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Fetal outcome after prenatal exposure to chemotherapy and mechanisms of
teratogenicity compared to alcohol and smoking
Article in Expert Opinion on Drug Safety · November 2014
DOI: 10.1517/14740338.2014.965677 · Source: PubMed
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Review
1.
Introduction
2.
Chemotherapy in pregnancy
3.
Other well-known fetotoxic
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exposures
4.
Discussion
5.
Expert opinion
Fetal outcome after prenatal
exposure to chemotherapy and
mechanisms of teratogenicity
compared to alcohol and smoking
Tineke Vandenbroucke, Magali Verheecke, Kristel Van Calsteren, Sileny Han,
Laurence Claes & Frederic Amant†
†
KU Leuven -- University of Leuven, Department of Oncology, Leuven, Belgium
Introduction: The treatment of cancer during pregnancy is challenging
because of the involvement of two individuals and the necessity of a multidisciplinary approach. An important concern is the potential impact of chemotherapy on the developing fetus.
Areas covered: The authors review the available literature on neonatal and
long-term outcome of children prenatally exposed to chemotherapy. Chemotherapy administered during first trimester of pregnancy results in increased
congenital malformations (7.5 -- 17% compared to 4.1 -- 6.9% background
risk), whereas normal rates are found during second or third trimester.
Intrauterine growth restriction is seen in 7 -- 21% (compared to 10%), but
children develop normal weight and height on the long term. Children are
born preterm in 67.1%, compared to 4% in general population. Normal intelligence, attention, memory and behavior are reported, although intelligence
tends to decrease with prematurity. Global heart function remains normal,
although small differences are seen in ejection fraction, fractional shortening
and some diastolic parameters. No secondary cancers or fertility problems are
encountered, but follow up periods are limited.
Expert opinion: Most evidence is based on retrospective studies with small
samples and limited follow up periods, methodology and lack of control
groups. A large prospective case--control study with long-term follow up is
needed in which confounding factors are well considered.
Keywords: cardiac functioning, chemotherapy, fetal outcome, neuropsychological development,
pregnancy
Expert Opin. Drug Saf. [Early Online]
1.
Introduction
The prescription of medication to pregnant women requires a thorough balancing
of maternal benefits of the treatment versus the potential risks for the fetus. History
showed that it is very challenging to say that a certain drug is safe to use during
pregnancy. It can take years to prove an association with congenital anomalies, as
was the case for thalidomide [1]. On the other hand, the (absence of an) association
with functional disorders, such as neurocognitive impairments and behavioral or
cardiac disorders, is even more difficult to examine since it requires years of study
in a large group of patients with many confounding factors (environmental factors,
education, socioeconomic status, maternal illness/death, etc.).
One of the situations in which the maternal benefit of treatment can outweigh
the potential fetal risks is when a life-threatening disease (e.g., cancer) is diagnosed
during pregnancy. Cancer is diagnosed in approximately 1 out of 1000 to 2000
pregnancies. The incidence of cancer during pregnancy has increased in the past
10.1517/14740338.2014.965677 © 2014 Informa UK, Ltd. ISSN 1474-0338, e-ISSN 1744-764X
All rights reserved: reproduction in whole or in part not permitted
1
T. Vandenbroucke et al.
Article highlights.
.
.
.
.
.
Chemotherapy during the first (but not second or third)
trimester of pregnancy results in an increase in
congenital malformations.
Prematurity has an important impact on
neuropsychological outcome and should be avoided
if possible.
First results on global intelligence, attention, memory
and heart function after prenatal exposure to
chemotherapy are within normal ranges.
A case--control study with large sample size and longer
follow up period is needed to strengthen these findings.
A multidisciplinary approach is required.
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This box summarizes key points contained in the article.
decades, due to delay of childbearing until later age. Malignancies most frequently encountered during pregnancy are
breast cancer, cervical cancer and hematological malignancies,
tumor types for which chemotherapy is one of the key
stones in treatment. Until recently, physicians often opted
to terminate pregnancy or to delay maternal treatment till
postpartum, due to the lack of studies on fetal outcome after
chemotherapy exposure.
Chemotherapy is by definition cytotoxic and so interferes
with cell growth. If it passes the placenta in relevant concentrations, fetal cell growth is inhibited. The nature of the
consequences for the fetus will depend on the timing of
exposure in pregnancy, the type of chemotherapy administered and the dose. During the third and fourth week of
gestation, when conception and cell division take place, cell
damage will result in an all-or-nothing phenomenon: a
miscarriage or a normal developing fetus. Interference with
cell growth during organogenesis (week 5 till 10 of gestation)
results in structural anomalies. Each organ has its own critical period [2]. The heart is the first organ to develop in the
fourth week of gestation. First, the heart tube is formed
from the mesoderm and starts to beat automatically around
five completed weeks of gestation. Afterward, the form of
the heart starts to take shape, which is called the heart looping stage. Finally, the heart starts to develop into four different chambers, which are completed around the 10th week of
gestation. Next to the development of the heart, the CNS
starts to develop in the fifth week of pregnancy. The CNS
has its origin in the neural plate by thickening of the
ectoderm [3]. Thereafter, when the neural groove is formed
and closed, it becomes the neural tube. One can consider
that the administration of chemotherapy during this critical
period may cause serious damage for the fetus. During the
fetal period of development (week 11 till delivery), which
is characterized by organ growth and maturation, cell death
will mainly result in functional damage, but for some organs
the risk of structural anomalies remains. For instance, the
development of the CNS proceeds throughout pregnancy
and continues even after birth [3], which places the fetus
2
exposed to teratogens during the second or third trimester
at risk of neuropsychological impairments.
There are a lot of different chemotherapeutic agents, all
with their own potential impact on fetal development based
on their working mechanism and adverse effects reported in
adults and children diagnosed with cancer. Methotrexate has
been associated with severe malformations, and therefore cannot be administered during pregnancy [4]. Four groups can be
distinguished that are most frequently administered in pregnant cancer patients. First, anthracyclines (e.g., daunorubicin,
doxorubicin, epirubicin, idarubicin) interfere with DNA
replication by inhibiting topoisomerases, which are enzymes
that regulate the overwinding or underwinding of the DNA
so it can be copied. The main side effect of anthracyclines is
cardiotoxicity [5,6]. Second, platinum-based antineoplastics
(e.g., cisplatin, carboplatin) bind to and cause crosslinking
of DNA, which leads to apoptosis. They may cause neurotoxicity when administered in high doses, resulting in peripheral
neuropathies such as polyneuropathy [7,8]. Also, ototoxicity,
especially hearing loss, has been described [8,9]. Third, cyclophosphamide is an alkylating agent commonly used in breast
and hematological malignancies. It directly damages the
DNA to prevent reproduction of cancer cells. Adverse effects,
especially when administered in high doses, may include
permanent infertility [10]. Finally, taxanes (e.g., paclitaxel,
docetaxel) inhibit mitosis by disrupting the microtubule
function, which is essential to cell division. Dose-limiting toxicity of taxanes is predominantly sensory or sensorimotor axonal polyneuropathy [7].
In this paper, we review current knowledge on fetal outcome after prenatal exposure to chemotherapy. Till date, there
are no studies comparing the differential impact of different
types of chemotherapeutic agents on fetal outcome, because
the number of children antenatally exposed to chemotherapy
is small and different types of chemotherapy are usually combined. To situate the risks of chemotherapy exposure during
fetal development and the underlying mechanisms of structural and functional damage, we will compare available data
on chemotherapy with other well-known fetotoxic agents
like alcohol and tobacco and highlight the impact of maternal
stress during pregnancy on fetal outcome.
2.
Chemotherapy in pregnancy
Prenatal and postnatal growth
The effect of in utero exposure to chemotherapeutic agents on
fetal growth has been investigated in several studies. Some
studies found normal birth weight and height according to
gestational age [11,12]. For instance, Loibl et al. [13] found 9%
of 175 children prenatally exposed to chemotherapy to have
a birth weight below the 10th percentile and this was not significantly different from those without prenatal exposure (4%
of 139 children). However, birth weight was related to chemotherapy exposure but not to the number of chemotherapy
cycles, when analyzed according to gestational age. Others
2.1
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Fetal outcome after prenatal exposure to chemotherapy and mechanisms of teratogenicity
reported an increased number of children born small for
gestational age. Amant et al. [14] found that 21% of 70 children
were born with a birth weight below the 10th percentile of
gender- and gestational age-matched controls. This frequency
of so-called intrauterine growth restriction (IUGR) is considerably higher than seen in the general population (10%).
Also, Cardonick and Iacobucci [15] reported presence of
IUGR ranging from 7 to 17% in a lot of studies, depending
on malignancies and chemotherapeutic agents. IUGR places
an infant at a significant risk of perinatal morbidity and
mortality and is known to have various potential causes [16].
Fetal causes are predominantly genetic factors, congenital
anomalies and infections. Placental causes include various
parenchymal and vascular lesions of structural, infectious or
inflammatory nature, causing a mismatch between nutritional
or respiratory demands and supply [17]. Maternal factors
include systemic medical conditions with impact on the uteroplacental blood flow, and other factors such as low caloric
intake, anemia, vitamin deficiency, substance use (alcohol,
smoking) and exposure to toxic agents, all of which can
directly affect the fetus (e.g., low intake, nausea/vomiting as
side effects of treatment, multidrug therapy, high maternal
stress, inflammatory reaction on the cytotoxic treatment) [16].
The influence of in utero exposure to chemotherapy on fetal
growth has not yet been examined. One can envisage that several of the abovementioned factors are present in pregnancies
complicated by cancer and/or cancer treatment.
2.2
Neonatal outcome
Congenital malformations
2.2.1
When chemotherapy is administered during the first trimester
of pregnancy, there is an increased risk of congenital malformations in the child, ranging from 7.5% [18], over 9.2% [19],
to 17% [20] as compared to a normal ratio of 4.1% [21] to
6.9% [22] for major congenital malformations, due to the
critical period of organogenesis (Table 1). After the first trimester, there is no increased incidence (3% major malformations, 7.5% minor) [23] or there are no specific types of
congenital malformations [11,14].
Prematurity
Amant et al. [14] described an increased incidence of prematurity (67.1%) in a case series as compared to an overall incidence of spontaneous preterm labor of 4% in the general
population (Table 1) [24]. In the past, delivery was often
induced to start cytotoxic treatment postpartum, resulting in
higher incidence of prematurity.
2.2.2
Hematologic toxicity
Neonatal hematopoietic suppression has been described when
delivery occurred in the first 2 weeks after chemotherapy
administration [15,23]. An interval of 3 weeks between the
last cycle of chemotherapy and delivery should be taken into
account to avoid a delivery at the nadir, with increased risk
of maternal and fetal hemorrhage and infections. Moreover,
2.2.3
it enables fetal drug clearance via the placenta since, especially
in preterm newborns, the hepatic and renal clearance is still
immature [15].
Neuropsychological development
As the CNS continues to develop after the first trimester,
neurocognitive changes in the child may also show up when
chemotherapy is administered in the second or third trimester
of pregnancy. There is a lack of case--control studies dedicated
to the neuropsychological outcome of children after antenatal
exposure to chemotherapy. However, three important studies
have been published on the long-term neuropsychological
outcome, although they were descriptive and did not compare
the results with a control group. The first study published
by Aviles and Neri [11] reported on 84 children born from
mothers treated with chemotherapy during pregnancy for
hematological malignancies (Table 2). Median age of follow
up of the children was 18.7 years (range: 6 -- 29 years).
Although the methodology was suboptimally described, neurological and psychological examinations were normal. Intelligence was not tested. Learning and academic performances
were also considered normal, according to information
retrieved from schools.
Hahn et al. [25] reported on 40 children (range: 2-157
months of age) in utero exposed to fluorouracil-adriamycincyclophosphamide chemotherapy for maternal breast cancer
(Table 2). Data on follow up of the children were obtained
by a parent or guardian survey. One child had Down’s syndrome, but all other children developed normal as compared
to peers. Two children had special educational needs, of
whom one was the child with Down’s syndrome and the other
one was diagnosed with attention deficit disorder.
A recent study reported on the long-term follow up of 70
children in utero exposed to chemotherapy for diverse
maternal malignancies (Table 2) [14]. Children from Belgium,
The Netherlands and Czech Republic were followed up at a
median age of 22.3 months (range: 16.8 months -- 17.6 years).
A standardized age-appropriate assessment was used to examine neurocognitive functioning, that is, intelligence, attention,
memory and executive functions. Results were compared to
normative data for the specific age-groups provided by the
validated tests. Both children of a twin pregnancy revealed
an important developmental impairment. However, all other
children were thought to have normal development. In most
children, scores on tests for cognitive development (as assessed
by Bayley Scales of Infant Development, Wechsler intelligence test or Snijders-Oomen nonverbal intelligence test)
were normal. Lower scores were usually found in children
born preterm. The average intelligence quotient (IQ) was
found to increase 11.6 points for each month increase in
pregnancy duration. Memory and attention did not show
abnormalities compared to norms. The average scores for
internalizing and externalizing behavior and total problems
were within normal ranges provided by the specific test.
2.3
Expert Opin. Drug Saf. (2014) 13(11)
3
4
N = 10
(dose-dense
chemotherapy)
N = 99
(conventional
chemotherapy)
Study:
N = 61
Controls:
N = 60 matched
for GA
N = 16
Cardonick
Abdel-Hady
Expert Opin. Drug Saf. (2014) 13(11)
2nd
3rd
2nd
3rd
(taxane-based
chemotherapy)
Breast or
ovarian
cancer
Not specified
1st
2nd
3rd
Trimester of
chemotherapy
exposure
Diverse
Diverse
Diverse
Malignancy
GA: Gestational age; IUGR: Intrauterine growth restriction; Med: Median; N: Sample size.
[93]
Cardonick
[12]
[92]
[23]
N = 185
(cancer in
pregnancy) of
which N = 62
(exposed to
chemotherapy)
Sample
Van
Calsteren
First author
Table 1. Neonatal outcome following prenatal exposure to chemotherapy.
Med = 46 months
(interquartile
range = 18.3 -- 96)
Duration of
follow up
Main results
Med GA: 36.9 weeks. Three children were born small for GA
(< 10%)
Neonatal complications: apnea of prematurity, gastroesophageal
reflux disease, neutropenia in one infant, hyperbilirubinemia and
respiratory distress syndrome due to prematurity. Hypertrophic
stenosis was diagnosed in one child. One child of a twin
pregnancy had Asperger’s syndrome and speech delay, dyslexia
and Tourette’s syndrome, whereas the other child developed
normal. Incidence of IUGR was 18.75%, comparable to other
chemotherapy regimens
Mean GA (n = 185): 36.3 weeks ± 2.9 weeks
54.2% (of n = 185) were born preterm with an increase of
12.9% (of n = 62) of children prenatally exposed to
chemotherapy
24.2% (of n = 62) were born small for GA
Admission to a neonatal intensive care unit in 51.2% (of
n = 185) (mainly because of prematurity)
Incidence of congenital malformations was not increased: 2.9%
major and 4.6% minor congenital malformations
Mean GA: 35.7 (dose-dense) and 36.6 weeks (conventional)
Birth weight, GA at delivery, rate of growth restriction,
congenital anomalies and incidence of maternal and neonatal
neutropenia did not differ significantly
No increased incidence of birth defects
Dose-dense group: one transient neutropenia and born with
congenital pyloric stenosis
Conventional group: three congenital anomalies
(holoprosencephaly, asymptomatic main pulmonary artery fistula
and hemangioma of an eye) and one neonatal death, but
resulting from a severe autoimmune disorder and thought to be
unrelated to prenatal exposure to chemotherapy
Delivery was planned at 34 -- 35 weeks
No significant difference between study and control children in
incidence of neonatal survival, preterm birth, small for GA and
no congenital malformations were identified
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T. Vandenbroucke et al.
Fetal outcome after prenatal exposure to chemotherapy and mechanisms of teratogenicity
Table 2. Long-term health and neuropsychological development following prenatal exposure to chemotherapy.
First author
Sample
Malignancy
N = 84
N = 12
secondgeneration
children
Hematological
malignancies
Hahn [25]
N = 40
Breast cancer
1st
2nd
3rd
Range 2 -157 months
General health and
development (by survey
of the parents or
guardians)
Amant [14]
N = 70
Diverse
2nd
3rd
Med =
22.3 months
(range:
16.8 -- 211)
Behavior by parent report
and tests for mental
development, intelligence,
attention and memory
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Aviles [11]
Trimester of
chemotherapy
exposure
Duration of
follow up
Measures
Main results
2nd
3rd
Med = 18.7
years (range:
Neurological,
psychological, educational
outcome and health
No congenital,
psychological or
neurological abnormalities
Normal biometry (weight,
height) at birth
Educational and learning
performances were
normal
No cancer or acute
leukemia was established
during follow up
After exposure in second
or third trimester, no
stillbirths, miscarriages or
perinatal deaths were
registered
Two children had
congenital anomalies
(club foot, congenital
bilateral ureteral reflux)
and one child had
Down’s syndrome. All
others had normal
development
Special educational needs
were required for one
child with attention
deficit disorder and for
the child with Down’s
syndrome
Med GA: 35.7 weeks
(range: 28.3 -- 41.0)
No increased morbidity of
CNS, heart or hearing
function. Normal general
health and growth
Overall neurocognitive
results were within
normal ranges. However,
two children of a twin
showed a severe
cognitive delay
Prematurity was
associated with lower
cognitive developmental
outcome
6 -- 29)
GA: Gestational age; Med: Median; N: Sample size.
2.4
Cardiac functioning
Anthracycline exposure, commonly used in combination with
other agents for breast and hematological cancers, is known to
be associated with acute and chronic cardiotoxicity in adults
and children [5,6]. The risk of this cardiotoxicity is influenced
by the cumulative dose (> 250 mg/m2), gender, age, association with radiotherapy, stem cell transplantation or other
cardiotoxic chemotherapeutic agents (herceptin, cyclophosphamide, amsacrine) [26,27].
Adverse cardiac fetal outcomes have been described after
exposure to anthracyclines despite low transplacental passage.
Idarubicin, a highly liposoluble anthracycline derivate may
cause cardiomyopathy [28,29]. In 2006, Aviles et al. [30]
reported on a normal cardiac outcome in 81 children who
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T. Vandenbroucke et al.
Table 3. Cardiac functioning following prenatal exposure to chemotherapy.
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First author
Sample
Malignancy
Trimester of
chemotherapy
exposure
Diverse
1st
2nd
3rd
(anthracyclines)
2nd
3rd
Aviles [30]
N = 81
Gziri [33]
Study:
Diverse
N = 10 fetuses
Controls:
N = 10
fetuses matched
for gender
and age
Amant [14]
N = 70
Diverse
2nd
3rd
Gziri [34]
Study:
N = 62
Controls:
N = 62
matched for
gender
and age
Diverse
2nd
3rd
Duration of
follow up
M = 17.1 years
(range: 9.3 -- 29.5)
Measures
Echocardiogram
Main results
Echocardiogram showed
normal values
Normal FSs
Biometry,
amniotic fluid
index, fetal 2D
echocardiography
Fetal Doppler flow
parameters were normal
but mild changes were
found in the myocardial
performance index and in
the tricuspid inflow
pattern
No incidence of IUGR
Med = 22.3 months Electro- and
Ejection fraction, FS, and
(range: 16.8 -- 211) echocardiography interventricular septum
thickness showed lower
but clinically normal
values
Med = 1.7 years
TDI and 2D
Significant differences
(range: 1 -- 9.8)
speckle tracking
between study and
echocardiography control groups were
found in LV FS, LV
ejection fraction, LV
posterior wall thickness
and interventricular
septum thickness,
although they were small
Lower FS and mildly
lower LV wall thickness
were found in study
children compared to
controls
TDI velocities and LV
global strains did not
differ significantly
Normal TDI and strain
measurements were
observed
Cardiac functional
parameters and number
of anthracycline cycles or
cumulative dose were not
associated
2D: Two-dimensional; FS: Fractional shortening; IUGR: Intrauterine growth restriction; LV: Left ventricle; M: Mean; Med: Median; N: Sample size; TDI: Tissue
Doppler imaging.
were prenatally exposed to anthracyclines during pregnancy
(Table 3). Besides these limited data, and different monitoring
strategies, suggestions have been presented as how to monitor
cardiotoxicity in children and perform research on preventive
measures [31]. In 2001, a case report was published by
Meyer-Wittkopf et al. [32] in which they described a sequential
assessment of the ventricular dimension and cardiac growth of
fetuses in utero exposed to chemotherapeutic agents to
increase a favorable neonatal outcome. A pilot study to evaluate maternal and fetal cardiac function by two-dimensional
echocardiography showed no significant effect of maternal
6
chemotherapy on both maternal and fetal cardiac function
during the acute phase [33]. In 2012, the results of a European
multicenter initiative collecting long-term prospective data on
cardiovascular outcome of children exposed to chemotherapy
in utero were published, concluding that global heart function
remained normal compared to controls (Table 3) [14,34]. Only
small differences in the ejection fraction (EF), fractional
shortening (FS) and some of the diastolic parameters (isovolumic relaxation time, mitral A-duration) were seen. However
these small differences as well as the knowledge that anthracycline cardiotoxicity may only become apparent after many
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Fetal outcome after prenatal exposure to chemotherapy and mechanisms of teratogenicity
years, underscore the importance of a long-term follow up, as
well as the assessment of global strain analysis and tissue
Doppler imaging (TDI) as early parameters of cardiotoxicity.
Recent investigations of global strain analysis and TDI show
that these parameters may be more sensitive parameters with
reasonable interobserver and intraobserver variability to detect
the early signs of cardiac dysfunction induced by anthracyclines. Moon et al. [35] showed a decreased circumferential
and longitudinal strain, respectively 8.5 and 7.4%, before
and after anthracycline treatment in 55 pediatric cancer
patients compared to controls, nevertheless maintaining a
normal FS. Dietz et al. [36] also demonstrated that radial displacement was significantly depressed in 17 adult survivors
of childhood cancer compared to controls and remained the
most stable measurement over time, whereas the FS and EF
are variable measurements and remained in the normal range.
Implementation of these novel measurements may improve
the detection of anthracycline-induced cardiotoxicity, however more large long-term studies are needed to address this
further as its impact for clinical use.
Auditory functioning
Platinum-based antineoplastics (e.g., cisplatin, carboplatin)
treatment in both child and adult cancer patients has been
associated with ototoxicity, especially hearing loss [8,9]. Amant
et al. [14] are the first to report on auditory functioning in a
long-term follow up study of children prenatally exposed to
chemotherapy (Table 2). Auditory functioning was assessed
in 21 children (median age: 6.5 years, range: 5.0 -- 17.4)
and no abnormalities were found in 18 children (86%;
4/21 mothers received cisplatin during pregnancy). Hearing
loss was reported in three children, but middle ear infection
in one child and neurodevelopmental problems in two children were confounding factors.
2.5
Secondary cancers
Studies that reported on long-term follow up until 17 [14] and
29 years of age [11] in 70 and 84 children, respectively, found
no secondary malignancies in children. However, longer follow up and larger sample sizes are needed to strengthen these
findings.
2.6
Fertility
There is a lack of evidence about the impact of chemotherapy
exposure during pregnancy on fertility of the child, because
most studies did not follow up until childbearing age. Only
Aviles and Neri [11] included 12 second-generation children
in their study, indicating normal fertility function for those
patients.
2.7
3.
Other well-known fetotoxic exposures
To describe the potential underlying mechanisms of fetotoxicity, we will summarize the knowledge obtained from other
well-known fetotoxic substances, such as tobacco and alcohol,
and review in short evidence on the impact of maternal stress
during pregnancy on fetal development.
Substance abuse
Only very few human studies have been able to address the
critical time periods of exposure to substance abuse, due to
the fact that women either quit these habits during pregnancy
or continue throughout pregnancy, which makes it hard to
distinguish between time periods of abuse [37]. Moreover,
mediating factors may be involved in the relationship between
substance abuse and fetal outcome, specifically environmental
factors (e.g., passive smoking, psychiatric disorders in the
parents, nutrition, socioeconomic status, etc.) [38-40], genetic
factors (e.g., similar personality traits in parents and children) [41] or the combined use of different substances. Therefore, the results of studies measuring outcome of children
in utero exposed to substance abuse have to be interpreted
with caution.
3.1
Smoking
Maternal smoking during pregnancy has been associated with,
among others, IUGR, changes in behavior and neurocognitive
development in the child. The most important mechanism is
the interference with normal placental function by reducing
blood flow to the uterus leading to deprivation of nutrients
and oxygen [37]. Moreover, nicotine, carbon monoxide and
other ingredients in tobacco tar can directly affect the fetal
brain and the developing CNS [37]. Prenatal exposure to
nicotine may also result in hypoactive cholinergic neurotransmission, which may account for learning and memory deficits
[37]. Finally, fetal exposure to nicotine may be responsible for
dysregulation of the hypothalamic-pituitary-adrenal (HPA)
axis, which is linked to psychopathology [37].
In the neonate, hypertonicity, heightened excitability, tremors, startles and signs of stress and abstinence were reported
[42,43], even after controlling for prematurity and other birth
outcome-related factors [43]. In childhood and adolescence,
attention deficit hyperactivity disorder (ADHD) [44-47] and
externalizing (e.g., oppositional and aggressive) behavior [48-50]
were found to be increased. Some studies suggest a
dose--response relationship in which externalizing behavior,
criminality and psychiatric inpatient treatment for substance
abuse disorder were more frequent with higher levels of
tobacco exposure during pregnancy [38,51]. However,
Milberger et al. [52] found that ADHD families more commonly smoke than non-ADHD families, which might suggest
a common genetic vulnerability for both ADHD and smoking.
This can explain part of the variation in behavioral outcome of
the child after in utero exposure to tobacco. Neurocognitive
changes such as lower IQ scores in 6- to 17-year-olds [53], deficits in verbal learning memory, problem solving and eye-hand
coordination in 10-year-olds [54], deficits in auditory processing and visual perceptual processing in 6- to 11-year-olds [55]
and problems with sustained attention, response inhibition
and memory in 6-year-olds [56,57] have also been reported. It
3.1.1
Expert Opin. Drug Saf. (2014) 13(11)
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T. Vandenbroucke et al.
is not clear whether these cognitive deficits can be explained by
a syndrome like ADHD.
Alcohol
When alcohol is present in maternal blood, it easily crosses
the placenta and the fetal blood--brain barrier [37]. Several
mechanisms through which alcohol can affect the fetus have
been described. First, the breakdown of ethanol by the liver
results in acetaldehyde, a toxic chemical consisting of small
molecules that can easily cross the placenta and accumulate
in the fetal brain [58]. Second, ethanol itself can lead to an
alteration of growth regulatory factors that inhibit or stimulate cell proliferation in the body [58]. Third, alcohol increases
the generation of free oxygen radicals and reactive oxygen
intermediates, which may lead to damage of proteins and
lipids in the cells and consequently increased apoptosis [58].
Finally, high levels of ethanol were found to inhibit alcohol
dehydrogenase-catalyzed retinol oxidation, which normally
results in retinoic acid, a signaling mechanism for embryonic
development [59].
Alcohol abuse during pregnancy can lead to fetal alcohol
syndrome (FAS) in the child, a condition characterized by
physical and mental retardation, craniofacial anomalies and
minor joint abnormalities [58]. More specifically, FAS is associated with prenatal and postnatal growth restriction, neurodevelopmental abnormalities (e.g., developmental delay,
mental retardation, learning difficulties with math and visual
spatial materials, microcephaly), dysmorphic face characteristics (e.g., small eyes, epicanthic folds, long hypoplastic
philtrum, thin upper lip, midfacial hypoplasia) and associated
congenital anomalies (e.g., hemangiomas, cardiac defects,
minor joint and limb abnormalities, genital abnormalities,
single palmar creases, ptosis, strabismus) [60]. Moreover,
cardiac malformations are common in children with FAS,
specifically ventricular septal defects, pulmonary artery hypoplasia and interruption of aortic arch type A [58].
Heavy drinking, defined as 5 or 6 alcohol units per
occasion and a minimum average intake of 1 -- 3 drinks a
day, results in FAS rates between 2 and 4% [61]. Hence,
only a minority of children of alcohol-abusing women exhibit
FAS. There may be genetic factors that program vulnerability,
as indicated by twin studies [62]. Maternal age is another
contributing factor, because of increased tolerance to alcohol,
deterioration of liver function due to many years of alcohol
abuse and increase in body fat to water ratio with older
age, leading to higher peaks of alcohol in maternal and fetal
blood [61].
However, when symptoms are present in a lesser degree, the
condition is described as fetal alcohol effects. Heavy drinking,
but not mild or moderate exposure, is associated with a
5 -- 7 points decrease in IQ score [63], hyperactive behavior,
attentional problems and abnormalities in executive functioning [64,65]. Attention deficit disorder, hyperkinetic behavior
and autistic disorder have also been reported [58]. As is the
case for smoking, it is not clear whether these cognitive
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3.1.2
8
deficits related to alcohol abuse can be accounted for by
syndromes like ADHD or autism spectrum disorders.
A topic of debate is the existence of a threshold above
which alcohol may have detrimental effects in the fetus.
Some researchers found alcohol effects in young children
starting from 0.5 absolute alcohol ounces [66], whereas others
did not find evidence for a threshold. Reviews on the effects
of low and moderate prenatal alcohol exposure [67] and on
fetal exposure to binge-drinking [68] did not find convincing
evidence of alcohol-induced fetal effects nor did they conclude that it might be safe, due to weaknesses in methodology
of reviewed studies.
Maternal stress
Pregnancy and suffering from cancer are challenging life
events that may cause prenatal maternal stress. In healthy
women, maternal stress and anxiety during pregnancy have
been associated with adverse birth outcomes, developmental
and cognitive impairments and psychopathology in the offspring. There is an increased risk of spontaneous abortion,
preterm labor, malformations, growth restriction and low
birth weight [69,70]. Huizink et al. [71] reported lower mental
and motor developmental scores at 8 months after high levels
of stress during pregnancy. Henrichs et al. [72] found prenatal
stress to be related to low word comprehension and poorer
nonverbal cognitive development at 18 months, as measured
by parent report. Some studies also reported cognitive
dysfunctions. Van den Bergh et al. [73] found increased impulsivity on a computerized attention task and lower scores on
two intelligence subtasks measured in 14- and 15-year-olds,
specifically Vocabulary and Block Design, which are highly
correlated to Full Scale IQ. Mennes et al. [74] reported lower
scores on tasks requiring integration and control of different
task parameters in 17-year-olds, but no impairment in working memory, response inhibition or visual orienting of
attention. Moreover, a link with psychopathology has been
described. Loomans et al. [75] studied antenatal maternal
state-anxiety in a large community-based cohort by parent
and teacher report and noticed more overall problem behavior, emotional symptoms, peer relationship problems, conduct problems and less prosocial behavior. Stronger evidence
for overall problem behavior was found in boys. Antenatal
anxiety was also related to hyperactivity and inattention problems in boys, but not in girls. Van den Bergh et al. [76] found
an association between antenatal exposure to maternal anxiety
and high, flattened cortisol day-time profiles in 14- to
15-year-old offspring, which was related to depressive symptoms for female adolescents only. However, Huizink et al.
[77] conclude in a review on fetal outcome after antenatal stress
exposure that prenatal stress enhances susceptibility to psychopathology, rather than exerting a direct effect on specific
disorders, based on the underlying mechanisms found in
animal models.
The role of maternal stress hormones during pregnancy has
been described as the main mechanism explaining the impact
3.2
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Fetal outcome after prenatal exposure to chemotherapy and mechanisms of teratogenicity
of maternal stress on fetal development. Gitau et al. [78,79]
found a linear relationship between maternal and fetal cortisol
levels in plasma. Two pathways are hypothesized [80]. First,
increased maternal stress hormone levels, especially glucocorticoids, may cross the placenta and thereby increase fetal
stress hormone levels. Second, maternal stress may result in
impaired uterine artery blood flow and therefore cause oxygen
restriction leading to direct stress for the fetus. Increased prenatal fetal cortisol levels may lead to disturbances in HPA axis
regulation [76]. This may contribute to regulation problems at
the cognitive, behavioral and emotional levels of children [80].
Moreover, the developmental processes that take place in different brain areas, such as the prefrontal cortex and the limbic
system, may be altered by antenatal maternal stress hormone
release [80]. Genetic susceptibility and other prenatal and postnatal environmental factors, such as smoking during
pregnancy or postnatal stress, may also play a role in the outcome of the child [80]. More research is needed to determine
the impact of maternal stress and anxiety due to cancer disease
and treatment on fetal development.
4.
carboplatin in the fetal plasma. Till date, there are no studies
on the differential impact of chemotherapeutic agents on
fetal development.
Based on the available research on cancer during pregnancy,
we can provide the following guidelines for the treatment of
patients with cancer during pregnancy. Administration of chemotherapy during the first trimester is contraindicated, due to
the increased risk of congenital malformations in the child.
Preterm delivery should be avoided, if possible, since prematurity has an important impact on cognitive development [83,84].
Delivery should be planned after a 3-week interval from the
last cycle of chemotherapy to avoid a delivery at the nadir
and to enable the fetus to eliminate the drugs via the placenta.
Chemotherapy administration should be avoided after
35 weeks of gestation because of the increased risk of spontaneous delivery. Cancer during pregnancy is a complex problem,
therefore requiring a multidisciplinary approach by gynecologists, oncologists, obstetricians, cardiologists, pharmacologists,
neonatologists, pediatricians and psychologists. Theory- and
evidence-based practice should be provided by centers
specialized in dealing with this specific problem.
Discussion
5.
We have reviewed the available literature on the general
health, neonatal outcome, long-term neuropsychological
development and cardiac functioning after prenatal exposure
to chemotherapy during the second and third trimester of
pregnancy and concluded on reassuring results. This is counterintuitive, given the known toxicity of chemotherapeutic
agents and the available evidence that alcohol and tobacco,
which are still frequently (ab)used substances during pregnancy, may have detrimental effects on fetal development.
The main explanation lies in the transplacental passage of
these teratogens, causing a direct impact on the fetus correlated with the maternal intake/uptake. Nicotine, carbon
monoxide and other ingredients in tobacco tar may cross the
placenta and impact on fetal development, although the
main mechanism of smoking-induced fetal effects lies in
the reduced uterine blood flow and consequently deprived
fetal nutrients and oxygen. While acetaldehyde, the breakdown product of ethanol, consists of small molecules that
cross the placenta easily and accumulate in the fetal brain,
most chemotherapeutic agents reach the fetus only in small
concentrations. Van Calsteren et al. [81] studied the transplacental passage of fluorouracil-epirubicin-cyclophosphamide
and doxorubicin-bleomycin-vinblastine-dacarbazine in a
baboon model and found low fetal exposure to these agents
in blood, tissue and plasma. Fetal exposure to doxorubicin
and epirubicin was < 10% of maternal concentrations. In
another study, Van Calsteren et al. [82] investigated the transplacental passage of paclitaxel, docetaxel, carboplatin and
trastuzumab in a baboon model. Variations of fetal plasma
concentrations between chemotherapeutic agents were found
to range from hardly detectable fetal plasma concentrations
of taxanes to 57% of maternal plasma concentrations of
Expert opinion
Most of the available studies on fetal outcome after antenatal
exposure to chemotherapy are retrospective, based on small
samples and have limited follow up periods. Methodology is
often not well described, measurements of fetal development
are mostly based on questionnaires or do not include validated tests, and all available studies lack a control group.
Till date, numbers of children antenatally exposed to chemotherapy are too small to investigate the differential impact of
chemotherapeutic agents on fetal outcome. A large prospective study is needed to further examine the fetal outcomes
following in utero exposure to chemotherapy and to evaluate
the impact of different chemotherapeutic agents. A case-control study with a control group matched for gestational
age, gender and age would be of improvement to examine
neuropsychological development, since prematurity has an
important impact on cognitive development. As maternal diseases, certain drugs, infections, substance abuse and maternal
stress during pregnancy can affect fetal development, one
should also consider these confounding factors when
examining the relationship between chemotherapy and fetal
outcome. Such a study is currently ongoing [85] within the
International Network for Cancer, Infertility and Pregnancy,
endorsed by the European Society of Gynecological Oncology. Children in utero exposed to chemotherapy are in
prespective follow up until 18 years at predefined ages and
tested by a full neuropsychological assessment, including
intelligence, attention and memory tests, a parent report
questionnaire of behavior, electrocardiography and echocardiography (including TDI, strain and strain rate analysis),
event-related potentials and a pediatric neurological examination to consider biopsychosocial health status and growth.
Expert Opin. Drug Saf. (2014) 13(11)
9
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T. Vandenbroucke et al.
Further, the transplacental passage of chemotherapeutic
agents has been investigated in animal models [81,82], and
ex-vivo placenta perfusion studies for a few chemotherapeutics
have been performed [86,87]. The underlying mechanisms of
transplacental transfer/barrier and the effect of multidrug
treatment still have to be investigated.
The influence of prenatal exposure to chemotherapy on
fetal growth has not yet been examined. Although accumulating evidence indicates that treating cancer during pregnancy
may become a standard of care, and the remaining normal
values of weight, height and head circumference during
long-term follow up of the children in utero exposed to chemotherapy compared to age- and gender-matched controls
[11,14], this lack of knowledge on the underlying mechanisms
in the IUGR cases remains an important concern of fetal
safety. Current research is focusing on regulators for the
placental angiogenesis (e.g., VEGF, placental growth factor,
IGF) and the metabolic adaptations (e.g., leptin, cortisol)
that may be disturbed, and/or increased inflammation, apoptosis and oxidative stress (e.g., interleukin, cortisol-releasing
hormone) that may appear [88-91].
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Flanders (FWO) and is supported by the Belgiam Ministry of
Health (National Kankerplan).M Verheecke is a research fellow for the Research Fund Flanders (FWO). The authors
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Affiliation
Tineke Vandenbroucke1,2 MSc,
Magali Verheecke1,2 MD,
Kristel Van Calsteren3 MD PhD,
Sileny Han1,2 MD, Laurence Claes4 PhD &
Frederic Amant†1,2 MD PhD
†
Author for correspondence
1
KU Leuven -- University of Leuven, Department
of Oncology, Herestraat 49, B-3000 Leuven,
Belgium
Tel: +32 16 34 42 52;
Fax: +32 16 34 42 05;
E-mail: frederic.amant@uzleuven.be
2
University Hospitals Leuven, Department of
Obstetrics and Gynecology, Gynecological
Oncology, Herestraat 49, B-3000 Leuven,
Belgium
3
KU Leuven -- University of Leuven, University
Hospitals Leuven, Department of Obstetrics and
Gynecology, B-3000 Leuven, Belgium
4
KU Leuven -- University of Leuven, Faculty of
Psychology and Educational Sciences,
B-3000 Leuven, Belgium
13