The importance of the 'uterine factor' in recurrent pregnancy loss: a retrospective cohort study on women screened through 3D transvaginal ultrasound.

STUDY QUESTION: What is the prevalence of congenital and acquired anomalies of the uterus in women with recurrent pregnancy loss (RPL) of unknown etiology examined using 3D transvaginal ultrasound (US)? SUMMARY ANSWER: Depending on the adopted diagnostic criteria, the prevalence of partial septate uterus varies between 7% and 14% and a T-shaped uterus is 3% or 4%, while adenomyosis is 23%, at least one of type 0, type 1 or type 2 myoma is 4%, and at least one endometrial polyp is 4%. WHAT IS KNOWN ALREADY: ESHRE and the Royal College of Obstetricians and Gynaecologists guidelines on RPL recommend the adoption of the 3D transvaginal US to evaluate the 'uterine factor'. Nevertheless, there are no published studies reporting the prevalence of both congenital and acquired uterine anomalies as assessed by 3D transvaginal US and diagnosed according to the criteria proposed by the most authoritative panels of experts in a cohort of women with RPL. STUDY DESIGN, SIZE, DURATION: This was a retrospective cohort study including 442 women with at least two previous first-trimester spontaneous pregnancy losses (i.e. non-viable intrauterine pregnancies), who referred to the obstetrics and gynecology unit of two university hospitals between July 2020 and July 2023. PARTICIPANTS/MATERIALS, SETTING, METHODS: Records of eligible women were reviewed. Women could be included in the study if: they were between 25 and 42 years old; they had no relevant comorbidities; they were not affected by infertility, and they had never undergone ART; they and their partner tested negative to a comprehensive RPL diagnostic work-up; and they had never undergone metroplasty, myomectomy, minimally invasive treatments for uterine fibroids or adenomyomectomy. Expert sonographers independently re-analyzed the stored 2- and 3D transvaginal US images of all included patients. Congenital uterine anomalies (CUAs) were reported according to the American Society for Reproductive Medicine (ASRM) 2021, the ESHRE/European Society for Gynaecological Endoscopy (ESGE) and the Congenital Uterine Malformation by Experts (CUME) criteria. Acquired uterine anomalies were reported according to the International Federation of Gynecology and Obstetrics (FIGO) and the Morphological Uterus Sonographic Assessment (MUSA) criteria. MAIN RESULTS AND THE ROLE OF CHANCE: The partial septate uterus was diagnosed in 60 (14%; 95% CI: 11-17%), 29 (7%; 95% CI: 5-9%), and 47 (11%; 95% CI: 8-14%) subjects, according to the ESHRE/ESGE, the ASRM 2021, and the CUME criteria, respectively. The T-shaped uterus was diagnosed in 19 women (4%; 95% CI: 3-7%) according to the ESHRE/ESGE criteria and in 13 women (3%; 95% CI: 2-5%) according to the CUME criteria. The borderline T-shaped uterus (diagnosed when two out of three CUME criteria for T-shaped uterus were met) was observed in 16 women (4%; 95% CI: 2-6%). At least one of FIGO type 0, type 1, or type 2 myoma was detected in 4% of included subjects (95% CI: 3-6%). Adenomyosis was detected in 100 women (23%; 95% CI: 19-27%) and was significantly more prevalent in women with primary RPL and in those with three or more pregnancy losses. At least one endometrial polyp was detected in 4% of enrolled women (95% CI: 3-7%). LIMITATIONS, REASONS FOR CAUTION: The absence of a control group prevented us from investigating the presence of an association between both congenital and acquired uterine anomalies and RPL. Second, the presence as well as the absence of both congenital and acquired uterine anomalies detected by 3D US was not confirmed by hysteroscopy. Finally, the results of the present study inevitably suffer from the intrinsic limitations of the adopted classification systems. WIDER IMPLICATIONS OF THE FINDINGS: The prevalence of CUAs in women with RPL varies depending on the classification system used. For reasons of clarity, the US reports should always state the name of the uterine anomaly as well as the adopted classification and diagnostic criteria. Adenomyosis seems to be associated with more severe forms of RPL. The prevalence rates estimated by our study as well as the replicability of the adopted diagnostic criteria provide a basis for the design and sample size calculation of prospective studies. STUDY FUNDING/COMPETING INTEREST(S): No specific funding was used. The authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: N/A.

Vaginal Hysterectomy: A Network Meta-Analysis Comparing Short-Term Outcomes of Surgical Techniques and Devices.

OBJECTIVE: To provide available evidence comparing surgical outcomes of different vaginal hysterectomy (VH) techniques and devices. DATA SOURCES: PubMed, Embase, and ClinicalTrials.gov databases were searched from inception to December 1, 2023, using relevant keywords. METHODS OF STUDY SELECTION: Studies comparing at least 2 surgical techniques and devices for VH were included. An arm-based random effect frequentist network meta-analysis was performed. All available surgical outcomes were evaluated. TABULATION, INTEGRATION, AND RESULTS: Ten randomized controlled trials and 7 observational studies were eligible reporting on 1577 women undergoing VH with different techniques and devices (50% conventional, 22.5% Ligasure, 17.3% BiClamp, and 9.2% transvaginal natural orifice transluminal endoscopic surgery [vNOTES]). All surgical techniques/devices had a comparable risk ratio (RR) in terms of intraoperative complications, but Clavien-Dindo grade III postoperative complications were significantly reduced in the vNOTES group (RR, 0.15; 95% confidence interval [CI], 0.03-0.82; I2 = 0%) compared with conventional VH. The pooled network analysis showed a lower standard mean deviation for blood loss when comparing energy-based vessel sealing technologies (Ligasure: standard mean deviation, -0.92; 95% CI, -1.47 to -0.37; BiClamp: standard mean deviation, -1.66; 95% CI, -2.77 to -0.55) with conventional VH. Total operative time, postoperative hemoglobin variation, and pain were significantly reduced only in the Ligasure group compared with conventional VH. Bilateral salpingectomy or bilateral salpingo-oophorectomy was most commonly performed in the vNOTES group (RR, 1.9; 95% CI, 1.17-3.10) compared with the conventional VH group. CONCLUSION: Modern surgical techniques/devices have the potential to improve anatomic exposure and to reduce morbidity of VH. This may drive resurgence of vaginal approach to hysterectomy.

Assessing the developmental competence of oocytes matured following rescue in vitro maturation: a systematic review and meta-analysis.

PURPOSE: To assess the developmental competence of oocytes matured following rescue in vitro maturation (IVM). METHODS: PubMed, EmBASE, and SCOPUS were systematically searched for peer-reviewed original papers using relevant keywords and Medical Subject Heading terms. Study quality was assessed using the Newcastle-Ottawa Scale. Odds ratios with a 95% confidence interval were calculated by applying a random effects model. The primary outcomes were fertilization and blastulation rates. Secondary outcomes included abnormal fertilization, cleavage, euploidy, clinical pregnancy, and live-birth rates. RESULT: Twenty-four studies were included in the meta-analysis. The oocytes matured following rescue IVM showed significantly reduced fertilization, cleavage, blastulation, and clinical pregnancy rates compared to sibling in vivo-matured oocytes. No significant differences were found for the euploidy and live-birth rates in euploid blastocyst transfer. In poor responders, a reduced fertilization rate was observed using in vitro-matured GV but not with in vitro-matured MI. A reduced cleavage rate in MI matured overnight compared to < 6 incubation hours was found. CONCLUSION: Our results showed compromised developmental competence in oocytes matured following rescue IVM. However, in poor responders, rescue IVM could maximize the efficiency of the treatment. Notably, our data suggests using in vitro MI matured within 6 incubation hours. CLINICAL TRIAL REGISTRATION NUMBER: CRD42023467232.

Female fertility preservation for family planning: a position statement of the Italian Society of Fertility and Sterility and Reproductive Medicine (SIFES-MR).

PURPOSE: This position statement by the Italian Society of Fertility and Sterility and Reproductive Medicine (SIFES-MR) aims to establish an optimal framework for fertility preservation outside the standard before oncological therapies. Key topics include the role of fertility units in comprehensive fertility assessment, factors impacting ovarian potential, available preservation methods, and appropriate criteria for offering such interventions. METHODS: The SIFES-MR writing group comprises Italian reproductive physicians, embryologists, and scientists. The consensus emerged after a six-month period of meetings, including extensive literature review, dialogue among authors and input from society members. Final approval was granted by the SIFES-MR governing council. RESULTS: Fertility counselling transitions from urgent to long-term care, emphasizing family planning. Age, along with ovarian reserve markers, is the primary predictor of female fertility. Various factors, including gynecological conditions, autoimmune disorders, and prior gonadotoxic therapies, may impact ovarian reserve. Oocyte cryopreservation should be the preferred method. Women 30-34 years old and 35-39 years old, without known pathologies impacting the ovarian reserve, should cryopreserve at least 12-13 and 15-20 oocytes to achieve the same chance of a spontaneous live birth they would have if they tried to conceive at the age of cryopreservation (63% and 52%, respectively in the two age groups). CONCLUSIONS: Optimal fertility counselling necessitates a long-term approach, that nurtures an understanding of fertility, facilitates timely evaluation of factors that may affect fertility, and explores fertility preservation choices at opportune intervals.

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.

Assisted reproductive technology outcomes in women with congenital uterine anomalies: a systematic review.

PURPOSE: The present systematic review aimed to assess the fecundity of women with congenital uterine anomalies (CUAs) undergoing assisted reproductive technology (ART). METHODS: The present systematic review of the literature was reported according to the PRISMA guidelines. We systematically searched PubMed, MEDLINE, Embase and Scopus, from database inception to 17th October 2023. Studies were deemed eligible only if they included women with CUAs clearly fitting into one of the categories of the ASRM Müllerian anomalies classification 2021. RESULTS: Data relevant to the reproductive outcomes of women with CUAs who underwent ART were extracted from 55 studies. Regarding Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome, studies on gestational surrogacy reported a live birth rate (LBR) ranging from 37 to 54%. Uterus transplant, although still experimental, showed promising results. Most studies reported a negative impact of unicornuate uterus and partial or complete septate uterus on both the miscarriage rate (MR) and the live birth rate (LBR). The reproductive prognosis of women with unicornuate uterus was shown to be particularly poor in case of twin pregnancy. Uterus didelphys, bicornuate and arcuate uterus seem not to negatively impact the ART reproductive outcomes. Uterus didelphys was associated with an increased risk of preterm birth (PTB), cesarean section and low birth weight (LBW). CONCLUSION: Women with CUAs should be informed regarding the impact (if any) of their congenital anomaly on both the chances of success of ART and on pregnancy-related complications. Elective single embryo transfer (eSET) should always be the first choice in patients with an increased baseline obstetric risk.

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.

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.

Obstetric and perinatal outcomes following programmed compared to natural frozen-thawed embryo transfer cycles: a systematic review and meta-analysis.

STUDY QUESTION: Is there an association between the different endometrial preparation protocols for frozen embryo transfer (FET) and obstetric and perinatal outcomes? SUMMARY ANSWER: Programmed FET protocols were associated with a significantly higher risk of hypertensive disorders of pregnancy (HDP), pre-eclampsia (PE), post-partum hemorrhage (PPH) and cesarean section (CS) when compared with natural FET protocols. WHAT IS KNOWN ALREADY: An important and growing source of concern regarding the use of FET on a wide spectrum of women, is represented by its association with obstetric and perinatal complications. However, reasons behind these increased risks are still unknown and understudied. STUDY DESIGN, SIZE, DURATION: Systematic review with meta-analysis. We systematically searched PubMed, MEDLINE, Embase and Scopus, from database inception to 1 November 2021. Published randomized controlled trials, cohort and case control studies were all eligible for inclusion. The risk of bias was assessed using the Newcastle-Ottawa Quality Assessment Scale. The quality of evidence was also evaluated using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. PARTICIPANTS/MATERIALS, SETTING, METHODS: Studies were included only if investigators reported obstetric and/or perinatal outcomes for at least two of the following endometrial preparation protocols: programmed FET cycle (PC-FET) (i.e. treatment with hormone replacement therapy (HRT)); total natural FET cycle (tNC-FET); modified natural FET cycle (mNC-FET); stimulated FET cycle (SC-FET). MAIN RESULTS AND THE ROLE OF CHANCE: Pooled results showed a higher risk of HDP (12 studies, odds ratio (OR) 1.90; 95% CI 1.64-2.20; P < 0.00001; I2 = 50%) (very low quality), pregnancy-induced hypertension (5 studies, OR 1.46; 95% CI 1.03-2.07; P = 0.03; I2 = 0%) (very low quality), PE (8 studies, OR 2.11; 95% CI 1.87-2.39; P < 0.00001; I2 = 29%) (low quality), placenta previa (10 studies, OR 1.27; 95% CI 1.05-1.54; P = 0.01; I2 = 8%) (very low quality), PPH (6 studies, OR 2.53; 95% CI 2.19-2.93; P < 0.00001; I2 = 0%) (low quality), CS (12 studies, OR 1.62; 95% CI 1.53-1.71; P < 0.00001; I2 = 48%) (very low quality), preterm birth (15 studies, OR 1.19; 95% CI 1.09-1.29; P < 0.0001; I2 = 47%) (very low quality), very preterm birth (7 studies, OR 1.63; 95% CI 1.23-2.15; P = 0.0006; I2 = 21%) (very low quality), placenta accreta (2 studies, OR 6.29; 95% CI 2.75-14.40; P < 0.0001; I2 = 0%) (very low quality), preterm premature rupture of membranes (3 studies, OR 1.84; 95% CI 0.82-4.11; P = 0.14; I2 = 61%) (very low quality), post-term birth (OR 1.90; 95% CI 1.25-2.90; P = 0.003; I2 = 73%) (very low quality), macrosomia (10 studies, OR 1.18; 95% CI 1.05-1.32; P = 0.007; I2 = 45%) (very low quality) and large for gestational age (LGA) (14 studies, OR 1.08; 95% CI 1.01-1.16; P = 0.02; I2 = 50%) (very low quality), in PC-FET pregnancies when compared with NC (tNC + mNC)-FET pregnancies. However, after pooling of ORs adjusted for the possible confounding variables, the endometrial preparation by HRT maintained a significant association in all sub-analyses exclusively with HDP, PE, PPH (low quality) and CS (very low quality). LIMITATIONS, REASONS FOR CAUTION: The principal limitation concerns the heterogeneity across studies in: (i) timing and dosage of HRT; (ii) embryo stage at transfer; and (iii) inclusion of preimplantation genetic testing cycles. To address it, we undertook subgroup analyses by pooling only ORs adjusted for a specific possible confounding factor. WIDER IMPLICATIONS OF THE FINDINGS: Endometrial preparation protocols with HRT were associated with worse obstetric and perinatal outcomes. However, because of the methodological weaknesses, recommendations for clinical practice cannot be made. Well conducted prospective studies are thus warranted to establish a safe endometrial preparation strategy for FET cycles aimed at limiting superimposed risks in women with an 'a priori' high-risk profile for obstetric and perinatal complications. STUDY FUNDING/COMPETING INTEREST(S): None. REGISTRATION NUMBER: CRD42021249927.

Recurrent implantation failure: a plea for a widely adopted rational definition.

Most proposed definitions of recurrent implantation failure (RIF) are based on clinical judgement, probably affected by patients' demands. They are not based on robust statistical considerations. As a result, a diagnosis of RIF is commonly made too early, exposing couples to the risk of overdiagnosis and overtreatment. However, the situation is changing, and three statistical approaches have recently been proposed. The first is a probability model based on the chances of success per cycle and suggests for the definition three failed oocyte retrieval cycles with all embryos being transferred in women younger than 40 years of age. The second approach suggests an individualized diagnosis that takes into consideration multiple factors, while the third is also based on individualization but mainly relies on anticipated euploidy rates across the female age range. All these approaches have their pros and cons. Regardless of the specific peculiarities, they represent steps in the right direction, with the intent of providing a statistically sound definition. However, these attempts will not be useful unless endorsed by the scientific community in general. There is a pressing need for a rigorous and shared definition of RIF that will be widely accepted by researchers, scientific societies and other stakeholders, including patients.

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.

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.

Fibroids and natural fertility: a systematic review and meta-analysis.

Available evidence from IVF studies supports a detrimental effect of submucosal and intramural fibroids on embryo implantation. It is misleading, however, to infer evidence obtained in IVF settings to natural fertility. Therefore, a systematic review and meta-analysis was conducted on the effect of fibroids on natural fertility. Studies comparing fertile and infertile women, and those investigating whether the presence of fibroids was a risk factor, were reviewed, as well as studies comparing women with and without fibroids. The aim was also to establish whether the frequency of infertility differed between the two groups. Seven out of 11 selected studies did not aim to establish whether fibroids caused infertility but, rather, whether a history of infertility could be a risk factor for fibroids. A meta-analysis of the four remaining studies that concomitantly evaluated the presence of fibroids and infertility studies highlighted a common odds ratio of fibroids in subfertile women of 3.54 (95% CI 1.55 to 8.11). When focusing on the two most informative studies, i.e. the studies comparing time to pregnancy in women with and without fibroids, the common OR was 1.93 (95% CI 0.89 to 4.18). In conclusion, the association between fibroids and infertility has been insufficiently investigated. Epidemiological studies suggest, but do not demonstrate, that fibroids may interfere with natural fertility. Given the high prevalence of these lesions in women seeking pregnancy, further evidence is urgently needed.

How common is real repeated implantation failure? An indirect estimate of the prevalence.

RESEARCH QUESTION: What is the real prevalence of repeated implantation failure (RIF) and what reliable estimates can be given on the risk of false-positive diagnosis after two or three failed IVF attempts. DESIGN: A recent theoretical model suggested that commonly used definitions (two or three failed IVF attempts in good-prognosis couples) may expose couples to substantial odds of overdiagnosis and overtreatment. This model, however, was theoretical and based on unproven assumptions that the pregnancy rate in the non-RIF population was 30% and the prevalence of RIF was 10%. In the present study, we applied this model to real data to distinguish the real prevalence of RIF and to provide more reliable estimates on the risk of false-positive diagnosis after two or three failed IVF attempts. To this aim, we retrospectively selected 1221 good-prognosis couples and evaluated pregnancy rates up to the third cycle. RESULTS: The clinical pregnancy rate at first, second and third IVF cycle was 52%, 41% and 28%, respectively. A pregnancy rate of 61% was extrapolated in the non-RIF population and 15% among women who had experienced RIF. Therefore, the rate of false-positive diagnoses of RIF after two, three and six failed cycles would be 46%, 25%, and 2%, respectively. CONCLUSIONS: Our analyses show that estimated prevalence of RIF is 15%. The frequently used definition of RIF based on three failed attempts (but not two) in good-prognosis couples seems justified. Physicians, however, should bear in mind that couples may be inappropriately labelled with this condition in one out of four cases.

Is early initiation of infertility treatment justified in women over the age of 35 years?

RESEARCH QUESTION: Natural fecundity and the success of IVF and intracytoplasmic sperm injection (ICSI) rate both decrease with age. For this reason, in women older than 35 years, it is generally recommended to start the infertility work-up after only 6 months. This assumption, however, may expose couples to over-diagnosis and over-treatment. DESIGN: A theoretical model aimed at assessing the effects of starting the infertility work-up after 6 rather than 12 months of trying to conceive naturally was developed. The assumptions of the model were as follows: infertile women are treated with IVF/ICSI for up to three cycles; IVF/ICSI success rate at first cycle linearly declines with age (3% per year between the ages of 35 and 45 years); the drop-out rate after the first and second cycle is 18% and 25%, respectively; the relative reduction of the success rate at second and third cycle is 16% and 26%, respectively. RESULTS: Early initiation of treatment moderately improved the cumulative chances of live birth resulting from a full IVF/ICSI programme. This improvement is dependent on age. Specifically, it increased from 2.0% at age 35 years to 3.0% at age 43 years. Conversely, the incremental success rate per single IVF cycle was mainly stable, varying only from 1.4% at age 35 years to 1.3% at age 43 years. CONCLUSIONS: In women older than 35 years, early initiation of the infertility work-up is associated with only a modest increase in the rate of success of IVF/ICSI. In most scenarios, this advantage may compare unfavourably with the chances of natural conception during the 6-month period.

Fertility in female cancer survivors: a systematic review and meta-analysis.

Data on the effects of cancer treatments on fertility are conflicting. The aim of the present systematic review and meta-analysis was to determine the chances of childbirth in women survivors of different types of cancer. PubMed, MEDLINE, Embase and Scopus were searched from database inception to 17 July 2019 for published cohort, case-control and cross-sectional studies that investigated the reproductive chances in women survivors of different cancer types. Random-effects models were used to pool childbirth hazard ratios, relative risks, rate ratios and odds ratios, and 95% confidence intervals were estimated; 18 eligible studies were identified. Childbirth chances were significantly reduced in women with a history of bone cancer (HR 0.86, 95% CI 0.77 to 0.97; I2 = 0%; P = 0.02 (two studies); RaR 0.76, 95% CI 0.61 to 0.95; I2 = 69%; P = 0.01 (two studies); breast cancer (HR 0.74, 95% CI 0.61 to 0.90 (one study); RaR 0.51, 95% CI 0.47 to 0.57; I2 = 0%; P < 0.00001 (two studies); brain cancer (HR 0.61, 95% CI 0.51 to 0.72; I2 = 14%; P < 0.00001 (three studies); RR 0.62, 95% CI 0.42 to 0.91 (one study); RaR 0.44, 95% CI 0.33 to 0.60; I2 = 95%; P < 0.00001 (four studies); OR 0.49, 95% CI 0.40 to 0.60 (one study); and kidney cancer (RR 0.66, 95% CI 0.43 to 0.98 (one study); RaR 0.69, 95% CI 0.61 to 0.78 (one study). Reproductive chances in women survivors of non-Hodgkin's lymphoma, melanoma and thyroid cancer were unaffected. Women with a history of bone, breast, brain or kidney cancer have reduced chances of childbirth. Thyroid cancer, melanoma and non-Hodgkin's lymphoma survivors can be reassured.

Infertility-related distress and female sexual function during assisted reproduction.

STUDY QUESTION: Is infertility-related distress a risk factor for impaired female sexual function in women undergoing assisted reproduction? SUMMARY ANSWER: Infertility-related distress, and especially social, sexual, and relationship concerns, is associated with female sexual dysfunction. WHAT IS KNOWN ALREADY: Women with infertility are more likely to present sexual dysfunction relative to those without infertility. Moreover, assisted reproduction is associated with increased risk for female sexual problems. To date, this higher proportion of sexual impairment in infertile women has been simplistically linked to the stress associated with the condition and investigated risk factors included mainly demographic and clinical variables. Quantitative studies aimed at identifying risk factors for sexual dysfunction that also included the evaluation of infertility-related distress are conversely lacking. STUDY DESIGN, SIZE, DURATION: This observational study was conducted at the Infertility Unit of the Fondazione Ca' Granda, Ospedale Maggiore Policlinico of Milan between 2017 and 2018. PARTICIPANTS/MATERIALS, SETTING, METHODS: We included 269 consecutive patients with infertility aged 24-45 (37.8 ± 4.0 years). Sexual function outcomes were sexual dysfunction (assessed with the Female Sexual Function Index), sexual distress (evaluated with the Female Sexual Distress Scale-Revised), dyspareunia, and number of intercourses in the month preceding ovarian stimulation. Infertility-related distress was measured with the Fertility Problem Inventory (FPI). The effects of potential confounders such as demographic variables (women's and partners' age and level of education) and infertility-related factors (type and cause of infertility, number of previous IVF cycles, and duration of infertility) were also examined. MAIN RESULTS AND THE ROLE OF CHANCE: Women with higher infertility-related distress were more likely to report sexual dysfunction (odds ratio = 1.02 per point of score; 95% CI, 1.01-1.03; P = 0.001). Three FPI domains (i.e. social, relational, and sexual concerns) were correlated with almost all sexual function outcomes (Ps < 0.05). LIMITATIONS, REASONS FOR CAUTION: Women who were not sexually active were not included, thus reasons for sexual inactivity should be further explored in future studies. Data regarding men (e.g. sexual function and infertility-related distress) were lacking, thus cross-partner effects were not examined. Recall bias (also due to the fact that questionnaires were administered on the day of oocytes retrieval) and social desirability bias may have also affected women's responses to the questionnaires. WIDER IMPLICATIONS OF THE FINDINGS: Social, relational, and sexual concerns should be assessed and addressed in psychological counselling with the infertile couple. STUDY FUNDING/COMPETING INTEREST(S): None. TRIAL REGISTRATION NUMBER: Not applicable.

Ovarian stimulation and endometriosis progression or recurrence: a systematic review.

Available evidence on the impact of ovarian stimulation on the progression of endometriosis or its recurrence was systematically reviewed. Data from ovarian stimulation alone, or associated with intrauterine insemination (IUI) or IVF, were included. Sixteen studies were selected. Initial case reports (n = 11) documented some severe clinical complications. However, subsequent observational studies were more reassuring. Overall, five conclusions can be drawn: (i) IVF does not worsen endometriosis-related pain symptoms (moderate quality evidence); (ii) IVF does not increase the risk of endometriosis recurrence (moderate quality evidence); (iii) the impact of IVF on ovarian endometriomas, if present at all, is mild (low quality evidence); (iv) IUI may increase the risk of endometriosis recurrence (low quality evidence); (v) deep invasive endometriosis might progress with ovarian stimulation (very low quality evidence). In conclusion, available evidence is generally reassuring (at least for IVF) and does not justify aggressive clinical approaches such as prophylactic surgery before assisted reproductive technology treatment to prevent endometriosis progression or recurrence. However, further evidence is required before being able to reach definitive conclusions. In particular, the potential effects on deep invasive endometriosis and the possible synergistic effect of stimulation and pregnancy are two areas that need to be explored further.

Oocyte retrieval difficulties in women with ovarian endometriomas.

RESEARCH QUESTION: What are the frequency, characteristics and consequences of technical diffiiculties encountered by physicians when carrying out oocyte retrieval in women with ovarian endometriomas? DESIGN: We prospectively recruited women undergoing IVF and compared technical difficulties between women with (n = 56) and without (n = 227) endometriomas. RESULTS: In exposed women, the cyst had to be transfixed in eight cases (14%, 95% CI 7 to 25%) and accidental contamination of the follicular fluid with the endometrioma content was recorded in nine women (16%, 95% CI 8 to 27%). Moreover, follicular aspiration was more frequently incomplete (OR 3.6, 95% CI 1.4 to 9.6). In contrast, the retrievals were not deemed to be more technically difficult by the physicians and the rate of oocytes retrieved per developed follicle did not differ. No pelvic infections or cyst ruptures were recorded (0%, 95% CI 0 to 5%). CONCLUSIONS: Oocyte retrieval in women with ovarian endometriomas is more problematic but the magnitude of these increased difficulties is modest.

Repeated implantation failure at the crossroad between statistics, clinics and over-diagnosis.

The most common definition of repeated implantation failure (RIF) is the failure to obtain a clinical pregnancy after three completed IVF cycles. This definition, however, may lead to misuse of the diagnosis. To disentangle this, we set up a mathematical model based on the following main assumptions: rate of success of IVF constant and set at 30%; and RIF postulated to be a dichotomous condition (yes or no) with a prevalence of 10%. On this basis, the expected cumulative chance of pregnancy after three and six cycles was 59% and 79%, respectively. Consequently, the false-positive rate of a diagnosis of RIF is 75% and 51%, respectively. Increasing the rate of success of IVF or the prevalence of RIF lowers but does not make unremarkable the rate of false-positive diagnoses. Overall, this model shows that the commonly used definition of RIF based on three failed attempts in a standard population with good prognosis leads to over-diagnosis and, potentially, to over-treatments.