School of Women’s & Children’s Health

William Ledger

Head & Professor of Obstetrics and Gynaecology

University of New South Wales

Medico-legal Aspects of Reproductive Medicine

• Research funding

• Merck Sharp & Dohme

• Merck Serono

• Ipsen Pharma

• Shareholding

– IVF-Australia

• Advisory Board/ lectures

• Merck Sharp & Dohme

• Merck Serono

• Swiss Precision

Diagnostics

• Ferring Pharmaceuticals

• Biopharma

Declaration of interest

The opinions expressed in this lecture are my own.

They do not necessarily agree with those of the University of New South Wales, IVF-Australia

or the National Health and Medical Research Council of Australia

About this talk:

What can we do with IVF?

How it works

Where it can go wrong

Some new innovations

Louise Brown

25 July 1978

102 failed attempts

Natural cycle – one oocyte, one embryo

From 1978 to 2013

6 million IVF children and adults worldwide

Australia 2010 57000 cycles

10500 children

1: 30 births

On average, every primary school class has one

IVF child

IVF in 2013

What happens in an IVF

treatment cycle?

Pre treatment investigations

Informed consent

Counselling

Pituitary downregulation with

GnRH agonist

Superovulation with FSH

‘LH’ surge with hCG

Egg collection 36 hours later

Insemination ‘in vitro’

Check of fertilisation

Embryo culture

Embryo transfer

Freeze ‘spare’ embryos

Luteal support

Pregnancy test

IVF - a complicated affair

Adjuvant Therapies

• Aspirin

• Heparin

• Sildenafil

• Dexamethasone

• Growth hormone

• Testosterone

• DHEA

• Immunoglobulins

• intralipid

• Alternative therapies

‘Soft’ or ‘mild’ IVF

Less patient discomfort

Less complex, shorter stimulation regimes

Less short term complications

Less chance of long term health risks

Less expensive

‘Soft’ or ‘mild’ IVF

Less patient discomfort

Less complex, shorter stimulation regimes

Less short term complications

Less chance of long term health risks

Less expensive

Fewer oocytes

Fewer spare embryos for

cryopreservation

Less programmable IVF

cycles

“Patient friendly”

Superovulation

Baseline USS at start of period

Ovarian cysts, endometrial or myometrial abnormalities, hydrosalpynx, free fluid

Daily injection of FSH plus agonist or antagonist to prevent ovulation

Day 5 onwards, scan and blood test every second day until hCG trigger

hCG when 3 follicles 17mm or greater (antagonist) or 18 – 20mm (long

protocol)

or use agonist trigger (antagonist)

Usually takes 10 – 14 days

Egg collection

Fertilisation

Embryo culture

D5 D3

18h D2 D2

D4

Development to blastocyst

Which culture medium?

How long to culture

– D2 v d3 vs d5

How to assess embryo quality?

– Morphology

– Embryoscope

– Metabolomics

– Biopsy/ PGS

Adjuvants

– Embryoglue

– GM CSF

Controversies in embryology

ICSI

Embryo transfer

Storage of eggs, sperm and embryos

How likely is it to work?

Age 30

First IVF cycle

Male factor/ tubal factor infertility

Single embryo transfer

~ 35% chance of healthy child

Additional 25% with later frozen

embryo transfer

Age 40

First IVF cycle

Male factor/ tubal factor infertility

Single embryo transfer

~ 12% chance of a healthy child

Frozen embryos unlikely

> 45

Less than 1% per cycle

How likely is it to work?

18.8%

8.6%

24.8% 23.2%

34.0%

29.8%

0%

5%

10%

15%

20%

25%

30%

35%

40%

2002 2003 2004 2005 2006 2007 2008

Mu

litp

le B

irth

Ra

te

Australia United Kingdom United States

▼1.6 %pts

▼10.3 %pts

▼4.2 %pts

High

subsidisation

United States

Australia

United Kingdom

Canada Japan

Belgium France

Indonesia

Israel

Sweden

Brazil

Poland Germany

Developing

countries NZ

Low

subsidisation

Thanks to Georgina Chambers, UNSW

Multiple pregnancy rates 2002 - 2008

Funding ART

Cost per cycle $8000 - $12000

With Medicare rebate

– $4420 reimbursement for first cycle

– $4930 for subsequent cycle

Unlimited number of cycles

No age cap

Where can it go wrong?

Potential for error in IVF

Clinical

Ovarian hyperstimulation syndrome

Other physical and psychological sequelae

Risks of the procedures

Risks to the child

(pregnancy complications)

Creation of embryos from the ‘wrong’ gametes

Loss of gametes/ embryos

Failure to survive of fresh or frozen gametes/ embryos

Transfer of the ‘wrong’ gametes/ embryos

Laboratory

Ovarian hyperstimulation syndrome (OHSS)

Severe OHSS in 1 – 2% of cycles Young age

Polycystic ovary syndrome

Excessive doses of gonadotrophin

Multi-system disorder defined by capillary endothelial cell dysfunction

ascites/ pleural effusion, intravascular haemoconcentration

6 direct deaths in UK & Ireland

Unreported cases of permanent handicap

“Severe OHSS should be a thing of the past” Professor Paul Devroey, December 2010

Psychological sequelae of ART

Involuntary infertility can result in levels of psychological distress similar to those seen in patients with cancer

Treatment carries a considerable burden

Many couples do not continue treatment even if there is a good prognosis

Patients may claim for costs of psychological distress when things go badly due to clinical error

Risks of procedures

Side effects of medications

Rarely serious (OHSS)

Can be distressing

Long term risk of malignancy?

Egg collection

Anaesthesia

Pelvic haematoma/ abscess

Damage to viscera

Embryo transfer

Risks of IVF to offspring

• UK MRC Survey

• Australian National data

• Long term follow-up of IVF

offspring

• Major adverse effects on

offspring effects are the result

of multiple pregnancy

• Increased risk of cerebral palsy

– Mainly prematurity related, but

still seen in singleton

pregnancies

(RR 1.3 - 5.8)

• Possible increase in imprinting abnormalities after ICSI (Angelmann, Beckwith)

• Possible increase in risk of birth defects after ICSI using sperm with increased DNA fragmentation

• Possible increase in abnormalities after embryo cryopreservation (large offspring syndrome)

Consent

An embryo is the product of two people’s DNA

Diane Blood

Natalie Evans

Some new challenges

Ovarian aging

So don’t delay!

Delaying IVF from age 35 to age 38 approximately halves the chance of livebirth per cycle

0

50

100

150

200

250

300

20 25 30 35 40 42

miscarriage per 1000births

Down's syndromeper 10000 births

0

5

10

15

20

25

30

35

<25 26 28 30 32 34 36 38 40

Clinical pregnancies

Live births

In 2010, the median age at first

birth for Australian mothers was

30.7 years

Egg freezing

Requires an IVF cycle to superovulate and collect oocytes

Takes 3 - 4 weeks to complete

Does not require a male partner

Vitrification

Fertilise later with ICSI

Over 5000 births reported

Slow freezing

• 2oC/min

• 0.3oC/min

• Ice crystal prevention by

dehydration during

cooling

• Ice crystals can form in

cells.

Vitrification

• 15,000 – 30,000oC/min

• Ice crystal prevention by

dehydration before

cooling

• Glass like state. No

crystallisation (600 times

faster)

Some recent reports of the success of

oocyte vitrification

Survival rate Fertilisation

rate

Implantation

rate

Clinical

pregnancy

rate

Jin et al

2011

88% 75% 37% 50%

Cobo et al

2010

92.5% 58% 39.9% 50.2%

Kim et al

2010

81.0% 73% 80%

Nagy et al

2010

89.1% 87% 55.3%

And the age of the patients was….?

Survival rate Fertilisation

rate

Implantation

rate

Age

<Jin et al

2011

88% 75% 37% <35

Cobo et al

2010

92.5% 58% 39.9% < 35

Kim et al

2010

81.0% 73% < 35

Nagy et al

2010

89.1% 87% 55.3% <35

So what does this mean for social egg

freezing?

If oocyte vitrification is to give > 50% chance of a live birth,

women should

a)Freeze their eggs below age 36

and

b) Aim to freeze at least 12 eggs

But what we see in practice are women over 40 who have little

chance of successful egg freezing

One solution – donor egg

Oocyte donation 2013

Legal in Australia with an altruistic donor

But very few donors

Legal to pay donors in many other countries

USA, Asia Pacific, Spain, Eastern Europe

Results in widespread reproductive tourism

The worst possible outcome?

Daily Telegraph 16 July 2009

Pre implantation genetic diagnosis

(PGD)

and screening (PGS)

Allows screening for known chromosomal and

single gene disorders (PGD)

Allows screening for aneuploidy (PGS)

Allows identification of embryonic sex

Should sex selection be permitted?

Conclusion

Having a family is one of the most fundamental things that most people do

Infertility is deeply distressing

IVF can help but is expensive and has clinical risks

IVF is unpleasant and stressful for the couple

IVF is often unsuccessful

Things can and will go wrong

Thank You