CLINICAL OBSTETRICS AND GYNECOLOGY
Volume 54, Number 4, 574–590
Cancer in Pregnancy:
Fetal and Neonatal
Outcomes
CARL H. BACKES, MD, PAMELA A. MOOREHEAD, BS and
LEIF D. NELIN, MD
Department of Pediatrics, The Ohio State University Medical
Center, Center for Perinatal Research, Nationwide Children’s
Hospital, Columbus, Ohio
Abstract: Cancer during pregnancy represents a
potential conflict between optimal maternal treatment
and fetal development. Traditionally, clinicians oper-
ated under the assumption that cancer treatment
during pregnancy is incompatible with normal fetal
development. However, recent evidence suggests that
many diagnostic and treatment modalities cause little
or no harm to the developing fetus. As such, both
maternal and neonatal interests should be considered
when developing management strategies for pregnant
cancer patients. In this review, we will discuss issues
related to fetal and neonatal health associated with
conventional diagnostic and treatment approaches in
the care of pregnant women with cancer. In addition,
we offer recommendations on strategies to maximize
fetal outcomes in pregnancies complicated by cancer.
Key Words: Pregnancy, cancer, neonate, fetus
Introduction
Cancer is the leading cause of nonacci-
dental death among women during the
reproductive years. It is estimated that
over 3500 new cases of pregnancy-
Correspondence: Carl H. Backes, MD, The Ohio State
University Medical Center, Department of Pediatrics,
N118 Doan Hall, 410W. 10th Avenue, Columbus, OH
43210-1228. E-mail: carl.backes@nationwidechildrens.
com
The authors declare that they have nothing to disclose.
CLINICAL OBSTETRICS AND GYNECOLOGY / VOLUME 54
574 | www.clinicalobgyn.com
r 2011, Lippincott Williams & Wilkins
associated cancer are diagnosed annually
in the United States, accounting for 19%
of mortality in women between the ages of
15 and 34 years.1 Although recent data
suggest that the incidence of cancer in preg-
nancy is 1 per 1000 pregnant women, this
number is expected to rise with a growing
number of women choosing to delay child-
bearing until more advanced ages.2
Fetal development is characterized by
rapid cellular division and early differen-
tiation, making this period vulnerable to
various cancer treatments. Historically,
this led some investigators to conclude
that treatment of cancer was incompatible
with normal fetal development and
should be avoided during pregnancy.
Contemporary management strategies
have attempted to address both maternal
and fetal interests. In fact, there is emer-
ging evidence that many diagnostic stu-
dies and treatments are safe for the
developing fetus. However, clinicians
continue to misinterpret the fetal risks
associated with the treatment of cancer
during pregnancy, often resulting in de-
lays in maternal diagnosis, iatrogenic pre-
term delivery, or pregnancy termination.
/ NUMBER 4 / DECEMBER 2011

In this review, we will address issues
related to fetal and neonatal health after
the treatment of cancer during pregnancy,
including an assessment of the fetal risks
associated with conventional diagnostic
and management strategies. Specifically,
we will investigate the fetal and neonatal
effects of the 3 primary modalities in
cancer treatment (chemotherapy, radia-
tion, and surgery) and discuss potential
strategies to optimize outcomes in the at-
risk mother-infant dyad.
Development
Fetal development is a highly regulated
biological process vulnerable to outside
influences. Although genetic susceptibil-
ities likely modify the teratogenic poten-
tial of chemotherapy or radiation, it is
clear the developing fetus is particularly
sensitive during critical periods of devel-
opment.3 Thus, an accurate assessment of
the gestational age of the fetus at the time
of exposure is important in determining
the nature of the insult.
Conceptual Period
(Week 0–2)
The conceptual period encompasses the
time from fertilization to the establish-
ment of pregnancy. This period is marked
by a lack of cell differentiation or orga-
nogenesis. Exposure of the conceptus to
chemotherapy or radiation during this
time period results in either spontaneous
abortion or no adverse effects, referred to
as the ‘‘all or nothing’’ phenomenon.4
Therefore, although extraneous influ-
ences can result in termination of the
pregnancy at this stage (ie, blastocyst fails
to implant), there is likely no increased
teratogenic risk if the embryo survives.
‘‘Early’’ First Trimester
(Weeks 3–8)
This period is one of rapid cell division
and differentiation, and represents the
period of greatest vulnerability to
Cancer in Pregnancy 575
teratogens. Exposure to chemotherapy
or radiation during this period significantly
increases the risk for malformations above
the 1% to 6% background risk inherent to
all pregnancies.5 For instance, previous
investigators have estimated that use of
multiagent chemotherapy during this stage
carries as much as a 25% risk of fetal
malformations.6
‘‘Late’’ First Trimester
(Weeks 8–15)
Whereas most of the organs are already
formed by 8 weeks, many organ systems
continue to develop throughout gesta-
tion, including the central nervous system
(CNS). Weeks 8 to 15 in fetal CNS devel-
opment are characterized by neuronal
proliferation and migration from prolif-
erative zones to the cerebral cortex, after
which neurons become perennial cells and
lose their capacity divide. Exposure to
ionizing radiation or chemotherapy dur-
ing this period can produce a number of
CNS abnormalities, including mental
retardation.3
Second and Third Trimester
Exposure (>15 Weeks)
Weeks 16 to 25 are marked by in situ
cellular differentiation and synaptogen-
esis. Exposure to cancer treatment during
this period produces more functional
CNS deficits, including a loss of intelli-
gence (IQ). Beyond 25 weeks of gestation,
most of the cryoarchitectural develop-
ment and cellular differentiation of the
brain is complete, so the adverse effects of
fetal radiation or chemotherapy on the
CNS are greatly diminished. However,
exposure after 25 weeks of gestation can
cause adverse effects on fetal growth,
most notably intrauterine growth restric-
tion (IUGR).4
Background Risk to the Fetus
Clinicians must be aware of the back-
ground incidence of adverse birth
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576 Backes et al
outcomes associated with all pregnancies.
In other words, there is an inherent risk of
malformations, developmental delay, and
IUGR associated with all pregnancies,
even in the absence of maternal cancer.
For instance, IUGR is a well-described
fetal effect after in utero exposure to
chemotherapy or radiation. However,
the background incidence of IUGR
among uncomplicated pregnancies is 4%
to 8%.7 Thus, risk for adverse fetal out-
comes in pregnancies complicated by can-
cer must always be placed in the context of
background risks.
Chemotherapy
Historically, the use of chemotherapy
during pregnancy was considered to be
incompatible with normal fetal develop-
ment. This led clinicians to recommend
either termination of the pregnancy or
suboptimal cancer treatment for the
mother. In contrast to previous assump-
tions, short-term outcomes after prenatal
exposure to chemotherapy seem to be
positive.8
Biological Properties
The majority of chemotherapeutic agents
have the biological characteristics neces-
sary to cross the placenta, including a
molecular weight less than 600 kd. The
Food and Drug Administration classifies
most chemotherapy drugs as class C,
meaning there is animal evidence to sug-
gest a teratogenic effect from drug expo-
sure.9 However, although there is
evidence in animal models that che-
motherapy causes genetic damage in so-
matic cells (such as chromosomal
breakage, cell-cycle alterations, muta-
tions, deletions) these mutagenic changes
have not translated into fetal abnormal-
ities, as most fetuses exposed to che-
motherapy develop normally.8
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Chemotherapy in First
Trimester of Pregnancy
The first trimester of pregnancy is a per-
iod of significant fetal growth and orga-
nogenesis. To that end, it is not surprising
that chemotherapy-induced malforma-
tions are primarily seen after exposure
during this time period. A study by Ebert
et al10 reviewed fetal outcomes in 217
cases where chemotherapy was given dur-
ing pregnancy for a variety of malignant
diseases. Over the 12-year period in re-
view, the authors identified 18 infants
with congenital malformation. Of those
infants, 15 (83.3%) were exposed to che-
motherapy in the first trimester. In addi-
tion, Randall et al11 reported on 210
children who were exposed to chemother-
apy during gestation. Of the 29 children
with malformations, 27 (93%) were ex-
posed to chemotherapy during the first
trimester.
It is important to recognize that the
teratogenic potential of chemotherapeu-
tic agents is influenced by the type of drug,
amount, and use of single or combination
chemotherapy regimens. For instance, a
landmark study by Doll et al6 reported on
139 cases of first trimester exposure to
chemotherapy. Although malformations
were observed in 17% of infants exposed
to single-agent regimens, the authors
noted a 25% incidence after multiple
agent regimens.
Chemotherapy Later in
Gestation: Effects on Fetal
Growth
These is a growing body of evidence
showing that chemotherapy use in the
second and third trimester of pregnancy
does not increase the risk of fetal malfor-
mations. For instance, one study found
that the incidence of fetal malformations
after in utero chemotherapy is 14% to
19% in the first trimester compared with
1.3% in the second and third trimesters.6

Of note, the background risk of major
malformations in uncomplicated preg-
nancies is 1% to 6%.2 In addition, a more
recent study by Ring et al12 evaluated the
fetal effects of a contemporary che-
motherapeutic regimen in the treatment
of 28 women with breast cancer. Sixteen
women received anthracycline-based che-
motherapy and 12 were treated with cy-
clophosphamide, methotrexate, and
fluorouracil (CMF). None of the 27 chil-
dren exposed to chemotherapy in the
second or third trimester had congenital
malformation. The only fetus that was
exposed to chemotherapy (CMF) in the
first trimester resulted in a spontaneous
abortion.
Although exposure to chemotherapy
after the first trimester of pregnancy does
not seem to increase the risk for malfor-
mations, there is an increased risk for
reduced fetal growth. A study by Zemlickis
et al13 evaluated the effects of chemo-
therapy during pregnancy on fetal out-
comes in 21 pregnancies over a 30-year
period. Although the authors found no
increased risk of malformations after the
use of chemotherapy in the second or
third trimester of pregnancy, they noted
a significantly lower birth weight than
age-matched controls (2227 ± 558 g vs.
3519 ± 272 g, P<0.001) even after con-
trolling for the higher rate of prematurity
in the exposed cohort. Specifically, the
number of infants born at less than the
50th percentile of weight for gestational
age was higher in the chemotherapy-ex-
posed cohort than controls (78% vs. 18%,
P<0.01). Considering that there is strong
evidence that lower birth weight is asso-
ciated with the increased risk of mortality,
the finding that chemotherapy in the sec-
ond and third trimester is associated with
reduced birth weight has important clin-
ical implications on fetal health.14
IUGR is a pathological process where
the infants fail to achieve their in utero
growth potential.15 Pregnancies compli-
cated by IUGR have a perinatal mortality
Cancer in Pregnancy 577
rate in excess of 6 times that of their
normally grown peers.16 Although the
background incidence of IUGR is 4% to
8% of uncomplicated pregnancies, it is
believed to occur 2 to 3 times as often in
pregnancies exposed to chemotherapy in
the second and third trimester.17
A study by Calsteren et al18 showed
that infants exposed to chemotherapy
after the first trimester are also at risk
for being small for gestational age (SGA),
defined as birth weight less than 10th
percentile for given gestational age. The
incidence of SGA was 32% (9/28 cases)
among women treated for hematological
cancers compared with 12% (17/147)
among women treated for all other types
cancers. This finding is consistent with
previous studies showing that hematolo-
gical cancers, most notably acute leuke-
mia, are at the greatest risk for poor fetal
growth.19 The above findings underscore
the need for close monitoring of fetal
growth patterns during pregnancies com-
plicated by malignancies requiring
chemotherapy.
Timing of Delivery: Emergence
of the ‘‘Late Preterm’’ Infant
In pregnancies requiring chemotherapy,
there is no consensus on the optimal time
to deliver the infant. After the final cycle
of chemotherapy, delivery is typically de-
layed for 3 weeks to avoid peak fetal or
maternal neutropenia and possible subse-
quent infection. In settings where che-
motherapy is being continued after
delivery, or in the setting of a planned
delay in treatment during pregnancy,
some clinicians advocate inducing deliv-
ery as early as 32 weeks.4 However, this
practice has led to an increased number of
premature births among pregnancies
complicated by cancer. For instance, a
recent study of pregnant mothers with
invasive cancer found that children are
born preterm (less than 37 wk) in over half
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578 Backes et al
of cases (54.2%), with most requiring
admission to the neonatal intensive care
unit (NICU). Importantly, 89.7% of the
preterm deliveries were iatrogenically in-
duced.18 Preterm birth accounts for 70%
of neonatal death and up to 75% of
neonatal morbidity, with surviving in-
fants at significant risk for a number of
short and long complications, including
neurodevelopmental delays.20 To that
end, some investigators have recently sug-
gested that neonatal morbidity is less a
function of exposure to various cancer
treatments and more related to premature
delivery.21
Recent evidence also suggests that in
pregnancies complicated by cancer, there
are a growing number of ‘‘late preterm’’
births, defined as delivery between 34 0/7
and 36 6/7 weeks of gestation. In fact, a
recent study of pregnancies complicated
by cancer found that 85% of preterm
infants were ‘‘late preterm.’’18 Histori-
cally, 34 weeks of gestation was a surro-
gate marker for lung maturity. However,
recent evidence suggests that ‘‘late pre-
term’’ infants are physiologically imma-
ture compared with infants born at term,
placing them at greater risk for a wide
range of complications, including tem-
perature instability, respiratory distress,
seizures, jaundice, feeding difficulties,
periventricular leukomalacia, re-hospita-
lization, and death.22 A 10-year (1992 to
2002) population-based study compared
the mortality rates between ‘‘late pre-
term’’ infants (n = 6391) and term infants
(n = 88, 867). The authors found that
neonatal mortality (deaths among infants
0 to 27 d chronological age) and infant
mortality (death among infants 0 to 364 d
chronological age) were 5.5 and 3.5 times
greater in the ‘‘late preterm’’ group, re-
spectively.23 Similarly, a study by Young
and colleagues showed that mortality and
the relative risk of death decreases with
each increasing week in gestational age.
Specifically, the relative risks of infant
mortality in pregnancies delivered at 34,
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35, and 36 weeks of gestation were 10.5,
7.2, and 5.3 times higher, respectively,
compared with term controls.24
We recognize that clinicians must also
take into account a number of important
maternal factors when deciding on the
timing of delivery, most notably the need
to avoid chemotherapy after 34 weeks of
gestation to minimize the risk of sponta-
neous delivery during the nadir period.
However, in the absence of clear maternal
or fetal indications for delivery, efforts to
deliver the infant at term (>37 wk gesta-
tion) have clear benefits to the health of
the neonate.
Chemotherapy Regimens
The teratogenic effects of chemotherapy
on the developing fetus not only depend
on the time of administration but also on
the biological properties of the drug ad-
ministered. Available information on the
teratogenic potential of various che-
motherapy drugs is largely based on case
reports and small cohort studies. In addi-
tion, most studies involve exposure to
multiple chemotherapeutic agents or con-
comitant radiation, limiting the ability to
estimate the effect of individualized drugs
on fetal health. However, a review of the
literature suggests that certain drugs have
a higher teratogenic potential and should
be avoided during the first trimester
(Table 1).
Antimetabolites
(Methotrexate, Aminopterin,
5-Fluorouracil)
Methotrexate (MTX) is one of the leading
causes of chemotherapy-related birth de-
fects.2 Historically, MTX was used as an
abortifacient, and continues to be used in
the medical treatment of ectopic preg-
nancy. Although low-dose MTX in the
treatment of various rheumatological dis-
eases has been reported to be safe during

TABLE 1. Risk of Congenital Malforma-
tion to Fetus After Exposure to
Chemotherapeutic Drugs During
the First Trimester of Pregnancy
Births With Congenital
Drug Name Malformations (%)
Chlorambucil 50.0
Aminopterin 33.3
5-flourouracil 33.3
Methotrexate 25.0
Cyclophosphamide 12.5
Busulfan 11.1
Modified from Pavlidis NA. Coexistence of pregnancy and
malignancy. Oncologist. 2002;7(4):279–287.
pregnancy, higher doses, particularly dur-
ing the first trimester of pregnancy, have
been associated with severe skeletal and
CNS defects.25 Aminopterin, also used as
an abortifacient, results in fetal malfor-
mation in half of pregnancies that fail
abortion. In a recent study, 5-flurouracil
did not result in any adverse fetal or
neonatal effects and appears to be well
tolerated during pregnancy.26
Alkylating Agents
(Cyclophosphamide, Busulfan,
Chlorambucil)
Cyclophosphamide remains an important
part of chemotherapy regimens for breast
cancer and non-Hodgkin lymphoma. The
use of cyclophosphamide in the first tri-
mester has been associated with a number
of teratogenic effects, including renal
agenesis, ocular abnormalities, and cleft
palate.26 Interestingly, cyclophospha-
mide is the only agent to be associated
with chemotherapy-induced childhood
cancer. Zemlickis et al27 described a case
of first trimester cyclophosphamide expo-
sure in a twin pregnancy. Although one of
the twins was healthy, the other was born
with multiple congenital anomalies, in-
cluding esophageal atresia, an abnormal
inferior vena cava, and limb deforma-
tions. At 11 years of age, the affected twin
Cancer in Pregnancy 579
was diagnosed with thyroid cancer, and
subsequently found to have a neuroblas-
toma at age 14. In 15 reported cases of
busulfan use during pregnancy, there
were 2 reported cases of malformations,
including pyloric stenosis and unilateral
renal agenesis. Importantly, both cases
were seen after second trimester exposure.
Given that chlorambucil is considered one
of the most teratogenic chemotherapeutic
agents, its use should be limited to life-
threatening maternal conditions in the
third trimester of pregnancy.28
Vinca Alkaloids (Vincristine,
Vinblastine)
This class of chemotherapy agents are
highly protein bound thereby limiting
the potential for transplacental move-
ment into the fetal circulation.6 A review
of 111 infants exposed in utero to vincris-
tine or vinblastine had rates of IUGR
(8%) similar to background rates seen in
the general population.26 Thus, this class
of chemotherapy is considered to be rela-
tively safe for the developing fetus.
Platinum Agents (Cisplatin)
Cisplatin has consistently been associated
with growth restriction and hearing loss.
However, the incidence of hearing ab-
normalities after exposure to platinum-
based therapy remains similar to the
background rates in uncomplicated preg-
nancies. A recent systematic review of the
literature by Mir et al29 included 43 preg-
nancies treated with platinum derivates
for a variety of maternal malignancies,
including melanoma, cervical, and ovar-
ian cancers. Of the 43 pregnancies, the
authors identified 2 cases (4%) of fetal
malformations after in utero exposure to
cisplatin; 1 case involved use of multia-
gent chemotherapy during the first
trimester.
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580 Backes et al
Anthracyclines (Doxorubicin,
Daunorubicin, Idarubicin,
Epirubicin)
Doxorubicin and daunorubicin are
widely used in the treatment of acute
lymphoblastic leukemia, acute myeloid
leukemia, breast cancer, non-Hodgkin
lymphoma, and sarcoma. The primary
concern with anthracycline use is the
development of cardiotoxicity, with
pediatric studies showing that higher
cumulative dosages of anthracyclines in-
crease the risk of cardiac damage.30 The
largest study evaluating the potential
long-term effects of in utero exposure to
anthracyclines was conducted by Aviles
et al.31 The authors evaluated 81 children
whose mothers were treated with anthra-
cycline-based chemotherapeutic regimens
during pregnancy. Clinical examinations
and echocardiograms evaluated for the
presence of cardiotoxicity at an average
age of 17.1 years (9.3 to 29.5). No children
showed any evidence of cardiac
dysfunction.
There is limited data on the safety of
more recent anthracycline agents, includ-
ing idarubicin and epirubicin. Both drugs
are more lipophilic than other anthracy-
cline agents, theoretically increasing their
risk for placental transfer.26 A study of
idarubicin use among 5 pregnancies re-
ported fetal complications in all cases,
including fetal cardiomyopathy, IUGR,
and intrauterine demise.32 In contrast, in
a recent study by Peccatori et al33 exam-
ining women given weekly epirubicin
(35 mg/m2) for locally advanced or meta-
static breast cancer, the authors reported
that only 1 of 20 infants had fetal mal-
formation (polycystic kidney disease).
Importantly, at a median age of 2 years,
all children were developing normally,
with no reported cases of neurological or
immunological deficits.
Although these reviews provide clini-
cians with valuable information on the
potential risks of various chemotherapeutic
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agents, they are unable to account for a
wide range of important variables that
likely influence fetal toxicity, including
dose, regimen, type of maternal cancer,
or maternal health status. In addition, the
lack of data on the pharmacokinetic and
pharmacodynamic properties of che-
motherapeutic agents during pregnancy
makes it difficult to predict the fetal ef-
fects of any single agent.
Targeted Therapies
Traztuzumab, a humanized IgG mono-
clonal antibody, has been shown to im-
prove survival of breast cancer patients
with tumors overexpressing HER2.34
However, the safety of trastuzumab’s
use in pregnancy has not been established.
A review of the literature by Azim et al35
identified 15 cases of trastuzumab expo-
sure during pregnancy. The primary ad-
verse effect of trastuzumab was a marked
reduction in amniotic fluid volume (anhy-
dramnios or oligohydramnios) seen in
over half of exposures (8/15, 53%). In
addition, in the 8 pregnancies with a
decreased amniotic fluid volume, 4
(50%) resulted in neonatal death second-
ary to respiratory or renal failure. Con-
sidering that HER-2 is important in renal
development and is highly expressed on
fetal kidneys, there may be a causative
link between the use of trastuzumab and
the development of oligohydramnios.36
To that end, available data do not support
trastuzumab’s use during pregnancy.
Taxanes
A systematic review of the literature by
Mir et al37 identified 23 publications de-
scribing 40 women treated with taxanes
(paclitaxel and/or docetaxal) during preg-
nancy primarily for breast or ovarian
cancer. The only malformation poten-
tially related to taxane exposure among
the 42 neonates reviewed was 1 case of
pyloric stenosis, seen after the use of a
multiagent chemotherapy regimen in the

first trimester (cyclophosphamide, doxo-
rubicin, paclitaxel, and docetaxal). Thus,
it appears that taxanes have a favorable
safety profile for use during the second
and third trimester of pregnancy.
Antiangiogenic Agents
(Bevacizumab, Bunitinib,
Sorafenib)
There is ongoing interest in the use of
antiangiogenic agents in the treatment of
cancer. Evidence from late stage human
trials suggest that antiangiogenic agents,
including bevacizumab, may play an im-
portant role in inhibiting the development
of tumors and the progression of various
malignancies.38 However, vascular en-
dothelial growth factor signaling in vas-
culogenesis and angiogenesis is critical for
normal fetal development. Although
there is limited evidence on the terato-
genic potential of antiangiogenic agents
in humans, animal studies have consis-
tently shown that vascular endothelial
growth factor-targeted agents result in
embryo-lethal effects and developmental
malformations.39 Thus, the use of anti-
angiogenic agents in the treatment of
cancer during pregnancy cannot be re-
commended at the present time.
Long-term Consequences of In
Utero Chemotherapy Exposure
There is limited data on the long-term
effects of in utero chemotherapy expo-
sure. One of the largest studies was con-
ducted by Hahn et al40 who described the
outcome of 40 children born to women
with breast cancer treated with FAC (5-
fluorouracil, doxorubicin, cyclophospha-
mide) in the adjuvant or neoadjuvant
setting. Most of the chemotherapy was
administered during the second trimester of
pregnancy (median 23, range 11 to 34 wk). At
the time of the survey, the authors reported
that 97% of children (range, 2–157 mo) ex-
posed to chemotherapy were developing
Cancer in Pregnancy 581
‘‘normally’’ compared with siblings or
children of a similar age. Among the 18
children of school age at the time of the
survey, only 2 were noted to have learning
or behavioral problems (1 child with
Down syndrome, 1 child with attention
deficit disorder). Although this effort to
provide longitudinal follow-up on these
at-risk children is commendable, the sub-
jective nature of the developmental as-
sessment may have limited their ability
to detect more subtle consequences of in
utero chemotherapy exposure on neuro-
development and behavior.
The largest study evaluating the long-
term outcomes of children exposed in
utero to chemotherapy was conducted
by Aviles et al.41 All children were ex-
posed to chemotherapy for the treatment
of maternal hematological malignancies.
Of note, 45% (38/84) received chemother-
apy during the first trimester of preg-
nancy. Children were evaluated across a
variety of parameters, including anthro-
pomorphic measurements, educational
performance, and neurological and psy-
chological testing. The median age of
available follow-up was 18.7 years (range,
6–29 y). For all children, the authors iden-
tified no abnormalities across any of the
outcome measures reviewed. The authors
concluded that chemotherapy for hema-
tological malignancies can be safely ad-
ministered during pregnancy without an
increased risk for adverse long-term neu-
robehavioral effects. However, given the
small numbers and lack of method-
ological detail provided, these results
should be interpreted with caution. Lar-
ger, well-designed follow-up trials are ne-
cessary before the long-term safety of
chemotherapy during pregnancy can be
established.
Radiation
Historically, many investigators believed
that all forms of radiation, including
diagnostic and therapeutic exposure,
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582 Backes et al
should be avoided during pregnancy.2
This not only led to concern in the general
public, but also led to delays in maternal
diagnosis; with potential for adverse ef-
fects on maternal or fetal health.
Although it remains prudent for clinicians
to minimize radiation exposure during
pregnancy, recent evidence suggests that
many contemporary diagnostic studies,
and even some forms of radiotherapy,
are safe for the developing fetus.42 How-
ever, misinterpretation of existing data on
the safety of radiation during pregnancy
continues. A recent study showed that 5%
of Canadian obstetricians would recom-
mend termination of pregnancy after an
abdominal computed tomography (CT)
scan early in pregnancy.43 However, the
radiation dose from an abdominal CT is
below described thresholds for adverse
fetal effects. In an effort to address any
misperceptions about the effects of pre-
natal radiation exposure, clinicians must
be familiar with currently accepted radia-
tion thresholds, as well as the theoretical
foundation for those levels. We will dis-
cuss the expected radiation dose from
conventional diagnostic and therapeutic
strategies, the magnitude of risk to the
developing fetus, and available techni-
ques to minimize fetal exposure.
Threshold Effects: What Level
Is Safe?
Threshold (‘‘deterministic’’) effects refer
to exposure levels below which no adverse
fetal and neonatal outcomes have been
observed. Contemporary threshold levels
are largely based on survivors of atomic
bomb explosions, wherein the adverse
fetal effects of high-dose radiation expo-
sure (>1 Gy) are used to predict the risk of
low-dose exposures. The reader is referred
to the chapter on therapeutic radiation for
a discussion of units of radiation.
A study by Otake and Schull (1998)
investigated 1566 subjects exposed in
utero to radiation after the Japanese
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atomic bomb. Of those subjects, 25
(1.6%) were found to be mentally re-
tarded (MR). Of the children with radia-
tion-induced MR, all were 8 to 25 weeks
of gestation at the time of exposure, with
most 8 to 15 weeks (83%, 15/18). These
finding led the authors to conclude that
the absolute risk of mental retardation
after exposure to high level radiation
(>1 Gy) at 8 to 15 weeks of gestation is
44% (95% CI, 26%–62%).44 In addition,
Schull et al45 found that 1 Gy of radiation
exposure at 8 to 15 weeks translates into a
21-point decrease in IQ at 10 to 11 years of
age (95% CI, 12–30). A similar, but smal-
ler, decrease in IQ of about 13 points
(95% CI, 3–24) per 1 Gy was also seen
among a cohort exposed at 16 to 25 weeks.
It is important to note that the adverse
consequences of high radiation doses on
mental retardation and IQ were not ap-
parent across other gestation ages (0 to
7 wk, >25 wk). Thus, the gestational age
of the fetus at the time of exposure, even in
the setting of high-dose radiation levels,
largely determines the nature of the fetal
insult and is consistent with developmen-
tal vulnerabilities of the CNS during that
time period. In addition, although the risk
of mental retardation or loss of intelli-
gence is significant after exposure to 1 Gy
of radiation, this level of exposure is not
achieved by over 20 consecutive CT scans
of the abdomen and pelvis. These findings
have important implications on the risk
assessment provided to pregnant patients
after various exposures.
Contemporary deterministic thresh-
olds for mental retardation after in utero
radiation exposure are highly speculative
in nature. A review of the literature re-
veals large discrepancies in what consti-
tutes lower threshold values for various
adverse fetal effects. For instance, despite
using similar data (survivors of atomic
bomb) to base their predictions, there is
marked variance in the threshold levels
for mental retardation reported in the
literature, ranging from 0.06 Gy to

0.31 Gy.46,47 In addition, some authors
have suggested that when the exposure is
less than 0.5 Gy, the risk of MR is similar
to background rates in the general popu-
lation.48 Threshold levels for in utero
radiation represent extrapolations from
high-dose exposures, wherein best-fit
curves based on small data sets are mod-
eled to predict the potential adverse ef-
fects of low-dose exposure. In light of
these inconsistencies, clinicians must be
aware that there is no evidence showing
that in utero radiation exposure to 0.1 Gy
is associated with any adverse fetal effects,
including mental retardation, intelligence
quotient, or malformations.42
Levels of Radiation in
Conventional Diagnostic
Studies
In pregnancies complicated by cancer,
clinicians must balance the fetal risks of
exposure to ionizing radiation versus the
risk to the pregnant mother of delayed
diagnosis. Most conventional diagnostic
studies result in fetal exposure well below
deterministic thresholds and should not
present fetal risks.42 The fetal radiation
doses from common diagnostic evalua-
tions are discussed below (Table 2).
X-ray
There is a wide variability in the estimated
fetal dose after radiological exposure,
TABLE 2. Estimates of Fetal Radiation
Exposure After Conventional
Maternal Diagnostic Procedures
Procedure Estimated Radiation Exposure (Gy)
Chest CT 0.001
Pelvic CT 0.01-0.045
Chest x-ray 0.4* 10 – 5
Lumbar x-ray 0.006
Abdominal 0.001-0.003
x-ray
Cancer in Pregnancy 583
including x-rays. However, the fetal ex-
posure after conventional abdominal and
lumbar x-ray is estimated to be as much as
0.003 Gy and 0.006 Gy, respectively.49
Studies distant from the fetus (chest, ex-
tremities) can be safely performed at any
time during pregnancy, as uterine shield-
ing with a lead apron greatly minimizes
fetal radiation exposure. Therefore, under
standard operating conditions, including
the use of uterine shielding with a lead
apron, with contemporary radiological
equipment, fetal exposure after x-ray ima-
ging is well below deterministic thresh-
olds. To that end, the risk of a delayed
diagnosis in the mother is greater than the
risk of fetal exposure with conventional
x-rays.42
CT
The absorbed fetal dose from a conven-
tional CT examination depends on the
gestational age of the fetus, scanning
parameters, and area of interest. The es-
timated fetal dose from a standard CT of
the chest and pelvis is 0.001 Gy and
0.025 Gy, respectively. There is also
marked variation in the literature on the
estimated fetal dose for any given CT
study. For instance, the estimated fetal
dose from a single pelvic CT is in the range
of 0.01 Gy to 0.045 Gy.49 The variability
noted is likely due to differences in fetal
absorption as a function of gestational
age and proximity to the isocenter and
highlights the great uncertainty in predict-
ing the risk of adverse fetal outcomes after
any given exposure.
As noted, exposure from a single diag-
nostic CT study during pregnancy does
not exceed even the most conservative
deterministic thresholds for adverse fetal
effects.50 However, the use of multiple,
consecutive CT studies with direct expo-
sure to the fetus has the potential to
exceed threshold levels. In the setting of
repeat exposures, consultation with a
medical physicist is necessary to verify
www.clinicalobgyn.com
584 Backes et al
the potential dose to the fetus. This in-
formation will allow clinicians to provide
parents with an accurate risk assessment
of the fetal risks before making any med-
ical decisions. The American College
of Obstetrics and Gynecology and the
American College of Radiology provide
recommendations on the use of CT in
pregnancy (Table 3). Both governing
bodies support the judicious use of CT
during pregnancy. However, although
they emphasize the importance of making
an accurate diagnosis, they reiterate the
need for clinicians to consider alternative
studies that may provide the necessary
diagnostic information.51
Magnetic Resonance Imaging
Magnetic resonance imaging (MRI) offers
several potential advantages over CT ex-
amination during pregnancy, most notably
a lack of radiation exposure to the devel-
oping fetus. A study of children exposed to
MRI (Tesla 1.5) during the third trimester
of gestation did not show any adverse
effects at 9 months of gestation, whereas
another study reporting no adverse
TABLE 3. Recommendations for the Use of
Computed Tomography in Pre-
gnancy From the American
College of Obstetrics and Gyne-
cology and the American College
of Radiology
ACOG Recommendations ACR Recommendations
Perform comprehensive Limit radiation
physical examination exposure as much as
before all radiographic reasonably possible
studies
Iodinated constrast Iodinated contrast
material is considered material is likely safe
safe
Counsel patients Counsel patients
regarding additional regarding additional
risk risk
Modified from Wieseler KM et al. Imaging in pregnant
patients: examination appropriateness. Radiographics.
2010;30(5):1215–1229; discussion 1230–1213.
www.clinicalobgyn.com
outcomes up to 9 years of age.52,53 Some
investigators have suggested that heat ef-
fects of MRI exposure could be teratogenic
for the developing fetus.54 However, a
more recent study showed that tissue heat-
ing markedly dissipates at the maternal
body surface and is negligible near the
fetus. Other investigators have noted the
potential risk for acoustic injury in animal
models, although more recent evidence
suggests that noise is attenuated through
amniotic fluid and is delivered to the fetus
at safe levels (less than 30 dB). Despite
evidence from animal studies on the poten-
tial teratogenic effects of MRI exposure, to
date, there have been no human studies
showing the use of MRI during pregnancy
is associated with adverse fetal effects.49 It
is important to note, however, there is no
existing long-term data on the safety of
MRI exposure during gestation at higher
magnetic fields (3.0 Telsa). To that end, the
American College of Radiology supports
the cautious use of MRI during pregnancy
when the risk-benefit ratio to the mother-
infant dyad warrants the study.55
Ultrasound
To date, there is no evidence showing that
ultrasound use during pregnancy has any
deleterious effects on the developing fe-
tus.56 In addition, the physiological
changes in the breast during pregnancy
make the use of breast ultrasound more
sensitive in the detection of cancerous
changes than mammography.57
Fluoroscopy
The use of fluoroscopy for diagnostic or
interventional purposes results in mark-
edly higher fetal radiation dosage. When
there is a clear maternal indication for the
use of fluoroscopy, dose reduction tech-
niques should be used, including use of
intermittent or pulsed techniques, low-
dose level settings, avoidance of image
magnification, and uterine shielding. In

terms of diagnostic fluoroscopy, these
efforts are likely to result in fetal exposure
levels well below deterministic thresholds.
However, in situations of medical uncer-
tainty, it is prudent to evaluate the poten-
tial fetal dose level with a medical
physicist before performing the study.51
Contrast Material
Intravenous iodinated contrast material
has been shown to traverse the placenta
and can accumulate in the fetal thyroid.
Although there is some evidence that
iodinated contrast material does not ad-
versely impact neonatal thyroid function,
additional studies that address safety con-
cerns are warranted. Gadolinium has
been shown to have adverse effects on
the developing fetus in animal studies,
although no direct toxic effects have been
shown in humans. Therefore, the neces-
sity of gadolinium in enhancing diagnos-
tic capabilities must be weighed against
the potential risk to the fetus.51
Finally, there is no evidence that the
short-lived radionuclide technetium-99
presents any increased risk to the devel-
oping fetus and can be safely used during
pregnancy.58
Stochastic Effects of Radiation
Stochastic effects (‘‘late effects’’) of radia-
tion represent cellular damage, likely at
the DNA level, wherein any exposure to
radiation increases the theoretical risk for
adverse long-term outcomes, primarily
cancer. In other words, there is always a
carcinogenic risk to the fetus after radia-
tion exposure, regardless of the dose.
However, the magnitude of the risk re-
mains unknown. Furthermore, to avoid
gross misperceptions of the fetal risk as-
sociated with in utero radiation exposure,
the risk of carcinogenesis must always be
evaluated relative to the background in-
cidence of childhood cancer in the general
population.42
Cancer in Pregnancy 585
The largest study investigating the po-
tential carcinogenic effects of in utero
radiation exposure is the Oxford Survey
of Childhood Cancers (OSCC). The case-
controlled study included 15,276 child-
hood cancer cases (age of 0 to 15) and a
similar number of cancer-free matched
controls based on sex, date of birth, and
region. The primary source of informa-
tion on prenatal x-ray exposure was an
interview with the mother, although over
half of the exposures were confirmed from
hospital records for both cases and con-
trols. About 92% of the x-rays occurred in
the first trimester of pregnancy. The
OSCC study showed that the risk of child-
hood cancer is related to the gestational
age at the time of exposure, with a relative
risk of childhood cancer after first, sec-
ond, and third trimester exposure of 3.19,
1.29, and 1.30, respectively.59 This finding
is consistent with other authors who have
suggested that x-ray exposure during ge-
station, particularly early in gestation,
increases the risk of childhood cancer by
as much as 2-fold above background
rates.51 It is imperative that clinicians
educate parents that this 2-fold risk repre-
sents an increase from 1 in 1000 (back-
ground incidence) to 2 in 1000.42
Some investigators have questioned the
validity of the OSCC study, noting that
the large risks described may grossly over-
estimate actual cancer risks after in utero
radiation exposure. For instance, risk es-
timates from the OSCC study would pre-
dict that over 8 cases of childhood cancer
would be seen among those exposed in
utero to the Japanese atomic bomb. In
fact, among the 1566 patients evaluated in
the Japanese atomic bomb study, only 1
child was diagnosed with cancer.60 In
addition, a more recent meta-analysis of
7 cohort studies on the potential carcino-
genic risk after in utero irradiation did not
find an increased risk of childhood cancer
(composite RR 1.02; 95% CI, 0.74–
1.41).60 Therefore, given the conflicting
evidence, no firm conclusions can be
www.clinicalobgyn.com
586 Backes et al
drawn on the magnitude of the carcino-
genic risk after in utero radiation expo-
sure. However, given that there is some
evidence showing that the adverse effects
of radiation are dependent on the gesta-
tional age of the fetus and the dose of
radiation, it is prudent for clinicians to
continue to develop strategies that limit
fetal radiation exposure, particularly dur-
ing early stages of gestation.
Techniques to Minimize Fetal
Exposure
Despite the small estimated fetal dose
from conventional x-rays, multidisciplin-
ary efforts should always be made to limit
the number of images obtained and mini-
mize the direct dose to the fetus, including
a restriction on the size of the x-ray beam.
For direct exposures, the use of a lead
shield is warranted.51 When using CT
scans, clinicians should work with radiol-
ogists and other colleagues to evaluate the
efficacy of limiting scans to specific areas
of interests rather than performing gen-
eralized studies. In addition, there is evi-
dence to support using low-dose CT
protocols for all pregnant patients, in-
cluding reducing the kilovoltage below
standard protocols. Therefore, working
collaboratively with radiologists and
medical physicists to develop a plan that
provides minimal fetal radiation expo-
sure, while at the same time accurately
staging the maternal cancer, are highly
desirable.61
Radiotherapy
Historically, radiotherapy was contrain-
dicated during pregnancy. Clinicians ad-
vised patients that radiotherapy must be
delayed until after delivery to avoid ad-
verse fetal consequence.2 Although adju-
vant chemotherapy and surgery continue
to allow clinicians to delay radio-
therapy, certain oncological cases require
www.clinicalobgyn.com
immediate radiotherapy. To that end,
there is a growing body of evidence that
radiotherapy can be performed safely
during pregnancy without compromising
fetal health, particularly in maternal dis-
eases distant from the abdomen and pelvis
(eg, breast). For instance, Mazonakis
et al62 estimated the radiation dose to
the fetus from tangential breast radio-
therapy using anthropomorphic phan-
toms at the first and third trimester of
gestation. Consistent with standard doses
used in breast radiotherapy, the authors
applied a total isocenter dose of 50 Gy
(using a standard 6-MV x-ray beam).
Importantly, the authors found an in-
crease in the estimated fetal dose with
advancing gestational age. Specifically,
upon delivering 50 Gy to the tumor, the
upper range of estimated exposure to the
fetus during the first and third trimester of
pregnancy was 0.07 Gy and 0.58 Gy, re-
spectively. As expected, this finding sug-
gests that the increased proximity of the
fetus to the treatment volume during the
third trimester of pregnancy results in a
greater exposure to ionizing radiation.
Therefore, although exposure to tangen-
tial breast irradiation in the first trimester
resulted in levels below threshold values,
exposure during the third may exceed safe
levels and should be avoided. Thus, radio-
therapy is not recommended during the
third trimester of pregnancy.
Surgery
In many cancer types, surgery is the pri-
mary treatment modality, with strong
evidence that anesthesia and surgery are
safe during pregnancy. A recent systema-
tic review by Cohen et al63 included over
12,000 females exposed to nonobstetric-
related surgery during pregnancy. The
authors found that the rate of miscar-
riage, malformation, and fetal loss was
similar to background rates. For instance,
the rate of major malformations after
undergoing surgery in the first trimester

was 3.9% (105/2663), compared with a
commonly cited background incidence of
1% to 6% in the general population.
Similarly, Mazze and Kallen, using the
Swedish health database, investigated the
potential link between nonobstetric-re-
lated surgery and adverse fetal outcomes.
Of the 5405 operations performed, the
authors found no increased risk for con-
genital malformations or stillbirth. Of
note, the authors found an increase in
the risk of miscarriage among surgeries
performed in the first trimester, but this
risk did not remain after excluding sur-
geries for emergent appendicitis.64 Thus,
modern advances in surgical and anes-
thetic techniques allow clinicians to offer
surgery to pregnant patients with cancer
with limited risk to the fetus.
Decisions at the Limits
of Viability
Treatment options in the care of pregnant
patients with cervical cancer highlight
potential conflict between maternal ben-
efits and adverse fetal effects. In the set-
ting of advanced cervical cancer,
treatment often needs to start at the time
of diagnosis. This includes a cesarean
section, if the fetus is viable, followed by
a radical hysterectomy.65 Therefore, in
the setting of advanced cervical cancer,
as well as other aggressive malignancies
warranting immediate treatment, an un-
derstanding of contemporary definitions
for fetal viability, and potential strategies
to optimize fetal outcomes at the limits of
viability, are warranted.
The accepted definition for fetal viabi-
lity in the medical community is the fetal
age at which there is a 50% chance of
long-term survival. Over the last 2 dec-
ades, advances in the fields of obstetrics
and neonatology, most notably prenatal
steroid and artificial surfactant adminis-
tration, have led to dramatic improve-
ments in the survival among infants
Cancer in Pregnancy 587
born extremely premature (<27 wk gesta-
tion). A landmark study by Hoekstra
et al66 compared the survival rate among
a cohort of infants (23 to 26 wk gestation)
born in 1986 and 2000. Overall, the survi-
val increased from 53% to 89% over the
15-year period in review. Notably, survival
at 23 weeks of gestation increased from
40% to 66%, wherein the survival at 24
weeks increased from 49% to 81%. More
recent data suggest that the survival of
infants born greater than 25 weeks is well
above 80%, with less than 50% having
major long-term complications.67 Thus,
24 weeks represent an appropriate age for
current definitions of the limit of viability.
In settings requiring immediate mater-
nal treatment, clinicians must be familiar
with strategies that maximize fetal out-
comes. First, the administration of beta-
methasone or dexamethasone to infants
less than 32 weeks results in a decrease in
mortality and morbidity.68 Recent evi-
dence suggests that exposure to antenatal
corticosteroids are associated with a re-
duction in the risk of death similar to
those associated with a 1-week increase
in gestational age.14 In addition, the place
of delivery impacts neonatal survival. For
instance, a study by Bartels et al69 com-
pared the survival rates of infants born at
large-volume delivery hospitals (>1000
births per year) with large-volume NICUs
(>36 very low birth weight admissions per
year) with those born at small-volume
delivery hospitals (<1000 births per year)
with small-volume NICUs (<36 very low
birth weight admissions per year). The
authors found that among neonates
24-30 weeks, neonatal mortality was in-
creased nearly 2-fold for infants born in a
small-volume delivery hospital and cared
for in a small-volume NICU (adjusted
OR, 1.94; 95% CI, 1.20–3.14). Thus, in
settings where maternal cancer warrants
immediate therapy, efforts to administer
antenatal steroids and deliver at large-
volume, tertiary care center will result in
improved fetal outcomes.
www.clinicalobgyn.com
588 Backes et al
Conclusion
Cancer during pregnancy represents a
potential conflict between optimal mater-
nal treatment and fetal development. On
the basis of available evidence, it appears
that most contemporary diagnostic stu-
dies and treatment strategies are safe for
the developing fetus. Parents should be
advised on the increased risk, but not the
certainty, of adverse fetal effects after
exposure to chemotherapy in the first
trimester. The task of appropriately edu-
cating parents on the risk of adverse fetal
outcomes after chemotherapy or radia-
tion exposure is difficult, as there is no
high-grade evidence on which to base
recommendations and limited data on
the potential long-term effects of in utero
exposure. As advances in the diagnostic
and treatment strategies for cancer during
pregnancy occur more rapidly than the
accumulation of safety data, there is a
clear need for longitudinal follow-up of
a large cohort to adequately evaluate the
potential risks to the fetus. We believe that
the care of pregnant women with cancer
should occur in high-risk centers with
adequate access to prenatal and perinatal
care providers to maximize fetal out-
comes. To that end, all management de-
cisions, as well as discussions with
caregivers on the fetal risks of various
treatments, should be made using the
educational resources of the entire
medical team.
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