OVARIAN STIMULATION:WHEN DOES LESS ACHIEVE MORE?

Milton K.H. Leong, M.D.

IVF Centre

Hong Kong Sanatorium & Hospital, China

Overview and Introduction

LEARNING OBJECTIVESAt 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

DISCLOSURE

Milton K.H. Leong, M.D.

None

History

• 1890s - Walter Heape; transferred embryos from one mother to another in rabbits

• 1959 – Chang; successful IVF in rabbits

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

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

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 inhumans by fertilization in vitro and embryo transfer in the controlledovulatory cycle. Science. 1981;212:681-2

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

Later steps in human IVF

• Transvaginal oocyte retrieval

• Gn Agonist

• Gn antagonist

• Embryo cryopreservation

• ICSI

0

10

20

30

40

50

60

0 1 3 5 6

20-24

25-29

30-34

35-39

40-45

N

% c

um

ula

tive

co

nce

pti

on

rat

e

Number of cycles/months

Age-Specific Cumulative Conception Rates

Tan et al, Lancet, 1990; 229Tan et al, Lancet, 1992; 1390-1394

Conventional IVF

• pregnancy and livebirth rates are higher with IVF than following natural conception in fertile couples

Pregnancy is more likely with multiple embryos transferred

Cochrane

Desire for pregnancy

Transfer of Multiple embryos

Ovarian stimulation

Increased chance of pregnancy

More oocytes retrieved

More embryos available Freeze the surplus embryos

Risk of OHSS

Medication side effectsCost of medication

Multiple pregnancy risk

Conventional IVF

Conventional IVF;concerns

• high success rates achieved at the expense of OHSS and multiple pregnancy

Multiple Pregnancies• Multiple pregnancies(MP) have increase

during the last 30 years.

• Main reason ART

Noted trends in multiple births in USA

For twin (upper) and triplet or higher order (lower) multiple births.

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 Child Family Single-survivor

Guilt Blamed by parents

Sibling Attention deficit Delayed

development Parents

Stress Isolation, depression Divorce

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.

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.

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.

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.

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

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)

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 Metabolism15, 84-90.

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.

• OHSS None / minimal ovarian

stimulation

• Multiple pregnancy SET

Reduce cost

Dilemma: These measures will result in lower pregnancy rate ?

Strategies to overcome the disadvantages

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.

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

Less embryos to transfer

• Need of less oocytes

• Less stimulation

Less aggressive approaches

• Natural cycle IVF

• Minimal stimulation IVF

• IVM

• Natural cycle IVF/IVM

Opposition from patients

• Cost of treatment

• Insurance

• Patient education

Acknolwedge

Dr. Ezgi Demirtas

Reproductive Centre

McGill University