1. Gonadotrofines en IUI moeten terugbetaald worden als eerstelijnsbehandeling bij Unexplained Infertility en Mild Male Subfertility  Thomas D’Hooghe, MD, PhD  Hoogleraar, Fac. Geneesk., K.U.Leuven  Coordinator Leuvens Univ Fertil Centrum

2. Current regulation reimbursement Gons, IVF and IUI in Belgium 1. Urinary FSH/LH (Menopur): 75% reimbursement -Fertility problems based on unsufficient endogenous stimulation of gonads -Controlled Ovarian Stimulation (COH) for Medically Assisted Reproduction (ART) 2. Recombinant FSH (Gonal-F, Puregon): -Same indications, -only reimbursed (75%) for indication COH and ART from 3 rd ART cycle onwards, if basal FSH less than 12 (measured at 2 different time periods during Early Foll Phase) 3. Laboratory reimbursement: IUI: none; IVF/ICSI: 1200 Euro if <43, 6 cycles lifetime

3. Current regulation reimbursement Gons, IVF and IUI in Belgium (2) 1. Urinary FSH/LH (Menopur): 75% reimbursement -Can be Prescribed by all gynecologists -Reimbursed for all patients for OI, IUI, IVF 2. Recombinant FSH (Gonal-F, Puregon): -Can be Prescribed by all gynecologists -Reimbursed only for IVF from 3 rd cycle onward 3. Cost for patient per IVF or per IUI cycle IVF (1200 Euro lab reimbursement): 300-400 Euro IUI: (no lab reimbursement or K number): 350 Euro 4. Cost for society per IVF or per IUI cycle: Much higher for IVF than for IUI

4. REIMBURSEMENT GONS EUROPE IUIIVF/ICSI BELGIUM75% DENMARK50%75-85%, max 3 FINLAND50% FRANCE100% GERMANY50%, max 650%, max 4

5. REIMBURSEMENT GONS EUROPE IUIIVF/ICSI Netherlands0 %100%, c2-3 NorwayPartial Portugal40% SPAIN90%, MAX 690%, MAX 3 UK100% (Cond)

6. Why should reimbursement Gons in Belgium be reduced ? (1) 1. INCREASED COST PARTLY RELATED TO INCREASED CONSUMPTION, ESPECIALLY SINCE 1/7/2003 (MORE IVF) Total Million IU used per year (Source) Overall 2/3 IVF/ICSI and 1/3 OI/IUI  24.6  27.4 (+11%)  32.5 (+19%)  42.6 (+ 31%, reimbursement Lab IVF since 1/7/2003) 2. INCREASE IN TOTAL COST HIGHLY RELATED TO REPLACEMENT CHEAPER HUMEGON BY MORE EXPENSIVE MENOPUR IN 2001

7. Why should reimbursement Gons in Belgium be reduced ? (2) 2. PREVENTION OF MULTIPLE PREGNANCIES? ANALYSIS SPE 1997-2001 NON-IVF: 6789 DELIVERIES, 743 TWINS (11%) 533 TWINS AFTER OI (7.8%) 210 TWINS AFTER IUI (3.1%) IVF: 5247 DELIVERIES, 1464 TWINS (28%) CONCLUSION: TWIN DELIVERY RATE 10X HIGHER AFTER IVF THAN AFTER IUI !!!

8. Why should reimbursement Gons in Belgium be reduced ? (3) 2. PREVENTION OF MULTIPLE PREGNANCIES? ANALYSIS SPE 1997-2001 ALL MULTIPLE DELIVERIES ANALYZED (N=2207) IUI: 210/2207 (9.5%) OI: 533/2207 (24.1%) IVF/ICSI: 1464/2207 (66.3%) CONCLUSION: IVF RESPONSIBLE FOR 2/3 OF ALL MULTIPLE DELIVERIES IUI RESPONSIBLE FOR LESS THAN 10% !!!

9. Why should reimbursement Gons in Belgium be reduced ? (4) STRATEGY TO REDUCE N MULTIPLE PREGNANCIES AFTER IVF (2/3 OF ALL MULTIPLE PREGNANCIES) -LIMITED N OF EMBRYOS FOR ET (EFFECT: 28% TO ??) ! LIMIT REIMBURSEMENT OF GONS TO MAX 6 CYCLES, MAX 2500 IU PER CYCLE, AGE<43 YRS, LIFETIME = FINANCIAL ISSUE, NOT PREVENTION STRATEGY FOR MULTIPLE BIRTHS

10. Why should reimbursement Gons in Belgium be reduced ? (5) STRATEGY TO REDUCE N OF MULTIPLE PREGNANCIES: NON-IVF: BOTH OI (25% MULTIPS) AND IUI (9% MULTIPS) CONSENSUS PROPOSAL VWRG-VVOG-GGOL (MINISTER F VANDENBROUCKE) = LIMIT REIMBURSEMENT OF GONS TO MAX 6 CYCLES, MAX 1200 IU PER CYCLE, AGE<43 YRS, LIFETIME = PREVENTION STRATEGY (LOW DOSE STEP UP) WITH SECONDARY COST REDUCTION

11. 9 REASONS FOR GONS TO BE REIMBURSED FOR COH AND IUI  COH AND IUI WORKS. EVIDENCE BASED FIRST LINE OF TREATMENT FOR MILD MALE SUBFERTILITY AND FOR UNEXPLAINED INFERTILITY  GONADOTROPHINS + IUI AT LEAST TWICE AS SUCCESSFUL AS CLOMIPHENE CITRATE + IUI  COH AND IUI RESPONSIBLE FOR LESS THAN 10% OF ALL MULTIPLE (ART) DELIVERIES IN FLANDERS  MULTIPLE PREGNANCY RATE NOT NECESSARILY HIGHER AFTER GONS + IUI THAN AFTER CC + IUI  PREVENTION OF MULTIPLE PREGNANCIES TO LESS THAN 10% PER CYCLE IS POSSIBLE USING LOW DOSE STEP-UP PROTOCOL, ULTRASOUND MONITORING, SELECTIVE FOLLICULAR ASPIRATION OR IVF OR CYCLE CANCELLATION

12. 9 REASONS FOR GONS TO BE REIMBURSED FOR COH AND IUI  SAFER THAN IVF: NO EVIDENCE OF INCREASED MORBIDITY SINGLETON PREGNANCIES, UNLIKE IVF  MORE COST-EFFECTIVE THAN IVF. If Gons only reimbursed for IVF, treatment with COH and IUI will become so expensive, that IVF will become the first line of treatment for all infertility with not only increased cost but also increased multiple pregnancies 8.FREEDOM OF CHOICE FOR PATIENT TO CHOOSE COH AND IUI AS AN EFFECTIVE BUT MORE NATURAL, LESS INVASIVE, LOWER DOSED TREATMENT THAN IVF 9.FREEDOM OF CHOICE FOR GYNECOLOGIST, ALSO THOSE WORKING OUTSIDE A OR B CENTRES

13. REASON 1: EVIDENCE BASED  MILD MALE SUBFERTILITY: COHLEN, COCHRANE LIBRARY 2002, UPDATED GOI 2004 COH + IUI BETTER THAN NATURAL CYCLE + TI (OR 6.2) COH + IUI BETTER THAN COH + TI (OR 2.1), BUT ONLY TRUE FOR GONS NOT FOR CLOMIPHENE COH + IUI BETTER THAN NATURAL CYCLE + IUI (OR 2), BUT ONLY TRUE FOR GONS, NOT FOR CLOMIPHENE CONCLUSION: ONLY GONS, NOT CLOMIPHENE ARE ADDED VALUE IN COMBINATION WITH IUI

14. REASON 1: EVIDENCE BASED 2. UNEXPLAINED INFERTILITY: META-ANALYSIS HUGHES 1997: INDEPENDENT POSITIVE EFFECT OF IUI (OR 2.8) AND GONS (OR 2.4) AND OF GONS + IUI (OR 5) META-ANALYSIS COHLEN, proceedings Doelen 2001; update GOI 2004 COH + IUI BETTER THAN COH + TI (OR 1.9) COH + IUI BETTER THAN NATURAL CYCLE + IUI (OR 1.9)

15. REASON 2: GONS + IUI MORE SUCCESSFUL THAN CC + IUI  MILD MALE SUBFERTILITY COHLEN, COCHRANE LIBRARY 2002, UPDATED GOI 2004 COH + IUI BETTER THAN COH + TI (OR 2.1), BUT ONLY TRUE FOR GONS NOT FOR CLOMIPHENE COH + IUI BETTER THAN NATURAL CYCLE + IUI (OR 2), BUT ONLY TRUE FOR GONS, NOT FOR CLOMIPHENE CONCLUSION: ONLY COH AND IUI WITH GONS, NOT CLOMIPHENE IS EVIDENCE BASED TREATMENT FOR MALE SUBFERTILITY

16. REASON 2: GONS + IUI MORE SUCCESSFUL THAN CC + IUI 2. UNEXPLAINED INFERTILITY: META-ANALYSIS HUGHES 1997: INDEPENDENT POSITIVE EFFECT OF IUI (OR 2.8) AND GONS (OR 2.4) AND OF GONS + IUI (OR 5) NO INDEPENDENT POSITIVE EFFECT OF CLOMIPHENE

17. REASON 2: GONS + IUI MORE SUCCESSFUL THAN CC + IUI 3. META-ANALYSIS COHLEN 2004 (IN PRESS, GOI) 4 RCTS COMPARING GONS AND CLOMIPHENE (UNEXPL INFERT, MALE, DONOR) (Karlstrom, Balasch, Ecochard, Matorras) PREGNANCY RATE: GONS 13% (48/373) CLOMIPHEN 6% (27/428) OR 2.2

18. REASON 2: GONS + IUI MORE SUCCESSFUL THAN CC + IUI 4. ADVISE EXPERT COMMISSION NETHERLANDS (TFO, 2004) 13 experts in reproductive medicine QUALITY INDICATORS FOR IUI: Amongst others: -6 cycles (male subfertility, unexplained subfert) -Gons for COH, Clomiphene not recommended -Start Gons at 75 IU per day -Increase dose Gons with increments of 37.5 IU per day

19. REASON 3: COH + IUI ONLY RESPONSIBLE FOR MINORITY OF MULTIPLE PREGNANCIES (ART) ANALYSIS SPE 1997-2001 ALL MULTIPLE DELIVERIES ANALYZED (N=2207) IUI: 210/2207 (9.5%) OI: 533/2207 (24.1%) IVF/ICSI: 1464/2207 (66.3%) CONCLUSION: IVF RESPONSIBLE FOR 2/3 OF ALL MULTIPLE DELIVERIES IUI RESPONSIBLE FOR LESS THAN 10%

20. REASON 4: MULTIPLE PREGNANCY RATE NOT NECESSARLY HIGHER AFTER GONS + IUI VS CC + IUI 1. META-ANALYSIS COHLEN 2004 (IN PRESS, GOI) 4 RCTS COMPARING GONS AND CLOMIPHENE (UNEXPL INFERT, MALE, DONOR) (Karlstrom, Balasch, Ecochard, Matorras); ONLY Balasch and Matorras with Multip Data MULTIPE PREGNANCY RATE/PREGNANCY: GONS 14% (6/42) CLOMIPHEN 10% (2/10) NS

21. REASON 4: MULTIPLE PREGNANCY RATE NOT NECESSARLY HIGHER AFTER GONS + IUI VS CC + IUI 2. RCTS PROVING THAT HIGH SUCCES CAN BE MAINTAINED USING LOW DOSE STEP-UP GONS + IUI - Spiessens et al 2003: RCT soft tip vs hard tip IUI catheter Preg Rate/IUI cycle: 20% (54/267) vs 19% (50/269) Multiple Birth Rate/pregnancy 4% (2/54) vs 6% (3/50) - Ragni et al, 2004: 50 IU FSH daily + GnRH antagonist + IUI: Preg Rate /initiated IUI cycle: 34% Multiple Pregnancy Rate: 0%

22. REASON 4: MULTIPLE PREGNANCY RATE NOT NECESSARLY HIGHER AFTER GONS + IUI VS CC + IUI 3. Retrospective studies. Dickey et al, 2001, 3608 cycles, 1983-1998 Multiple Implantation Rate per Pregnancy CC: 17/176 or 10% Gon: 33/179 or 18% Multiple Live Birth Rate per Total Live Births: CC: 12/127 or 9.4% (twins) Gon: 19/79 or 24% (20% twins and 4% triplets)

23. REASON 4: MULTIPLE PREGNANCY RATE NOT NECESSARLY HIGHER AFTER GONS + IUI VS CC + IUI 3. Retrospective studies. -Spiessens, Castelain and D’Hooghe, 2004, 2423 cycles, database LUFC 1996-2003 Overall LBR/IUI 12.5%; Overall Multiple LBR/Total LB: 11% LB/ IUI MLB/ LB ALL 2423 12.5% 303/2423 11.2% 34/303 CC 653 9% 61/653 14.7% 9/61 Gons 1722 14% 234/1722 10.7% 25/234

24. REASON 4: MULTIPLE PREGNANCY RATE NOT NECESSARLY HIGHER AFTER GONS + IUI VS CC + IUI 3. Retrospective studies. Spiessens, Castelain and D’Hooghe, 2004, 2423 cycles, database LUFC 1996-2003 MONOFOLLICULAR GROWTH (n=1170) LBR/ IUI MLB/ LB CC 327 8.3% 27 11% 3 Gons 843 13.2% 234 3.6 % 4

25. REASON 4: MULTIPLE PREGNANCY RATE NOT NECESSARLY HIGHER AFTER GONS + IUI VS CC + IUI CONCLUSION BASED ON CURRENT EVIDENCE: Multiple Preg (LB) /Total Preg (LB) 1.RCTS: CC (10%) = Gon (14%) 2.Low dose step up protocols: 0-6% (Ragni et al, 2004; Spiessens et al, 2003) 3.Retrospective studies: variable according to center and stimulation/monitoring style LUFC (1996-2004): Gon 11%; Clomiphene 15% Dickey (1983-1998): Gon 24%; Clomiphen 9.4%

26. REASON 5: PREVENTION OF MULTIPLE PREGNANCY RATE POSSIBLE USING GONS + IUI LEUVEN GUIDELINES FOR COH WITH GONS AND IUI:  LOW DOSE STEP UP (50 OR 75 iu)  ULTRASOUND MONITORING (AVAILABLE ON DAILY BASIS)  OBJECTIVE: MONOFOLLICULAR DEVELOPMENT,  IF 2 DOMINANT FOLLICLES: DISCUSS WITH PATIENT  IF MORE THAN 2 FOLLICLES OF 14 MM OR MORE: -SELECTIVE FOLLICULAR ASPIRATION (SHOULD BE AVAILABLE) -GO TO IVF -CANCEL CYCLE AND NO SEXUAL INTERCOURSE

27. 4 OTHER REASONS FOR GONS TO BE REIMBURSED FOR COH+IUI  SAFER THAN IVF: NO EVIDENCE OF INCREASED MORBIDITY SINGLETON PREGNANCIES, UNLIKE IVF  MORE COST-EFFECTIVE THAN IVF. If Gons only reimbursed for IVF, treatment with COH and IUI will become so expensive, that IVF will become the first line of treatment for all infertility with not only increased cost but also increased multiple pregnancies 8.FREEDOM OF CHOICE FOR PATIENT TO CHOOSE COH AND IUI AS AN EFFECTIVE BUT MORE NATURAL, LESS INVASIVE, LOWER DOSED TREATMENT THAN IVF 9.FREEDOM OF CHOICE FOR GYNECOLOGIST, ALSO THOSE WORKING OUTSIDE A OR B CENTRES

28. VOTE FOR VWRG-VVOG-GGOLF PROPOSAL REIMBURSEMENT GONS AND IUI MUST BE GUARANTEED BUT LIMITED TO PREVENT MULTIPLE PREGNANCIES (SECONDARY EFFECT: COST REDUCTION) 1.MAX 6 CYCLES, MAX 1200 IU/CYCLE, <43 YRS, LIFETIME 2.ONLY TO BE PRESCRIBED BY GYNECOLOGISTS WORKING IN OR AFFILIATED WITH A RECOGNIZED A OR B CENTER 3.IUI SHOULD BE RECOGNIZED WITH A K NUMBER 4.PROSPECTIVE REGISTRATION PR AND MULTIP PR VIA COLLEGE PHYSICIANS REPRO MED