1. IUI with gonadotrophins P Devroey Centre for Reproductive Medicine Dutch - speaking Brussels Free University Laarbeeklaan 101 1090 Brussels Belgium

2. Debate is an intellectual game between friends Stimulation of ovulatory women Is IUI not an intellectual blunder ?

3. Intellectual blunder ? Of miskleun ? Ovulation induction in anovulatory women Ovarian (superovulation) in IVF Ovarian stimulation in ovulatory women (ovarian enhancement)

4. Primary endpoint Singleton life birth (Significant) reduction of multiple pregnancies At present ~ 35 children / 100 are members of a multiple pregnancy ~

5. Ovulation enhancement in ovulatory women (IUI) Clomiphene citrateGonadotrophins Cheep drugExpensive drug Limited monitoringExtensive monitoring Limited multiple pregnancy rate Substantial multiple pregnancy rate (3x higher)

6. Aanbevelingen voor ovulatie inductie Monitoring van clomifeen stimulatie –Echografische monitoring met hormonale screening op dag 10 is nuttig –Zuiver echografische screening zonder hormonale screening kan een alternatief zijn Monitoring tijdens stimulatie met gonadotrophines –Is essentieel om multiple zwangerschappen te voorkomen –Hormonale bepalingen dag 5 van de cyclus –Hormonale follow-up om de 2/3 dagen of frequenter –Echografische follow-up Werkgroep Reproductieve Geneeskunde VVOG

7. Ovulation enhancement in ovulatory women (IUI) (continued) Clomiphene citrateGonadotrophins Reduced need for selective follicular aspiration Substantial need for selective follicular aspiration Reduced need for cancellation Substantial need for cancellation Reduced need for conversion to IVF Substantial need for conversion to IVF

8. Dickey FS 2001 % multiple pregnancies age

9. Strategies to prevent (high order) multiple pregnancies (IUI) Selective follicular aspiration of supernumerary follicles –Might be useful in experienced hands –Needs further investigation in large RCT –Applicability in non - IVF centers needs further investigation Cohlen 2004

10. Strategies to prevent (high order) multiple pregnancies (IUI) Conversion to IVF –Suddenly surprise –Non - informed couples –Treatment more expensive –Treatment more invasive Conversion to IVF / ET should be discouraged Cohlen 2004

11. IUI versus IVF - cost effectiveness Goverde Karande IUI is more cost effective but no costs for multiple pregnancies !!

12. Clomiphene citrate versus gonadotrophins Small RCT ! Balasch HR 1994 FSH is superior Matorras HR 2002 FSH is superior Echocard FS 2000 FSH is not superior Hughes HR 1997 CC seems less effective Cohlen Data Base Syst Rev 2002 CC seems less effective

13. Clomiphene citrate versus gonadotrophins “ However large RCTs with sufficient power to detect clinical relevant differences in cost effectiveness between CC and gonadotrophins in IUI cycles are still lacking” Cohlen 2004

14. Current best evidence for advanced treatment of unexplained subfertility There is a call for a large international factorial study –No treatment –CC IUI –FSH IUI –IVF Collins HR 2003

15. Current best evidence for advanced treatment of unexplained subfertility (continued) While such a study might cost millions of dollars, if it is not done many more millions could be wasted on treatments that are not as effective as they now seem Collins HR 2003

16. Published data IUI and gonadotrophines Male factor infertility (1998 - 2000) –Pregnancy rate 14 % –Multiple 12.3 % Unexplained infertility (1998 - 2000) –Pregnancy rate 22 % –Multiple 20 % D’Hooghe TG 2002

17. Published data IUI and gonadotrophines Male factor infertility (1994 - 2000) –Pregnancy rate 12.7 % –Multiple 15.6 % Normospermic group (1994 - 2000) –Pregnancy rate 21.3 % –Multiple 15.6 % Spiessens FS 2003

18. “ Ovarian stimulation for IUI was performed either with clomiphene citrate (CC 50 or 100 mg / d) from day 3 to day 7 of the menstrual cycle (n : 271) or with hMG (75 or 150 IU / d) from day 2 of the cycle (n : 601) “ Spiessens D’Hooghe page 1186 FS 2003

19. “ When women had two or more mature follicles (> 14 mm) at the time of hCG injection, selective follicle aspiration was offered and usually one or two follicles were kept intact after this procedure“ Spiessens D’Hooghe page 1186 FS 2003

20. IUI donor PeriodenZwanger% UZ Antwerpen1999 - 2000 351 5917.0 UZ Gent1991 - 2003127519915.6 UZ KUL1996 - 2002 486 9118.7 LIFE1989 - 2000182134619.0 GIFT GENK1989 - 2002 398 7318.7 AZ - VUB1996 - 2000 44211225.4 Clasen (Werkgroep)

21. Multiple pregnancies - cost Twins AZ - VUB 6 926 - 51 348 Euro USA51 715 US dollar Singleton 9 000 US dollar Infertility therapy - associated multiple pregnancies : an ongoing epidemic RBM OnLine 2003

22. Comparison between clomiphene citrate and gonadotrophins Subject of several small RCTs Regret fully, the conclusions are contradictory Cohlen

23. Conclusions IUI is an effective option (10 % pregnancy rate) If 1 000 000 sperm cells after sperm preparation But lowe dose step-up protocols (50 U) not withstanding close monitoring Stillstrict cancellation criteria to prevent multiple pregnancies Probablyin experienced hands selective aspiration may be an effective alternative

24. Coda IUI associated with gonadotrophins treatment Invasive –Follicular aspiration –Cancellation –IVF Enhance ovulation Results in 30 % of children, member of a multiple pregnancy