In the future , IVF will not only be for infertile women but will be directed to help fertile couples getting health babies!! How !! this talk will help to illustrate that

1. IVF for Fertile Couples
Hesham Al-Inany, M.D, PhD

2. focus of this Talk
• Fertile couples who are likely to conceive
spontaneously but still need IVF
treatment!!!

3. For Tomorrow Better health
• Preservation of fertility
• Prevention of disease
• Improvement of health

4. Fertility Preservation

5. Incidence of Cancer in Young Women
AND
PRESERVATION OF FERTILITY

6. Why it is needed!
• ~15% of women cancer occur in
women<45 years of age
• Increasing survival rates among women
with cancer

7. Cancer treatments can results in
infertility.

8. ASAP
• The decision for fertility preservation
should be considered as soon as possible
to maximize the likelihood of success.

9. Jeruss and Woodruff (2009) New England Journal of Medicine.
What
Technique
is
Appropriate
?

10. Female : embryo cryopreservation
• Requires 10–14 days of ovarian stimulation
from the beginning of menstrual cycle
• It is a surgical procedure
• Requires husband
• Cost: per cycle, storage fees

11. Oocyte cryopreservation
• Still experimental
• (3-4 times lower success rate than
standard IVF)
• Vetrification can be a good option

12. Male: Sperm cryopreservation
• Outpatient procedure;
• Cost approximately 1,500 for three
samples stored for 3 years
• Most effective way

13. Safety
• no detectable increased risk of disease
recurrence associated with most fertility
preservation methods and pregnancy,
even in hormonally sensitive tumors.

14. Offspring
• no evidence that a history of cancer
therapy, or fertility interventions increase
the risk of cancer or congenital
abnormalities in the offspring.

15. In brief
• The two methods of fertility preservation
with the highest likelihood of success are
sperm cryopreservation for males and
embryo freezing for females.

16. For Tomorrow Better health
• Preservation of fertility
• Prevention of disease
• Improvement of health

17. Prevention
Of What!!

18. 1% of births affected
• Online Mendelian Inheritance in Man (OMIM:
http://www.hgmp.mrc.ac.uk/omim/)

19. Genetic Risk is significant
Autosomal recessive (CF) 1:4 risk
X-linked recessive (Haemophilia, DMD) 1:2 males
Autosomal dominant 1:2
• Early onset (Myotonic dystrophy, achondroplasia)
• Late onset (Huntington’s disease)

20. X linked
(sex linked)
Carrier
female
Normal
female
AFFECTED
MALE
Unaffected
Male
Risk 1 in 2 males

21. Demographics: Thalassemia
• Found most
frequently in the
Mediterranean

22. Effects of haemophilia.
(a) Bleeding around elbow. (b) A retinal bleed. (c) Repeated bleeds into joints
produce severe arthritis.

23. IVF + PGD
Transfer only unaffected embryos to the woman
affected affectedaffected

24. Embryo biopsy
Diagnosis
by
Transfer
2 unaffected
embryos
Fertilisation in vitro
(IVF or ICSI)
PCRFISH
Accurate
genetic
diagnosisAppropriate
Genetic
Counselling
DENATURING
ANNEALING
EXTENSION
PRIMER
TAQ
TAQ

25. Using FISH for PGD of
X-linked disorders
• Three colour FISH
• X ( green)
• Y (red)
• Chromosome 18 to
control for normal
diploidy
Male
Female

26. Al-Gazali, L. et al. BMJ 2006;333:831-834
Fig 1 Two Arab pedigrees showing high level of consanguinity, large family size, and
several affected children in different sibships

27. Al-Gazali, L. et al. BMJ 2006;333:831-834
Fig 2 Average rates of marriages between first cousins among Arabs

28. Premarital
• Some countries have started prevention
programs for certain common genetic
disorders, such as premarital carrier
screening for haemoglobinopathies

29. Iran
• A premarital thalassaemia screening and
counselling programme resulted in
reduction in birth of affected babies by
70% within five years.

30. But
• This approach is used in Bahrain, Saudi
Arabia, and Jordan. However, experience
from SA shows that most couples choose
to marry despite a high risk of inherited
genetic disease in their offspring.

31. IVF + PGD
Transfer only unaffected embryos to the woman
affected affectedaffected

32. How effective is it?
Single gene disorders
Guy’s 97-04 Rome 99-04* ESHRE 98-03
>40 centres
Cycles 159 - -
Recovery 135 - 2868
Biopsy 125 182 2701
ET 113 173 2173
Clin Preg
(%/ET/biop/OR)
38
(33/30/28)
48
(28/26/?)
514
(24/20/18)
Livebirth 33 37 411
* Fiorentino et al Hum Rep 2005•Assume 80% continue

33. monogenic disease
• may be a therapeutic tool in families with
an already affected offspring

34. Options
• not having children
• natural conception and hoping that the
coming child is unaffected
• natural conception and genetic testing of
the fetus with an option of termination if
the child is affected (Ethical??)
• IVF and PGD, replacing only unaffected
embryos.

35. IVF + PGD + HLA

36. The Aim
• not only to avoid the birth of affected child
(prevention),
• At delivery, haematopoietic stem cells
HSC from the newborn umbilical cord
blood are collected and used for the
haematopoietic reconstruction of the
affected sibling (cure)

37. It is already done
• The first case performed for Fanconi
anaemia complementation group C (FA-
C), resulted in successful haematopoietic
reconstitution in the affected sibling by
transplantation of stem cells obtained from
the HLA-matched offspring (Verlinsky Y et
al, 2001).

38. • For Thalassemia, when an HLA identical
sibling marrow donor is available, the
chance of cure is currently over 90%.
Locatelli 2003
• whereas in the case of a acquired disease
such as leukemia it is much lower
(50%)(Eapen 2006) because here the
patient also has to be cured from the
tumour.

39. Preimplantation Genetic
Haplotyping (PGH)

40. Nash Case : Fanconi anaemia
• did her parents choose to have a healthy
baby because they wanted another child,
or because they wanted a source to help
cure their daughter?

42. ESHRE 2005
• Affected previous child of these parents
has malignant disorder or genetic disorder,
and the child is likely to be cured or life
expectancy to be substantially prolonged
by cord blood stem cell transplantation
from an HLA matched identical sibling

43. For Tomorrow Better health
• Preservation of fertility
• Prevention of disease
• Improvement of health

44. Prevention of Cancer

45. Families with Cancer
• Familial Adenomatous Polyposis (FAP)
• Multiple Endocrine Neoplasia 2
• Retinoblastoma
• Breast cancer (BRCA1 and BRCA2
genes )
• Hereditary non-polyposis colorectal cancer
• All these cancers are autosomal dominant
traits that usually manifest in adulthood,
but can occur occasionally in children

46. Options
• not having children
• natural conception and hoping that the
child is unaffected
• natural conception and genetic testing of
the fetus with an option of termination if
the child is affected (Ethical??)
• IVF and PGD, replacing only unaffected
embryos.

47. IVF + PGD
Transfer only unaffected embryos to the woman
affected affectedaffected

48. Susceptibility testing

49. Sex selection
• For family balancing
• poses numerous clinical, social, psychological,
ethical dilemma

50. Ethical issues
• Islamic legal viewpoint is that fetal sex
selection is lawful when it is practiced on
an individual basis, to fulfill the wish of a
married couple to have a boy or a girl
through available medical means.

51. Other conditions

52. What after screening!!
• Doctors successfully screened embryos
for gene mutation linked to early onset
Alzheimer's
JAMA, March, 2002

53. Late-onset Disorders
• are complex and have both genetic and
environmental causes.
• such as Alzheimer’s, With no current
prospect for the treatment of Alzheimer's
disease, prevention of an inherited
predisposition to Alzheimer's is the only
option for couples at risk

55. Limitations
Transfer only unaffected embryos to the woman
affected affectedaffected

56. 10 oocytes
8 fertilized
5 survive biopsy
6 cleave to 8-16 cell
1 no diagnosis
1 aneuploid
2 males
1 female for replacement
Practical realities 6
Attrition of embryos
Example for a sex linked disorder
e.g. Haemophilia / Duchenne MD

57. IVF associated risks
- high cost
- risk of not getting pregnant;
- increased risk of a multiple birth
- risk of OHSS (Difficult to balance
adequate egg numbers and the risk of
OHSS ).

58. • embryo biopsy may lower embryo
implantation rates (Mastenbroek et al,
2007)

59. For Tomorrow Better health
• Preservation of fertility
• Prevention of disease
• Improvement of health

60. To achieve this
• The Egyptian IVF-ET center has started its
Thalathemia prevention program and is
ready to help