive women delivering in a referral hospital located in Lombardy, Italy in the early phase of the epidemic. Restriction of the recruitment to this peculiar historical time period allowed to exclude infections occurring early in pregnancy and to limit the recall bias. All recruited subjects underwent a nasopharyngeal swab to assess the presence of Sars-Cov-2 using Real-time PCR. In addition, two different types of antibodies for the virus were evaluated in peripheral blood, those against the spike proteins S1 and S2 of the envelope and those against the nucleoprotein of the nucleocapsid. Women were considered to have had SARS-CoV-2 infection in pregnancy if at least one of the three assessments was positive., Results: Overall, 28 women had a diagnosis of SARS-CoV-2 infection in pregnancy (8.9%). Women diagnosed with the infection were more likely to report one or more episodes of symptoms suggestive for Covid-19 (n = 11, 39.3%) compared to unaffected women (n = 39, 13.6%). The corresponding OR was 4.11 (95%CI: 1.79-9.44). Symptoms significantly associated with Covid-19 in pregnancy included fever, cough, dyspnea and anosmia. Only one woman necessitated intensive care. Pregnancy outcome in women with and without SARS-CoV-2 infection did not also differ., Conclusions: SARS-CoV-2 infection is asymptomatic in three out of five women in late pregnancy and is rarely severe. In addition, pregnancy outcome may not be markedly affected., (© 2021. The Author(s).)

Objective: We investigated whether lifestyle affects assisted reproduction technology (ART) outcomes., Design: Cohort study., Setting: Italian fertility unit., Participants: From September 2014 to December 2016, women from couples presenting for evaluation and eligible for ART were invited to participate. Information on alcohol intake, current smoking and leisure physical activity (PA) during the year before the interview was collected, using a structured questionnaire. We considered the ART outcomes of the cycle immediately following the interview., Primary and Secondary Outcome Measures: The primary outcome measure was cumulative pregnancy rate per retrieval. Secondary measures were number of retrieved oocytes, embryo transfer and live birth., Results: In 492 women undergoing an ART cycle, 427 (86.8%) underwent embryo transfer, 157 (31.9%) had at least one clinical pregnancy and 121 (24.6%) had live birth. The cumulative pregnancy rate per retrieval was 33.3% (95% CI 28.5% to 38.7%). In women in the third tertile of alcohol intake, adjusted relative risk was 0.97 (95% CI 0.87 to 1.08), 0.90 (95% CI 0.62 to 1.30) and 0.89 (95% CI 0.57 to 1.37) for embryo transfer, clinical pregnancy and live birth, respectively. The corresponding figures in women currently smoking more than 5 cigarettes/day were 1.00 (95% CI 0.88 to 1.16), 0.94 (95% CI 0.60 to 1.48) and 1.14 (95% CI 0.68 to 1.90), and in women with PA ≥5 hours/week were 0.93 (95% CI 0.79 to 1.08), 0.44 (95% CI 0.22 to 0.90) and 0.48 (95% CI 0.22 to 1.05), respectively., Conclusion: There were no significant differences in in vitro fertilisation outcomes among women who used alcohol or tobacco in the year prior to treatment. Conservatively, all women should be advised to limit substance abuse. Moreover, our study suggested that maintaining a moderate, but not high, level of PA could be beneficial., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

In recent decades, increasing attention has been paid to the influence of diet on reproductive health. Carbohydrates in diet affect glucose metabolism and multiple evidences showed the key role of insulin sensitivity in regulating female fertility. We designed a prospective cohort study to investigate the relation between dietary carbohydrate intake, glycemic load (GL) and the outcomes of assisted reproduction. A population of 494 female partners of couples referring to an Italian Fertility Center and eligible for in vitro fertilization (IVF) were enrolled in the study. On the day of the oocyte retrieval, information on their diet was obtained using a validated food frequency questionnaire (FFQ). We calculated the relative risk and 95% confidence interval of embryo transfer, clinical pregnancy and live birth according to the following dietary exposures: GL, glycemic index (GI) as well as the daily carbohydrate and fiber intake. A multiple regression model was used to account for the confounders. After adjusting for age, college degree, body mass index (BMI), leisure physical activity and previous assisted reproduction techniques (ART) cycles, no significant association was observed between the considered dietary exposures and the IVF outcomes. The roles of GL, carbohydrate intake and GI were assessed in strata of the cause of infertility and body mass index and no relation emerged in this further analysis. We found no clear association between the dietary carbohydrate quantity and quality and IVF outcomes in a cohort of infertile Italian women., Competing Interests: E.S. reports grants from Ferring, grants and personal fees from Merck-Serono, grants and personal fees from Theramex, outside the submitted work. The remaining authors have no competing interests.

Background: Detrimental lifestyle habits have been indicated as potential causes of reduced fertility. Recently studies have suggested an association between healthy diets and increased live birth rates after assisted reproduction techniques. However, the issue remains under debate, and evidence is still accumulating., Objective: The objective of the study was to study the relationship between a Mediterranean diet and outcomes of assisted reproduction techniques in subfertile couples in an Italian population., Study Design: This was a prospective cohort study, conducted in an Italian fertility clinic. Couples undergoing in vitro fertilization were interviewed on the day of oocyte retrieval to obtain information on personal and health history, lifestyle habits, and diet. Adherence to a Mediterranean diet was evaluated using a Mediterranean diet score. Relative risks and 95% confidence intervals for embryo transfer, clinical pregnancy, and live birth were calculated. Potential confounders were included in the equation model., Results: Among 474 women (mean age, 36.6 years, range, 27-45), 414 (87.3%) performed embryo transfer, 150 (31.6%) had clinical pregnancies, and 117 (24.7%) had live births. In a model including the potential confounders (age, leisure physical activity, body mass index, smoking, daily calorie intake, and previous failed in vitro fertilization cycles), findings showed that the Mediterranean diet score was not significantly associated with in vitro fertilization outcomes. Adjusted analyses were performed in strata of age, previous assisted reproduction technique cycles, and reasons for infertility, with consistent findings. The only exception was observed in women >35 years old with an intermediate Mediterranean diet score, who showed a lower risk of not achieving clinical pregnancy (adjusted relative risk, 0.84, 95% confidence interval, 0.71-1.00, P = .049)., Conclusion: No clear association was observed between adherence to a Mediterranean diet and successful in vitro fertilization., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Introduction: Being able to have children could have an important positive effect on the future lives of pediatric cancer survivors. Working at a cancer institute makes us responsible for filling the gaps in our knowledge in this area of patient care., Methods: We describe our activities in a series of young females diagnosed with cancer and evaluated for fertility preservation options. We discuss the developed skills and organization as well as the practical difficulties encountered in managing fertility preservation., Results: Since September 2012, laparoscopy and cryopreservation of cortical ovarian tissue has been performed in 16 girls (with ovary transposition in 3, and after several cycles of chemotherapy in 5) and egg banking in 4 young women (before chemotherapy in 2 and several years after treatment in 2)., Conclusions: Recommendations on fertility preservation indicate that discussing the problems early on is crucial to future success. It is unthinkable to simply provide information and offer the opportunity to choose a fertility preserving technique without helping and accompanying patients and their families in their decisions and choices on the matter.

Objective: To evaluate whether iron contained in ovarian endometriomas can diffuse through the cyst wall and negatively affect ovarian function., Design: Prospective case series., Setting: Infertility unit in an academic setting., Population: Thirty-nine infertile women with unilateral endometriomas who underwent in vitro fertilization., Methods: Iron and ferritin assessments in pools of follicular fluids obtained from affected and contralateral intact gonads., Main Outcome Measures: Iron and ferritin concentrations., Results: Follicular fluid iron content did not differ between the two gonads. The median [interquartile range (IQR)] follicular concentrations in the affected and unaffected ovaries were 59 (IQR 44-74) and 59 (IQR 47-73) μg/dL, respectively (p = 0.77). Conversely, ferritin concentration was significantly higher in affected gonads. The median (IQR) concentrations of ferritin in the affected and unaffected ovaries were 57 (IQR 31-146) and 33 (IQR 23-67) μg/mL, respectively (p = 0.026). When considering together the 78 studied ovaries, no significant correlations emerged between follicular iron and ferritin and variables reflecting ovarian responsiveness and oocyte developmental competence., Conclusions: Iron may diffuse from ovarian endometriomas into the adjacent ovarian tissue. However, this phenomenon does not appear to markedly affect ovarian function. Some effective biological mechanisms such as ferritin storage may effectively sequester free iron, so limiting its detrimental effects., (© 2015 Nordic Federation of Societies of Obstetrics and Gynecology.)

Purpose: Aim of this study was to investigate the association between congenital malformations and type of conception (spontaneous or medically assisted)., Methods: This is a population based study using data from the regional data base of Lombardy, a Northern Italian Region with a population of about 10 million inhabitants. Included in the study were 277,043 neonates born in Lombardy during the study period 2010-2012. Adjusted and unadjusted odds ratios (OR), and corresponding 95% confidence intervals (CI), of congenital abnormalities were calculated using unconditional multiple logistic regression., Results: A total of 7057 births (2.5%) were reported after non spontaneous conception. Overall, the frequency of birth defects was 4.4% among births after spontaneous conception and 6.7% among births after non spontaneous ones (OR = 1.67, 95%CI = 1.5-1.9). The association disappeared after taking into account the confounding effect of maternal age and factors associated with non spontaneous conception. The crude OR of abnormalities was higher than unity for any defect (OR = 1.67, 95%CI = 1.5-1.9), multiple defects (OR = 1.76, 95%CI = 1.3-2.3), cardiovascular (OR = 2.05, 95%CI = 1.8-2.4), musculoskeletal (OR = 2.05, 95%CI = 1.7-2.5) and metabolic system abnormalities (OR = 1.97, 95%CI = 1.1-3.5). Almost all these associations, however, disappeared after taking into account potential confounding with the exception of musculoskeletal defects (adjusted OR = 1.31, 95%CI = 1.1-1.6). In this case also, if adjustment for multiple comparison is taking into account, results did not reach statistical significance., Conclusions: The results of this analysis confirm the recently emerging view that the increased frequency of birth defects observed after ART/medically induced ovulation only is largely due to confounders.

Study Question: Do the Bologna criteria for poor responders successfully identify women with poor IVF outcome?, Summary Answer: The Bologna criteria effectively identify a population with a uniformly low chance of success., What Is Already Known: Women undergoing IVF who respond poorly to ovarian hyper-stimulation have a low chance of success. Even if improving IVF outcome in this population represents a main priority, the lack of a unique definition of the condition has hampered research in this area. To overcome this impediment, a recent expert meeting in Bologna proposed a new definition of poor responders ('Bologna criteria'). However, data supporting the relevance of this definition in clinical practice are scanty., Study Design, Size, Duration: Retrospective study of women undergoing IVF-ICSI between January 2010 and December 2012 in two independent infertility units. Women could be included if they fulfilled the definition of poor ovarian response (POR) according to Bologna criteria prior to initiation of the cycle. Women were included only for one cycle. The main outcome was the live birth rate per started cycle. The perspective of the cost analysis was the one of the health provider., Participants/materials, Setting, Methods: Three-hundred sixty-two women from two independent Infertility Units were selected. A binomial distribution model was used to calculate the 95% CI of the rate of success. Characteristics of women who did and did not obtain a live birth were compared. A logistic regression model was used to adjust for confounders. The economic analysis included costs for pharmacological compounds and for the IVF procedure. The benefits were estimated on quality-adjusted life years (QALY). To develop the model, we used the local life-expectancy tables, we applied a 3% discount of life years gained and we used a 0.07 improvement in quality of life associated with parenthood. Sensitivity analyses were performed varying the improvement of the quality of life and including/excluding the male partner. The reference values for cost-effectiveness were the Italian and the local (Lombardy) gross domestic product (GDP) pro capita per year in the studied period and the upper and lower limits suggested by NICE., Main Results and the Role of Chance: Overall, 23 women had a live birth (6%, 95% CI: 4-9%), in line with the previous evidence. This proportion did not significantly differ in the different subgroups of poor responders. Positive predictive factors of success were previous deliveries (adjusted OR = 3.0, 95% CI: 1.1-8.7, P = 0.039) and previous chemotherapy (adjusted OR = 13.9, 95% CI: 2.5-77.2, P = 0.003). Age, serum AMH, serum FSH and antral follicle count were not significantly associated with live birth. The total cost per live birth was 87 748 Euros, corresponding to 49 919 Euros per QALY. This is above both the limits suggested by NICE for cost-effectiveness and the Italian and local GDP pro capita. Sensitivity analyses mainly support the robustness of the conclusion., Limitations, Reasons for Caution: We lack a control group and we cannot thus exclude that an alternative definition of poor responders may be equally if not more valid. Moreover, independent validations are warranted prior to concluding that IVF is not cost-effective. Women should thus not be denied treatment based on our findings. Noteworthy, there is also not yet a consensus on the most appropriate economic model to be used., Wider Implications of the Findings: We recommend the use of the Bologna criteria when designing future studies on poor responders. Large multi-centred international studies are now required to draw definite conclusions on the economic profile of IVF in this situation., (© The Author 2014. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Levothyroxine has been shown to enhance pregnancy outcomes in women with hypothyroidism requiring in vitro fertilization (IVF). However, the precise magnitude of these benefits remains to be determined. In particular, it has yet to be clarified whether levothyroxine may fully overcome the detrimental effects of hypothyroidism or, conversely, whether affected women remain at reduced prognosis for pregnancy outcomes., Methods: Patients who underwent IVF-intracytoplasmic sperm injection (ICSI) over a 3-year period were reviewed. Cases were deemed eligible if they were diagnosed with clinical or subclinical hypothyroidism and were receiving levothyroxine. Controls were two subsequently age-matched euthyroid women for every case. Both cases and controls were selected only if serum thyrotropin was ≤2.5 mIU/L., Results: In total, 137 women with treated hypothyroidism and 274 controls were included. Baseline characteristics of the two study groups were similar with the exception of body mass index, which was slightly higher among the cases (22.9±3.9 vs. 21.9±3.3 kg/m2, p=0.013). Most IVF-ICSI cycle outcome variables were also similar, with the exception of a higher rate of cancellation for poor response (3.6% vs. 0.7%, p=0.04), a longer duration of stimulation (10.9±2.2 vs. 10.1±2.0 days, p=0.001), a higher proportion of women failing to obtain viable embryos (17% vs. 7%, p=0.006), and a lower fertilization rate (75% vs. 86%, p=0.017) among cases. Conversely, the clinical pregnancy rate per started cycle, the implantation rate, and the live birth rate per started cycle did not differ; they were 36% and 34% (p=0.93), 28% and 22% (p=0.11), and 30% and 27% (p=0.50) in cases and controls, respectively. Subgroup analyses comparing women with (n=79) and without (n=58) thyroid autoimmunity and comparing women who were diagnosed with overt hypothyroidism (n=70) or subclinical hypothyroidism (n=67) failed to identify relevant differences., Conclusions: In our population, IVF-ICSI outcome was not significantly hampered in women with adequately treated hypothyroidism. The magnitude of the detected differences in cycle outcome was mild, and we failed to document any differences for the most relevant outcomes, i.e., pregnancy rate, implantation rate, and delivery rate. In conclusion, adequate levothyroxine treatment maintaining thyrotropin serum levels below 2.5 mIU/L may overcome the detrimental effects of hypothyroidism.

Objective: To assess the impact of rectovaginal endometriosis on pain at intercourse and sexual functioning., Design: Case-control study., Setting: Academic department., Patient(s): Case subjects were women with rectovaginal endometriosis (n = 100), and control subjects were women with a surgical diagnosis of peritoneal and/or ovarian endometriosis (n = 100) or without endometriosis (n = 100)., Intervention(s): Questionnaires (visual analogue scale [VAS] and revised Sabbatsberg Sexual Self-Rating Scale [SRS])., Main Outcome Measure(s): Frequency and severity of deep dyspareunia and sexual functioning., Result(s): Deep dyspareunia was reported by 67/100 (67%) women in the rectovaginal endometriosis group, 52/99 (53%) in the peritoneal and/or ovarian endometriosis group, and 24/93 (26%) in the nonendometriosis group. Mean ± SD dyspareunia VAS scores were, respectively, 44 ± 34, 30 ± 32, and 13 ± 26. Women in both endometriosis groups performed significantly worse than those in the nonendometriosis group in several SRS subdomains. No significant difference in overall SRS score was detected between women in the two endometriosis groups., Conclusion(s): Women with endometriosis experienced more frequent and severe deep dyspareunia and worse sexual functioning compared with women without endometriosis, whereas differences between women with diverse endometriosis forms were marginal., (Copyright © 2012 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: This study aims to investigate the clinical relevance of confined placental mosaicism (CPM) detected at chorionic villous sampling (CVS) and to identify risk factors for this condition., Method: Women diagnosed with CPM between January 2005 and December 2009 were identified. They were matched to women with unremarkable CVS in a 1 : 2 ratio by study period and contacted by phone for interview., Results: One hundred fifteen exposed and 230 unexposed women were selected. Baseline characteristics did not differ between the study groups apart from maternal body mass index, which is mildly higher in the CPM group (+0.6 kg/m(2), p = 0.047), and maternal age, which is higher in women with type III CPM (39.7 ± 2.6 vs 37.1 ± 3.2 years, p = 0.005). A higher frequency of gestational hypertension was observed in exposed women (10% vs 2%) (p = 0.003). Small for gestational age newborns were more frequent in women with type I CPM (15% vs 5%, p = 0.03). The incidence of other main complications of pregnancy (stillbirth, prematurity, preeclampsia and gestational diabetes mellitus) was similar. Neonatal complications and subsequent infant health and development did not also differ., Conclusion: Women with the diagnosis of CPM at CVS can be generally reassured regarding the course of pregnancy and infant health and development., (© 2012 John Wiley & Sons, Ltd.)

Purpose: Aims of the study were to determine the risk of stroke recurrence in a case series of women with a history of ischemic stroke and to review current available literature on this issue., Methods: Charts from patients referring to the obstetrical service of our Institute were reviewed to identify pregnant women with a history of ischemic stroke. Demographic, historical and clinical data were collected from outpatient and inpatient charts. Women were contacted at least 6 months after delivery to assess maternal and neonatal health. A review of the literature regarding pregnancy in women with a history of ischemic stroke was also performed., Results: Twenty-four pregnant women with a history of ischemic stroke referred to our Institution. All women received prophylaxis to prevent stroke recurrence during pregnancy. No recurrent episode was recorded in our series (0.0 %, 95% CI 0.0-11.3 %). One woman had a TIA. Considering collective data from the literature and from the present study, five cases of stroke recurrence out of 184 pregnancies were identified, corresponding to a rate of 2.7 % (95% CI 1.0-5.8 %). All of them were under prophylactic treatment at the time of stroke. Thrombophilia and preeclampsia may represent predisposing conditions for recurrence during pregnancy., Conclusions: Stroke recurrence in pregnant women with a history of ischemic stroke is uncommon, but not rare and prophylactic treatment does not fully protect against it. Further evidence is required to better clarify clinical factors predisposing to recurrence.

Background/aims: Perinatal environmental exposure may affect fetal development and reprogram the developing organism for adult-onset disease. In this case-control study, we aimed at assessing this pathogenetic model in endometriosis., Methods: Consecutive patients with a first laparoscopic diagnosis of endometriosis were selected as cases. Controls were women who underwent laparoscopy during the same study period, but who were found to be free of the disease. Selected women and their mothers were interviewed., Results: Ninety-one women with endometriosis and 82 controls were selected. Handedness, a variable believed to be determined prenatally by hormonal environment in utero significantly differed between the study groups. Women with the disease were less likely to be left- or mixed-handed (adjusted OR: 0.24, 95% CI: 0.08-0.71). In contrast, we failed to detect any association with birth order, maternal age, smoking, nausea, weight gain, prematurity, birth weight and breast-feeding., Conclusions: Our results generally do not support the view that in utero exposure may play a major role in the pathogenesis of endometriosis. The association with handedness, however, is intriguing in this regard and deserves further investigation., (Copyright © 2011 S. Karger AG, Basel.)

Objectives: Some controversy exists for the potential association of the plasminogen activator inhibitor-1 (PAI-1) gene polymorphism 4G/5G and susceptibility to endometriosis. To clarify this issue, we have examined the prevalence of this polymorphism in a case-control study in the Italian population., Study Design: The PAI-1 4G/5G polymorphism was evaluated in n=368 reproductive year aged Caucasian women who underwent gynaecological laparoscopy for chronic pelvic pain, infertility, ovarian cysts and myomas. A second group of controls included n=329 normal subjects., Results: The 697 women enrolled were divided as follows: the endometriosis group (n=204), the gynaecological control group (n=164) and the general population control group (n=329). No statistical significant differences emerged between endometriosis patients and gynaecological controls with regard to the allele frequencies and co-dominant and dominant models of genotype distribution. A borderline statistical difference was only observed for the recessive model of inheritance in which, contrary to previous findings, the PAI-1 4G/4G genotype seems to be less linked to the disease development., Conclusion: The findings reported herein do not support the previously reported data indicating a greater susceptibility to endometriosis in patients harbouring the PAI-1 4G/5G and 4G/4G genotypes and exclude a significant role of polymorphism in endometriosis development.

Objective: To report the results of the routine application of Italian guidelines that apply to infertile patient candidates for any assisted reproduction technique (ART). The guidelines recommend performing a karyotype analysis in each couple and the screening test for mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) in one of the two partners., Design: Case series., Setting: Infertility unit., Patient(s): Two thousand seven hundred ten consecutive infertile couple candidates for ART., Intervention(s): Peripheral blood evaluation of karyotype and CFTR gene., Main Outcome Measure(s): Frequency of aberrant karyotype and mutated CFTR gene., Result(s): A total of 74 aberrant karyotypes were diagnosed, corresponding to 1.3% (95% confidence interval [CI], 0.9%-1.7%) in women and to 1.5% (95% CI, 1.0%-2.0%) in men. In men, the frequency of chromosomal abnormalities differed according to the treatment group (0.3%, 1.1%, and 2.2% in IUI, IVF, and ICSI, respectively). The same was not observed in women. Excluding the 5T variant, 3.8% of the screened patients showed a mutated CFTR gene (95% CI, 3.1%-4.5%), and the mutation was found in both partners in 0.2% of the couples (95% CI, 0.0-0.4%)., Conclusion(s): The frequency of aberrant karyotypes is higher in infertile couples than in the general population, whereas the frequency of a mutation of the CFTR gene is similar.

Objective: To clarify whether the presence of ovarian endometriomas is associated with a reduced responsiveness to ovarian hyperstimulation., Design: Observational study., Setting: University teaching hospital., Patient(s): Women selected for in vitro fertilization-intracytoplasmic sperm injection (IVF-ICSI) cycles who were found to have unilateral ovarian endometriomas and who did not undergo previous ovarian surgery., Intervention(s): Ovarian hyperstimulation using gonadotropins., Main Outcome Measure(s): Number of codominant follicles (mean diameter >15 mm) in the affected and in the contralateral intact gonads., Result(s): Thirty-six patients were enrolled. They underwent 56 IVF-ICSI cycles. The number of codominant follicles in the intact and affected ovaries were 4.0 +/- 2.2 and 3.0 +/- 1.7, respectively (P=.01). This difference corresponded to a mean reduction (95% confidence interval [CI]) of 25% (6%-44%). This deleterious effect was more evident in women with larger cysts, in those with more than one cyst, and in those who were more responsive to ovarian hyperstimulation., Conclusion(s): The presence of ovarian endometriomas is associated with a reduced responsiveness to gonadotropins.

An autoimmune etiology has been suggested for endometriosis mostly on the basis of an increased prevalence of autoimmune diseases in affected women. Cytotoxic T lymphocyte antigen (CTLA) 4 gene is recognized as a primary determinant for autoimmunity since specific polymorphisms have been associated with predisposition to most autoimmune disorders. This study was aimed to evaluate whether two variants of CTLA4 gene might be associated with endometriosis in an Italian population. We examined the +49A/G polymorphism and the CT60A/G dimorphism in n = 146 endometriosis subjects classified according to Holt and Weiss criteria. Controls were represented by n = 165 women without laparoscopic evidence of the disease. We found no statistically significant difference in the genotype frequencies between women with and without endometriosis. The proportion of the mutant G allele of the +49A/G polymorphism in the former and in the latter group resulted 34 and 30%, respectively. The proportion of the susceptible G allele of the CT60 A/G dimorphism resulted 51% in both groups. No association was demonstrated between the polymorphisms and the clinical forms of the disease and no susceptibility haplotypes were found. These findings suggest that endometriosis aetiology is not primarily associated with the development of CTLA4-linked autoimmunity.

Background: A specific and still poorly investigated issue in the field of infertility is represented by the impact that the need for IVF techniques may have on health-related quality of life (HRQoL)., Methods: A total of 1000 consecutive couples (1000 women and 1000 men) were invited to complete the Health Survey Short Form (SF-36) questionnaire separately, prior to initiating their first IVF attempt in our unit. Patients were also invited to report about demographic and clinical characteristics., Results: A total of 1936 (96.8%) agreed to participate. Male SF-36 scores were higher than those reported by women. Duration of infertility and previous IVF attempts significantly influenced HRQoL (P < 0.01). When scores were plotted in relation to the normative source of the Italian general population stratified by gender, corresponding age and geographical area, the subjective health profile did not significantly differ from the normative sample for both women and men., Conclusion: The need for IVF did not seem to markedly influence subjective health status. Conversely, duration of infertility and failure to achieve a pregnancy through IVF might have a negative impact.

Preterm birth remains one of the most serious problems facing obstetricians. The aim of this study was to investigate the risk factors for spontaneous preterm birth in northern Italy. Nine different collaborating institutions participated in this multicenter case-control study. Cases were defined as women who were spontaneously delivered of a live singleton newborn between 20 and 37 weeks of gestation. One control was matched to each case by delivery date, maternal age and parity. Seven hundred and fifty-four cases and 754 controls were available for data analysis. Demographic and clinical characteristics were obtained using a standardized questionnaire. At the time of hospital admission, urine and cervico-vaginal samples were collected and tested for bacterial infections and bacterial vaginosis, respectively. Variables found to be statistically significant in the univariate analysis were entered in a multivariate model to examine their independent effects. In order of decreasing odds ratios (ORs), the factors that showed a significant association with preterm delivery were: previous preterm birth (OR 5.7, confidence interval (CI) 2.5-12.9); second-trimester miscarriages (OR 4.4, CI 1.3-15.3); genital bleeding before 24 weeks of gestation (OR 2.5, CI 1.6-3.8); bacterial vaginosis (OR 2.0, CI 1.3-3.1), and previous genital infections (OR 1.6, CI 1.1-2.5). This study confirms that infections play a role in the etiology of preterm birth and that reproductive history is still the most important factor in identifying women at increased risk., (Copyright 2002 S. Karger AG, Basel)