Andr Van Steirteghem Centre for Reproductive Medicine Research Centre Reproduction and Genetics Vrije Universiteit Br

1. Andr� Van SteirteghemCentre for Reproductive Medicine Research Centre Reproduction and GeneticsVrije Universiteit Brussel

2. OUTLINE LECTURE Introduction ICSI for male infertility ICSI outcome Prevention of all multiple births after ART Conclusions and acknowledgments

3. 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

4. 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

5. 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?

6. OUTLINE LECTURE Introduction ICSI for male infertility ICSI outcome Prevention of all multiple births after ART Conclusions and acknowledgments

7. 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

8. (a) PZD

9. ICSI

10. 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

11. 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

12. OUTLINE LECTURE Introduction ICSI for male infertility ICSI outcome Prevention of all multiple births after ART Conclusions and acknowledgments

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

14. 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

15. VUB FOLLOW-UP PROTOCOL Genetic counseling Prenatal diagnosis Data on pregnancy and delivery Health of children Malformations Follow-up at different ages Psyhomotor development �

16. 1586 foetal karyotypes were obtained by CVS sampling or amniocentesis 698 CVS results 892 Amnios results Mean age in the tested group was 33.5y 902 sing 684 mult1586 foetal karyotypes were obtained by CVS sampling or amniocentesis 698 CVS results 892 Amnios results Mean age in the tested group was 33.5y 902 sing 684 mult

17. 1586 foetal karyotypes were obtained by CVS sampling or amniocentesis For the non inherited anomalies the absolute risk is low , but higher than in the general population. Severity... Detection is possible from the11 th week on 50% of the parents, fully informed of the risks, (abortion rate and risk for a chromosomal anomaly), agree to do a prenatal test 1586 foetal karyotypes were obtained by CVS sampling or amniocentesis For the non inherited anomalies the absolute risk is low , but higher than in the general population. Severity... Detection is possible from the11 th week on 50% of the parents, fully informed of the risks, (abortion rate and risk for a chromosomal anomaly), agree to do a prenatal test

18. 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 < 5x106/ml or if low motility

19. 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

20. liveborn ICSI major Children malformations MALFORMATIONS IN ICSI LITERATURE Definitions different, methods different, timing different !!! Palermo Written reports from gynec ped or both 20% of the children examined in the institution with detailed questions Minor 1.03% (6/578) Wennerholm MBR (Swedish medical birth registry) medical records retrieved plus checked in the birth registry, only children in Sweden born Higher rate than in general population due to multiples. Excess of hypospadias. Minor 3.5% (40/1139) Ericson??? Is this the same study?? Control group Yes compared to congenital malf register and birth register Loft: M Malf ICD10, Questionnaire sent to parents to fill in malf, if reported, these were checked through discharge reports from different departments. Minor 1.2% (9/730) Minor malf as reported by the parents Control group NO Hansen info collected from registers (3 different). �Major� malformations evaluated (indicated in the abstract0 but ICD 10 includes a number of minor anomalies Possible observation bias, since observer not blind for treatment procedure Control group Results twice as high as in general population (4.0%) CONTROL GROUP TO INDICATE ON THE SLIDEDefinitions different, methods different, timing different !!! Palermo Written reports from gynec ped or both 20% of the children examined in the institution with detailed questions Minor 1.03% (6/578) Wennerholm MBR (Swedish medical birth registry) medical records retrieved plus checked in the birth registry, only children in Sweden born Higher rate than in general population due to multiples. Excess of hypospadias. Minor 3.5% (40/1139) Ericson??? Is this the same study?? Control group Yes compared to congenital malf register and birth register Loft: M Malf ICD10, Questionnaire sent to parents to fill in malf, if reported, these were checked through discharge reports from different departments. Minor 1.2% (9/730) Minor malf as reported by the parents Control group NO Hansen info collected from registers (3 different). �Major� malformations evaluated (indicated in the abstract0 but ICD 10 includes a number of minor anomalies Possible observation bias, since observer not blind for treatment procedure Control group Results twice as high as in general population (4.0%) CONTROL GROUP TO INDICATE ON THE SLIDE

21. 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

22. 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)

23. OUTLINE LECTURE Introduction ICSI for male infertility ICSI outcome Prevention of all multiple births after ART Conclusions and acknowledgments

24. 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

25. 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

26. 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

27. 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)

28. 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

29. 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

30. 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)

31. 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

32. CONDITIONS FOR IVF-ICSI REIMBURSEMENT Six cycles will be reimbursed Age limit 43 years Patients < 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

33. CONDITIONS FOR IVF-ICSI REIMBURSEMENT Patients ? 36 years and < 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

34. OUTLINE LECTURE Introduction ICSI for male infertility ICSI outcome Prevention of all multiple births after ART Conclusions and acknowledgments

35. Clinic Laboratory