Leuven University Fertility Center Research Articles

The ultra-long study: a randomized controlled trial evaluating long-term GnRH downregulation prior to ART in women with endometriosis.

Does ultra-long downregulation with a GnRH agonist (triptorelin depot) in previously operated patients with endometriosis improve the rate of clinical pregnancy with positive fetal heart beat (CPHB) in the subsequent initiated fresh ART cycle? Ultra-long downregulation with a GnRH agonist prior to ART did not improve the rate of CPHB in the subsequent fresh ART cycle in previously completely operated patients but the trial was underpowered due to early termination. Administration of GnRH agonists for a period of 3-6 months prior to ART in women with endometriosis may increase the odds of clinical pregnancy. However, the quality of the studies on which this statement is based is questionable, so these findings need confirmation. A controlled, randomized, open label trial was performed between 1 June 2013 and 31 December 2016 (start and end of recruitment, respectively). Patients with prior complete laparoscopic treatment of any type or stage of endometriosis and an indication for ART were randomized (by a computer-generated allocation sequence) into two groups: the control group underwent ART stimulation in a classical long agonist protocol using preparation with oral contraceptives, the ultra-long group first underwent at least 3 months downregulation followed by a long agonist protocol for ART stimulation. The sample size was calculated to detect a superiority of the ultra-long downregulation protocol, based on the hypothesis that baseline CPHB rate in the control group of 20% would increase to 40% in the ultra-long group. For a power of 20% at a significance level of 5%, based on two-sided testing, including 5% of patients lost to follow-up, the necessary sample size was 172 patients (86 per group). This trial was conducted at the Leuven University Fertility Center, a tertiary care center for endometriosis and infertility, and a total of 42 patients were randomized (21 in the control group and 21 in the ultra-long group). Baseline characteristics were similar in both groups. The primary outcome studied-CPHB after the initiated ART treatment-did not differ and was 25% (5/20) in the control group, and 20% (4/20) in the ultra-long group (P > 0.999; relative risk (RR) 1.25, 95% CI 0.41-3.88). Cumulative (fresh + associated frozen) CPHB rates were also similar in the control versus ultra-long group (8/20, 40% vs 6/20, 30%, P = 0.7411; RR = 1.33, 95% CI 0.57-3.19). When other secondary outcomes were compared with the ultra-long group, patients from the control group had a shorter duration of stimulation (mean 11.8 days (SD ± 2.4) versus 13.2 days (SD ± 1.5), P = 0.0373), a lower total dose of gonadotrophins used (mean 1793 IU/d (SD ± 787) vs 2329 (SD ± 680), P = 0.0154), and a higher serum estradiol concentration (ng/ml) at the end of ovarian stimulation on the day of ovulation triggering or cycle cancellation (mean1971 (SD ± 1495) vs 929 (± 548); P = 0.0326), suggesting a better ovarian response in the control group. Due to a strong patient preference, nearly exclusively against ultra-long downregulation (even though patients were thoroughly informed of the potential benefits), the targeted sample size could not be achieved and the trial was stopped prematurely. Conditional power analysis revealed that the probability of confirming the study hypothesis if the study were completed would be low. We hypothesize that in patients with prior complete surgical treatment of endometriosis, the ultra-long protocol does not enhance ART-CPHB rates. Patient's concerns and preferences regarding possible side-effects, and delay of ART treatment start with the ultra-long protocol should be taken into account when considering this type of treatment in women with endometriosis. C.T. was during 2 years funded by a grant from the Clinical research Foundation of UZ Leuven (KOF) and during 2 years by the Research Foundation-Flanders (FWO grant number: 1700816N). C.T. reports grants from Clinical Research Foundation of the University Hospitals of Leuven (KOF), grants from Fund for Scientific Research Flanders (FWO), during the conduct of the study; grants, non-financial support and other from Merck SA, non-financial support and other from Gedeon Richter, non-financial support from Ferring Pharmaceuticals, outside the submitted work. T.D. is vice president and head of Global Medical Affairs Fertility, Research and Development, Merck KGaA, Darmstadt, Germany. He is also a professor in Reproductive Medicine and Biology at the Department of Development and Regeneration, Group Biomedical Sciences, KU Leuven (University of Leuven), Belgium and an adjunct professor at the Department of Obstetrics and Gynecology in the University of Yale, New Haven, USA. Neither his corporate role nor his academic roles represent a conflict of interest with respect to the work done by him for this study. A.C. reports personal fees from Merck S.p.A., outside the submitted work. The other co-authors have no conflict of interest. UZ Leuven trial registry SS55300, EudraCT number 2013-000993-32, clinicaltrials.gov NCT02400801. Registration for EudraCT on 1 March 2013. 4 September 2013.

Estimation of the Endometriosis Fertility Index prior to operative laparoscopy.

Can the Endometriosis Fertility Index (EFI) be estimated accurately before surgery? The EFI can be estimated accurately based on mere clinical/ultrasound information, with some improvement after adding data from diagnostic laparoscopy. The EFI is a validated clinical instrument predicting the probability of pregnancy after endometriosis surgery without the use of ART. Being an end-of-surgery-score, it implies the decision for operative laparoscopy to be made in advance-hence, its role in the pre-surgical decision-making process remains to be established. Single-cohort prospective observational study in 82 patients undergoing complete endometriosis excision (between June and December 2016). Two methods were used to estimate the final EFI: type A based on non-surgical clinical/ultrasound findings only, and type B based on the combination of non-surgical clinical/ultrasound findings and diagnostic laparoscopy data. To calculate EFI type A, an algorithm was created to translate non-surgical clinical/imaging information into rASRM (revised American Society of Reproductive Medicine)-and EFI points. EFI type A and type B estimates were assessed for their clinical and numerical agreement with the final EFI score. Agreement was defined as clinical if EFI scores were within the same range (0-4, 5-6, 7-10), and numerical if their difference was ≤1. All 82 patients underwent complete laparoscopic CO2-laser excision of any rASRM stage of endometriosis in the Leuven University Fertility Centre (LUFC) of University Hospitals Leuven, a tertiary referral centre for both endometriosis and infertility. An anonymized clinical research file was created. For each patient, three different data sets were created, in order to allow the estimation of the (surgical part) EFI and of the rASRM scores, defined as follows: 'Estimated type A' contained only non-surgical clinical/imaging data, 'Estimated type B' included type A information plus the information of the diagnostic laparoscopy and 'Final EFI' included information of type A, type B and all intra-operative information required to calculate the final EFI. To calculate EFI type A without surgical information, a set of rules was used to translate pre-surgical clinical/imaging information into (rASRM and EFI points). Scoring was done by one person (C.T.), with a time interval of 4 weeks between sessions for each EFI type. Next to the EFI, also rASRM score and stage were calculated. Agreement rate between estimated EFI type A and final EFI was high for both the clinical (0.915; 95% CI 0.832-0.965) and numerical definition (0.878; 95% CI 0.787-0.940). Agreement rates between estimated EFI type B and final EFI were even higher (clinical (0.988; 95% CI 0.934-1.000), numerical (0.963; 95% CI 0.897-0.992)). Type A estimation is dependent on high-level gynaecological ultrasound expertise, which may not be available in all clinics. A small number of patients had no prior clinical, ultrasound (hard markers) or surgical confirmation of the diagnosis of endometriosis. When applying the estimated EFI type A in clinical practice, a priori assumptions of the presence or absence of endometriosis will need to be made in adjunct to the estimation of the estimated type A EFI when counselling patients on the potential benefit of an (at least diagnostic) laparoscopy. The level of agreement for type A or B should also be taken into account when counselling patients on the type of efforts undertaken to attempt to diagnose or rule out endometriosis. As this study reports, the EFI can be estimated accurately based on clinical/ultrasound data only without the need for any surgical data. This means that the EFI could be used as an instrument to guide joint physician-patient decision-making between surgery, ART or other fertility management options for the individualized treatment of women with endometriosis-related infertility. During this study period, C.T. was supported by FWO (Research Fund Flanders, Grant number 1700816N) and UZ Leuven KOF (University Hospitals Leuven, Klinisch Onderzoeksfonds).The LUFC received unrestricted research grants from Ferring Pharmaceuticals and Merck SA. Gedeon Richter and MSD sponsored travel to and attendance at scientific meetings. C.M. received consultancy fees from Lumenis (paid to KU Leuven, no private revenue). T.D. has been vice-president and head of global medical affairs infertility for the multinational pharmaceutical company Merck (Darmstadt, Germany) since 1 October 2015. He continues his academic appointment on a part-time basis as Professor of Reproductive Medicine at the University of Leuven (KU Leuven). T.D. has been vice-president and head of global medical affairs infertility for the multinational pharmaceutical company Merck (Darmstadt, Germany) since October 2015. He is also a Guest Professor in Reproductive Medicine and Biology at the Department of Development and Regeneration, Group Biomedical Sciences, KU Leuven (University of Leuven), Belgium, and an Adjunct Professor at the Department of Obstetrics and Gynecology in the University of Yale, New Haven, USA. This work was initiated before he joined Merck KGaA in October 2015, and completed during the subsequent years. study registration number at UZ Leuven Clinical Trial Centre: S59221.

Male age interferes with embryo growth in IVF treatment.

Does male age affect embryo growth or quality in couples undergoing IVF treatment? Advanced paternal age (APA) is negatively associated with the chance of an optimal eight-cell embryo on the third day of development. Literature shows that APA is associated with decreased sperm quality and fecundity. However, the effect of male age on embryo growth in an IVF setting remains inconclusive. Literature concerning male influences on IVF success is scarce and approaches used to analyse embryo outcomes differ by study. This study was part of the longitudinal Epigenetic Legacy of Paternal Obesity (ELPO) study for which fathers and mothers were followed from pre-pregnancy until the birth of their child. Couples were recruited from April 2015 to September 2017. A total of 1057 embryos from 87 couples were studied. Dutch-speaking couples planning to undergo an IVF treatment were recruited at the Leuven University Fertility Center in Flanders, Belgium. Anthropometrics were documented and compared to the general Flemish population. Semen characteristics, pregnancy rates and the following embryo characteristics were recorded: number of blastomeres, symmetry and percentage fragmentation. Statistical modelling was applied taking into account correlation of within-cycle outcomes and use of multiple cycles per couple. We observed a significant inverse association between APA and a key determinant for scoring of embryo quality: older men were less likely to produce an embryo of eight blastomeres at Day 3, compared to younger fathers; odds ratio for the effect of 1 year equals 0.960 (95% CI: 0.930-0.991; P = 0.011). Our finding remained significant after adjusting for female age and male and female BMI. Degree of fragmentation and symmetry were not significantly related to male age. Because of the study's small sample size and its monocentric nature, a larger study is warranted to confirm our results. In addition, distribution of BMI and level of education were not representative of the general Flemish population. Although we corrected for BMI status, we do not exclude that obesity may be one of the determinants of infertility in our study population. Furthermore, it is known from other European countries that a higher education eases access to fertility treatment. Hence, caution should be taken when interpreting our findings from a fertility setting to the general population. We suggest a heightened need for future research into male age and its potential effects on embryo growth, embryo quality and ART outcomes. Clinical decision-making and preventative public health programmes would benefit from a better understanding of the role of men, carried forward by the Paternal Origins of Health and Disease (POHaD) paradigm. We hope the current finding will encourage others to examine the role of the sperm epigenome in embryo development according to paternal age. This work was supported by a research grant from KU Leuven University (OT/14/109). The authors declare no competing financial, professional or personal interests. KU Leuven S57378 (ML11309), B322201523225.

Efficacy, safety and tolerability of progesterone vaginal pessaries versus progesterone vaginal gel for luteal phase support after in vitro fertilisation: a randomised controlled trial.

Efficacy, safety and tolerability of progesterone vaginal pessaries versus progesterone vaginal gel for luteal phase support after in vitro fertilisation: a randomised controlled trial.

Industry is not the dark side, but an essential partner to make progress in reproductive health.

For the last 20 years, Thomas D'Hooghe has been coordinator of the Leuven University Fertility Center at Leuven University Hospitals, Belgium, one of the largest teaching hospitals in Europe. Since 1995, he has also been Professor of Reproductive Medicine and Biology at KU Leuven (University of Leuven) and Adjunct Professor at Yale University, USA. Since 1 October 2015, he has been the Vice President and Head of Global Medical Affairs Fertility at Merck's headquarters in Darmstadt, Germany. He has published nearly 300 papers in internationally peer-reviewed journals and has contributed to reproductive health serving major international organizations such as the WHO, the European Society of Human Reproduction and Embryology, the Society of Reproductive Investigation and the World Endometriosis Research Foundation.

Predicting pregnancy rate and live birth rate in the IVF clinic by analysing patient profiles

This study used data of in vitro fertilization (IVF) cycles from 3,221 patients during 2004 to 2013, collected in Leuven University Fertility Center, aiming to identify patient and cycle characteristics to predict pregnancy and live birth rate. Variables include age, gonadotrophin dose, year of the IVF cycle, implantation problems, transport problems, ovulation problems, male pathology, pituitary inhibition, treatment, medication, and endometriosis status. One major issue of our dataset was the presence of missing data and unknown' fill-in in some of the variables. Due to the conceptual overlapping between missing and unknown', we employed two different setups to treat the unknowns': 1) as a new category; 2) as missing values. As ignoring the missingness would have significant impact on potential conclusions, we conducted multiple imputation on the missing data. The logistic regression model inclusive of a subject-specific random intercept was next fitted to the imputed dataset to assess the effect of the variables on the probability of transfer/pregnancy success. A sensitivity analysis was carried out to check for the influence of missing mechanism. For the prediction purpose, the non-parametric Random Forest model was used, and 10-fold cross-validation was performed to obtain the prediction accuracy. Our results suggest that the outputs of these two setups are mostly comparable in the generalized linear mixed model. Other than the most well-known factor-age, we found that gonadotrophin dose, transport problems, ovulation problems, pituitary inhibition also have significant main effects on pregnancy rate. The same set of variables plus implantation problems and treatment have significant fixed effect on live birth rate. The random forest model can achieve average prediction accuracy of 53% on transfer outcome and 52% on pregnancy outcome, which indicates that our current set of variables are not enough to yield good prediction performance on IVF outcomes.

The effects of paternal obesity on sperm characteristics and early embryonic development: results from a retrospective study

In humans, it is widely demonstrated that maternal obesity negatively affects fertility, pregnancy outcomes and offspring's health. Less is known about the effects of paternal obesity on fertility and offspring's development. Recent observations in animal models show that diet-induced obese males have impaired sperm quality, delayed preimplantation growth of the fertilized oocyte, and reduced implantation rate. Our aim was to evaluate the effects of paternal obesity on sperm quality and subsequently embryonic development and implantation in humans. Body mass index (BMI), sperm and embryo parameters of 192 men who participated in a fertility program (IVF or ICSI) at the Leuven University Fertility centre between March and September 2014 were evaluated. Sperm parameters included: concentration, total sperm count, motility and morphology. Embryo parameters included number and asymmetry of blastomeres, degree of fragmentation and implantation success. The embryonic development parameters were obtained using a new computer assisted scoring system (CASS) based on multilevel image analyses. Our analytic study included sperm data from 192 men and embryo characteristics from 138 couples. Multiple regression models were used to determine potential associations between paternal obesity/BMI and sperm or embryo parameters. No significant associations were found between paternal obesity/BMI and the sperm parameters measured. After adjusting for potential confounding, we found a borderline significant effect of paternal obesity/BMI on the degree of asymmetry of blastomeres: coefficient was +0.05 (p=0.047) if men were obese, and coefficient was +0.004 (p=0.059) with increasing paternal BMI. This effect was only seen on day 2 of embryonic development. No effect of paternal obesity/BMI on implantation success was found. In order to confirm a potential effect of obesity on embryonic development our analyses will be further extended on a larger dataset. We further aim to gain insights on the underlying epigenetic mechanisms that have been reported as being mediated by paternal obesity.

Effect of laparoscopic surgery for moderate and severe endometriosis on depression, relationship satisfaction and sexual functioning: comparison of patients with and without bowel resection

Is there a difference between women with endometriosis who underwent laparoscopic surgery with bowel resection or without bowel resection regarding depressive symptoms, relational adjustment and sexual functioning? Radical surgery for endometriosis in both groups improved the levels of depression and sexual functioning, but only the bowel resection patients showed improvements in relationship satisfaction. WHAT IS KNOWN ALREADY?: The frequent pain symptoms in endometriosis patients can have an impact on psychological issues, relationships and sexual functioning. There are no data available on depression and relationship adjustment after endometriosis surgery. Sexual dysfunction problems have been described after bowel resection for rectal cancer, but no data are available for endometriosis surgery. This prospective cohort study included 203 consecutive women operated at the Leuven University Fertility Center (LUFC) between 1 September 2006 and 30 September 2008 for moderate (n = 67) or severe (n = 136) endometriosis. The preoperative response rate was respectively 84% in the bowel resection group and 79% in the no bowel resection group. The beck depression inventory (BDI) measured depression, the dyadic adjustment scale (DAS) measured relationship satisfaction and the short sexual functioning scale (SSFS) measured sexual functioning before and 6, 12 and 18 months after women had laparoscopic surgery at the LUFC, a tertiary referral centre for fertility exploration, treatment and surgery. Both groups had better post-operative outcomes when compared with the preoperative assessments. Mean BDI and DAS levels were comparable with the normal population. Overall assessment points, the bowel resection patients had better outcomes for DAS (P < 0.05) and SSFS 'arousal' (P < 0.05) than the no bowel resection patients. At 6 months after the operation, when compared with the no bowel resection group, the bowel resection group reported lower mean levels of BDI (P < 0.05), a lower incidence of SSFS 'pain during intercourse' and 'orgasm problems' (P < 0.05), and a lower proportion of patients with severe orgasm problems (P < 0.05). The data show that radical but fertility sparing surgery, with or without bowel resection, for the treatment of endometriosis results in comparable and good psychological outcomes concerning depression levels, relationship satisfaction and sexual functioning. Although the initial response rate was good, response dropped over time and was significantly higher for bowel resection patients compared with the no bowel resection patients (P = 0.05). A responder/non-responder analysis for the whole study population showed no significant differences concerning pain problems. This reduces the possible risk of (positive) bias in the results. Endometriosis is a complex condition and the focus should not be on a one-dimensional end-organ gynaecological outcome, but should take into account the role of psychological factors in pain-related outcome. To this end, more prospective data are needed on sexual functioning and psychological outcomes.

External validation of the endometriosis fertility index (EFI) staging system for predicting non-ART pregnancy after endometriosis surgery

Can the ability of the endometriosis fertility index (EFI) to predict non-assisted reproductive technology (ART) pregnancy after endometriosis surgery be confirmed by an external validation study? The significant relationship between the EFI score and the time to non-ART pregnancy observed in our study represents an external validation of this scoring system. The EFI was previously developed and tested prospectively in a single center, but up to now no external validation has been published. Our data provide validation of the EFI in an external fertility unit on a robust scientific basis, to identify couples with a good prognosis for spontaneous conception who can therefore defer ART treatment, regardless of their revised American Fertility Society (rAFS) endometriosis staging. Retrospective cohort study where the EFI was calculated based on history and detailed surgical findings, and related to pregnancy outcome in 233 women attempting non-ART conception immediately after surgery; all data used for EFI calculation and analysis of reproductive outcome had been collected prospectively as part of another study. The EFI score was calculated (score 0-10) for 233 women with all rAFS endometriosis stages (minimal-mild, n = 75; moderate-severe, n = 158) after endometriosis surgery (1 September 2006-30 September 2010) in a university hospital-based reproductive medicine unit with combined expertise in reproductive surgery and medically assisted reproduction. All participants attempted non-ART conception immediately after surgery by natural intercourse, ovulation induction with timed intercourse or intrauterine insemination (with or without ovulation induction or controlled ovarian stimulation). All analyses were performed for three different definitions of pregnancy [overall (any HCG >25 IU/l), clinical and ongoing >20 weeks]. Six groups were distinguished (EFI scores 1-3, 4, 5, 6, 7+8, 9+10), and Kaplan-Meier (K-M) estimates for cumulative pregnancy rate were calculated. Subjects were censored when they were lost to follow-up, had subsequent surgery for endometriosis, started ovarian suppression or underwent ART. As K-M estimates might overestimate the actual event rate, cumulative incidence estimates treating ART as competing event were also calculated. Cox regression analysis was used to assess the performance of EFI and constituting variables. Performance of the score (prediction, discrimination) was quantified with the following methods: mean squared error of prediction (Brier score), areas under the receiver-operating curve and global concordance index C(τ). There was a highly significant relationship between the EFI and the time to non-ART pregnancy (cumulative overall pregnancy rate, P = 0.0004), with the K-M estimate of cumulative overall pregnancy rate at 12 months after surgery equal to 45.5% [95% confidence interval (CI) 39.47-49.87]-ranging from 16.67% (95% CI 5.01-47.65) for EFI scores 0-3, to 62.55% (95% CI 55.18-69.94) for EFI scores 9-10. For each increase of 1 point in the EFI score, the relative risk of becoming pregnant increased by 31% (95% CI 16-47%; i.e. hazard ratio 1.31). The 'least function score'-which assesses the tubal/ovarian function at conclusion of surgery-was found to be the most important contributor to the total EFI score among all the other variables (age, duration of infertility, prior pregnancy, AFS endometriosis lesion and total score). The EFI score had a moderate performance in the prediction of the pregnancy rate. Indeed, the decrease in prediction error was rather small, as shown by the decrease in Brier score from 0.213 to 0.198, and low estimates for R&sup2; (13%) and C(τ) (0.629). As the EFI was validated externally in our own European population after initial testing by Adamson and Pasta (Endometriosis fertility index: the new, validated endometriosis staging system. Fertil Steril 2010;94:1609-1615) in an American population, it appears that the EFI can be used clinically to counsel infertile endometriosis patients receiving reproductive surgery in specialized centers about their post-operative conception options. This research was supported by funds obtained via the Clinical Research Fund of the University Hospitals Leuven, Belgium, via the Ferring Chair in Reproductive Medicine and Surgery, and the Serono Chair in Reproductive Medicine granted to the Leuven University Fertility Center. The authors have no conflicts of interest to declare.

Semi-automated morphometric analysis of human embryos can reveal correlations between total embryo volume and clinical pregnancy

Is there a link between morphometric characteristics measured by a computer-assisted scoring system and clinical pregnancy outcome? The results confirm that computer-assisted assessment of the total embryo volume is associated with clinical pregnancy outcome and can be used to complement current procedures of embryo selection. Morphometric analysis of a large group of embryos has revealed the potential to optimize algorithms for image-analysis systems for the grading of embryos and predicting pregnancy outcomes. Oocytes and embryos were obtained from 458 patients who underwent single embryo transfer on Day 3 after IVF/ICSI, between September 2006 and December 2010 at the Leuven University Fertility Center, Belgium. In total, the data set contained 2796 embryos including 458 embryos that were transferred on Day 3. Ongoing pregnancy was defined as the presence of at least one intrauterine gestational sac at 20 weeks. Patients included in this study were younger than 36 years, entering their first (n = 375) or second (n = 83) IVF/ICSI cycle and were only included once. Patients were excluded if the cycle included biopsy for PGD or if donor sperm/donor oocytes were used. Based on the 26 sequential images of the same embryo taken at one time point in different planes, the software calculates the total cytoplasmic volume for each time point, from which any reduction or change in the volume with time can be assessed (which helps interpret the degree of fragmentation) and the size of blastomeres. The diameter of the smallest and largest blastomere and the total volume of each embryo were extracted from the computer-assisted scoring system database and the coefficient of diversity was calculated for Days 1, 2 and 3. A logistic regression analysis was performed to determine the range of embryo volume associated with an increased chance of pregnancy. On Day 3, blastomeres of 8-cell stage embryos were less divergent in size than those of 6-, 7-, 9-cell stage embryos. Although, the coefficients of diversity (ratio of the largest:smallest blastomeres) of implanted embryos tended to be lower than for non-implanted embryos, the difference was only significant for 6-cell stage embryos (P = 0.02). After logistic regression, an association between total embryo volume and pregnancy was observed which had a quadratic nature: both lower and higher volumes were associated with a lower probability of successful pregnancy. A significant association was identified between total embryo volume and pregnancy rate on both Days 2 (P = 0.003) and 3 (P = 0.0003). Diagnostic measures (sensitivity, specificity, positive predictive value, accuracy and c-statistics) of the defined volume range were relatively poor. However, results showed a good negative predictive value [76.86% (95% confidence interval 71.03-82.02) on Day 3]. A general disadvantage of studies evaluating the impact of a characteristic on the implantation potential of an embryo is the fact that the best embryo is chosen for transfer. No comparisons can therefore be made with the other embryos. Moreover, the decision process is currently based on a non-automated, standard scoring system, which means that a 'bias' in the selection process is always present. Our results are an important step towards the development of an automated computer-assisted scoring system for the morphological characteristics of human embryos to improve embryo selection for optimizing implantation potential. Total embryo volume appears to be one of the objective characteristics that should be included. None. Not applicable.

Does the European Union Tissues and Cells Directive Improve Quality in the in Vitro Fertilization Laboratory? A Case Study in a Tertiary Referral Center

Since 2004, assisted conception is encompassed by the European Directive on the Quality and Safety of Tissues and Cells (2004/23/EC). The aim of a standard for quality and safety is to minimize risks of errors, contamination, and accidents and to maximize efficiency of use. This article presents a case study of the implementation of the Tissues and Cells Directive in the Leuven University Fertility Center (LUFC) with a focus on the assisted reproductive technologies laboratory with respect to laboratory facilities, quality management system, traceability, storage conditions as well as serological screening. Although the current European Union (EU) Directive can be considered a step in the right direction to improve patient safety, questions remain as to whether the implementation of this EU Directive, requiring extra time and money, has resulted in higher quality with respect to the quality dimensions of effectiveness, efficiency, timeliness, equity, and patient centeredness.

Has the Prevalence of Congenital Abnormalities after Intracytoplasmic Sperm Injection Increased? The Leuven Data 1994–2000 and a Review of the Literature

Background: Although intracytoplasmic sperm injection (ICSI) is now accepted as the treatment of choice for severe male infertility, concerns about its safety and the potential risks for the offspring remain. We reviewed the literature with respect to the prevalence of major congenital malformations after the ICSI technique and supplemented these data with the results of a prospective follow-up study performed in our center. Methods: From January 1994 till June 2000, 776 ICSI cycles were carried out at the Leuven University Fertility Center. The resulting pregnancies (n = 172) were followed for biochemical and obstetrical parameters, prenatal diagnosis and congenital abnormalities. Results: A total of 134/172 (78%) ongoing pregnancies resulted in 132 deliveries of 166 live born children. Two terminations of pregnancy were carried out due to the presence of major congenital anomalies, diagnosed at prenatal ultrasound. Prenatal diagnosis was carried out in 55 fetuses. Two de novo chromosomal aberrations were found. Major congenital abnormalities were observed at birth in 9/150 (6.0%) children. The total malformation rate was 6.5%. Conclusions: The prevalence of congenital abnormalities in children born after ICSI in our center (6.5%) was comparable to the prevalence of congenital abnormalities after ICSI reported in the literature.

Density of small diameter sensory nerve fibres in endometrium: a semi-invasive diagnostic test for minimal to mild endometriosis

The aim of our study was to test the hypothesis that multiple-sensory small-diameter nerve fibres are present in a higher density in endometrium from patients with endometriosis when compared with women with a normal pelvis, enabling the development of a semi-invasive diagnostic test for minimal-mild endometriosis. Secretory phase endometrium samples (n = 40), obtained from women with laparoscopically/histologically confirmed minimal-mild endometriosis (n = 20) and from women with a normal pelvis (n = 20) were selected from the biobank at the Leuven University Fertility Centre. Immunohistochemistry was performed to localize neural markers for sensory C, Adelta, adrenergic and cholinergic nerve fibres in the functional layer of the endometrium. Sections were immunostained with anti-human protein gene product 9.5 (PGP9.5), anti-neurofilament protein, anti-substance P (SP), anti-vasoactive intestinal peptide (VIP), anti-neuropeptide Y and anti-calcitonine gene-related polypeptide. Statistical analysis was done using the Mann-Whitney U-test, receiver operator characteristic analysis, stepwise logistic regression and least-squares support vector machines. The density of small nerve fibres was approximately 14 times higher in endometrium from patients with minimal-mild endometriosis (1.96 +/- 2.73) when compared with women with a normal pelvis (0.14 +/- 0.46, P < 0.0001). The combined analysis of neural markers PGP9.5, VIP and SP could predict the presence of minimal-mild endometriosis with 95% sensitivity, 100% specificity and 97.5% accuracy. To confirm our findings, prospective studies are required.

Reasons for Dropout in Infertility Treatment

Background: The objective of this study was to explore the reasons why couples discontinue fertility treatment. Methods: A retrospective exploratory study was performed at the Leuven University Fertility Centre, a university hospital-based fertility center. Women who discontinued treatment between September 2000 and December 2001 were contacted in 2004–2005 by telephone for a standardized interview which covered 9 dropout reasons. For each reason, its importance on the decision to stop treatment was measured on an 11-point Likert scale. Results: On average, psychological burden (x = 5.96) had the highest impact on the decision to stop treatment followed by physical burden (x = 4.48) and female age (x = 3.64). Perceived lack of staff expertise (x = 1.84), negative impact on social contacts (x = 2.12) and financial burden (x = 2.16) had the lowest impact on the decision to stop treatment. Longer duration of infertility was significantly positively correlated with a higher rating of physical burden as a reason to discontinue treatment (r = 0.48; p < 0.05). Discussion: On average, psychological burden appears to be most frequently named as the number one reason to discontinue infertility treatment, whereas financial burden had the lowest impact. Longer duration of infertility is associated with more externalizing reasons to discontinue treatment.

Personality and intrapersonal and interpersonal functioning of women starting their first IVF treatment

IVF treatment involves a reassessment of issues concerning autonomy and relatedness. This study aims to extend prior studies on the psychological impact of IVF/ICSI by studying the association between the personality dimensions of Self-Criticism and Dependency with the psychological well-being and quality of the couple relationship for women starting their first IVF treatment. This is a cross-sectional study of 68 women starting their first IVF treatment at the Leuven University Fertility Centre of the University of Leuven, Belgium. All women were administered validated self-report measures assessing Self-Criticism and Dependency, negative life events, psychological well-being, relationship satisfaction, and relationship and sexual concerns. Pearson's correlation coefficients were calculated between all study variables, followed by four separate hierarchical multiple regression analyses for psychological well-being, relationship satisfaction, and relationship and sexual concerns. High Self-Criticism was negatively associated with psychological well-being (r = -0.63, P < 0.001) and relationship satisfaction (r = -0.29, P < 0.05), and positively associated with relationship (r = 0.39, P < 0.01) and sexual (r = 0.37, P < 0.01) concerns. High Dependency was negatively associated with psychological well-being (r = -0.30, P < 0.05), not significantly associated with relationship satisfaction and relationship concerns, and positively related to sexual concerns (r = 0.31, P < 0.05). This cross-sectional study suggests that the personality dimensions of Self-Criticism and Dependency may enhance our understanding of the psychological well-being and quality of the couple relationship of women starting their first IVF treatment. However, further prospective research on this topic is needed.

Construction of a patient questionnaire to evaluate infertility management at the Leuven University Fertility Centre (LUFC), Belgium

OBJECTIVE: Quality management according to ISO 9001:2000 guidelines includes the need for continuous assessment of infertility management to improve delivery of care. The study describes the development and psychometric evaluation of a questionnaire to evaluate infertility management at the Leuven University Fertility Centre.

Special Focus: The Challenge of Endometriosis

10.2217/17455057.3.5.615 © part of Short biography Thomas D’Hooghe Clinical Head, Leuven University Fertility Center; Chair, European Society for Human Reproduction and Embryology Special Interest Group for Endometriosis; Editor-in-Chief, Gynecologic and Obstetric Investigation; Research Associate and Chair International Advisory Board, Institute of Primate Research, Kenya; Fundamental Clinical Investigator for Endometriosis, Belgian Research Foundation; Full Professor and Serono Chair of Reproductive Medicine, Leuven University.

No difference in cycle pregnancy rate and in cumulative live-birth rate between women with surgically treated minimal to mild endometriosis and women with unexplained infertility after controlled ovarian hyperstimulation and intrauterine insemination

The association between infertility and minimal to mild endometriosis is controversial and poorly understood. The clinical pregnancy rate (PR) per cycle after controlled ovarian hyperstimulation (COH) with or without intrauterine insemination (IUI) is reportedly lower in women with surgically untreated minimal to mild endometriosis than in women with unexplained infertility. It is possible that prior laparoscopic removal of endometriosis has a positive effect on the clinical PR after COH and IUI. Therefore, we tested the hypothesis that after COH and IUI the PR per cycle and the cumulative live-birth rate (CLBR) are equal or higher in women with recently surgically treated minimal to mild endometriosis when compared with women with unexplained infertility. A retrospective, controlled cohort study. Leuven University Fertility Centre, a tertiary academic referral center. One hundred seven women treated during 259 cycles with COH and IUI including patients with endometriosis (n = 58, 137 cycles) and unexplained infertility (n = 49, 122 cycles). All patients with endometriosis had minimal (n = 41, 100 cycles) or mild (n = 17, 37 cycles) disease that had been laparoscopically removed within 7 months before the onset of treatment with COH and IUI. Controlled ovarian hyperstimulation using clomiphene citrate (23 cycles) or gonadotrophins (236 cycles) in combination with IUI. Clinical PR per cycle and CLBR within four cycles of treatment with COH and IUI. The clinical PR per cycle was comparable in women with minimal or mild endometriosis (21% or 18.9%, respectively) and in women with unexplained infertility (20.5%). The CLBR within four cycles of COH and IUI was also comparable in women with minimal endometriosis, mild endometriosis, and unexplained infertility (70.2%, 68.2 %, 66.5%, respectively). The data from our study suggest that COH and IUI shortly after laparoscopic excision of endometriosis is as effective as COH and IUI in patients with unexplained subfertility.

Is the endometriosis recurrence rate increased after ovarian hyperstimulation?

To test the hypothesis that the cumulative endometriosis recurrence rate (CERR) after fertility surgery for endometriosis stage III or IV is increased in women exposed to very high E(2) levels during ovarian hyperstimulation (OH) for IVF when compared with women exposed to less high E(2) levels during OH for intrauterine insemination (IUI). Retrospective cohort study including infertility patients with endometriosis stage III or IV. Leuven University Fertility Center, between 1990 and 2001. Patients (n = 67) with endometriosis stage III (n = 45) or IV (n = 22) who underwent pelvic reconstructive surgery and subsequently started fertility treatment with either IVF only (n = 39), both IVF and IUI in different cycles (n = 11), or IUI only (n = 17). Life table analysis was used to calculate the CERR. The CERR based on histologic or cytologic proof of disease recurrence. At 21 months after the start of OH the overall CERR was 31% and was significantly lower in patients treated with IVF only (7%) or women treated with both IVF and IUI in different cycles (43 %) than in those treated with IUI only (70%). At 36 months after the start of OH, the overall CERR was 63%. In contrast to our hypothesis, the results from this study showed that the CERR is lower after ovarian hyperstimulation for IVF than after lower-dose ovarian stimulation for IUI, suggesting that temporary exposure to very high E(2) levels in women during OH for IVF is not a major risk factor for endometriosis recurrence in women treated with assisted reproductive technology.

New Belgian legislation regarding the limitation of transferable embryos in in vitro fertilization cycles does not significantly influence the pregnancy rate but reduces the multiple pregnancy rate in a threefold way in the Leuven University Fertility Center

After the introduction of new Belgian legislation limiting the number of transferable embryos to prevent multiple pregnancies after assisted reproductive technology, the implantation rate per embryo remained stable at 26% and the clinical pregnancy rate per embryo transfer did not change significantly (37.5% before and 32.5% after legislation), whereas the multiple pregnancy rate per clinical pregnancy decreased threefold from 25.9% to 8.0%) in the Leuven University Fertility Center.