IVF for Fertile Couples

Hesham Al-Inany, M.D, PhD

focus of this Talk

• Fertile couples who are likely to conceive spontaneously but still need IVF treatment!!!

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

Fertility Preservation

Incidence of Cancer in Young Women

AND

PRESERVATION OF FERTILITY

Why it is needed!

• ~15% of women cancer occur in women<45 years of age

• Increasing survival rates among women with cancer

Cancer treatments can results in infertility.

ASAP

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

Jeruss and Woodruff (2009) New England Journal of Medicine.

What Technique

is Appropriate

?

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

Oocyte cryopreservation

• Still experimental• (3-4 times lower success rate than

standard IVF) • Vetrification can be a good option

Male: Sperm cryopreservation

• Outpatient procedure; • Cost approximately 1,500 for three

samples stored for 3 years • Most effective way

Safety

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

Offspring

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

In brief

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

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

Prevention

Of What!!

1% of births affected

• Online Mendelian Inheritance in Man (OMIM: http://www.hgmp.mrc.ac.uk/omim/)

Genetic Risk is significant

Autosomal recessive (CF) 1:4 riskX-linked recessive (Haemophilia, DMD) 1:2 males

Autosomal dominant 1:2• Early onset (Myotonic dystrophy, achondroplasia)

• Late onset (Huntington’s disease)

X linked(sex linked)

Carrier female

Normal female

AFFECTED MALE

Unaffected Male

Risk 1 in 2 males

Demographics: Thalassemia• Found most

frequently in the Mediterranean

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

IVF + PGD

Transfer only unaffected embryos to the woman

affected affectedaffected

Embryo biopsyDiagnosis

by

Transfer2 unaffectedembryos

Fertilisation in vitro (IVF or ICSI)

PCRFISH

Accurate genetic

diagnosisAppropriate Genetic

Counselling

DENATURING

ANNEALING

EXTENSION

PRIMER

TAQ

TAQ

Using FISH for PGD of X-linked disorders

• Three colour FISH

• X ( green)

• Y (red)

• Chromosome 18 to control for normal diploidy

Male

Female

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

Al-Gazali, L. et al. BMJ 2006;333:831-834

Fig 2 Average rates of marriages between first cousins among Arabs

Premarital

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

Iran

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

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.

IVF + PGD

Transfer only unaffected embryos to the woman

affected affectedaffected

How effective is it?Single gene disorders

Guy’s 97-04 Rome 99-04* ESHRE 98-03>40 centres

Cycles 159 - -Recovery 135 - 2868Biopsy 125 182 2701ET 113 173 2173Clin 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

monogenic disease

• may be a therapeutic tool in families with an already affected offspring

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.

IVF + PGD + HLA

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)

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).

• 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.

Preimplantation Genetic Haplotyping (PGH)

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?

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

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

Prevention of Cancer

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

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.

IVF + PGD

Transfer only unaffected embryos to the woman

affected affectedaffected

Susceptibility testing

Sex selection• For family balancing• poses numerous clinical, social, psychological,

ethical dilemma

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.

Other conditions

What after screening!!

• Doctors successfully screened embryos for gene mutation linked to early onset Alzheimer's

JAMA, March, 2002

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

Limitations

Transfer only unaffected embryos to the woman

affected affectedaffected

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 6Attrition of embryos

Example for a sex linked disordere.g. Haemophilia / Duchenne MD

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 ).

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

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

To achieve this

• The Egyptian IVF-ET center has started its Thalathemia prevention program and is ready to help