Objectives: In pregnant patients with early stage cervical cancer, the preferred mode of delivery is a caesarean section (CS), which can be combined with a radical hysterectomy and pelvic lymphadenectomy (RHLD). The aim of this study was to compare this group of patients with non-pregnant cervical cancer patients treated by RHLD alone with regard to perioperative morbidity, oncological outcomes, and perinatal outcomes. Methods: We retrospectively reviewed all consecutive patients diagnosed with early stage cervical cancer during pregnancy who were treated by CS and RHLD at our institution. Non-pregnant counterparts served as controls and were matched on a 1 : 2 ratio. Key outcomes were perioperative complications, cancer outcome and perinatal outcome. Results: Nineteen pregnant women treated with a CS and RHLD were matched with 38 non-pregnant control patients with cervical cancer who underwent a RHLD. The only difference in morbidity was a higher estimated perioperative blood loss in the pregnant group (1600 mL) compared to the control group (800 mL; P = 0.001), resulting in seven (36.8%) and eight (21.1%) blood transfusions (P = 0.22; OR 2.19; 95% CI 0.65 to 7.38), respectively. Conclusion: Oncological outcomes were similar with 5-year overall survival rates of 94% in the pregnant group and 95% in the non-pregnant group. The neonatal survival rate was 100%. Complication rates and oncological outcomes after treatment with RHLD were comparable for pregnant and non-pregnant patients with early stage cervical cancer. Therefore we feel that it is safe to combine a CS with a RHLD in pregnant patients with early stage cervical cancer.
Cervical cancer is the fourth most common cancer in women worldwide, most frequently diagnosed in women between the ages of 35 and 44 years [1]. Approximately 1–3% of cervical cancers are diagnosed in pregnant patients, during delivery or shortly thereafter [2]. Over the past years the mean age at which women have their first child has increased in developed countries [3]. As a consequence of the increasing maternal age, the incidence of cancer during pregnancy in the developed world is expected to rise. Standard treatment for early stage cervical cancer in non-pregnant patients is a radical hysterectomy with pelvic lymphadenectomy (RHLD). Similar management can be offered during pregnancy. However, delay of local definitive treatment, with or without neo-adjuvant chemotherapy, is an option in response to maternal request in order to improve neonatal outcomes [4]. The preferred mode of delivery is a caesarean section (CS) with a classical incision in the uterus to avoid surgical tumour spread. This procedure can be combined with local definitive treatment: a RHLD [4,5]. During pregnancy, the uterus is enlarged and well vascularized, which might impede operative treatment and potentially result in an increased risk of perioperative complications [6].
In a recently published population based, retrospective study, the perioperative morbidity in pregnant cervical cancer patients treated by CS combined with radical hysterectomy was found to be higher compared to a non-pregnant control group treated by radical hysterectomy alone [7]. The authors of this study therefore, advised to consider performing the radical hysterectomy four to six weeks after the CS. Delayed surgery, however, carries a potential risk of progression of the cervical cancer. In addition, patients have to be scheduled for a second operation after the CS. In this population based study, no data were available on the extent of the radical hysterectomy, stage of disease, pathological characteristics and oncological outcome. As this information is essential to guide treatment decisions, more studies are needed on this subject. Currently, there are limited additional data in larger patient sets reporting on complication rates, morbidity, and perinatal and oncological outcomes in pregnant patients with cervical cancer. For that reason, the aim of this study was to evaluate these outcomes in cervical cancer patients, in whom a caesarean delivery was combined with a RHLD. These patients were matched with non-pregnant cervical cancer patients who underwent only a RHLD.
This was a single centre, retrospective, case-control study. All consecutive
patients diagnosed with cervical cancer during pregnancy between 1995 and 2019
who underwent a CS and RHLD in the same session were identified and included in
the pregnancy group. Patients were all treated at a tertiary referral centre for
gynaecological cancer and obstetrics in the Netherlands. All radical
hysterectomies were open procedures and performed according to the Okabayashi
method (Querleu type C2 radical hysterectomy) [8]. Controls were non-pregnant
cervical cancer patients treated with RHLD, matched on a 1 : 2 ratio for year of
treatment, age (both with a 5 year interval), International Federation of
Gynaecology and Obstetrics (FIGO) 2009 stage and clinical tumour size (
All information was extracted from the electronic patient records. Information
was collected regarding pre-operative haemoglobin level, American Society of
Anaesthesiologists (ASA) classification, body mass index, smoking status,
histopathological tumour type, tumour grade, lympho-vascular space invasion,
invasion depth, parametrial invasion, lymph nodes, resection margin (pathological
close tumour margin was defined as
Continuous variables were tested for normality using the Shapiro-Wilk test. Normally distributed data were compared with the use of the independent samples t-test, whereas data with non-normal distribution with the Mann-Whitney U-test. Discrete variables were compared using the Chi-square independence or the Fisher’s exact test. Survival analysis were performed with a Kaplan-Meier-curve using the log rank to statistically test for differences. Furthermore, cox and logistic regression analysis were used for calculating hazard ratios (HR) or odds ratios (OR) with 95% confidence intervals (CI). We considered a P-value below 0.05 as indicating a statistically significant difference.
Nineteen pregnant women met the inclusion criteria and were matched with 38
non-pregnant control patients. Clinical and pathological characteristics of the
patients are summarized in Table 1. Since matching was based on age, year of
treatment, FIGO stage and tumour size, these characteristics did not differ
between both groups. In the pregnant group, the ASA classification was higher
(P = 0.001) and the preoperative haemoglobin was lower (P
| Pregnant group n = 19 | Control group n = 38 | P-value | |
| Characteristics | |||
| Age (mean) | 34 |
35 |
0.23 |
| Body mass index (kg/m |
26 (19–34) | 23 (16–41) | 0.18 |
| American Society of Anaesthesiologists classification | 0.001 | ||
| American Society of Anaesthesiologists 1 | 8 (42.1%) | 32 (84.2%) | |
| American Society of Anaesthesiologists 2 | 11 (57.9%) | 6 (15.8%) | |
| Year of treatment | 2013 (2001–2019) | 2008 (1996–2017) | 0.053 |
| Smoking | 0.57 | ||
| Yes | 4 (21.0%) | 13 (34.2%) | |
| Former smoker | 3 (15.8%) | 6 (15.8%) | |
| No | 12 (63.2%) | 19 (50.0%) | |
| Preoperative haemoglobin (mmol/L) | 6.8 |
8.0 |
|
| Mean gestational age at diagnosis (weeks) | 26 |
- | - |
| Median gestational age at radical hysterectomy (weeks) | 35 (21–37) | - | - |
| Diagnosis-treatment interval (median days) | 46 (6–158) | 30 (3–84) | 0.22 |
| Median follow-up (months) | 56 (7–186) | 61 (12–261) | 0.28 |
| Tumour stage (FIGO |
1.00 | ||
| FIGO stadium IB1 | 13 (68.4%) | 26 (68.4%) | |
| FIGO stadium IB2 | 5 (26.3%) | 10 (26.3%) | |
| FIGO stadium IIA | 1 (5.3%) | 2 (5.3%) | |
| Tumour size | 0.42 | ||
| 3 (15.8%) | 10 (26.3%) | ||
| 2–4 cm | 12 (63.2%) | 17 (44.7%) | |
| 4 (21.1%) | 11 (28.9%) | ||
| Histologic type | 0.40 | ||
| Squamous cell carcinoma | 10 (52.6%) | 24 (63.1%) | |
| Adenocarcinoma | 6 (31.6%) | 12 (31.6%) | |
| Adenosquamous carcinoma | 3 (15.8%) | 2 (5.3%) | |
| Invasion depth (mean mm) | 9.7 |
11.7 |
0.34 |
| lympho-vascular space invasion | 11 (57.9%) | 19 (51.4%) | 0.64 |
| Positive lymph nodes | 3 (15.8%) | 9 (23.7%) | 0.73 |
| Close resection margin | 1 (5.3%) | 4 (10.5%) | 0.51 |
| Parametrial invasion | 1 (5.3%) | 5 (13.2%) | 0.65 |
| Neo-adjuvant therapy | 9 (47.4%) | 1 (2.6%) | |
| Cycles (number of) | 3 (2–5) | 5 | 0.20 |
| Response rate | 8 (88.9%) | 1 (100%) | 1.00 |
| Adjuvant therapy (any) | 5 (26.3%) | 13 (34.2%) | 0.55 |
| Radiation | 2 (10.5%) | 6 (15.8%) | 0.71 |
| Chemoradiation | 3 (15.8%) | 7 (18.4%) | 1.00 |
Two out of 19 cases underwent a sectio parva, immature surgical termination of
pregnancy, at the gestational age of 21 and 23 weeks. One out of 19 cases was
treated by a laparoscopic pelvic lymphadenectomy at the gestational age of 15
weeks, before definitive treatment at 32 weeks. In all other pregnant patients,
the radical hysterectomy was combined with a lymphadenectomy. The complication
rate in both groups was almost 50%, mostly caused by urinary tract infections
and blood loss requiring transfusions grade II (Table 2). Pregnant patients
receiving combined treatment had more excessive perioperative blood loss compared
to non-pregnant patients receiving RHLD alone (blood loss 1000–2000 mL; OR 20.63;
95% CI 4.38 to 97.03 and blood loss
| Operation and complications | Pregnant group n = 19 | Control group n = 38 | P-value |
| Operation time (min) | 349 (210–998) | 317 (208–525) | 0.24 |
| Estimated blood loss (mL) | 1600 (250–3000 mL) | 800 (150–3500 mL) | 0.001 |
| Complications | 10 (52.6%) | 16 (42.1%) | 0.45 |
| Blood loss requiring transfusion (grade II |
7 (36.8%) | 8 (21.1%) | 0.22 |
| Intraoperative injury | 0 (0%) | 0 (0%) | - |
| Infections | 3 (15.8%) | 12 (31.6%) | 0.34 |
| Wound infection | 0 (0%) | 0 (0%) | - |
| Urinary tract infection (grade II) | 3 (15.8%) | 11 (28.9%) | 0.34 |
| Sepsis (grade III) | 0 (0.0%) | 1 (2.6%) | - |
| Pneumonia | 0 (0%) | 0 (0%) | - |
| Intensive-care admission | 0 (0%) | 0 (0%) | - |
| Ileus (grade I) | 0 (0%) | 2 (5.3%) | 0.55 |
| Thromboembolic events |
2 (10.5%) | 0 (0%) | 0.11 |
| Pulmonary embolism (grade II) | 1 (5.3%) | 0 (0%) | - |
| Deep vein thrombosis | 0 (0%) | 0 (0%) | - |
| Thrombophlebitis (grade II) | 1 (5.3%) | 0 (0%) | - |
| Duration of hospital admission (days) | 11 (6–22) | 11 (6–22) | 0.61 |
With a median follow-up of 56 months, one patient in the pregnant group died of recurrent cervical cancer. The median follow-up in the control group was 61 months and three patients in this group died due to recurrence. The 5-years overall survival rate was 94% for the pregnant group and 95% for the non-pregnant group (P = 0.92; HR 0.88; 95% CI 0.08 to 9.75) (Fig. 1). Characteristics that might affect oncological outcomes like lympho-vascular space invasion, parametrial invasion, tumour size, FIGO stage, histopathological type, tumour grade, invasion depth and lymph node metastases were equally distributed in both groups. Seven patients suffered from cancer recurrence, three (15.8%) in the pregnant and four (10.5%) in the control group (P = 0.68). There was no difference in 5-years progression-free survival rates between both groups (P = 0.33; HR 0.46; 95% CI 0.09 to 2.29) (Fig. 2). One pregnant patient had a locoregional recurrence, and she was treated successfully with chemoradiation. All other recurrences were distant metastases. Five patients with a distant recurrence received palliative chemotherapy and one control patient refused life-prolonging therapy.
Fig. 1.Oncological outcomes presented by Kaplan-Meier estimates of overall survival for 5 years. Radical hysterectomy and pelvic lymphadenectomy (RHLD) group, caesarean section with radical hysterectomy and pelvic lymphadenectomy (CS + RHLD) group.
Fig. 2.Oncological outcomes presented by Kaplan-Meier estimates of progression-free survival for 5 years. Radical hysterectomy and pelvic lymphadenectomy (RHLD) group, caesarean section with radical hysterectomy and pelvic lymphadenectomy (CS + RHLD) group.
In two out of 19 a CS was performed before the gestational age of 24 weeks. In the remaining 17 patients, pregnancy was continued beyond the threshold for neonatal viability and all of their 18 neonates, including one set of twins, survived (Table 3). The caesarean delivery in two patients were carried out a week ahead of schedule, because of severe pregnancy complications due to severe vaginal bleeding and persistent contractions. The median gestational age at birth was 35 weeks with a mean birth weight of 2708 gram and corresponding percentile of 61%, including one small for gestational age neonate with a birth percentile below 1%. No congenital defects were observed. Two-thirds (66.7%) of the neonates were admitted to the neonatal intensive care unit for a median duration of seven days (range 1 to 25 days).
| Neonatal outcomes | n = 18 |
| Twin pregnancies | 1/17 (5.9%) |
| Severe pregnancy complications | 2/17 (11.8%) |
| Median gestational age at birth (weeks) | 35 (31–37) |
| Survival rate | 18 (100%) |
| Birth weight (gram) | 2708 ( |
| Birth weight percentile (%) | 61 ( |
| Small for gestational age | 1 (5.6%) |
| Congenital defects | 0 (0%) |
| Neonatal intensive care unit admission | 12 (66.7%) |
| Time of neonatal intensive care unit admission (days) | 7 (1–25) |
In this case-control study, we found increased perioperative blood loss, but no more need for blood transfusions, after RHLD combined with a CS compared to RHLD alone. We found no other differences between both study groups in terms of perioperative morbidity or any of the predefined oncological outcomes.
In our series, we found a median blood loss of 1600 mL in RHLD combined with a CS, which is comparable with the 1500–2000 mL found in literature in combined (CS and RHLD) per laparotomy [13-16]. The observed blood loss could be an overestimation, because it may have included amniotic fluid. Although we objectified more blood loss in the pregnant group and a lower preoperative haemoglobin level, the number of blood transfusions did not differ between both groups. Therefore, the difference in blood loss may not have been clinically relevant. In approximately half of our patients a complication occurred, regardless of the patient group. However, only one complication was classified as grade III and the majority of these complications consisted of blood loss requiring blood transfusion and urinary tract infections. The urinary tract infections were possibly due to the prolonged presence of the urinary catheter after radical hysterectomy.
Our finding of increased blood loss, but otherwise no increase in morbidity when a CS is combined with a radical hysterectomy, is supported by others [14-16]. Bigelow et al. compared the operative outcome of pregnant patients with cervical cancer based on the timing of radical hysterectomy [16]. Six women who had a CS combined with a radical hysterectomy had statistically significantly higher estimated blood loss compared to eight women who had a postpartum radical hysterectomy (2033 vs 425 mL; P = 0.0064), although there was no difference in blood transfusions or surgical complications. On the contrary, a recently published population-based study by Matsuo et al. found an increase in total perioperative morbidity in 257 patients with a combined procedure compared to 15,420 patients who underwent an open radical hysterectomy [7]. The increased total perioperative morbidity for the combined group in this study was mainly caused by an increase in perioperative blood loss with an incidence of 27.1% vs 13.8% in the control group. Our study and Bigelow et al. found more haemorrhage in the combined group too, but without an increase in blood transfusions, although this might be the result of an insufficient sample size to detect a difference [16]. Because the variable blood transfusion was lacking in the Matsuo study, the clinical impact of the increased blood loss as found in their study, was not evaluated. Comparing morbidity in one surgical group versus another demands matching for variables impacting on morbidity, such as radicality of the procedure, tumour size and stage of disease. Unfortunately, this was not done in both previous mentioned studies [7,16].
In our study, there was no difference in oncological outcomes between pregnant and non-pregnant women with early stage cervical cancer. These data should be interpreted with caution due to the small sample size. Potentially, combining RHLD with a CS could have a negative impact on maternal survival due to the fact that surgical treatment is often delayed in the interest of the fetus. In addition, technical difficulties, either caused by insufficient access to the deeper pelvis due to the increased size of the uterus, or caused by increased blood loss, can potentially result in less radical surgery and consequently inferior oncological outcome.
There are few studies reporting on survival in patients treated by CS combined with radical hysterectomy. Bigelow et al. reported a 5-years survival rate of 100% (6/6), after combined treatment, which was similar to the survival rate after postpartum radical hysterectomy [16]. In a study by Monk et al, both the disease free and overall survival in 21 pregnant cervical cancer patients was 95%, with a mean follow-up of 40 months [14]. There was no control group in this study. In a case-control study, oncological outcomes of 30 pregnant women with early stage cervical cancer were found to be comparable with non-pregnant cervical cancer patients [15]. Twenty-nine of the pregnant patients (97%) were alive after 148 months of follow-up versus 27 control patients (90%) after 145 months of follow-up. Lee et al. described the effect of delayed treatment on survival in patients with pregnancy associated cervical cancer [17]. Twenty-one pregnant patients with stage IB cervical cancer treated by surgery (RHLD combined with caesarean delivery) were matched with 63 non-pregnant patients. The 5-year survival rates of both groups did not differ with 75% and 89%, respectively. Overall, it is likely that similar oncological safety can be achieved by combining CS and RHLD in the same operative session.
In our series of 19 pregnant patients with cervical cancer, two underwent a sectio parva and 17 continued their pregnancy. All 18 neonates, including one set of twins, survived. The mean birth weight in this series was 2708 gram, which is an adequate birth weight for the median gestational age of 35 weeks at delivery [12]. Administration of chemotherapy after the first trimester appears to be safe in terms of congenital anomalies, this was already shown by others [13,18]. The vast majority of children in our series was born preterm. This explains the high number of neonatal intensive care unit admission for respiratory support because of lung immaturity. In our study, preterm delivery was induced to prevent a prolonged delay in the mothers’ definitive oncological treatment. Despite the prematurity, our neonatal survival rate was 100%. Nevertheless, preterm birth is associated with an increased risk for adverse neurodevelopmental outcomes [19]. Therefore, considerations on fetal maturity and a delay of a potentially curative maternal treatment should be carefully made in a multidisciplinary team.
The strength of this study is that it is a relatively large single centre study, in which we were able to match pregnant patients with controls, and therefore compare outcomes regarding morbidity and oncological outcome. A study cohort of 19 patients within this research field is relatively large compared to available literature and considering the low incidence of cervical cancer in pregnancy. Studies on this topic often lack a control group of non-pregnant patients. Limitations of our study include the ones that are associated with a retrospective design. Although pregnant patients were matched with controls, and no major differences were observed between both treatment groups, heterogeneity is still a potential bias.
With the increasing age at which women become pregnant in the developed world, expecting to result in more women diagnosed with cancer in pregnancy, there is a growing need for knowledge on how to adequately treat these patients. Information on the safety of surgical procedures is important to guide treatment decisions. Our findings indicate that combining CS with RHLD is likely to achieve similar oncological safety, without a substantial additional burden of perioperative complications. Therefore, we recommend to consider combining these procedures in pregnant patients with early stage cervical cancer.
JvdV and CHM designed the research study. EPO performed the research by collecting and analysing the data. JvdV, CHM, EPO and RCP wrote the manuscript. All authors contributed to editorial changes in the manuscript. All authors read and approved the final manuscript.
Ethical approval for the study was obtained from the Medical Ethics Review Committee of the Academic Medical Centre (reference number W20_265#).
Thanks to all the peer reviewers for their opinions and suggestions.
This research received no external funding.
The authors declare no conflict of interest.