Frank Vandekerckhove

The history of Belgian assisted reproduction technology cycle registration and control: a case study in reducing the incidence of multiple pregnancy

STUDY QUESTION What is the effect of a legal limitation of the number of embryos that can be transferred in an assisted reproductive technology (ART) cycle on the multiple delivery rate? SUMMARY ANSWER The Belgian national register shows that the introduction of reimbursement of ART laboratory costs in July 2003, and the imposition of a legal limitation of the number of embryos transferred in the same year, were associated with a >50% reduction of the multiple pregnancy rate from 27 to 11% between 2003 and the last assessment in 2010, without any reduction of the pregnancy rate per cycle. WHAT IS KNOWN ALREADY Individual Belgian IVF centres have published their results since the implementation of the law, and these show a decrease in the multiple pregnancy rate on a centre by centre basis. However, the overall national picture remains unpublished. STUDY DESIGN, SIZE, DURATION Cohort study from 1990 to 2010 of all ART cycles in Belgium (2685 cycles in 1990 evolving to 19 110 cycles in 2010), with a retrospective analysis from 1990 to 2000 and prospective online data collection since 2001. PARTICIPANTS/MATERIALS, SETTING, METHODS Registration evolved from paper written reports per centre to a compulsory online registration of all ART cycles. From 2001 up to mid-2009, data were collected from Excel spread sheets or MS Access files into an MS Access database. Since mid-2009, data collection is done via a remote and secured web-based system (www.belrap.be) where centres can upload their data and get immediate feedback about missing data, errors and inconsistencies. MAIN RESULTS AND THE ROLE OF CHANCE National Belgian registration data show that reimbursement of IVF laboratory costs in July 2003, coupled to a legal limitation in the number of embryos transferred in utero, were associated with a 50% reduction of the multiple pregnancy rate from 27 to 11% without reduction of the pregnancy rate per cycle, and with an increase in the number of fresh and frozen ART cycles due to improved access to treatment. LIMITATIONS, REASONS FOR CAUTION There is potential underreporting of complications of ART treatment, pregnancy outcome and neonatal health. WIDER IMPLICATIONS OF THE FINDINGS Over the 20 years of registration, the pregnancy rate has remained constant, despite the reduction in the number of embryos transferred, optimization of laboratory procedures and stimulation protocols, introduction of quality systems and implementation of the EU Tissue Directive over the period 2004-2010. STUDY FUNDING/COMPETING INTEREST(S) No external funding was sought for this study. None of the authors has any conflict of interest to declare.

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).

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.

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

Abstract 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. Chinese abstract 我们在一项非随机、对照、前瞻性研究中（416例患者）比较了IVF/ICSI中两个平行对照组的结果：一组患者应用超声联合血雌二醇进行监测（ultrasound plus serum estradiol monitoring，UHM），一组患者仅应用超声监测（ultrasound monitoring，UM）。本研究以取卵时成熟卵母细胞的数量为主要研究终点。在对年龄、孕次、拮抗剂方案、AMH水平、不孕症诊断进行校正后，UHM组和UM组的成熟卵母细胞数量的平均差异是-0.4（(95% CI： -1.7- 1.0），这与临床等效的定义相符（调整后的平均差的95% CI介于-2到2之间）。仍需要更大型的研究来评估周期活产率及进一步确定IVF/ICSI中采血检测对卵巢刺激监测的最终结果无附加价值。

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.

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.

Guidelines on sperm DNA fragmentation testing

Male factor subfertility is present in more than 50% of the couples treated with assisted reproductive techniques. Routine semen analysis provides information on semen volume as well as sperm concentration, motility, and morphology. Standardized methods have been published by the World Health Organization (WHO) (1). Nevertheless the investigation of male factor involvement should always include a complete medical history and physical examination. Endocrine evaluation, ultrasonography, specialized tests on semen and sperm, and genetic screening are additional tests to be used if required.