Diane De Neubourg

Cross-border reproductive care in Belgium

BACKGROUND Cross-border reproductive care indicates the cross-border movements made by patients to obtain infertility treatment they cannot obtain at home. The problem at present is that empirical data on the extent of the phenomenon are lacking. This article presents the data on infertility patients going to Belgium for treatment. METHODS A survey was conducted among the centres for reproductive medicine that are allowed to handle oocytes and create embryos (B-centres). Data were collected on the nationality of patients and the type of treatment for which they attended during the period 2000-2007. RESULTS Sixteen of 18 centres responded to the questionnaire. The flow of foreign patients has stabilized since 2006 at approximately 2100 patients per year. The majority of foreign nationals seeking treatment in Belgium were French women for sperm donation. The next highest group was patients entering the country to obtain ICSI with ejaculated sperm. CONCLUSIONS There are clear indications that numerous movements are motivated by the wish to evade legal restrictions in ones home country, either because the technology is prohibited or because the patients have characteristics, which exclude them from treatment in their own countries.

BMI-related metabolic composition of the follicular fluid of women undergoing assisted reproductive treatment and the consequences for oocyte and embryo quality

STUDY QUESTION Is the metabolic composition of the follicular fluid of women undergoing assisted reproductive treatment (ART) related to serum composition and BMI and is it associated with oocyte and embryo quality? SUMMARY ANSWER We showed that metabolic alterations in the serum are reflected in the follicular fluid and that some of these alterations may affect oocyte quality, irrespective of BMI. WHAT IS KNOWN ALREADY Many studies have focused on the effect of metabolic disorders, such as obesity and type 2 diabetes, on assisted reproduction outcomes. There are, however, only few studies focusing on the importance of the correlation between serum and follicular fluid compositions and the composition of the follicular fluid as the oocytes micro-environment, affecting its development and subsequent embryo quality. DESIGN, PARTICIPANTS AND SETTING In this prospective cohort study, patient information, fertility treatment outcome data, follicular fluid and serum were obtained from women undergoing ART. Patients were categorized according to their BMI (kg/m(2)) as normal (n = 60), overweight (n = 26) or obese (n = 20). Serum and follicular fluid samples were analyzed for urea, total protein, albumin, cholesterol, high-density lipoprotein cholesterol, triglycerides, non-esterified fatty acids, apolipoprotein A1, apolipoprotein B, glucose, lactate, C-reactive protein, insulin-like growth factor -1 (IGF-1), IGF-binding protein 3 (only in follicular fluid), free carnitine and total carnitine. Metabolite concentrations in serum and follicular fluid samples were correlated and were associated with BMI and fertility treatment outcome. MAIN RESULTS Most serum metabolite differences between patients were reflected in the follicular fluid (P < 0.05). Follicular fluid apolipoprotein A1 and follicular fluid total protein concentrations negatively affected oocyte quality parameters (P < 0.05). However, overall BMI-related associations were poor. BIAS, CONFOUNDING AND OTHER REASONS FOR CAUTION In this study, we included every patient willing to participate. Within this cohort, women with a BMI transcending 35 kg/m(2) were scarce (n = 2), because extremely overweight women are mostly advised to lose weight before starting ART. Furthermore, the number of patients in each BMI group was different, possibly masking associations between the metabolic composition of serum and follicular fluid and oocyte quality parameters. GENERALIZABILITY TO OTHER POPULATIONS There were significant associations indicating that metabolic changes in the serum are reflected in the follicular fluid, potentially affecting oocyte quality, irrespective of the patients BMI. For ethical reasons, this study only focused on women already in need of artificial reproductive treatment. From a metabolic point of view, we consider this cohort as a representative sample of all women of reproductive age. STUDY FUNDING This study was funded by the special research fund, university of Antwerp (BOF UA). None of the authors has any conflict of interest to declare.

Single embryo transfer – state of the art

Every practitioner active in the field of assisted reproduction treatment is aware of the risks and complications related to twin and higher-order multiple pregnancies. Introduction of single embryo transfer (SET) into IVF/intracytoplasmic sperm injection (ICSI) is one of the possible ways of reducing the rate of twin pregnancy. Careful selection of patients, in combination with elective SET, has been shown to decrease the twin pregnancy rate while maintaining a stable ongoing pregnancy rate. The combination of a woman younger than 38 years of age, in her first or second IVF/ICSI cycle and with an embryo with a high implantation potential is the key to successful SET. This article will discuss embryo selection and patient selection and review the data published on SET. In the Centre for Reproductive Medicine at Middelheim Hospital, 39% of all transfers in 2002 were SET; the ongoing pregnancy rate remained stable at 30.6%. The twin (multiple) pregnancy rate declined to 11.7%. Particular attention should be drawn to the augmenting effect of the pregnancy rate of frozen-thawed cycles. Health economic data available so far subscribe the plea for SET.

Cryopreservation as a tool to reduce multiple birth

The potential role of embryo cryopreservation from the point of view of prevention of multiple pregnancies is analysed. Cryopreservation is an unavoidable option in stimulated IVF/intracytoplasmic sperm injection (ICSI), but at the same time an underestimated tool in the prevention of twins. There is a need for an evaluation system not only of the cryotechnology process per se, but also of the true augmenting effect of cryopreservation on the total reproductive potential of a single oocyte harvest. Only cryopregnancies occurring after an unsuccessful fresh cycle (possibly followed by one or more unsuccessful freeze-thaw cycles with embryos from the same harvest) truly reflect the augmentation potential of cryopreservation. This potential is greater than generally thought. First, the efficacy of cryopreservation is suboptimal with survival rates between 30 and 70%. Second, if single-embryo transfer were applied in a much larger proportion of cycles than is presently the case, more embryos would be available for cryopreservation, resulting in more and more successful freeze-thaw cycles. In the future, the combination of elective single-embryo transfer with an optimized cryopreservation programme is likely to become the standard of care for routine IVF/ICSI treatment.

How do cumulative live birth rates and cumulative multiple live birth rates over complete courses of assisted reproductive technology treatment per woman compare among registries

STUDY QUESTION How do the national cumulative (multiple) live birth rates over complete assisted reproduction technology (ART) courses of treatment per woman in Belgium compare to those in other registries? SUMMARY ANSWER Cumulative live birth rates (CLBRs) remain high with a low cumulative multiple live birth rate when compared with other registries and publications. WHAT IS KNOWN ALREADY In ART, a reduction in the multiple live birth rate could be achieved by reducing the number of embryos transferred. It has been shown that by doing so, live birth rates per cycle were maintained, particularly when the augmentation effect of attached frozen-thawed cycles was considered. STUDY DESIGN, SIZE, DURATION A retrospective cohort study included all patients with a Belgian national insurance number who were registered in the national ART registry (Belrap) and who started a first fresh ART cycle between 1 July 2009 until 31 December 2011 with follow up until 31 December 2012. We analysed 12 869 patients and 38 008 cycles (both fresh and attached frozen cycles). PARTICIPANTS, MATERIALS, SETTINGS, METHODS CLBRs per patient who started a first ART cycle including fresh and consecutive frozen cycles leading to a live birth. Conservative estimates of cumulative live birth assumed that patients who did not return for treatment had no chance of achieving an ART-related live birth, whereas optimal estimates assumed that women discontinuing treatment would have the same chance of achieving a live birth as those continuing treatment. A maximum of six fresh ART cycles with corresponding frozen cycles was investigated and compared with other registries and publications. MAIN RESULTS AND ROLE OF CHANCE The CLBR was age dependent and declined from 62.9% for women <35 years, to 51.4% for women 35-37 years, to 34.1% for women 38-40 years and 17.7% for women 41-42 years in the conservative analysis after six cycles. In the optimal estimate, the CLBR declined from 85.9% for women <35 years, to 72.0% for women 35-37 years, to 50.4% for women 38-40 years and 36.4% for women 41-42 years. The cumulative multiple live birth rates for the whole population were 5.1 and 8.6% for the conservative and optimal estimate, respectively. LIMITATIONS, REASONS FOR CAUTION Conservative and optimal estimates use assumptions for the whole ART population and do not take the individual patient into account. WIDER IMPLICATIONS OF THE FINDINGS These data reinforce the validity of the Belgian model of coupling reimbursement of ART costs to a restriction in the number of embryos transferred. Our data can improve decision-making in medical ART practice both on the patient level and for society at large and could provide health care takers and insurance companies with a valid model. STUDY FUNDING COMPETING INTERESTS none.

The spatial arrangement of blastomeres at the 4-cell stage and IVF outcome

This study compared the developmental and implantation potential of tetrahedrally arranged versus non-tetrahedrally arranged 4-cell-stage embryos. If the cleavage planes of a 4-cell-stage embryo were perpendicularly orientated, blastomeres were defined as tetrahedrally arranged, while embryos with parallel-orientated cleavage axes were considered as non-tetrahedral embryos. The 4-cell-stage embryos (n=862) examined in this study were obtained from 299 patients aged <36 years. A total of 299 embryos were transferred as a single-embryo transfer on day 3. This study showed that tetrahedral embryos developed into a 8-cell-stage embryo on day 3 more frequently (307, 45% versus 42, 24%; P<0.0001) and also developed more frequently into good-quality embryos (461, 67% versus 67, 38%; P<0.0001) and into excellent-quality embryos (290, 42% versus 34, 19%; P<0.0001). Tetrahedral embryos had a significantly higher implantation potential (98, 38% versus 9, 21%; P=0.038), ongoing pregnancy rate (84, 33% versus 7, 16%; P=0.032) and live birth rate (84, 33% versus 7, 16%; P=0.032). In conclusion, tetrahedral 4-cell-stage embryos on day 2 developed into embryos of better quality on day 3 with a higher implantation potential and live birth rate compared with non-tetrahedral 4-cell-stage embryos. In this study, an additional characteristic of 4-cell-stage embryos has been evaluated. The aim of the study was to evaluate the spatial arrangement of blastomeres in a 4-cell-stage embryo. If the cleavage planes of a 4-cell-stage embryo were perpendicularly orientated (indicating that both axes meet a right angle), blastomeres were defined as tetrahedral arranged while the other embryos were considered as non-tetrahedral embryos. The 4-cell-stage embryos (n=862) examined in this study were obtained from 299 patients aged <36 years. A total of 299 embryos were transferred as a single-embryo transfer on day 3. This study showed that tetrahedral embryos developed into an 8-cell-stage embryo on day 3 more frequently (307, 45% versus 42, 24%; P<0.0001) and also developed more frequently into good-quality embryos (461, 67% versus 67, 38%; P<0.0001) and excellent-quality embryos (290, 42% versus 34, 19%; P<0.0001). Tetrahedral embryos had a significantly higher implantation potential (98, 38% versus 9, 21%; P=0.038), ongoing pregnancy rate (84, 33% versus 7, 16%; P=0.032) and live birth rate (84, 33% versus 7, 16%; P=0.032). In conclusion, tetrahedral 4-cell-stage embryos on day 2 developed into embryos of better quality on day 3 with a higher implantation potential and live birth rate compared with non-tetrahedral 4-cell-stage embryos.

Belgium model of coupling reimbursement of ART costs to restriction in number of embryos transferred

Multiple pregnancy rates after treatment with assisted reproductive technology (ART) remain high (20.2% in Europe; 26.9% worldwide) and are associated with major societal costs (usually reimbursed and paid for by public health funds).1 2 They represent the most important side effect of ART treatment (usually not reimbursed and provided in private practice). In view of the Human …

A Multi-Center Prospective, Randomized, Double-Blind Trial Studying the Effect of Misoprostol on the Outcome of Intrauterine Insemination

Background: Because seminal prostaglandins play a role at natural fertilization, it was hypothesized that vaginal supplementation of prostaglandins at the time of intrauterine insemination (IUI) might enhance chances of conception. We investigated the effect of misoprostol, a prostaglandin analogue, on the success rate of IUI. Methods: A multi-center double-blind randomized controlled trial, using a cross-over design with alternating sequence, was designed. Vaginal tablets of misoprostol or placebo were used in conjunction to intrauterine insemination. In total, 199 women, comprising 466 cycles, were analyzed. Main outcome measures were pregnancy rate and prevalence of vaginal bleeding and uterine cramps. Results: The misoprostol group accounted for 146 cycles with 19 pregnancies, whereas the placebo group cycles totaled 164 cycles with 21 pregnancies (13.0 vs. 12.8%, not significant). There was a statistically significant increase in vaginal bleeding (12.3 vs. 1.8%; OR 7.55; 95% CI 2.31–24.48) and abdominal cramping rates (15.1 vs. 4.3%; OR 3.98; 95% CI 1.68–9.39) after application of misoprostol. Due to these severe adverse events the study was prematurely terminated. Conclusion: Although prostaglandins surely play a role in natural human reproduction, vaginal administration of misoprostol at the time of IUI is associated with a high rate of side effects and does not seem to enhance the outcome.

Selecting the embryo with the highest implantation potential using a data mining based prediction model

BackgroundEmbryo selection has been based on developmental and morphological characteristics. However, the presence of an important intra-and inter-observer variability of standard scoring system (SSS) has been reported. A computer-assisted scoring system (CASS) has the potential to overcome most of these disadvantages associated with the SSS. The aims of this study were to construct a prediction model, with data mining approaches, and compare the predictive performance of models in SSS and CASS and to evaluate whether using the prediction model would impact the selection of the embryo for transfer.MethodsA total of 871 single transferred embryos between 2008 and 2013 were included and evaluated with two scoring systems: SSS and CASS. Prediction models were developed using multivariable logistic regression (LR) and multivariate adaptive regression splines (MARS). The prediction models were externally validated with a test set of 109 single transfers between January and June 2014. Area under the curve (AUC) in training data and validation data was compared to determine the utility of the models.ResultsIn SSS models, the AUC declined significantly from training data to validation data (p < 0.05). No significant difference was detected in CASS derived models. Two final prediction models derived from CASS were obtained using LR and MARS, which showed moderate discriminative capacity (c-statistic 0.64 and 0.69 respectively) on validation data.ConclusionsThe study showed that the introduction of CASS improved the generalizability of the prediction models, and the combination of computer-assisted scoring system with data mining based predictive modeling is a promising approach to improve the selection of embryo with the highest implantation potential.

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.