1. OVARIAN STIMULATION: WHEN DOES LESS ACHIEVE MORE? Milton K.H. Leong, M.D. IVF Centre Hong Kong Sanatorium & Hospital, China Overview and Introduction

2. LEARNING OBJECTIVES At the conclusion of this presentation, participants should be able to: 1.Explain the developmental steps in human IVF 2.Outline the disadvantages of conventional IVF approaches 3.Describe the strategies to overcome the disadvantages of conventional IVF treatments

3. DISCLOSURE Milton K.H. Leong, M.D. None

4. History 1890s - Walter Heape; transferred embryos from one mother to another in rabbits 1959 – Chang; successful IVF in rabbits

5. History; The first pregnancy achieved following in- vitro human fertilisation of a human oocyte De kretzer D et al. Transfer of a Human Zygote. Lancet. 1973; ii: 728-729 a biochemical pregnancy

6. First test-tube baby natural cycle laparoscopic oocyte retrieval one mature oocyte IVF born in July 25, 1978 Steptoe PC, Edwards RG (1978). "Birth after the reimplantation of a human embryo". Lancet 2 (8085): 366

7. Candice Reed born in Melbourne in 1980 It was the subsequent use of stimulated cycles with clomiphene citrate and the use of human chorionic gonadotrophin (hCG) to control and time oocyte maturation, thus controlling the time of collection. Trounson AO, Leeton JF, Wood C, Webb J, Wood J. Pregnancies in humans by fertilization in vitro and embryo transfer in the controlled ovulatory cycle. Science. 1981;212:681-2

8. Controlled Ovarian Stimulation The Jones team in Norfolk, Virginia, further improved stimulated cycles by incorporating the use of a follicle stimulating hormone (uHMG). Then became known as controlled ovarian hyperstimulation (COH) Jones HW Jr. et al. The program for in vitro fertilization at Norfolk Fertil Steril.1982;38:14-21

9. Later steps in human IVF Transvaginal oocyte retrieval Gn Agonist Gn antagonist Embryo cryopreservation ICSI

10. % cumulative conception rate Number of cycles/months Age-Specific Cumulative Conception Rates Tan et al, Lancet, 1990; 229 Tan et al, Lancet, 1992; 1390-1394

11. Conventional IVF pregnancy and livebirth rates are higher with IVF than following natural conception in fertile couples

12. Pregnancy is more likely with multiple embryos transferred Cochrane

13. Desire for pregnancy Transfer of Multiple embryos Ovarian stimulation Increased chance of pregnancy More oocytes retrieved More embryos availableFreeze the surplus embryos Risk of OHSS Medication side effects Cost of medication Multiple pregnancy risk Conventional IVF

14. Conventional IVF; concerns high success rates achieved at the expense of OHSS and multiple pregnancy

15. Multiple Pregnancies Multiple pregnancies(MP) have increase during the last 30 years. Main reason ART

16. Noted trends in multiple births in USA For twin (upper) and triplet or higher order (lower) multiple births.

17. Risks of multiple pregnancy Obstetric –Miscarriage –Fetal reduction –Pregnancy complications Anemia Pre-eclampsia Gestational diabetes Growth retardation –C/S –Post-partum hemorrhage –Mortality Postnatal –Infection –Bleeding –Isolation, stress, depression –Bonding with child or children Perinatal Prematurity Low birth weight Mortality, morbidity Malformations Long-term Cerebral palsy Disability Learning difficulties Infant mortality Adult health risks Maternal ChildFamily Single-survivor Guilt Blamed by parents Sibling Attention deficit Delayed development Parents Stress Isolation, depression Divorce

18. Multiple pregnancy – preterm delivery Blickstein I. Does assisted reproduction technology, per se, increase the risk of preterm birth? BJOG 2006;113(Suppl. 3):68–71. Based on data Martin JA et al. Births: final data for 2003. Natl Vital Stat Rep 2005;54:1–116.

19. Conventional IVF; Concerns 40% of children born as a result of IVF/ICSI are twins. These babies had a 7,4-fold increase in delivery before 32 weeks compared to singletons. Also, significant increases in stillbirth, C/S and admission to the NICU. Pinborg A et al., 2004. Neonatal outcome in a Danish national cohort of 8602 children born after in vitro fertilization or intracytoplasmic sperm injection: the role of twin pregnancy. Acta Obstet et Gynecol Scandinavica 83, 1009-1011.

20. Conventional IVF; Concerns Maternal well being in IVF/ICSI twin pregnancies was compromised with a significant increase in sick leave and hospitalization compared with singleton IVF/ICSI pregnancies. Pinborg A et at. 2004 Maternal risk and perinatal outcome in a Danish national cohort of 1005 twin pregnancies: the role of in-vitro fertilization. Acta Obstet et Gynecol Scan 83, 75-84.

21. Conventional IVF; Concerns The cost to the healthcare budget of multiple births is considerable. average hospital cost per multiple gestation delivery is greater than the average cost of IVF and ICSI cycles European Society for Human Reproduction and Embryology Capri Workshop, 2000.

22. OHSS incidence of severe OHSS 0.6 to 1.9% but may be as high as 6% in high-risk groups; e.g., young women with PCO although there are a number of strategies to predict and prevent this potentially life- threatening complication, none is universally successful only reliable way is to avoid ovarian stimulation

23. Other disadvantages of conventional IVF Cost of medication Immediate side effects of the stimulation hormones Long-term health implications of the gonadotropins –The long-term effects of conventionally stimulated cycles have thrown up the possibility of an increased risk of endometrial cancer but not of ovarian cancer (Brinton, 2004; Althuis et al., 2005)

24. Conventional IVF; Concerns endometrial receptivity may be adversely affected by ovulation induction therapy. This may be due to advanced endometrial maturation and dysfunctional progesterone receptor activity. Basir GS et al., 2001 Morphometric analysis of peri-implantation endometrium in patients having excessively high- oestradiol concentrations after ovarian stimulation. Human Reprod 6,435. Devroey P et al., BCJM 2004 Reproductive biology and IVF: ovarian stimulation and endometrial receptivity. Trends in Endocrinology and Metabolism 15, 84-90.

25. Conventional IVF; Concerns ovulation induction may induce oocyte abnormalities. The reduced viability of in-vitro matured oocytes from stimulated cycles could be related to a significantly higher proportion of chromosomal abnormalities Magli MC et al. 2006 First meiosis errors in immature oocytes generated by stimulated cycles. Fertiliand Steril 86, 629- 635.

26. OHSS None / minimal ovarian stimulation Multiple pregnancy SET Reduce cost Dilemma: These measures will result in lower pregnancy rate ? Strategies to overcome the disadvantages

27. Some countries changed policy to decrease multiple pregnancy rates Kallen B et al., Temporal trends in multiple births after in vitro fertilisation in Sweden, 1982-2001: a register study. BMJ 2005;331;382-383.

28. Twinning rates have dropped without significant decrease in overall PR-Belgium

29. Less embryos to transfer Need of less oocytes Less stimulation

30. Less aggressive approaches Natural cycle IVF Minimal stimulation IVF IVM Natural cycle IVF/IVM

31. Opposition from patients Cost of treatment Insurance Patient education

32. Acknolwedge Dr. Ezgi Demirtas Reproductive Centre McGill University