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. 2013 Jul;5(4):211–219. doi: 10.1177/1758834013494988

Cervical cancer in pregnant women: treat, wait or interrupt? Assessment of current clinical guidelines, innovations and controversies

Sileny N Han 1, Mina Mhallem Gziri 2, Kristel Van Calsteren 3, Frédéric Amant 4,✉
PMCID: PMC3707341  PMID: 23858330

Abstract

Cervical cancer during pregnancy is relatively uncommon. However, the incidence is expected to increase as more women delay childbearing. When preservation of the pregnancy is desired, optimal treatment is a major challenge to all. Whereas delay of treatment is an option for pre-invasive disease, and also small invasive carcinomas without lymph node involvement, management of tumours >2 cm remains experimental. Type of treatment needs to be individualized and depends mainly on gestational age, disease stage, and histology. Extensive counselling regarding the maternal and foetal risks is required. In this current review, we aim to summarize available data and treatment guidelines concerning cervical cancer in pregnancy. Controversies and research priorities are also identified.

Keywords: cervical cancer, chemotherapy, neonatal, pregnancy

Introduction

Cervical cancer is the most commonly diagnosed gynaecological malignancy during pregnancy. Incidence rates vary from 0.1 to 12 per 10,000 pregnancies [Al-Halal et al. 2012; Takushi et al. 2002]. For cervical intraepithelial neoplasia (CIN), reported incidence rates vary between 1.30 and 2.7 per 1000 pregnancies [Al-Halal et al. 2012]. Owing to the rarity of the disease, and the complexity of all factors that have to be taken into consideration, standardization of treatment is very difficult. The treatment of cancer during pregnancy is most challenging in the case of cervical cancer, since the pregnant uterus itself is affected. The rarity of the situation makes large trials or randomized studies impossible, and guidelines up to now are based on small case series and expert opinion. Several clinical practice guidelines [Amant et al. 2010; Hunter et al. 2008; Morice et al. 2009] as well as a Lancet series paper have been published [Morice et al. 2012] in an attempt to reach a consensus on treatment options during pregnancy.

When treating a pregnant patient with cervical cancer, several issues are important: histological subtype, disease stage, nodal status, gestational age, obstetrical complications and also patients’ wishes concerning continuation versus termination of pregnancy. These factors have to be taken into consideration and discussed in a multidisciplinary team as well as with the patient and her partner, before deciding on the treatment plan. Traditionally, treatment of cervical cancer during pregnancy was avoided: the usual course of action was termination of pregnancy during the first two trimesters, or delay of treatment until foetal maturity in the third trimester, followed by standard treatment postpartum. In the last decade, pregnancy preservation and treatment during pregnancy has become more common. In this current review, we aim to summarize available data and treatment guidelines concerning cervical cancer in pregnancy. Controversies and research priorities are also identified.

Pre-invasive disease

The main treatment of pre-invasive disease during pregnancy is observation. Pregnancy does not influence cervical lesions, and progression to invasive disease during pregnancy is very rare (0–0.4%) [Paraskevaidis et al. 2002]. Colposcopy and directed biopsies can be safely performed during pregnancy, but endocervical curettage is contraindicated [Jain et al. 1997]. Physiological cervical changes during pregnancy, such as increased vascularity, hypertrophy and hyperplasia of the endocervical glands could mimic CIN; therefore, colposcopy needs to be performed by experienced colposcopists. Also, several physiological cellular changes, such as degenerated decidual cells (Arias–Stella phenomena) and trophoblastic cells with variably staining cytoplasm and enlarged nucleus could mimic high-grade squamous intraepithelial lesions (HSILs), and lead to false-positive results if the pathologist is unaware of the pregnant state.

The American Society for Colposcopy and Cervical Pathology (ASCCP) has provided consensus guidelines for abnormal cervical screening tests and cervical histology [Apgar et al. 2009; Wright et al. 2007]. In the case of atypical squamous cells of undetermined significance (ASC-US) or low-grade squamous intraepithelial lesions (LSILs) during pregnancy, the rate of finding CIN 2–3 on postpartum follow up is only 3.7% [Dunn et al. 2001]. Initial colposcopic examination can therefore be postponed until at least 6 weeks postpartum.

In the case of HSILs during pregnancy, prenatal colposcopy (with directed biopsy) is recommended. When CIN 2–3 is biopsy proven, or when the colposcopist is absolutely certain of the absence of invasion based on colposcopy alone, repeat cytology and colposcopy may be performed every 12 weeks to monitor disease progression. Treatment during pregnancy, such as ablation or excision, is not indicated. A diagnostic excisional procedure (such as conization), is only indicated if uncertainty persists: in case the suspicion for microinvasive disease is high, colposcopy is unsatisfactory, or cytology and colposcopy do not correlate. The risks for obstetric complications such as haemorrhage, cervical incompetence and foetal loss need to be discussed with the patient.

Postpartum spontaneous regression of CIN 2–3 lesions is fairly common, 48–70% regress during the course of pregnancy [Ahdoot et al. 1998; Paraskevaidis et al. 2002; Yost et al. 1999]. Caesarean section is not required in the case of CIN lesions.

Invasive disease: symptomatology

In general, pregnancy-associated complaints can mask cancer-related symptoms, resulting in patient and physician’s delay, and in higher stages when cancer is diagnosed during pregnancy. In contrast, pregnancy is an opportunity to screen for cervical cancer by performing a PAP smear, in patients without routine gynaecologic checkups. Sadugor and colleagues described as early as 1949 that in 8% of their cases, cervical cancer was discovered during routine examination in the asymptomatic patient [Sadugor et al. 1949].

Symptomatology of cervical cancer during pregnancy is similar to the nonpregnant patient. The most common symptom is (postcoital) vaginal bleeding, which is usually painless and can differ in quantity. Abnormal vaginal discharge (bloody, watery, malodorous or purulent), although less frequent, can also be found [Nguyen et al. 2000]. Symptoms can be mistaken for complications of pregnancy, and diagnosis delay occurs if the level of suspicion is low. Pelvic or lower back pain and bowel or urinary symptoms, which may also mimic frequently occurring pregnancy-related complaints, can be found with advanced disease.

Staging

Zemlickis and colleagues analysed data of 40 patients with cervical cancer during pregnancy, and found that pregnant women were more likely to present with early disease because of regular, pregnancy-related obstetric examinations [Zemlickis et al. 1991]. However, this was not found by Stensheim and colleagues who reported no differences in extent of disease when comparing 80 pregnant patients with 111 lactating patients and 5865 nonpregnant patients diagnosed with cervical cancer [Stensheim et al. 2009]. Accurate staging is one of the main issues in cancer management, in order to tailor treatment with the aim of optimizing oncologic outcome. The International Federation of Gynecology and Obstetrics (FIGO) schema for staging, is primarily based on clinical examination, also in the pregnant state [Pecorelli, 2009].

Physical examination

If pelvic examination and accurate clinical staging is difficult in the ambulatory setting, examination under anaesthesia is suggested.

Pelvic lymph node assessment

Histopathologic assessment of lymph nodes remains the most accurate method for assessment of nodal status. Lymph node status is one of the most significant prognostic factors for patients with cervical cancer [Delgado et al. 1990]. Especially in early-stage cervical cancer, lymph node status can guide management. Information on the lymph node involvement can be obtained either by magnetic resonance imaging (MRI) or surgical removal. Laparoscopic lymphadenectomy as a staging procedure for pregnant women with stage I disease is feasible during pregnancy and allows for reliable risk stratification. In 31 reported cases, maternal and neonatal morbidity was low [Morice et al. 2012]. However, it is wise to bear in mind that lymphadenectomy has no therapeutic effect by itself [Petry, 2012]. The usefulness of this invasive diagnostic procedure has to be evaluated on an individual basis.

MRI

MRI is the reference diagnostic examination which can help determine tumour size in three dimensions, stromal invasion, amount of healthy stroma, vaginal and parametrial invasion, and also lymph node infiltration (Figure 1) [Nicolet et al. 2000]. As stated by the American College of Radiology, present data have not documented any deleterious effects of MRI exposure on the developing foetus in any trimester of the pregnancy [Kanal et al. 2007]. Gadolinium (a category C drug according to the US Food and Drug Administration) should only be used if absolutely essential. No adverse effects to the neonate have been found after gadolinium exposure in all three trimesters [Sundgren and Leander, 2011]. However, gadolinium crosses the placenta and is excreted by the foetal kidney into amniotic fluid; it remains unknown how long it stays in this space with the potential for dissociation of gadolinium ion from its chelate molecule (which then becomes toxic) [Kanal et al. 2007]. MRI during pregnancy for staging of locoregional spread has been described by Zanetta and colleagues in 6 patients [Zanetta et al. 1998] and also Balleyguier and colleagues in 12 patients [Balleyguier et al. 2013]. MRI features of cervical cancer in pregnant patients were comparable to the nonpregnant patient, and allowed for tailored treatment planning. A good correlation between MRI findings and pathology specimens was also found [Zanetta et al. 1998]. Possible difficulties of MRI interpretation during pregnancy were: physiological hyperintensity of the cervix, making the tumour either isointense or hypointense; foetal movement impairing image quality (especially for small lesions); and also scanning without gadolinium [Balleyguier et al. 2013]. A possible pitfall may be mistaking dilated pelvic veins for pelvic adenopathy when evaluating the axial plane; this can be prevented by also examining the other planes. Estimation of tumour size can be difficult when a patient has already undergone diagnostic conisation.

Figure 1.

Figure 1.

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MRI of the cervix in the midsagittal plane. Upper arrow: uterus containing the foetus (16 weeks gestation).

Lower arrow: tumour of the cervix, 6 cm diameter. Biopsy confirms a squamous cell carcinoma of the cervix. FIGO stage IB2.

Ultrasound

In recent years, sonographic examination of local disease extension has also been shown feasible for preoperative staging. Some prospective studies have shown that transrectal or transvaginal ultrasound is comparable to the diagnostic accuracy of MRI [Epstein et al. 2013; Fischerova et al. 2008]. If an ultrasound expert is available, this can be a good alternative to MRI during pregnancy.

Distant metastases

In general, nonionizing imaging modalities including ultrasonography and MRI are used in the diagnostic workup of distant metastases. The general rule when performing radiologic and nuclear medicine examinations during pregnancy is that the radiation doses should be kept as low as reasonably achievable and avoided when possible. Diagnostic pelvic computed tomography (CT) and fluorodeoxyglucose positron emission tomography (FDG-PET)/CT can often be avoided, but are both possible without compromising foetal heath, if they may provide significant diagnostic information of the maternal state [McCollough et al. 2007]. CT of the thorax with abdominal shielding is indicated, in cases of high suspicion for pleural and/or lung metastases. Special effort can also be made to limit exposure by reducing radiation dose and scanning field [Stabin et al. 2012]. The foetal dose from nuclear medicine examinations is variable and depends on factors related to maternal uptake and excretion of the radiopharmaceutical, passage across the placenta and also foetal uptake [McCollough et al. 2007]. Takalkar and colleagues have estimated foetal radiation exposure in five pregnant women with a diagnosis of malignancy who underwent FDG-PET studies [Takalkar et al. 2011], they found foetal exposure levels ranging between 1.1 and 2.43 mGy, which is significantly below the threshold dose for deterministic effects (50–100 mGy).

The clinical value of serum tumour markers for cervical cancer in nonpregnant patients is questionable. Also, during pregnancy, the value of tumour markers is limited, and the physiological circulating levels throughout gestation have not been well studied [Caluwaerts et al. 2006; Han et al. 2012b]. Maternal serum levels of squamous cell carcinoma antigen have been reported in two studies to date, with rising levels in the third trimester, although mean levels remained below the cutoff throughout the entire pregnancy [Schlageter et al. 1998; Touitou et al. 1989].

Treatment

Type of treatment depends mainly on gestational age, disease stage, histology and the patient’s personal preference. We strongly recommend centralisation of treatment and multidisciplinary management due to the complexity of the issue at hand; the team should consist of (at least) a gynaecological oncologist, medical oncologist, radiologist, radiotherapist, perinatologist and neonatologist, experienced in treating cancer during pregnancy [Han et al. 2012a]. With other types of malignancy, e.g. breast cancer, we advocate that the proposed management should adhere to standard treatment as much as possible [Amant et al. 2012a]. However, this is often not possible in the case of cervical cancer, without termination of pregnancy or delay of treatment. Patients need to be aware that any type of treatment during pregnancy is experimental. When preservation of pregnancy is not needed, standard treatment with radical hysterectomy (with foetus in utero) and chemoradiation are both feasible options.

When cervical cancer is diagnosed during the first trimester of a wanted pregnancy, a conservative approach is proposed to reach the second trimester. During the third trimester, foetal maturity is awaited and a Caesarean section followed by standard treatment is proposed. During the second trimester, interventions including lymphadenectomy, conisation, trachelectomy and neoadjuvant chemotherapy can be considered [Amant et al. 2009].

Treatment during pregnancy

Stage IA

If there is a high suspicion for invasive disease, the optimal time to perform a conization during pregnancy is between 14 and 20 weeks gestation. Stage IA1 disease is usually diagnosed after conization, when maximum depth of invasion and horizontal diameter of the lesion can be evaluated microscopically. This is also acceptable as final treatment if there are negative margins present. Positive section margins have been reported by Dunn and colleagues (46%; 6/13) [Dunn et al. 2003] and also Yahata and colleagues (50%; 2/4) [Yahata et al. 2008], in the latter study, both patients underwent a second conization with no residual disease. In the case of adenocarcinoma, Smith and colleagues [Smith et al. 2002] reported an analysis of 560 nonpregnant women with stage IA1 and IA2 disease; of the patients who underwent lymphadenectomy, only 1.5% had positive pelvic lymph nodes. The censored survival rate was 99.1% and no recurrences were reported in the 98 cases managed by conisation as only surgery.

Delivery should be vaginal unless there are obstetric indications for Caesarean section.

Stage IB1, tumour size ≤2 cm

In patients with significant risk for lymph node metastases, staging lymphadenectomy during pregnancy can provide information on lymph node status. Positive lymph nodes warrant prompt initiation of definitive therapy.

In the case of negative lymph nodes, Morice and colleagues [Morice et al. 2012] advocated that foetal maturation can be awaited before receiving appropriate therapy after delivery, and found an average treatment delay of 16 weeks in published case reports. However, there are no studies of what constitutes a safe period of delay, and the risk of tumour progression is always present [Takushi et al. 2002]. Radical trachelectomy was first described by Dargent, as a possibility for fertility preservation in the nonpregnant woman. The cervix together with the surrounding parametria is removed with preservation of the uterine corpus and the ovaries, and a pelvic lymphadenectomy is also performed. It is considered safe in the case of stage IB1 disease with a tumour size ≤2 cm, and no nodal involvement [Plante et al. 2004]. There are few published cases of antepartum trachelectomy, with a foetal loss rate of 33% (5/15) within 16 days after surgery [Karateke et al. 2010; Morice et al. 2012; Ungar et al. 2006]. This procedure can be undertaken via the abdominal or vaginal approach, and mainly depends on the surgeon’s experience and personal preference. The major concern is perioperative and postoperative bleeding, and also diminished blood supply of the uterus if the uterine arteries are sacrificed [Karateke et al. 2010]. Postoperative placenta hypoperfusion might be the explanation for the high foetal loss rate. Although oncologic outcome is good after this procedure, antepartum trachelectomy is not the preferred type of treatment during pregnancy due to the poor obstetric outcome.

Alternatively, trachelectomy can be replaced by conization or simple trachelectomy in selected cases with tumour size ≤2 cm and negative nodal status. Simple trachelectomy consists of amputation of the cervix, about 1 cm above the endocervical tumour margin, then removal of the endocervical canal with use of a loop electrosurgical excision procedure with a small loop electrode [Rob et al. 2011]. The removal of parametrium significantly adds to the morbidity and poor obstetric outcome of radical trachelectomy. The rationale for removal of the parametrium is to obtain a clear margin of the cervical tumour and to prevent local recurrence due to remaining cancerous parametrial lymph nodes [Benedetti-Panici et al. 1996]. Several studies [Covens et al. 2002; Frumovitz et al. 2009; Kinney et al. 1995; Stegeman et al. 2007; Wright et al. 2007] have shown a parametrial involvement rate of <1% in patients with tumour size ≤2 cm, negative pelvic lymph nodes, and stromal invasion ≤10 mm; this supports the option of less radical surgery without parametrectomy in patients that fulfil these criteria [Rob et al. 2011; Schmeler et al. 2011].

Stages IB1, tumour size >2 cm and higher stages

When conservative surgical treatment during pregnancy is not possible, neoadjuvant chemotherapy (NACT) is an option to achieve disease control until foetal maturation, followed by radical hysterectomy postpartum [Karam et al. 2007].

For the nonpregnant patient, NACT is sometimes used for the treatment of bulky or locally advanced disease, with the aim to reduce tumour volume, and thus increase operability. In a recent Cochrane review on the treatment of the nonpregnant patient, NACT plus surgery versus surgery alone in women with early or locally advanced cervical cancer was evaluated (stages IB to IIIB) [Rydzewska et al. 2012]. In 6 trials consisting of 1078 women, both progression-free survival and overall survival were improved with NACT. There was also a significant decrease in adverse pathological findings with NACT (lymph node status: odds ratio [OR] 0.54, 95% confidence interval [CI] 0.40–0.73, p ≤ 0.0001; parametrial infiltration: OR 0.58, 95% CI 0.41–0.82, p = 0.002). There were also no differences in the effect of neoadjuvant chemotherapy on survival according to total cisplatin dose, chemotherapy cycle length or by cervical cancer stage. Cisplatin-based chemotherapy was used in all trials and administered in 2–4 cycles at 10- to 21-day intervals; cisplatin dose varied from 17 to 50 mg/m2 per week. The total cisplatin dose ranged from 140 to 300 mg/m2. Cisplatin was used in combination with vincristine (with or without bleomycin and/or mitomycin) in four studies and with 5-fluorouracil (with or without mitomycin) in two studies.

During pregnancy, NACT can be used to aim for down staging or stabilization, while awaiting foetal maturation. Cisplatin 50–100 mg/m2 every 3 weeks has been proposed as the standard treatment during pregnancy because this has been used most often during pregnancy [Morice et al. 2012]. However, meta-analyses have shown that in studies in nonpregnant patients, using chemotherapy at shorter intervals (<14 days) was associated with improvement in survival, and also that paclitaxel with platinum combination therapy was superior to single-agent cisplatin [Moore et al. 2004]. Carboplatin has a more favourable toxicity profile with less nephrotoxicity and ototoxicity, combined with similar efficacy [Moore et al. 2007]. Although paclitaxel during pregnancy has not been described in many cases, preclinical studies have shown that the transplacental passage of paclitaxel is minimal [Van Calsteren et al. 2010]. Fruscio and colleagues summarized data of 36 patients who received NACT during pregnancy for FIGO IB1 to IIIB disease with a tumour diameter of at least 3 cm [Fruscio et al. 2012]. In this series, all patients that received paclitaxel with platinum combination therapy had partial remission in contrast to single-agent treatments [Fruscio et al. 2012]. Based on its toxicity profile and also experience in ovarian cancer, paclitaxel with cisplatin or carboplatin is recommended during pregnancy [Amant et al. 2009; Zagouri et al. 2013]. The use of ifosfamide during pregnancy is not recommended due to its reported foetal toxicity, although Mir and colleagues have treated five patients with sarcoma during pregnancy using doxorubicin and ifosfamide without adverse events [Mir et al. 2012]. In order to ensure foetal safety, all types of chemotherapy should be avoided during the period of organogenesis in the first trimester of pregnancy [Han et al. 2013].

Pregnancy-related physiologic changes influence the pharmacokinetic processes of all drugs, including chemotherapeutic agents. These changes are mainly initiated by progesterone and oestrogen, and cause an increase of plasma volume by 45% and cardiac output by 50%, which leads to an increase of hepatic and renal perfusion and also enlargement of the distribution volume. Based on these changes, a reduced drug concentration is possible when the chemotherapeutic dosages are based on body surface area. A small pharmacokinetics study in pregnant women who received chemotherapy during pregnancy confirmed this hypothesis [Van Calsteren et al. 2010]; a decreased area under the curve and peak plasma concentration, and increased distribution volume and clearance were observed for all chemotherapeutics in this study (doxorubicin, epirubicin, carboplatin and paclitaxel). The clinical significance of these results is still undetermined; theoretically, standard dosing might be too low for the pregnant patient, but up to now, no survival differences were observed between women with cancer treatment during pregnancy and stage-matched nonpregnant women.

Many questions still remain on the subject of NACT during pregnancy: optimal chemotherapy regimen, interval, dose, number of cycles are still unknown. Randomized trials are not possible, but we advocate staying as close as possible to the standard schemes. Also, longer follow up is needed of maternal outcome after NACT during pregnancy. Fruscio and colleagues reported a death rate of 25% (9/36 patients) [Fruscio et al. 2012]; although the majority of these patients had negative prognostic factors, and prognosis seems similar to the nonpregnant patient when stage-matched, oncologic efficacy needs to be studied of a larger group before NACT can become standard treatment during pregnancy. The patient needs to be aware of the experimental character of this treatment.

Neonatal outcome after chemotherapy in utero

In an interim analysis of 70 children exposed to chemotherapy in utero, long-term follow up is reassuring (median follow up of 22.3 months) [Amant et al. 2012b]. General cognitive development was within the normal range for most children. Prematurity was an important factor that was associated with impaired neurodevelopmental outcome. Three of these children had impaired hearing, of which one child had been exposed to cisplatin at 28, 31 and 34 weeks gestation. However, CT showed a retracted tympanic membrane, which was the result of chronic middle ear infections, which confounds the explanation of hearing loss. In 4 of the 70 cases, the tumour type was cervical cancer. It is important to note that none of these patients received chemotherapy during the first trimester of pregnancy. Further long-term follow up is still needed to address the risk of infertility and malignancy for this group of children.

Conclusion

Cervical cancer is the most challenging cancer type during pregnancy since the pregnant uterus itself is involved. Many questions and controversies still remain on this subject. The facts and also the uncertainties should be discussed with the pregnant patient, so she can make an informed decision. We encourage referral of patients to treatment centres with experience with the treatment of cancer during pregnancy. Curing the disease is the main objective. Treatment during pregnancy is possible but more research is needed. NACT is still in an experimental setting and participation in ongoing studies is strongly recommended. Maternal survival must not be compromised in favour of treatment delay. When considering any modifications in the standard treatment, this must be thoroughly discussed with the patient.

Footnotes

Funding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Conflict of interest statement: FA is senior clinical investigator for the Research Foundation-Flanders (F.W.O.).

Contributor Information

Sileny N. Han, Leuven Cancer Institute (LKI), Gynaecologic Oncology, University Hospitals Leuven, and Department of Oncology, KU Leuven, Belgium

Mina Mhallem Gziri, Leuven Cancer Institute (LKI), Gynaecologic Oncology, University Hospitals Leuven, and Department of Oncology, KU Leuven, Belgium.

Kristel Van Calsteren, Foeto-Maternal Unit, University Hospitals Leuven, KU Leuven, Belgium.

Frédéric Amant, Leuven Cancer Institute (LKI), University Hospitals Leuven, and Department of Oncology, KU Leuven, Herestraat 49, Leuven 3000, Belgium.

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