Minimal Monitoring of Ovulation Induction (OI) Is It Safe?

1. Minimal Monitoring of Ovulation Induction (OI)Is It Safe? Mustafa Uğur Zekai Tahir Burak Women’s Health Education and Research Hospital, Ankara, Turkey

2. Outline • Why to monitor OI in IVF? • How to monitor OI in IVF? • What does “minimal stimulation-monitoring” mean? • What is the evidence in the literature? • Which patients are (not) suitable? • What is my opinion?

3. Milestones in OI for IVF • Gonadotrophins to induce multiple follicles • GnRH agonist/antagonist for premature luteinization • TVUS guided OPU • Hormonal assays and US for monitoring OI • Simple and cheap IVF? • “Patient friendly” protocols and monitoring? • Do we alter outcome? • Success? • Complications?

5. Keys of success in OI • Choose the optimal protocol, drug and dose • Age, FSH, ovarian follicles, previous OI • Assess ovarian response to OI (Monitoring) • Successful completion of therapy

6. Why to monitor OI? • Evaluate ovarian suppression (long GnRH-a protocol) • Evaluate endometrial maturily • Find out optimal dose of gonadotrophin • Identify • Hypo responders • Hyper responders • Avoid OHSS • Reduce multiple pregnancies

7. How to monitor OI? • Ultrasound • Size and number of ovarian follicles • Endometrial thickness and pattern • Hormonal assays • Estradiol • Progesterone • LH • Combining US and E2

8. Monitoring OI (long protocol) normoresponder -E2 -E2 -E2 -E2 -us -us -us -us 1 2 3 4 5 6 7 8 9 10 4-5 E2 4-5 us

9. Monitoring OI long protocol hyper responder -E2 -E2 -E2 -E2 -E2 -E2 -us -us -us -us -us -us 1 2 3 4 5 6 7 8 9 10 6-7 E2 6-7 us

10. Monitoring OI Antagonist Protocol -E2 -E2 -E2 -E2 -us -us -us -us 1 2 3 4 5 6 7 8 9 10 4-5 E2 4-5 us

11. E2+US are mainstay in many IVF programmes • How about LH and Progesterone?

15. What does “Minimal Monitoring” mean? • Reduced number of US and hormonal assays? • E2 only monitoring? • How many? • US only monitoring? • How many?

16. Estradiol Only Monitoring • In the early days of IVF Levran et al. Fertil Steril, 1985 Wramsby et al. Human Reproduction, 1987 • Today, not accepted.

17. Why Ultrasound Only Monitoring? • Hormonal assays not available • Satellite IVF induction • Assays not reported on the same day • To minimize the cost

18. Ultrasound only monitoring us us us us 1 2 3 4 5 6 7 8 9 No E2, P, LH 2-4 us

19. Can Ultrasound Only Monitoring • Predict ovarian down regulation? • Follicular and endometrial development? • Timely administration of hCG? with • No decrease in pregnancy rates • No increase in OHSS

20. Can Ultrasound Predict Ovarian Down Regulation? • 183 IVF cycles (long GnRH-a protocol) • E2+US before ovarian stimulation • E2>55 pg/ml when endometrium >8mm=93.3% cycles • E2<55 pg/ml when endometrium <6mm=95.6% cycles • Endometrium <6 mm predicts down regulation in over 95% of cases Barash et al, Fertil Steril 1998

21. Endometrial Thickness vs. Estradiol Barash et al, Fertil Steril 1998

22. Which Patients are Suitable for US Only Monitoring? • Patients with a predicted ovarian response • not poor or hyper responders • Fixed dose milder stimulation • CC+HMG Vlaisavljevic 1992, Kemeter 1989 • HMG Golan 1995, Murad 1998 • rec FSH Lass 2003, Berger 2004

23. Ultrasound only monitoring -Nilsson et al. J In Vitro Fert Embry Transf, 1985 RE -Howard et al. J In Vitro Fert Embry Transf, 1988 RE -Kemeler et al. Human Reproduction, 1989 RE -Vlaisavljevic et al. Int J Gynecol Obstet, 1992 NO CONTROL -Massey et al. J. Assist Reprod Genet, 1994 RE -Wikland et al. Human Reproduction, 1994 RE -Roest et al. Fertil Steril, 1995 RE -Golan et al. Human Reproduction, 1995 PR -Murad et al. Int J. Gynecol Obslet, 1998 PR -Ben-Shlomo et al. Fertil Steril, 2001 RE -Hurst et al. Fertil Steril, 2002 PR ANALYZE -Thomask et al. Acta Obstet Gynecol Scanol,2002 RE -Lass et al. Fertil Steril, 2003 PR

24. USG vs. USG+E2Long GnRH-a +HMG USG USG,E2,LH,P P Duration OI 10,9 11,5 NS HMG ampoules 34,8 37,9 NS Oocytes retrieved 11,7 13,4 NS Embryos transferred 2,6 2,8 NS Embryos frozen 1,9 1,3 NS Pregnancy rates 27,2 26,5 NS No difference in OHSS Golan at al, Hum Reprod, 1995 n=114

25. USG vs. USG+E2Long GnRH-a +HMG USG every otherday daily USG+E2 P (n:110) (n:96) Patients underwent retrieval 110 87 NS Oocytes retrieved 1078 811 NS Mature oocytes 812 (75%) 735 (90%) <0,0072 Immature oocytes 201 (18%) 55 (5,8%) <0,001 Fertilized oocytes 711 (66%) 652 (80%) <0,001 Patients embryo transferred 81 (73%) 70 (80%) NS Clinical pregnany 19/81 (23%) 16/70 (22%) NS OHSS 1 1 NS Take home baby 12/81 (14%) 10/70 (14%) NS Monitorization cost 110 USD314 USD<0,001 (hormone+US+Transport) Murad et al. Int J Gynecol Obtet, 1998

26. USG vs. US+E2Long GnRH-a+rec FSH Multicenter PR study E2/Follicle ratio (n=143) us only (n=145) P Duration OI 10,2 10,1 NS FSH dose 2442 2483 NS Oocytes retrieved 11,4 11,7 NS Fertilized oocytes 6,6 6,4 NS Embryos transferred 2,3 2,3 NS Clinical pregnancies 49 (34,3 %) 46 (31,7%) NS Lass A, UK timing of hCG Group Fertil Steril, 2003

27. The addition of E2/follicle criteria to ultrasound monitoring of IVF cycles in normal responders seldom changes the timing of hCG and does not increase pregnancy rates or the risk of OHSS

30. Pitfalls of Minimal Monitoring • Not suitable for step-up, step-down protocols • Dose adjustment, changing drugs, coasting not possible • Follicle / E2 discrepancy over looked • Does it alter outcome?

31. Cost of IVF in Turkey (Turkish Medical Association 2008) OI and Monitorization 280 YTL 200 USD(6% of total cost) OPU 1100 YTL 780 USD ICSI 840 YTL 600 USD Embryoculture 1680 YTL 1200 USD Embriyotransfer 840 YTL 600 USD TESE 840 YTL 600 USD Overall IVF Cost=OI+OPU+ICSI+EC+ET4212 YTL 3000 USD

32. Conclusion • Standard monitoring of OI is with serial E2+US • Minimal monitoring mainly refers to US only monitoring • Normo responder patients can be monitored with US only with limited number of scans • Minimal monitoring is not suitable for all patients and should not be “routine” of an IVF programme