Long-term follow-up of cervical cancer incidence after normal cytological findings.

An increase in cervical cancer incidence in Sweden from 2014 to 2015 has been attributed to an increase in false-negative cytological findings before cancer diagnoses. Years later, we performed a long-term follow-up to investigate whether the problem persisted. At each calendar year from 2016 to 2020, we identified women with prior normal cervical screening results through linkage to the Swedish National Cervical Screening Registry. We reported their incidence rates (IRs) of invasive cervical cancer in consecutive years and compared the IRs over time. For the years 2016 to 2020, there was no overall change in cervical cancer incidence after two normal cytology in the last two screening intervals. However, there was a further 62% increase among women 50 to 60 years of age with normal cytology in the past two screening intervals. The incidence rate of cervical cancer was high among nonscreened women and low among HPV-screened women with negative results, with no trends over time. Our results imply that the previously reported decrease in sensitivity of cervical cytology is persisting. Although primary cytology screening is no longer used, cytology is used in triaging among HPV-positive women. Our findings suggest that improved triaging is needed, for example, improved quality assurance and/or use of alternative triage tests.

Accuracy of colposcopy in the Swedish screening program.

INTRODUCTION: Sensitivity and specificity of colposcopy vary greatly between studies and efficacy in clinical studies seldom corresponds with effectiveness in a real-life setting. It is unclear whether colposcopists' experience affects assessment; studies show divergent results. The study's objective was to investigate the accuracy of colposcopies in the Swedish screening program, the variability in colposcopists' assessments and whether degree of experience affects accuracy in a routine setting. MATERIAL AND METHODS: Cross-sectional register study. All colposcopic assessments with a concomitant histopathological sample from women aged at least 18 years, performed between 1999 and September 2020 in Sweden. The main outcome measure was accuracy. The accuracy of colposcopic assessments was calculated as overall agreement with linked biopsies, with three outcomes: Normal vs Atypical, Normal vs Low-Grade Atypical vs High-Grade Atypical, and Non-High-Grade Atypical vs High-Grade Atypical. A time-trend analysis was performed. The accuracy of identifiable colposcopists related to experience was analyzed. RESULTS: In total, 82 289 colposcopic assessments with linked biopsies were included for analysis of the outcome Normal vs Atypical; average accuracy was 63%. Overrating colposcopic findings was four times more common than underrating. No time trend in accuracy was noted during the study period. Accuracy in distinguishing High-Grade from Non-High-Grade lesions was better: 76%. Among identifiable colposcopists, overall accuracy was 67%. Some had significantly better accuracy than others, but no correlation with experience was found. CONCLUSIONS: Colposcopy, including in a referral setting, has low accuracy in distinguishing Normal from Atypical. Increased experience alone does not lead to improvement. This is supported by the substantial differences in performance between colposcopists.

Pregnancy Outcomes in Women With a Prior Cervical Intraepithelial Neoplasia Grade 3 Diagnosis : A Nationwide Population-Based Cohort Study With Sibling Comparison Design.

BACKGROUND: Treatment of cervical intraepithelial neoplasia grade 3 (CIN 3) removes or destroys part of the cervix and might subsequently influence pregnancy outcomes. OBJECTIVE: To investigate pregnancy outcomes in women diagnosed with CIN 3. DESIGN: Population- and sibling-matched cohort study. SETTING: Sweden, 1973 to 2018. PARTICIPANTS: The general population comparison included 78 450 singletons born to women diagnosed with CIN 3 and 784 500 matched singletons born to women in the general population who had no CIN 3 diagnosis; the sibling comparison included 23 199 singletons born to women diagnosed with CIN 3 and 28 135 singletons born to their sisters without a CIN 3 diagnosis. MEASUREMENTS: Preterm birth, including spontaneous or iatrogenic preterm birth; infection-related outcomes, including chorioamnionitis and infant sepsis; and early neonatal death, defined as death during the first week after birth. RESULTS: Compared with the matched general population, women previously diagnosed with CIN 3 were more likely to have a preterm birth, especially extremely preterm (22 to 28 weeks; odds ratio [OR], 3.00 [95% CI, 2.69 to 3.34]) or spontaneous preterm (OR, 2.12 [CI, 2.05 to 2.20]); infection-related outcomes, including chorioamnionitis (OR, 3.23 [CI, 2.89 to 3.62]) and infant sepsis (OR, 1.72 [CI, 1.60 to 1.86]); or early neonatal death (OR, 1.83 [CI, 1.61 to 2.09]). Sibling comparison analyses rendered largely similar results. Over time, the risk difference attenuated for all outcomes and disappeared for early neonatal death. LIMITATION: Lack of data on CIN 3 treatment and spontaneous abortion. CONCLUSION: History of CIN 3 is associated with adverse pregnancy outcomes even after accounting for familial factors. Decreasing risk estimates over time suggest that adverse pregnancy outcomes among women diagnosed with CIN 3 may be minimized by improving treatment methods. PRIMARY FUNDING SOURCE: The Swedish Research Council, the Swedish Cancer Society, and the Swedish Research Council for Health, Working Life and Welfare.

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.

Active expectancy as alternative to treatment for cervical intraepithelial neoplasia grade 2 in women aged 25 to 30 years: ExCIN2-a prospective clinical multicenter cohort study.

BACKGROUND: The management of cervical intraepithelial neoplasia grade 2 is a clinical dilemma. Cervical intraepithelial neoplasia grade 3 is considered a cancer precursor and is always treated with excision. Most of the cervical intraepithelial neoplasia grade 1 cases regress spontaneously, and it is internationally mostly monitored with expectant management. Surgical treatment of cervical intraepithelial neoplasia entails increased risk of preterm birth in future pregnancies. Cervical intraepithelial neoplasia grade 2 in women aged under 25 years is quite well-studied; the regression rate is high and the cervical cancer risk is low. Cervical intraepithelial neoplasia grade 2 in women aged 25 years and above, in whom the risk of occult cancer is higher, has been less studied. OBJECTIVE: This study aimed to evaluate the natural course, over 2 years, of untreated cervical intraepithelial neoplasia grade 2 in women aged 25 to 30 years and its association with human papillomavirus 16. STUDY DESIGN: The study was conducted as a prospective longitudinal multicenter clinical study during February 2017 to June 2021 at 5 colposcopy clinics managing referrals after abnormal cervical screening in Region Västra Götaland, Sweden. The per protocol group comprised 127 women, aged 25 to 30 years, with fully visible squamocolumnar junction and histologically verified cervical intraepithelial neoplasia grade 2. The patients were followed up for 2 years with colposcopy, cytology, human papillomavirus tests, and at least 2 cervical biopsies every 6 months until progression or regression. The main outcome measures were the rates of regression of cervical intraepithelial neoplasia grade 2 at 6, 12, 18, and 24 months in cases with human papillomavirus 16 and those without human papillomavirus 16. The secondary outcomes were persistence and progression. RESULTS: In the per protocol analysis, partial or total regression during the 2-year period was found in 72% of patients (95% confidence interval, 63-79). In patients with human papillomavirus 16, the regression rate was 51% (95% confidence interval, 36-66) and the progression rate was 47% (95% confidence interval, 32-62). In the human papillomavirus-non-16 group, 83% (95% confidence interval, 73-90) regressed and 16% (95% confidence interval, 9-26) progressed. Most of the regression and progression in both the groups occurred within 15 months. The difference in regression between human papillomavirus 16 and human papillomavirus-non-16 cases was statistically significant (P value=.0001), as was the difference in progression (P=.0002). CONCLUSION: The regression rate of cervical intraepithelial neoplasia grade 2 is high, and human papillomavirus 16 is a strong determinant of the natural course. Patients aged 25 to 30 years with a fully visible squamocolumnar junction and without human papillomavirus 16 should generally be recommended active surveillance for 15 months, whereas immediate treatment should be considered in cases with human papillomavirus 16.

Colposcopic assessment by Swedescore, evaluation of effectiveness in the Swedish screening programme: a cross-sectional study.

OBJECTIVE: To evaluate the effectiveness and performance of Swedescore in the Swedish screening programme. DESIGN: Cross-sectional register study. SETTING AND POPULATION: All Swedish women aged over 18 years with a colposcopic assessment linked to a biopsy in the Swedish National Cervical Screening Registry, 2015-20. METHODS: Colposcopies with Swedescore were compared with the histopathological diagnosis of cervical intraepithelial neoplasia grade 2 or higher (CIN2+). The respective influence of cytology and human papillomavirus (HPV) testing, at referral for colposcopy and concurrently with colposcopy, were investigated in regression models. MAIN OUTCOME MEASURES: CIN2+. RESULTS: A total of 11 317 colposcopic assessments with Swedescore were included. Odds ratios for CIN2+ increased for every step in the Swedescore scale. At Swedescore ≥0-1, the proportion of CIN2+ was 9.8%. At Swedescore ≥8, the specificity was 93.3% and the positive predictive value was 60.1%, Area under the receiver operating characteristics curve (AUC) was 0.71. If the smear had been abnormal at referral, a normal colposcopy (Swedescore 0-1) was still associated with a CIN2+ risk of more than 5%. In the regression model, cytology and HPV had higher odds ratio for CIN2+ than colposcopy; the combination resulted in an AUC of 0.88. CONCLUSIONS: Swedescore works well in a routine clinical setting but colposcopy assessed with Swedescore was inferior to that reported in previous clinical studies. No safe cutoff level was identified for refraining from biopsy. See-and-treat at Swedescore 8-10 is feasible only if referral cytology showed high-grade squamous intraepithelial lesion. TWEETABLE ABSTRACT: No safe cutoff level for refraining from biopsy nor for see-and-treat with Swedescore.

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.

Increase of cervical cancer incidence in Sweden in relation to screening history: population cohort study.

Background: Cervical cancer incidence in Sweden decreased from 24/100,000 in 1965 to 8/100,000 in 2011, but has from 2014 increased to 11/100,000. The increase appears to correlate to screening history. We perform a study of the cancer risk change in relation to screening history over two screening rounds to verify the correlation.Material and methods: We studied the cohorts of all 3,047,850 individual women living in Sweden in each year from 2002-2015. Registry linkages between the Total Population Register, the Swedish National Cervical Screening Registry, the Swedish Cervical Cancer Audit database and the National Quality Register for Gynecological Cancer, defined the incidence rates of invasive cervical cancer comparing time periods 2002-2013 to 2014-2015, in women whose screening history in 2 screening intervals prior to each year were either (i) adequately screened with normal results (almost exclusively cytology, 52% of the population) or (ii) unscreened (13% of the population). We also investigated the incidence increase by time since a normal smear performed in 2002-2012.Results: Among women adequately screened with normal results there was a strong incidence increase in 2014-2015 compared to previous years (Incidence rate ratio (IRR) = 1.59, 95%CI = 1.36-1.85), but no significant increase among unscreened women (IRR = 1.09, 95%CI = 0.94-1.27). There was no increase in incidence 0-2.5 years after a normal smear over the study period (IRR = 1.04, 95% CI = 0.88-1.24), but a strong increase 3-4 years after a normal smear since year 2009 (IRR = 1.52, 95% CI = 1.25-1.84).Conclusion: The results suggest that the overall increase is associated with an increased cancer risk in women adequately screened with normal cytological results. Possibly, precursor lesions missed in one screening round might result in detection of early stage invasive cancer in the subsequent screening.

Risk of vaginal cancer among hysterectomised women with cervical intraepithelial neoplasia: a population-based national cohort study.

OBJECTIVE: To study the risk of vaginal cancer among hysterectomised women with and without cervical intraepithelial neoplasia (CIN). DESIGN: Population-based national cohort study. SETTING AND POPULATION: All Swedish women, 5 million in total, aged 20 and up, 1987-2011 using national registries. METHODS: The study cohort was subdivided into four exposure groups: hysterectomised with no previous history of CIN3 and without prevalent CIN at hysterectomy; hysterectomised with a history of CIN3/adenocarcinoma in situ (AIS); hysterectomised with prevalent CIN at hysterectomy; non-hysterectomised. MAIN OUTCOME MEASURE: Vaginal cancer. RESULTS: We identified 898 incident cases of vaginal cancer. Women with prevalent CIN at hysterectomy and those with a history of CIN3/AIS had incidence rates (IR) of vaginal cancer of 51.3 (95% CI 34.4-76.5) and 17.1 (95% CI 12.5-23.4) per 100 000, respectively. Age-adjusted IR-ratios (IRRs) compared with hysterectomised women with benign cervical history were 21.0 (95% CI 13.4-32.9) and 5.81 (95% CI 4.00-8.43), respectively. IR for non-hysterectomised women was 0.87 (95% CI 0.81-0.93) and IRR was 0.37 (95% CI 0.30-0.46). In hysterectomised women with prevalent CIN, the IR remained high after 15 years of follow up: 65.7 (95% CI 21.2-203.6). CONCLUSIONS: Our findings suggest that hysterectomised women with prevalent CIN at surgery should be offered surveillance. Hysterectomised women without the studied risk factors have a more than doubled risk of contracting vaginal cancer compared with non-hysterectomised women in the general population. Still, the incidence rate does not justify screening. TWEETABLE ABSTRACT: High risk of contracting vaginal cancer among hysterectomised women having prevalent CIN at surgery.

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.

Participation in a Swedish cervical cancer screening program among women with psychiatric diagnoses: a population-based cohort study.

BACKGROUND: In Sweden, organized screening programs have significantly reduced the incidence of cervical cancer. For cancers overall, however, women with psychiatric diagnoses have lower survival rates than other women. This study explores whether women with psychiatric diagnoses participate in cervical cancer screening programs to a lesser extent than women on average, and whether there are disparities between psychiatric diagnostic groups based on grades of severity. METHODS: Between 2000 and 2010, 65,292 women within screening ages of 23-60 had at least two ICD-10 (International Statistical Classification of Diseases and Related Health Problems - Tenth Revision) codes F20*-F40* registered at visits in primary care or psychiatric care in Region Västra Götaland, Sweden. Participation in the cervical cancer screening program during 2010-2014 was compared with the general female population using logistic regression adjusted for age. RESULTS: Relative risk for participation (RR) for women diagnosed within psychiatric specialist care RR was 0.94 compared with the general population, adjusted for age. RR for diagnoses outside specialist care was 0.99. RR for psychoses (F20*) was 0.81. CONCLUSIONS: Women with less-severe psychiatric diagnoses participate in the screening program to the same extent as women overall. Women who have received psychiatric specialist care participate to a lesser extent than women overall. The lowest participation rates were found among women diagnosed with psychoses.

Colposcopy telemedicine: live versus static swede score and accuracy in detecting CIN2+, a cross-sectional pilot study.

BACKGROUND: This cross-sectional pilot study evaluates diagnostic accuracy of live colposcopy versus static image Swede-score evaluation for detecting significant precancerous cervical lesions greater than, or equal to grade 2 severity (CIN2+). METHODS: VIA or HrHPV positive women were examined using a mobile colposcope, in a rural clinic in Kolkata, India. Live versus static Swede-score colposcopy assessments were made independently. All assessments were by gynecologists, junior or expert. Static image assessors were blinded to live scoring, patient information and final histopathology result. Primary outcome was the ability to detect CIN2+ lesions verified by directed biopsies. Diagnostic accuracy was calculated for live versus static Swede-score in detecting CIN2+ lesions, as well as for interclass correlation. RESULTS: 495 images from 94 VIA positive women were evaluated in this study. Thirteen women (13.9%) had CIN2+ on biopsy. No significant difference was found in the detection of CIN2+ lesions between live and static assessors (area under curve = 0.69 versus 0.71, p = 0.63). A Swede-score of 4+, had a sensitivity of 76.9% (95% CI 46.2-95.0%) and 84.6% (95% CI 54.6-98.1%), for live- and static-image assessment respectively. The corresponding positive predictive values were found to be 90.9% (95% CI 75.7-98.1%) and 92.6% (95% CI 75.7-99.1%). The interclass correlation was good (kappa statistic = 0.60) for the senior static assessors. CONCLUSIONS: Swede-score evaluation of static colposcopy images was found to reliably detect CIN2+ lesions in this study. Larger studies are needed to further develop the colposcopy telemedicine concept which may offer reliable guidance in management where direct specialist input is not available. TRIAL REGISTRATION: Ethical approval of the study was obtained by the Chittaranjan National Cancer Institute (CNCI) Human Research Ethics Committee (4.311/27/2014). The trial was retrospectively registered in the Clinical Trails Registry of India CTRI/2018/03/012470 .

Increasing participation in cervical cancer screening: offering a HPV self-test to long-term non-attendees as part of RACOMIP, a Swedish randomized controlled trial.

RACOMIP is a population-based, randomized trial of the effectiveness and cost-effectiveness of different interventions aimed at increasing participation in a well-run cervical cancer screening program in western Sweden. In this article, we report results from one intervention, offering non-attendees a high-risk human papillomavirus (HPV) self-test. Comparison was made with standard screening invitation routine or standard routine plus a telephone call. Women (8,800), aged 30-62, were randomly selected among women without a registered Pap smear in the two latest screening rounds. These women were randomized 1:5:5 to one of three arms: 800 were offered a high-risk HPV self-test, 4,000 were randomized to a telephone call (reported previously) and 4,000 constituted a control group (standard screening invitation routine). Results were based on intention to treat analysis and cost-effectiveness was calculated as marginal cost per cancer case prevented. The endpoint was the frequency of testing. The total response rate in the self-testing arm was 24.5%, significantly higher than in the telephone arm (18%, RR 1.36, 95% CI 1.19-1.57) and the control group (10.6%, RR 2.33, 95% CI 2.00-2.71). All nine women who tested positive for high-risk HPV attended for a cervical smear and colposcopy. From the health-care sector perspective, the intervention will most likely lead to no additional cost. Offering a self-test for HPV as an alternative to Pap smears increases participation among long-term non-attendees. Offering various screening options can be a successful method for increasing participation in this group.

Attending cervical cancer screening, opportunities and obstacles: a qualitative study on midwives' experiences telephoning non-attendees in Sweden.

AIM: As part of a research project aimed at increasing participation in the cervical cancer screening program (CCS), we explored midwives' unique experiences of telephoning non-attendees and offering Pap smear appointments. METHODS: Twenty midwives, in four focus groups, discussed their experiences of a study investigating ways to increase participation in the CCS. The group discussions were tape-recorded and transcribed verbatim and underwent qualitative content analysis. RESULTS: Speaking with more than 1000 non-attendees provided the midwives with new perspective on the CCS and they realised that improving it might address a number of reasons for not participating. These reasons were often related to logistics, such as scheduling flexibility and appointment booking. The telephone conversations revealed that some women required more individual attention, while it was discovered that others did not require screening. The midwives considered the CCS to be life-saving; participating in this screening activity gave them a sense of satisfaction and pride. CONCLUSIONS: This study shows that midwives can improve access and prevent non-attendance at the cervical cancer screening program when they are aware of women's varying requirements for attending screening.

Increasing participation in cervical cancer screening: telephone contact with long-term non-attendees in Sweden. Results from RACOMIP, a randomized controlled trial.

Non-participation is the foremost screening-related risk factor for cervical cancer. We studied the effectiveness and cost-effectiveness of an intervention to increase participation in the context of a well-run screening program. Telephone contact with non-attendees, offering an appointment to take a smear, was compared with a control group in a population-based randomized trial in western Sweden. Of 8,800 randomly selected women aged 30-62, without a registered Pap smear in the two latest screening rounds, 4,000 were randomized to a telephone arm, another 800 were offered a high-risk human papillomavirus (HPV) self-test by mail (not reported in this article) and 4,000 constituted a control group. Endpoints were frequency of testing, frequency of abnormal smears and further assessment of abnormal tests. Participation during the following 12 months was significantly higher in the telephone arm than in the control group, 718 (18.0%) versus 422 (10.6%) [RR: 1.70, 95% confidence interval (CI): 1.52-1.90]. The number of detected abnormal smears was 39 and 19, respectively (RR: 2.05, 95% CI: 1.19-3.55). The respective numbers of further assessed abnormalities were 34 and 18 (RR: 1.89, 95% CI: 1.07-3.34). Twice as many high-grade intraepithelial neoplasia (CIN2+) were detected and treated in the telephone arm: 14 and 7, respectively. Telephone contact with women who have abstained from cervical cancer screening for long time increases participation and leads to a significant increase in detection of atypical smears. Cost calculations indicate that this intervention is unlikely to be cost-generating and this strategy is feasible in the context of a screening program.

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.

Role of human papillomavirus (HPV) vaccination on HPV infection and recurrence of HPV related disease after local surgical treatment: systematic review and meta-analysis.

OBJECTIVE: To explore the efficacy of human papillomavirus (HPV) vaccination on the risk of HPV infection and recurrent diseases related to HPV infection in individuals undergoing local surgical treatment. DESIGN: Systematic review and meta-analysis DATA SOURCES: PubMed (Medline), Scopus, Cochrane, Web of Science, and ClinicalTrials.gov were screened from inception to 31 March 2021. REVIEW METHODS: Studies reporting on the risk of HPV infection and recurrence of disease related to HPV infection after local surgical treatment of preinvasive genital disease in individuals who were vaccinated were included. The primary outcome measure was risk of recurrence of cervical intraepithelial neoplasia grade 2 or higher (CIN2+) after local surgical treatment, with follow-up as reported by individual studies. Secondary outcome measures were risk of HPV infection or other lesions related to HPV infection. Independent and in duplicate data extraction and quality assessment were performed with ROBINS-I and RoB-2 tools for observational studies and randomised controlled trials, respectively. Grading of Recommendations Assessment, Development, and Evaluation (GRADE) was implemented for the primary outcome. Observational studies and randomised controlled trials were analysed separately from post hoc analyses of randomised controlled trials. Pooled risk ratios and 95% confidence intervals were calculated with a random effects meta-analysis model. The restricted maximum likelihood was used as an estimator for heterogeneity, and the Hartung-Knapp-Sidik-Jonkman method was used to derive confidence intervals. RESULTS: 22 articles met the inclusion criteria of the review; 18 of these studies also reported data from a non-vaccinated group and were included in the meta-analyses (12 observational studies, two randomised controlled trials, and four post hoc analyses of randomised controlled trials). The risk of recurrence of CIN2+ was reduced in individuals who were vaccinated compared with those who were not vaccinated (11 studies, 19 909 participants; risk ratio 0.43, 95% confidence interval 0.30 to 0.60; I2=58%, τ2=0.14, median follow-up 36 months, interquartile range 24-43.5). The effect estimate was even stronger when the risk of recurrence of CIN2+ was assessed for disease related to HPV subtypes HPV16 or HPV18 (six studies, 1879 participants; risk ratio 0.26, 95% confidence interval 0.16 to 0.43; I2=0%, τ2=0). Confidence in the meta-analysis for CIN2+ overall and CIN2+ related to HPV16 or HPV18, assessed by GRADE, ranged from very low to moderate, probably because of publication bias and inconsistency in the studies included in the meta-analysis. The risk of recurrence of CIN3 was also reduced in patients who were vaccinated but uncertainty was large (three studies, 17 757 participants; 0.28, 0.01 to 6.37; I2=71%, τ2=1.23). Evidence of benefit was lacking for recurrence of vulvar, vaginal, and anal intraepithelial neoplasia, genital warts, and persistent and incident HPV infections, although the number of studies and participants in each outcome was low. CONCLUSION: HPV vaccination might reduce the risk of recurrence of CIN, in particular when related to HPV16 or HPV18, in women treated with local excision. GRADE assessment for the quality of evidence indicated that the data were inconclusive. Large scale, high quality randomised controlled trials are required to establish the level of effectiveness and cost of HPV vaccination in women undergoing treatment for diseases related to HPV infection. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42021237350.

Risk of invasive cervical cancer in relation to clinical investigation and treatment after abnormal cytology: a population-based case-control study.

A substantial proportion of women with cervical cancer that have participated in cervical screening have a history of an abnormal cytology result. Our objective was to assess the impact of histological investigation and treatment of women with abnormal cytology on the subsequent risk of invasive cervical cancer. All invasive cervical cancer cases in Sweden 1999-2001 and five population-based control women per case were investigated. Clinical investigations and treatment were analysed in case women (N = 143) and control women (N = 176) below 67 with abnormal cytology results 0.5-6.5 years before the cases' diagnosis. Cervical cancer risk in relation to investigation [histology or not, punch biopsy, cervical curettage or cone/large loop excision of the transformation zone (LLETZ)], and treatment (treatment or not, excisional or ablative) was estimated as odds ratios (ORs) using logistic regression. Absence of histological assessment was associated with increased cancer risk, both after low-grade [OR 2.37; 95% confidence intervals (CI): 1.27-4.43] and high-grade squamous atypia (8.26; 2.37-28.8). Among women with histology, absence of treatment was associated with increased cancer risk (3.68; 1.53-8.84), also when biopsy showed low-grade atypia or normal findings (3.57; 1.18-10.8). Ablative therapy associated with increased risk compared with excisional (3.82; 1.01-14.4), and laser conisation associated with decreased risk compared with LLETZ (0.06; 0.01-0.36). In conclusion, low-grade as well as high-grade squamous atypical cytology results may warrant histological investigation, treatment reduced cancer risk even when histology was negative or showed low-grade atypia indicating a need for improvements in the diagnosis of high-grade lesions, and laser conisation was the most effective treatment.