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DisclosureIrena 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
• Anomalies• Malformations
• Growth • Growth • Function
• Neonatal “Adaptation?”• Function (BT)• Mutagenicity• Fertility
1st Trimester 2nd Trimester
3rd Trimester
Postnatal
Teratology Domains
CNS Development
1st Trimester 2nd Trimester 3rd Trimester Postnatal
Death
1st Trimester 2nd Trimester 3rd Trimester
MajorStructural 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
Malformations
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 Test Estimated fetal dose (rad*)
Computerized Tomography (CT) Scan Abdomen (10 slices) 0.240-2.600 Abdomen and pelvis 0.640-4.000 Pelvis 0.730-4.600 Lumber spine 3.500 Chest 0.100-0.450 Head <0.050 Radiography Abdomen (kidneys, ureter, bladder) 0.100-0.300 Pelvis 0.040-0.238 Urography (intravenous pyelography) 0.358-1.398 Upper gastrointestinal series (barium) 0.048-0.360 Hip and femur series 0.051-0.370 Cholecystography 0.005-0.060 Mammography 0.007-0.020 Lumbar spine 0.346-0.620 Chest (2 views) <0.010 Retropyelography 0.800 Lower extremity <0.001 Upper extremity <0.001 Barium enema (fluoroscopic exam) 0.700-3.986 Position Emission Tomography (PET) Scan Bone scan 0.400-0.500 Whole-body PET scan 1.00-1.500 Thyroid scan 0.010-0.020 Other Ventilation -perfusion scan 0.060-1.000
Estimated fetal ionizing radiation dose from common diagnostic procedures
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, butincreased 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 non-pregnant 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 pregnancyGROUP 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 NSBirth weight (grams) 3115±486 2600±884 NS
Neonatal Complications (yes)
26.66% 33.30% NS
Age at Testing (months) 77.29±34.94100.46±32.
82NS
Height (percentile) 69.84±27.3263.90±19.7
7NS
Weight (percentile) 69.33±24.4170.17±22.7
1NS
Head Circumference (percentile)
59.83±31.34 61.50±34.5 NS
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
Children’s Cognitive Outcome (mean + SD)
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 Understand the confounding of stress, maternal
disorder, and other factors 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
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)
