Efficacy and safety of follitropin delta for ovarian stimulation in vitro fertilization/ intracytoplasmic sperm injection cycles: a systematic review with meta-analysis.

BACKGROUND: Follitropin delta is a novel recombinant follicle stimulating hormone preparation uniquely expressed in a human fetal retinal cell line by recombinant DNA technology. To date, no systematic review was available about the safety and the efficacy of the follitropin delta. The objective of this study was systematically reviewing the available literature and to provide updated evidence regarding the efficacy-safety profile of follitropin delta when compared to other gonadotropin formulations for ovarian stimulation in in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) cycles. METHODS: An extensive search was performed to identify phase 1, phase 2 and phase 3 RCTs in humans focused on follitropin delta use for ovarian stimulation in IVF/ICSI cycles. The risk of bias and the overall quality of the evidence was analyzed. All data were extracted and analyzed using the intention-to-treat principle and expressed per woman randomized. RESULTS: A total of 7 RCTs (1 phase 1 RCT, 2 phase 2 RCTs and 4 phase 3 RCTs) were included in the qualitative analysis, whereas data of three phase 3 RCTs were meta-analyzed. All trials compared personalized recombinant follitropin delta treatment versus conventional recombinant follitropin alfa/beta administration in potentially normo-responder patients who receive ovarian stimulation in GnRH antagonist IVF/ICSI cycles. No difference between two regimens was detected for clinical pregnancy rate [odds ratio (OR) 1.06; 95% confidence intervals (CI): 0.90, 1.24; P = 0.49; I2 = 26%], ongoing pregnancy rate (OR 1.15; 95%CI: 0.90, 1.46; P = 0.27; I2 = 40%), and live birth rate (OR 1.18; 95%CI: 0.89, 1.55; P = 0.25; I2 = 55%). No data were available regarding cumulative success rates. The rate of adoption of strategies to prevent ovarian hyperstimulation syndrome (OHSS) development (OR 0.45; 95%CI: 0.30, 0.66; P < 0.0001; I2 = 0%), and the rate of both early OHSS (OR 0.62; 95%CI: 0.43, 0.88; P = 0.008; I2 = 0%) and all forms of OHSS (OR 0.61; 95%CI: 0.44, 0.84; P = 0.003; I2 = 0%) were significantly lower in the group of patients treated with personalized follitropin delta treatment compared to those treated with conventional follitropin alfa/beta administration. CONCLUSION: Personalized follitropin delta treatment is associated with a lower risk of OHSS compared to conventional follitropin alfa/beta administration in potentially normo-responder patients who receive ovarian stimulation in GnRH antagonist IVF/ICSI cycles. The absence of cumulative data does not allow definitive conclusions to be drawn regarding the comparison of the effectiveness of the two treatments. PROTOCOL STUDY REGISTRATION: CRD42023470352 (available at http://www.crd.york.ac.uk/PROSPERO ).

Ovarian Torsion in a Young Adolescent with Rokitansky Syndrome.

A case report of a premenarcheal patient with ovarian torsion and mullerian agenesis is presented. A 12-year-old prepubertal girl is presented with severe right lower quadrant abdominal pain and mild rebound. Laparoscopy showed mullerian agenesis and twisted right adnexa. Detorsion and cystectomy of the right ovary were done, and the ovary was fixed to the pelvic sidewall. The postoperative course was uneventful. An association between the lax attachment of the adnexa and torsion may be a contributing factor in this condition.

Correction: Peripheral mitochondrial DNA, telomere length and DNA methylation as predictors of live birth in in vitro fertilization cycles.

[This corrects the article DOI: 10.1371/journal.pone.0261591.].

Opportunistic salpingectomy at the time of vaginal hysterectomy: A systematic review and meta-analysis.

BACKGROUND: Despite the rising rates of opportunistic salpingectomy at the time of surgery for non-malignant conditions, salpingectomy is not widely adopted during vaginal hysterectomy (VH) and has not been extensively investigated. OBJECTIVES: The aim of the primary study was to determine the feasibility of bilateral opportunistic salpingectomy at the time of VH. Secondary aims included surgical outcomes, factors associated with patient selection, and the prevalence of incidental tubal malignancies. SEARCH STRATEGY: In this systematic review and meta-analysis we searched Pubmed, Embase and ClinicalTrials.gov databases from inception to September 1, 2023, using relevant keywords. SELECTION CRITERIA: Original articles with no language restriction reporting outcomes of women undergoing planned VH with opportunistic salpingectomy, were considered eligible. Studies including patients undergoing VH with and without opportunistic salpingectomy were also included. DATA COLLECTION AND ANALYSIS: The Newcastle-Ottawa scale was used to assess quality of observational studies. DerSimonian-Laird random effects meta-analysis was performed and pooled effect estimates and proportions with corresponding 95% confidence intervals were computed. Heterogeneity was assessed using the I2 statistic. RESULTS: Seven observational cohort studies including 4808 women undergoing opportunistic salpingectomy at the time of VH and 10 295 patients undergoing VH alone were selected. The pooled proportion of success was 81.83 per 100 observations (95% CI: 75.35-87.54). Opportunistic salpingectomy at the time of VH, when feasible, was associated with a significant reduction in intraoperative complications (OR 0.06, 95% CI: 0.01, -0.37, P = 0.03) and total operative time (95% CI: -17.80, -1.07, P = 0.03) compared to those where it failed. Successful salpingectomy was significantly hindered by nulliparity (OR 0.12, 95% CI: -17.69, -1.21, P < 0.001) and favored by pelvic organ prolapse (OR 3.20, 95% CI: 1.35, 7.55, P = 0.008). Immunohistochemical tubal abnormalities were found in 13/579 (2.1%) patients. The overall quality of the evidence, according to the GRADE assessment, was low. CONCLUSION: Opportunistic salpingectomy is safe, effective, and feasible at the time of VH. Nulliparity and pelvic organ prolapse are factors potentially influencing surgical outcomes.

Isthmocele, not cesarean section per se, reduces in vitro fertilization success: a systematic review and meta-analysis of over 10,000 embryo transfer cycles.

IMPORTANCE: Previous reviews have shown that a history of cesarean section (CS) is associated with a worse in vitro fertilization (IVF) prognosis. To date, whether the decline in the IVF chances of success should be attributed to the CS procedure itself or to the presence of isthmocele remains to be clarified. OBJECTIVE: To summarize the available evidence regarding the impact of isthmocele on IVF outcomes. DATA SOURCES: Electronic databases and clinical registers were searched until May 30, 2023. STUDY SELECTION AND SYNTHESIS: Observational studies were included if they assessed the effect of isthmocele on IVF outcomes. Comparators were women with isthmocele and women without isthmocele with a previous CS or vaginal delivery. Study quality was assessed using the modified Newcastle-Ottawa Scale. MAIN OUTCOMES: The primary outcome was the live birth rate (LBR). The effect measures were expressed as adjusted odds ratios (aORs) and unadjusted odds ratios (uORs) with 95% confidence intervals (95% CIs). The body of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation working group methodology. RESULTS: Eight studies (n = 10,873 patients) were included in the analysis. Women with isthmocele showed a lower LBR than both women with a previous CS without isthmocele (aOR, 0.62; 95% CI, 0.53-0.72) and those with a history of vaginal delivery (aOR, 0.55; 95% CI, 0.42-0.71). The LBRs in women with a previous CS without isthmocele and those with a history of vaginal delivery were similar (aOR, 0.74; 95% CI, 0.47-1.15). Subgroup analysis suggested a negative effect of the intracavitary fluid (ICF) in women with isthmocele on the LBR (uOR, 0.36; 95% CI, 0.18-0.75), whereas the LBRs in women without ICF and those without isthmocele were similar (uOR, 0.94; 95% CI, 0.61-1.45). CONCLUSION AND RELEVANCE: We found moderate quality of evidence (Grading of Recommendations Assessment, Development and Evaluation grade 3/4) supporting a negative impact of isthmocele, but not of CS per se, on the LBR in women undergoing IVF. The adverse effect of isthmocele on IVF outcomes appears to be worsened by ICF accumulation before embryo transfer. CLINICAL TRIAL REGISTRATION NUMBER: CRD42023418266.

Neovagina creation methods in Müllerian anomalies and risk of malignancy: insights from a systematic review.

PURPOSE: This systematic review aims to provide a data synthesis about the risk of neovaginal cancer in women with Müllerian anomalies and to investigate the association between the adopted reconstructive technique and the cancer histotype. METHODS: PubMed, MEDLINE, Embase, Scopus, ClinicalTrials.gov and Web of Science databases were searched from inception to March 1st, 2023. Studies were included if: (1) only women affected by Müllerian malformations were included, (2) the congenital defect and the vaginoplasty technique were clearly reported, (3) the type of malignancy was specified. RESULTS: Literature search yielded 18 cases of squamous cell carcinoma and two cases of vaginal intraepithelial neoplasia 3 (VAIN 3). Of these, 3 had been operated on according to the Wharton technique, 8 according to the McIndoe technique, 3 with a split-skin graft vaginoplasty, 2 according to the Davydov technique, 2 with a simple cleavage technique, 1 according to the Vecchietti technique and 1 with a bladder flap vaginoplasty. A total of 17 cases of adenocarcinoma and 1 case of high-grade polypoid dysplasia were also described. Of these, 15 had undergone intestinal vaginoplasty, 1 had been operated on according to the McIndoe technique and 1 had undergone non-surgical vaginoplasty. Finally, 1 case of verrucous carcinoma in a woman who had undergone a split-skin graft vaginoplasty, was reported. CONCLUSION: Although rare, neovaginal carcinoma is a definite risk after vaginal reconstruction, regardless of the adopted technique. Gynaecologic visits including the speculum examination, the HPV DNA and/or the Pap smear tests should be scheduled on an annual basis.

Surgical repair of post-cesarean vesicouterine fistula: A systematic review and a plea for prevention.

BACKGROUND: Vesicouterine fistula (VUF) is a iatrogenic injury in the vast majority of cases. The worldwide increase of cesarean delivery rates is expected to lead to increased complications. OBJECTIVES: To assess current evidence on VUF pathogenesis and surgical management. SEARCH STRATEGY: Pubmed and Embase databases were searched from January 2000 to January 2023 using relevant key words. SELECTION CRITERIA: Only original articles including either transabdominal or transvaginal surgical routes for post-cesarean VUF repair, in English language, were included. DATA COLLECTION AND ANALYSIS: Two authors independently screened the references for eligibility, data extraction, and assessment of methodologic quality. All available surgical outcomes were recorded. MAIN RESULTS: Of the 1160 studies retrieved, 67 were selected for analysis. Most of these were case reports, case series, or observational cohort studies including a total of 284 patients. The majority (78.6%) of patients had more than one cesarean section, and approximately 10% of them experienced an overt bladder injury and/or uterine rupture at the time of cesarean delivery. The supratrigonal part of the bladder was most commonly involved (92.5%). The majority of patients (88.8%) underwent delayed VUF repair through laparotomy. Length of stay and blood loss were significantly less in patients treated via a minimally invasive approach (P < 0.001 and P = 0.02, respectively). Most patients had double-layer bladder repair and single-layer uterine repair. The overall success rate was 100% on first attempt for each independent combination of different surgical approaches and techniques. Live birth following VUF repair was reported in 23 patients. CONCLUSIONS: Paying close attention to surgical details is crucial to reduce the incidence of this complication and recurrence rates. Double-layer bladder closure and delayed timing of repair of VUF are recommended.

Recurrent pregnancy loss: a male crucial factor-A systematic review and meta-analysis.

BACKGROUND: Recurrent pregnancy loss (RPL), defined as two or more failed clinical pregnancies, affects 1%-3% of couples trying to conceive. Nowadays up to 50% of cases remain idiopathic. In this context, paternal factors evaluation is still very limited. The aim is to address the topic of the male factor in RPL with a broad approach, analyzing collectively data on sperm DNA fragmentation (SDF) and semen parameters. We systematically searched in Pubmed/MEDLINE and Google Scholar from inception to February 2023. A protocol has been registered on PROSPERO (ID number CRD42022278616). PRISMA guidelines were followed. METHODS: Pooled results from 20 studies revealed a higher DNA fragmentation rate in the RPL group compared to controls (mean difference [MD] 9.21, 95% CI 5.58-12.85, p < 0.00001, I2 98%). Age, body mass index (BMI), smoking, and alcohol intake were not associated with DNA fragmentation. Subgroup analysis by different SDF assays (TUNEL and COMET at a neutral pH vs. indirect assessment with other assays) and ethnicity did not highlight different results (p = 0.25 and 0.44). RESULTS: Results pooled from 25 studies showed a significant difference comparing RPL and control groups regarding ejaculation volume (MD -0.24, 95% CI -0.43; -0.06, p 0.01, I2 66%), total sperm number (MD -10.03, 95% CI -14.65; -5.41, p < 0.0001, I2 76%), total sperm motility (MD -11.20, 95% CI -16.15; -6.25, p < 0.0001, I2 96%), progressive sperm motility (MD -7.34, 95% CI -10.87; -3.80, p < 0.0001, I2 97%), and normal sperm morphology (MD -5.99, 95% CI -9.08; -2.90, p 0.0001, I2 98%). A sub-analysis revealed that Asian and Africans, but not white-European RPL men had lower progressive sperm motility compared to controls. CONCLUSION: In conclusion, current review and meta-analysis findings suggested that SDF and some specific semen parameters were associated with RPL in a multi-ethnic evaluation. This effort opens future direction on a growing awareness of, first, how the male factor plays a key role and, second, how appropriate would be to establish a direct dialogue between the gynecologist and the urologist. PATIENT SUMMARY: We performed a systematic review and meta-analysis on the male component of RPL. We found that sperm DNA fragmentation and some specific sperm parameters are significantly associated with RPL.

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.

Polycystic ovary syndrome and thyroid disorder: a comprehensive narrative review of the literature.

Background: Published data on the relationship between polycystic ovary syndrome (PCOS) and thyroid dysfunction are sparse and confusing. Objective: To comprehensively review data available in the literature regarding the relationship between PCOS and the thyroid function, and its abnormalities. Methods: Nine main areas of interest were identified and analyzed according to the available evidence: 1) Evaluation of thyroid function for PCOS diagnosis; 2) Epidemiology data on thyroid function/disorders in patients with PCOS, and vice versa; 3) Experimental data supporting the relationship between thyroid function/disorders and PCOS; 4) Effects of thyroid function/disorders on PCOS features, and vice versa; 5) Effect of thyroid alterations on the cardiometabolic risk in women with PCOS; 6) Effect of thyroid abnormalities on reproductive outcomes in women with PCOS; 7) Relationship between thyroid function/abnormalities in patients with PCOS who are undergoing fertility treatment; 8) Effect of treatments for thyroid diseases on PCOS; and 9) Effect of treatments for PCOS on thyroid function. An extensive literature search for specific keywords was performed for articles published from 1970 to March 2023 using PubMed and Web of Science. Data were reported in a narrative fashion. Results: PCOS is a diagnosis of exclusion for which diagnosis is possible only after excluding disorders that mimic the PCOS phenotype, including thyroid dysfunctions. However, the tests and the cutoff values used for this are not specified. Many experimental and clinical data suggest a relationship between perturbations of the thyroid function and PCOS. Direct and unequivocal evidence on the effects of thyroid function/disorders on PCOS features are lacking. High thyroid-stimulating hormone levels and subclinical hypothyroidism may be associated with significant worsening of several intermediate endpoints of cardiometabolic risk in women with PCOS. Thyroid abnormalities may worsen reproductive outcomes, especially in patients undergoing fertility treatment. To date, there are no data demonstrating the efficacy of thyroid medications on fertility and cardiometabolic risk in women with PCOS. Lifestyle modification changes, metformin, and vitamin D seem to improve thyroid function in the general population. Conclusion: PCOS and thyroid disorders are closely related, and their coexistence may identify patients with a higher reproductive and metabolic risk. Regular screening for thyroid function and thyroid-specific autoantibodies in women with PCOS, particularly before and during pregnancy, is highly recommended.

Vesicouterine Fistula After Cesarean Delivery at Full Cervical Dilation.

IMPORTANCE: Vesicouterine fistula (VUF) is an iatrogenic consequence of cesarean section in the vast majority of cases. The worldwide increase of cesarean delivery rates is likely to be accompanied by a rise of this complication, and surgery is the mainstay treatment. OBJECTIVE: The aim of the study is to assess current evidence on VUF pathogenesis and management. STUDY DESIGN: The study is a case report and literature review on PubMed and Embase spanning over the past 2 decades. RESULTS: An early VUF developed after a cesarean section at full cervical dilation and concurrent incidental bladder injury. A transabdominal extravesical repair was performed 3 months after cesarean delivery. Both the cystotomy and hysterotomy were repaired in a double-layer fashion with no interposition flap. A contemporary literature review including 25 patients showed that VUF was repaired transabdominally in 21 patients (84%), and an open approach was adopted in 18 patients (85.7%). In most patients, the uterine side was closed with a single-layer suture and an interposition flap was used to reinforce the repair. Concomitant hysterectomy was performed in 6 patients (24%). Overall, successful term pregnancies were reported in 2 patients after VUF repair. CONCLUSIONS: Vesicouterine fistula is a rare event and is commonly associated with cesarean sections, especially those with a concurrent bladder injury. Careful and meticulous surgical technique may prevent the occurrence of this condition. Delayed repair and double-layer closure of both bladder and uterus, with or without an interposition flap, are recommended.

Implementing preconception expanded carrier screening in a universal health care system: A model-based cost-effectiveness analysis.

PURPOSE: The limited evidence available on the cost-effectiveness (CE) of expanded carrier screening (ECS) prevents its widespread use in most countries, including Italy. Herein, we aimed to estimate the CE of 3 ECS panels (ie, American College of Medical Genetics and Genomics [ACMG] Tier 1 screening, "Focused Screening," testing 15 severe, highly penetrant conditions, and ACMG Tier 3 screening) compared with no screening, the health care model currently adopted in Italy. METHODS: The reference population consisted of Italian couples seeking pregnancy with no increased personal/familial genetic risk. The CE model was developed from the perspective of the Italian universal health care system and was based on the following assumptions: 100% sensitivity of investigated screening strategies, 77% intervention rate of at-risk couples (ARCs), and no risk to conceive an affected child by risk-averse couples opting for medical interventions. RESULTS: The incremental CE ratios generated by comparing each genetic screening panel with no screening were: -14,875 ± 1,208 €/life years gained (LYG) for ACMG1S, -106,863 ± 2,379 €/LYG for Focused Screening, and -47,277 ± 1,430 €/LYG for ACMG3S. ACMG1S and Focused Screening were dominated by ACMG3S. The parameter uncertainty did not significantly affect the outcome of the analyses. CONCLUSION: From a universal health care system perspective, all the 3 ECS panels considered in the study would be more cost-effective than no screening.

Low ovarian reserve and risk of miscarriage in pregnancies derived from assisted reproductive technology.

STUDY QUESTION: Do low levels of anti-Müllerian hormone (AMH) or antral follicle count (AFC) properly predict miscarriage in young women conceiving with ART? SUMMARY ANSWER: Low ovarian reserve, as indicated by AMH or AFC, is not associated with miscarriage in young women conceiving with ART. WHAT IS KNOWN ALREADY: Presently, the impact of low ovarian reserve on the risk of miscarriage remains controversial. Some studies have reported an association between serum AMH levels and AFC and miscarriage, but others have failed to confirm these findings. The main limitation that undermines the reliability and consistency of the results is the confounding effect of female age. Indeed, after 35 years of age, on the one hand, the risk of miscarriage starts increasing because of impaired oocyte quality while, on the other, the physiological decline in AMH and AFC levels continues, thus hampering the possibility to properly explore the real effects of reduced ovarian reserve. Indeed, the two processes, i.e. the gradual loss of resting primordial follicles and the loss of oocyte quality, progress in parallel. In other words, the older the woman becomes, the higher is the risk of miscarriage, but one cannot distinguish between the effects of biological aging on oocyte quality and those mediated by a lower ovarian reserve. STUDY DESIGN SIZE DURATION: The present retrospective monocentric cohort study was carried out at Fondazione IRCSS Ca Granda Ospedale Maggiore Policlinico, Milan. All women referred to the ART Unit between 2014 and 2021 and who underwent either conventional IVF (c-IVF), ICSI, or IUI were reviewed. Only women younger than 35 were eligible because, up to this age, the risk of miscarriage is steady and not strictly related to age. PARTICIPANTS/MATERIALS SETTING METHODS: Women younger than 35 who achieved a singleton clinical pregnancy with c-IVF, ICSI, or IUI were selected. Women with patent causes of recurrent miscarriage were excluded, as well as those undergoing pregnancy termination for fetal or medical causes. Women who did and did not have a pregnancy loss before 20 weeks' gestation were compared. Detailed information was obtained from charts of the consulting patients. ART procedures were performed according to the standardized policy of our Unit. All women underwent serum AMH measurement and a transvaginal assessment of AFC prior to initiation of treatment. AMH levels were measured by a commercially available ELISA assay. To assess AFC, all identifiable antral follicles 2-10 mm in diameter at ultrasound were recorded. The primary outcome was the risk of miscarriage for women with serum AMH levels below 5 pmol/l. MAIN RESULTS AND THE ROLE OF CHANCE: There were 538 women were included, of whom 92 (17%) had a miscarriage. The areas under the ROC curves for prediction of miscarriage based on AMH levels and AFC were 0.51 (95% CI: 0.45-0.58) and 0.52 (95% CI: 0.45-0.59), respectively. The odds ratio (OR) of miscarriage for women with serum AMH levels below 5.0 pmol/l was 1.10 (95% CI: 0.51-2.36); the adjusted OR was 1.12 (95% CI: 0.51-2.45). Analyses were repeated considering other thresholds for AMH (2.9, 3.6 and 7.9 pmol/l) and for AFC (thresholds of 7 and 10). No associations emerged. LIMITATIONS REASONS FOR CAUTION: The retrospective design of the study hampered the collection of more precise but potentially relevant clinical information of the couples. We did not exclude women suffering from PCOS, a condition possibly associated with miscarriage. Moreover, the baseline characteristics of women who did and did not have a miscarriage differed in some characteristics. Thus, we adjusted the OR using a multivariate analysis, but we cannot fully exclude residual confounding effects. Finally, our results cannot be inferred to women older than 35. The mechanisms causing premature exhaustion of ovarian reserve may be different in younger and older women and this may lead to a different impact on the risk of miscarriage. WIDER IMPLICATIONS OF THE FINDINGS: Women embarking on ART with low ovarian reserve should be informed of their likely poor response to ovarian stimulation but can be reassured that, if conception occurs, their risk of miscarriage is not increased. STUDY FUNDING/COMPETING INTERESTS: This study was partially funded by Italian Ministry of Health-Current research IRCCS. E.S. reports grants from Ferring and honoraria for lectures from Merck-Serono and Gedeon-Richter. All the other authors do not have any competing interest to declare. TRIAL REGISTRATION NUMBER: N/A.

Investigating the "Fetal Side" in Recurrent Pregnancy Loss: Reliability of Cell-Free DNA Testing in Detecting Chromosomal Abnormalities of Miscarriage Tissue.

(1) Background: The aim of our study is to evaluate whether cell-free DNA testing can overlap the genetic testing of miscarriage tissue in women with early pregnancy loss (EPL) and length of recurrent pregnancy loss (RPL); (2) Methods: We conducted a prospective cohort study at the Pregnancy Loss Unit of the Fondazione Policlinico Universitario A. Gemelli (IRCCS), Rome, Italy between May 2021 and March 2022. We included women with EPL and length of RPL. Gestational age was >9 weeks + 2 days and <12 weeks + 0 days of gestation corresponding to a crown rump length measurement of >25 and <54 mm. Women underwent both dilation and curettage for the collection of miscarriage tissue and for blood sample collection. Chromosomal microarray analysis (CMA) on miscarriage tissues was performed by oligo-nucleotide- and single nucleotide polymorphisms (SNP)-based comparative genomic hybridization (CGH+SNP). Maternal blood samples were analyzed by Illumina VeriSeq non-invasive prenatal testing (NIPT) to evaluate the cell-free fetal DNA (cfDNA) and the corresponding fetal fraction and the presence of genetic abnormalities; (3) Results: CMA on miscarriage tissues revealed chromosome aneuploidies in 6/10 cases (60%), consisting of trisomy 21 (5 cases) and monosomy X (one case). cfDNA analysis was able to identify all cases of trisomy 21. It failed to detect monosomy X. A large 7p14.1p12.2 deletion concomitant to trisomy 21 was, in one case, detected by cfDNA analysis but it was not confirmed by CMA on miscarriage tissue. (4) Conclusions: cfDNA largely reproduces the chromosomal abnormalities underlying spontaneous miscarriages. However, diagnostic sensitivity of cfDNA analysis is lower with respect to the CMA of miscarriage tissues. In considering the limitations when obtaining biological samples from aborted fetuses suitable for CMA or standard chromosome analysis, cfDNA analysis is a useful, although not exhaustive, tool for the chromosome diagnosis of both early and recurrent pregnancy loss.

Different management strategies for cesarean scar pregnancy: Short-term outcomes and reproductive prognosis.

PURPOSE: To investigate the impact on future reproductive potential of systemic methotrexate (MTX) administration, uterine artery embolization (UAE) and expectant management as treatments of caesarean scar pregnancy (CSP) and to assess their efficacy and safety. BASIC PROCEDURES: We retrospectively analysed patients with a diagnosis of CSP treated in a five years' period (2014-2018). Hospitalization, hCG normalization, menstrual cycle recovery, ultrasound restitutio ad integrum times, reproductive desire accomplishment after the resolution of the picture, and outcomes of subsequent pregnancies were considered. Only patients for whom complete diagnosis, treatment and follow-up data were available could be considered for study entry. MAIN FINDINGS: A total of 21 patients were included. Three of them were managed expectantly. In two cases spontaneous abortion occurred and one case underwent caesarean delivery at 35 weeks of gestation for complete placenta previa with hysterectomy for post partum haemorrhage. Seven patients were treated with systemic MTX. Median [IQR] times of hospitalization, hCG normalization, menstrual cycle recovery and ultrasound restitutio ad integrum were 21 days [10-26 days], 52 days [18-64 days], 8 weeks [6-10 weeks] and 8 weeks [6-11 weeks] respectively. At the end of follow up, 80% (95%CI [38-96%]) of patients with reproductive desire achieved at least one live birth. Eleven patients were treated with UAE combined with MTX. Median [IQR] times of hospitalization, hCG normalization, menstrual cycle recovery and ultrasound restitutio ad integrum were 14 days [12-20 days], 43 days [30-52 days], 8 weeks [4-12 weeks] and 8 weeks [8-10 weeks], respectively. Of those who expressed a reproductive desire after treatment, 80% (95%CI [49-94%]) achieved at least one live birth. In all included patients, the menstrual cycle was restored. PRINCIPAL CONCLUSIONS: Reproductive potential of women treated for CSP was preserved after both systemic MTX administration and systemic MTX combined with UAE. Both strategies proved to be safe.

Efficacy of ferric carboxymaltose for treatment of iron deficiency anemia diagnosed in the third trimester of pregnancy: A case-control study.

AIM: To assess the efficacy of intravenous ferric carboxymaltose (IV FCM) for the treatment of iron deficiency anemia (IDA) diagnosed de novo in the third trimester of pregnancy. METHODS: Case-control study conducted in pregnant women with IDA newly diagnosed in the third trimester of pregnancy. Women treated with a single IV FCM injection were included as cases and those who received daily 210 g of oral ferrous sulphate (FS) as controls. Controls were matched to cases in a 2:1 ratio by basal hemoglobin (Hb) concentration (±0.5 g/dl). RESULTS: A total of 35 cases and 70 controls were included in the study. The mean Hb concentration level significantly increased after iron treatment in both cases (from 9.3 ± 0.8 to 11.1 ± 0.8 g/dl, p < 0.0001) and controls (from 9.6 ± 0.9 to 10.9 ± 1 g/dl, p < 0.0001). The rate of women who exceeded the recommended threshold of 11 g/dl after treatment did not significantly differ between cases (63% (95%CI, 45%-79%)) and controls (56% (95%CI, 44%-68%)) (p = 0.48). Comparison of maternal and neonatal outcomes and adverse effects did not show any significant difference between groups. CONCLUSIONS: Our results suggest that IV FCM and oral FS can be considered equally effective in the treatment of IDA newly detected in the third trimester of pregnancy.

Sperm DNA fragmentation and idiopathic recurrent pregnancy loss: Results from a multicenter case-control study.

BACKGROUND: Sperm DNA fragmentation was hypothesized to have a role in the pathogenesis of recurrent pregnancy loss. Unfortunately, the quality of already published evidence is low. OBJECTIVES: To investigate the association between sperm DNA fragmentation and idiopathic recurrent pregnancy loss by limiting, as much as possible, the interference of confounding factors. MATERIALS AND METHODS: This was a retrospective multicenter case-control study conducted in two Italian University Hospitals (i.e., Policlinico Gemelli, Rome and Humanitas S. Pio X, Milan) from July 2020 to March 2022. Cases were men belonging to couples affected by first trimester idiopathic recurrent pregnancy loss, defined as the previous loss of two or more pregnancies. Two control groups were selected: (i) men belonging to couples with proven fertility (i.e., at least two previous full-term pregnancies) (control group A); (ii) men belonging to couples with proven infertility (i.e., the failure to achieve a pregnancy after 12 months or more of regular unprotected sexual intercourse) (control group B). The sperm DNA fragmentation index was measured by the terminal deoxynucleotidyl transferase dUTP nick end labeling assay. RESULTS: We included 74 cases, 37 men with proven fertility (control group A) and 100 men belonging to infertile couples (control group B). The median sperm DNA fragmentation index was significantly lower in control group A (17%, interquartile range: 14.3%-20.6%) compared to both case group (24.5%, interquartile range: 17%-32%; p < 0.0001) and control group B (24%, interquartile range: 18.9%-30%; p = 0.001). The rate of subjects with sperm DNA fragmentation index greater than 30% was significantly higher in both case groups (28%, 95% confidence interval [18%-40%]) and control group B (26%, 95% confidence interval [18%, 36%]) compared to control group A (0%, 95% confidence interval [0%-10%]) (p < 0.001). Multivariate regression models yielded a significant association between sperm DNA fragmentation index and recurrent pregnancy loss (adjusted odds ratio 1.13, 95% confidence interval [1.04-1.23], p = 0.006), but failed to show an association between sperm DNA fragmentation index and infertility (adjusted odds ratio 1.13, 95% CI [1-1.29], p = 0.05). CONCLUSIONS: Men within couples affected by recurrent pregnancy loss or infertility had a significantly higher rate of sperm DNA fragmentation compared to fertile controls. However, after adjusting for covariates, sperm DNA fragmentation index was associated only with recurrent pregnancy loss.

Sperm human papillomavirus infection and risk of idiopathic recurrent pregnancy loss: insights from a multicenter case-control study.

OBJECTIVE: To test the hypothesis claiming an association between human papilloma virus (HPV) sperm infection and idiopathic recurrent pregnancy loss (RPL). DESIGN: Multicenter retrospective case-control study. SETTING: Three university hospitals. PATIENT(S): Cases included men belonging to couples affected by first trimester idiopathic RPL. Controls included men belonging to couples with proven fertility and no history of pregnancy loss; RPL was defined as the previous loss of 2 or more pregnancies. Couples were defined as "fertile" if they achieved a full-term pregnancy within the year before enrollment in the study. All participants conceived without assistance. MAIN OUTCOME MEASURE(S): The association between HPV DNA sperm infection, as identified using polymerase chain reaction, and RPL. RESULTS: The HPV DNA sperm infection was detected in 23 of 117 cases (20%; 95% confidence interval [CI]: 13%, 28%) and in 3 of 84 controls (4%; 95% CI; 1%, 10%) (P<.001). A comparison across baseline characteristics and multiple regression analysis did not identify any potentially confounding factors. Multivariate regression models showed a significant association between HPV DNA sperm infection and RPL (adjusted odds ratio, 7.44; 95% CI: 2.08, 26.58; P=.002 [Model 1]; adjusted odds ratio, 8.96; 95% CI: 2.41, 33.44; P=.001 [Model 2]). CONCLUSIONS: The prevalence of HPV sperm infection was significantly higher in couples affected by RPL than in their fertile counterparts. Notably, the semen sample was infected by HPV in approximately 1 out of 5 patients.