Cognitive, emotional, communicative, and motor development in children born from couple's gametes cryopreserved oocytes. A 20 years single-center experience.

OBJECTIVE: To study if social and emotional, communicative, cognitive, motor development of children born from cryopreserved oocytes are comparable to general population. DESIGN: Survey study. EXPOSURE: This is a single-center population study, focusing on all children born from cycles of in vitro fertilization of cryopreserved oocytes at Humanitas Fertility Center from January 1st,2003, until December 31st, 2021. MAIN OUTCOME MEASURES: General information about birth history were collected from all parents. Then, screening for developmental delay was performed by administration of a questionnaire, edited according to milestones set for age by the Center for Disease Control and Prevention. Primary outcomes included the percentage of children, for each age range, that reached related milestones. In children younger than 6 years of age, milestones were considered to be reached by each age-based population subgroup studied when ≥ 75 % of included children expressed the tested competences. RESULTS: A total of 355 live births fulfilled the inclusion and exclusion criteria and were included in the study. Results showed that each age-based population subgroup, younger than 6 years of age, scored ≥ 75 % in all the milestones included in the questionnaire. In preadolescents and adolescents, it was noted a decrease in unstructured in-person socializing. Indeed, milestones that scored the lowest values, based on parents' judgement, included tasks concerning peer-to-peer interaction (72.31%) and sexuality and sentimental relationships (63.08%). CONCLUSIONS: Results indicated that the achievement of emotional, communicative, cognitive, and motor milestones in infants, toddlers, and preschoolers was comparable to the general pediatric population. Similarly, emotional wellbeing and social engagement in school-aged children, preadolescents, and adolescents were in line with their peers.

Predicting the pregnancy outcome: Uncovering the link between ß-hCG, patient factors and live birth in IVF.

OBJECTIVE: The objectives of the study were to correlate live birth rate with the initial level of ß-hCG in all patients undergoing embryo transfer and develop a predictive model of live birth based on patients' and assisted reproductive technology (ART) characteristics. STUDY DESIGN: Single-center retrospective cohort study, including a total of 7587 positive first serum ß-hCG from women who performed fresh and frozen embryo transfer. Twenty-one variables related to patient characteristics and treatment modalities were analyzed by step-wise univariate analysis followed by multivariate analysis. The study included women between 18 and 45 years with a positive (>20 IU/L) serum ß-hCG between January 2011 and December 2020 while it excluded cycles from donation of gametes, PGT and >3 embryos transferred simultaneously. MAIN RESULTS AND THE ROLE OF CHANCE: Among the positive serum ß-hCG measurements 5085 (67.0 %) resulted in live births. ß-hCG was higher in the live birth group (691 IU/L) compared to the failed pregnancies group (304 IU/L) (p500 IU/mL provided a positive predictive value for live birth of 85.3 % (95 %CI 84.0-86.4). Failed pregnancies were more common among older maternal and paternal age. Previous abortions were more common in the failed pregnancies group (25.0 %) compared to the live birth group (19.4 %). The most common indication to treatment was male infertility, accounting for a larger portion in the live birth group (41.7 %). At multivariate analysis, the factors independently associated with live birth were: first serum ß-hCG (OR 1.35, 95 %CI 1.32-1.37), maternal age (OR 0.93, 95 %CI 0.91-0.95), previous abortions (OR 0.77, 95 % CI 0.68-0.88). The number of embryos transferred showed a positive correlation below a maternal age of 39 (<35 years old OR 1.60, CI 95 % 1.32-1.94; <39 years old OR 1.27 CI 95 % 1.09-1.47). The prediction model incorporating these four variables resulted in a sensitivity and specificity with an area under the ROC curve of 0.798. CONCLUSION: The study confirms the importance of the first value of ß-hCG and proposes a predictive model that takes into account maternal age, number of embryos transferred, and obstetric history, thereby aiding in couples' counseling and ultimately improve patients' care.

Untangling the independent effect of endometriosis, adenomyosis, and ART-related factors on maternal, placental, fetal, and neonatal adverse outcomes: results from a systematic review and meta-analysis.

BACKGROUND: Women with endometriosis may constitute a group at a particularly increased risk of pregnancy-related complications. Furthermore, women selected for assisted reproductive technology (ART) are exposed to additional endocrinological and embryological factors that have been associated with adverse pregnancy outcomes. OBJECTIVE AND RATIONALE: This study aimed to investigate the independent effect of endometriosis, adenomyosis, and various ART-related factors on adverse maternal, placental, fetal, and neonatal outcomes. SEARCH METHODS: Published randomized controlled trials, cohort studies, and case-control studies were considered eligible. PubMed, MEDLINE, ClinicalTrials.gov, Embase, and Scopus were systematically searched up to 1 March 2024. This systematic review and meta-analysis was performed in line with the PRISMA and the MOOSE reporting guidelines. To thoroughly investigate the association between endometriosis/adenomyosis and adverse pregnancy outcomes, sub-analyses were conducted, whenever possible, according to: the method of conception (i.e. ART and non-ART conception), the endometriosis stage/phenotype, the coexistence of endometriosis and adenomyosis, any pre-pregnancy surgical treatment of endometriosis, and the form of adenomyosis. The odds ratio (OR) with 95% CI was used as effect measure. The quality of evidence was assessed using the GRADE approach. OUTCOMES: We showed a higher risk of placenta previa in women with endometriosis compared to controls (34 studies, OR 2.84; 95% CI: 2.47, 3.26; I2 = 83%, moderate quality). The association was observed regardless of the method of conception and was particularly strong in the most severe forms of endometriosis (i.e. rASRM stage III-IV endometriosis and deep endometriosis (DE)) (OR 6.61; 95% CI: 2.08, 20.98; I2 = 66% and OR 14.54; 95% CI: 3.67, 57.67; I2 = 54%, respectively). We also showed an association, regardless of the method of conception, between endometriosis and: (i) preterm birth (PTB) (43 studies, OR 1.43; 95% CI: 1.32, 1.56; I2 = 89%, low quality) and (ii) cesarean section (29 studies, OR 1.52; 95% CI: 1.41, 1.63; I2 = 93%, low quality). The most severe forms of endometriosis were strongly associated with PTB. Two outcomes were associated with adenomyosis both in the main analysis and in the sub-analysis that included only ART pregnancies: (i) miscarriage (14 studies, OR 1.83; 95% CI: 1.53, 2.18; I2 = 72%, low quality) and (ii) pre-eclampsia (7 studies, OR 1.70; 95% CI: 1.16, 2.48; I2 = 77%, low quality). Regarding ART-related factors, the following associations were observed in the main analysis and confirmed in all sub-analyses conducted by pooling only risk estimates adjusted for covariates: (i) blastocyst stage embryo transfer (ET) and monozygotic twinning (28 studies, OR 2.05; 95% CI, 1.72, 2.45; I2 = 72%, low quality), (ii) frozen embryo transfer (FET) and (reduced risk of) small for gestational age (21 studies, OR 0.59; 95% CI, 0.57, 0.61; P < 0.00001; I2 = 17%, very low quality) and (increased risk of) large for gestational age (16 studies, OR 1.70; 95% CI, 1.60, 1.80; P < 0.00001; I2 = 55%, very low quality), (iii) artificial cycle (AC)-FET and pre-eclampsia (12 studies, OR 2.14; 95% CI: 1.91-2.39; I2 = 9%, low quality), PTB (21 studies, OR 1.24; 95% CI 1.15, 1.34; P < 0.0001; I2 = 50%, low quality), cesarean section (15 studies, OR 1.59; 95% CI 1.49, 1.70; P < 0.00001; I2 = 67%, very low quality) and post-partum hemorrhage (6 studies, OR 2.43; 95% CI 2.11, 2.81; P < 0.00001; I2 = 15%, very low quality). WIDER IMPLICATIONS: Severe endometriosis (i.e. rASRM stage III-IV endometriosis, DE) constitutes a considerable risk factor for placenta previa and PTB. Herein, we recommend against superimposing on this condition other exposure factors that have a strong association with the same obstetric adverse outcome or with different outcomes which, if coexisting, could determine the onset of an ominous obstetric syndrome. Specifically, we strongly discourage the use of AC regimens for FET in ovulatory women with rASRM stage III-IV endometriosis or DE. We also recommend single ET at the blastocyst stage in this high-risk population. REGISTRATION NUMBER: CRD42023401428.

Reproductive and obstetric outcomes in TESE-ICSI cycles: A comparison between obstructive and non-obstructive azoospermia.

PURPOSE: Comparison of intracytoplasmic sperm injection cycles with testicular sperm extraction in obstructive azoospermia and non-obstructive azoospermia are limited, and few studies have addressed obstetric and neonatal outcomes. DESIGN: This study analyzed couples who underwent testicular sperm extraction-intracytoplasmic sperm injection cycles for obstructive azoospermia and non-obstructive azoospermia to determine whether impaired spermatogenesis in non-obstructive azoospermia patients would lead to worse reproductive outcomes and higher rates of pregnancy complications and fetal anomalies. This study is a retrospective, single-center analysis of all testicular sperm cycles performed between January 1, 2001 and December 31, 2020. RESULTS: A total of 392 couples were considered in the study, leading to 1066 induction cycles, 620 (58.2%) from patients with obstructive azoospermia and 446 (41.8%) from non-obstructive azoospermia. The cumulative delivery rate did not significantly differ between the two groups (34% vs. 31%; p = 0.326). The miscarriage rate was similar between obstructive azoospermia and non-obstructive azoospermia patients. Fertilization rate instead showed a statistically significant difference (obstructive azoospermia: 66.1 ± 25.7 vs. non-obstructive azoospermia: 56.1 ± 27.0; p < 0.001). The overall maternal complication rate in the non-obstructive azoospermia group was higher (10.7% vs. 18.4%; p = 0.035), but there was no statistical significance for each pathology. There was no statistical difference in gestational age between the two groups for both single and twin pregnancies. Seven cases of congenital defects occurred in the obstructive azoospermia group, while two cases occurred in the non-obstructive azoospermia group. CONCLUSIONS: Despite impaired spermatogenesis in non-obstructive azoospermia patients, there were no substantial differences in reproductive outcomes compared to patients with obstructive azoospermia, even in terms of obstetric safety and neonatal well-being.

High sperm DNA fragmentation: do we have robust evidence to support antioxidants and testicular sperm extraction to improve fertility outcomes? a narrative review.

To date, infertility affects 10% to 15% of couples worldwide. A male factor is estimated to account for up to 50% of cases. Oral supplementation with antioxidants could be helpful to improve sperm quality by reducing oxidative damage. At the same time, there is a growing interest in the literature on the use of testicular sperm in patients with high DNA fragmentation index (DFI). This narrative review aims to evaluate the effectiveness of supplementation of oral antioxidants in infertile men with high DFI compared to testicular sperm retrieval. The current evidence is non-conclusive because of serious risk of bias due to small sample sizes and statistical methods. Further large well-designed randomised placebo-controlled trials are still required to clarify the exact role of these to different therapeutic approaches.

Steps forward in embryo transfer technique: a retrospective study comparing direct versus afterload catheters at different time frames.

PURPOSE: To assess whether embryo transfer (ET) technique can influence the clinical pregnancy rate (CPR) and its correlation with the embryo transfer difficulty. DESIGN: This single center retrospective cohort analysis of fresh and frozen single blastocyst transfers performed between January 2016 and December 2021 included fresh and frozen single blastocyst transfers performed during the study timeframe. Direct technique was the only one used from January 2016 to September 2017. From September 2017 to March 2019, the choice between the two techniques was given by randomization, due to a clinical trial recruitment. From April 2019, only the afterload technique was used. Preimplantation genetic testing cycles and gamete donation procedures and cycles performed with external gametes or embryos were excluded. CPR was the primary outcome, while difficult transfer rate the secondary one. Univariate and multivariate logistic regressions were performed. RESULTS: During the period, 8,189 transfers were performed. CPR of the afterload group resulted significantly higher compared to the direct group (44.69% versus 41.65%, OR 1.13, 95% CI 1.02-1.25, p = 0.017) and the rate of difficult transfers two-thirds lower (9.06% versus 26.85%, OR 0.27, 95% CI 0.24-0.31, p < 0.001). CONCLUSION: Our study demonstrated that CPR is significantly affected by the ET technique. In particular, with the afterload protocol, both CPR and easy transfer rates increased. TRIAL REGISTRATION: http://clinicaltrials.gov registration number: NCT05364528, retrospectively registered on 3rd of May 2022.

A Monocentric Randomized Controlled Clinical Trial to Compare Single- and Double-Lumen Needles in Oocyte Retrieval Procedure in Assisted Reproductive Technologies.

The purpose was to determine any difference in outcomes, primarily in terms of number of retrieved oocytes per procedure, between two different needles used for oocytes retrieval procedure in Assisted Reproductive Technologies: the single-lumen needle (SLN) versus the double-lumen needle (DLN) with follicle flushing after aspiration. This randomized controlled trial included oocyte retrieval (OR) cycles for IVF and ICSI performed in 18 to 42-year-old women between March 2019 and January 2021 at a tertiary-care Fertility Center. A total of 200 ORs were randomized, 100 in each group. The mean number of retrieved oocytes was not different between groups (10.2 ± 6.5 for DLNs vs. 10.7 ± 7.0 for SLNs, p = 0.810). No significant differences were observed also in terms of number of retrieved oocytes/punctured follicles (83.0% ± 27.0% vs. 81.0% ± 22.0%, p = 0.916), number of retrieved oocytes/follicles at trigger (78.0% ± 29.0% vs. 78.0% ± 27.0%, p = 0.881), number of mature oocytes (7.6 ± 5.3 vs. 8.0 ± 5.1, p = 0.519), and pregnancy rate (27% vs. 23%, p = 0.514). However, the time required to retrieve each oocyte was longer using the DLN (1.5 ± 1.3 vs. 1.1 ± 0.9 minutes, p = 0.002). The present study confirmed the new perspectives on the sole use of SLNs in terms of saving time, without affecting the number of retrieved oocytes. Trial registration number and date of registration NCT03611907; July 26, 2018.

Why are they not coming back? A single-center follow-up study on oncological women oocyte's storing for fertility preservation.

Introduction: Oocyte cryopreservation is a valid option for female cancer patients to preserve fertility. The number of patients undergoing fertility preservation (FP) cycles has increased over the past years. Nevertheless, the rates of patients returning to use their cryopreserved material have shown to be considerably low, ranging from 5-8%, but significant data regarding the reasons of such low return rates are scarce. Methods: This study is a single-center follow-up retrospective study evaluating the return rate of oncological women who underwent FP at a tertiary care Fertility Center and assessing the reasons influencing the patients who did not return. Data about patients who returned to attempt pregnancy were retrieved from internal registries. Non-returned patients were assessed with a standardized phone survey investigating health condition, marital status and family projects, spontaneous conceptions, and the reasons why they had not returned to use their gametes. A univariate analysis between returned and non-returned patients was performed. Results: Of the 397 patients who received counseling about FP, 171 (43.1%) underwent oocyte cryopreservation between 2001 and 2017. Nine (5%) died, and 17 (10%) were lost at follow-up. A total of 20 patients (11.7%) returned and 125 did not. In the non-returned group, 37 (29.6%) did not have a partner, 10 (8%) had a previous spontaneous conception, and 15 (12%) had recurrent malignancy at the time of follow-up. In the univariate analysis, younger age at freezing (31.8±6.2 vs. 35.2±4.7; p 0.018), lack of a partner (p 0.002), type of cancer (other than breast cancer; p 0.024) were the significant factors in the non-returned group. As for the personal reason for not coming back, patients mainly answered as follows: lack of a partner (29, 23.2%), the desire for spontaneous motherhood (24, 19.2%), previous spontaneous pregnancies after FP procedures (16, 12.8%), and still ongoing hormonal therapy for breast cancer (13, 10.4%). All patients confirmed their will to keep the storage of their oocytes. Discussion: The impact of a cancer diagnosis on a woman's maternal desire, sentimental status and life priorities should be studied more thoroughly. Studies investigating hormonal therapy suppression in breast cancer patients seeking pregnancy should be encouraged. Clinical trial registration: https://clinicaltrials.gov, identifier NCT05223764.

Ectopic pregnancy risk factors in infertile patients: a 10-year single center experience.

The present retrospective study included both intrauterine insemination and in vitro assisted reproductive technologies (ART) procedures performed from January 2009 to December 2018 at a tertiary-care Fertility Centre. The purpose was to assess the incidence of ectopic pregnancy (EP) in infertile population who undergoes ART and to identify any risk factor impacting the occurrence of EP after ART. Among 27,376 cycles, 7352 pregnancies were achieved, of which 132 were EPs, the 1.80% (95% CI 1.5-2.1) of all pregnancies. In fresh embryo transfer cycles, a history of prior pelvic adhesions showed the greatest impact on the incidence of EP (aOR 2.49 95% CI 1.53-4.07 p < 0.001). Other factors associated with EP incidence were also identified, such as female age, basal FSH, the transfer of blastocyst embryos and difficulties during the embryo transfer procedure. In frozen embryo transfer cycles, the only factor influencing the incidence of EP was anti Müllerian hormone (AMH) serum concentration (aOR 0.81 95% CI 0.65-1.00, p = 0.048). To conclude, the incidence of EP observed was comparable to that reported after natural conception. On the other hand, pre-existing risk factors, traditionally more common in infertile population, appeared to influence the incidence of EP and should thus be modified if possible.

Luteinizing hormone supplementation in women with hypogonadotropic hypogonadism seeking fertility care: Insights from a narrative review.

The management of infertile women affected by hypogonadotropic hypogonadism (HH) or conditions mimicking it is particularly challenging. In the present narrative review, we aimed to synthesize the available evidence on the benefit (if any) of exogenous luteinizing hormone (LH) supplementation in this group of patients. Available data support LH supplementation in women with organic or functional HH. On the contrary, the benefit of exogenous LH on reproductive outcomes both in advanced maternal age patients and in cases of depletion of FSH and LH levels induced by GnRH analogues has not been demonstrated. unfortunately, the inhomogeneous study populations as well as the methodological heterogeneity between studies focused on women affected by conditions mimicking HH do not allow reliable conclusions to be drawn.

Oxidative Stress and Human Ovarian Response-From Somatic Ovarian Cells to Oocytes Damage: A Clinical Comprehensive Narrative Review.

Basic scientific research on human reproduction and oxidative damage has been extensively performed; however, a more clinical view is still lacking. As a result, exhaustive data on the influence of oxidative stress on human ovarian response and, consequently, on fertility are still lacking. This narrative review aims at summarizing the role of oxidative stress in different conditions associated to female infertility and to list some of the main antioxidant agents. A systematic literature search was performed in May 2022 to retrieve studies regarding the oxidative stress and the human ovarian response from somatic ovarian cells to oocytes damage. Only human studies were included and the authors focused their review, in particular, on clinical implications in order to define a new research perspective on the assessment of any eventual strategy to preserve women's fertility. Thereby, the authors evaluated the contribution of DNA repair pathways in improving women's fertility by reducing the DNA damage associated with aging or diseases, such as endometriosis or polycystic ovary syndrome, and eventually, in prolonging the reproductive lifespan after cancer treatment.

Impact of Thyroid Autoimmunity on Assisted Reproductive Technology Outcomes and Ovarian Reserve Markers: An Updated Systematic Review and Meta-Analysis.

Background: Thyroid autoimmunity (TAI) has a high prevalence among women of reproductive age. Investigating its possible impact on ovarian function and fertility is, thus, of utmost relevance. The aim of this systematic review and meta-analysis was to elucidate the effect of TAI on both assisted reproductive technology (ART) outcomes and ovarian reserve. Methods: This systematic review and meta-analysis was restricted to two groups of research articles investigating the association between TAI and: (1) autologous ART outcomes (i.e., fertilization rate [FR], implantation rate, clinical pregnancy rate [CPR], miscarriage rate, and live birth rate), (2) markers of ovarian reserve (i.e., anti-Müllerian hormone, basal follicle stimulating hormone, antral follicle count, and number of oocytes retrieved). Studies including women affected by overt hypo/hyperthyroidism were excluded. Relevant studies were identified by a systematic search in PubMed, MEDLINE, ClinicalTrials.gov, Embase, and Scopus, from database inception to May 1, 2022. Results: From a total of 432 identified publications, 22 studies were included in Group 1 and 26 studies in Group 2. The presence of TAI was associated with a higher risk of miscarriage (7606 participants, odds ratio [OR] 1.52, confidence interval [CI 1.14-2.01], p = 0.004, I2 = 53%), lower chance of embryo implantation (7118 participants, OR 0.72, [CI 0.59-0.88], p = 0.001, I2 = 36%), and live birth (11417 participants, OR 0.73, [CI 0.56-0.94], p = 0.02, I2 = 71%). These associations were no longer observed in a subgroup analysis of patients who exclusively underwent intracytoplasmic sperm injection (ICSI). The FR and CPR as well as the mean values of surrogate markers of oocyte quantity appeared not to be affected by TAI. Conclusions: This data synthesis suggest a higher risk of adverse ART outcomes in women with positive TAI. However, the reliability of these findings is hampered by the relatively low quality of the evidence and significant heterogeneity in many of the meta-analyses. The possible protective effect of ICSI is promising but should be confirmed in controlled prospective clinical trials. PROSPERO Registration ID: CRD42021236529.

Different actors for the same play: the impact of the embryologist performing the embryo transfer.

RESEARCH QUESTION: Does the embryologist performing the embryo transfer impact the cycle outcome, in terms of ongoing pregnancy rate (OPR)? DESIGN: This single-centre retrospective study analysed the results, corrected for main confounders, from 28 embryologists and 32 physicians who performed respectively 24,992 and 24,669 fresh embryo transfers (either at cleavage or blastocyst stage) during a 20-year period from January 2000 to December 2019, in a university-affiliated tertiary care assisted reproductive technology (ART) centre. Primary outcome was OPR, defined as the number of viable pregnancies that had completed at least 12 weeks of gestation on the total number of embryo transfers performed. The study also assessed whether the embryologist's experience, measured in terms of number of embryo transfers performed prior to the day of the procedure, had an impact on their performance. The secondary aim was to assess which variable, between the embryologist and physician, more significantly impacted OPR. RESULTS: The overall unadjusted OPR was 22.54%. The embryologist performing the embryo transfer was found to significantly affect the OPR (P < 0.0001), corrected for potential confounders. However, the physician factor made a slightly greater contribution to the model (likelihood ratio 21.86, P < 0.001 versus likelihood ratio 17.20, P < 0.0001). No significant association was found between the experience of the embryologist and OPR (P = 0.067). CONCLUSIONS: These results show how the 'human factor' influences the chances of a positive outcome in the final step of a high-tech procedure and underline the importance of implementing an operator quality performance programme (both for physicians and embryologists) to ensure the maintenance of benchmark results and eventually retrain underperforming operators.

Inflammatory Bowel Disease and Reproductive Health: From Fertility to Pregnancy-A Narrative Review.

Despite the fact that knowledge on obstetrical management of Inflammatory Bowel Diseases (IBDs) has greatly improved over the years, many patients still actively avoid pregnancy for fear of adverse maternal or neonatal outcomes, of adverse effects of pregnancy on the disease activity, of eventual IBD inheritance, or of an increased risk of congenital malformations. Indeed, though data prove that fertility is hardly affected by the disease, a reduced birth rate is nevertheless observed in patients with IBD. Misconceptions on the safety of drugs during gestation and breastfeeding may influence patient choice and negatively affect their serenity during pregnancy or lactation. Moreover, physicians often showed concerns about starting IBD medications before and during pregnancy and did not feel adequately trained on the safety of IBD therapies. IBD-expert gastroenterologists and gynecologists should discuss pregnancy and breastfeeding issues with patients when starting or changing medications in order to provide appropriate information; therefore, pre-conception counselling on an individualized basis should be mandatory for all patients of reproductive age to reassure them that maintaining disease remission and balancing the eventual obstetrical risks is possible.

Is the lack of prior exposure to sperm antigens associated with worse neonatal and maternal outcomes? A 10-year single-center experience comparing ICSI-TESE pregnancies to ICSI pregnancies.

BACKGROUND: Nowadays, pathogenesis of preeclampsia (PE) is still unknown. Among the different etiological hypotheses, some authors proposed that it might be because of an abnormal immunologic response to a foreign fetal antigen derived from the father's spermatozoa. Indeed, the fetus is considered a semi-allograft, being one half paternally derived in its antigenicity, and the first pathogenic insult of PE may be an abnormal maternal immune response toward this semi-allogenic implant. In the context of artificial reproductive techniques, it has been shown that the use of donor and surgically retrieved spermatozoa (e.g., testicular sperm extraction [TESE]) increases the risk of PE, confirming the protective effect of sperm exposure on maternal complications. OBJECTIVE: Determining whether the lack of exposure to sperm antigens is associated with worse maternal and neonatal outcomes in pregnancies obtained through intracytoplasmic sperm injection after TESE (ICSI-TESE) for obstructive azoospermia (OA). MATERIALS AND METHODS: This is a single-center case-control retrospective study, focusing on all first pregnancies obtained through ICSI-TESE for OA at Humanitas Fertility Center between January 1, 2010 and December 31, 2019. Controls included patients that achieved their first pregnancy with ICSI and ejaculated spermatozoa, for a diagnosis other than azoospermia, in the same time period. Cases were matched with controls in a 1:2 ratio, considering female age, female BMI, and year of controlled ovarian stimulation. The primary outcome measure was the delivery rate, defined as the number of deliveries divided by the total number of clinical pregnancies. Secondary outcome measures focused on maternal and neonatal complications, such as miscarriage rate, rate of main obstetric complications, prematurity rate, and rate of congenital malformations. RESULTS: By analyzing overall 113 pregnancies among cases and 214 pregnancies among controls, this study showed that the delivery rate was higher in controls with respect to cases (92.06% vs. 84.07%, p = 0.026); among deliveries, live births were 98.95% and 100%, respectively, whereas only one stillbirth occurred in cases. The first trimester miscarriage rate was higher in the cases than controls (13.27% vs. 6.07%, p = 0.027), whereas no difference was found among the rate of second trimester miscarriages, therapeutic abortions, and ectopic pregnancies. There was no difference regarding the rate of maternal complications, including gestational hypertension, PE, HELLP syndrome, gestational diabetes, placenta previa, placental abruption, and premature rupture of the membranes. Considering neonatal complications, it was shown that twins belonging to controls had a higher prematurity rate with respect to cases (65.79% vs. 50.00%) but without a statistical relevance. Lastly, the rate of congenital malformations did not differ among the two groups. DISCUSSION: This study showed that, once couples diagnosed with OA achieve a pregnancy, they have a much higher risk of miscarriage in the first trimester in respect to non-azoospermic patients. Moreover, controls had a higher delivery rate in respect to cases; however, when the fetal status at birth was compared, no difference was found between live births and stillbirths. CONCLUSIONS: Differently from the findings in the literature, no association with PE was found. This might be related to a collider bias/left truncation bias: As azoospermic patients are at higher risk of early termination of pregnancy, it results that they do not have the possibility to develop PE and other adverse outcomes.

Retrospective comparison of pregnancy outcomes of fresh and frozen-warmed single blastocyst transfer: a 5-year single-center experience.

PURPOSE: To assess whether live birth rates (LBR) and maternal/neonatal complications differed following single fresh and frozen-warmed blastocyst transfer. METHODS: The present retrospective observational study analyzed 4,613 single embryo transfers (SET) (646 fresh and 3,967 frozen) from January 1, 2014, to December 31, 2018. Fresh embryo transfer at blastocyst stage was considered according to the age of the patient and her prognosis. In case of the risk of ovarian hyperstimulation syndrome, premature progesterone rise, non-optimal endometrial growth, or supernumerary embryos, cryopreservation with subsequent frozen embryo transfer (FET) was indicated. RESULTS: No differences in LBR were recorded. Fresh embryo transfers yielded an increase both in neonatal complications OR 2.15 (95% CI 1.20-3.86, p 0.010), with a higher prevalence of singletons weighting below the 5th percentile (p 0.013) and of intrauterine growth retardation (p 0.015), as well as maternal complications, with a higher placenta previa occurrence OR 3.58 (95% CI 1.54-8.28, p 0.003), compared to FET. CONCLUSION: LBR appears not to be affected by the transfer procedure preferred. Fresh embryo transfer is associated with higher risk of neonatal complications (specifically a higher prevalence of singletons weighting below the 5th percentile and of intrauterine growth retardation) and placenta previa. Reflecting on the increased practice of ART procedures, it is imperative to understand whether a transfer procedure yields less complications than the other and if it is time to switch to a "freeze-all" procedure as standard practice. TRIAL REGISTRATION: Clinical Trial Registration Number: NCT04310761. Date of registration: March 17, 2020, retrospectively registered.

Influence of inguinal hernia repair on sperm autoimmunity: The largest single center experience.

BACKGROUND: Studies on immunological infertility after inguinal hernia correction are few and not very representative. Anti-sperm antibodies have been shown to reduce male fertility. Although the extent of infertility due to anti-sperm antibodies alone is not very clear, data indicates that about 8%-10% of infertile patients have immunological infertility DESIGN: This retrospective study includes all infertile male patients (n = 2258) who underwent mixed antiglobulin reaction tests and urologic examination from 2000 to 2020. Sperm quality (assessed by the number of spermatozoa, their motility, vitality, and normal form) was also evaluated. Among these patients, 191 had previously undergone unilateral or bilateral inguinal hernia surgery repair. The aim of the study is to evaluate if there is a higher incidence of positive mixed antiglobulin reaction test among patients undergoing inguinal hernioplasty compared to the unselected infertile population. RESULTS: Anti-sperm antibodies would seem to increase in both patients who performed general andrological surgery and groin hernia correction, respectively 3.48 (95% Confidence Interval: 1.70-7.10; p < 0.001) and 2.45 (95% Confidence Interval: 1.01-5.99; p < 0.05) times more than the unselected infertile population. CONCLUSIONS: Mixed antiglobulin reaction test could be useful in patients undergone previous scrotal surgery or hernia correction men, to avoid false unexplained infertility diagnoses and to direct the couple to assisted reproductive technology procedures. Basal evaluation of spermatozoa does not actually consider andrological surgery as an indication to autoimmunity investigation.

Ovarian Hyperstimulation: Diagnosis, Prevention, and Management.

Ovarian hyperstimulation syndrome (OHSS) is a severe complication of controlled ovarian stimulation (COS). Pathogenesis of the disease is based on massive transudation of protein-rich fluid from the vascular compartment into the peritoneal, pleural and pericardial spaces, with a variable picture of clinical manifestations depending on its severity. Nowadays OHSS can easily be avoided by several prevention methods, ranging from identification of high-risk patients, choice of a correct protocol stimulation, trigger with gonadotropin-releasing hormone (GnRH) agonists or, finally, the freeze-all strategy. When OHSS occurs, it can usually be managed as outpatient care. Only if severe/critical cases are diagnosed hospitalization is necessary for appropriate rehydration, monitoring of fluid balance and eventual drainage of ascitic fluid. One of the most dangerous complications of OHSS is venous thromboembolism (VTE). Thromboprophylaxis has shown to be cost effective and widely used, while there are controversies regarding the usage of low dose aspirin (LDA) as a preventive measure.

Is diminished ovarian reserve a risk factor for miscarriage? Results of a systematic review and meta-analysis.

BACKGROUND: Anti-Müllerian hormone (AMH) serum concentration and antral follicle count (AFC), as measured by transvaginal ultrasonography, accurately reflect the antral follicle pool. However, AMH and AFC association with fertility surrogates (i.e. age at menopause, probability of conceiving naturally and ART success rate) is questioned. Miscarriage is often considered an alternative measure of reproductive capacity. Nonetheless, the impact of diminished ovarian reserve (DOR) on miscarriage incidence remains an understudied and unresolved issue. OBJECTIVE AND RATIONALE: The aim of this systematic review and meta-analysis was to elucidate associations between DOR and miscarriage risk, both in women who conceived naturally and in those who achieved pregnancy through ART. SEARCH METHODS: Relevant studies were identified by a systematic search in PubMed, MEDLINE, Embase and Scopus, from database inception to 1 March 2021. Studies were included only if all the following conditions were met: DOR was defined using serum AMH concentration or AFC; miscarriage rate was reported separately for different groups of women categorized according to the AMH and/or AFC level; authors reported either the rate of intrauterine pregnancy loss before 22 weeks of gestation or enough data were available to calculate it. OUTCOMES: From a total of 347 publications initially identified, 16 studies were included. Pooled results from 13 retrospective studies focusing on ART pregnancies showed a significantly higher rate of miscarriage in women with a low AMH, as compared to women with a medium or high serum AMH concentration (12 042 women, random effects model, odds ratio (OR) 1.35; 95% CI, 1.10-1.66; P = 0.004; I2=50%). The only prospective study on ART pregnancies failed to show any association (61 women, risk ratio (RR) 2.95; 95% CI, 0.66-3.18; P = 0.16). Data from two prospective studies, which included naturally conceived pregnancies, showed a significantly increased miscarriage risk for women with low serum AMH. However, these data could not undergo meta-analysis owing to differing study designs. Using three retrospective studies, we observed an association between low AFC and miscarriage incidence (three retrospective studies on ART pregnancies, random effects model, OR 1.81; 95% CI, 1.02-3.21; P = 0.04; I2=64%). WIDER IMPLICATIONS: Our meta-analysis findings suggest that within the DOR patient subgroup, serum AMH and AFC biomarker levels may correlate with both the quantitative and qualitative aspects of ovarian reserve. However, owing to study limitations, the aetiology of this effect remains unclear and we are unable to define a causal relationship between DOR and increased miscarriage or to provide clinical recommendations based on this information. However, if confirmed by future well-designed studies, these findings would be profoundly informative for guiding women in family planning decisions.

Thyroid function modifications in women undergoing controlled ovarian hyperstimulation for in vitro fertilization: a systematic review and meta-analysis.

OBJECTIVE: To investigate the impact of controlled ovarian hyperstimulation (COH) for in vitro fertilization (IVF) on thyroid function. DESIGN: Systematic review and meta-analysis. SETTING: Not applicable. PATIENT(S): Infertile women undergoing conventional IVF or intracytoplasmic sperm injection. INTERVENTION(S): Systematic search of PubMed, MEDLINE, Embase, Scopus, and Web of Science from inception until November 2020. Studies could be included only if they met the following criteria: subjects were classified as euthyroid or hypothyroid; serum thyroid-stimulating hormone (TSH) and/or free thyroxine (FT4) levels were evaluated before COH; and the same thyroid function test was reassessed after COH (i.e., at the time of trigger for final follicle maturation and/or at pregnancy test). MAIN OUTCOME MEASURE(S): Mean difference (MD) between the serum TSH or FT4 levels assessed after COH and before COH. RESULT(S): In euthyroid women, the serum TSH levels assessed at the time of trigger and at the time of pregnancy test were significantly higher than those at baseline (MD: 0.69 mIU/L, 95% confidence interval [CI]: 0.30-1.08, I2 = 93% and MD: 0.67, 95% CI: 0.49-0.85, I2 = 72%, respectively). The serum FT4 levels did not undergo significant changes. Subanalysis confirmed an increase in the TSH level after restricting the analysis to women treated with gonadotropin-releasing hormone agonist protocols and to those who achieved pregnancy. A pronounced increase in the TSH level was observed in women treated for hypothyroidism (MD: 1.50 mIU/L, 95% CI: 1.10-1.89, I2 = 0%). CONCLUSION(S): Pooling of the results showed a significant increase in serum TSH level in women undergoing COH for IVF. This change was particularly pronounced in women treated for hypothyroidism. New thyroid function screening strategies for women undergoing COH are warranted.