ESHRE Campus Workshop, Luebeck, January 2008

The IVF problem patient: pre-

existing diseases in infertile patients
William Ledger
University of Sheffield
Centre for Reproductive Medicine and Fertility

The IVF patient with medical

problems
Questions to answer
Is IVF safe?
Is pregnancy safe?
For the mother?
For the child?
Will the disorder reduce chance of
pregnancy?

Common health disorders of young

women leading to subfertility
Cancer and late effects
Endocrinopathies
Diabetes
Thyroid disorders
Thrombophilias
Autoimmune disorders
Renal failure
Obesity

1
Late Effects of cancer treatment
1:950 people aged 16 - 35 is a long term cancer
survivor
Improving survival rates are increasing this
number every year
Multi disciplinary approach to cover wide variety
of complications of treatment
Cardiovascular/ CNS
Late recurrence/ second primary cancer
Reproductive health

Medical aspects of late effects

4% (6x background risk) develop secondary malignancy, up to 25
years post treatment
Common second malignancies include osteosarcoma & leukaemias
Mostly a consequence of older regimes of treatment
Effects of therapy
Anthracyclines on CVS
Mediastinal damage from radiation/ BMT
Renal effects of chemotherapy
Growth failure/ precocious puberty
Endocrinopathies including thyroid/ adrenal/leptin and bone effects
GVH disease after transplant

Chemotherapy
Risk of gonadal damage according to
treatment used

High risk Moderate risk

Cyclophosphamide Cisplatinum
Ifosfamide Adriamycin
Chlorambucil Actinomycin
Melphelan
Busulfan
Low risk
Methotrexate
Nitrogen mustard
Vincristine
Procarbazine
Vinblastine
Nitrosureas
Bleomycin

2
 Radiotherapy
Effect determined by dose and fractionation
Males
Permanent azoospermia in most males treated with >
4Gy
Effects on testosterone production less pronounced
Females
Primordial follicles are radiosensitive - risks of POF
increase with dose
Uterine effects include loss of elasticity, reduction in
blood flow and failure of endometrial growth

Fertility after cancer treatment

Will fertility be affected?
Can we preserve fertility before cancer
treatment?
Will fertility recover after cancer treatment?

Will fertility be affected?

Incidence of permanent ovarian failure after
cyclophosphamide chemotherapy
Age <20 13%
Age 20 - 30 50%
Age >30 100%
Rates will be higher after high dose rescue
chemotherapy, after pelvic radiotherapy or after
conditioning chemotherapy pre-stem cell
transplant
Newer chemotherapy regimes for most breast
cancers are less gonadotoxic (eg ABVD -
adriamycin, bleomycin, vinblastine, dacarbazine)
Presli et al, 2004

3
 Likelihood of preserving natural
fertility?
Depends on treatment
given and age at treatment
Even patients treated with
high dose chemo/
radiotherapy occasionally
maintain gameteogenesis
and fertility
Possibility of late
resumption of ovulation

Storing fertility
Cryopreservation of
Embryos
Gametes
Ovarian tissue

Possible drawbacks to superovulation in

young women with cancer
Delay in initiating cancer treatment
GnRH antagonist controlled superovulaton
Risk of elevation of oestradiol concentration
Most breast cancers in young women are ER positive
Aromatase inhibitors
Tamoxifen
Low dose FSH
Is transient elevation of plasma oestradiol concentration
harmful?

Casper 2004, Oktay 2003

4
Pregnancy after cancer treatment
Children born from cryopreserved embryos appear healthy
Low chance of long term damage to uterine function after
chemotherapy
Severe effects of abdominal radiotherapy
Miscarriage
Premature birth
Low birthweight
Effect is maximal if given pre-pubertally
Risk of long term damage to DNA after chemo- or
radiotherapy - unknown

Common endocrinopathies

Diabetes mellitus
Women with type I diabetes are less fertile and offspring
have increased risk of congenital malformation (6.9%)
Tight pre-IVF control of blood glucose can reduce risk of
malformation and normalise response to gonadotropins
Metformin
Insulin
Single embryo transfer to reduce risk of pregnancy
complications
Close liason with diabetic physician and specialist
obstetrician

Jonasson 2007, Laven 2005, Dicker 1992

5
 Thyroid disorders
Androgen & estrogen metabolism are altered by
thyroid hormone deficiency and excess
Frequent chronic anovulation
Also subfertility in cycling women with
thyrotoxicosis
Restoration of normal thyroid function (or
adequate replacement) is mandatory before
pregnancy
Patients on adequate thyroxine replacement
respond normally to gonadotropins
Careful follow up during pregnancy
Laven 2005

Connective tissue disorders

Systemic lupus erythematosus

Chronic inflammatory
multisystem disorder
May affect 1.5% of
women
Multiple immunologic
abnormalities
Remission/ excerbation
Hypertension, renal and
skin manifestations
Alkylating
immunosuppressants,
NSAIDs, antimalarials,
glucocorticoids

6
 Systemic lupus erythematosus
Chronic inflammatory Offer IVF if
multisystem disorder Normal creatinine
May affect 1.5% of Normal BP
women Remission for 12 months
Multiple immunologic Superovulation may
abnormalities induce flare in symptoms
Remission/ excerbation Pregnancy complications
Hypertension, renal and Placental infarction/ pre-
eclampsia
skin manifestations
Fetal death, prematurity
Alkylating Fetal abnormality, neonatal
immunosuppressants, lupus, heart block
NSAIDs, antimalarials,
glucocorticoids Guballa 2000, Huong 2003

Thrombo-embolic disorders

Thrombo-embolic disorders
History of DVT/ PE pre-IVF
Thrombophilia diagnosed during investigation of
recurrent miscarriage/ subfertility
Family history
Smokers
Hyperhomocysteinemia
Superovulation with raised plasma oestrogens may
produce a hypercoagulable state although studies
during IVF are reassuring
Significant activation of clotting cascade after
hCG, worsened by OHSS
Lox 1995, 1998, Biron 1997

7
 Coagulopathy in OHSS
0.8% OHSS cases develop VTE
Arterial and venous thrombotic complications
CVA
Myocardial infarction
Death
Low dose gonadotropins & modest target for
superovulation
Coasting, cycle cancellation, freeze all if over
response
Aspirin, low MW heparin, compression stockings
Adequate but not over hydration
Macklon 2005

Renal failure and infertility

Anovulation common in chronic renal
failure
Restoration of normal cycles is often seen
after transplantation
No increase in abnormalities after exposure
to cyclosporin from conception
Some (reassuring) data for tacrolimus and
Neoral

US National Transplant Pregnancy Register, 1997

IVF in the renal transplant patient

Offer IVF if
stable transplant with
normal serum creatinine
(1.4mg/dl)
at least two years post
transplant
CyA +/- prednisolone
Transvaginal oocyte
collection is possible in
the presence of a pelvic
kidney
Avoid OHSS - risk of
impairment of transplant
function
Single embryo transfer
Khalaf 2000, Pezeshki 2005, Nadalo 2007

8
Pregnancy in the renal transplant
patient
Increased risk of
miscarriage
hypertension/ pre-eclampsia (45 - 70%)
IUGR/ prom
44% neonates had bw >2500g
premature delivery/ stillbirth
Recurrent UTI in >10%
Severe hydronephrosis in 10% but no increased
risk of graft rejection
Pezeshki 2005

The obese infertile patient

WHO Classification:

Normal weight : BMI 19-24.9 kg/m2

Pre-obese or overweight: BMI 25- 29.9 kg/m

Obese: BMI 30 kg/m2.

Prevalence of overweight and obesity in

schoolchildren aged 10 - 16 years
USA

Canada

Spain

England

Italy

Greece

Scotland

Ireland

Austria

France

Germany

Sweden

Czech Rep
BMI 25 - 29.9
Switzerland

P oland BMI > 29.9

Netherlands

0 5 10 15 20 25 30
Int Soc Stud Obesity survey 2001 - 2

9
 Medical and reproductive disorders
commonly associated with obesity
Disorders worsened by Reproductive disorders
obesity associated with obesity
Type II DM Menstrual irregularity
Cholestasis
Anovulation
Hypertension
Hypercholesterolaemia Subfertility
CHD Miscarriage
Asthma
Osteoarthritis
Thromboembolism

Adverse obstetric and perinatal outcomes

associated with obesity
Obstetric factors Perinatal factors
Maternal hypertension/ PET Neural tube defect
Impaired glucose tolerance and Omphalocoele
gestational diabetes
Cardiac defects
Venous thromboembolism
Opthalmic defects
Macrosomia and shoulder dystocia
Oesophageal and upper GI defects
Intrauterine death
Increased Caesarean section rate Urogenital defects
and associated surgical Limb defects
complications
Wound infection and dehiscience
Postnatal respiratory complications

Sebire, 2001; Cedergren, 2004; Linne, 2004, Yu, 2006

Obesity and infertility

Multiple endocrine and metabolic disturbances (+/- PCOS)
Adverse effect on IVF cycle
increased FSH requirement
longer stimulation period
fewer oocytes and embryos
Effects on
ovulation
follicle growth and endocrinology
endometrial growth and implantation
embryo development
Increased risks of
miscarriage
pregnancy complications
problems at/ after delivery

Spandorfer, 2004, Fedorcsak, 2004, Wittemer, 2000

10
 Normal BMI Overweight Obese P value
n (%) 165 (58.7) 76 (27) 40 (14.2)
Total dose of FSH 1647 ( 40) 1811 ( 54) 1951 ( 89) 0.01
(IU)
Days of 11.2 11.0 12.0 NS
stimulation Age < 35
Peak E2 7149 (767) 5334.1 (539.2) 6914 (628) NS
concentrations
(pmol/l)
Cancellation rate 8 (5) 8 (10.5) 5 (12.5) NS
n (%)
Number of 8.1 ( 0.41) 8.1 ( 0.54) 9 ( 6) NS
oocytes collected
Oocytes 6.9 (0.35) 6.6 (0.5) 7.2(0.54) NS
inseminated
Fertilisation rate 69.4 (2.2) 73 (2.5) 78 ( 3.6) NS
(%) ( SEM)
Embryo grade 2 (0.6) 1.9 ( 0.09) 2.3 ( 1.4) 0.02
Embryos 4.5 (0.3) 4.0 (0.4) 6.4 (0.7) 0.007
discarded

Utilisation rate 49.1 (2.85) 50.34 (4.27) 31.14 (3.93) 0.01

Clinical 56 (34) 25 (33) 8 (20) NS

pregnancy rate
n(%)
Post Hoc test (LSD), p< 0.05
Metwally et al, 2007

Impact of weight loss and exercise on

ovulation and pregnancy

0
Weight loss (Kg)

-6

- 12
Ovular (%)

100

0
Pregnant

1 2 3 4 5 6 7 8 9

Benefits of diet and exercise in obese

PCOS
Hypocaloric diet (even before weight loss)
reduces insulin resistance
Reduction in saturated fat intake alters lipid
profile
Exercise reduces insulin resistance
Exercise without a hypo caloric diet does
not produce much weight loss

11
 But..

Consequences of ovarian ageing

35 300
miscarriage per
Clinical pregnancies
births
30 250
Live births Down's syndrom
10000 births
25
200
20
150
15
100
10

50
5

0 0
<25 26 28 30 32 34 36 38 40 20 25 30 35 40 42

Age at first birth 1980 - 2002

Czech Republic
30
Denmark
Germany
29
Estonia
28 Greece
Spain
Mean age at first child birth

27 France
Ireland
26 Italy
Lithuania
25 Luxembourg
Hungary
24 Netherlands
Austria
23
Poland
Portugal
22
Slovenia
Slovakia
21
Finland
20 Sweden
United Kingdom
19 0
19 2
64

19 6
19 8
70
72

19 4
19 6
78
80

19 2
19 4
86

19 8
19 0
92
94

19 6
20 8
00
02
6
6

6
6

7
7

8
8

8
9

9
9
19

19

19
19

19
19

19

19
19

20

12
 Do weight loss programmes
work?
Weight loss programmes have poor results (only 15%
maintain normal weight, when reached, for > 6 months)
Audit - Jessop Hospital for Women showed only 6% of
women reached target weight in 4 years despite access to
dietician
Pharmacological interventions are only sporadically
effective (metformin, orlistat)
Bariatric surgery shows promise but carries risk

Age related decline in ovarian reserve and

impact of diet/ exercise on body mass

Ovarian Reserve
Weight

10 15 20 25 30 35 40 45
Female Age

Should we offer ART to obese women?

No

Risks to mother and baby are

too high
78/261 deaths in 2000 - 02
Confidential Enquiry were
obese - 25% had BMI >35
Why not just wait until they
lose weight?

13
 Should we offer ART to obese women?
No Yes
Risks to mother and baby are Careful antenatal and
too high intrapartum care can lead to
78/261 deaths in 2000 - 02 good outcome in most cases
Confidential Enquiry were Obese women should be
obese - 25% of there had BMI informed of their increased
>35 medical risk but should make
Why not just wait until they their own decisions
lose weight? Non-infertile obese women
conceive frequently, and no
Governmental licence is
required
Weight loss programmes have
poor results

Obese-ism?
Denial of access to treatment on grounds of obesity
may transgress Article 12 (The right to marry and
found a family) and Article 14 (prohibition of
discrimination) of the Human Rights Act

Conclusion
Modern medicine frequently offers cure or long
term remission to young women with medical
disorders
These patients wish as normal a life as possible
Many will want to start a family
Management of infertility in the medically
complex patient demands:
Careful pre-treatment optimisation of health
Multidisciplinary team approach
Hospital based IVF
Consideration of risk as well as benefit

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