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Cervical intraepithelial neoplasia during pregnancy
Barbara Suchonska, Małgorzata Gajewska, Anna Madej, Mirosław Wielgoś
Department of Obstetrics and Gynecology, Medical University of Warsaw, Pl. Starynkiewicza 1/3, Warszawa, Poland
Department of Obstetrics and Gynecology, Medical University of Warsaw, Pl. Starynkiewicza 1/3, Warszawa
Source of Support: None, Conflict of Interest: None
Objectives: The aim was to analyze the unaffected course of cervical intraepithelial neoplasia (CIN) in pregnant women and to compare the rates of lesion persistence, progression, and regression.
Materials and Methods: Patients with abnormal cytology included in the study underwent colposcopy, followed by a biopsy of the cervix. At the end of the postpartum period, all patients underwent Pap smear, colposcopy, and endocervical curettage to obtain tissue samples. The findings were compared to the baseline to assess the rates of persistence, regression, and progression of CIN.
Results: The study group were 53 pregnant women. CIN was confirmed in 35 (66%) of them: CIN1 (n = 8, 22.9%); CIN 2+ (n = 26, 74.3%); and stage IA1 cervical cancer (n = 1, 2.9%). At the end of the postpartum period in 50% cases, there was no change compared to the baseline. Progression was seen in 2.9% and regression in 47.1%. A tendency for persistence and spontaneous regression of the lesions was observed.
Conclusions: Although in many cases CIN tends to regress spontaneously after delivery, such outcome is not to be expected in all patients. When invasive cervical cancer has been excluded, definitive treatment for cervical dysplasia may be deferred to the postpartum period without any harm to the mother.
Keywords: Cervical Intraepithelial Neoplasia, persistence, pregnancy, progression, regression
| » Introduction|| |
Cervical cancer is the most common neoplasm encountered during pregnancy, and it is estimated to occur in 1–10 per 10,000 pregnancies. In recent years, the incidence of cervical dysplasia diagnosed in pregnant women has substantially increased which is related to a general increase in the prevalence of cervical intraepithelial neoplasia (CIN) in women of reproductive age. In pregnant women, CIN is diagnosed 100 times more frequently than invasive cancer. In the past few decades, the management of CIN diagnosed during pregnancy has changed. Aggressive surgery has been replaced by a more conservative approach. The diagnostic and treatment guidelines have been revised and updated. Studies by several authors indicate that the course of CIN during pregnancy may vary. Regression of the lesions has been described in 10%–70% of patients, while in 3%–30% of cases, dysplasia progresses after delivery. Persistence of the lesions is observed in 25%–47% of patients.
| » Objectives|| |
The aim of the study was to assess the natural history of cervical intraepithelial lesions during pregnancy and postpartum.
| » Materials and Methods|| |
The group studied in the years 2013-2016 included 53 pregnant women with abnormal cytology (the Bethesda categories ASC-US [atypical squamous cells of undetermined significance], AGUS [atypical glandular cells of undetermined significance], LSIL [low-grade squamous epithelial lesion], HSIL [high-grade squamous epithelial lesion]) in the first trimester (60.4%), second trimester (32.1%), or third trimester (7.5%). All patients attended the outpatient clinic at the first Department of Obstetrics and Gynaecology, Medical University of Warsaw. The total number of smears evaluated in these years in OPD was around 3000. During this period, around 1060 pregnant women were under the care of the clinic. All of these women had Pap smear More Detailss.
The patients underwent a colposcopic examination, followed by colposcopy-guided biopsy of the areas of the cervix suspicious for dysplasia. In 18 (34%) patients who had a colposcopy, the result was normal, and there were no indications for biopsy during pregnancy. The patients were advised to have a follow-up colposcopy with histology at the end of the postpartum period. In 35 (66%) patients, CIN was confirmed by colposcopy and histopathology, and they were included in the next stage of the assessment. In 12 (34.3%) patients, a colposcopic examination was performed once during pregnancy, while in the remaining 23 (65.7%) patients, it was performed twice or thrice. These differences in the number of colposcopic examinations performed resulted from different times of the first visitor lack of adherence to examination schedule in some patients. On colposcopy, biopsy samples were taken from any areas suggestive of CIN, but endocervical curettage was not performed. In all patients who reported at the end of the postpartum period, colposcopy, ectocervical biopsy, and endocervical curettage were performed. Conization or amputation of the cervix was performed in 71.4% (n = 25) patients. Histological specimens were fixed in 10% neutral buffered formalin and embedded in paraffin using the routine method. The slices (4 μ thickness) were stained with hematoxylin/eosin for subsequent histopathologic assessment. The following terms were used to describe the diagnosis: LSIL, HSIL, and microinvasion. Regression was defined as a reduction in the grade of dysplasia or absence of intraepithelial lesions while the term progression referred to an increase in the grade of dysplasia or the appearance of microinvasion. When the degree of dysplasia remained unchanged, the disease was considered stable.
This prospective study was approved by the bioethics committee of Medical University of Warsaw (AKBE/9/2019).
| » Results|| |
The study group consisted of 35 patients aged 23–40 years (mean age: 31 ± 4.2) with CIN diagnosed during pregnancy. Eighteen patients (51.4%) were primiparas. Ten (28.6%) were smokers. None of the study patients had a significant medical history, had been treated with immunosuppressants, was infected with HIV, or declared first sexual intercourse before age 15.
The cytology results were analyzed. The mean gestational age at cytology was 12.3 weeks (5–30 weeks). In 26 (74.3%) patients, the result was indicative of a high-grade lesion (ASC-H in 4 patients and HSIL in 22 patients), and in the remaining 9 (25.7%) patients, it suggested a low-grade lesion (ASC-US in 3 patients and LSIL in 6 patients). Colposcopy-guided biopsy yielded the following results: LSIL (CIN1) in 8 (22.9%) patients and HSIL (CIN2+) in 26 (74.3%). One patient was diagnosed with stage IA1 cervical cancer.
One colposcopic examination was performed during pregnancy in 12 (34.3%) patients, with 75% of the colposcopies (9 patients) in the second trimester. One patient had a colposcopy in the first trimester and two in the third trimester. In nine patients (25.7%), a colposcopy was performed twice, and in 14 (40%) patients, thrice. Of the patients who had at least two colposcopic examinations during pregnancy (n = 23), in 16 (69.6%) patients, colposcopic and histopathologic results remained stable, progression was observed in 13%, and regression in 17.4%.
The histopathologic findings postpartum were analyzed by the mode of delivery and compared with the findings during pregnancy. Vaginal deliveries were performed in 19 (55.9%) and cesarean sections in 15 (44.1%) patients. The indications for an operative delivery included stage IA1 cervical cancer in one patient and HSIL in two patients. In the remaining 12 patients, the indications for cesarean delivery were of obstetric nature.
Histopathologic assessment of the cervix was performed postpartum in 34 (97.1%) patients (1 patient with the report of LSIL in pregnancy declined further investigations and treatment). Of this group, six (17.6%) women did not attend a scheduled follow-up appointment and remained without assessment after delivery and postpartum until a reminder was sent. Surgical treatment for advanced cervical lesions was required in 25 (73.5%) of these women. At the end of the postpartum period, cervical amputation was performed in two (5.9%) patients and cervical electro-conization in 23 (67.6%) patients, while nine (26.5%) patients did not require treatment and only colposcopy-guided ectocervical biopsies were taken.
After delivery in 17 (50%) women, the result was in line with the histologic assessment in pregnancy, while in one patient (2.9%), the progression of the dysplasia diagnosed in pregnancy was observed. In another 16 (47.1%) women, the lesions regressed [Table 1].
The association between the mode of delivery and the histopathology result postpartum was analyzed. Of the women who had a vaginal delivery, the persistence of the lesions was found in 11 (57.9%) patients and progression in 1 patient (5.3%). In the group who had cesarean delivery, the lesions persisted in six patients (40%) and regressed in six (60%) patients [Table 2].
|Table 2: The course of CIN postpartum depending on the method of delivery|
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Newborn condition was assessed by Apgar scale score. In the study group, all neonates were delivered in good condition.
| » Discussion|| |
HPV infections are most common in young women, and approximately 25% of women between the ages of 20 and 30 years are infected. Most women become pregnant between the ages of 18 and 35 years, which is the period when this oncogenic infections are most likely. Abnormal cytology is found in approximately 5%–8% of pregnant women while the prevalence of CIN in pregnancy is estimated at approximately 1% of the pregnant population.,, First prenatal visit early in pregnancy allows performing a cervical screening test in the first trimester. In the group assessed in this study, the mean gestational age at first cytology was 12.3 weeks (30 weeks maximum). A late cervical smear test necessitated more complex investigations to be performed late in pregnancy; in the second trimester, in 32.1% of the pregnant women; and in the third trimester in 7.5%. If invasive carcinoma is not confirmed by a cervical biopsy, in cases of CIN, the American Society of Colposcopy and Cervical Pathology recommends conservative management with cytologic and colposcopic assessment, possibly with a colposcopic-guided biopsy, the safety of which in pregnancy has been confirmed by many authors., Usually, the final diagnostic evaluation of the cervix takes place at the end of the postpartum period. Apart from suspected invasive cancer, microinvasive cancer invading to a depth of 3 mm or less diagnosed on biopsy is the indication for conization in pregnancy. Due to its potential complications, such as infection, bleeding, or premature delivery, according to the guidelines of 2001, the procedure should be performed not later than week 24 of pregnancy. Complications of conization occur in 7.8%–33% of pregnant women. Conization is ineffective in another 30%–78% because either it has not been complete or new foci of neoplasia appear after the procedure.,, The management of HSIL in pregnancy has changed. In their paper published in 2005, Kowalska-Koperek et al. reported induced abortion or hysterectomy in pregnant women with the diagnosis of CIN or stage IA1 cervical cancer. Today, this approach seems too aggressive and without justification in view of the current knowledge on the development of cervical dysplasia and cancer. Among our patients, microinvasion in a cervical polyp was found in the second trimester in one patient, but there were no features suggestive of invasive carcinoma in the remaining ectocervix. The patient was closely monitored and she continued her pregnancy.
Regression or reduction of cervical intraepithelial lesions after delivery may be accounted for by the immunosuppressive effect of sex hormones during pregnancy and by multiple previous biopsies. On biopsy, the dysplastic epithelium may be excised in its entirety. In addition, disruption of the epithelial integrity may trigger a local immune response leading to the loss of dysplastic foci., Advocates of vaginal delivery argue that loss of the dysplastic epithelium during ripening of the cervix and the fetus's passage through the birth canal may be another possible mechanism responsible for total or partial remission of dysplasia.,,,, According to the literature, the remission rates for cervical intraepithelial lesions are higher in pregnancy and postpartum than in non-pregnant patients. After delivery, a significantly higher rate of spontaneous remission of even advanced intraepithelial lesions was observed while progression or persistence of CIN was less frequent. Total remission was found in 41.2% of cases versus27.5% in non-pregnant women. In the group reported in this paper, regression of CIN was observed in 16 (47.1%) patients, while in 7 (20.6%) patients with HSIL in pregnancy and 1 patient with microinvasion detected in the second trimester, no features of dysplasia were found postpartum, which was also defined as regression.
In two patients with HSIL in pregnancy, LSIL was diagnosed postpartum. In six patients with LSIL in pregnancy, there was no dysplasia postpartum. Of the 16 patients with remission of the lesions postpartum, 9 (56.2%) had cesarean deliveries. At present, no significant differences in the regression rates related to the mode of delivery are reported, although a vaginal delivery was traditionally considered a route of choice for patients with CIN found in pregnancy. This is not supported by our observations as regression of the lesions was seen in nine (56.3%; 9/16) patients who had cesarean sections and in seven (43.7%; 7/16) of those who had vaginal deliveries. However, any definitive conclusions would require the analysis of CIN natural history in a much larger patient series. The rates of CIN regression postpartum reported in the literature range from 37% to 74% and the data are heterogeneous. Mailath-Pokorny et al. found remission of the lesions in 53.6% of women who delivered vaginally and 66.6% of women who delivered by cesarean section. Yost et al. described the regression of HSIL in 70% of patients, most of whom (71%) had vaginal deliveries. In the study by Kaneshiro et al., postpartum regression of intraepithelial lesions was confirmed in 64%, 55%, and 47% of women with the prepartum diagnosis of ASC-US, LSIL, and HSIL, respectively. Regardless of the degree of dysplasia, similar regression rates were observed contrary to other published studies which claim that regression of high-grade lesions is less common. Coppolillo et al. in their postpartum assessment of patients with HSIL detected during pregnancy found persistence in 70%, progression in 13.3%, and regression of the lesions in 16.7%. Possibly, the authors who reported higher regression rates after delivery did not take into consideration the effect on the ectocervical epithelium of hormonal changes associated with early lactation.,, Thus, it was assumed that the mode of delivery did not affect the natural history of intraepithelial neoplasia, which was in agreement with our observations. Also, the findings of Coppola et al. do not confirm any special effect of vaginal delivery on the clinical course of CIN. Lesions classified as HSIL persisted after delivery in 88% of the evaluated patients. None of the studies cited reported the progression of cervical intraepithelial lesions to cervical cancer, and we did not observe it in our series. Patients with cancer diagnosed during pregnancy already had cancer at the time of their inclusion in the study because it was detected in the first histologic assessment. As the progression of high-grade lesions to cancer is very rare in pregnancy, the algorithm of observation/conservative management seems appropriate as it does not increase the risk of disease progression during pregnancy.
| » Conclusions|| |
A Pap smear should be mandatory in pregnancy, preferably as a part of the first prenatal visit. This will allow detecting CIN during pregnancy, especially in case of women who have never had this test before.
When invasive cervical cancer has been excluded, treatment for cervical dysplasia may be deferred to the postpartum period without any harm to a mother and a developing fetus. Although in many cases CIN tends to regress spontaneously after delivery, such outcome is not to be expected in all patients. It seems to be irrelevant for the unaffected course of CIN, if the childbirth is natural or cesarean. It is important to keep contact with patients. Those of them with CIN who miss their scheduled follow-up visits are at the highest risk of developing cervical cancer.
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Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2]