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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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10815-021-02362-3.

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.

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.

In vitro fertilization (IVF) is associated with a higher incidence of monozygotic twin pregnancies, which are known to be burdened by a higher risk of main obstetric complications. The reasons behind this association are still unclear. In the present study, we therefore investigate the risk factors for monozygotic twinning in pregnancies achieved by IVF. We conducted a multicenter retrospective case-control study. All IVF cycles performed between 2014 and 2019 at the infertility units of two Italian academic institutes were retrospectively reviewed. Only pregnancies obtained with single embryo transfer were eligible. A total of 50 monozygotic twin pregnancies (cases) were identified and matched in a 1:5 ratio to 250 singleton pregnancies (controls) by study center and study period. Monozygotic twin pregnancies were diagnosed by ultrasound. Women experiencing miscarriage could be included provided that the pregnancy loss occurred after a definitive diagnosis of monozygotic twin pregnancy. Demographic, clinical, and embryological characteristics were retrieved from patients' charts. Overall, the incidence of monozygotic twin pregnancies was 1.2% (50 out of 4016 single embryo transfers). At univariate analyses, statistically significant differences emerged for BMI, peripheral levels of estradiol and progesterone at the time of hCG administration, total number of retrieved suitable oocytes, freezing-thawing cycles, and assisted hatching. After performing a multivariate logistic analysis, only assisted hatching remained significantly associated with monozygotic twinning (adjusted odds ratio 2.32, 95%CI 1.03-5.25). Blastomere separation during the passage through this artificial hole or interference with the signaling pathway within the embryo could be the mechanisms involved.

Objective To investigate the impact of serum vitamin D level on in vitro fertilization (IVF) outcomes. Design Systematic review and meta-analysis. Setting Not applicable. Patients Infertile women undergoing conventional IVF or intracytoplasmic sperm injection (ICSI). Interventions Systematic search of PubMed, MEDLINE, EMBASE, Global Health, The Cochrane Library, Health Technology Assessment Database, and Web of Science from inception until July 2019 with cross-checking of references from relevant articles in English. Vitamin D levels were categorized into three groups: deficient ( 30 ng/mL). Before starting the data extraction, we registered the review protocol in PROSPERO (CRD42019134258). Main Outcome Measures We consider clinical pregnancy rate (CPR), live birth rate (LBR), and/or ongoing pregnancy rate (OPR) as primary outcomes. Likewise, the miscarriage rate was considered as a secondary outcome. Results Primary analysis showed that women with a replete level of vitamin D had higher CPR and LBR/OPR compared to those with a deficient of insufficient level of vitamin D. However, sensitivity analysis led to non-significant differences between the comparators for CPR (odds ratio 0.71, 95% confidence interval 0.47−1.08, I2 = 61%) and OPR/LBR (odds ratio 0.78, 95% confidence interval 0.56−1.08], I2 = 61%). Also, for miscarriage a statistically different rate was not reached. Conclusion Serum vitamin D levels do not influence IVF outcomes in terms of CPR, LBR/OPR, and miscarriage rate. Future large cohort studies are warranted to determine whether the threshold of vitamin D affects reproductive outcomes. Currently, there is a lack of consensus between the appropriate vitamin D threshold to predict reproductive outcomes compared to the one established for bone health. PROSPERO Number CRD42019134258.

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

The advent of random start protocols to shorten the time needed to store oocytes in women with malignancies has represented an important improvement in the field of fertility preservation. However, Randomized Controlled Trials are difficult to implement in this area and available evidence that supports this approach remains modest. To shed more light on this issue, we compared the follicular development between the ovary carrying the dominant follicle or the corpus luteum and the contralateral resting ovary in 90 women who underwent random start controlled ovarian stimulation (COS). In fact, ovarian response did not differ between the two ovaries. Subgroup analyses according to the phase of the cycle at the initiation of COS, the type of malignancy, the use of letrozole and the magnitude of the ovarian response did not allow to identify any condition showing a difference in the follicular response between the active and the resting ovaries. In conclusion, follicular growth does not seem to be perturbed by the presence of a dominant follicle or a corpus luteum.

Controlled ovarian hyperstimulation (COH) determines an anticipation of endometrial maturation and a premature occurrence of the implantation window, as shown by histological, histochemical, and molecular studies and indirectly by clinical trials. There is growing agreement that in patients hyper-responding to COH and in those undergoing transfer at the blastocyst stage, deferring the transfer in a subsequent frozen cycle could increase pregnancy outcomes. For blastocysts, implantation after a fresh transfer may be limited as the implantation window is already closed while, in hyper-responders to COH, the anticipation magnitude could be more marked thus hampering implantation also for cleavage-stage embryos. Research should focus in depth on pregnancy outcomes and on the most suitable modality to prepare the endometrium for frozen transfers.

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.

A consistent body of in vitro evidence supports a detrimental effect of endometriosis on ovarian steroidogenesis, in particular the synthesis of estrogens. However, clinical evidence is scanty and methodologically weak. This study aimed at clarifying whether peripheral 17-β-estradiol during IVF are influenced by the presence of endometriosis. Women undergoing IVF were retrospectively reviewed. Cases were women with a diagnosis of endometriosis. Controls were matched to cases in a 1:1 ratio by study period, age, total number of developed follicles on the day of hCG administration, protocol of hyperstimulation, gonadotropin used, and starting dose. The primary outcome was the ratio between serum levels of 17-β-estradiol and the total number of developed follicles. Fifty-three women with endometriosis and 53 controls were selected. The median ratio (interquartile range) between serum 17-β-estradiol and the total number of developed follicles in the two groups was 207 (164–282) and 201 (144–268) pg/ml, respectively (p = 0.46). Sensitivity analyses on the magnitude of the follicular response, the history of surgery for endometriomas, and the presence of endometriomas did not show any subgroup at increased risk of peripheral estrogens impairment. Endometriosis does not influence peripheral levels of 17-β-estradiol during IVF. Our findings argue against a biologically relevant effect of the disease on ovarian estrogen-synthesis.

Objective To evaluate whether telomere length (TL), mitochondrial-DNA (mt-DNA) or epigenetic age estimators based on DNA methylation (DNAm) pattern could be considered reliable predictors of in-vitro-fertilization (IVF) success in terms of live birth rate. Design Prospective cohort study Setting Infertility Unit of the Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico Patients 181 women aged 37–39 years who underwent IVF at a single-centre between January 2017 and December 2018. Interventions On the day of recruitment, blood samples were collected, and genomic DNA was isolated from white blood cells. TL, mt-DNA and DNAm assessment was performed using quantitative real-time polymerase chain reaction (qPCR). Biological age (DNAm age) was computed as the algorithm based on methylation pattern of five genes. Epigenetic age acceleration was estimated from the residuals of the linear model of epigenetic age regressed on chronological age. Long Interspersed Nuclear Elements (LINE)-1 methylation pattern was used as a surrogate for global DNA methylation. Main outcome measures This study investigated whether peripheral TL, mt-DNA and DNAm could predict live birth in IVF cycles. Results TL, mt-DNA and LINE-1 methylation were not associated with IVF success. Conversely, DNAm age resulted significantly lower in women who had a live birth compared to women who did not (36.1 ± 4.2 and 37.3 ± 3.3 years, respectively, p = 0.04). For DNAm age, odds ratio (OR) for live birth per year of age was 0.90 (95%CI: 0.82–0.99, p = 0.036) after adjusting for FSH and antral follicle count (AFC) and 0.90 (95%CI: 0.82–0.99, p = 0.028) after adjusting also for number of oocytes retrieved. A significant association also emerged for epigenetic age acceleration after adjustments (OR = 0.91, 95%CI: 0.83–1.00, p = 0.048). Conclusion DNAm age is associated with IVF success but the magnitude of this association is insufficient to claim a clinical use. However, our findings are promising and warrant further investigation. Assessment of biological age using different epigenetic clocks or focusing on different tissues may reveal new predictors of IVF success.

Here we present a case of severe post-partum pneumonia that we observed at the end of January 2020. Specimen of blood was cultured and revealed Klebsiella pneumoniae bacteremia. However, the course of infection was atypical and the recovery time particularly long. Subsequently emerged COVID-19 hallmarks suggested to re-evaluate the case. After a multidisciplinary consultation, we concluded that, considering the clinical and imaging characteristics, the most likely hypothesis was that the patient was affected by novel Coronavirus pneumonia. The present case supports the hypothesis that Coronavirus might have circulated in northern Italy for weeks before its official detection.

Objective: The aim of the present study was to analyze the IVF success rates and the economic cost per delivery in all the public funded IVF Units in Lombardy in the 2017–2018 period and to assess any significant difference in ART outcomes among the enrolled centers.Methods: Analysis of costs for the 2017 and 2018 fresh transfer delivery rate (DR) and Cumulative delivery rate (CDR) considering both fresh and frozen cycles were extracted from the ART Italian Registry on oocytes retrievals, fresh and frozen embryos and oocytes embryo transfer performed in 22 Lombardy IVF Units.Results: In 2017, 29,718 procedures were performed, resulting in 4,543 pregnancies and 3,253 deliveries. In 2018, there were 29,708 procedures, 4,665 pregnancies and 3,348 deliveries. Pregnancies lost to follow up were 5.0% with a (range of 0–67.68%) in 2017 and 3.4% (range of 0–45.1%) in 2018. The cost reimbursement for the cycles were €2,232 ($2,611) for oocyte retrieval and €2,194 ($2,567) for embryo transfer, excluding ovarian stimulation therapy and luteal phase support. 19.33 (5.80). The DR was 13.23 ± 5.69% (range 2.86–29.11%) in 2017 and 19.33 ± 5.80% in 2018 (range 11.82–34.98 %) and the CDR was 19.86 ± 9.38% (range 4.43–37.88%) in 2017 and 21.32 ± 8.84% (range 4.24–37.11%). The mean multiple pregnancy delivery rate (MDR) was 11.08 ± 5.55% (range 0.00–22.73%) in 2017 and 10.41 ± 4.99% (range 1.33–22.22%) in 2018. The mean CDR cost in euros was 26,227 ± 14,737 in 2017 and 25,018 ± 16,039 in 2018. The mean CDR cost among centers was 12,480 to 76,725 in 2017 and 12,973 to 86,203 in 2018.Conclusions: Our findings show impressive differences in the DR and CDR among centers and the importance of cryopreservation in patients' safety and economic cost reduction suggesting the formulation of specific KPI's (Key performance indexes) and minimal performance indexes (PI) as a basis for the allocation of public or insurance resources. In particular, the reduction of multiple pregnancy rates costs, may lead to a more widespread use of ART even in lower resources countries.

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.

The aim of the present systematic review and meta-analysis was to assess the effect of the different therapeutic options for repeated embryo implantation failure (RIF) on a subsequent IVF cycle outcome. Twenty-two RCTs and nineteen observational studies were included. Pooling of results showed a beneficial effect of intrauterine PBMC infusion on both CPR (RR 2.18; 95% CI 1.58–3.00; p

Several pathogenetic mechanisms have been postulated to explain the association between endometriosis and subfertility. However, to date, definitive conclusions cannot be drawn. In this study, we hypothesized that the reduced exploitation of the natural chances of conception could be an additional detrimental factor. Due to dyspareunia or the need for hormonal treatment to temper pelvic pain, one may expect affected women to exploit less the chances of natural pregnancy. In this cross-sectional study of 292 women undergoing IVF, we investigated the severity of pelvic pain symptoms, the sexual function (using the Female Sexual Function Index [FSFI]), and the reproductive strategies of women with (n = 62) and without (n = 230) endometriosis. Basal clinical and demographic characteristics did not differ between the two groups. Conversely, all pelvic pain symptom scores were increased in women with endometriosis. Endometriosis patients also showed greater pain at the FSFI, but no other significant differences were detected as regards sexual function. The use of hormonal contraceptive agents did not differ between the study groups. Moreover, questions aimed at disentangle whether affected women exploited less the natural chances of pregnancy did not reveal any significant difference. In conclusion, this study does not support the hypothesis that women with endometriosis exploit less the chances of natural pregnancy, despite the presence of pelvic pain.

In the last decade, testosterone replacement therapy (TRT) has been increasingly prescribed to treat a controversial condition known as 'late-onset hypogonadism (LOH)'. This syndrome is diagnosed in men who, for no discernible reason other than older age, obesity or ill health have serum testosterone concentrations below the normal range for healthy young men and report one or more of the following symptoms: muscle weakness or wasting, mood, behaviour and cognition-related symptoms and sexual function or libido impairment. However, recent evidence has demonstrated that testosterone drugs do not substantially ameliorate these symptoms and, more worryingly, that their long-term use may be associated with severe adverse effects (i.e. increased risk of prostate cancer, stroke and myocardial infarction, worsening of benign prostatic hyperplasia symptoms and testicular atrophy). Nonetheless, testosterone drugs have exhibited extraordinary commercial success and their pharmaceutical sales are steadily rising. Behind this apparently unjustifiable trend there are deliberate, well designed direct and indirect pharmaceutical marketing initiatives that exploit the conviction rooted in contemporary society that testosterone can reverse the effects of ageing and ensure social accomplishment. Commercial mechanisms have laid the foundation for disease mongering of LOH and also have resulted a considerable expansion of the indications for treatment. This promotion model deserves particular attention since it is applicable to any drug with a purportedly favourable risk-benefit ratio not supported by evidence.

The clinical management of women with deep peritoneal endometriosis remains controversial. The debate focuses mainly on the precise role of hormonal medical treatment and surgery and on the most suitable surgical technique to be used. In particular, considering the risks of second-line surgery, prevention of recurrences after first-line surgery is a priority in this context. Post-surgical medical therapy has been advocated to improve the effectiveness of surgery and prevent recurrences. However, adjuvant therapy, i.e. a short course of 3-6 months of hormonal therapy after surgery, has been proven to be of limited or no benefit for endometriosis in general and for deep peritoneal endometriosis in particular. On the other hand, two cohort studies suggest a beneficial effect of prolonged hormonal therapy after surgery for deep endometriosis. Even if this evidence is too weak to confidently advocate systematic administration of prolonged medical therapy after surgery, we argue in favour of this approach because of the strong association of deep endometriosis with other disease forms. In fact, women operated on for deep endometriosis may also face recurrences of endometriomas, superficial peritoneal lesions and pelvic pain in general. The demonstrated high effectiveness of prolonged postoperative therapy for the prevention of endometriomas' formation and dysmenorrhea recurrence should thus receive utmost consideration in the decision-making process.

This systematic review of the literature reports on the use and effectiveness of sperm banking programmes for cancer patients. Thirty studies with 11798 patients were included. The aggregated rate of use of cryopreserved semen was 8% (95% CI 8 to 9%). A statistically significant correlation emerged between the mean and median duration of follow-up and the rate of use (R(2) = 0.46; P = 0.03). The rate of patients discarding their frozen sample was reported in 11 studies. The aggregated rate was 16% (95% CI 15 to 17%). The rate of patients who used their frozen semen and achieved parenthood was reported in 19 papers. The aggregated rate was 49% (95% CI 44 to 53%). The rate of patients achieving parenthood with the use of frozen sperm is low and, from an economical perspective, the effectiveness of programmes of sperm banking might therefore be questioned. On the other hand, the low rate of patients discarding their frozen samples and the correlation between rate of use and duration of follow-up suggest that the calculated 8% rate of use may be an under-estimation and that cumulative rate of use may be substantially higher. Specific studies are, however, required to clarify this issue.

STUDY QUESTION Is the predictive model for IVF success proposed by van Loendersloot et al. valid in a different geographical and cultural context? SUMMARY ANSWER The model discriminates well but was less accurate than in the original context where it was developed. WHAT IS ALREADY KNOWN Several independent groups have developed models that combine different variables with the aim of estimating the chance of pregnancy with IVF but only four of them have been externally validated. One of these four, the van Loendersloot's model, deserves particular attention and further investigation for at least three reasons; (i) the reported area under the receiver operating characteristics curve (c-statistics) in the temporal validation setting was the highest reported to date (0.68), (ii) the perspective of the model is clinically wise since it includes variables obtained from previous failed cycles, if any, so it can be applied to any women entering an IVF cycle, (iii) the model lacks external validation in a geographically different center. STUDY DESIGN, SIZE, DURATION Retrospective cohort study of women undergoing oocyte retrieval for IVF between January 2013 and December 2013 at the infertility unit of the Fondazione Ca' Granda, Ospedale Maggiore Policlinico of Milan, Italy. Only the first oocyte retrieval cycle performed during the study period was included in the study. Women with previous IVF cycles were excluded if the last one before the study cycle was in another center. The main outcome was the cumulative live birth rate per oocytes retrieval. PARTICIPANTS/MATERIALS, SETTING, METHODS Seven hundred seventy-two women were selected. Variables included in the van Loendersloot's model and the relative weights (beta) were used. The variable resulting from this combination (Y) was transformed into a probability. The discriminatory capacity was assessed using the c-statistics. Calibration was made using a logistic regression that included Y as the unique variable and live birth as the outcome. Data are presented using both the original and the calibrated models. Performance was evaluated correlating the mean predicted chances of live births in the five quintiles and the observed rates. MAIN RESULTS AND THE ROLE OF CHANCE Two-hundred-eleven live births (27%) were obtained. The c-statistic was 0.64 (95% CI: 0.61-0.67, P < 0.001). The slope of the linear predictor (calibration slope) expressed as an Odds Ratio was 1.81 (95% CI: 1.46-2.24, P < 0.001), corresponding to a beta of 0.630. The calibration intercept was +0.349 (P = 0.13). While a clear discrepancy exists using the original model, data appear properly distributed with the calibrated model. The Pearson coefficient of the correlation between the mean predicted chances of live births in the five quintiles and the observed rates was 0.99 (P = 0.002). LIMITATIONS, REASONS FOR CAUTION Data were collected retrospectively, thus exposing them to potential inaccuracies. The selection criteria for access to IVF adopted in our center might be too stringent, leading to the exclusion of women with a poor, yet acceptable chance of live birth. Therefore, the validity of the model in women with a very low chance of live birth could not be tested. WIDER IMPLICATIONS OF THE FINDINGS The van Loendersloot's model can be used in other contexts but it is important that it has local calibration. It may help in counseling couples about their chance of success but it cannot be used to exclude treatments. Further research is needed to improve the discriminatory performance of IVF predictive models. STUDY FUNDING/COMPETING INTERESTS None. TRIAL REGISTRATION NUMBER Not applicable.

A diagnosis of unexplained infertility is commonly made when clinical investigations fail to identify any obvious barriers to conception. As a consequence, unexplained infertility includes several heterogeneous conditions, one being women with age-related infertility. However, the latter represent a peculiar and different situation. Women with age-related infertility may have a different prognosis and may benefit from different treatments. Unfortunately, since fecundity declines with age, discerning between unexplained infertility and age-related infertility becomes more and more difficult as the woman's age increases. In this opinion, with the use of a mathematical model we show that the rate of false positive diagnoses of unexplained infertility increases rapidly after 35 years of age. Using a threshold of 2 years of unfruitful, regular unprotected intercourse, this rate exceeds 50% in women starting pregnancy seeking after 37 years. The scenario is much worse using a threshold of 1 year. From a clinical perspective, extrapolating results obtained in a population of young women with unexplained infertility to those with age-related infertility is not justified. It is noteworthy that, if Assisted Reproductive Technologies are unable to overcome age-related infertility, the older women erroneously labeled with unexplained infertility may receive inappropriate therapies. These may expose women to unjustified risks and waste financial resources. Unfortunately, the available literature about older women is scanty and does not provide valid evidence. Randomized controlled trials aimed at identifying the most suitable clinical management of older women with a normal infertility work-up are pressingly needed.

Evidence on the long-term impact of controlled ovarian hyperstimulation (COH) on thyroid function is scarce. To investigate this, we report on serum thyroid-stimulating hormone (TSH) modifications in euthyroid and hypothyroid women during COH and 3 months after the end of the stimulation cycle.Women who underwent in vitro fertilization (IVF) and who did not become pregnant were eligible. Cases were women with treated hypothyroidism and basal serum TSH2.5 mIU/L. Controls were euthyroid women matched to cases by age and basal serum TSH. Women could be included if serum TSH was available at 4 time points: prior to initiating COH (time 1); at the time of human chorionic gonadotropin (hCG) administration (time 2); 16 days after hCG administration (time 3); and 3 months after the end of the IVF cycle (time 4).Thirty-seven case-control pairs were included. Serum TSH at times 1, 2, 3, and 4 was 1.7 ± 0.6, 3.1 ± 1.4, 3.1 ± 1.3, and 2.7 ± 1.7 mIU/L, and 1.7 ± 0.6, 2.9 ± 1.0, 2.7 ± 1.0, and 1.9 ± 0.7 mIU/L among cases and controls, respectively. A statistically significant difference emerged at time 4 (P.001). In both groups, serum TSH was higher at time 4 compared to time 1. Serum TSH exceeded the recommended threshold of 2.5 mIU/L at time 4 in 51% of cases (95% confidence interval [CI], 35 to 68%) and in 16% of controls (95% CI, 4 to 28%) (P = .003).COH seems to have a long-term impact on TSH levels. The magnitude of this effect is particularly pronounced in hypothyroid women.

The reduction of female fertility over time is considered as a natural consequence of ovarian aging. The exact mechanism underlying this process is not fully elucidated. However, it is becoming increasingly evident that qualitative and quantitative mitochondrial genome alterations might play a relevant role. The former include mitochondrial DNA (mtDNA) damage caused by oxidative stress, the accumulation of acquired mtDNA mutations, the effects of inherited mtDNA mutations, and alterations in the mitochondrial stress response mechanism. The latter refer to alterations in the oocytes, granuolosa cells, and embryonic cells mtDNA content. The present review aims to investigate the evidence about: (1) the effect of qualitative and quantitative mtDNA alterations on female fertility, paying particular attention to those with a pathophysiology characterized by a relevant role of oxidative stress; (2) the use of oocytes, granulosa cells (GCs), embryonic cells, and peripheral blood cells mtDNA copy number as a female fertility surrogate biomarker; (3) experimental therapies tested to try to subvert the ovarian aging process with particular reference to antioxidant treatments.

Objective: Ovarian hyper-stimulation during IVF is associated with a significant raise in serum estrogens and one may expect detrimental effects on estrogen-dependent diseases such as endometriosis. However, available evidence from large case series of affected women performing IVF is generally reassuring with the possible exception of women carrying deep invasive lesions. On this basis we deemed important investigating more in depth whether women with deep invasive endometriosis could be a subgroup at higher risk of recurrence or disease progression during IVF. Study design: Women with endometriosis who underwent IVF and who had a second evaluation after 3–6 months from a failed cycle were retrospectively reviewed. The main inclusion criteria were the presence of deep invasive endometriosis and/or a history of surgery for this form of the disease. The primary aim of the study was to determine the frequency of endometriosis-related complications in the interval between the two evaluations. Secondary aims were pain symptoms and lesion size modifications. Results: Eighty-four women were ultimately selected: baseline ultrasound documented deep invasive lesions in 60 of them. One case of possible endometriosis-related complication was recorded, corresponding to a rate of 1.2% (95%: 0.05%–5.5%) for the whole cohort and 1.7% (95%CI: 0.08–7.6%) for the subgroup of women with ultrasound detected lesions. This rate appears similar to the reported frequency of endometriosis progression in women not receiving IVF. No significant modifications in pain symptoms or lesions size occurred. Conclusions: Women with deep invasive endometriosis who underwent IVF do not seem to be exposed to a substantially increased risk of recurrence/disease progression. Larger evidence from independent groups is however required for a definitive conclusion. Keywords: Deep invasive endometriosis, IVF, Recurrence

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 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.

Objective To evaluate the economical benefit of preimplantation genetic testing of aneuploidies (PGT-A) when applied in an extended culture and stringent elective single ET framework. Design Theoretical cost-effectiveness study. Setting Not applicable. Patients/Animal(s) None. Intervention(s) Comparison of the cost-effectiveness between two IVF treatment strategies: serial transfer of all available blastocysts without genetic testing (first fresh transfer and subsequent frozen-thawed transfer); and systematic use of genetic testing (trophectoderm biopsy, freeze-all, and frozen-thawed transfers of euploid blastocysts). The costs considered for this analysis are based on regional public health system provider. Main Outcome Measure(s) Costs per live birth. Result(s) Cost-effectiveness profile of PGT-A improves with female age and number of available blastocysts. Sensitivity analyses varying the costs of ET, the costs of genetic analyses, the magnitude of the detrimental impact of PGT-A on live birth rate, and the crude live birth rates change to some extent the thresholds for effectiveness but generally confirm the notion that PGT-A can be economically advantageous in some specific subgroups. Conclusion(s) PGT-A can be cost-effective in specific clinical settings and population groups. Economic considerations deserve attention in the debate regarding the clinical utility of PGT-A.

To establish the risk factors for monozygotic twin (MZT) and monochorionic twin (MCT) pregnancies after in vitro fertilization (IVF).Systematic review and meta-analysis.Not applicable.Women who achieved MZT and non-MZT pregnancies through IVF.Systematic search of Medline from January 1995 to October 2018 with cross-checking of references from relevant articles in English.Possible risk factors for MZT or MCT pregnancies after IVF, comprising extended embryo culture, insemination method (conventional IVF and intracytoplasmic sperm injection [ICSI]), embryo biopsy for preimplantation genetic testing for aneuploidies or for monogenic/single-gene defects (PGT-A or PGT-M) programs, assisted hatching (AH), oocytes donation, female age, and embryo cryopreservation.A total of 40 studies were included. Blastocyst transfer compared with cleavage-stage embryo transfer, and female age35 years were associated with a statistically significant increase in the MZT and MCT pregnancy rate after IVF: (23 studies, OR 2.16, 95% CI, 1.74-2.68, IBlastocyst transfer is associated with an increased risk of both MZT and MCT pregnancies after IVF. Further evidence is needed to clarify the impact of female age, insemination method and AH on the investigated outcomes.

PURPOSE: Low mitochondrial DNA (mtDNA) content in oocytes and in cumulus cells is an indicator of poor oocyte quality. Moreover, initial evidence showed a correlation between mtDNA content in cumulus cells and mtDNA copy number in peripheral blood cells. On these bases, we deemed of interest investigating the correlation between mtDNA copy number in peripheral blood and natural fecundity. METHODS: This is a nested case–control study drawn from a prospective cohort of pregnant women referred for routine first trimester screening for aneuploidies (from 11 + 0 to 12 + 6 weeks of gestation) between January 2012 and March 2013 at the “Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico” of Milan, Italy. Cases were subfertile women who attempted to become pregnant for 12–24 months. Controls were the two subsequently age-matched women who became pregnant in less than 1 year. MtDNA was quantified using real-time PCR and normalized to nuclear DNA. RESULTS: One hundred and four subfertile women and 208 controls were selected. The median (IQR) mtDNA copy number was 95 (73–124) and 145 (106–198), respectively (p

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.

Poor ovarian response (POR) to controlled ovarian hyperstimulation for in vitro fertilization (IVF) is one of the most challenging issue in the field of reproductive medicine. However, even if improving IVF outcome in poor responders (PORs) represents a main priority, the lack of a unique definition of POR has hampered research in this area. In order to overcome this impediment, an ESHRE Campus Workshop was organized in Bologna in 2010 and reached a consensus on the criteria for the diagnosis of POR ("Bologna Criteria"). In this review we aimed to estimate the prognostic potential of the ESHRE definition, to elucidate its possible weaknesses and to analyze the economic aspects of IVF in a population of poor responders (PORs). Available evidence confirmed that the Bologna criteria are able to select a population with a poor IVF prognosis thus supporting their validity. Nonetheless, different aspects of the definition have been criticized. The main points of debate concern the homogeneity of the population identified, the cut-off values chosen for the ovarian reserve tests and the risks factors other than age associated with POR. Data concerning the economic profile of IVF in PORs are scanty. The only published study on the argument showed that IVF in these cases is not cost-effective. However, considering the potential substantial impact of cost-effectiveness analyses on public health policies, there is the need for further and independent validations.

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.

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.

While there is a large body of evidence showing a significant impact of controlled ovarian hyperstimulation (COH) on thyroid function in euthyroid patients undergoing in vitro fertilization (IVF), information on the effect of this treatment on thyroid axis equilibrium in hypothyroid-treated patients is insufficient. The goal of this prospective study was to investigate serum thyroid-stimulating hormone (TSH) modifications in hypothyroid-treated patients during IVF.Hypothyroid-treated women selected for IVF between November 2010 and December 2011 were considered for study entry. They were eligible if serum TSH tested the month preceding the IVF cycle was 0.4-2.5 mIU/L. Additional inclusion criteria were as follows: (1) a certified diagnosis of clinical or subclinical hypothyroidism; (2) consumption of at least 25 μg of levothyroxine daily; (3) serum free triiodothyronine and free thyroxine tested the month preceding the IVF cycle within the reference range; (4) no previous IVF cycles; (5) regular menstrual cycles; and (6) day 3 serum follicle-stimulating hormone12 IU/mL and anti-Müllerian hormone0.5 ng/mL. Serum TSH was tested at three time points: between day 1 and day 8 of the cycle during the month preceding the start of controlled ovarian hyperstimulation (COH), at the time of human chorionic gonadotropin (hCG) administration and at 16 days after hCG administration.Seventy-two women met our selection criteria. The serum levels of TSH at basal assessment, at the time of hCG administration, and at 16 days after hCG administration were 1.7 ± 0.7, 2.9 ± 1.3, and 3.2 ± 1.7 mIU/L, respectively. All pairwise comparisons were statistically significant. Serum TSH exceeded the threshold of 2.5 mIU/L in 46 subjects at the time of hCG administration (64%, [CI: 53-75%]) and in 49 subjects 16 days after hCG administration (68%, [CI: 57-79%]).Serum TSH increased considerably during COH in adequately treated hypothyroid women undergoing IVF. We suggest strictly monitoring these women during IVF cycles and, if necessary, promptly adjusting the levothyroxine dose. This is the most pragmatic approach but, to date, it is not supported by clinical evidence. Further studies aimed at clarifying the most suitable therapeutic strategy are thus warranted.

To evaluate the rate of euthyroid women encountering an elevation of serum TSH above the threshold of 2.5 mIU/L during controlled ovarian hyperstimulation (COH) for IVF.Six-month prospective cohort study on 175 consecutive euthyroid women undergoing their first IVF cycle. Serum TSH assessments were performed before COH, at the time of hCG administration and at +16 days after hCG administration. Women were eligible if serum TSH tested the month preceding the IVF cycle was 0.4-2.5 mIU/L. A history of thyroid disorders was an exclusion criterion.Serum concentrations of TSH at the three scheduled assessments were 1.5±0.5, 2.2±1.0 and 2.1±1.1 mIU/L, respectively. A statistically significant increase occurred between basal levels and levels at the time of hCG administration (p0.001). Afterwards, levels remained stable (p=0.49). Serum TSH at the time of hCG administration exceeded the threshold of 2.5 mIU/L in 61 subjects, corresponding to 35% (95% CI: 28-42%). At +16 days after hCG administration, this event was observed in 47 subjects (27%, 95% CI: 21-34%). Baseline characteristics of women who did and did not exceed the threshold were similar apart from basal serum TSH, which was higher in the former group. The OR was 7.6 (95%CI: 2.9-20.2) per mIU/L (p0.001). Cycle outcome and pregnancy rate were also similar.Serum TSH exceeds the threshold of 2.5 mIU/L during COH in one out of three women who are euthyroid prior to enter an IVF cycle. Further evidence is warranted to elucidate the clinical relevance of our findings.

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

There is a general belief that pregnancy has a beneficial effect on endometriosis but evidence is scanty. Moreover, some recent warning reports documented progression-growth of ovarian endometriomas during pregnancy. To further elucidate this aspect, we set up a prospective cohort study. We recruited 24 women carrying endometriomas at the time of in vitro fertilization who got pregnant. Selected women were contacted about 12-18 months after oocyte retrieval and invited to refer for ultrasound. The primary aim was to evaluate the modifications of endometriotic cysts after pregnancy. Twenty-four women carrying 40 endometriomas accepted to participate. The number of cysts per patient was significantly reduced following pregnancy (p = 0.003). It was unchanged in eight cases (33%), increased in two cases (8%) and reduced in three cases (13%). In the remaining 11 women (46%), no cyst could be detected. A comparison of the size of the endometrioma could be done in 21 cysts; the mean ± SD diameter before and after pregnancy was 20 ± 9 and 18 ± 7 mm, respectively (p = 0.27). In conclusion, pregnancy has a beneficial effect on endometriomas. A consistent proportion of cysts becomes undetectable after delivery. Further studies are warranted to clarify the mechanisms determining the disappearance of these cysts.

Background: The routine assessment of day 3 serum progesterone prior to initiation of ovarian hyper-stimulation with the use of GnRH antagonists is under debate. In this study, we evaluated the clinical utility of this policy. Methods: Retrospective cohort study of women undergoing in vitro fertilization (IVF) with the use of GnRH antagonists aimed at determining the frequency of cases with progesterone levels exceeding the recommended threshold of 1,660 pg/ml and at evaluating whether this assessment may be predictive of pregnancy. Results: Serum progesterone exceeded the recommended threshold in one case (0.3%, 95% CI 0.01-1.5). The median (interquartile range) basal progesterone in women who did (n = 95) and did not (n = 217) become pregnant were 351 (234-476) and 380 (237-531) pg/ml, respectively (p = 0.28). The 90th percentile of the basal progesterone distribution in women who became pregnant was 660 pg/ml. Cases with serum progesterone exceeding this threshold in successful and unsuccessful cycles were 10 (10%) and 30 (14%), respectively (p = 0.47). The capacity of basal progesterone to predict pregnancy was evaluated using receiver operating characteristic curve (area under the curve = 0.54, 95% CI 0.47-0.61, p = 0.28). No graphically evident threshold emerged. Conclusion: Routine day 3 serum progesterone assessment in IVF cycles with the use of GnRH antagonists is not justified. Further evidence is warranted prior to claiming its systematic use.

ObjectiveAbout one out of two women with primary hypothyroidism has to increase the dosage of exogenous levothyroxine (l-T4) during pregnancy. Considering the detrimental impact of IVF on thyroid function, it has been claimed but not demonstrated thatl-T4dose adjustment may be more significant in hypothyroid women who become pregnant after IVF.DesignRetrospective cohort study.MethodsHypothyroid-treated women who achieved a live birth through IVF were reviewed. Women could be included if thyroid function was well compensated withl-T4before the IVF cycle (i.e., serum TSH 4within the normal range). Serum TSH and dose adjustment were evaluated at five time points during pregnancy. The trimester ranges for serum TSH considered as reference to adjustl-T4therapy were 0.1–2.5 mIU/l for the first trimester, 0.2–3.0 mIU/l for the second trimester, and 0.3–3.0 mIU/l for the third trimester.ResultsThirty-eight women were selected. During the whole pregnancy 32 women (84%; 95% CI: 72–96%) required an increase in the dose ofl-T4. In most cases (n=28), this occured within the first 5–7 weeks of gestation (74%, 95% CI: 58–85%). At 5–7 weeks of gestation, the median (interquartile range) increase ofl-T4dose for the whole cohort was 26% (0–50%). At 30–32 weeks, it was 33% (14–68%). In order to identify predictive factors of dose adjustment, we compared women who did (n=28) and did not (n=10) adjustl-T4dosage at 5–7 weeks' gestation. Significant differences emerged for thyroid autoimmunity prevalence and for the distribution of hypothyroidism aetiology.ConclusionsThe vast majority of hypothyroid-treated women who achieve pregnancy through IVF need an increase in thel-T4dose during gestation. This requirement tends to occur very early during gestation.

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

Objective To evaluate the accuracy of antral follicular count (AFC) in predicting ovarian responsiveness in ovaries with endometriomas or with a past history of surgical excision of endometriomas. Design Retrospective review. Setting Academic hospital. Patient(s) Eighty-three women for a total of 166 gonads. Intervention(s) None. Main Outcome Measure(s) Total number of developing follicles. Result(s) The ovaries were characterized as four groups: [1] unoperated gonads without endometriomas (n = 42, control group), [2] unoperated gonads with endometriomas (n = 46), [3] operated gonads without endometriomas (n = 55), and [4] operated gonads with endometriomas (n = 23). The analyses subsequently considered all ovaries with endometriomas (groups 2 + 4, n=69) and all operated ovaries (groups 3 + 4, n=78). The capacity of AFC to predict low response (≤2 follicles) or hyperresponsiveness (≥7 follicles) was evaluated using receiver operating characteristic curves. We used a linear regression model to calculate the adjusted B coefficients. The adjusted B coefficients in unaffected ovaries, in all ovaries with endometriomas, and in all operated ovaries were 0.55 (95% confidence interval [CI], 0.07–1.03), 0.76 (95% CI, 0.54–0.98), and 0.51 (95% CI, 0.26–0.76), respectively. The area under the curve (AUC) for the prediction of low response was 0.83 (95% CI, 0.68–0.99), 0.83 (95% CI, 0.73–0.93), and 0.74 (95% CI, 0.63–0.85), respectively. The AUC for the prediction of hyperresponse was 0.84 (95% CI, 0.70–0.97), 0.74 (95% CI, 0.63–0.85), and 0.77 (0.60–0.94), respectively. Conclusion(s) The accuracy of AFC for predicting ovarian response is similar in unaffected ovaries, ovaries with endometriomas and ovaries with a history of surgery for endometriomas.

Classical surgical management of endometriotic ovarian cysts using the laparoscopic stripping technique has been recently questioned because of the surgical-related injury to the ovarian reserve. Accordingly, available guidelines suggest that endometriomas with a mean diameter below 4 cm should not be systematically removed before IVF procedures. However, conservative management may have some potential drawbacks and risks. The presence of the endometrioma may theoretically interfere with ovarian responsiveness to hyperstimulation and oocyte competence, the retrieval of the oocytes may be more difficult and risky, the disease may progress during the procedure, pregnancy outcome may be affected and there is the risk of missing occult malignancies with cancer development later in life. In the present review, we aimed at assessing whether these risks do exist and, if so, at estimating their clinical relevance.We searched PubMed for articles published in the English language between January 1990 and August 2014 that reported on endometriomas and assisted reproductive techniques. Special care was given to studies reporting data purporting to distinguish the effects of ovarian endometriomas per sé from those consequent to surgery for endometriosis or from endometriosis in general.Based on the evidence reviewed in the present study, it can be concluded that conservative management may actually expose women to four of the following theoretical risks, i.e. infection of the endometriomas, follicular fluid contamination with the endometrioma content, higher risk of pregnancy complications and cancer development later in life. The first three conditions do not justify surgery because these events are uncommon and the number of women needed to be treated would be exceedingly high and would not justify the costs and risks of the intervention. Albeit also very rare, the possibility of developing ovarian cancer later in life is more troublesome because it is a life-threatening condition. However, this alarmism is supported by only one cohort study and this risk can be effectively prevented by postponing surgery until after the IVF programme is concluded or when women have definitely satisfied their reproductive wishes.The available evidence on the risks of conservative management does not support systematic surgery before IVF in women with small ovarian endometriomas.

The high rate of disease recurrence after surgery is critical and frustrating for women with endometriosis. Adjuvant treatments using a 3- to 6-months course of hormone therapy after surgery have been extensively investigated during the last 2 decades; however, results have been unsatisfactory, primarily because the benefits of hormone therapy rapidly vanish once treatment is discontinued. The protective effect is limited to the period of use. Accordingly, it is recognized that suppressive hormone therapy after surgery markedly prevents recurrent episodes only if given over the long term. The emerging view is that estroprogestins do not ameliorate the effects of surgery but demonstrate tertiary prevention of the disease. They prevent ovulation and reduce retrograde menstrual flow, two crucial events in the pathogenesis of endometriosis. The available literature strongly supports the benefits of prolonged administration of estroprogestins after surgery in preventing recurrence of endometriomas and dysmenorrhea. In contrast, data on dyspareunia and nonmenstrual pelvic pain remain scanty and unconvincing, and there is no information about recurrence of other forms of endometriosis such as peritoneal implants and adhesions. Overall, estroprogestin therapy after surgery to treat endometriosis should be recommended in women who do not seek to become pregnant. Further evidence is warranted to better delineate the beneficial effects of this emerging but convincing strategy.

This study postulated that poor-responder women failing to obtain viable embryos would represent a subgroup of subjects with extremely poor prognosis. To elucidate this aspect, women in this condition over a 4-year period were retrospectively identified and their IVF outcomes in subsequent cycles were evaluated. A total of 108 women satisfied the selection criteria and underwent at least one further IVF cycle. There were 19 women excluded because they opted for a mild approach using clomiphene citrate alone, leaving 89 women for data analyses. Four women had a live birth during this first cycle, corresponding to a delivery rate per started cycle of 4.5% (95% CI 1.5-10.0%). From a public health perspective, the mean cost per delivery was € 124,540. Younger age emerged as the unique predictive factor of success. In conclusion, women with poor ovarian response failing to obtain viable embryos have extremely low chances of success in subsequent cycles. Considering the costs and risks of IVF, the appropriateness of pursuing treatments in these women is questionable. Younger women may represent a possible exception since their chances of delivery are higher.