DOI: 10.1002/ijgo.

12621

FIGO CANCER REPORT 2018

Cancer in pregnancy

Matthys H. Botha1,* | Shalini Rajaram2 | Kanishka Karunaratne3

1
Department of Obstetrics and
Gynecology, Stellenbosch University and Abstract
Tygerberg Hospital, Stellenbosch, South Africa The incidence of cancer in pregnancy is increasing. The most frequent malignancies
2
Department of Obstetrics and
include breast and cervical cancers. Diagnosis may be complicated by late presentation.
Gynecology, University College of Medical
Sciences and Guru Teg Bahadur Hospital, Imaging during pregnancy should consider risks to the fetus. Diagnostic work-­up,
Delhi, India
including tumor markers, can be influenced by the physiology of pregnancy. Treatment
3
National Cancer Institute of Sri Lanka,
of cancer can often be safely administered with good maternal and fetal outcomes.
Maharagama, Sri Lanka
Chemotherapy, radiotherapy, and surgery must be adapted to the pregnancy state.
*Correspondence
Counselling and emotional support are an essential part of management.
Matthys H. Botha, Department of Obstetrics
and Gynecology, Stellenbosch University,
Stellenbosch, South Africa. KEYWORDS
Email: mhbotha@sun.ac.za Cancer in pregnancy; Cancer treatment; Chemotherapy; FIGO Cancer Report;
Pregnancy; Radiotherapy

1 |  INTRODUCTION
Cancer in pregnancy, although uncommon, has been increasing in
recent years as demonstrated by various epidemiological studies.
The Danish registry showed a rise in the proportion of cancer asso-
ciated with pregnancy from 5.4% (n=572) to 8.3% (n=1052) over a
30-­year period—the most common cancers being melanoma, cervical,
1
and breast cancer. The increased incidence could not be explained
by advanced maternal age alone. An Australian study on pregnancy-­
associated cancer reported 1798 cancers over a 14-­year period, 499
during pregnancy and 1299 in the postpartum period, giving a crude
incidence of 137.3 per 100 000 pregnancies.2 There was a statisti-
cally significant increase in pregnancy-­associated malignancy during
this period and the number of mothers aged over 35 years increased
from 13.2% to 23.6%. However, age explained only a 14% increase
in incidence. The postpartum period (up to 12 months after delivery)
was included, bearing in mind a delay in diagnosis during pregnancy or
considering it part of the cancer-­in-­pregnancy continuum.
In a recent Italian population-­based linkage study, breast cancer
was the most common cancer (32%, n=479) and the risk of developing
a pregnancy-­related cancer increased significantly with age, from 60
per 100 000 for women younger than 30 years to 265 per 100 000 for
women older than 40 years.3 Melanoma, breast, and thyroid cancers
were more common in the Australian population than those reported
from other registries, and cervical and ovarian cancer incidence was
lower.2 In an international cohort of 1170 woman diagnosed with
cancer during pregnancy, the most common invasive cancers in preg-
nancy were breast cancer (39%, n=462), followed by cervical (13%,
n=147), lymphoma (10%, n=113), ovarian (7%, n=88), and leukemia
(6%, n=68).4 A population-­based study from Sweden found that the
most common cancer during pregnancy was melanoma (25%, n=232),
followed by breast (15%, n=139), cervical (15%, n=139), and ovarian
cancer (6%, n=54).5
The change in treatment and outcome of cancer in pregnancy was
reflected in the international cohort study.3 For every five years of the
study (1996–2016), treatment increased by 10% (95% CI 5–15) and
use of chemotherapy increased by 31% (95% CI 20–43). Live birth
rates increased and preterm births decreased. Maternal survival was
similar to nonpregnant women treated for cancer and encouraging
fetal, neonatal, and early childhood outcomes were observed in this
study. As such, oncologic treatment is possible during pregnancy,
often without significantly endangering maternal or fetal safety.
2 | DIAGNOSIS
Diagnosis of cancer is vital for successful treatment regardless of
pregnancy status. Diagnosis of cancer in pregnancy is, unfortunately,

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium,
provided the original work is properly cited.
© 2018 The Authors. International Journal of Gynecology & Obstetrics published by John Wiley & Sons Ltd on behalf of International Federation of Gynecology and
Obstetrics

Int J Gynecol Obstet 2018; 143 (Suppl. 2): 137–142 wileyonlinelibrary.com/journal/ijgo  |  137
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138       Botha ET AL.
often delayed; this is in part because many symptoms of malignancy
are similar to the symptoms of pregnancy, including nausea/vomit-
ing, breast changes, abdominal pain, anemia, and fatigue. Breast
changes and the pregnant uterus may make physical examination
difficult. In addition, the clinician may be more hesitant to assign the
appropriate tests because of concerns that laboratory results may
be inaccurate or that radiologic testing is harmful. Owing to its rar-
ity, cancer might not be considered in the differential diagnosis. This
delay in diagnosis can lead to late presentation, complex treatment,
and poor prognosis.6
2.1 | Laboratory testing
Tumor markers should be used with caution owing to pregnancy-­
induced elevation. The sensitivity and specificity of tumor markers
may be lower during pregnancy.7 Physiological changes in pregnancy
and accompanying alteration of commonly used laboratory values
may complicate the diagnosis of malignancy. Hemoglobin and hema-
tocrit values are typically lower, whereas alkaline phosphatase and
lactate dehydrogenase are typically higher in pregnancy. CA 15-­3
used in breast cancer, CA 125 used in epithelial ovarian cancer, and
alpha-­fetoprotein used in germ cell tumors are physiologically ele-
vated in pregnancy.8,9
2.2 | Imaging
Imaging in pregnancy to diagnose and stage cancer may create con-
flict between maternal benefit and fetal risk. Therefore, the following
issues need to be taken into account when choosing the appropriate
imaging technique:
1. Safety of the fetus.
2. Risk of metastasis.
3. Viability of the fetus.
Radiation exposure above 100 mGy is associated with fetal
malformation and childhood cancer.10 If X-­rays are needed, proper
abdominal shielding should be provided. Mammogram images are
increasingly difficult to interpret owing to physiological hypervascu-
larity and density of the breast tissue.11 Computed tomography (CT
scan) is best avoided during pregnancy because of the unaccept-
able cumulative radiation and contrast doses.12 Positron-­emission
tomography (PET) imaging in pregnancy is debatable owing to the
13
risk to the fetus of radiation exposure.
Ultrasound as a tool for diagnosis and staging is used worldwide.
It is noninvasive and helps to perform guided biopsies of the breast
and lymph nodes.
Magnetic resonance imaging (MRI) is safe in all trimesters of preg-
nancy. It is the imaging technique of choice for diagnosis and staging.14
Histopathology of tissues provides definitive diagnosis of tumor
type and grading. The pathologist should always be informed of the
patient’s pregnancy status to avoid incorrect diagnosis resulting from
pregnancy-­associated tissue changes.15 Aside from the changes to the
uterine corpus and ovaries, pregnancy has various effects on benign
conditions that may mimic malignancy.
3 | SPECIFIC CANCERS
3.1 | Cervical cancer
Cervical cancers are best diagnosed by cytology in early pregnancy,
but may also present with abnormal bleeding, vaginal discharge, and
abdominopelvic pain.16 Cervical cancers in pregnancy generally pre-
sent as Stage I disease at diagnosis. Pregnant women are three times
more likely to have Stage I disease than nonpregnant women with
cervical cancer.17
Management of preinvasive disease (CIN 1 to CIN 3) can be
deferred until 6–8 weeks after delivery. However, it is recommended
that a colposcopy is performed in each trimester to assess lesion size
and disease progress. Colposcopy can be challenging during pregnancy
owing to increased vascularity and an increase in genital edema.18
Immediate definitive treatment, regardless of gestational age, is
generally appropriate for invasive cancer in the following settings19:
1. Documented lymph node metastases.
2. Progression of disease during the pregnancy.
3. Patient choice to terminate the pregnancy.
Stage IA1 disease can be managed by conization and is best done
between 12 and 20 weeks of pregnancy.19 The term “coin biopsy” is
sometimes used in pregnancy to highlight that the incision should not be
deep enough to cause damage to the fetal membranes. This is best per-
formed in theatre with adequate anesthesia. Prophylactic cerclage may
be an option both for prevention of premature labor and management of
operative bleeding.
In stages IA2–IB1 (less than 2 cm) disease, conization or simple
trachelectomy can be performed because parametrial extension is
seen in less than 1% of women. Simple trachelectomy is a less com-
plicated procedure and is defined as excision of the cervix 1 cm above
the tumor border.20 However, it is necessary to assess lymph node
status by laparoscopic pelvic lymphadenectomy before conservative
surgery. In the event of node-­positive disease, the woman should be
told that immediate treatment is recommended. Laparoscopic lymph-
adenectomy is best performed before 20 weeks of pregnancy.17,19 The
second international consensus guidelines recommend this treatment
in pregnancies of less than 22–25 weeks.19 Abdominal and vaginal
radical trachelectomy have also been performed during pregnancy,
with variable pregnancy outcomes. Abdominal radical trachelectomy
is technically more challenging and is associated with significant
blood loss and prolonged surgery (3.5–7.5 hours, median 5.3 hours).21
Obstetric outcome is poor and, therefore, radical trachelectomy is not
recommended during pregnancy.19
Stage IB1 tumors larger than 2 cm may be treated with neoad-
juvant chemotherapy (NACT) with or without pelvic lymphadenec-
tomy. Chemotherapy is relatively safe in the second trimester
although there is a higher risk of preterm labor, premature rupture of
Botha ET AL.
membranes, and fetal growth restriction. NACT stabilizes the tumor
until fetal maturity is achieved so that cesarean delivery and radical
hysterectomy can be performed. In women with advanced pregnancy
(greater than 22–25 weeks), pelvic lymphadenectomy is not possible
and those with Stage IA1 to Stage IB1 disease can postpone defini-
tive treatment until fetal maturity is achieved without compromising
survival. NACT can also be given for locally advanced cancers and in
advanced pregnancy to preserve pregnancy until optimal fetal survival
(35–36 weeks) is reached. Cesarean delivery followed by radical sur-
gery or definitive chemotherapy/radiotherapy showed good obstetric
and oncological outcome.22
Cesarean delivery is the preferred choice for delivery of the fetus
in the presence of bulky tumors. Vaginal delivery risks the possibility of
catastrophic bleeding and implant metastases in vaginal tears or epi-
siotomy scars. In locally advanced tumors a lower segment transverse
cesarean delivery should be avoided owing to the risk of cutting or
tearing into tumor tissue. A classical incision will minimize blood loss
and avoid the large tumor vessels.
Where pregnancy preservation is not desired or in advanced cases,
pregnancy termination and treatment as in nonpregnant women
is advocated. In early gestation (less than 12 weeks), spontaneous
abortion occurs after pelvic radiation. In second trimester cases, hys-
terotomy followed by definitive chemoradiation is preferred because
obstetric complications are fewer.
3.2 | Breast cancer
Breast cancer, although uncommon, is the most prevalent malig-
nancy encountered in pregnancy and the postpartum period. The
difficulty and delay in diagnosis may be attributed to pregnancy-­
related changes in the breast and diagnostic challenges that allow
these cancers to go undetected until the first postpartum year.
Breast cancers in pregnancy are usually larger in size, node posi-
tive, Stage II or III, high-­grade invasive ductal cancer, and usually
ER/PR/HER2/neu-­negative.23,24 Prognosis is related to tumor
characteristics and delay in starting treatment and not to preg-
nancy alone.
When breast cancer is suspected in pregnancy, delay in diagno-
sis should be avoided. Mammography and ultrasound are the best
imaging modalities; mammography has a sensitivity of more than 80%
despite pregnancy-­associated breast changes.25 Ultrasound can be
used to assess the extent of the disease in breast and lymph nodes and
for guiding biopsies.26 Core needle biopsy is the preferred modality.
Experience with MRI in pregnancy is limited and gadolinium-­enhanced
contrast is contraindicated in the first trimester because it crosses the
placenta. A recent study of breast MRI showed 98% sensitivity in
diagnosis of pregnancy-­associated breast cancer and changed treat-
ment modality in 28% of women.27 Comprehensive staging studies are
needed because breast cancer in pregnancy may present in advanced
stage. Chest X-­ray with abdominal shielding to evaluate the lungs and
ultrasound for liver involvement are safe in pregnancy. Bone scans can
be performed postpartum, but if a woman is symptomatic, noncon-
trast skeletal MRI is safe.25
|
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Treatment is as for nonpregnant women with the goal of achieving
local control and preventing distant metastases. Modified radical mas-
tectomy with axillary staging is the treatment of choice in the first tri-
mester. Adjuvant chemotherapy can be started in the second trimester
and radiation therapy given postpartum.28,29 Breast conserving sur-
gery can be done safely in the second and third trimesters. Experience
in using sentinel lymph node biopsy (SLNB) in pregnancy is limited.
Blue dye is contraindicated but technetium-­99m has been used safely.
Adjuvant chemotherapy with anthracycline-­based regimes, such as
various combinations of cyclophosphamide, doxorubicin, and fluoro-
uracil, can be started in the second and third trimester. There are insuf-
ficient data to recommend taxanes, but paclitaxel can be used after
the first trimester if indicated by disease status. Trastuzumab is con-
traindicated and oligohydramnios/anhydramnios have been reported.
Endocrine treatments including tamoxifen, aromatase inhibitors, and
LHRH analogues are contraindicated in pregnancy due to the high risk
of birth defects. If a woman becomes pregnant while on tamoxifen,
pregnancy termination should be advised.28,29
3.3 | Ovarian cancer
Adnexal masses are not uncommon in pregnancy and occur in roughly
1 in 600 to 1 in 1500 pregnancies. The majority of these are benign
and only 1%–3% may be malignant. The most commonly encountered
ovarian malignancy is germ cell, followed by sex cord stromal tumors,
borderline tumors, and lastly invasive epithelial cancers.30 The most
common symptom is abdominal or pelvic pain and one-­third of ovar-
ian cancers are diagnosed incidentally. The majority of tumors pre-
sent as Stage I, with a mean age of 25.8 years and 31.6 years in germ
cell tumors and invasive epithelial cancers, and mean size of 18 and
12 cm, respectively.31,32
Transvaginal and abdominal ultrasound have high sensitivity
and specificity in the diagnosis of ovarian masses. However, MRI
has the best diagnostic accuracy in the diagnosis of ovarian malig-
nancy in pregnancy.33 MRI (without contrast) and diffusion-­weighted
imaging are useful in assessing the extent of peritoneal disease and
nodal metastases. Tumor markers are not useful as CA 125, alpha-­
fetoprotein, and beta hCG are elevated in pregnancy. Inhibin B, anti-­
Müllerian hormone, HE4, CA 19-­9, and lactate dehydrogenase are not
elevated in pregnancy and can be used for diagnosis.
Early-­stage ovarian cancer can be treated surgically in the second
and third trimester with surgical staging, salpingo-­oophorectomy,
omentectomy, peritoneal biopsies, and evaluation of suspicious
lymph nodes. Both laparoscopy and laparotomy are accepted pro-
cedures. Care should be taken to avoid ovarian rupture and spillage.
Paclitaxel/carboplatin-­based chemotherapy can be given safely in
the second and third trimester in epithelial ovarian cancer, stop-
ping before 37 weeks to avoid myelosuppression in the neonate.
Bevacizumab is not recommended during pregnancy. Vaginal delivery
is ideal in early-­stage ovarian cancer treated surgically. In germ cell
tumors, a BEP regime is considered too toxic because fetal growth
restriction and neonatal complications are high. Weekly paclitaxel
and cisplatin is recommended as per ESMO guidelines.29 Advanced
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140       Botha ET AL.
cancers (Stage III and IV) detected in the first trimester and early
second trimester will need complete debulking surgery and adju-
vant chemotherapy. In the late second and third trimesters, NACT is
given until fetal maturity is reached. Cesarean delivery followed by
complete cytoreductive surgery is feasible. Although pregnancy out-
comes are good, prematurity, fetal loss due to surgical complications,
and fetal growth restriction do occur. Oncological outcomes are the
same as in nonpregnant women.34
4 |  CANCER TREATMENT IN PREGNA NCY
4.1 | Radiotherapy
Radiotherapy in a pregnant patient should be planned carefully.
The radiation oncologist and the physicist must minimize direct and
indirect sources of radiation to the fetus. The fetal dose should not
exceed 50–100 mGy.35 The risks at various times of fetal develop-
ment are summarized in Table 1.
Scatter and leakage radiation are a concern even with proper
shielding, although adequate shielding can minimize risks. Shielding
of the gravid uterus, especially in advanced pregnancy, can be diffi-
cult owing to the heavy materials used. Some obstetric experts advise
regular clinical and ultrasound examinations to determine the lie of
the fetus to get the position of the fetal head out of the potential field
of radiotherapy; for example, in the case of chest radiotherapy, the
fetus should be in a cephalic position and external cephalic version
may be indicated.
4.2 | Chemotherapy
After the first trimester, most chemotherapeutic agents can be used
with relative safety. Transplacental transport of chemotherapeutic
agents differs widely, with some agents such as paclitaxel crossing
the placenta at a low rate, anthracyclines crossing the placenta at an
intermediate rate, and carboplatin at a high rate.8,9 Despite this, car-
boplatin administered after 12–14 weeks of pregnancy seems to do
little harm to the developing fetus.37
T A B L E   1   Risks to the fetus of radiotherapy during pregnancy.a
Gestational age (weeks) Risks
Preimplantation (1) Lethality
Organogenesis (2–7) Lethality, gross malformations, growth
retardation, sterility, cataracts, other
neuropathology, malignant disease
Early fetal (8–15) Lethality, gross malformations, growth
retardation, mental retardation,
sterility, cataracts, malignant disease
Midfetal (16–25) Gross malformations, growth
retardation, mental retardation,
sterility, cataracts, malignant disease
Late fetal (>25) Growth retardation, sterility, cataracts,
malignant disease
a
Adapted from Stovall et al.36
Trastuzumab is generally contraindicated in pregnancy because of
HER2 receptors on the kidneys of the fetus, resulting in oligo-­ or anhy-
dramnios and fetal lung hypoplasia. The antifolates, such as metho-
trexate, are also contraindicated.
The risk of congenital malformation is linked directly to gesta-
tional age and before 12 weeks there is a risk for abnormalities of the
eyes, ears, and blood systems; the risk decreases significantly after
complete organogenesis.
Chemotherapy may cause a significant reduction in maternal blood
production, leading to low platelet counts and risk of overwhelming
infection. When chemotherapy is used, timing of delivery should be
planned carefully. Elective delivery should not be planned within three
weeks after chemotherapy. For this reason, chemotherapy should not
be administered after 37 weeks of pregnancy owing to risk of sponta-
neous onset of labor.
Long-­term follow-­up of children born to mothers who received
chemotherapy during pregnancy does not indicate an increased risk
of congenital abnormalities or mental delay. The number of children
with long-­term follow-­up is still small and the data should be inter-
preted with caution. Potential risks include concern for cardiac func-
tion in children exposed to anthracyclines during the fetal period.
Anthracyclines are commonly used for breast cancer treatment and
have a direct effect on cardiac function. In a follow-­up study of 17
children, no changes in electrocardiogram or echocardiography could
be found after the use of anthracyclines.
4.3 | Surgery
Cancer surgery in pregnancy may be indicated for diagnosis, treat-
ment, and staging. Surgery is urgent but not an emergency and may be
delayed until fetal maturity is established without compromising total
care. As a principle, surgical procedures are best undertaken in the
second trimester to prevent spontaneous abortion.38,39
Surgery in the second trimester is technically less complicated com-
pared with in the third trimester owing to the size of the uterus. When
surgery is performed after 28 weeks, tocolytics should be admin-
istered to prevent premature labor and corticosteroids to enhance
lung maturity. Handling of the uterus should be kept to a minimum.
Unilateral or bilateral oophorectomy can be carried out safely after
the first trimester. Whenever possible, regional anesthesia is preferred
over general anesthesia owing to the potential risk of aspiration.40
A lateral tilt during surgery may help to prevent aortocaval com-
pression.41 The patient should be consented for emergency cesarean
delivery in the third trimester if fetal compromise is encountered.
Therapeutic surgery can be performed in any trimester.
5 | PLACENTAL AND FETAL
TUMOR INVOLVEMENT
Metastatic disease to the placenta and the fetus is rare. The most
likely tumors to metastasize to the placenta include melanomas and
hematological malignancies. In all cases where malignant spread is
Botha ET AL.
possible, the placenta should be submitted for careful histologic evalu-
ation. The fetus should be examined carefully at birth and at regular
intervals after birth for any signs of metastatic disease.
6 | COUNSELLING
Cancer during pregnancy represents both a psychological and biologi-
cal dilemma given that treatment should be directed to save two lives:
maternal and fetal. Using a multidisciplinary approach, counselling can
help to reduce the distress of the patient and her family. It is essential
that the obstetrician, oncologist, pediatrician, and psychotherapist take
leading roles. The patient and her family should be actively involved in
the decision-­making process, which will enhance confidence and support.
6.1 | Breaking bad news
Receiving bad news is painful for any patient.42 Counselling should
always include information on the ongoing pregnancy and impact of
the disease on the mother and baby.43 Certain guidelines should be
adhered to42:
 1. Assess the mental state of the patient.
 2. Ensure privacy.
 3. Take adequate time to assess the situation.
 4. Be honest.
 5. Provide accurate information.
 6. Show empathy.
 7. Arrange for family members to be present.
 8. Provide evidence-based treatment options.
 9. Inform about other supportive services.
10. Clearly indicate that the patient has the final decision regarding
their care.
11. Briefly explain the process by which the diagnosis was reached.
12. Provide varied methods to convey the information, for example,
written material and video.
6.2 | Counselling about prognosis
Patients require information about the prognosis to make treatment
decisions. Most patients want specific and honest information about
the prognosis:
1. Specific: median survival.
2. General: “I think your chances are good.”
3. Statistical: average time gain.
4. Exceptional cases: survival against the odds.
A realistic and honest approach is essential to maintain the
patient’s confidence and support. Providing too much information
using medical jargon, hiding news, false reassurance, and a pater-
nalistic approach disregarding the patient’s concerns all reduce their
confidence.44 The basis of shared decision making is to exchange
|
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information in a clear, evidence-­based, and unbiased manner, giv-
ing due consideration to the patient’s values, concerns, beliefs, and
priorities in life.
AU T HO R CO NT R I B U T I O NS
MB, SR, and KK each contributed to the research and writing of the
manuscript.
CO NFL I C TS O F I NT ER ES T
The authors have no conflicts of interest to declare.
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