Transcript Long-term Neurodevelopmental Outcomes in Children Exposed to

Cancer in Pregnancy
[email protected]
416 813 7887
www.motherisk.org
416 813 6780 press 9
Disclosure
Irena Nulman holds the
Canadian Breast Cancer
Foundation (CBCF) Grant
Reproduction Today



Women delay childbearing (older age at conception)
High-risk pregnancies
 CVD, Diabetes, Obesity, Infections (HIV)
 IVF (available modern obstetric care)
 Organ transplant
 Age-dependent malignancies and cancer survivors
Exposure to diagnostic and treatment procedures
during gestation is unavoidable
Cancer in Women



Is the second leading cause of mortality
in women of childbearing age
In Canada 9% of cancers is diagnosed in
ages 20 to 44; 2/3 are women
Breast, cervical, lymphoma, thyroid, and
melanoma the most prevalent
Cancer in Pregnancy




Cancer in pregnancy is not common, but
is not a rare disorder anymore
Cancer in pregnancy increased from
1/1550 in 1990 to 1/1180 in 2004 and is
on the rise
Complicates up to 0.02% of pregnancies
annually
Termination of a cancer pregnancy is not
always an option
Cancer in Pregnancy, con’t




Associated with anxiety and stress
Creates a conflict between optimal maternal
care and fetal safety
Fetal risk of cancer treatment should be
weighed against maternal risk if treatment is
delayed
Women decline treatment because of fear of
teratogenicity even in life - threatening
conditions
Teratology Domains
•
•
Anomalies
Malformations
1st Trimester
1st Trimester
•
Growth
•
•
2nd Trimester
2nd Trimester
Growth
Function
3rd Trimester
Neonatal
“Adaptation?”
• Function (BT)
• Mutagenicity
• Fertility
•
Postnatal
3rd Trimester
Death
1st Trimester
2nd Trimester 3rd Trimester
CNS Development
Postnatal
Malformations

Major
Structural and/or functional deficits for which medical
or surgical intervention is necessary or a defect that
can impair the child’s future lifestyle
The baseline risk for general population is
1 – 3%, 5%, 7%

Minor
Morphologic traits of no serious medical or cosmetic
consequence, but might signify a major malformation
complex
Factors Modifying Teratogenic
Risks



Dose, rate, duration of administration,
interaction with other environmental factors
may modify action of a teratogen
Genetic characteristics of maternal/fetal
enzymatic bouquet (individual drug handling)
Time of exposure during gestation
Critical Windows of Vulnerability


All or none period (preimplantation 8-14 days)
Gastrulation period is the most central to all of
teratology - 3weeks PC



Cell proliferation and migration
Medial and lateral growth is developing
Axes of neural tubes are associated with genetic
expression, interruption of proliferation in this
period can cause detrimental long-term outcomes

Organogenesis (up to 12 weeks)

Synapse formation and Myelination continue
throughout childhood and adolescence
Behavioral Teratology


Behavioral Teratology is a science of
neurocognitive effects or impairments of prenatal
origin
The long-term continuous development of the CNS
have consequences for vulnerability to adverse
conditions
Even small interference with the process of CNS development
may have a profound impact across the life span of an
individual
“It is not birth, marriage or
death, but gastrulation which is
truly the most important time in
your life”
Lewis Wolpet, 1938
Cancer Management



Risk/benefit model should be used to
individualize and optimize maternal
treatment
Most cytotoxic drugs cross the placenta and
reach the fetus
Decision-making is complicated by medical,
ethical, religious and psychological
considerations
Cancer Management, con’t




Provision of clear information on all potential
effects on mother and fetus
Avoidance of assumptions about women's
pregnancy intentions
Discuss breastfeeding
Address sexual activity and future
reproductive health.
Cancer Management, con’t




Dispel misconception about cancer therapy in pregnancy
Reach optimal as in non-pregnant women anti-cancer
regimen protecting the fetus
Involve multidisciplinary team: oncologist, hematologist,
obstetrician/gynecologist, toxicologist, perinatologist,
psychologist, psychiatrist, social workers, and spiritual
advisors
Provide support in complex treatment decisions, often in
absence of definitive evidence
Challenges






Limited knowledge due to :
High rates of pregnancy termination
Decision not to treat during critical periods of
fetal development
Multiple protocols
Multiple-drug regiments limits the ability to
estimate the individual drug safety
Pregnancy physiological changes and long-term
outcomes
Challenges con’t




Outcomes confounded by concomitant therapies
and co-morbidities
Associated with stress - a known teratogen
Misperception of reproductive risk/safety of
antineoplastic agents (patients and care
providers)
Evidence-based information should be used in
decision making
Challenges con’t





No RCTs
Case reports
Small retrospective studies using different
methodologies (under-powered, association vs.
causality)
Registries: limited by a lack of a denominator,
control group, unknown treatment compliance, and
possible selection and recall biases
Consensus guidelines
Outcomes





Death, Malformations
Prematurity, Impaired growth - IUGR
Fetal/neonatal myelosuppression
Metastases to placenta and fetus
Long-term outcomes



Cognitive and behavioral
Childhood cancers
Fertility
Diagnostic Radiation
Deterministic Effects
 Conservative safe threshold: 5 cGy
 Likely safe clinical threshold: 10-20 cGy
 Fetal dose depends on:
 Cumulative dose, size of radiation field
 Distance from field to fetus
 If fetus 30cm away from field
edge, dose may only be 4-20 cGy
 Equipment type
Non-ionizing Radiation: MRI




FDA: Fetal safety not established
Most research has not found adverse effects
Acoustic damage (Baker et al 1994)
Contrast media
 Preference should be given to Gadobenate
dimeglumine or Gadoterate meglumine

Gadolinium – nephrogenic systemic sclerosis
Diagnostic Procedures & Fetal Risk
Estimated fetal ionizing radiation dose from common diagnostic procedures
Test
Computerized Tomography (CT) Scan
Abdo men (10 slices)
Abdo men and pelvis
Pelvis
Lumber spine
Chest
Head
Radiogr aphy
Abdo men (kidneys , ureter, bladder)
Pelvis
Urog raphy (intravenous pyelography)
Upp er gastrointestinal series (bariu m)
Hip and femur series
Cholecystography
Mammography
Lumbar spine
Chest (2 views)
Retropyelography
Lower extremity
Upp er extremity
Bariu m enema (fluoroscopic exam)
Position Emission Tomography (PE T) Scan
Bone s can
Whole -body PET scan
Thyroid s can
Other
Ventilation -perfusion s can
Estimate d fetal dose (rad*)
0.240-2.600
0.640-4.000
0.730-4.600
3.500
0.100-0.450
<0.050
0.100-0.300
0.040-0.238
0.358-1.398
0.048-0.360
0.051-0.370
0.005-0.060
0.007-0.020
0.346-0.620
<0.010
0.800
<0.001
<0.001
0.700-3.986
0.400-0.500
1.00-1.500
0.010-0.020
0.060-1.000
Risk of Childhood Cancer

Diagnostic Radiation

Oxford Survey of Childhood Cancer, nationwide case-control study (Doll,
Br J Radiol 1997)


OR: 1.39 (95% CI 1.30 -1.49)
Population-based study of 1.8 million of mother-child pairs exposed to
CT or radionuclide imaging in Ontario between 1991 – 2008 (Ray, PLoS
Med 2010)





The rate of testing increased from 1.1 to 6.3 per 1000 pregnancies
Median duration of follow-up of 8.9 years
1.13 per 10.000 in exposed group vs 1.56 per 10.000 in unexposed
A crude hazard ratio of 0.69 (95%CI 0.26-1.82)
The absolute annual risk remains about 1 in 10.000, considering the
upper confidence limit of 1.8 times that of unexposed, the authors did
not exclude that exposure to CT or radionuclide imaging is carcinogenic
Childhood Cancer cont’

A case-control study (Rajaraman, BMJ 2011)
2690 cases and 4858 matched controls, 305 children exposed to 319
procedures

A slight, non- stat. sig. increase risk (OR 1.14 (95% CI 0.90 -1.45)
for all cancers

For leukemia OR 1.36 (95% CI 0.91 -2.02)
 Exposure to diagnostic x-rays in early infancy was associated with
small, non- significant excess risk for all cancers and leukemia, but
increased risk of lymphoma OR 5.14 (95% CI 1.27-20.78)
 Conclusion: indicate a possible risk of cancer from radiation
 Results for lymphoma need to be replicated
 Caution use of diagnostic radiation during pregnancy and in children in very
young age
 No evidence of increased risk with in utero exposure to ultrasound

Surgery


0.5-2% of pregnant women in North America undergo
non-obstetric surgery
Mazze and Kallen (1989)- 5404 women
• No overall increased risk of malformations
• Increased risk of neural tube defect in subgroup who
had surgery at gestational age 4-5 weeks (n=572)
•

These effect were not found in subsequent studies
Cohen-Kerem et al. (2005) review of 12,452 pregnancy
 No increase in malformation rates
 Risk of miscarriages was comparable to baseline
Radiotherapy



Common misbelieve that any dose of radiation is
teratogenic
Not completely contraindicated
 First and second trimester radiotherapy can be
considered
 Fetal dose during first and second trimester not
as high as during the third trimester
Shielding reduces fetal dose up to 50-75%
Chemotherapy Outcomes

1st trimester exposure
Malformations – 10 to 20%; 6% when folate antagonists
were excluded


2 and 3 trimester exposure (n=376)





Fetal death – 5%
Neonatal growth – 1%
Premature delivery – 5%
IUGR – 7%
Myelosuppression – 4%
(Cardonic, Lancet Oncol 2004)

High rates of prematurity, regardless time of exposure
Chemotherapy Outcomes con’t

American registry, 2nd and 3 trimester exposure
(n=152)





1 fetal death
1 neonatal death
Malformations rates - 3.8%
IUGR - 7.6%
Transient myelosuppression – 2 neonates
(Cardonick , Am J Clin Oncol 2010)
Chemotherapy Outcomes con’t


2nd and 3rd trimester exposure
Chemotherapy exposed 117 vs 58 controls
 17.9% of low birth weight in
chemotherapy group vs 8.6% in controls
 Most infants were of mothers treated for
hematological cancer
Van Calsteren, J Clin Oncol 2010
Breast Cancer




The choice to accept chemotherapy rather than
delay it until after pregnancy may significantly
impact the woman’s survival
Delaying treatment by 3-6 months can increase the
risk for metastases
Pregnant BC patients who receive comparable
chemotherapy to non-pregnant BC patients have
same survival when controlling for stage at diagnosis
Termination of pregnancy does not improve survival
of BC women
BC in Pregnancy: Recommendations of
an international consensus meeting
Eur J Cancer, 2010

Efficient treatment of BCP is possible
BCP treatment should adhere to standardized protocols of nonpregnant patients and should be discussed by a multidisciplinary
team
Surgery can be performed in all 3 trimesters
Radiation – 1st and 2nd trims, considering fetal dose

Deliveries should not be induced before 37 weeks




Patient should be included in a registry in order to promote
research for further knowledge (International study on cancer in
pregnancy: http://www.cancerinpregnancy.org)

Termination of pregnancy does not improve maternal prognosis
Metastases





87 patients with placental or fetal metastases were
reported, melanoma - most common (31%)
In placental melanomas patients, 22% of the fetuses
were affected as well
Poor outcome in mothers, fatal in infants was reported
Placentas of women with malignancies known to affect
placenta should be carefully examined grossly and by a
pathologist
Neonates delivered with placental metastases should be
considered high-risk population and monitored
Alexander et al, J Clin Oncol 2003
Long-term Neurodevelopmental
Outcomes


Neurocognitive outcomes of 111 children
No adverse effects, but formal tests often lacking
Nulman et al. (2001)




Neurocognitive outcomes of 84 children, treatment for
maternal hematological cancer
Formal tests employed
Did not differ from controls on school performance or
standardized IQ test
Neurodevelopment of 12 second generation children
reported
Aviles and Neri (2001)
Long-term cognitive and cardiac outcomes after
prenatal exposure to chemotherapy in children aged
18 months or older: an observational study




Multicentre observational cohort of 236 cycles of
chemotherapy (adjusted for maternal weight gain) in 70
children
Anthracyclines were the most common agents (53 patients)
Children were assessed at birth, age 18 months, and ages
5-6, 8-9, 11-12, 14-15, or 18 years
Bayley or IQ tests, electro/echo cardiography, and
audiometry were performed, and general health was
documented
Frédéric Amant, Lancet, 2012
Frédéric Amant, Results







40 children achieved 96.8 on Bayley MDI scores
IQ scores for 13 children born at term were 103.1
27 preterm children scored 94.6
Fetal exposure to chemotherapy was not associated with
increased CNS, cardiac, auditory, or other pediatric morbidity
morbidity
Prematurity was common and was associated with impaired
cognitive development
IQ increased by 11.6 points (95% CI 6·0–17·1) for each
additional month of gestation (p<0·0001)
Iatrogenic preterm delivery should be avoided when possible
Pregnancy outcome and child
neurodevelopment following in
utero exposure to maternal
cancer.
Division of Clinical Pharmacology and Toxicology, The Hospital for Sick
Children, University of Toronto
The Cohort
The cohort was recruited from the prospectively
collected Motherisk database and other Cancer
Centers in Ontario.
GROUP 1: Mother-child pairs exposed to
chemotherapy and/or radiation during pregnancy
GROUP 2: Mother-child pairs exposed to
maternal cancer and surgery alone, who served as
controls.
Objective

To define cognitive developmental and
pediatric outcomes of children exposed in
utero to maternal malignancy and its
treatment
Results
24 mother – child pairs (aged 3 to 12) were
assessed.
 15 - exposed to chemotherapy and/or
radiation and
 9 were exposed to surgery only.

Children’s Characteristics
(mean + SD)
GROUP 1 (n=15)
GROUP 2
(n=9)
P
Gestational Age (weeks)
37.20±2.51
35.16±4.39
NS
Birth weight (grams)
3115±486
2600±884
NS
Neonatal Complications (yes)
26.66%
Age at Testing (months)
Height (percentile)
Weight (percentile)
Head Circumference
(percentile)
33.30%
100.46±32.8
77.29±34.94
2
69.84±27.32 63.90±19.77
NS
69.33±24.41 70.17±22.71
NS
59.83±31.34 61.50±34.5
NS
NS
NS
Children’s Cognitive Outcome
(mean + SD)
GROUP 1 (n=15)
GROUP 2 (n=9)
P
FSIQ
105 ± 14.77
104 ± 11.73
NS
VIQ
106 ± 11.73
104 ± 11.2
NS
PIQ
98 ± 15.22
101 ± 15.45
NS
Results

Three children were exposed to
radiation during the first trimester, one
of which was also exposed to
chemotherapy throughout pregnancy.
Their Full-Scale IQ were: 112,124, 87
(maternal IQ=62).
Summary




Child’s physical and neurological development was within
population norms for both groups.
Shorter gestations and low birth weights among controls
were due to planned deliveries in order to start
treatment.
In the assessed cohort, children between groups were no
different in the main outcome (IQ), which were also no
different than population norms.
This finding is reassuring for the patients who need
treatment for maternal malignancy during pregnancy.
Concluding Remarks




Cancer in pregnancy can be successfully treated in
collaboration with multidisciplinary team
State - of the art treatment management should be
provided
Individualization of treatment and effective
psychological support is imperative
Risks of most diagnostic procedures and surgery is
small
Concluding Remarks

Serious concerns should be given to iatrogenic
prematurity


Associated with increased child mortality, morbidity and
neurocognitive impairments
1st trimester pharmaco/chemotherapies are
associated with normal outcomes in up to 80% of
pregnancies

Individual differences in drug handling (including
pharmacogenetics)
Concluding Remarks

If MM rates following chemotherapy in 2 and 3
trimester are above the baseline


Radiotherapy not completely contraindicated
May be considered in 1 and 2 trimester and if the tumor is
far from the fetus
 Appropriate fetal protection should be employed
Breast feeding should be considered based on individual drug
safety/kinetics and neonatologist –breastfeeding experts
consult http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?LACT


Understand the confounding of stress, maternal disorder,
and other factors
Concluding Remarks

Chemotherapy should be avoided after 35 weeks, or 3
weeks before planned delivery




Fetus has a limited capacity to metabolize and eliminate
drugs due to liver and kidney immaturity
To allow drug excretion by the placenta
To allow bone marrow recovery
Long term neurodevelopment is a strong predictor of
child quality of life - more research should focus on
this outcome
Pregnancy-Induced Physiological
and PK Changes





Changes in gastric motility may delay absorption
50% expansion in plasma volume – lower drug
concentration
Hypoalbuminemia - results in decrease in protein binding
Changes in hepatic function (enhanced metabolism)
Increased glomerular filtration rate and renal plasma flow
(increased clearance)
Decrease in blood drug concentration
Higher drug doses may be needed
Future Aims Research




Acquire knowledge on the need of chemotherapy
dose adjustment, considering pregnancy
physiological changes
Individual drug risk/safety - pharmacogenetics
Long term maternal outcomes following treatment
in pregnancy (reproductive health)
Long-term pediatric outcomes: pediatric
health/cancers, fertility, neurocognitive
development
Future Aims Research




Develop standardized effective guidelines on
management of cancer in women of childbearing
age
Effective pregnancy prevention while on
chemotherapy
Develop standardized effective guidelines on
management of cancer in pregnancy in order to
reach optimal maternal treatment and protect the
fetus
Run multicentre research and registries





Further knowledge reached in collaboration
(national and international) will assist
physicians and families in making informed
decisions
Safe mothers lives while protecting the fetus
[email protected] 416 813 7887
www.motherisk.org 416 813 6780 press 9
[email protected]
Stress


Low birth weight and prematurity
Severe life events during 1st trimester have been
associated with increased rates of malformations in
26.6%.
OR for cranial-neural-crest defects = 8.36
(Hansen et al., Lancet 2000)
Stress and anxiety in early and mid–pregnancy
(n=52)
Associated with lower mental and motor scores in
8 months old children
(Huizink et al., Journal of Child Psychology and Psychiatry,
2003)
