CLINICAL OBSTETRICS AND GYNECOLOGY

Volume 54, Number 4, 602–618

r 2011, Lippincott Williams & Wilkins

Chemotherapy in
Pregnancy
MOLLY BREWER, DVM, MD, MS* , ANGELA KUECK, MD*
and CAROLYN D. RUNOWICZ, MD* w
* Division of Gynecologic Oncology, Department of Obstetrics and
Gynecology, Carole and Ray Neag Comprehensive Cancer Center,
University of Connecticut Health Center, Farmington, Connecticut
and w Herbert Wertheim College of Medicine, Florida International
University, Miami , Florida

Abstract: One in 1000 pregnancies is complicated with

cancer with the most common tumors being breast
cancer, cervical cancer, thyroid, leukemia, lymphoma,
and ovarian cancer. It is often assumed that cancer
during pregnancy necessitates sacrificing the well-
being of the fetus but in most cases appropriate
treatment can be offered to the mother without pla-
cing the fetus at serious risk. The care of a pregnant
woman with cancer involves evaluation of competing
maternal and fetal risks and benefits. Although it is
rare to administer chemotherapy during pregnancy,
the risks depend on the drugs used and the gestational
age of the fetus. During the period of organogenesis (4
to 13 wk), administration of cytotoxic drugs carries an
increased risk of fetal malformations and fetal loss.
Chemotherapy in the second or third trimester is
associated with intrauterine growth retardation, pre-
maturity, and low birth weight and bone marrow
toxicity in many exposed infants.
Key words: chemotherapy, pregnancy, cancer
Correspondence: Molly A. Brewer, DVM, MD, MS,
Division of Gynecologic Oncology, Carole and Ray
Neag Comprehensive Cancer Center University of Con-
necticut Health Center, 263 Farmington Ave MC 1614,
Farmington, CT 06030-2875. E-mail: mbrewer@uchc.
edu.
The authors declare that they have nothing to disclose.
Introduction
It is estimated that 1 in every 1000 preg-
nancies is complicated with cancer. In a
population-based hospital registry series
of malignancies identified during preg-
nancy using birth records linked to hospi-
tal discharge data, the most common
cancer was breast, followed by thyroid,
cervical cancer, Hodgkin lymphoma
(HL), and ovarian cancer.1 It is a common
assumption by both patients and physi-
cians that if a cancer is diagnosed during
pregnancy, treatment necessitates sacrifi-
cing the well-being of the fetus. However,
in most cases, it is possible to offer appro-
priate treatment to the mother without
placing the fetus at serious risk. Preg-
nancy is often associated with a delay in
diagnosis, particularly for breast cancer,
which may worsen the prognosis.2
The care of a pregnant woman with
cancer involves evaluation of sometimes
competing maternal and fetal risks and
benefits. The approaches presented attempt
to balance these risks and benefits; how-
ever, they should be considered advisory
and should not replace interdisciplinary

CLINICAL OBSTETRICS AND GYNECOLOGY / VOLUME 54 / NUMBER 4 / DECEMBER 2011

602 | www.clinicalobgyn.com

consultation with specialists. In order to
optimize the individual clinical situation, a
pregnant woman with a diagnosis of cancer
should be the subject of a multidisciplinary
consultation including experts in maternal-
fetal medicine, oncology, pediatrics, and
pathology.
Chemotherapy
Chemotherapy may be indicated for treat-
ment of cancer during pregnancy. Fortu-
nately, having to start chemotherapy
during pregnancy is a rare event. With
approximately 50% of pregnancies un-
planned, women may be inadvertently
exposed to drugs not necessarily intended
to be used during pregnancy. In addition,
a large number of pregnant women need
continuous therapy such as anticoagu-
lants for chronic conditions. Use of many
of these drugs is complicated by the fact
that medications are almost never tested
in pregnant women at the time they
are introduced into the clinical setting.3
There are only a limited number of drugs
proven to be human teratogens, including
thalidomide, isotretinoin, warfarin deri-
vates, valproic acid, and folate antago-
nists. In some cases, the combination of
multiple drugs may increase the terato-
genic risk in ways that have not been
identified.
Although it may be lifesaving for the
mother, chemotherapy has the potential
to adversely impact the pregnancy. Con-
cerns about administration of cytotoxic
chemotherapy during pregnancy arise be-
cause chemotherapy preferentially kills
rapidly proliferating cells, and the fetus
represents a rapidly proliferating cell
mass. The risks of chemotherapy admin-
istration during pregnancy depend on the
drugs used and the gestational age of the
fetus. Chemotherapy given in the first
trimester (ie, during the period of organo-
genesis) can result in neural tube defects,
cleft lip, amelia, cardiac defects, fetal loss,
and other defects. The risk of fetal
Chemotherapy in Pregnancy 603
malformation is diminished when used
after the first trimester; however, the fetus
is still at risk of intrauterine growth re-
tardation (IUGR).4
All chemotherapy agents used in the
treatment of cancers are pregnancy cate-
gory D, meaning that adverse effects have
occurred in human fetuses exposed to the
individual drugs. However, the risk of
spontaneous abortion, fetal death, and
major malformations varies with the spe-
cific agent used and the trimester of preg-
nancy. Pregnancy is associated with
physiologic changes that may affect the
pharmacokinetics of chemotherapeutic
agents such as increased plasma volume,
third spacing in the amniotic fluid, and
increased renal clearance and hepatic me-
tabolism of drugs. 5–8 As pharmacokinetic
studies in pregnant women are lacking, it
is unknown whether dose modification
may be needed.9 Teratogenicity is the
main concern when treating pregnant wo-
men. Most cytotoxic agents have a mole-
cular weight <400 kDa and can thus
freely cross the placenta and reach the
fetus. Most information regarding che-
motherapy in pregnancy is from series
that used multiagent protocols, and it is
therefore difficult to separate the fetal
effects of individual drugs.9
In general
 During the first 4 weeks of gestation
(first 2 weeks postconception) the em-
bryo is undifferentiated. Fetal exposure
to cytotoxic agents at this point results
in ‘‘all or none’’ phenomena: either
pregnancy loss or no adverse effect.6–9
 From 4 weeks of gestation until the end
of the first trimester, which is the period
of organogenesis, administration of cy-
totoxic drugs (particularly antimetabo-
lites) carries an increased risk of fetal
malformations. A review of 217 preg-
nant women treated with cytotoxic
therapies between 1983 and 1995 for a
variety of malignancies and other med-
ical conditions reported 18 newborns
with congenital abnormalities, 2 with
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604 Brewer et al
chromosomal abnormalities, 4 were
stillborn, and there were 15 sponta-
neous abortions.7 The majority of still-
born infants and infants with
chromosomal or congenital abnormal-
ities had mothers who were given che-
motherapy in the first trimester. The
risk is higher with multiagent than
single-agent chemotherapy (approxi-
mately 25% vs. 10%).8,9 By compa-
rison, the baseline risk of congenital
malformations in the general popula-
tion is 3% to 4%.
 During the second and third trimesters
of pregnancy, the risk of fetal malfor-
mation is significantly reduced. In
1 review, the incidence of fetal malfor-
mations in 150 women given che-
motherapy during the second or third
trimesters of pregnancy was 1.3%.10
However, chemotherapy in the second
or third trimester is associated with
intrauterine growth retardation, pre-
maturity, and low birth weight in about
one half of exposed infants.5 Moreover,
chemotherapy may also cause fetal
toxicities similar to those observed in
the mother (eg, bone marrow suppres-
sion, ototoxicity). These risks must be
weighed against the benefit of immedi-
ate versus delayed chemotherapy for
the mother. Ethical considerations of
treatment in these settings have empha-
sized the role of patient autonomy and
the concept of beneficence and nonmal-
feasance for both the mother and the
fetus.11
 Administration of chemotherapy within
3 weeks of anticipated delivery or be-
yond 35 weeks of gestation is not re-
commended to avoid transient neonatal
myelosuppression and potential compli-
cations of bleeding, sepsis, and death at
the time of delivery. In addition, neona-
tal toxicity may be higher if chemother-
apy is administered peripartum because
placental drug clearance is generally
more effective than neonatal hepatic
and/or renal drug clearance.12
www.clinicalobgyn.com
 Information on the effects of antineo-
plastic drugs administered during preg-
nancy has largely been derived from
case reports, small case series, and col-
lected reviews of treatment of a variety
of cancers. Unfortunately, there are
little data on the pregnancy effects of
the major drugs used for cancer diag-
nosed during pregnancy, as this is an
uncommon clinical problem in preg-
nancy. There are even less data on
long-term outcomes in offspring.
BREAST CANCER
The incidence of breast cancer in preg-
nancy and the postpartum period ranges
from 2.3 to 40 cases per 100,000 women
and has increased over the last several
decades.11 A study from the Swedish Na-
tional Health Registry demonstrated that
the incidence of pregnancy-associated
breast cancer (PABC), which encom-
passes diagnoses during pregnancy and
within 1 year postpartum, increased be-
tween 1963 and 2002 from 16.0 to 37.4 per
100,000 deliveries.13 Over 90% of patients
with breast cancer in pregnancy or during
lactation present with a palpable mass,
and 84% of these are self-reported by
patients. Less frequently, breast cancer
will present as breast erythema, which
may mimic mastitis, breast swelling,
bloody nipple discharge, nipple retrac-
tion, palpable supraclavicular nodes, skin
metastasis, or distant metastasis.14
Although the dismal prognosis for wo-
men developing breast cancer has im-
proved, breast cancer in pregnancy may
still carry a worse prognosis when preg-
nant women are compared with age-
matched nonpregnant controls. There
are no data to suggest that termination
of pregnancy improves survival outcomes
especially as the majority of these tumors
are estrogen receptor negative, but it does
remove the concerns of potential terato-
genicity of chemotherapy. A woman may
be advised to terminate a pregnancy if it is

felt that her life expectancy may not be
longer than gestation, and historically, it
was often assumed that termination was
warranted in all cases. However, with the
increasing data on the safely of both
surgery and chemotherapy, that trend is
changing.
The pregnancy-associated increase in
breast density renders examination of
the breast more difficult, potentially lead-
ing to delays in detection from 1.5 to 6
months.14 During pregnancy, the breast
undergoes considerable hypertrophy that
increases breast density and the lobular
changes in the breast. Many physicians
are reluctant to biopsy a breast during
pregnancy,4,15 which may further delay
diagnosis. In the majority of studies, preg-
nant women presented on average with
more advanced cancer than nonpregnant
women and thus have a worse prognosis
than nonpregnant women, although that
is not consistent between studies.4,15 The
majority of these cancers are high grade
with lymph-vascular space invasion and
50% to 72% are estrogen receptor nega-
tive.4,16 An elevated risk of PABC was
found in both BRCA1 and BRCA2 fa-
milies with more women found to have
PABC in the BRCA1 women (odds ratio,
3.9) than BRCA2 women.17
As the major sites of metastatic disease
are bone, lung, and liver, guidelines have
been established for ordering liver ultra-
sound, magnetic resonance imaging with-
out contrast of the spine, and chest x-ray
with fetal shielding to evaluate for meta-
static disease in women with suspected
stage II or greater cancers.15 Computed
tomographic scans and bone scans are not
recommended for routine staging studies
in the pregnant patient because of con-
cerns of fetal radiation exposure. Sites
concerning for metastatic disease should
be biopsied whenever possible to confirm
distant metastases. Surgery is typically
delayed until the second trimester and
radiation until delivery, if possible. Adju-
vant chemotherapy is not contraindicated
Chemotherapy in Pregnancy 605
during pregnancy and should be consid-
ered in women with tumors >1 to 2 cm or
who are discovered to have lymph node
involvement.16,18,19 Gene assays such as
Oncotype Dx are frequently used to de-
termine the potential benefit/role of ad-
juvant therapy in nonpregnant patients
with estrogen receptor-positive tumors
and estrogen receptor-negative nodes;
however, their use has not been examined
in PABC. Consideration of an echocar-
diogram before anthracycline-based che-
motherapy is warranted.
Neoadjuvant chemotherapy should be
considered for treatment in patients who
have large breast tumors where removal of
the mass would be difficult without per-
forming a mastectomy or if the patient
does not desire to have a mastectomy.
Neoadjuvant treatment typically involves
4 to 6 months of therapy. Surgery can be
performed at the end of this treatment or
can be delayed until after delivery but
should not be done within 3 to 4 weeks of
chemotherapy because of the risk of neu-
tropenia of both the mother and the fe-
tus.14,18,19 PABC is as chemosensitive as
non-PABC and most studies suggest that
taxanes should be part of the neoadjuvant
chemotherapy regimen for PABC. During
pregnancy, dosages should not differ from
those used outside pregnancy, even if few
pharmacokinetic and pharmacodynamic
data are available during pregnancy.8
Cardonick et al20 reported on 113 wo-
men who continued their pregnancy, and
the mean gestational age at delivery was 36
weeks. Eight of the women delivered infants
with birth weights <10% for gestational
age. There were pregnancy complications in
19 of the patients and a malformation rate
of 3.8%, not significantly different from
that in the general population. Additional
long-term outcomes of children exposed
to chemotherapy in utero were provided
by Aviles et al,21,22 who followed 84 chil-
dren whose mothers were given chemother-
apy during pregnancy for a hematologic
malignancy. They reported no significant
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606 Brewer et al
cardiac, physical, neurologic, or psycholo-
gical abnormalities. Zoccarato et al23 re-
ported on a retrospective multicenter trial
of 30 patients diagnosed with cancer during
pregnancy, with 27 women who continued
their pregnancy. Fifty-nine percent had ce-
sarean deliveries, with 63% of the neonates
with a low birth weight resulting from pre-
mature delivery. No excess in congenital
malformations was noted. In the ad-
vanced/metastatic setting, anthracyclines
and anthracycline-based regimens remain
the best choice for treatment of breast
cancer. For patients who are not good
candidates for anthracycline-based regi-
mens (previous exposure in the adjuvant
setting), single agent taxane (paclitaxel or
docetaxel) would be a preferred option.
Weekly administration of paclitaxel has
been shown to be associated with higher
efficacy and better tolerability compared
with the 3-weekly schedule.24,25 Trastuzu-
mab is an IgG monoclonal antibody that
targets the HER2 oncogene. The addition
of trastuzumab to chemotherapy has been
shown to improve survival of breast cancer
patients with tumors over-expressing
HER2, both in the adjuvant and in the
metastatic setting, but the safety profile of
trastuzumab during early pregnancy is un-
clear. However, IgG does not typically
cross the placenta although it has been
associated with oligohydramnios24,25 Fetal
monitoring during chemotherapy is indi-
cated due to the risk of IUGR and prema-
ture delivery. Thus, we conclude that breast
cancer in the pregnant patient should be
treated much as the nonpregnant patient,
except that chemotherapy and surgery
should be delayed to the second trimester
and radiation delayed to postdelivery, if
possible.
HEMATOLOGIC MALIGNANCIES
The incidence of hematologic malignan-
cies in pregnancy range from 1:1000 to
1:10,000, but these conditions pose major
challenges to the hematologist/oncologist
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and the obstetrician. As the peak inci-
dence of HL is during the age range of
20 to 40 years, its association with preg-
nancy is not uncommon, occurring in
1:1000 to 1:6000 deliveries.22,25,26 The
majority of published studies have been
case reports or small series due to the
relatively rare occurrence of the combina-
tion of HL and pregnancy, so guidelines
for evaluation and treatment of HL in
pregnancy are not well established. As
computed tomographic scans and isotope
studies are not recommended during
pregnancy, and the current trend is to
administer chemotherapy initially even
in early stages (stages I and II) of Hodgkin
disease, a limited initial staging workup is
suggested. The clinical behavior of HL
during pregnancy does not seem to differ
from the nonpregnant setting, and preg-
nant women are not more likely to present
at a higher stage than nonpregnant wo-
men of reproductive age. As well, the
histologic subtypes are similar to the non-
pregnant patient. In general, it is recom-
mended to avoid chemotherapy during
the first 12 to 16 weeks of pregnancy if
possible, and to postpone radiotherapy
until after the delivery. If combination
chemotherapy is considered, the recom-
mended protocol is adriamycin, bleomy-
cin, vinblastine, and dacarbazine.9,24,25,27
In women with early-stage disease limited
to the neck region, radiotherapy has been
suggested, using proper shielding to the
abdomen. However, such an option must
be considered carefully because of the
potentially severe adverse effects of radio-
therapy to the fetus. Another alternative
to multiagent chemotherapy is therapy
with single-agent vinblastine, which is
effective for HL with modest toxicity
and lower likelihood of fetal adverse out-
come. A series of women were treated
with single-agent vinblastine, delaying
combination chemotherapy until after de-
livery, with favorable fetal outcome.26,27
Indolent non-Hodgkin lymphoma
(NHL) tends to progress slowly, so

treatment is often not given initially.
When therapy is needed, single-agent
(chlorambucil) or combination che-
motherapy such as CVP (cyclophospha-
mide, vincristine, and prednisone) or
CHOP (cyclophosphamide, doxorubicin,
vincristine, and prednisone) is used. A few
case reports of women with NHL treated
with these protocols during pregnancy are
available in the literature and none re-
ported congenital anomalies, including
4 cases treated during the first trime-
ster.27,28 Neonatal leukopenia and colitis
were reported in an infant whose mother
was exposed to chemotherapy in the third
trimester. An alternative approach is the
use of single-agent rituximab without che-
motherapy. The use of rituximab was not
associated with fetal morbidity or mortal-
ity in several case reports.27–29 NHL also
includes diffuse large B-cell lymphoma,
mantle cell lymphoma, and mature T-cell
and natural killer-cell lymphomas. The
most common regimen used for these
malignancies is CHOP, with the addition
of rituximab in CD20+ tumors.27,28 Stu-
dies on treatment with CHOP during
pregnancy are limited to a few case re-
ports and small series.
The occurrence of leukemia during
pregnancy is very rare, with an estimated
incidence of 1:100,000 pregnancies an-
nually. It has been estimated that during
pregnancy most leukemias are acute: two
thirds are myeloid [acute myeloid leuke-
mia (AML)] and one third are lymphatic
[acute lymphoblastic leukemia (ALL)].
Chronic myeloid leukemia is found in
<10% of leukemias during pregnancy,
and chronic lymphocytic leukemia is
extremely rare.28 Remission rates of leu-
kemia of 70% to 75% are reported for
pregnant women, whereas survival is de-
pendent on many factors, including the
type of acute leukemia and the presence of
cytogenetic abnormalities. Acute leuke-
mia can affect the pregnancy and the
fetus. Intrauterine growth retardation
has been reported in mothers not treated
Chemotherapy in Pregnancy 607
with chemotherapy.28,29 In addition, pre-
term labor, induced and spontaneous
abortion, and stillbirth are common in
acute leukemia. Although there is an esti-
mated teratogenic risk rate of 10% when
chemotherapy is administered in the first
trimester, Aviles and Niz29 reported no
fetal malformations and no late side ef-
fects in children born to mothers who
were treated for acute leukemia during
early pregnancy. Treatment of AML con-
sists of remission induction with cytara-
bine and an anthracycline, usually
daunorubicin or idarubicin, and postre-
mission therapy with consolidation using
high-dose cytarabine or with allogeneic
stem cell transplantation. For patients
who are diagnosed with AML during the
first trimester, termination of pregnancy
and immediate induction chemotherapy
should be considered.28,29 Several retro-
spective series reported on patients diag-
nosed and treated during the second and
third trimesters of pregnancy. Preterm
delivery, IUGR, spontaneous abortions,
and stillbirths were noted but there were
no congenital anomalies. Anthracyclines
are an important component of AML
chemotherapy and should be used cau-
tiously, with close neonatal follow-up.
Idarubicin is more lipophilic and with
increased placental transfer and potential
toxicity, and thus, daunorubicin is pre-
ferred over idarubicin.28,29
ALL is rare among adults, and informa-
tion regarding treatment of pregnant women
with ALL is very limited. ALL is an aggres-
sive malignancy, which necessitates prompt
initiation of multiagent chemotherapy,
usually with cyclophosphamide, corticoster-
oids, anthracyclines, vincristine, cytarabine,
and asparaginase.29
Chronic myeloid leukemia during preg-
nancy should be treated as it is in nonpreg-
nant patients. As the disease has an initial
chronic phase, it is usually managed con-
servatively during pregnancy, whereas
an aggressive approach, such as bone mar-
row transplantation, may be considered
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608 Brewer et al
after delivery. If therapy is needed, inter-
feron A, which seems to be safe during
pregnancy, should be administered until
after delivery. Hydroxyurea may be used
during the second or third trimester
for patients who do not tolerate interferon
side effects. Hydroxyurea is contraindi-
cated during the first trimester due to
teratogenicity.27
LUNG CANCER
The association between lung cancer and
pregnancy is very rare, but it is expected to
increase due to the increasing rates of
cigarette smoking among young women.
A recent systematic review of the litera-
ture has identified 44 pregnant women
who were diagnosed with lung cancer
during pregnancy. The vast majority was
diagnosed with adenocarcinoma and had
advanced disease.29
OVARIAN CANCER
The lifetime risk of developing ovarian
cancer is 1.4% to 1.7% for women living
in the United States; the majority of cases
occur after menopause.30 The probability
of developing ovarian cancer during the
reproductive years is low, approximately
0.01%. In hospital-based series, 0.2% to
2% of pregnancies are complicated by an
adnexal mass, and approximately 1% to
6% of these masses are malignant.31 A
separate review from 1958 to 2007 included
41 cases,32 with the mean age at presenta-
tion of 32.6 years (range, 23 to 46 y); stage at
diagnosis was recorded in 39 cases: FIGO I
(59%), FIGO II (5%), FIGO III (26%),
and FIGO IV (10%). In a separate publica-
tion using this same population-based hos-
pital registry database, there were 87
ovarian cancers among 9375 ovarian
masses diagnosed during pregnancy (malig-
nancy rate, 0.93%) and 0.018 ovarian can-
cers diagnosed per 1000 deliveries.33 There
was also a high proportion of tumors of low
malignant potential (LMP) (n = 115),
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reported separately, with the majority in
early stage and associated with favorable
maternal and neonatal outcomes. Cause-
specific maternal mortality for all patients
with a malignant ovarian tumor was low (9
of 191, 4.7%) at a mean of 2.43 years after
diagnosis, likely due to the predominance of
tumors of LMP and germ cell tumors (24 of
the 87 ovarian cancers).34
Epithelial ovarian tumors comprise
37% of all ovarian malignancies in preg-
nant women, germ cell ovarian malignan-
cies make up about 45%, and stromal
tumors 10% and a variety of other tumor
types (such as sarcomas and metastatic
tumors) account for the remainder.34 Ap-
proximately, 50% of epithelial ovarian
tumors detected in pregnancy are of
LMP (also called ‘‘borderline’’ tumors)
and the other 50% are invasive. Epithelial
ovarian tumors of LMP diagnosed in
pregnancy may exhibit atypical character-
istics suggestive of invasive cancer. These
findings include nuclear enlargement, an-
isocytosis, and multifocal microinvasion.
For this reason, it is important that the
pathologist be informed of the coexistent
pregnancy and that pregnancy-associated
ovarian malignancies be evaluated by
a pathologist skilled in reading the patho-
logic findings in the context of the on-
going pregnancy. In 1 series, 8 of 10 serous
borderline neoplasms diagnosed in
pregnancy had microscopic and clinical
features, suggesting aggressive behav-
ior.35 In 2 patients, however, follow-up
biopsy after pregnancy showed that
these features either regressed postpartum
or implants disappeared in this small
series, confirming that the neoplasms,
although appearing aggressive, behaved
like a LMP tumors, suggesting that these
patients do not need adjuvant chemo-
therapy.
About three fourths of ovarian germ cell
tumors occurring in pregnancy are dysger-
minomas. Endodermal sinus tumors, im-
mature teratomas, and mixed germ cell
tumors comprise the remainder.36 Most

germ cell tumors are grossly limited to 1
adnexa, but lymphatic spread to pelvic or
paraaortic nodes is relatively common.
Dysgerminomas are bilateral in 10% to
15% of cases; other germ cell tumors are
almost always unilateral. Approximately,
one half of all pregnancy-associated stro-
mal tumors are granulosa cell tumors, one
third are Sertoli-Leydig cell tumors, and
the remainder are unclassified stromal tu-
mors.37 Between 10% and 15% of stromal
tumors secrete androgens and produce
virilization. Although estrogen secretion
also occurs, symptoms of a hyperestro-
genic state are masked by the already high
estrogen concentration associated with
pregnancy.
Several of the tumor markers used to
follow epithelial and nonepithelial ovar-
ian cancers in nonpregnant women are
difficult to interpret in pregnancy because
oncofetal antigens (eg, AFP, hCG, CEA,
CA125) are involved in biological func-
tions associated with fetal develop-
ment, differentiation, and maturation.
The levels are normally elevated during
gestation and fluctuate with gestational
age, or they may be abnormally elevated
due to abnormal placentation or fetal
abnormalities (eg, preeclampsia, Down
syndrome, open neural tube defect).38
Serum levels of CA 125 are elevated in
most cases of epithelial ovarian cancer
(EOC). CA 125 is also produced by nor-
mal tissues, including endometrium, and
may be elevated during early gestation
and immediately after delivery.38 Mater-
nal serum levels of AFP (MSAFP) nor-
mally rise during pregnancy. Although
they are rare, because elevated MSAFP
levels can be associated with ovarian
germ cell tumors in pregnant women,
evaluating the ovaries is indicated for
the workup of an abnormal maternal
serum AFP screening test. Some investi-
gators suggest that a MSAFP level above
9 multiple of the mean should prompt
concern for germ cell tumors of either
gonadal or nongonadal origin in the
Chemotherapy in Pregnancy 609
absence of fetal abdominal wall defects
or anencephaly.39
Serum lactate dehydrogenase is ele-
vated in the serum of women with ovarian
dysgerminomas, and is a reliable marker
for diagnosis and follow-up of these tu-
mors in pregnant women.40 Although ser-
um inhibin is a useful tumor marker for
following the course of treatment for
ovarian granulosa cell tumors in nonpreg-
nant women, inhibin is made in the devel-
oping placenta, and serum levels are
elevated in early gestation.41,42
The general consensus regarding man-
agement of adnexal masses in pregnancy
is to surgically resect masses that have any
of the following characteristics43–46:
 Persist into the second trimester (unless
it is a simple cyst),
 Are >10 cm in diameter, or
 Have solid or mixed solid and cystic
ultrasound characteristics suspicious
for malignancy on imaging.
Tumors of LMP do not require che-
motherapy. Two types have been de-
scribed, an atypical proliferative serous
tumor that has benign behavior and a
low-grade serous carcinoma (noninvasive
micropapillary serious carcinomas) that
may be a precursor to invasive low-grade
serous carcinoma. Regardless of stage,
chemotherapy is not generally recom-
mended after diagnosis. The use of che-
motherapy for those that exhibit invasive
peritoneal implants is controversial.47
Conservative surgery alone is recom-
mended for women with ovarian tumors
of LMP, regardless of stage. Staging has
not shown a benefit in this group of
patients and can be deferred.
If a metastatic ovarian cancer is identi-
fied, cytoreduction should be attempted.
The extent of surgical cytoreduction in-
volves individual judgment, balancing the
extent of surgery with the expected bene-
fit. It is rare that removal of the gravid
uterus is required for maximal cyto-
reductive surgery at the initial surgery,
as it is possible to return for secondary
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610 Brewer et al
cytoreduction after chemotherapy and
successful completion of the pregnancy.
This management strategy is not thought
to adversely impact survival, although as
a general rule, survival is poor for women
who have a late-stage disease.
Platinum analogs (carboplatin or cis-
platin) plus a taxane represent the stan-
dard first-line chemotherapy for EOC
in the United States. Experience with
maternal administration of platinum and
taxanes in pregnancy is limited. More
recent case reports have described the
use of carboplatin, whereas the older
literature reports the use of cisplatin.48–60
In general, these case reports document
the feasibility of administering these
drugs to pregnant women. However, sev-
eral have documented adverse fetal
outcomes.
A systematic review of reports on use of
platinum derivatives during pregnancy
included 43 pregnancies: 36 cases of in
utero cisplatin exposure (6 of 36 were
single-agent exposure, 2 of 36 exposures
occurred in the first trimester), 6 cases of
carboplatin exposure, and 1 case of ex-
posure to both drugs.60 The type and
frequency of adverse effects in cisplatin-
exposed pregnancies were intrauterine
growth restriction (3), preterm birth (3),
oligohydramnios (2), polyhydramnios
(1), ventriculomegaly (1), and micro-
phthalmus (1). Ventriculomegaly was di-
agnosed at 26 weeks of gestation, 1 week
after first exposure to cisplatin, and thus,
was probably unrelated; microphthal-
mus, a rare malformation, occurred
after first trimester exposure to the com-
bination therapy with tamoxifen, dacar-
bazine, carmustine, and cisplatin. The
causative link between cisplatin and
these malformations remains speculative.
Transplacental transfer of cisplatin and
carboplatin was documented and may
have caused the toxicity (eg, anemia, leu-
kopenia, pancytopenia, creatinine eleva-
tion), which was observed in 5 neonates.
A more recent report evaluated 15
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patients diagnosed between 6.5 and 36
weeks gestation and only half of the pa-
tients received chemotherapy while preg-
nancy and 11 of 15 mothers were alive and
without recurrence.61 No malformations
or toxicity were reported in carboplatin-
exposed neonates, but there were only
7 such pregnancies (including the 1 pa-
tient with cisplatin and carboplatin
exposure).
There are even fewer case reports of
taxane administration for ovarian cancer
during pregnancy.48–50,57–62 Fetal ab-
normalities have not been reported in
these few case reports. Several preclinical
reports indicate that the placental P-gly-
coprotein could prevent the transplacen-
tal transfer of taxanes. There are small
series of pregnant patients with breast
cancer treated with taxanes.63 Although
these case reports document the short-
term safety of taxanes for breast cancer
during the second and third trimesters of
pregnancy, the number of patients has
been small and long-term outcomes have
not been reported. Based primarily on
data obtained from women with breast
cancer, an international group of experts
in 2006 did not recommend the routine
use of taxanes during pregnancy.63 Con-
sidering this recommendation for patients
with breast cancer, caution in the use of
taxanes in pregnant patients with ovarian
cancer is advised.
Given that 2 trials conducted by the
International Collaborative Ovarian
Neoplasm group in nonpregnant women
with advanced ovarian cancer did not
show a significant survival advantage for
taxane plus carboplatin as compared
with single-agent carboplatin alone or a
nontaxane-containing, platinum-based
combination regimen (CAP),64,65 some
oncologists (particularly in Europe) con-
sider a nontaxane-containing regimen to
be an acceptable chemotherapy option.
However, this is a very controversial issue,
particularly among US oncologists who
prefer the use of taxanes for EOC.

ADJUVANT TREATMENT FOR
EARLY-STAGE DISEASE
Compared with surgery alone, the addi-
tion of platinum and taxane-based che-
motherapy significantly improves 5-year
survival rates in women with high-risk
stage I or stage II EOC.66 The criteria
for adjuvant treatment include the
following:
 Resected grade 2 or 3 stage IA or IB
disease
 Grades 1, 2, or 3 stage IC disease
 Resected stage II disease
 Clear cell histology.
For pregnant women who fit these
high-risk, early-stage categories and who
have no gross residual disease present
following resection, a reasonable strategy
is to delay adjuvant therapy until after
delivery. Extrapolation of results from a
randomized controlled trial of different
adjuvant treatment strategies support the
view that delay of adjuvant therapy may
not necessarily worsen outcomes.67 In this
trial, 271 nonpregnant women were ran-
domly assigned to immediate adjuvant
cisplatin versus observation (trial 1) or
immediate adjuvant cisplatin versus P-32
(trial 2), with cisplatin given at the time of
relapse. There was no difference in overall
survival between all study arms (although
a difference in disease-free survival was
observed). These data have been inter-
preted as providing support for giving a
platinum analog at the time of relapse
instead of in the immediate postoperative
adjuvant setting. By analogy, these data
could also support the safety of a modest
delay to allow delivery of the infant, be-
fore initiating adjuvant chemotherapy.
After completion of pregnancy, the pa-
tient may complete her course of adjuvant
carboplatin and paclitaxel.
Patients who are left with gross residual
disease, even when limited to pelvic organs,
probably should not delay the initiation of
chemotherapy beyond 6 to 8 weeks past
surgery, although the risks to the mother of
prolonged delay of adjuvant chemotherapy
Chemotherapy in Pregnancy 611
in the setting of early-stage disease with
small volume residual are not known. After
delivery, the standard of care in the United
States would be to use the combination of
paclitaxel and carboplatin.
ADVANCED DISEASE
For women with advanced EOC, it is a
widely held view that platinum and taxane
combination therapy is more effective
treatment than either single-agent plati-
num or platinum combinations that do
not include a taxane. As noted above, the
International Collaborative Ovarian
Neoplasm trials did not find a significant
survival benefit from paclitaxel plus car-
boplatin versus carboplatin alone or cy-
clophosphamide plus doxorubicin and
cisplatin (CAP), but interpretation of
these results is controversial because of
issues related to trial design.64
Indirect evidence from randomized
trials also provides some support for the
view that the combination of paclitaxel
and carboplatin remains active when ad-
ministered sequentially rather than con-
currently. GOG-132 compared a cisplatin
plus paclitaxel ‘‘doublet’’ to either cispla-
tin or paclitaxel monotherapy.68 Twenty-
four percent of patients who were
randomized to cisplatin monotherapy
subsequently underwent early preemptive
crossover to single-agent paclitaxel before
reaching the stipulated clinical criteria for
disease progression.68 These women had
equivalent overall survival to those who
received the cisplatin/paclitaxel doublet
upfront. Although indirect, these data
have been interpreted as providing sup-
port for the sequential use of platinum
derivatives followed by a taxane as an
alternative to concurrent use of both
drugs.69
Given these data, the risk to the fetus
could be minimized by giving the preg-
nant women single-agent platinum during
pregnancy, followed by a paclitaxel-con-
taining regimen postpartum. At least in
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612 Brewer et al

theory, this approach should be feasible
without compromising maternal survival.
INTRAPERITONEAL THERAPY
Results from the large Gynecologic Oncol-
ogy Group (GOG) 172 trial suggest a sig-
nificant survival benefit for intraperitoneal
as compared with all intravenous che-
motherapy in a subset of women with
optimally cytoreduced stage III EOC (to
<0.5 cm), but at the expense of significant
toxicity.70 A similar conclusion was reached
in a meta-analysis of 8 randomized trials
comparing standard intravenous therapy
with chemotherapy that included a compo-
nent of intraperitoneal administration.71
Intraperitoneal chemotherapy has not
been tested in pregnant patients with
ovarian cancer. However, if treatment
can be safely delayed until after delivery,
intraperitoneal therapy is an appropriate
option for women with advanced disease
who have undergone optimal surgical
cytoreduction.
For women with high-risk resected
early-stage EOC (grade 2 or 3 or clear cell
histology, stage IA or IB, all grades stage
IC or stage II), the goal of initial surgery is
to completely resect all residual disease,
without disturbing the pregnancy. Women
found to have advanced-stage disease dur-
ing pregnancy should receive optimal sur-
gical cytoreduction to the extent possible
consistent with maternal and fetal safety.
GERM CELL TUMORS
Most germ cell ovarian malignancies occur
in young women and are limited to 1 ovary.
Despite being diagnosed at a relatively
early stage, adjuvant chemotherapy is re-
commended to reduce the risk of recurrence
for all women with completely resected
malignant ovarian germ cell tumors except
those with stage IA dysgerminomas or
stage I, grade 1 immature teratomas.
The most commonly used regimen is
bleomycin, etoposide, and cisplatin (BEP).
Use of this regimen (or the related PVB,
cisplatin plus vinblastine and bleomycin) in
pregnant women has been described in
several case reports,59,72–76 only 1 of which
details a potential adverse fetal outcome.
This case report described a fetus that was
delivered at 28 weeks of gestation and noted
to have ventriculomegaly, cerebral atrophy,
anemia, and neutropenia after surgical sta-
ging and 1 cycle of adjuvant BEP adminis-
tered 1 week before delivery.75 As the
cerebral atrophy was identified only 1
week before the BEP, it could have been
due to other factors, such as maternal
hypotension. The patient had suffered a
large blood loss at the time of resection of
the primary germ cell tumor, with the
development of a pelvic hematoma requir-
ing transfusion of 2 units of blood. Etopo-
side has been associated with growth
restriction and neonatal bone marrow de-
pression, but there are no reports of fetal
malformations.5,6 Germ cell neoplasms are
very sensitive to platinum-based che-
motherapy. For this reason, several inves-
tigators have attempted to delay adjuvant
chemotherapy until after the completion of
the pregnancy.
In 1 report, a woman with an endoder-
mal sinus tumor resected at 19 weeks of
gestation successfully awaited delivery of
the infant at 36 weeks before initiating
BEP chemotherapy.77 There was no evi-
dence of recurrence at 27 months after
initial treatment. Another report described
a patient with an endodermal sinus tumor
resected at 22 weeks of gestation who was
found to have recurrent disease 12 weeks
later.78 After secondary debulking and de-
livery of the infant, the mother was success-
fully salvaged with BEP. A third report
involved a patient with an endodermal
sinus tumor that was resected at 19 weeks
of gestation.79 Chemotherapy was delayed
and at 32 weeks of gestation, tumor recur-
rence necessitated a cesarean hysterectomy
and bowel resection with colostomy. Three
weeks later, the colostomy was taken down
and another suprahepatic tumor mass was
resected. The patient was then given BEP

www.clinicalobgyn.com

for 4 cycles. These reports suggest that
delaying chemotherapy increases the risk
of recurrence. However, in these 2 cases,
maternal survival apparently was not com-
promised by the delay, despite a tumor
recurrence and increased complications,
probably because of the sensitivity of germ
cell tumors to chemotherapy.
Postoperative adjuvant chemotherapy
using the BEP regimen is indicated to
reduce the risk of recurrence for all wo-
men with completely resected malignant
ovarian germ cell tumors except those
with stage IA dysgerminomas, or stage I
grade 1 immature teratomas. When indi-
cated, chemotherapy should be delayed at
least until completion of the first trimester
of pregnancy, but not longer.
SEX CORD-STROMAL TUMORS
Most of these tumors carry a favorable
prognosisor are slowly progressive. In
most cases, the benefit of adjuvant che-
motherapy is controversial. Therefore, we
suggest surgery alone for disease diag-
nosed during pregnancy and the decision
for chemotherapy, if any, can be deferred
to the postpartum period.
SUMMARY OF OVARIAN CANCER
There is no evidence that pregnancy wor-
sens the prognosis of ovarian tumors com-
pared with nonpregnant patients matched
for tumor histology, stage, and grade.
Approximately, 75% of invasive ovarian
malignancies in pregnant women are
early-stage disease. Owing to the favor-
able mix of stage, grade, and histology, the
5-year survival rate for ovarian tumors
associated with pregnancy is between
72% and 90%. The presence of ascites at
diagnosis implies advanced disease and
poor prognosis.80
Breastfeeding
Cytotoxic agents may reach significant
levels in breast milk and thus breastfeeding
Chemotherapy in Pregnancy 613
while on chemotherapy is generally con-
traindicated. The American Academy of
Pediatrics lists agents transferred into hu-
man milk and describes their possible ef-
fects on the infant or on lactation, if
known. The cytotoxic drugs listed include
cyclophosphamide, cyclosporine, doxoru-
bicin, and methotrexate. Their reasons
were listed as possible immune suppres-
sion, unknown effect on growth, or asso-
ciation with carcinogenesis.81
Cisplatin is transferred into breast
milk; the World Health Organization
does not recommend nursing during che-
motherapy with cisplatin.82 Paclitaxel is
lipophilic and, because of this, has the
potential to be concentrated in breast
milk. No data exist to confirm or refute
this concern. For this reason, breastfeed-
ing is not advised for women who need
taxanes in the postpartum period.
Postpartum Considerations
Once the pregnancy is complete, the cancer
may be further treated without concern
about fetal effects. One cohort study found
that postpartum lactating women diag-
nosed with ovarian cancer had a poorer
prognosis than women diagnosed before
or during pregnancy, but the numbers of
cases was small.83 This finding needs to be
confirmed in larger studies. Although che-
motherapy has been given antepartum,
there are essentially no pharmacokinetic
data regarding the use of antineoplastic
drugs during pregnancy. Renal function
changes dramatically during the course of
pregnancy and the puerperium. It is un-
known if chemotherapy doses calculated
using the methods regularly used for non-
pregnant women are also optimal for preg-
nant women. Carboplatin is usually dosed
based on renal function.
For women with advanced-stage ovar-
ian cancer being treated during pregnancy,
it is prudent to consider completion of the
hysterectomy and contralateral oophorect-
omy, as well as a secondary cytoreductive
www.clinicalobgyn.com
614 Brewer et al
surgery at the conclusion of pregnancy.
This approach was taken by a number of
investigators who reported managing ad-
vanced EOC cases during pregnancy.49–52
Persistent disease was frequent: in 4 such
patients, 2 had disease involving the ad-
nexa,46,47 2 involved the bowel,49,50 and
1 also involved the pelvic peritoneum,
omentum, and appendix.49
Summary and
Recommendations
The clinical care of women who are diag-
nosed with a malignancy in the context of
an ongoing pregnancy requires multidisci-
plinary consultation.84 As many treatment
decisions require balancing competing ma-
ternal and fetal risk, consultants with ex-
pertise in maternal-fetal medicine,
oncology, and pediatrics should work to-
gether to advise the pregnant woman and
her family as the treatment is being planned.
If chemotherapy is indicated, unless deliv-
ery can be accomplished within a few weeks
of diagnosis, chemotherapy should be in-
stituted during pregnancy rather than wait-
ing until after delivery.84 In general, if
chemotherapy is indicated and cannot be
delayed, it is preferable to initiate che-
motherapy in the second or early third
trimester than to deliver a premature baby.
Early delivery to avoid fetal exposure to
maternal chemotherapy is reasonable if
fetal lung maturity can be documented
and the fetus is closer to term. In this setting,
the risks of prematurity are relatively low.
Chemotherapy administration should be
avoided within 3 weeks of anticipated
delivery.
Breast cancer in pregnancy should be
treated much as it is treated in the non-
pregnant patient except that chemother-
apy is delayed until the second trimester
and radiation is avoided. Hematologic
malignancies are also treated much as in
the nonpregnant patient. Ovarian cancer
in the pregnant patient should be
www.clinicalobgyn.com
evaluated by a pathologist skilled in read-
ing the pathologic findings in the context
of the ongoing pregnancy. The patholo-
gist should be informed of the coexistent
pregnancy except that women found to
have advanced-stage EOC should consid-
er having completion of the cytoreductive
surgery of the reproductive organs at the
conclusion of the pregnancy. After deliv-
ery, chemotherapy should be switched to
a paclitaxel-containing regimen such that
a total of 6 cycles of combined taxane/
platinum are administered. Intraperito-
neal chemotherapy is an alternative to
intravenous chemotherapy in the postpar-
tum period for those who have had opti-
mal cytoreductive surgery (r0.5 cm
residual disease) for stage III disease.
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