Associations between cervical intraepithelial neoplasia during pregnancy, previous excisional treatment, cone-length and preterm delivery: a register-based study from western Sweden.

BACKGROUND: Excisional treatment of cervical intraepithelial neoplasia (CIN) has been associated with increased risk of preterm delivery (PTD), although the underlying mechanism is as yet unclear. Studies on formalin-fixed excised tissue indicate that the risk increases with cone-length, but the magnitude of increase is uncertain, especially in case of minor excisions (≤10 mm), as well compared to women with untreated CIN during pregnancy. This study assesses the impact of cone-length at previous treatment for CIN as well as diagnosis of CIN during pregnancy on the risk of PTD. METHODS: A register-based cohort study in western Sweden linking cervical cytology, histology, and treatment data from the Swedish National Cervical Screening Registry to data on obstetric outcomes in singleton pregnancies 2008-2016 from the Swedish Medical Birth Registry. These groups were compared for PTD and other obstetric outcomes: (1) women with one excisional treatment (n=3250, including a subgroup (n=2408) with cone-length measured before fixation; (2) women with untreated CIN diagnosed during pregnancy (n=1380); and (3) women with normal cytology (n=42,398). Logistic regression analyses were adjusted for socioeconomic and health-related confounders. RESULTS: Treated women had increased risk of PTD (adjusted odds ratio (aOR) 1.60, 95% confidence interval (CI) 1.21-2.12), spontaneous PTD (aOR 1.95, 95% CI 1.40-2.72) and preterm prelabor rupture of membranes (pPROM) (aOR 2.74, 95% CI 1.66-4.51) compared to the CIN during pregnancy group. ORs were similar when compared to the normal cytology group. Risks of these outcomes increased with cone-length. Mean cone-length was 9.1 mm. Cone-length ≤10 mm was associated with increased risk of PTD (aOR 1.41, 95% CI 1.02-1.94), spontaneous PTD (aOR 1.73, 95% CI 1.18-2.54), and pPROM (aOR 2.44, 95% CI 1.40-4.28), compared to the CIN during pregnancy group. The PTD risk was similar for cone-lengths 3-10 mm, thereafter increasing by 15% with each additional millimeter. CONCLUSIONS: This study suggests that all excisional treatment, including small cones, are associated with increased risk of PTD and pPROM. Risks increase further with cone-length. In women of reproductive age, clinicians should aim to remove all CIN but minimal healthy cervical tissue. Cone-length should be recorded at treatment, for future prenatal risk estimation.

Associations of treated and untreated human papillomavirus infection with preterm delivery and neonatal mortality: A Swedish population-based study.

BACKGROUND: Treatment of cervical intraepithelial neoplasia (CIN) is associated with an increased risk of preterm delivery (PTD) although the exact pathomechanism is not yet understood. Women with untreated CIN also seem to have an increased risk of PTD. It is unclear whether this is attributable to human papillomavirus (HPV) infection or other factors. We aimed to investigate whether HPV infection shortly before or during pregnancy, as well as previous treatment for CIN, is associated with an increased risk of PTD and other adverse obstetric and neonatal outcomes. METHODS AND FINDINGS: This was a retrospective population-based register study of women with singleton deliveries registered in the Swedish Medical Birth Register 1999-2016 (n = 1,044,023). The study population had a mean age of 30.2 years (SD 5.2) and a mean body mass index of 25.4 kg/m2 (SD 3.0), and 44% of the women were nulliparous before delivery. Study groups were defined based on cervical HPV tests, cytology, and histology, as registered in the Swedish National Cervical Screening Registry. Women with a history of exclusively normal cytology (n = 338,109) were compared to women with positive HPV tests (n = 2,550) or abnormal cytology (n = 11,727) within 6 months prior to conception or during the pregnancy, women treated for CIN3 before delivery (n = 23,185), and women with CIN2+ diagnosed after delivery (n = 33,760). Study groups were compared concerning obstetric and neonatal outcomes by logistic regression, and comparisons were adjusted for socioeconomic and health-related confounders. HPV infection was associated with PTD (adjusted odds ratio [aOR] 1.19, 95% CI 1.01-1.42, p = 0.042), preterm prelabor rupture of membranes (pPROM) (aOR 1.52, 95% CI 1.18-1.96, p < 0.001), prelabor rupture of membranes (PROM) (aOR 1.24, 95% CI 1.08-1.42, p = 0.002), and neonatal mortality (aOR 2.69, 95% CI 1.25-5.78, p = 0.011). Treatment for CIN was associated with PTD (aOR 1.85, 95% CI 1.76-1.95, p < 0.001), spontaneous PTD (aOR 2.06, 95% CI 1.95-2.17, p < 0.001), pPROM (aOR 2.36, 95% CI 2.19-2.54, p < 0.001), PROM (aOR 1.11, 95% CI 1.05-1.17, p < 0.001), intrauterine fetal death (aOR 1.35, 95% CI 1.05-1.72, p = 0.019), chorioamnionitis (aOR 2.75, 95% CI 2.33-3.23, p < 0.001), intrapartum fever (aOR 1.24, 95% CI 1.07-1.44, p = 0.003), neonatal sepsis (aOR 1.55, 95% CI 1.37-1.75, p < 0.001), and neonatal mortality (aOR 1.79, 95% CI 1.30-2.45, p < 0.001). Women with CIN2+ diagnosed within 3 years after delivery had increased PTD risk (aOR 1.18, 95% CI 1.10-1.27, p < 0.001). Limitations of the study include the retrospective design and the fact that because HPV test results only became available in 2007, abnormal cytology was used as a proxy for HPV infection. CONCLUSIONS: In this study, we found that HPV infection shortly before or during pregnancy was associated with PTD, pPROM, PROM, and neonatal mortality. Previous treatment for CIN was associated with even greater risks for PTD and pPROM and was also associated with PROM, neonatal mortality, and maternal and neonatal infectious complications.

Abnormal cervical cytology is associated with preterm delivery: A population based study.

INTRODUCTION: Increasing evidence suggests that cervical intraepithelial neoplasia, with or without subsequent treatment, is associated with preterm delivery. We aimed to explore the association between abnormal cervical cytology of different severity and the subsequent obstetric outcomes such as preterm delivery. MATERIAL AND METHODS: The historical register-based cohort study comprised 19 822 women in the Western Region of Sweden who had at least one abnormal cervical cytology from 1978 to 2012 before the age of 45 and a subsequent singleton delivery. The reference group comprised 39 644 women with normal cervical cytology and a subsequent singleton delivery, matched by age and parity. Data were retrieved from the Swedish National Cervical Screening Registry, linked to the Swedish Medical Birth Register and Statistic Sweden. The study outcomes were spontaneous preterm delivery before 37 and 34 weeks, low birthweight (≤2500 g), small-for-gestational-age, preterm premature rupture of membranes and neonatal mortality. Multivariable log binominal regression analyses were applied. RESULTS: Preterm delivery before 37 weeks was more common among women with abnormal cervical cytology compared with reference group: 6% vs 4.5%; adjusted relative risk 1.30 (95% confidence interval 1.21-1.39). High vs low-grade abnormal cervical cytology implied a higher risk: 7% vs 5.8% (P < 0.001). Early preterm delivery before 34 weeks, preterm premature rupture of membranes and low birthweight, but not small-for-gestational-age and neonatal mortality, were significantly more common in women with abnormal cervical cytology compared with the reference group. CONCLUSIONS: Abnormal cervical cytology may imply an increased risk of preterm delivery. Further studies are needed to investigate whether that risk is related to treatment.

Support for down-staging of pregnancy-associated cervical cancer.

OBJECTIVE: To evaluate all cases of cervical cancer associated with pregnancy during 16 years in the Western Region of Sweden. DESIGN: Retrospective, descriptive cohort study. SETTING AND POPULATION: All women with cervical cancer, diagnosed during pregnancy or within 6 months after parturition, between 1993 and 2008. METHODS: The study was based on data from different registers and medical records. MAIN OUTCOME MEASURES: Incidence, diagnostic measures, treatment and outcome of disease. RESULTS: Cervical cancer was diagnosed in 47 women (15.6/100 000 deliveries). Sixteen women had abnormal vaginal bleeding and/or discharge. The other women were asymptomatic and diagnosed by abnormal cervical smear or clinical signs at vaginal examination. Nine women had atypical squamous cells of uncertain significance as presenting by cervical atypia. Twenty-two women had stage IA, 17 stage IB1, six stage IB2 and two stage IIA cancer. Cancer was diagnosed in the first trimester in two, in the second trimester in 14, in the third trimester in five and postpartum in 26 women. Histology revealed squamous cell carcinoma in 36 women, adenocarcinoma in eight, and adenosquamous carcinoma in three. Twenty women underwent cesarean section due to diagnosed or clinically suspected cancer, combined with the Wertheim-Meigs radical hysterectomy in six women. Sixteen women with stage IA1 cancer without signs of vascular invasion underwent conization as definitive therapy. Six women died of the disease. CONCLUSION: Early detection of cervical cytological atypia and proper follow-up during pregnancy led to detection of a high proportion of stage I cancer cases, which could be cured with fertility-sparing therapy.

Colposcopically directed cervical biopsy during pregnancy; minor surgical and obstetrical complications and high rates of persistence and regression.

OBJECTIVE: To evaluate whether colposcopically directed cervical biopsies during pregnancy are associated with surgical/obstetric complications and to examine the natural course (regression, persistence, progression) of dysplasia during pregnancy. DESIGN: Prospective clinical study. SETTING AND POPULATION: University Hospital and 251 pregnant women with atypical cervical cytology in early pregnancy. METHODS: The patients were investigated by colposcopically directed punch biopsies, colposcopically directed loop-biopsies or LEEP-cones. The histology results during pregnancy were compared with those after delivery to evaluate the natural course of dysplastic lesions during pregnancies. Postoperative complications were recorded. Obstetric outcome was recorded and compared with the 54,919 other births in the same geographical area during the study period. MAIN OUTCOME MEASURES: Persistence, regression and progression of cervical dysplasia, surgical complications after diagnostic procedure, incidence of preterm birth, mode of delivery. RESULTS: Only a minor part (12.3%) of the dysplastic lesions showed progression during pregnancy, with 54.6 and 33.1% showing persistence and regression, respectively. No surgically related postoperative bleeding that needed surgical (diathermy/suture) treatment occurred and the miscarriage rate was low (0.8%). There were no differences in mode of delivery, preterm birth or other obstetrical variables between the study group and the large control cohort. CONCLUSION: Investigation of atypical cytology during pregnancy with biopsy including large loop excisions is a safe procedure with regard to surgical complications and obstetrical outcome. There is a high rate of persistence and regression of dysplasia during pregnancy.

Histological diagnosis and evaluation of the Swede score colposcopic system in a large cohort of pregnant women with atypical cervical cytology or cervical malignancy signs.

OBJECTIVE: We evaluated the distribution of histological diagnoses in pregnant women with atypical cytology or cervical malignancy signs, as well as the usefulness of the Swede score colposcopic scoring system to reduce the need for diagnostic cervical biopsy. DESIGN: Prospective clinical study. SETTING AND POPULATION: The study comprised 261 pregnant women undergoing colposcopic investigation because of atypical cervical cytology, dysplastic biopsy changes, recurrent non-obstetric bleeding or pathological appearance of the cervix. METHODS: Five colposcopic variables (acetowhiteness, margins plus surface, vessel patterns, lesion size and iodine staining) were scored with 0, 1 or 2 points. Colposcopically directed biopsies or loop electrosurgical excision biopsies were taken from all lesions. Histology was compared with the colposcopic score. Sensitivity and specificity were calculated for each variable, and the combination of all five variables, with high-grade lesions (i.e. cervical intraepithelial neoplasia (CIN2, CIN3 or adenocarcinoma-in-situ (AIS)) as endpoints. MAIN OUTCOME MEASURES: Colposcopic score (Swede score) and histology (CIN1, 2, 3; AIS; cancer). RESULTS: The specimens consisted of normal tissue in 19.5% of cases, low-grade lesions (i.e. CIN1, koilocytosis, glandular dysplasia of lower grade than AIS) in 26.1%, high grade lesions in 52.9% and cancer in 1.5%. All high grade lesions and cancers had total Swede scores of ≥ 5 and ≥ 8, respectively. Vessel patterns, lesion size and margins plus surface were most important for high grade lesion detection. CONCLUSION: The Swede score seems to be a useful tool in evaluating atypical cervical cytology in pregnant women and may reduce the need for diagnostic biopsies.

Type-specific human papillomavirus E6/E7 mRNA detection by real-time PCR improves identification of cervical neoplasia.

DNA-based human papillomavirus (HPV) assays show high sensitivity but poor specificity in detecting high-grade cervical lesions. Assays detecting mRNA of the oncoproteins E6 and E7 show higher specificity but lack either detection of all high-risk HPV genotypes or the capacity to specify the detected genotypes. Therefore, a real-time PCR assay detecting type-specific E6/E7 mRNA was developed and the clinical performance evaluated. A total of 210 cervical LBC (liquid-based cytology) samples from 204 women were analyzed for HPV DNA and mRNA with the in-house real-time PCR as well as PreTect HPV-Proofer. The sensitivity of real-time PCR mRNA detection to identify histologically confirmed CIN2+ (cervical intraepithelial neoplasia, grade 2 or higher) was 0.91, compared to 0.95 for DNA analysis. The specificity was 0.68 compared to 0.38, and the positive predictive value (PPV) was higher for mRNA (0.67 versus 0.52) without any loss in negative predictive value (NPV). The sensitivity of the real-time PCR mRNA test was somewhat higher than that for PreTect HPV-Proofer (0.83 versus 0.75) in analyses for the same genotypes. The specificities were similar (0.76 versus 0.77). In analyses for mRNA of the eight most common genotypes in cervical cancer (HPV16, -18, -31, -33, -35, -45, -52, and -58), the sensitivity of detection of CIN2+ lesions was 0.87 and the specificity 0.74, with a PPV of 0.70. In conclusion, real-time PCR for detection of HPV E6/E7 mRNA transcripts can be a sensitive and specific tool in screening and investigation of cervical neoplasia. The composition of HPV types in mRNA testing needs to be further investigated to optimize sensitivity and specificity.

Type-dependent E6/E7 mRNA expression of single and multiple high-risk human papillomavirus infections in cervical neoplasia.

BACKGROUND: Coinfection with multiple HPV types is common in cervical lesions, but the biological significance of the individual infections is difficult to establish. Expression of oncogenic E6/E7 HPV mRNA is correlated to risk of malignant progression, commercial assays for genotyping E6/E7 mRNA of all HR-HPV are lacking. OBJECTIVES: To characterize the tendency of 12 HR-HPV to express mRNA, correlated to the severity of the cervical lesion. Furthermore, we wanted to analyse mRNA expression in multiple infections, in order to establish which genotype may be responsible for cellular transformation. STUDY DESIGN: 245 samples from women with normal histology, various grades of dysplasia (cervical intraepithelial neoplasia grade 1-3), and cancer, were analysed for presence and genotyping of HPV DNA and mRNA using an in house real-time PCR test. RESULTS: Presence of mRNA was detected for 64% of the in total 422 HPV infections present in the samples, and more commonly in high-grade lesions. In 88% of DNA-positive samples from CIN2+ lesions, mRNA could be detected, compared to 33% of DNA-positive samples from women in screening with normal cytology. The genotype most prone to express mRNA in high-grade lesions was HPV45, followed by HPV16 and HPV31, less prone was HPV59. Expression of mRNA was significantly enhanced in CIN2+ lesions, an association also found for HPV16. In 52% of multiple infections (in which mRNA expression was generally more common), more than one genotype expressed mRNA, a phenomenon increasing with severity of lesion. Presence of mRNA could more often be detected in samples with multiple infections than in samples with single infections. CONCLUSIONS: The frequent expression of E6/E7 by HPV45 may promote oncogenicity and could be of clinical importance. Since presence of E6/E7 mRNA was common in multiple infections regardless of histology, multiple infection could be a clinically important finding. In multiple HPV infections, mRNA testing may identify the genotype that causes transformation. However, since mRNA expression of several genotypes in one sample is common, further and larger studies using complementary techniques are required.