Björn Strander

Evaluation of primary HPV-based cervical screening among older women: Long-term follow-up of a randomized healthcare policy trial in Sweden

Background Evidence on invasive cervical cancer prevention among older women is limited, especially with the introduction of human papillomavirus (HPV)-based screening and longer interval. We conducted a long-term follow-up of the first phase of a randomized healthcare policy trial in cervical screening, targeting women aged 56 to 61 years old, to investigate the effectiveness of primary HPV-based screening in preventing invasive cervical cancer (ICC) and the safety of extending screening interval. Methods and findings The randomized healthcare policy trial of primary HPV-based cervical screening targeted women residing in Stockholm-Gotland region during 2012 to 2016, aged 30 to 64 years. The trial aimed to investigate the detection rate of cervical intraepithelial neoplasia grade 2 or worse (CIN2+) within 24 months and long-term protection against invasive cervical cancer, comparing primary HPV-based screening to primary cytology-based screening. The initial phase of the trial, which was the focus of this study, targeted women aged 56 to 61 years old in 2012 to 2014 who were randomized to primary cytology arm (n = 7,401) or primary HPV arm (n = 7,318). We used national registries to identify the subsequent cervical tests and all histopathological diagnoses including ICC before December 31, 2022. We calculated cumulative incidence, incidence rate (IR) and IR ratio (IRR) of ICC, by baseline test result. Furthermore, we calculated longitudinal sensitivity and specificity for detecting cervical intraepithelial neoplasia grade 2 or worse (CIN2+) by receipt of primary cytology or primary HPV test for the recommended screening intervals in this age group. We found that the IR of ICC among women in the primary HPV arm was 7.2/100,000 person-years (py) and 3.0 for women who tested HPV negative, compared to 18.4/100,000 py among women in the primary cytology arm and 18.8 for women who tested cytology negative. We further found that the overall point estimate for the risk of ICC over 10 years of follow-up among women in the primary HPV arm was 0.39 compared to women in the primary cytology arm, but this was not statistically significant (IRR: 0.39; 95% confidence interval, CI [0.14, 1.09]; p = 0.0726). However, among women with a negative test result at baseline, women in the primary HPV arm had an 84% lower risk of ICC compared to women in the primary cytology arm (IRR: 0.16; 95% CI [0.04, 0.72]; p = 0.0163). Moreover, primary HPV testing had a higher sensitivity for detecting CIN2+ within a 7-year interval than primary cytology testing within a 5-year interval (89.6% versus 50.9%, p < 0.0001). We were limited by a partial imbalance of invitations during the follow-up between the 2 arms which may have led to an underestimation of the effectiveness of primary HPV-based screening. Conclusions In this study, we observed that women over 55 years of age who received a primary negative HPV test result had substantially lower risk of CIN2+, and ICC, compared to women who received a primary negative cytology result. This should apply even if the screening interval were prolonged to 7 years. Trial Registration NCT01511328.

Assessment of a colposcopic scoring system (Swedescore) to reduce the number of cervical biopsies: a protocol for a clinical multicentre non-randomised intervention study in Denmark

Introduction Colposcopy is a standard procedure for evaluating cervical abnormalities and collecting cervical biopsies. The procedure is associated with intra- and inter-observer variation. A colposcopic scoring system, Swedescore, has been designed to standardise and facilitate colposcopy training. Swedescore has performed well in a routine clinical setting when used by expert colposcopists to find or exclude high-grade lesions. Danish clinical guidelines for colposcopy differ from other countries, as they recommend collecting four cervical biopsies in all women regardless of risk factors or colposcopy findings. Swedescore has never been examined to assess the reduction of cervical biopsies in a real-world clinical setting. This study aims to investigate whether the implementation of Swedescore can optimise the diagnostic work-up for whom the collection of biopsies can be safely omitted or reduced. Methods and analysis The design is a clinical multicentre non-randomised intervention study in Denmark. According to a power calculation, we will need to include 586 women referred for colposcopy. Colposcopy with Swedescore will be compared with conventional colposcopy with no Swedescore. Cervical biopsies will be divided into two separate vials (target and random biopsies). The primary outcome will be normal or cervical intraepithelial neoplasia grade 1 detected in cervical biopsies. χ 2 and logistic regression will be used to compare estimates between arms. Ethics and dissemination The study protocol has been submitted to the Ethical Committee in Central Denmark region and is not notifiable to the Committee (j.no.: 1-10-72-124-22). Results will be published in a peer-reviewed journal and presented at scientific meetings. Trial registration number NCT05870787 . Protocol version Version 3 (date 12. November 2024).

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

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

AbstractObjectiveTo evaluate the effectiveness and performance of Swedescore in the Swedish screening programme.DesignCross‐sectional register study.Setting and PopulationAll Swedish women aged over 18 years with a colposcopic assessment linked to a biopsy in the Swedish National Cervical Screening Registry, 2015–20.MethodsColposcopies 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 MeasuresCIN2+.ResultsA 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.ConclusionsSwedescore 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 AbstractNo 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.

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

Abstract 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.

Pregnancy Outcomes in Women With a Prior Cervical Intraepithelial Neoplasia Grade 3 Diagnosis

Treatment of cervical intraepithelial neoplasia grade 3 (CIN 3) removes or destroys part of the cervix and might subsequently influence pregnancy outcomes. To investigate pregnancy outcomes in women diagnosed with CIN 3. Population- and sibling-matched cohort study. Sweden, 1973 to 2018. 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. 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. 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. Lack of data on CIN 3 treatment and spontaneous abortion. 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. The Swedish Research Council, the Swedish Cancer Society, and the Swedish Research Council for Health, Working Life and Welfare.

iMproving thE DIagnostics And Treatment Of ceRvical Precancer

Cervical cancer screening is important as it enables identification of women at increased risk of the disease, but high-quality diagnostics of screen-positive women and effective treatment of those with precancer are critical in preventing progression to cancer. With the current transition from cytology-based to primary human papillomavirus (HPV)-screening and a growing proportion of HPV-vaccinated women, diagnostics of screen-positive women will become more challenging in the decades to come. Thus, there is a need to explore how to improve diagnostics while ensuring a low number of unnecessary procedures such as colposcopy and the collection of multiple cervical biopsies. The overall purposes are: Purpose 1: To investigate the diagnostic accuracy of cervical precancer when using a colposcopic scoring system in the diagnostic work-up of screen-positive women. Purpose 2: To investigate the performance of a colposcopic scoring system to identify women without cervical precancer in whom collection of biopsies can be safely omitted.

Randomized Implementation of Primary HPV Testing in the Organized Screening for Cervical Cancer in Stockholm

The purpose is to evaluate whether implementation of primary human papillomavirus (HPV) screening in the screening programme for cervical cancer improves the programme in terms of better cancer protection and better cost efficiency.