Andrй Van Steirteghem Centre for Reproductive Medicine Research Centre Reproduction and Genetics Vrije Universiteit Brussel

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André Van SteirteghemCentre for Reproductive
Medicine Research Centre Reproduction and
GeneticsVrije Universiteit Brussel
ISSUES IN ICSI
Cardiff Centre for Ethics, Law and Society, June
12, 2004
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OUTLINE LECTURE

• Introduction
• ICSI for male infertility
• ICSI outcome
• Prevention of all multiple births after ART
• Conclusions and acknowledgments

Cardiff Centre for Ethics, Law and Society, June
12, 2004
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INFERTILITY IS A PUBLIC HEALTH PROBLEM

• One of the most frequently occurring health
  problems
• Is a problem for active young adults
• Is time consuming and has a high cost
• Is a problem for all social classes and all races

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PREVALENCE OF INFERTILITY

• 10 of women of 18-44 years are infertile
• 25 of women between 18-44 years experience some
  problems to become pregnant
• Male and female partners represent at least 2 of
  the population in developed countries

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MILESTONES IN REPRODUCTIVE MEDICINE

• 1960 reproductive endocrinology
• 1970 (micro)surgery
• 1980 in-vitro fertilisation
• 1990 intracytoplasmic sperm injection and
  preimplantation genetic diagnosis
• 2000 embryonic stem cells?

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OUTLINE LECTURE

• Introduction
• ICSI for male infertility
• ICSI outcome
• Prevention of all multiple births after ART
• Conclusions and acknowledgments

Cardiff Centre for Ethics, Law and Society, June
12, 2004
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ICSI

• Conventional IVF unsuitable for (severe) male
  infertility
• Failed fertilization in the presence of severe
  semen abnormalities
• Assisted fertilization procedures were developed
• Partial zona dissection
• Subzonal insemination
• Intracytoplasmic sperm injection

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• (a) PZD

(b) SUZI
(c) ICSI
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ICSI
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ICSI

• First birth 14 January 1992
• Better results than PZD SUZI
• Applied worldwide
• ICSI is for male-factor infertility what cIVF is
  for female-factor infertility

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INDICATIONS FOR ICSI

• With spermatozoa from ejaculate in
  oligo-astheno-teratozoospermia
• With spermatozoa from epididymis in obstructive
  azoospermia
• With spermatozoa from testis in obstructive and
  non-obstructive azoospermia

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OUTLINE LECTURE

• Introduction
• ICSI for male infertility
• ICSI outcome
• Prevention of all multiple births after ART
• Conclusions and acknowledgments

Cardiff Centre for Ethics, Law and Society, June
12, 2004
13
CONCERN ABOUT ICSI

• Invasive procedure ? meiotic spindle and
  cytoplasm
• Spermatozoa unsuitable for cIVF and may carry
  genetic abnormalities
• Natural selection does not occur
• Genomic imprinting may be incomplete

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PROSPECTIVE FOLLOW-UP OF IVF AND ICSI PREGNANCIES
AND CHILDREN

• Collaboration Centres for Medical Genetics and
  Reproductive Medicine
• Funding from different sources
• Multidisciplinary approach
• Geneticists-pediatricians
• Reproductive endocrinologists
• Psychologists
• Research nurses
• Data managers

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VUB FOLLOW-UP PROTOCOL

• Genetic counseling
• Prenatal diagnosis
• Data on pregnancy and delivery
• Health of children
• Malformations
• Follow-up at different ages
• Psyhomotor development

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PRENATAL DIAGNOSIS IN 1586 ICSI FOETUSES
Mean maternal age of women tested 33.5 years
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PRENATAL DIAGNOSIS IN 1586 ICSI FOETUSES

• Abnormal results n Confidence normal
• Interval population1, 2, 3
• De novo 25 1.6 1.02 - 2.32 0.45 - 0.87
• Sex chrom 10 0.6 0.30 - 1.16 0.19 - 0.27
• Autosomal 15 0.9 0.53 - 1.56 0.26 - 0.60
• Numerical 8 0.5 0.22 - 0.99 0.14 -
  0.33
• Structural 7 0.4 0.18 - 0.91 0.11 -
  0.22
• Inherited 22 1.4 0.87 - 2.09 0.47 - 0.37
• Total 47 3.0 2.19 - 3.92 0.92

1 Jacobs et al., 1992 on 34 910 newborns
significant 2 Ferguson-Smith et al., 1984 on 52
965 prenatal samples 3 Hook et al., 1982 1982
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PRENATAL DIAGNOSIS IN ICSI

• A small increase (1.6) of de-novo chromosomal
  abnormalities unknown for cIVF
• Abnormalities correlated with sperm concentration
  and motility
• PND is indicated if sperm count lt 5x106/ml or if
  low motility

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CONGENITAL ANOMALIES

• Major and minor anomalies
• Many biases and pittfalls in registration
• Classification systems
• Questionnaires ? full examination
• Time of registration
• Lost to follow-up
• Control group

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MALFORMATIONS IN ICSI LITERATURE

• liveborn ICSI major
• Children malformations

• Palermo/USA 578 1.61
• Wennerholm/Sweden 1139 3.32 0R 1.19 (CI
  0.8-1.8)6
• Loft/Denmark 730 2.22
• Bonduelle/Belgium 2840 3.43
• Hansen/Australia 301 8.64 RR 2.0 (CI
  1.3-3.2)6
• Ludwig/Germany 3372 8.65 RR 1.25 (CI
  1.1-1.4)6

1 at birth major malformations 6
compared to the general 2 at birth ICD 9/10
population 3 at birth 2 months
major malformations 4 at 1 year ICD 9 5 at 2
months EUROCAT coding system
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DEVELOPMENT OF IVF AND ICSI CHILDREN

• Bayley test indicates comparable and normal
  mental scores in 2-year old ICSI and IVF children
• Results correlated with duration of pregnancy,
  parity, singleton or twins
• IVF and ICSI children are comparable
• IVF and ICSI boys do less well

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FURTHER RESEARCH TOPICS

• Carefully controlled studies are still needed
• Attention needed for children from azoospermic
  men
• Children after replacement of cryopreserved
  embryos
• Long-term follow-up studies
• Attention to rare disorders such as genomic
  imprinting (Beckwith-Wiedeman syndrome, Angelman
  syndrome and retinoblastoma)

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OUTLINE LECTURE

• Introduction
• ICSI for male infertility
• ICSI outcome
• Prevention of all multiple births after ART
• Conclusions and acknowledgments

Cardiff Centre for Ethics, Law and Society, June
12, 2004
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PREVENTION OF ALL MULTIPLE BIRTHS

• More than 1 million children have been born after
  25 years of IVF and 12 years of ICSI
• About half of the children do not come from
  singleton pregnancies ? ? 500,000 children from
  twin, triplet or higher order gestations
• Possible risks after IVF-ICSI are in number far
  less important in comparison to morbidity
  generated by multiple births

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PREVENTION OF ALL MULTIPLE BIRTHS

• Twins are sometimes considered as a positive
  outcome they generate more problems than
  singletons cerebral palsy, harmful consequences
  for the family, cost for society 50x106 in UK
  per year

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PREVENTION OF ALL MULTIPLE BIRTHS

• How has it been possible that this occurred since
  physicians and other caretakers are concerned
  about wellbeing of patients and their children?
• To achieve higher pregnancy rate
• Because of professional and intellectual
  competition
• Because of market-drive goals

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PREVENTION OF ALL MULTIPLE BIRTHS

• There is a simple solution ? single embryo
  transfer (SET)
• You can has many embryos put back as you like,
  but one at a time (Carl Nygren, Sweden)

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SINGLE EMBRYO TRANSFER IS UNAVOIDABLE IN THE
FUTURE

• What is needed for SET?
• Educational task to everybody concerned
  caretakers, patients and health authorities
• Couples must be fully informed about risks
  generated by multiple births

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SINGLE EMBRYO TRANSFER IS UNAVOIDABLE IN THE
FUTURE

• Better selection of embryos for transfer
• Is there a place for PGD-AS?
• More efficient cryopreservation of embryos
• RCT is needed to answer the question if SET
  decreases the chance to have a family or not

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DECREASE OF IVF-ICSI MULTIPLE BIRTHS IN BELGIUM

• College of Physicians organized in April 2001
  Consensus Meeting on Prevention of IVF-ICSI
  multiple births including twins
• After consulting all Centres strategy was
  proposed to Secretary of Health to reduce number
  of multiple births and have better reimbursement
  (laboratory procedures were so far not reimbursed)

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DECREASE OF IVF-ICSI MULTIPLE BIRTHS IN BELGIUM

• Aim of strategy is to reduce by half in two years
  the number of multiple IVF-ICSI births
• Reimbursement laboratory procedures has started
  in July 2003
• College has been asked to organize registration
  of non-IVF ART

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CONDITIONS FOR IVF-ICSI REIMBURSEMENT

• Six cycles will be reimbursed
• Age limit 43 years
• Patients lt 36 years can have only 1 embryo
  replaced the first two cycles
• If no good embryo is available the second cycle
  they can have 2 embryos replaced
• A maximum of 2 embryos can be replaced from the
  3rd to the 6th cycle

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CONDITIONS FOR IVF-ICSI REIMBURSEMENT

• Patients ? 36 years and lt 40 years can have a
  maximum of 2 embryos in cycles 1 and 2 a maximum
  of 3 embryos in cycles 3 to 6
• A maximum of two embryos can be replaced in
  frozen embryo transfers
• Strategy will be evaluated by the College

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OUTLINE LECTURE

• Introduction
• ICSI for male infertility
• ICSI outcome
• Prevention of all multiple births after ART
• Conclusions and acknowledgments

Cardiff Centre for Ethics, Law and Society, June
12, 2004
35
CENTRE FOR REPRODUCTIVE MEDICINE
Paul Devroey André Van Steirteghem

• Clinic Laboratory

• Michel Camus
• Herman Tournaye
• Valérie Vernaeve
• Peter Platteau
• Carola Albano
• Willem Verpoest
• Residents
• Visiting fellows
• Gi De Mesmaeker
• Luc De Munck
• Rosette Vermeulen
• Nurses

• Endocrinology
• Johan Smitz
• Linda Van Waesberghe
• Johan Schiettecatte
• MLT
• Reproductive Biology
• Greta Verheyen
• Catherine Staessen
• Etienne Van den Abbeel
• Anick De Vos

• Hilde Van de Velde
• Lisbet Van Landuyt
• Ronny Janssens
• Hubert Joris
• Walter Meul
• MLT

Secretariats
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RESEARCH CENTRE REPRODUCTION AND GENETICS
André Van Steirteghem Inge Liebaers Paul
Devroey

• Willy Lissens
• Karen Sermon
• Martine De Rycke
• Catherine Staessen
• Sarah Seneca
• Hilde Van de Velde
• Anick De Vos
• Greta Verheyen
• Elvire Van Assche

• Etienne Van den Abbeel
• Lisbet Van Landuyt
• Ileana Mateizel
• Urielle Ullmann
• Ariane Stengers
• Nele De Temmerman
• Elke Geuns
• Veerle Goossens
• Claudia Spits
• Pascale Henderix
• Griet Meersdom

• Katrien Stouffs
• An Michiels
• Pierre Hilven
• Véronique Maerten
• Stéphanie Mertens
• Bart Saerens
• Nele Van Ranst
• Deborah Vandermaelen
• Sylvie Mertens
• Marleen Carlé