A risk prediction model of sperm retrieval failure with fine needle aspiration in males with non-obstructive azoospermia.

Ma Y ，Li F ，Wang L ，Zhao W ，Li D ，Xian Y ，Jiang X ... -  《-》

Prediction model for obtaining spermatozoa with testicular sperm extraction in men with non-obstructive azoospermia.

Can an externally validated model, based on biological variables, be developed to predict successful sperm retrieval with testicular sperm extraction (TESE) in men with non-obstructive azoospermia (NOA) using a large nationwide cohort? Our prediction model including six variables was able to make a good distinction between men with a good chance and men with a poor chance of obtaining spermatozoa with TESE. Using ICSI in combination with TESE even men suffering from NOA are able to father their own biological child. Only in approximately half of the patients with NOA can testicular sperm be retrieved successfully. The few models that have been developed to predict the chance of obtaining spermatozoa with TESE were based on small datasets and none of them have been validated externally. We performed a retrospective nationwide cohort study. Data from 1371 TESE procedures were collected between June 2007 and June 2015 in the two fertility centres. All men with NOA undergoing their first TESE procedure as part of a fertility treatment were included. The primary end-point was the presence of one or more spermatozoa (regardless of their motility) in the testicular biopsies.We constructed a model for the prediction of successful sperm retrieval, using univariable and multivariable binary logistic regression analysis and the dataset from one centre. This model was then validated using the dataset from the other centre. The area under the receiver-operating characteristic curve (AUC) was calculated and model calibration was assessed. There were 599 (43.7%) successful sperm retrievals after a first TESE procedure. The prediction model, built after multivariable logistic regression analysis, demonstrated that higher male age, higher levels of serum testosterone and lower levels of FSH and LH were predictive for successful sperm retrieval. Diagnosis of idiopathic NOA and the presence of an azoospermia factor c gene deletion were predictive for unsuccessful sperm retrieval. The AUC was 0.69 (95% confidence interval (CI): 0.66-0.72). The difference between the mean observed chance and the mean predicted chance was <2.0% in all groups, indicating good calibration. In validation, the model had moderate discriminative capacity (AUC 0.65, 95% CI: 0.62-0.72) and moderate calibration: the predicted probability never differed by more than 9.2% of the mean observed probability. The percentage of men with Klinefelter syndrome among men diagnosed with NOA is expected to be higher than in our study population, which is a potential selection bias. The ability of the sperm retrieved to fertilize an oocyte and produce a live birth was not tested. This model can help in clinical decision-making in men with NOA by reliably predicting the chance of obtaining spermatozoa with TESE. This study was partly supported by an unconditional grant from Merck Serono (to D.D.M.B. and K.F.) and by the Department of Obstetrics and Gynaecology of Radboud University Medical Center, Nijmegen, The Netherlands, the Department of Obstetrics and Gynaecology, Jeroen Bosch Hospital, Den Bosch, The Netherlands, and the Department of Obstetrics and Gynaecology, Academic Medical Center, Amsterdam, The Netherlands. Merck Serono had no influence in concept, design nor elaboration of this study. Not applicable.

Cissen M ，Meijerink AM ，D'Hauwers KW ，Meissner A ，van der Weide N ，Mochtar MH ，de Melker AA ，Ramos L ，Repping S ，Braat DD ，Fleischer K ，van Wely M ... -  《-》

Prediction model for live birth in ICSI using testicular extracted sperm.

Which parameters have a predictive value for live birth in couples undergoing ICSI after successful testicular sperm extraction (TESE-ICSI)? Female age, a first or subsequent started TESE-ICSI cycle, male LH, male testosterone, motility of the spermatozoa during the ICSI procedure and the initial male diagnosis before performing TESE were identified as relevant and independent parameters for live birth after TESE-ICSI. In reproductive medicine prediction models are used frequently to predict treatment success, but no prediction model currently exists for live birth after TESE-ICSI. A retrospective cohort study between 2007 and 2015 in two academic hospitals including 1559 TESE-ICSI cycles. The prediction model was developed using data from one centre and validation was performed with data from the second centre. We included couples undergoing ICSI treatment with surgically retrieved sperm from the testis for the first time. In the development set we included 526 couples undergoing 1006 TESE-ICSI cycles. In the validation set we included 289 couples undergoing 553 TESE-ICSI cycles. Multivariable logistic regression models were constructed in a stepwise fashion (P < 0.2 for entry). The external validation was based on discrimination and calibration. We included 224 couples (22.3%) with a live birth in the development set. The occurrence of a live birth was associated with lower female age, first TESE-ICSI cycle, lower male LH, higher male testosterone, the use of motile spermatozoa for ICSI and having obstructive azoospermia as an initial suspected diagnosis. The area under the receiver operating characteristic (ROC) curve was 0.62. From validation data, the model had moderate discriminative capacity (c-statistic 0.67, 95% confidence interval: 0.62-0.72) but calibrated well, with a range from 0.06 to 0.56 in calculated probabilities. We had a lack of data about the motility of spermatozoa during TESE, therefore, we used motility of the spermatozoa used for ICSI after freeze-thawing, information which is only available during treatment. We had to exclude data on paternal BMI in the model because too many missing values in the validation data hindered testing. We did not include a histologic diagnosis, which would have made our data set less heterogeneous and, finally, our model may not be applicable in centres which have a different policy for the indication for performing sperm extraction. The prognostic value of the model is limited because of a low 'area under the curve'. This model enables the differentiation between couples with a low or high chance to reach a live birth using TESE-ICSI. As such it can aid in the counselling of patients and in clinical decision-making. This study was partly supported by an unconditional grant from Merck Serono (to D.D.M.B. and K.F.) and by the Department of Obstetrics and Gynaecology of Radboud University Medical Center, Nijmegen, The Netherlands, the Department of Obstetrics and Gynaecology, Jeroen Bosch Hospital, Den Bosch, The Netherlands, and the Department of Obstetrics and Gynaecology, Academic Medical Center, Amsterdam, The Netherlands. Merck Serono had no influence in concept, design, nor elaboration of this study. Not applicable.

Meijerink AM ，Cissen M ，Mochtar MH ，Fleischer K ，Thoonen I ，de Melker AA ，Meissner A ，Repping S ，Braat DD ，van Wely M ，Ramos L ... -  《-》

Prediction of sperm extraction in non-obstructive azoospermia patients: a machine-learning perspective.

Can a machine-learning-based model trained in clinical and biological variables support the prediction of the presence or absence of sperm in testicular biopsy in non-obstructive azoospermia (NOA) patients? Our machine-learning model was able to accurately predict (AUC of 0.8) the presence or absence of spermatozoa in patients with NOA. Patients with NOA can conceive with their own biological gametes using ICSI in combination with successful testicular sperm extraction (TESE). Testicular sperm retrieval is successful in up to 50% of men with NOA. However, to the best of our knowledge, there is no existing model that can accurately predict the success of sperm retrieval in TESE. Moreover, machine-learning has never been used for this purpose. A retrospective cohort study of 119 patients who underwent TESE in a single IVF unit between 1995 and 2017 was conducted. All patients with NOA who underwent TESE during their fertility treatments were included. The development of gradient-boosted trees (GBTs) aimed to predict the presence or absence of spermatozoa in patients with NOA. The accuracy of these GBTs was then compared to a similar multivariate logistic regression model (MvLRM). We employed univariate and multivariate binary logistic regression models to predict the probability of successful TESE using a dataset from a retrospective cohort. In addition, we examined various ensemble machine-learning models (GBT and random forest) and evaluated their predictive performance using the leave-one-out cross-validation procedure. A cutoff value for successful/unsuccessful TESE was calculated with receiver operating characteristic (ROC) curve analysis. ROC analysis resulted in an AUC of 0.807 ± 0.032 (95% CI 0.743-0.871) for the proposed GBTs and 0.75 ± 0.052 (95% CI 0.65-0.85) for the MvLRM for the prediction of presence or absence of spermatozoa in patients with NOA. The GBT approach and the MvLRM yielded a sensitivity of 91% vs. 97%, respectively, but the GBT approach has a specificity of 51% compared with 25% for the MvLRM. A total of 78 (65.3%) men with NOA experienced successful TESE. FSH, LH, testosterone, semen volume, age, BMI, ethnicity and testicular size on clinical evaluation were included in these models. This study is a retrospective cohort study, with all the associated inherent biases of such studies. This model was used only for TESE, since micro-TESE is not performed at our center. Machine-learning models may lay the foundation for a decision support system for clinicians together with their NOA patients concerning TESE. The findings of this study should be confirmed with further larger and prospective studies. The study was funded by the Division of Obstetrics and Gynecology, Soroka University Medical Center, there are no potential conflicts of interest for all authors.

Zeadna A ，Khateeb N ，Rokach L ，Lior Y ，Har-Vardi I ，Harlev A ，Huleihel M ，Lunenfeld E ，Levitas E ... -  《-》

How successful is TESE-ICSI in couples with non-obstructive azoospermia?

What are the chances of a couple with infertility due to non-obstructive azoospermia (NOA) having their genetically own child by testicular sperm extraction combined with ICSI (TESE-ICSI)? Candidate TESE-ICSI patients with NOA should be counselled that, when followed-up longitudinally, only a minority (13.4%) of men embarking for TESE eventually become a biological father. Data available in the literature are only fragmentary because they report either on sperm retrieval rates after TESE or on the outcome of ICSI once testicular spermatozoa has been obtained, mostly in a selected subpopulation. Unfortunately, reliable data to counsel men with NOA on their chance to become a biological father are still lacking. This is a retrospective cohort study performed in the Centre for Reproductive Medicine, University Hospital of Brussel, approved by the institutional review board of the hospital. We identified all patients with NOA, based on histology, who had their first testicular biopsy between 1994 and 2009. Patients were followed longitudinally during consecutive ICSI cycles with testicular sperm. The primary outcome measure was live birth delivery. The cumulative live birth delivery rate was calculated, based only on ICSI cycles with testicular sperm (fresh and/or frozen) available for injection. When patients delivered after transfer of supernumerary frozen embryos, this delivery was tallied up to the (unsuccessful) original fresh ICSI cycle. The sperm retrieval rate and pregnancy rate were secondary outcome measures. Among the 714 men with NOA, 40.5% had successful sperm retrieval at their first TESE. In total, 261 couples had 444 ICSI cycles and 48 frozen embryo transfer cycles, leading to 129 pregnancies and 96 live birth deliveries. Crude and expected cumulative delivery rates after six ICSI cycles were 37 and 78%. A retrospective cohort study design was the only way to study the cumulative delivery rate after TESE-ICSI in couples with NOA. Intrinsic limitations are related to the observational study design. TESE-ICSI is a breakthrough in the treatment of infertility due to NOA, with almost 4 out of 10 (37%) couples having ICSI obtaining a delivery. However, unselected candidate NOA patients should be counselled, before undergoing TESE, that only one out of seven men (13.4%) eventually father their genetically own child. None declared.

Vloeberghs V ，Verheyen G ，Haentjens P ，Goossens A ，Polyzos NP ，Tournaye H ... -  《-》