Chemotherapy of ovarian cancer in pregnancy

Authors: Carolyn D Runowicz, MD, Molly Brewer, DVM, MD, MS

Section Editors: Barbara Goff, MD, Don S Dizon, MD, FACP
Deputy Editors: Sadhna R Vora, MD, Alana Chakrabarti, MD
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Feb 2025. | This topic last updated: Nov 22, 2024.

INTRODUCTION
A gynecologic malignancy is estimated to complicate four to eight of every 100,000
pregnancies [1-4]. Unfortunately, the data on the effects of antineoplastic drugs
administered during pregnancy have largely been derived from case reports, small
case series, and collected reviews of pregnant patients treated for a variety of
cancers. There are even less data on long-term outcomes in offspring.
This topic will address the administration of chemotherapy for patients diagnosed
with ovarian cancer in pregnancy. In order to optimize treatment outcomes, a
pregnant patient with a diagnosis of ovarian cancer should be managed by a
multidisciplinary team that includes experts in the fields of maternal-fetal medicine,
gynecologic oncology, pediatrics, and pathology.
The clinical manifestations and diagnosis of ovarian cancer in pregnancy and
surgical management of this disease are reviewed separately. (See "Adnexal mass:
Evaluation and management in pregnancy".)

GENERAL PRINCIPLES
Most infants born to individuals with cancer during pregnancy have favorable long-
term outcomes, even following exposure to chemotherapy during pregnancy.
However, as chemotherapy preferentially kills rapidly proliferating cells, and the
fetus represents a rapidly proliferating cell mass, chemotherapy during pregnancy
may result in adverse effects to the fetus, including [5]:
● Bone marrow suppression
 ● Intrauterine growth restriction
● Low birth weight
● Major malformations
● Pregnancy loss
● Preterm birth – Preterm birth is likely responsible for the increased rates of
other neonatal outcomes. In one retrospective study of 1150 incident cases of
cancer during pregnancy, exposure to chemotherapy (12 percent of cases) was
associated with a higher risk of severe neonatal morbidity and mortality (risk
ratio [RR] 1.67, 95% CI 1.13-2.46) [6]. Preterm birth <34 and <37 weeks
contributed to most of these observed associations. By contrast, exposure to
chemotherapy was not associated with increased rates of neurodevelopmental
disorders and disabilities or pediatric complex chronic conditions.
The impact of chemotherapy on these adverse events is predominantly dependent
on the agent used and the trimester of pregnancy when the treatment is
administered:
● During the first four weeks of gestation (first two weeks post conception) the
embryo is undifferentiated. Fetal exposure to cytotoxic agents at this point
results in "all or none" phenomena: either the pregnancy is lost or it continues
with no apparent adverse effect [5,7].
● Organogenesis occurs during weeks 5 to 10 weeks of gestation. The
administration of cytotoxic drugs, particularly antimetabolites (eg, fluorouracil
and methotrexate) and alkylating agents (eg, busulfan, chlorambucil,
cyclophosphamide), during this period carries an increased risk of fetal
malformations. In a review of the literature, rates of adverse pregnancy
outcomes (APOs) for anti-neoplastic agents in single and combination therapy
were 33, 27, and 25 percent for the first, second, and third trimesters. Rates of
congenital malformations (included in the APOs) were 16, 8, and 6 percent for
the first, second, and third trimesters [8]. The majority of stillborn infants and
infants with chromosomal or congenital abnormalities occur when
chemotherapy is administered in the first trimester.
● When chemotherapy is delivered to the mother during the second and third
trimesters of pregnancy, the risk of fetal malformation is lower. First trimester
 exposure poses a larger and more permanent risk to the fetus. Administration
of chemotherapy within three weeks of anticipated delivery or beyond 35
weeks of gestation may induce neonatal myelosuppression and complicate
delivery due to adverse effects of treatment on bone marrow reserves. This
includes potential complications such as bleeding, sepsis, and death.
Additionally, neonatal toxicity may be higher if chemotherapy is administered
peripartum because placental drug clearance is generally more effective than
either hepatic and/or renal drug clearance in the neonate [9].
Thus, the risks of chemotherapy to the fetus must be weighed against the benefits
of immediate versus delayed (ie, postdelivery) chemotherapy for the mother.
Ethical considerations of treatment during pregnancy have emphasized the role of
patient autonomy and the concept of beneficence and nonmaleficence for both the
mother and fetus [10].

HISTOLOGIC TYPES OF OVARIAN CANCER

There are several different histologic types of malignancy that can arise within the
ovary including epithelial ovarian cancer (EOC), ovarian germ cell tumors, and sex-
cord stromal tumors. In some series of ovarian malignancy in pregnancy, germ cell
tumors predominate, while others report a higher frequency of EOC. (See "Adnexal
mass: Evaluation and management in pregnancy", section on 'Malignant
neoplasms'.)

EPITHELIAL OVARIAN CANCER

Indications for chemotherapy — Following surgery, the indications for adjuvant
treatment of epithelial ovarian cancer (EOC) are similar for pregnant and
nonpregnant patients. However, administration of chemotherapy during the first
trimester should be avoided. We recommend chemotherapy for:
● Patients with early-stage EOC ( table 1) if any of the following high-risk
features is present: stage IA/IB, grade 2/3; stage IC or II (any histology); serous
or clear cell carcinoma (stage IA, IB, IC, or II)
● Patients with stage III or IV EOC
Regimen — As with nonpregnant patients, we recommend the use of a platinum
drug plus taxane for patients with EOC in pregnancy because, in general, this
combination results in the best survival outcomes. For patients diagnosed during
pregnancy, we prefer carboplatin to cisplatin because it is a better tolerated agent
and reduces the risk of long-term side effects (eg, renal and neurotoxicity).
Although there are few data to guide the use of taxanes in pregnancy, it has been
used to treat breast cancer in pregnancy without apparent adverse events [11-13].
We prefer paclitaxel rather than docetaxel because it is generally less myelotoxic.
Targeted therapy has been incorporated into treatment regimens for nonpregnant
patients, eg, poly(ADP-ribose) polymerase inhibitors, which have the capacity to
cross the placenta. Large molecules (for example, monoclonal antibodies) can cross
the placenta and reach the fetus after 14 weeks. Animal data has demonstrated
potential embryotoxicity and risk of adverse fetal outcomes with these agents
( table 2) [14]. Angiogenesis inhibitors, eg, bevacizumab, a humanized anti-
vascular endothelial growth factor antibody, are teratogenic and induce
intrauterine growth restriction, pregnancy loss, and skeletal malformation in
animal models [15]. Therefore, these agents should not be used until after delivery.
All patients with EOC in pregnancy should be informed of the limited data on
maternal and fetal outcomes associated with treatment. In one of the largest
cohort studies of pregnant patients with all types of cancer treated at multiple
institutions, 84 were exposed to taxanes and 74 were exposed to platinum-based
chemotherapy [16]. Both drugs were associated with an increased risk of delivery of
a small for gestational age infant: platinum odds ratio (OR) 3.12, 95% CI 1.45-6.70
and taxanes OR 2.07, 95% CI 1.11-3.86. However, it was not possible to determine
whether these findings were related to in-utero drug exposure or to other factors,
such as effects of other medications, maternal stress, lack of adequate gestational
weight gain, and other prenatal factors.
Administration — Patients can be treated with single agent carboplatin or a
combination of carboplatin and a taxane. A decision should be made on an
individual basis taking into account potential risks and benefits of treatment.
Intraperitoneal therapy — In the absence of a larger experience, we do not
administer intraperitoneal (IP) chemotherapy in these patients. There is only one
case report of a woman with ovarian cancer treated with IP therapy for four cycles
during pregnancy. She underwent a cesarean section at 37 weeks; the baby was
male and had bilateral congenital talipes equinovarus [17]. The role of IP therapy
for advanced ovarian cancer is discussed separately. (See "First-line chemotherapy
for advanced (stage III or IV) epithelial ovarian, fallopian tube, and peritoneal
cancer", section on 'Females with optimally cytoreduced disease'.)
Timing of chemotherapy
Early-stage disease — For pregnant patients with high-risk, early-stage EOC, we
suggest initiation of chemotherapy following completion of the first trimester. The
approach is similar to the treatment of nonpregnant patients with early-stage EOC.
(See 'Indications for chemotherapy' above and "Adjuvant therapy of early-stage
(stage I and II) epithelial ovarian, fallopian tube, or peritoneal cancer", section on
'Choice of adjuvant treatment'.)
For patients who prefer not to receive treatment during pregnancy due to concerns
for fetal safety, it may be reasonable to delay adjuvant chemotherapy until after
delivery. The evidence to support this comes from two studies that evaluated the
impact of a treatment start delay [18]. In these trials, 271 nonpregnant patients
with high-risk stage I EOC were randomly assigned treatment with adjuvant
cisplatin versus observation (trial 1) or P-32 (trial 2). In both trials, patients who
were not treated with cisplatin received cisplatin at the time of relapse. The main
results were:
● Administration of cisplatin reduced the risk of relapse in both trials (compared
with observation, hazard ratio [HR] 0.35, 95% CI 0.14-0.89; compared with P-32,
HR 0.39, 95% CI 0.19-0.77).
● There was no difference in five-year overall survival (88 and 82 percent with
cisplatin or observation; HR 1.15, 95% CI 0.44-2.98; 81 and 79 percent with
cisplatin or P-32; HR 0.72, 95% CI 0.72, 95% CI 0.37-1.43).
Advanced-stage disease — Patients with advanced disease should begin
chemotherapy as soon as they are out of the first trimester and have recovered
from surgery. We generally prefer to initiate treatment in two to four weeks after
surgery for ovarian cancer. The approach to treatment is similar to that for
nonpregnant patients with advanced EOC. Although dose-dense (weekly) paclitaxel
has been reported to improve progression-free survival, other groups have been
unable to duplicate these data [19,20]. (See "First-line chemotherapy for advanced
(stage III or IV) epithelial ovarian, fallopian tube, and peritoneal cancer", section on
'Females with suboptimally cytoreduced disease' and "First-line chemotherapy for
advanced (stage III or IV) epithelial ovarian, fallopian tube, and peritoneal cancer",
section on 'Females with optimally cytoreduced disease'.)

GERM CELL TUMORS

Most germ cell ovarian malignancies occur in young patients and are limited to one
ovary [1]. Maximal surgical cytoreduction is usually undertaken initially. (See
"Treatment of malignant germ cell tumors of the ovary" and "Management of
residual masses in advanced testicular germ cell tumors following initial systemic
therapy".)
Despite being diagnosed at a relatively early stage, we recommend adjuvant
chemotherapy for most patients with completely resected malignant ovarian germ
cell tumors except those with stage IA dysgerminoma ( table 1) or stage I grade
one immature teratoma. When indicated, chemotherapy should be delayed at least
until completion of the first trimester of pregnancy [21-23]. The most commonly
used regimen is bleomycin, etoposide, and cisplatin (BEP ( table 3)). (See "Ovarian
germ cell tumors: Pathology, epidemiology, clinical manifestations, and diagnosis"
and "Treatment of malignant germ cell tumors of the ovary".)
In other series, use of etoposide during pregnancy has been associated with
growth restriction and neonatal bone marrow suppression [5,7]. Etoposide is
teratogenic in mice and rats at doses much lower than the human dose and should
not be used in the first trimester. A consensus report suggested paclitaxel-
carboplatin or cisplatin-vinblastine-bleomycin as alternatives to BEP in pregnancy
[24].
Timing of chemotherapy — Given that germ cell neoplasms are exquisitely
sensitive to platinum-based chemotherapy, several investigators have published
case reports addressing a treatment delay until after the completion of the
pregnancy [25-27]. A summary of findings is presented below:
● One case report documents a woman with a yolk sac (endodermal sinus) tumor
that was surgically resected at 19 weeks of gestation [25]. The pregnancy was
allowed to continue and BEP was not initiated until after the baby was
 delivered at 36 weeks. At a follow-up of 27 months, there was no evidence of
recurrence disease.
● Another report described a patient with a yolk sac tumor resected at 22 weeks
of gestation, after which the pregnancy was allowed to continue [26].
Unfortunately, at 34 weeks she was found to have tumor regrowth. After
secondary debulking and delivery of the infant, the mother was successfully
treated with BEP and was without evidence of disease 39 months after her last
treatment with chemotherapy.
These reports suggest that delaying adjuvant chemotherapy may increase the risk
of recurrence, although without an apparent risk to long-term recurrence free
survival. Given the low quality of the data, however, a decision on the timing of
adjuvant chemotherapy for patients with a germ cell tumor should take into
account the individual circumstances and preferences of the mother.

TUMORS OF LOW MALIGNANT POTENTIAL

Tumors of low malignant potential have an excellent prognosis and management is
the same as that for nonpregnant patients [28]. In general, treatment is surgical
and most patients do not require adjuvant chemotherapy. (See "Borderline ovarian
tumors".)

SEX CORD-STROMAL TUMORS

Most of these tumors are limited to one ovary, of low malignant potential and/or
slowly progressive. The benefit of postoperative treatment for patients with stage
1B to IV disease ( table 1) is unclear and practice is variable. Therefore, we
suggest oophorectomy alone for disease diagnosed during pregnancy. The
decision for chemotherapy, if any, can be deferred to the postpartum period. (See
"Sex cord-stromal tumors of the ovary: Epidemiology, clinical features, and
diagnosis in adults".)

BREASTFEEDING
Cytotoxic agents may reach significant levels in breast milk and thus breastfeeding
while on chemotherapy is generally contraindicated [29]. The United States
National Library of Medicine Drugs and Lactation Database ( LactMed) is an
excellent resource for information on transfer of specific drugs into human milk
and possible effects on the infant or on lactation, if known. Possible adverse effects
include immune suppression, impaired growth, or association with carcinogenesis
[30]. We agree with the World Health Organization’s recommendation against
nursing while receiving chemotherapy [31].

SOCIETY GUIDELINE LINKS

Links to society and government-sponsored guidelines from selected countries and
regions around the world are provided separately. (See "Society guideline links:
Ovarian, fallopian tube, and peritoneal cancer".)

SUMMARY AND RECOMMENDATIONS

● Introduction – The development of a gynecologic cancer during pregnancy is
a rare event, affecting 4 to 8 pregnancies in 100,000. (See 'Introduction' above.)
The risks of chemotherapy administration during pregnancy depend on the
specific drugs used and the gestational age of the fetus ( table 2). (See
'General principles' above.)
● General principles – Early delivery to avoid fetal exposure to chemotherapy is
reasonable provided the fetus is ≥34 weeks of gestation and/or fetal lung
maturity can be documented. In this setting, the risks of prematurity are
relatively low (see "Adnexal mass: Evaluation and management in pregnancy").
Prematurity can be associated with impaired cognitive development, and
therefore iatrogenic prematurity should be avoided when possible.
If chemotherapy is indicated, we initiate platinum-based chemotherapy during
pregnancy rather than waiting until after delivery. However, we wait until at
least the second trimester in order to minimize the potential for fetal injury.
(See 'General principles' above.)
 ● Choice of chemotherapy regimen – For patients with epithelial ovarian cancer
in pregnancy, we recommend platinum-based therapy (Grade 1B). Patients
should be informed of the limited data on maternal and fetal outcomes
associated with platinum and/or taxane therapy. (See 'Regimen' above.)
For most patients with germ cell tumors, we recommend adjuvant platinum-
based combination chemotherapy (Grade 1B). However, patients with stage IA
dysgerminomas or stage I grade 1 immature teratomas have a good
prognosis. We recommend not treating these patients with chemotherapy
(Grade 1A). (See "Treatment of malignant germ cell tumors of the ovary".)
● Sex cord stromal tumors – Salpingo-oophorectomy is the standard treatment
for tumors of low malignant potential and sex cord stromal tumors diagnosed
during pregnancy. These patients should not receive chemotherapy in
pregnancy. (See 'Sex cord-stromal tumors' above.)
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