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

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?

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?

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

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

How to monitor OI? Ultrasound Size and number of ovarian follicles Endometrial thickness and pattern Hormonal assays Estradiol Progesterone LH Combining US and E 2

Monitoring OI (long protocol) normoresponder -E 2 -E 2 -E 2 -E 2 -us -us -us -us E us

Monitoring OI long protocol hyper responder -E 2 -E 2 -E 2 -E 2 -E 2 -E 2 -us -us -us -us -us -us E us

Monitoring OI Antagonist Protocol -E 2 -E 2 -E 2 -E 2 -us -us -us -us E us

E 2 +US are mainstay in many IVF programmes How about LH and Progesterone?

What does “Minimal Monitoring” mean? Reduced number of US and hormonal assays? E 2 only monitoring? How many? US only monitoring? How many?

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

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

Ultrasound only monitoring us us us us No E 2, P, LH 2-4 us

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

Can Ultrasound Predict Ovarian Down Regulation? 183 IVF cycles (long GnRH-a protocol) E 2 +US before ovarian stimulation E 2 >55 pg/ml when endometrium >8mm=93.3% cycles E 2 <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

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

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

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

USG vs. USG+E 2 Long GnRH-a +HMG USG USG,E 2,LH,PP Duration OI10,911,5NS HMG ampoules34,837,9NS Oocytes retrieved11,713,4NS Embryos transferred2,62,8NS Embryos frozen1,91,3NS Pregnancy rates27,226,5NS No difference in OHSS Golan at al, Hum Reprod, 1995 n=114

USG vs. USG+E 2 Long GnRH-a +HMG USG every otherdaydaily USG+E 2 P (n:110) (n:96) Patients underwent retrieval110 87NS Oocytes retrieved NS Mature oocytes812 (75%) 735 (90%) <0,0072 Immature oocytes201 (18%) 55 (5,8%) <0,001 Fertilized oocytes711 (66%) 652 (80%) <0,001 Patients embryo transferred 81 (73%) 70 (80%) NS Clinical pregnany 19/81 (23%) 16/70 (22%)NS OHSS1 1 NS Take home baby12/81 (14%) 10/70 (14%)NS Monitorization cost 110 USD 314 USD <0,001 (hormone+US+Transport) Murad et al. Int J Gynecol Obtet, 1998

USG vs. US+E 2 Long GnRH-a+rec FSH Multicenter PR study E2/Follicle ratio (n=143) us only (n=145)P Duration OI10,2 10,1NS FSH dose NS Oocytes retrieved11,4 11,7NS Fertilized oocytes6,6 6,4NS Embryos transferred2,3 2,3NS Clinical pregnancies49 (34,3 %) 46 (31,7%)NS Lass A, UK timing of hCG Group Fertil Steril, 2003

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

Pitfalls of Minimal Monitoring Not suitable for step-up, step-down protocols Dose adjustment, changing drugs, coasting not possible Follicle / E 2 discrepancy over looked Does it alter outcome?

Cost of IVF in Turkey (Turkish Medical Association 2008) OI and Monitorization280 YTL200 USD (6% of total cost) OPU1100 YTL780 USD ICSI840 YTL600 USD Embryoculture1680 YTL1200 USD Embriyotransfer840 YTL600 USD TESE840 YTL600 USD Overall IVF Cost=OI+OPU+ICSI+EC+ET4212 YTL3000 USD

Conclusion Standard monitoring of OI is with serial E 2 +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