Evolution of cumulative live birth and dropout rates over six complete IVF/ICSI cycles: a large prospective cohort study.

RESEARCH QUESTION: How do cumulative live birth rates (CLBR), cumulative multiple live birth rates (CMLBR) and dropout rates over six IVF and intracytoplasmic sperm injection (ICSI) cycles change over time? DESIGN: Prospective longitudinal cohort (n = 16,073 patients; 48,946 cycles) starting a first fresh assisted reproductive technology cycle between 1 January 2014 and 31 December 2016, with follow-up until 31 December 2017. Outcomes between the periods 2014-2017 and 2009-2012 were compared. RESULTS: Conservative estimates of CLBR after six complete cycles were significantly higher in women younger than 35 years after every cycle: one to three, adjusted P-value [p adj] < 0.0001; four, p = 0.01; five, p adj = 0.03; six, p adj = 0.04) and after the first cycle in women aged 35-37 years (p adj = 0.04) in 2014-2017 versus 2009-2012. For an optimal estimate, the CLBR was significantly higher after the first three cycles in women younger than 35 years (all p adj < 0.0001) and after the first cycle in women aged 35-37 years (p adj = 0.04). The CMLBR rate decreased from 5.1% ± 0.19 (SE) to 4.1% ± 0.16 for the conservative estimate and from 8.6% ±0.37 (SE) to 6.7% ± 0.30 for the optimal estimate after six complete cycles for the whole cohort. Dropout rates of complete cycles were 26.5% 29.4%, 33.4%, 38.9% and 47.3% after the first to fifth cycle, respectively. Compared with 2009-2012, the dropout rate in the current period was significantly higher for the first (P < 0.0001) and second (P = 0.0124) cycle. CONCLUSION: Over six complete IVF/ICSI cycles, CLBR and dropout rates increased and multiple live birth rates decreased when 2014-2017 was compared with 2009-2012.

Recommendations for good practice in ultrasound: oocyte pick up†.

STUDY QUESTION: What is good practice in ultrasound (US), and more specifically during the different stages of transvaginal oocyte retrieval, based on evidence in the literature and expert opinion on US practice in ART? SUMMARY ANSWER: This document provides good practice recommendations covering technical aspects of US-guided transvaginal oocyte retrieval (oocyte pick up: OPU) formulated by a group of experts after considering the published data, and including the preparatory stage of OPU, the actual procedure and post-procedure care. WHAT IS KNOWN ALREADY: US-guided transvaginal OPU is a widely performed procedure, but standards for best practice are not available. STUDY DESIGN SIZE DURATION: A working group (WG) collaborated on writing recommendations on the practical aspects of transvaginal OPU. A literature search for evidence of the key aspects of the procedure was carried out. Selected papers (n = 190) relevant to the topic were analyzed by the WG. PARTICIPANTS/MATERIALS SETTING METHODS: The WG members considered the following key points in the papers: whether US practice standards were explained; to what extent the OPU technique was described and whether complications or incidents and how to prevent such events were reported. In the end, only 108 papers could be used to support the recommendations in this document, which focused on transvaginal OPU. Laparoscopic OPU, transabdominal OPU and OPU for IVM were outside the scope of the study. MAIN RESULTS AND THE ROLE OF CHANCE: There was a scarcity of studies on the actual procedural OPU technique. The document presents general recommendations for transvaginal OPU, and specific recommendations for its different stages, including prior to, during and after the procedure. Most evidence focussed on comparing different equipment (needles) and on complications and risks, including the risk of infection. For these topics, the recommendations were largely based on the results of the studies. Recommendations are provided on equipment and materials, possible risks and complications, audit and training. One of the major research gaps was training and competence. This paper has also outlined a list of research priorities (including clarification on the value or full blood count, antibiotic prophylaxis and flushing, and the need for training and proficiency). LIMITATIONS REASONS FOR CAUTION: The recommendations of this paper were mostly based on clinical expertise, as at present, only a few clinical trials have focused on the oocyte retrieval techniques, and almost all available data are observational. In addition, studies focusing on OPU were heterogeneous with significant difference in techniques used, which made drafting conclusions and recommendations based on these studies even more challenging. WIDER IMPLICATIONS OF THE FINDINGS: These recommendations complement previous guidelines on the management of good laboratory practice in ART. Some useful troubleshooting/checklist recommendations are given for easy implementation in clinical practice. These recommendations aim to contribute to the standardization of a rather common procedure that is still performed with great heterogeneity. STUDY FUNDING/COMPETING INTERESTS: The meetings of the WG were funded by ESHRE. The other authors declare that they have no conflict of interest. TRIAL REGISTRATION NUMBER: NA.ESHRE Pages content is not externally peer reviewed. The manuscript has been approved by the Executive Committee of ESHRE.

Sperm Chromatin Dispersion Test before Sperm Preparation Is Predictive of Clinical Pregnancy in Cases of Unexplained Infertility Treated with Intrauterine Insemination and Induction with Clomiphene Citrate.

BACKGROUND/AIMS: A large proportion of men with normal sperm results as analyzed using conventional techniques have fragmented DNA in their spermatozoa. We performed a prospective study to examine the incidence of DNA fragmentation in sperm in cases of couples with previously unexplained infertility and treated with intrauterine insemination. We evaluated whether there was any predictive value of DNA fragmentation for pregnancy outcome in such couples. METHODS: The percentage of DNA fragmentation and all classical variables to evaluate sperm before and after sperm treatment were determined. We studied the probable association between these results and pregnancy outcome in terms of clinical and ongoing pregnancy rate per started first cycle. We also assessed the optimal threshold level to diagnose DNA fragmentation in our center. RESULTS: When using threshold levels of 20, 25, and 30%, the occurrence of DNA fragmentation was 42.9, 33.3, and 28.6%, respectively. Receiver operating characteristic (ROC) analysis of all cases revealed an area under the curve of 80% to predict the clinical pregnancy rate per cycle from testing the sperm motility (a + b) before treatment. We failed to generate an ROC curve to estimate pregnancy outcome from the amount of DNA fragmentation before treatment. However, when selecting only those men with a pretreatment DNA fragmentation of at least 20%, the pretreatment result was statistically different between couples who achieved a clinical pregnancy and those who did not. CONCLUSION: DNA fragmentation is often diagnosed in couples with unexplained infertility. Each center should evaluate the type of test it uses to detect DNA fragmentation in sperm and determine its own threshold values.

Self-operated endovaginal telemonitoring versus traditional monitoring of ovarian stimulation in assisted reproduction: an RCT.

STUDY QUESTION: Does self-operated endovaginal telemonitoring (SOET) of the ovarian stimulation phase in IVF/ICSI produce similar laboratory, clinical, patient reported and health-economic results as traditional monitoring (non-SOET)? SUMMARY ANSWER: SOET is not inferior to traditional monitoring (non-SOET). WHAT IS KNOWN ALREADY: Monitoring the follicular phase is needed to adapt gonadotrophin dose, detect threatening hyperstimulation and plan HCG administration. Currently, patients pay visits to care providers, entailing transportation costs and productivity loss. It stresses patients, partners, care providers and the environment. Patients living at great distance from centres have more difficult access to treatment. The logistics and stress during the follicular phase of assisted reproduction treatment (ART) is often an impediment for treatment. STUDY DESIGNS, SIZE, DURATION: The study was a non-inferiority RCT between SOET and non-SOET performed between February 2012 and October 2013. Sample size calculations of number of metaphase II (MII) oocytes (the primary outcome): 81 patients were needed in each study arm for sufficient statistical power. Block randomization was used with allocation concealment through electronic files. The first sonogram was requested after 5 days of stimulation, after that mostly every 2 days and with a daily sonograms at the end. PARTICIPANTS/MATERIALS, SETTINGS, METHODS: Inclusion criteria were age <41 years, undergoing ICSI, no poor response and having two ovaries. We used a small laptop with USB connected vaginal probe and developed a specific web site application. Sonographic training was given to all women at the initiation of a treatment attempt at the centre. The website contained demonstration material consisting of still images and video sequences, as well as written instructions regarding the use of the instrument and probe handling. In total, 185 eligible patients were recruited in four centres: 123 were randomized; 121 completed SOET (n = 59) or non-SOET (n = 62), and 62/185 (33%) eligible patients declined participation for various reasons. MAIN RESULTS AND THE ROLE OF CHANCE: Patient characteristics were comparable. The clinical results showed similar conception rates (P = 0.47) and ongoing pregnancy rates (SOET: 15/59 = 25%; non-SOET: 16/62 = 26%) (P = 1.00) were obtained. Similar numbers of follicles >15 mm diameter at oocyte retrieval (OR), ova at OR, MII oocytes, log2 MII oocytes, embryos available at transfer, top quality embryos and embryos frozen were obtained in the two groups, indicating non-inferiority of SOET monitoring. Regarding patient-reported outcomes, a significantly higher contentedness of patient and partner (P < 0.01), a higher feeling of empowerment, discretion and more active partner participation (P < 0.001) as well as a trend towards less stress (P = 0.06) were observed in the S versus the NS group. In the economic analysis, the use of SOET led to reduced productivity loss, lower transportation costs, and lower sonogram and consultation costs (all P < 0.001 but higher personnel cost than NS). LIMITATIONS, REASONS FOR CAUTION: The study was stopped (no further funding) before full sample size was reached. There were also a few cases of unexpected poor response, leading to a wider SD than anticipated in the power calculation. However, although the study was underpowered for these reasons, non-inferiority of SOET versus non-SOET was demonstrated. WIDER IMPLICATIONS OF THE FINDINGS: Home monitoring using SOET may provide a patient-centred alternative to the standard methods. ART sonograms can be made, and then sent to the care provider for analysis at any appropriate time and from anywhere if an internet connection is available. This approach offers several advantages for patients as well as care providers, including similar results to the traditional methods with less logistical stress and potentially bringing care to patients in poor resource settings. STUDY FUNDING/COMPETING INTERESTS: Supported by an IOF (industrial research fund) of Ghent University (full protocol available at iBiTech) and as a demonstration project of Flanders Care (Flemish Government). There are no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: EC/2011/669 (Ghent University Hospital), B670201112232 (Belgian registration) and NCT01781143 (clinical trials number).

Adding serum estradiol measurements to ultrasound monitoring does not change the yield of mature oocytes in IVF/ICSI.

In a non-randomized, comparative prospective study (416 patients) we compared the outcome of IVF/ICSI in two parallel control groups: one in which patients were followed up using combined monitoring (ultrasound plus serum estradiol monitoring, the UHM group) and one in which only ultrasound monitoring was used (the UM group). This study has taken the number of mature oocytes at the moment of egg retrieval as its primary end variable. After adjustment for age, gravidity, antagonist protocol, AMH and infertility diagnosis, the average difference in number of mature oocytes between the UHM group and the UM group was -0.4 (95% CI: -1.7 to 1.0), which met our definition of clinical equivalence (95% CI for the adjusted mean difference between -2 and 2). Larger studies are still needed to evaluate the differences in the live birth rates per cycle and to further confirm that blood sampling definitively has no added value in monitoring ovarian stimulation for IVF/ICSI.

Delaying the oocyte maturation trigger by one day leads to a higher metaphase II oocyte yield in IVF/ICSI: a randomised controlled trial.

BACKGROUND: The negative impact of rising progesterone levels on pregnancy rates is well known, but data on mature oocyte yield are conflicting. We examined whether delaying the oocyte maturation trigger in IVF/ICSI affected the number of mature oocytes and investigated the potential influence of serum progesterone levels in this process. METHODS: Between January 31, 2011, and December 31, 2011, 262 consecutive patients were monitored using ultrasound plus hormonal evaluation. Those with > =3 follicles with a mean diameter of > =18 mm were divided into 2 groups depending on their serum progesterone levels. In cases with a progesterone level < = 1 ng/ml, which was observed in 59 patients, 30-50% of their total number of follicles (only counting those larger than 10 mm) were at least 18 mm in diameter. These patients were randomised into 2 groups: in one group, final oocyte maturation was triggered the same day; for the other, maturation was triggered 24 hours later. Seventy-two patients with progesterone levels > 1 ng/ml were randomised in the same manner, irrespective of the percentage of larger follicles (> = 18 mm). The number of metaphase II oocytes was our primary outcome variable. Because some patients were included more than once, correction for duplicate patients was performed. RESULTS: In the study arm with low progesterone (<= 1 ng/ml), the mean number of metaphase II oocytes (+/-SD) was 10.29 (+/-6.35) in the group with delayed administration of the oocyte maturation trigger versus 7.64 (+/-3.26) in the control group. After adjusting for age, the mean difference was 2.41 (95% CI: 0.22-4.61; p = 0.031). In the study arm with elevated progesterone (>1 ng/ml), the mean numbers of metaphase II oocytes (+/-SD) were 11.81 (+/-9.91) and 12.03 (+/-7.09) for the delayed and control groups, respectively. After adjusting for PCOS (polycystic ovary syndrome) and female pathology, the mean difference was -0.44 (95% CI: -3.65-2.78; p = 0.79). CONCLUSIONS: Delaying oocyte maturation in patients with low progesterone levels yields greater numbers of mature oocytes.

The Value of Automated Follicle Volume Measurements in IVF/ICSI.

BACKGROUND/AIMS: The objective of this literature study is to investigate the place of recent software technology sonography-based automated volume count (SonoAVC) for the automatic measurement of follicular volumes in IVF/ICSI. Its advantages and disadvantages and potential future developments are evaluated. METHODS: A total of 74 articles were read via a PubMed literature study. The literature study included 53 articles, 32 of which for the systematic review. RESULTS: The SonoAVC software shows excellent accuracy. Comparing the technology with the "golden standard" two-dimensional (2D) manual follicle measurements, SonoAVC leads to a significantly lower intra- and inter-observer variability. However, there is no significant difference in clinical outcome (pregnancy rate). We noted a significant advantage in the time gained, both for doctor and patient. By storing the images, the technology offers the possibility of including a quality control and continuous training and further standardization of follicular monitoring can be expected. Ovarian reserve testing by measuring the antral follicle count with SonoAVC is highly reliable. CONCLUSION: This overview of previously published literature shows how SonoAVC offers advantages for clinical practice, without losing any accuracy or reliability. Doctors should be motivated to the general use of follicular volumes instead of follicular diameters.

Follicle measurements using sonography-based automated volume count accurately predict the yield of mature oocytes in in vitro fertilization/intracytoplasmic sperm injection cycles.

AIMS: We define criteria to predict the number of mature oocytes using automated three-dimensional (3D) ultrasound follicle measurements. METHODS: Fifty in vitro fertilization/intracytoplasmic sperm injection patients underwent automated 3D echographic monitoring by a single researcher following the stimulation procedure. Classic criteria for triggering oocyte maturation as defined in the literature were utilized. 3D parameters, including the follicular volume and follicle diameter calculated from the volume measurement, were related to the oocyte count, mature oocyte count and the number of observed fertilized oocytes. RESULTS: We found that when oocyte maturation was induced, 55% of the total follicles with a diameter of at least 10 mm had a volume of at least 1.5 cm³. The number of mature eggs that were retrieved was correlated with the number of follicles observed with a volume of at least 1 cm³ or a calculated follicle diameter of at least 12 mm. CONCLUSION: Sonography-based automated volume count measurements of follicle volume and reconstructed follicle diameter can be used to reliably predict the number of mature oocytes.

Discrepancy between sperm acrosin activity and sperm morphology: significance for fertilization in vitro.

BACKGROUND: In routine semen analysis, discrepancies may occur between sperm acrosin activity test results and sperm acrosomal morphology. METHODS: Discrepant test results of sperm acrosin activity (spectrophotometric assay) vs. sperm morphology (strict criteria) in the initial diagnostic investigation of 107 infertile couples were evaluated with respect to fertilization rate (% oocytes with 2 pronuclei) further obtained in IVF treatment. RESULTS: Acrosin activity positively correlated with sperm morphology (% normal forms) (r=0.537) and fertilization rate (r=0.526). ROC curves for the prediction of > or =50% fertilization rate were comparable for acrosin activity and sperm morphology, with optimal cutoff values at 25 microIU/10(6) sperm and 10%, respectively. In multiple regression analysis, sperm acrosin activity (P=0.002) predicted fertilization rate independently of sperm morphology (P<0.001) and sperm vitality (eosin-nigrosin stain) (P=0.03). Acrosin activities > or =25 microIU/10(6) sperm were observed in 36% of severe teratozoospermic samples (< or =4% normal spermatozoa) associated with low fertilization rate. Twenty percent of the morphologically normal ejaculates showed a low acrosin activity (<25 microIU/10(6) sperm) and low hypoosmotic swelling test (HOST) scores (31.4+/-7.6%) and were associated with low fertilization rate. CONCLUSION: The sperm acrosin assay can help to predict sperm fertilizing capacity in IVF independently of sperm morphology.