Impact of Belgian legislation on reproductive outcome of medical assisted conception in the Leuven University Fertility Center

In this research project we investigated the impact of the Belgian legislation on practice and outcome of assisted reproductive technology (ART) treatment. We also investigated the impact of these legislations from a health-economic point of view. How can we still improve reproductive outcome in the context of new legislation that forced us to change our daily clinical practice? In order to address these questions, several studies and randomized controlled trials were performed.

To decrease multiple pregnancies and the associated perinatal costs, a new legislation was introduced in July 2003 (Belgisch Staatsblad) regulating the reimbursement of the laboratory costs of 6 in-vitro fertilization (IVF) cycles for Belgian women under the age of 43. This strategy was linked to a restriction of the number of transferable embryos, depending on the female age and the cycle ranking.

In an initial retrospective cohort study, we compared the cumulative delivery rate (CDR) between a study group after introduction of new legislation (N=795 patients) and a control group before legislation (N=463 patients) within six ART cycles or 36 months. Based on realistic estimates, CDR within 36 months was 60.8% in the study group after introduction of new legislation and 65.6% in the control group before introduction. CDR within 6 ART cycles was also comparable between both groups. We concluded that Belgian public health policy combining reimbursement of six ART cycles with a legally enforced reduction in the number of embryos transferred, did not had a negative impact on the CDR in spite of a 50% reduction in multiple live birth rate (MLBR) from 24% to 12%. In an additional retrospective economic analysis, we reported that a 50% reduction in MLBR led to a 13% reduction in cost based on high quality real life data obtained in the Leuven University Fertility Center.the health-economic effect of the reduction of the multiple delivery rate with 50% since the introduction of Belgian legislation of July 1st 2003 the health-economic effect of the reduction of the multiple delivery rate with 50% since the introduction of Belgian legislation of July 1st 2003 the health-economic effect of the reduction of the multiple delivery rate with 50% since the introduction of Belgian legislation of July 1st 2003 (chapter 2) The substantial budget saved by this policy can be used to improve patient access to ART by selective reimbursement. These results have implications for public health policies worldwide with respect to quality, safety, regulation, and financial control of treatments with ART. From a public health point of view, the ‘Belgian model’ can now be considered by other policy makers for application worldwide.

In September 2006, a law came into force regulating the reimbursement of gonadotrophins in the context of controlled ovarian stimulation (COS) with or without intrauterine insemination (IUI). Before this law, COS in combination with IUI could be performed with either clomiphene citrate (CC) or gonadotrophin. This law states that gonadotrophins are only refunded in selected cases. This decision, taken from a health economic concern, is opposed to observational and randomized studies that suggest that IUI after treatment with gonadotrophins results in a higher pregnancy rate than with CC.

As expected, our RCT including 330 women scheduled for IUI during 657 IUI cycles to ovarian stimulation with low dose gonadotrophins (hMG) subcutaneous or CC orally administered showed that hMG was superior to CC with respect to the clinical pregnancy rate (12.4% versus 6.7%) and live birth rate (11.8% versus 6.4%) per started cycle. Additionally, the cancellation rate per started cycle was considerably lower when hMG is administered instead of CC (4.7% versus 15.4%). In an additional cost-effectiveness analysis (CEA) based on real life health care costs,  we demonstrated that ovarian stimulation with hMG is associated with increased cost-effectiveness when compared to CC.

The question remains whether luteal phase support (LPS) is needed in IUI cycles stimulated with gonadotrophins? In both the single center RCT and multicenter RCT performed, we found no significant difference in clinical pregnancy rate after HMG stimulated IUI cycles with or without LPS with vaginal progesterone. These results should be interpreted cautiously since sample size was never reached in both studies due to recruitment problems. However, in the multicenter RCT, there was an absolute risk difference for clinical pregnancy rate of 6% and for live birth rate of 5% in the treatment group with LPS. The clinical pregnancy rate, was 16.8% in the LPS group and 11% in the control group. Similarly, live birth rate was 14.9% in the LPS group and 9.4% in the control group. And, to the best of our knowledge, this RCT includes the highest number of patients (N=393) ever included in an RCT allowing only one cycle per patient, testing this hypothesis.

In July 2007, a new legislation stated that supernumerary embryos created by ART need to be thawed and used before a new oocyte aspiration is allowed to create new embryos. Due to the limited number of reimbursed ART cycles in Belgium, the demand for a healthy child within these cycles has become very compelling. Therefore, it is important to continuously improve the implantation potential of embryos during freeze-thaw cycles.

In a first RCT, the implantation rate (IR) per embryo transferred after an embryo transfer (ET) of frozen-thawed embryos with thinned zona pellucida (ZP) after assisted hatching (AH) by laser was compared to an ET of frozen-thawed embryos without AH. A total of 647 thawing cycles were randomized to either the AH group (N=324) or control group (N=323) and no significant difference in IR per embryo transferred was observed between the AH group (13.3%) and control group (15.6%). In a second RCT, the IR per frozen-thawed embryo transfer cycle (FET) stimulated with gonadotrophins (hMG) was compared to natural cycle (NC) FET cycles. To the best of our knowledge, no RCTs have been published testing this hypothesis in women with a regular ovulatory cycle. A total of 672 embryos were transferred during 434 cycles. In this study we demonstrated that the IR per embryo transferred, was not statistically different between the hMG FET group (16%) and the NC FET group (12%). However, there was a trend towards a slightly higher IR (4% higher) in the hMG FET group.