A. Mukhopadhyay et al.

/ Best Practice & Research Clinical Obstetrics and Gynaecology xxx (2015)
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Best Practice & Research Clinical

Obstetrics and Gynaecology
j o u r n a l h o m e p a g e : w w w . e l s e v i e r. c o m / l o c a t e / b p
obgyn

Ovarian cysts and cancer in pregnancy

Asima Mukhopadhyay, MD, MRCOG, PhD, Consultant
a, b, *
Gynaecological Oncology ,
Aditi Shinde, MS, DNB, Clinical Fellow in the Department of
a
Gynaecological Oncology ,
c
Raj Naik, MD, FRCOG, Consultant Gynaecological Oncology
a
Tata Medical Center, 14 Main Arterial Road, Rajarhat, Kolkata 700156, India
b
Newcastle University, New Castle, UK
c
Northern Gynaecological Oncology Centre, Gateshead, UK

Adnexal masses are diagnosed in 5% pregnancies and pose diag-

Keywords:
nostic and management challenges. Ultrasound and magnetic
ovarian cyst
ovarian cancer resonance imaging (MRI) are the mainstay as an evaluation pro-
pregnancy cedure; surgery is warranted for persistent masses with a diameter
of >5 cm and sonographic signs of possible malignancy. Optimal
timing for a planned surgery is the second trimester and does not
adversely affect neonatal outcome. Laparoscopy is safe in preg-
nancy. Management for ovarian cancer during pregnancy should
be individualised and formulated by a multidisciplinary team in a
specialised centre while also considering the patients' wishes to
preserve pregnancy. The following options can be considered: (i)
induced abortion followed by standard management of ovarian
cancer, (ii) pregnancy-preserving surgery followed by chemo-
therapy, planned delivery and secondary surgical completion or
(iii) neoadjuvant chemotherapy followed by surgery during the
postpartum period. Standard chemotherapy administered in non-
pregnant population can only be used during the rst trimester
of pregnancy.
2015 Elsevier Ltd. All rights reserved.

* Corresponding author. Tata Medical Center, Kolkata, India. Tel.: 91 7044088132, 44 7951040818.
E-mail address: asima7@ yahoo.co.in (A. Mukhopadhyay).

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2015 Elsevier Ltd. All rights reserved.
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Introduction

Ovarian masses in pregnancy, which can range from innocuous corpus luteal cysts to malignant
ovarian tumours, pose a challenge from both a diagnostic and management point of view. The inci-
dence of adnexal masses in pregnancy has been variably reported as 0.15e5.7%; clinically signicant
masses range from one in 25 to one in 8000 pregnancies [1e5]. A higher trend in reporting is
possibly explained by the increasing use of ultrasound (USS) as a routine antenatal evaluation and
postponing childbearing to an older age.
Malignant adnexal masses during pregnancy range between 0.8% and 13% [5e12]. The reported
incidence of ovarian cancer (OC) in pregnancy varies from 1 in 15,000 to 1 in 32,000 and it is
amongst the top ve cancers diagnosed during pregnancy [13e17]. With the increasing maternal
age, it is ex- pected that more women will be diagnosed with OC in pregnancy in the future,
therefore management guidelines should be formulated with a regular update and review of recent
literature [15,16].
Several articles have addressed the issues pertaining to the diagnosis of an adnexal mass, man-
agement algorithms specic to each trimester, use of laparoscopy and laparotomy during pregnancy
while also considering the foetus. In this study, we intend to focus on the complexities of managing
OC in pregnancy, especially when the role of primary cytoreduction to no macroscopic residual
disease or extensive staging procedures is gaining momentum and increasingly debated within
the gynaeco- logical oncologist community.

Ovarian cysts in pregnancy

Dermoid cyst, cystadenoma, functional corpus luteal cysts and endometrioma are the most com-
mon causes for benign ovarian cysts in pregnancy [5e8]. In addition, ovarian hyper-stimulation
and polycystic ovaries should be kept in mind, especially with a history of infertility (Tables 1e3).
Most adnexal masses are diagnosed incidentally in the rst trimester during the routine dating
scan, unless investigated earlier for infertility: 65e80% are asymptomatic, and almost three-fourth
resolve spontaneously, with those persisting beyond 16e20 weeks indicating denitive pathology.
Mature cystic teratoma and borderline ovarian tumour (BOT) are the most common
histopathological diagnosis amongst persistent masses [18e22].

Table 1
Incidence of ovarian cysts and ovarian cancer in pregnancy.

Author n Incidence of Ovarian cysts (%) Incidence of malignancy including tumours

of low malignant potential (%)

Sherard [5] 60 0.15 13

Balci [6] 36 5.8
Trkog lu [7] 35 0.3 8.5
Bromley [8] 131 0.8
Schmeler [9] 63 0.05 7.9
Cohen-Herriou [10] 71 0.35 4.2
Leiserowitz [11] 9375 0.19 2.15
Chittacharoen [12] 118 0.10 2.9

Table 2
Ovarian cysts in pregnancy.

Author Gestation age at diagnosis Gestation age at surgery Commonest histopathology

Sherard [5] 12 20 Mature cystic teratoma (50%)

Balci [6] 17 (5e36) 24 (6e41) Functional ovarian cyst (41.1%)
Trkog lu Dermoid cyst (40%)
nd
[7] Bromley 12 2 trimester Dermoid cyst (30%)
Schmeler
[8] [9] 12 Dermoid cyst (42%)
Cohen-Herriou [10] Functional ovarian cyst (74.39%)
Hoover [17] First trimester 12e27 weeks Dermoid (25%)
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Table 3
Differential diagnoses of adnexal masses in pregnancy e adapted from RCOG Green Top Guidelines No. 62.

Benign ovarian Functional cysts Serous cystadenoma

Endometrioma Mucinous cystadenoma
Mature teratoma
Benign non-ovarian Distended bladder Pelvic kidney
Para-tubal cyst Urachal cyst
Hydrosalpinx Tubo-ovarian abscess
Pedunculated myoma. Appendicular mass
Peritoneal pseudocyst
Malignant primary Germ-cell tumour
Epithelial malignancies
Sex-cord stromal tumours
Malignant secondary Breast and gastrointestinal malignancies
Gestational Ectopic pregnancy
IUP in bicornuate uterus.

Assessment of ovarian masses during pregnancy

Clinical assessment and imaging are the mainstay; histopathological diagnosis may be indicated
only in selected cases. Tubo-ovarian abscess and ectopic pregnancy should be excluded as it is
potentially life threatening. The goal of the diagnostic workup of an adnexal mass should be to
differentiate between ovarian and non-ovarian causes, and if ovarian, to differentiate between benign
and malignant masses [23].

Clinical assessment

A thorough physical examination after excluding a full bladder should evaluate signs of infection
or neoplasm including assessment of cervical/supraclavicular/groin lymphadenopathy, breast
examina- tion, pleural effusion or ascites. Bimanual and rectovaginal examinations are useful for
endometriosis; masses felt anterior to the uterus may suggest dermoid cysts. With the advent of
better imaging modalities, routine per vaginal examination during pregnancy is being performed less
frequently due to a generally poor sensitivity for detection of ovarian masses and the risk of
introducing ascending infection. It may, however, help to rule out obstetric complications such as
miscarriage, ectopic gestation and preterm labour and in resource poor settings, triaging prior to
referral for transvaginal USS.

Radiological assessment

USS is considered the investigation of choice [24,25]; routine USS during pregnancy is usually
done at 11e136 weeks and then at 18e20 weeks of gestation. Up to 70% cysts identied during
the rst trimester resolve spontaneously by 18e20 weeks (Table 4). Size and morphology are used
to decide
between intervention and surveillance as well as identifying which patients need an elective lower
uterine caesarean section (LUCS) at term. The B and M rules for USS diagnosis of malignancy
described by the International Ovarian Tumour Analysis (IOTA) group have 78% specicity and 87%
sensitivity (Tables 5 and 6) [23,26,27]. Doppler indices change rapidly during pregnancy, hence is not
consistently used and reported in pregnancy [28,29].

Table 4
Resolution of masses detected on USS in the rst trimester with size.

Author N Incidence <5 cm simple >5 cm or Complex Disappearance

Bernhard 1999 [19] 432 2.6% 76% 24% 68.6%

Zanetta 2003 [23] 82 1.2% 50% 19.4% 58%
Condous 2004 [24] 182 5.4% e 29.51% 71.1%
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Table 5
IOTA simple rules for categorization of adnexal mass e adapted from RCOG Green Top Guidelines No.

62. B Rules M Rules

Unilocular cyst Irregular solid tumor

Presence of solid component, largest <7 mm Ascites
Acoustic shadowing At least four papillary structures
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Smooth multilocular tumor with largest Irregular multilocular solid tumor with largest
diameter <10 cm diameter 10 cm
No blood ow Very strong blood ow

Table 6
USS features and predicted resolution of ovarian masses.

Diagnosis USG Features Resolution

Simple cyst anechoic cyst without septa or vegetations 69%

Endometriosis or corpus hypoechoic content, either homogeneous or trabecular, no papillae 77%
luteum like
Dermoid like combination of hyperechogenic and hypoechogenic content, shadows 0%
Complex benign septa, thick content but no papillae 57%
Borderline-like smooth capsule, presence of intracystic papillae, absence of gross solid parts 0
Suspicious solid parts, irregular capsule or border, ascites, irregular vascularization e

Contrast-enhanced magnetic resonance imaging (MRI) has a sensitivity and specicity of 100% and
94%, respectively, in the diagnosis of malignancy and has negligible risks to the foetus; it may be a
useful adjunct when USS is inconclusive/insufcient to guide management [30]. Contrast
enhancement may help to delineate solid components in a cystic mass and non-enhanced areas in
a tarted mass. Gadolinum is teratogenic in animal studies and is classied as a category C drug by the
Food and Drug Administration (FDA); more stable macrocyclic agents, that is, gadoteridol and
gadobuterol may be considered. Left lateral decubitus positioning should be considered to avoid caval
compression by the gravid uterus.
The American College of Radiology recommends MRI and USS for imaging during pregnancy
[31e33]. Use of computed tomography (CT) scans is disfavoured; ionising radiation or the contrast
crossing the placental barrier may pose a risk in terms of neurological and cardiological damage to
the foetus and the risk of developing childhood cancers. If the MRI is not available, the use of CT scan
after weighing the potential risks to the foetus with maternal benet may be justied. Hurwitz et
al. rec- ommended the following to reduce radiation exposure to the foetus [34]; (i) lowering the
current tube, (ii) limiting the coverage in z axis (iii) increasing the helical pitch (iv) reducing gantry
cycle time. A single multidetector-row computed tomography (MDCT) protocol exposes the foetus
to 3.5 cGy; the safe limit of neurological damage is <10 cGy.

Role of tumour markers

CA 125 is an antigenic determinant expressed with epithelial ovarian tumours, but it is physio-
logically elevated during pregnancy; increased CA 125 is seen at 30e40 days peaking at 35e60 days
of gestation and a fall by the end of the rst trimester [35]. In addition, majority of pregnant
patients present with stage I disease, and only 50% of early-stage tumours have a CA 125 above 30
IU [36]. Tumour markers that are typically elevated in germ-cell tumours including
alphafetoprotein (AFP), lactate dehydrogenase (LDH) and human chorionic gonadotropin (hCG) are
also altered during preg- nancy, limiting their clinical utility. Baseline values for prognostication
may be obtained in the puer- peral period after 4e6 weeks.

Complications

Persisting masses have the potential to cause complications in 10e30% of pregnancies including
acute sequelae like torsion, haemorrhage, rupture and obstruction of labour, which cause potential
adverse perinatal outcome [7,19]. Persistence of abdominal pain and hemodynamic instability may
indicate emergency laparotomy irrespective of the gestational age of the patient. Rarer presentations
include diagnosis during caesarean section [37] or hormonally active tumours like granulosa, Serto-
lieLeidig cell and sex cordestromal tumours, which may present with features like abdominal pain,
swelling, shock, virilisation and vaginal bleeding [38].

Torsion

Pregnancy increases the risk of torsion (19.9 % vs. 9%) due to displacement of the ovaries from
the pelvis during uterine enlargement [39e41]. Majority of torsion events occur between 15 and 17
weeks of gestation. Additional risk factors include in vitro fertilisation and tumour sizes of 6e8 cm.

Rupture

Rupture of functional cyst is common; however, it rarely causes symptoms severe enough for
intervention or spontaneous rupture during pregnancy. Iatrogenic rupture after ne-needle aspiration
or intraoperative cyst rupture due to tumour handling should be minimized to avoid chemical peri-
tonitis and accidental peritoneal seedling of an early-stage ovarian malignancy.

Obstruction of labour

Similar to obstructing broids, large adnexal masses may predispose to labour dystocia (2e17%) if
located near the lower uterine segment and below the presenting part [7].

Management

There is no consensus in the literature regarding surgical or conservative management of benign

adnexal masses during pregnancy [42e44]. Generally, ovarian cystectomy or a salpingo-
oophorectomy (BSO) is performed for a benign pathology. There is a theoretical risk of pregnancy
loss with oopho- rectomy before 9e11 weeks of gestation; surgery at 16e20 weeks may ensure (i)
spontaneous reso- lution of masses, (ii) better uterine visualisation and exclusion of congenital
anomalies in foetus and (iii) reduced risk of preterm labour. Surgery should not be delayed beyond 23
weeks in view of poorer outcomes with the delayed treatment of the malignancy. Improvements in
imaging assessment have led to a reduction in the rate of negative surgeries performed to identify an
ovarian malignancy from
14:1 to 2.5:1 [9,45]. For lesions suspicious of malignancy on preoperative imaging, a frozen section is
helpful. Poorer outcomes are associated with emergency surgeries as compared with elective ones
[46]. Aggarwal and Kehoe elucidate certain principles of managing an adnexal mass in their evidence-
based review (Fig. 1) and summarized as follows [47]:

1. A conservative approach is justied for asymptomatic masses detected incidentally on rst

trimester USS.
2. If symptomatic or USS shows features of malignancy, surgery should be undertaken. MRI is advised
if malignancy cannot be condently excluded. If surgery is planned, it should be performed in the
second trimester.
3. If USS shows no features of malignancy, repeat the USS at 18e20 weeks at the time of the
congenital anomaly scan. A mass detected in the third trimester with no features of malignancy
should be left undisturbed until the time of CS or 6 weeks' postpartum.

General surgical considerations and management during the perioperative period

This entirely depends on the gestational age and is applicable for any abdominal surgery e
whether for benign/malignant ovarian masses or surgery for ovarian/non-ovarian pathology
[48e51]. The incidence of ovarian masses for which a surgical procedure is warranted during
pregnancy ranges from
 Adnexal mass in T1

Symptomac
Asymptomac
 Suspicious of Doubul Not suspicious of
malignancy malignancy

Repeat USS
Surgery MRI
evaluaon at 1820

Persistence, increase in size, Resoluon

solid consistency

Observaon Laparotomy <23 Review at the me

weeks of LUCS/6 weeks
post-partum

Fig. 1. Management algorithm adapted from Aggarwal, Kehoe.

one in 600 to one in 1500 pregnancies, and the rate of malignant disease in patients treated surgically
is
1e3% [9]. Generally, surgeons operating on pregnant patients must be familiar with the following
specic pathophysiologic aspects of pregnancy:(i) elevated haemostatic capacity, (ii) reduced anti-
coagulation activity and major alterations in the brinolytic systems, (iii) cardiovascular changes
specic to each trimester during pregnancy and (iv) change in surgical incision site to conform to
the size of gravid uterus to maximise exposure and displacement of other pelvic and extra-pelvic
organs.
If surgery is indispensable during the rst trimester, progestin support should be provided post-
operatively. Corticosteroids for foetal lung maturation should be given at least 48 h before surgery
between 24 and 34 weeks whenever possible. Prophylactic perioperative tocolytic therapy is contro-
versial. In a study by Visser et al. [52], preoperative tocolytic (Indocin or Terbutaline) was
administered in 28 patients; 24 (86%) had no uterine contractions. Before induction of
anaesthesia, the patient should be placed in a left lateral oblique position to prevent inferior vena
cava compression and supine hypotension syndrome as well as to improve the uterine blood ow
[53]. Proper precautions against maternal aspiration must be ensured.

Perioperative foetal monitoring

Intrauterine asphyxia is one of the most serious foetal risks during maternal surgery, which may
be minimised by maintaining haemodynamic stability. Surgery should be performed at an institution
with
neonatal and paediatric services. Before the age of foetal viability, it may be sufcient to ascertain the
foetal heart rate before and after the procedure. If the foetus is considered to be viable,
simultaneous electronic foetal heart rate and contraction monitoring should be performed before
and after the procedure (ACOG Committee Opinion 2011) [54].

Postoperative considerations

KleihauereBetke (KB) test, measuring foetal haemoglobin in the maternal blood, should be per-
formed in the post-operative period, and all Rhesus-negative patients should receive Rh immune
globulin (RhIG) at the recommended doses within 72 h after surgery. For women with positive KB
test, more RhIG can be administered according to the measurable extent of fetomaternal
haemorrhage. The need of thromboprophylaxis should be individualised; the hypercoagulable state
during pregnancy may increase the risk of thromboembolic events in the postsurgical period.
Subcutaneous enoxaparin
40 mg can be used perioperatively and is listed by the FDA in pregnancy as category B. Especially, in
case of a malignancy, an extended prophylaxis of up to 4e6 weeks post delivery following discharge
from the hospital should be considered [55].

Obstetric outcome after surgery during pregnancy

Non-obstetric surgery is carried out in 1.6e2.2% of pregnancies [51]. Surgical intervention for
majority of the adnexal masses in pregnancy generally does not adversely impact on the overall ob-
stetric outcome. However, prospective studies need to validate probable associations with preterm
birth and low birthweight.
Several recent publications have shown that laparoscopy is generally safe at all gestational ages,
without increasing maternal or foetal risks. In a retrospective study by Reedy et al. [56,57], 2181
lap- aroscopies and 1522 laparotomies were performed during pregnancy. Five foetal outcome
parameters were recorded; there was an increased risk for birthweight <2500 g, foetal growth
restriction and delivery <37 weeks compared with the general population. There was no
difference in the foetal outcome between laparoscopy and laparotomy in singleton pregnancies
between 4 and 20 weeks' gestational age.

Considerations for laparoscopic surgery during pregnancy

During pregnancy, level II evidence favours use of laparoscopy over laparotomy [58]. Benets of
laparoscopy in pregnancy include (1) rapid return of post-operative bowel function, (2) lesser post-
operative incisional pain and narcotic use, (3) lower morbidity from atelectasis and thromboembolic
events, (4) lesser need for uterine traction leading to less irritability, (5) faster post-operative ambu-
lation and return to regular activity. Table 7 lists the benets, associated risks and risk-reduction
strategy in laparoscopy.
Laparoscopic techniques require modication compared with that in non-pregnant women
[59e65]; supra-umbilical primary trocar placement for the optic port (halfway between the umbilicus
and the xiphoid, depending on the fundal height) is recommended because of the increased risk of
perforation of the enlarged uterus. An open technique (Hasson's) for trocar or Palmer's point entry
with Veress needle, 1e2 cm below the costal margin in either the left or the right upper quadrants
at the midclavicular line may also be used. Pneumo-pertioneal pressure should be capped at
approximately
8e12 mmHg; increased intra-abdominal pressure may cause a decrease in the uterine blood ow
leading to foetal hypotension and hypoxia [2,51].

Ovarian cancer in pregnancy

Histology
 Approximately 50% of OCs in pregnancy are epithelial in origin. Germ-cell and stromal tumours
account for 30%, and the remaining 20% consist of rare tumour entities, for example, sarcomas and
Table 7
Laparoscopic surgery in pregnancy: risks and risk reduction.

Risks of laparoscopy during pregnancy Risk Reduction Strategy

 Enlarged uterine size leading to inadvertent
uterine injury from trocar placement.
Veress needle insufating the intrauterine cavity
leading to CO2 embolism.
Hypercarbia and acidebase imbalance.
Intra-abdominal pressure leading to reduced
cardiac output.
Inferior vena cava compression leading to supine
hypotension.
Alteration of foetal BP, pulse respiration with
ventilator settings.
Increased carbon monoxide in the foetal blood due to
smoke from electrosurgical instruments.
Port placement in the sub-xiphoid, left upper quadrant
and supra-umbilical region 6 cm above the fundus.
Use of Hassons' technique. Selected use of closed
pneumoperitoneum.
Use of Laprolift instead of CO2 pneumoperitoneum
Intraoperative capnography
IAP <15 mm Hg in Trendelenburg position.
Left lateral tilt of patient during surgery.
Intraoperative foetal monitoring.
Use of bipolar/ultrasound energy source instead
of monopolar.

secondary metastases to the ovary [4,66]. Thus, epithelial ovarian cancer (EOC) is more commonly
reported in pregnant patients compared with germ-cell tumours, contrary to the distribution seen in
non-pregnant patients of the same age group [2].

Diagnostic workup in cases of suspected malignancy

As mentioned previously, the USS criteria for suspected malignancy are similar to those in non-
pregnant women. There is limited role for tissue diagnosis before surgery unless in case of advanced
malignancy where neoadjuvant chemotherapy (NACT) is being contemplated.

Effect of cancer on pregnancy and pregnancy on cancer

Pregnancy per se does not cause OC progression as most cases are not hormone dependent [67]. In
addition, there may be earlier identication of malignant masses during the dating scan. On the
contrary, there may be a delay in initiating aggressive therapy during pregnancy or major
cytoreductive surgery which in turn can lead to cancer progression. Increased blood ow to pelvic
organs, hyper- coagulopathy, hypo-albuminaemia can occur both in pregnancy and in advanced
cancer which may add to the complications and management. Cancer in itself does not affect the
physiology of pregnancy, except for psychological consequences, but its management does.
Leiserowitz reported an increase in hysterectomy, caesarean section, blood transfusion and
prolonged hospitalisation, but no signicant difference in neonatal outcomes of low birth weight,
prematurity, newborn and infant death between OC during pregnancy and non-malignant controls
[11]. In a registry-based cohort study in Norway, patients with breast (hazard ratio (HR), 1.95; 95%
condence interval (CI), 1.36 to 2.78) and OC (HR,
2.23; 95% CI, 1.05 to 4.73) diagnosed during lactation had an increased risk of cause-specic death [3].

Management of ovarian cancer: General principles

To date, there are no standardised therapeutic guidelines regarding the treatment of OC during
pregnancy; each case needs to be addressed individually [68]. Treatment in specialised centres
should be intended at any time and depends upon stage, type, gestational age (GA), patient's
wishes and attitude towards pregnancy continuation, performance status and extent of metastatic
spread [15,16]. Unlike in some other cancers during pregnancy, where consideration may be given
for expectant management till attainment of foetal maturity, OC diagnosis and treatment should be
expedited and treated as in non-pregnant women in order to prevent disease progression. Medically
induced abortion followed by standard treatment of EOC is a potential option, especially in the
rst trimester. If a pregnancy-preserving approach is warranted, surgery and chemotherapy should
be avoided during the rst trimester because of higher miscarriage rates, most likely due to
disruption of the corpus luteum.
Termination of pregnancy or delivery, pregnancy-preserving surgery and adjuvant chemotherapy or
NACT with pregnancy preservation and postpartum surgery can be offered to patients with EOC
during the second and third trimester.
Any therapeutic considerations, that is, surgery/chemotherapy carries risks related to the
pregnancy and therefore should be balanced against the risk related to the presumed OC. Even the
diagnostic workup could lead to considerable stress to the woman and the family. Therefore, a
multidisciplinary discussion involving experienced gynaecological oncologists, medical oncologists,
obstetricians, pae- diatricians, midwives, psychologists and anaesthesiologists should be
considered mandatory and thoroughly discussed with the patient and the family [69]. Cancer
management should be integrated with routine antenatal care. This discussion should also include
impact on life expectancy, quality of life, issues for parenting and pregnancy termination if
considered necessary. The psychological impact of this discussion should never be disregarded,
especially the risk of post-partum stress or depression. Thorough foetal USS before any intervention
(surgery/chemotherapy) is advisable for planning as well as judicial reasons.

Surgical management of ovarian cancer

If laparotomy is indicated, a vertical midline incision provides adequate exposure. Considering the
low frequency of OC in pregnant patients with adnexal mass, laparoscopy is an important alternative
to determine the diagnosis and minimise perioperative complications. However, laparoscopy carries
an increased risk of tumour rupture, port-site metastases and inadequate surgical staging if
adnexal histology is malignant [58].
Generally, management of EOC in pregnancy follows the same surgical principles as in non-
pregnant patients [70,71]. According to International Federation of Gynaecology and Obstetrics
(FIGO), proper staging of early EOC (FIGO stage I and II) includes hysterectomy, bilateral BSO as well
as omentectomy, peritoneal washing with cytology, systematic peritoneal biopsies in all areas of
the abdomen, pelvic and para-aortic lymphadenectomy. However, hysterectomy cannot be
performed when pregnancy preservation is planned. Pelvic exploration is more complicated with
increased GA due to the size of the gravid uterus which may also limit the ability to perform a
systematic lymph- node dissection.
In early-stage disease, fertility-sparing surgery (preserving uterus and non-affected ovary) should
be considered in selected cases, especially in cases of borderline histology, stage 1 EOC and majority
of the germ-cell tumours. Frozen section facility is highly desirable. Alternatively, a two-stage
approach may be adopted for presumed early-stage pathology e laparotomy or laparoscopic removal
of the mass followed by full histological examination. The planning for completion staging surgery
depends on the histology and stage and may be contemplated early, that is, during caesarean section
or immediately after delivery (6e8 weeks after initial surgery). In cases where adjuvant
chemotherapy is unlikely, completion surgery may be delayed until the puerperium to ensure
uterine involution. Completion staging/subsequent chemotherapy should not be delayed in
advanced malignancy.
In advanced disease, complete removal of all macroscopic tumour lesions represents the surgical
aim during primary or interval surgery and may be an option even in the second and third trimester,
while the uterus remains in situ. However, due to inadequate access, it may be necessary to limit
surgery to establish the diagnosis and perform a thorough clinical staging. The obvious limitations of
surgical resections in the pouch of Douglas as well as systematic lymph-node dissection need to be
considered. In addition, extensive peritoneal stripping and multi-organ resections to achieve complete
cytoreduction may not be possible in the presence of a gravid uterus with a viable foetus.
Neoadjuvant chemotherapy until foetal maturity and delivery is then the regime of choice. Vaginal
delivery followed by radical surgery in the post-partum period or planned laparotomy for
caesarean section and (in- terval) debulking may also be considered. Pregnancy-induced tissue
oedema, redistribution of uid in extravascular components, increased pelvic organ vascularity,
hydro-ureter and anatomic changes in the pelvis should always be kept in mind whenever
contemplating cytoreduction in pregnancy, and therefore surgery should only be performed by
experienced gynaecological oncologists. In addition, pregnancy-related common medical disorders,
that is, pre-eclampsia, coagulopathy, gestational dia- betes, obstetric cholestasis and
immunosuppression, may also limit the surgical effort required to
achieve complete cytoreduction and exacerbate post-operative morbidity leading to fetomaternal
compromise.

Chemotherapy: General considerations

For malignant ovarian tumours, chemotherapy is usually necessary to achieve a cure. There are
three major concerns of using chemotherapy in pregnancy: risk of miscarriage, congenital malfor-
mations and neonatal outcome. The risk of a congenital malformation or abortion is very high during
the rst trimester (particularly between 2 and 8 weeks' gestation), and consideration of a therapeutic
abortion versus delayed treatment should be discussed with the patient. In a study by Ebert et al.,
217 cases of pregnant women were treated with antineoplastic agents mostly during the rst
trimester between 1983 and 1995; congenital malformations were documented in 18 cases and
spontaneous abortions in 15 cases [72]. Doll et al. described a teratogenic risk of only 1.3% for the
combination of carboplatin in the second and third trimester in contrast to an elevated risk up to
25% in the rst trimester [73]. Second and third trimester should therefore be the preferred time
of chemotherapy administration and should follow the usual standard chemotherapy guidelines for
germ-cell tumours and EOC.

Chemotherapy dosage and scheduling

General physiological changes during pregnancy lead to increased hepatic oxidation, higher renal
blood ow (higher glomerular ltration rate and creatinine clearance) and an increase in the total
amount of body water resulting in larger dilution of water-soluble agents. This in turn causes
decreased absorption, re-distribution and increased elimination of many chemotherapeutic agents
leading to a decrease in the peak drug concentration following bolus administration and a risk of
potential under- dosing on one hand and enhanced drug half-life especially for hydrophilic agents,
on the other hand [74e77]. In addition, pregnancy-associated increase of plasma proteins, for
example, placental hor- mones and decreased concentration of albumin due to haemodilution may
create a pharmacologic third space that can actually increase toxicity. It has not been proven so far
that amniotic uid serves as a third space; however, ascitic or pleural uid may delay elimination
and increase toxicity. Despite a theoretical possibility of under-dosage of chemotherapeutics, there
are, however, so far no data that pregnant cancer patients treated with standard heighteweight-
based chemotherapy agents are at a higher risk for reduced efcacy than non-pregnant patients
treated with the same drugs and dosages. Until more information is available, the recommended
dosages in pregnancy should be similar to that of non-pregnant OC patients [78e80].
Chemotherapy schedule needs to be planned with regard to delivery. Sutcliffe proposed that
labour should be induced or caesarean section performed when maternal blood counts and
performance are optimal [81]. In a series of 215 patients with cancer in pregnancy, an induction of
delivery in about
71.7% led to 51.2% of neonates requiring admission to neonatology because of prematurity [82]. Van
Calsteren et al. suggested an interval of at least 3 weeks between last chemotherapy and anticipated
delivery to prevent myelosuppression in the mother and neonate [83].

Neonatal outcome

Most case reports describing chemotherapy for gynaecological cancers during pregnancy show a
good outcome for the neonate. Cisplatin-DNA or platinum-DNA adducts have been identied in neo-
nates exposed to platinum derivatives during the third trimester of pregnancy, but in general they
do not seem to have a long-term effect [84,85]. In a review of 36 pregnant patients who received
cisplatin- based chemotherapy between 1977 and 2008 (for various cancers), two foetal
malformations were reported [86]; one case of microphthalmia in a patient with metastatic
melanoma and one case of ventriculomegaly with cerebral atrophy (prenatal USS) in a patient
given one course of bleomycin, etoposide and cisplatin at 25 weeks' gestation for a non-epithelial OC
(a week after the administration of chemotherapy). No malformation has been reported in patients
exposed to taxane regimens for gynaecological disease [87,88]. Cooper University Hospital, NJ, USA,
has created a cancer and pregnancy
registry, with details of cancer treatment, pregnancy outcome and annual neonatal follow-up [89];
data on 231 women over a 13-year period showed that 13 women chose termination, 157 neonates
were exposed to chemotherapy in utero, mean GA at delivery was 358 (SD 28), mean birthweight
was
2647 g (SD 713), six babies (4%) were born with a congenital anomaly, one foetus died in utero and
one neonate died. Of the 67 women with cancer, who did not receive chemotherapy during
pregnancy, the mean GA at delivery (70 neonates) was 365 weeks (SD 33), and the mean
birthweight was 2873 g (SD
788). Van Calsteren et al. reported the outcome for 62 chemotherapy-exposed pregnancies [83];
preterm labour and of small-for-gestational age (weight <10th percentile) occurred in 24% of the
neonates exposed to cytotoxic agents in utero versus 9% in those who were not exposed.
Between 1977 and 2008, Mir et al. reviewed 43 pregnancies with platinum exposure during
pregnancy (including two in the rst trimester) [86]; 36 patients received cisplatin, six carboplatin,
and one both. Cisplatin was administered on 22/28 patients with OC. Foetal adverse effects
included in- trauterine growth restriction and preterm birth (each 8.3%), oligohydramnion
(5.6%) and poly- hydramnios (2.8%). Neonatal toxicity included acute respiratory distress, anaemia,
microphthalmos, leucopenia, pancytopenia, hearing impairment and creatinine elevation (2.8e8.3%).
With carboplatin, no foetal malformations/toxicity were reported and all newborns appeared to be
healthy at a median follow-up of 13.5 months.
Data on taxane administration during pregnancy are even more restricted and result mainly from
patients with breast cancer [87]. Despite haematological toxicities, no foetal abnormalities have
been reported so far. Since side effects of carboplatin and paclitaxel for mother and child appear
to be tolerable, it may be recommended as the standard regimen for EOC during pregnancy
[90e93]. Literature on the long-term effect and follow-up data on children are limited and should be
reported.

Targeted therapy in pregnancy

For bevacizumab, a humanised monoclonal antibody against vascular endothelial growth factor
(VEGF), and poly (ADP-ribose) polymerases (PARP) inhibitors, new classes of antineoplastic agents
that are currently tested in clinical trials, information on treatment during pregnancy is limited
[94,95]. Four cases of choroidal neovascularisation (CNV) was reported when bevacizumab was
administered intravitreally during pregnancy with uneventful prenatal course and neonatal
outcome. However, dosage within the ophthalmological context (range 1e2 mg, vs. 5e15 mg/kg in
oncology) is low and administration not systemic; results are therefore not transferable to OC. VEGF
plays a key role in the production and reabsorption of the amniotic uid produced by the foetal
kidney [96]. Regarding treatment of OC patients, antiangiogenic therapy is contraindicated.

Non-epithelial cancers

Most patients with non-epithelial tumours (germ-cell and sex-cord stromal tumours) have bulky
masses and are more likely to have symptoms [38]. The incidence of stage I disease is >90%. Fertility-
preserving surgical management should be considered. In pregnant patients, the indications and
regimen for adjuvant chemotherapy are similar to those in non-pregnant patients and include a
combination of bleomycin, etoposide, and cisplatin [97,98]. Majority of germ-cell tumours are
extremely chemosensitive; therefore, restaging may not be required, especially if partial staging sur-
gery was performed during pregnancy.

Ovarian tumours of low malignant potential

Tumours with low malignant potential or BOT comprise up to 63% of malignancies [5] and have an
excellent prognosis. A total of 95% of these tumours are diagnosed in stage I, and most patients can be
treated by surgery alone. Mooney et al. reported a series of 10 serous low malignant potential
(LMP) tumours during pregnancy; the disease had microscopic and clinical features suggestive of
aggressive behaviour, but the lesions regressed after delivery with no effect on survival [99]. In a
French multi- centre study, BOTs in pregnancy were mucinous, serous and mixed in 48%, 42%
and 10% cases, respectively; 21% of mucinous BOTs exhibited intraepithelial carcinoma or
microinvasion, and 47% of
serous BOTs exhibited micropapillary features, non-invasive implants or microinvasion [100].
Restaging surgery performed in 52% of patients resulted in upstaging in 24% of cases. Recurrence rate
of serous BOT with micropapillary features or peritoneal implants was 7.5%.
During a surgical procedure, when a serous ovarian tumour of LMP is diagnosed, resection of
affected cyst and all macroscopic disease is necessary, but the macroscopically normal ovary can be
spared. Routine peritoneal staging (appendicectomy in mucinous tumours) without
lymphadenectomy should be performed in the absence of macroscopic peritoneal disease and any
extra ovarian lesions should be removed. Restaging surgery should be offered after delivery to
patients with serous LMP ovarian tumours with micropapillary pattern or invasive implants. If it
shows up before 20 weeks' gestation, a laparoscopic approach may be preferred.

Summary of recommendations for clinical practice

Surgery should be considered for adnexal masses with a diameter of >5 cm, persisting >16 weeks
of gestation and with sonographic signs of possible malignancy. Optimal timing for planned surgery is
the second trimester. Information on treatment of EOC during pregnancy is limited; therefore,
manage- ment should be individualised and formulated by a multidisciplinary team in a specialised
centre while also considering the patients' wishes to preserve pregnancy. The following options can
be considered: Induced abortion followed by standard management of EOC, pregnancy-preserving
surgery followed by chemotherapy in the second/third trimester, planned delivery and secondary
surgical completion or NACT followed by cytoreductive surgery post delivery. Concurrent
pregnancy apparently does not inuence the growth rate or spread of EOC, and treatment delay to
achieve foetal viability or improve foetal outcome might be reasonable in cases of early-stage cancer.
Children with in utero exposure to antineoplastic agents should be followed up in a registry to
evaluate potential long-term complications [101].

Practice points

Ultrasound and magnetic resonance imaging (MRI) is the investigation of choice for
adnexal masses in pregnancy.
The best time for surgery is the second trimester of pregnancy.
Laparoscopy is safe in pregnancy.
Cancer in pregnancy should be managed by experienced and multidisciplinary team.
Obstetric outcome is not adversely affected by the management of ovarian cancer.
Standard chemotherapy for ovarian cancer can be administered only during the first
trimester of pregnancy.

Research agenda

Maintenance of central registry and database for pregnancy and cancer

Role of cytoreductive surgery in ovarian cancer during pregnancy
Obstetric and perinatal outcome after chemotherapy in pregnancy
Physiological and psychological consequences on pregnancy after ovarian cancer

Conict of interest

None.
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