OVARIAN STIMULATION: WHEN DOES LESS ACHIEVE MORE?

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OVARIAN STIMULATIONWHEN DOES LESS ACHIEVE MORE?
Overview and Introduction

• Milton K.H. Leong, M.D.
• IVF Centre
• Hong Kong Sanatorium Hospital, China

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LEARNING OBJECTIVES

• At the conclusion of this presentation,
  participants should be able to
• Explain the developmental steps in human IVF
• Outline the disadvantages of conventional IVF
  approaches
• Describe the strategies to overcome the
  disadvantages of conventional IVF treatments

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DISCLOSURE

• Milton K.H. Leong, M.D.
• None

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History

• 1890s - Walter Heape transferred embryos from
  one mother to another in rabbits
• 1959 Chang successful IVF in rabbits

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HistoryThe 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

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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
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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. 1981212681-2
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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.19823814-21
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Later steps in human IVF

• Transvaginal oocyte retrieval
• Gn Agonist
• Gn antagonist
• Embryo cryopreservation
• ICSI

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

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

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Pregnancy is more likely with multiple embryos
transferred

• Cochrane

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

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

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Multiple Pregnancies

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

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Noted trends in multiple births in USA
For twin (upper) and triplet or higher order
(lower) multiple births.
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Risks of multiple pregnancy
Maternal
Child
Family

• 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

• Single-survivor
• Guilt
• Blamed by parents
• Sibling
• Attention deficit
• Delayed development
• Parents
• Stress
• Isolation, depression
• Divorce

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Multiple pregnancy preterm delivery

• Blickstein I. Does assisted reproduction
  technology, per se, increase the risk of preterm
  birth? BJOG 2006113(Suppl. 3)6871. Based on
  data Martin JA et al. Births final data for
  2003. Natl Vital Stat Rep 2005541116.

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Conventional IVFConcerns

• 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.
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Conventional IVFConcerns

• 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.
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Conventional IVFConcerns

• 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.
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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

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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)

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Conventional IVFConcerns

• 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.

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Conventional IVFConcerns

• 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.
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Strategies to overcome the disadvantages

• OHSS None / minimal
  ovarian
• 
  stimulation
• Multiple pregnancy SET

Reduce cost
Dilemma These measures will result in lower
pregnancy rate ?
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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
2005331382-383.
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Twinning rates have dropped without significant
decrease in overall PR-Belgium

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Less embryos to transfer

• Need of less oocytes
• Less stimulation

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Less aggressive approaches

• Natural cycle IVF
• Minimal stimulation IVF
• IVM
• Natural cycle IVF/IVM

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Opposition from patients

• Cost of treatment
• Insurance
• Patient education

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Acknolwedge

• Dr. Ezgi Demirtas
• Reproductive Centre
• McGill University