Best Practice & Research Clinical Obstetrics and Gynaecology 33 (2016) 58e72

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Best Practice & Research Clinical

Obstetrics and Gynaecology
journal homepage: www.elsevier.com/locate/bpobgyn

Ovarian cysts and cancer in pregnancy

Asima Mukhopadhyay, MD, MRCOG, PhD, Consultant
Gynaecological Oncology a, b, *,
Aditi Shinde, MS, DNB, Clinical Fellow in the Department of
Gynaecological Oncology a,
Raj Naik, MD, FRCOG, Consultant Gynaecological Oncology c
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 first trimester
of pregnancy.
© 2015 Elsevier Ltd. All rights reserved.

* Corresponding author. Tata Medical Center, Kolkata, India. Tel.: þ91 7044088132, þ44 7951040818.
E-mail address: [email protected] (A. Mukhopadhyay).

http://dx.doi.org/10.1016/j.bpobgyn.2015.10.015
1521-6934/© 2015 Elsevier Ltd. All rights reserved.
 A. Mukhopadhyay et al. / Best Practice & Research Clinical Obstetrics and Gynaecology 33 (2016) 58e72 59

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 significant
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 five 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 specific 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 first 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 definitive 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
Türkçüog
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%)
Türkçüog
lu [7] Dermoid cyst (40%)
Bromley [8] 12 2nd trimester Dermoid cyst (30%)
Schmeler [9] 12 Dermoid cyst (42%)
Cohen-Herriou [10] Functional ovarian cyst (74.39%)
Hoover [17] First trimester 12e27 weeks Dermoid (25%)
60 A. Mukhopadhyay et al. / Best Practice & Research Clinical Obstetrics and Gynaecology 33 (2016) 58e72

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 11e13þ6 weeks and then at 18e20 weeks of gestation. Up to 70% cysts identified during the first
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% specificity 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 first 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%
 A. Mukhopadhyay et al. / Best Practice & Research Clinical Obstetrics and Gynaecology 33 (2016) 58e72 61

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
Smooth multilocular tumor with largest Irregular multilocular solid tumor with largest
diameter <10 cm diameter  10 cm
No blood flow Very strong blood flow

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 specificity 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/insufficient 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 classified 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 benefit may be justified. 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 first 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
62 A. Mukhopadhyay et al. / Best Practice & Research Clinical Obstetrics and Gynaecology 33 (2016) 58e72

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 fine-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 fibroids, 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 justified for asymptomatic masses detected incidentally on first

trimester USS.
2. If symptomatic or USS shows features of malignancy, surgery should be undertaken. MRI is advised
if malignancy cannot be confidently 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
 A. Mukhopadhyay et al. / Best Practice & Research Clinical Obstetrics and Gynaecology 33 (2016) 58e72 63

Adnexal mass in T1

SymptomaƟc

AsymptomaƟc

Suspicious of Doubƞul Not suspicious of

malignancy malignancy

Repeat USS
Surgery MRI
evaluaƟon at 18–20

Persistence, increase in size, ResoluƟon

solid consistency

ObservaƟon Laparotomy <23 Review at the Ɵme

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
specific pathophysiologic aspects of pregnancy:(i) elevated haemostatic capacity, (ii) reduced anti-
coagulation activity and major alterations in the fibrinolytic systems, (iii) cardiovascular changes
specific 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 first 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 flow [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
64 A. Mukhopadhyay et al. / Best Practice & Research Clinical Obstetrics and Gynaecology 33 (2016) 58e72

neonatal and paediatric services. Before the age of foetal viability, it may be sufficient 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]. Benefits 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 benefits, associated risks and risk-reduction
strategy in laparoscopy.
Laparoscopic techniques require modification 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 flow
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
 A. Mukhopadhyay et al. / Best Practice & Research Clinical Obstetrics and Gynaecology 33 (2016) 58e72 65

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 Port placement in the sub-xiphoid, left upper quadrant
injury from trocar placement. and supra-umbilical region 6 cm above the fundus.
Veress needle insufflating the intrauterine cavity Use of Hassons' technique. Selected use of closed
leading to CO2 embolism. pneumoperitoneum.
Hypercarbia and acidebase imbalance. Use of ‘Laprolift’ instead of CO2 pneumoperitoneum
Intraoperative capnography
Intra-abdominal pressure leading to reduced IAP <15 mm Hg in Trendelenburg position.
cardiac output.
Inferior vena cava compression leading to supine Left lateral tilt of patient during surgery.
hypotension.
Alteration of foetal BP, pulse respiration with Intraoperative foetal monitoring.
ventilator settings.
Increased carbon monoxide in the foetal blood due to Use of bipolar/ultrasound energy source instead
smoke from electrosurgical instruments. 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 identification 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 flow 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 significant
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% confidence 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-specific 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 first trimester. If a
pregnancy-preserving approach is warranted, surgery and chemotherapy should be avoided during the
first trimester because of higher miscarriage rates, most likely due to disruption of the corpus luteum.
66 A. Mukhopadhyay et al. / Best Practice & Research Clinical Obstetrics and Gynaecology 33 (2016) 58e72

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 fluid 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
 A. Mukhopadhyay et al. / Best Practice & Research Clinical Obstetrics and Gynaecology 33 (2016) 58e72 67

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 first 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 first 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 first
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 flow (higher glomerular filtration 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 fluid serves as
a third space; however, ascitic or pleural fluid 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 efficacy 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 identified 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
68 A. Mukhopadhyay et al. / Best Practice & Research Clinical Obstetrics and Gynaecology 33 (2016) 58e72

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 35þ8 (SD 2þ8), 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 36þ5 weeks (SD 3þ3), 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 first 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 fluid 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
 A. Mukhopadhyay et al. / Best Practice & Research Clinical Obstetrics and Gynaecology 33 (2016) 58e72 69

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
influence 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

Conflict of interest

None.
70 A. Mukhopadhyay et al. / Best Practice & Research Clinical Obstetrics and Gynaecology 33 (2016) 58e72

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