Morbidity following robot-assisted surgery in a gynecological oncology setting: A cohort study.

INTRODUCTION: The objective of the study was to provide a comprehensive description of perioperative morbidity associated with robot-assisted surgery (RAS) in a gynecological oncology setting in order to improve the preoperative counseling of women and support shared decision-making. MATERIAL AND METHODS: All women scheduled for intended RAS between January 2015 and December 2022 were prospectively included in an electronic morbidity database for the analyses of perioperative complications. RESULTS: In total, 2225 women were included. Sixty-four patients (2.9%) experienced an intraoperative complication. Intraoperative complications were associated with a higher rate of conversion to laparotomy (15.6% vs. 1.8%, p < 0.001), a higher rate of major postoperative morbidity (9.3% vs. 2.4%, p < 0.001), and a higher rate of reoperation (9.3% vs. 1.7%, p < 0.001), compared to cases without intraoperative complications. Thirty-day postoperative morbidity was evaluated according to the Memorial Sloan-Kettering Cancer Center Surgical Secondary Events Grading System. Grade 3-5 events were considered major. A total of 57 patients (2.6%) experienced a major event after surgery, postoperative rupture of the vaginal vault being the most common complication requiring surgical intervention. Conversion to laparotomy occurred in 49 cases (2.2%) and was associated with higher intraoperative blood loss (300 mL vs. 25 mL, p < 0.001), a higher rate of postoperative major events (20.4% vs. 2.2%, p < 0.001), and a higher rate of reoperation (11.8% vs. 1.6%, p < 0.001). CONCLUSIONS: Our study demonstrates low rates of major perioperative morbidity and conversion to laparotomy after RAS performed by trained high-volume surgeons in a gynecological oncology setting.

Improving diagnostic of cervical dysplasia among postmenopausal women aged ≥50 years using local vaginal oestrogen treatment prior to colposcopy: study protocol for a multicentre randomised controlled trial (the IDEAL study).

INTRODUCTION: Colposcopy is the most important diagnostic tool to detect cervical precancerous lesions and thereby prevention of cervical cancer. Due to age-dependent changes of the cervix, colposcopy is challenging in postmenopausal women, as the majority will have a non-visible transformation zone, resulting in increased risk of missing disease, a diagnostic cone biopsy and prolonged follow-up with repeated colposcopies. This study will be among the first to investigate, if treatment with vaginal oestrogen prior to colposcopy will improve the colposcopy performance, to ensure accurate and timely diagnosis of precancerous cervical lesions among postmenopausal women. METHODS AND ANALYSIS: A randomised blinded controlled multicentre study. Enrolment will be performed at gynaecology departments in Central Denmark Region and Region of Southern Denmark. A total of 150 postmenopausal women aged ≥50 years referred for colposcopy due to abnormal cervical screening results will be randomised 1:1 to either pretreatment with vaginal application of Vagifem 30 µg or placebo once a day for 14 days prior to colposcopy. The primary outcome will be to compare the percentage of women in the two groups with a visible transformation zone at colposcopy, and biopsies representative of the transformation zone. Secondary outcomes will be the proportion of detected cervical intraepithelial neoplasia grade 2 or higher in the cervical biopsies; the proportion of diagnostics cone biopsies; the patients' report on possible side effects and compliance to the pretreatment. ETHICS AND DISSEMINATION: The study has been approved by the Central Denmark Region Committee on Biomedical Research Ethics (1-10-72-34-22), the Central Denmark Regions' Research Unit (1-16-02-72-22) and The Danish Health Authority (Danish Medicine Agency; 2022015030). The study's EudraCT number is (1-23-456; 2022-000269-42) and it is registered on www. CLINICALTRIALS: gov. The local Good Clinical Practice (GCP) unit will supervise and monitor the study closely before, during and after the study period. Findings will be disseminated in peer-reviewed scientific journals and presented in relevant conferences. TRIAL REGISTRATION NUMBER: NCT05283421.

The Incidence of Cervical Intraepithelial Neoplasia or Cervical Cancer in Women Referred With Postcoital Bleeding.

OBJECTIVES: The incidence of cervical cancer among patients with postcoital bleeding (PCB) was the primary objective of this study. Furthermore, the proportion of cervical intraepithelial neoplasia requiring treatment and the correlation between PCB and the presence of high-risk human papillomavirus (HPV) was determined. Lastly, the study aimed to identify risk factors among the referred women. METHODS: A retrospective cohort study was conducted at a university hospital in Denmark between January 1, 2017 and December 31, 2019. Women referred with PCB were identified with the ICD diagnosis codes "DN930 Postcoital and contact bleeding" and "DN930B Contact bleeding." Demographic and paraclinical data were extracted from the journals and the supportive systems: Patoweb and the Danish Microbiology Database. RESULTS: A total of 789 women were included in this study, with only 0.25% (n = 2) diagnosed with cervical cancer and 2.5% (n = 20) diagnosed with cervical intraepithelial neoplasia II-III and adenocarcinoma in situ. Human papillomavirus testing was only conducted in a minority of cases, and a low incidence of high-risk human papilloma virus was detected in the 22 cases, n = 5. CONCLUSIONS: A very low incidence of cervical cancer and high-grade cervical intraepithelial neoplasia reported among women referred with PCB. Prognostic factors as body mass index, smoking, and HPV vaccination status may predict the risk of cervical cancer. Selection criteria like primary testing for hrHPV and cytology as cotests before referral to colposcopy may reduce the number of unnecessary colposcopies.

Preterm Birth Following Active Surveillance vs Loop Excision for Cervical Intraepithelial Neoplasia Grade 2.

Importance: Active surveillance for cervical intraepithelial neoplasia grade 2 (CIN2) is being implemented in many high-income countries due to the association of excisional treatment with preterm birth. However, it is unknown whether active surveillance results in lower risk of preterm birth given that cervical dysplasia itself is associated with higher risk of preterm birth. Objective: To compare the preterm birth risk between women with CIN2 undergoing active surveillance or immediate loop electrosurgical excision procedure (LEEP). Design, Setting, and Participants: This historical population-based cohort study included women with a first-time diagnosis of CIN2 and a subsequent singleton birth from 1998 to 2018 in Denmark. Women with prior CIN grade 3 or greater or LEEP were excluded. Data were collected from 4 Danish health care registries. Analyses were conducted from October 2022 to June 2023. Exposure: Women were categorized into active surveillance (cervical biopsy and/or cytology) or immediate LEEP based on their first cervical sample after CIN2 diagnosis. The active surveillance group was further subdivided based on whether a delayed LEEP was performed within 28 months from CIN2 diagnosis. Main Outcomes and Measures: Risk of preterm birth (<37 + 0 weeks) was assessed and relative risks (RRs) were calculated using modified Poisson regression. Analyses used inverse probability treatment weighting of the propensity scores to adjust for age, parity, calendar year, index cytology, and smoking. Results: A total of 10 537 women with CIN2 and a singleton birth were identified; 4430 (42%) underwent active surveillance and 6107 (58%) were treated with immediate LEEP. For both groups, most were aged 23 to 29 years at CIN2 diagnosis (3125 [70%] and 3907 [64%], respectively). Overall, 869 births (8.2%) were preterm. The risk of preterm birth was comparable between active surveillance and immediate LEEP (RR, 1.03; 95% CI, 0.90-1.18). However, for women undergoing delayed LEEP after active surveillance (1539 of the active surveillance group [35%]), the risk of preterm birth was higher than for women treated with immediate LEEP (RR, 1.29; 95% CI, 1.08-1.55). Conclusions and relevance: In this cohort study of women with CIN2, the risk of preterm birth was comparable between active surveillance and immediate LEEP. However, delayed LEEP was associated with 30% higher risk of preterm birth than immediate LEEP. Thus, risk stratification at CIN2 diagnosis is important to identify women with increased risk of delayed LEEP.

Human papillomavirus genotypes and risk of persistence and progression in women undergoing active surveillance for cervical intraepithelial neoplasia grade 2.

BACKGROUND: In recent years, active surveillance has been introduced as an alternative to excisional treatment in younger women with cervical intraepithelial neoplasia grade 2 because regression rates are high and excisional treatment is associated with increased risk of preterm birth. However, early identification of women at increased risk of persistence/progression is important to ensure timely treatment. Evidence is limited on biomarkers that may be used to identify women at increased risk of persistence/progression. OBJECTIVE: This study aimed to describe human papillomavirus HPV type-specific persistence/progression in women undergoing active surveillance for cervical intraepithelial neoplasia grade 2. STUDY DESIGN: We conducted a historical cohort study of women aged 23 to 40 years diagnosed with cervical intraepithelial neoplasia grade 2 at Aarhus University Hospital from 2000 to 2010. Women were identified through the Danish Pathology Data Bank (DPDB) and were considered as undergoing active surveillance if they had a first record of a cervical biopsy within 2 years after index diagnosis and no loop electrosurgical excision procedure before this. Human papillomavirus genotyping was performed on archived tissue samples using the HPV SPF10-DEIA-LiPA25 system (DNA ELISA [enzyme-linked immunosorbent assay] HPV SPF10 kit and RHA HPV SPF10-LiPA25 kit). Persistence/progression was defined as having a record of cervical intraepithelial neoplasia grade ≥2 in the DPDB determined on the last and worst diagnosis on a biopsy or loop electrosurgical excision procedure specimen during follow-up. We estimated the relative risk (95% confidence interval) of persistence/progression using a modified Poisson model. RESULTS: A total of 455 women were included. Two-thirds were aged ≤30 years (73.8%) at index diagnosis, and nearly half had a high-grade index cytology (48.8%). Overall, 52.2% of all women had cervical intraepithelial neoplasia grade ≥2 during follow-up; 70.5% were human papillomavirus-16-positive and 29.5% were positive for other human papillomavirus types. Human papillomavirus-16 was associated with a significantly higher risk of persistence/progression (relative risk, 1.64; 95% confidence interval, 1.37-1.95) compared with non-human papillomavirus-16. The risk of persistence/progression was highest in human papillomavirus-16-positive women with a high-grade index cytology compared with human papillomavirus-16-positive women with a low-grade cytology (relative risk, 1.29; 95% confidence interval, 1.03-1.61), whereas no differences were observed across age groups. CONCLUSION: The highest risk of persistence/progression was observed among human papillomavirus-16-positive women, particularly those with associated high-grade cytology. These findings suggest that early excisional treatment should be considered in this group of women.

The risk of vaginal, vulvar and anal precancer and cancer according to high-risk HPV status in cervical cytology samples.

High-risk human papillomavirus (hrHPV) is the cause of virtually all cervical cancers, most vaginal and anal cancers, and some vulvar cancer cases. With HPV testing becoming the primary screening method for cervical cancer, understanding the link between cervical hrHPV infection and the risk of other anogenital cancers is crucial. We assessed the risk of vulvar, vaginal and anal cancer and precancer (VIN2+, VaIN2+ and AIN2+) in a prospective cohort study including 455,349 women who underwent cervical hrHPV testing in Denmark from 2005 to 2020. We employed Cox proportional hazard models, adjusting for age, calendar year and HPV vaccination status, and estimated hazard ratios (HRs) and 95% confidence intervals (CI). We used the Aalen Johansen estimator to calculate the absolute risks of VIN2+, VaIN2+ and AIN2+. In total, 15% of the women were hrHPV positive at baseline. A positive cervical hrHPV test was associated with increased incidence of vulvar, vaginal and anal squamous cell carcinoma (SCC). Five-year risk estimates of VIN2+, VaIN2+ and AIN2+ among hrHPV-positive women (0.45%, 0.14% and 0.12%) were higher than among hrHPV-negative women (0.14%, 0.01% and 0.05%). Particularly high risk was observed among the hrHPV-positive women of the oldest age, with a history of anogenital precancer and those not HPV vaccinated. In conclusion, our study confirms the association between cervical hrHPV infection and non-cervical anogenital precancers and cancers. Currently, no established risk threshold or guidelines for follow-up. As HPV testing becomes the primary method for cervical cancer screening, future data will help define high-risk groups and acceptable risk thresholds.

Untreated cervical intraepithelial neoplasia grade 2 and subsequent risk of cervical cancer: population based cohort study.

OBJECTIVE: To describe the long term risk of cervical cancer in women with untreated (that is, undergoing active surveillance) or immediately treated cervical intraepithelial neoplasia grade 2 (CIN2). DESIGN: Nationwide population based historical cohort study. SETTING: Danish healthcare registries. PARTICIPANTS: Women with CIN2 diagnosed in 1998-2020 and aged 18-40 years at diagnosis, who had either active surveillance or immediate treatment with large loop excision of the transformation zone (LLETZ). Women with a previous record of CIN2 or worse or LLETZ were excluded. MAIN OUTCOME MEASURE: A Weibull survival model for interval censored time-to-event data was used to estimate the cumulative risk of cervical cancer. Inverse probability treatment weighting was used to adjust estimates for age, index cytology, calendar year, and region of residence. RESULTS: The cohort included 27 524 women with CIN2, of whom 12 483 (45%) had active surveillance and 15 041 (55%) had immediate LLETZ. During follow-up, 104 cases of cervical cancer were identified-56 (54%) in the active surveillance group and 48 (46%) in the LLETZ group. The cumulative risk of cervical cancer was comparable across the two groups during the active surveillance period of two years. Thereafter, the risk increased in the active surveillance group, reaching 2.65% (95% confidence interval 2.07% to 3.23%) after 20 years, whereas it remained stable in the LLETZ group at 0.76% (0.58% to 0.95%). CONCLUSIONS: Undergoing active surveillance for CIN2, thereby leaving the lesion untreated, was associated with increased long term risk of cervical cancer compared with immediate LLETZ. These findings show the importance of continued follow-up of women having active surveillance.

HPV vaccination for immunosuppressed women.

Immunocompromised women are at increased risk of having HPV detected and developing HPV-related diseases such as genital warts, anogenital dysplasia, and cancer. This review aims to summarize the current literature regarding the immunogenicity of the HPV vaccine in immunocompromised women and to discuss whether HPV vaccination may be able to reduce the risk of cervical dysplasia and cancer. HPV vaccination induces an immune response in these women; however, it is unknown whether vaccination is effective in reducing the risk of cervical dysplasia and cancer. Further research is needed.

High prevalence of HPV16 and high-grade cytology in women undergoing active surveillance for cervical intraepithelial neoplasia grade 2.

INTRODUCTION: Many countries have adopted active surveillance in women with cervical intraepithelial neoplasia grade 2 (CIN2), leaving the lesion untreated. However, there is a lack of consensus on the eligibility criteria for active surveillance across countries, with some abstaining from active surveillance in women with human papilloma virus 16 (HPV16) or a high-grade cytology. Here, we aimed to describe the distribution of HPV genotypes, age, and cytology in women undergoing active surveillance for CIN2. MATERIAL AND METHODS: We conducted a single-center cross-sectional study on women aged 23-40 undergoing active surveillance for CIN2 during 2000-2010. Women were identified through the Danish Pathology Data Bank (DPDB) at Aarhus University Hospital, Denmark. We collected information on basic characteristics and results of histopathological examinations via DPDB. Women were deemed eligible for inclusion if they had a subsequent biopsy after index CIN2, and had no prior record of CIN2+, hysterectomy, or cone biopsy. Archived biopsies underwent HPV genotyping using the HPV SPF10 - DEIA-LiPA25 system, and the diagnosis was re-evaluated by three expert pathologists. We used the Chi squared-test (p-value) for comparison across groups. RESULTS: We identified 3623 women with CIN2 of whom 455 (12.6%) were included. Most women were 30 years or younger (73.8%), and half (48.8%) had a high-grade index cytology. The prevalence of any high-risk HPV was 87.0%, with HPV16 being the most prevalent genotype (35.6%). The prevalence of HPV16 was significantly higher in women aged 30 or younger (39.3%) compared to women older than 30 years (25.2%) (p = 0.006). Upon expert review, 261 (57.4%) had CIN2 confirmed, whereas 56 (12.3%) were upgraded to CIN3 and 121 (26.6%) were downgraded to CIN1/normal. While the HPV16 prevalence was similar between community and expert confirmed CIN2, the prevalence of HPV16 was significantly higher in women with expert CIN3 compared to women with expert CIN1/normal (64.3% vs. 19.0%, p = 0.001). CONCLUSIONS: The high prevalence of HPV16 and high-grade cytology imply that these women may be perceived as a high-risk population and non-eligible for active surveillance in countries outside Denmark. Future studies should investigate the importance of HPV, age, cytology, and expert review on risk of progression to help refine criteria for active surveillance.

Value of a catch-up HPV test in women aged 65 and above: A Danish population-based nonrandomized intervention study.

BACKGROUND: High-risk human papillomavirus (HPV) test is replacing cytology as the primary cervical cancer screening test due to superior sensitivity, but in most countries women ≥65 years have never had an HPV test despite they account for around 50% of cervical cancer deaths. We explored the effect of a catch-up HPV test among 65- to 69-year-old women without previous record of HPV-based screening. METHODS AND FINDINGS: This population-based nonrandomized intervention study (quasi-experimental design) included Danish women aged 65 to 69 with no record of cervical cancer screening in the last ≥5.5 years and no HPV-exit test at age 60 to 64 at the time of study inclusion. Eligible women residing in the Central Denmark Region were invited for HPV screening either by attending clinician-based sampling or requesting a vaginal self-sampling kit (intervention group, n = 11,192). Women residing in the remaining four Danish regions received standard care which was the opportunity to have a cervical cytology collected for whatever reason (reference group, n = 33,387). Main outcome measures were detection of cervical intraepithelial neoplasia (CIN) grade 2 or worse (CIN2+) per 1,000 women eligible for the screening offer and the benefit-harm ratio of the intervention and standard practice measured as the number of colposcopies needed to detect one CIN2+ case. The minimum follow-up time was 13 months for all tested women (range: 13 to 25 months). In the intervention group, 6,965 (62.2%) were screened within 12 months from the date of study inclusion and 743 (2.2%) women had a cervical cytology collected in the reference group. The CIN2+ detection was significantly higher in the intervention group (3.9, 95% confidence interval (CI): [2.9, 5.3]; p < 0.001; n = 44/11,192) as compared to the reference group (0.3, 95% CI: [0.2, 0.6]; n = 11/33,387). For the benefit-harm ratio, 11.6 (95% CI: [8.5, 15.8]; p = 0.69; n = 511/44) colposcopies were performed to detect one CIN2+ in the intervention group as compared to 10.1 (95% CI: [5.4, 18.8]; n = 111/11) colposcopies in the reference group. The study design entails a risk of confounding due to the lack of randomization. CONCLUSIONS: The higher CIN2+ detection per 1,000 eligible women in the intervention group supports that a catch-up HPV test could potentially improve cervical cancer prevention in older women. This study informs the current scientific debate as to whether women aged 65 and above should be offered a catch-up HPV test if they never had an HPV test. TRIAL REGISTRATION: ClinicalTrials.gov NCT04114968.

Levels of anxiety in women aged ≥45 years undergoing diagnostic large loop excision of the transformation zone: A longitudinal study.

OBJECTIVE: To measure anxiety levels in women aged ≥45 years undergoing diagnostic large loop excision of the transformation zone (LLETZ) at the first colposcopy visit. DESIGN: Longitudinal study. SETTING: Three colposcopy clinics in the Central Denmark Region. POPULATION: Women aged ≥45 years undergoing diagnostic LLETZ. METHODS: Women completed the State-Trait Anxiety Inventory (STAI) and Short Form 12 (mental and physical health) questionnaires before, immediately after, and at 1 and 6 months after LLETZ. MAIN OUTCOME MEASURES: STAI state anxiety median scores were calculated and stratified by health status, by letter with information about screening result and by LLETZ results. RESULTS: Of 109 eligible women, 11 were excluded, leaving 98 women for the final analyses. Response rates ranged from 84.7% to 100%. Overall, state anxiety levels were low; however, a decrease was observed from before to immediately after the LLETZ (33.4 vs 29.3, p < 0.001). The anxiety levels remained stable up to 6 months after LLETZ. Women with poor mental health were more likely to have higher anxiety levels compared with women with good mental health (before LLETZ, RR 3.77, 95% CI 2.12-6.70; 1 month after LLETZ, RR 3.37, 95% CI 1.59-7.15; 6 months after LLETZ, RR 1.93, 95%CI 1.06-3.51). CONCLUSIONS: Overall, colposcopy and diagnostic LLETZ in women aged ≥45 years were not associated with high levels of anxiety. Anxiety levels were highest before colposcopy, and the women seemed to experience immediate relief afterwards. Women with poor mental health had the highest anxiety levels throughout the study, which might call for special attention.

Clinical utility of p16/Ki67 dual-stain cytology for detection of cervical intraepithelial neoplasia grade two or worse in women with a transformation zone type 3: A cross-sectional study.

OBJECTIVE: To evaluate the clinical utility of p16/Ki67 dual-stain (DS) compared with cytology for detecting cervical intraepithelial lesion grade two or worse (CIN2+) in women with a transformation zone type 3 (TZ3). DESIGN: Cross-sectional study. SETTING: Colposcopy clinics in Central Denmark Region. POPULATION: Women aged 45 years or older referred for colposcopy because of an abnormal screening test. METHODS: All women had a cervical sample collected for cytology and DS testing and underwent large-loop excision of the transformation zone (LLETZ). MAIN OUTCOME MEASURE: Sensitivity, specificity and negative (NPV) and positive (PPV) predictive values of DS for CIN2+ detection were compared to those of cytology. RESULTS: Of 166 women eligible, 93 (56.0%) were included in the final analysis. Median age was 68 years (interquartile range [IQR] 63.4-70.5 years). Most women were postmenopausal (95.7%) and referred based on a positive human papillomavirus screening test (86.0%). Fifty-two women (55.9%) were DS-positive, 29 (55.8%) of whom had CIN2+ detected. Twenty-seven (29.0%) women had atypical squamous cells of undetermined significance or worse (ASC-US+), and CIN2+ was detected in 21 women (77.8%). DS had a higher sensitivity (96.7% versus 70.0% p = 0.021) and NPV (97.6% versus 86.4%, p = 0.018) compared with cytology for CIN2+ detection. In contrast, the specificity (63.5% versus 90.5% p < 0.001) and PPV (55.8% versus 77.8%, p = 0.001) were lower for DS compared with cytology. CONCLUSIONS: Dual stain may be a valuable risk marker to guide clinical management of women with a TZ3. The superior NPV of DS suggests that a diagnostic excision may safely be avoided in DS-negative women.

Three birds with one stone: a protocol for a randomised intervention study to increase participation in cervical and colorectal cancer screening among women attending breast cancer screening.

INTRODUCTION: The participation rate is higher in breast cancer screening than in cervical cancer (CCU) and colorectal cancer (CRC) screening. In this cluster-randomised study, we aim to evaluate an intervention offering home-based CCU and CRC screening to women when attending breast cancer screening if they are overdue for CCU and/or CRC screening. METHODS AND ANALYSIS: On intervention days, one of the five breast cancer screening units in the Central Denmark Region will be randomly allocated to intervention, whereas the remaining units will serve as control. Women attending breast cancer screening in the intervention unit will be offered information regarding their CCU and CRC screening history, and, if overdue, they will be offered self-sampling screening kits. For CCU screening, women aged 50-64 years will be offered a vaginal self-sampling kit for human papillomavirus testing. For CRC screening, women aged 50-69 years will be offered a kit to obtain a faecal immunochemical test. Women attending the control units will receive only standard care.After the intervention, a survey will be sent to all women in the intervention and control group, asking about their experience while attending breast cancer screening.Primary outcomes will be difference in the coverage in CCU and CRC screening 6 months after intervention between the intervention and the control group, and difference in participation rates 6 months after intervention for those who were overdue for CCU and/or CRC screening at the time of the intervention. ETHICS AND DISSEMINATION: The project is listed in the record of processing activities for research projects in the Central Denmark Region (R. No.: 1-16-02-217-21). According to the Danish Consolidation Act on Research Ethics Review of Health Research Project, this study was not notifiable to the Committee (R. No.: 1-10-72-1-21). The findings will be disseminated in peer-reviewed scientific journals. TRIAL REGISTRATION NUMBER: NCT05022511.

Endocervical sampling in women with suspected cervical neoplasia: a systematic review and meta-analysis of diagnostic test accuracy studies.

OBJECTIVE: Endocervical sampling in women with suspected cervical neoplasia can be performed by either endocervical brush or endocervical curettage. This study aimed to estimate the diagnostic accuracy, discomfort, and number of inadequate samples with either test. DATA SOURCES: Four bibliographic databases were searched on June 9, 2022, with no date or language restrictions. STUDY ELIGIBILITY CRITERIA: We included all diagnostic studies and randomized clinical trials that compared the endocervical brush with endocervical curettage in women with an indication for colposcopy. METHODS: The review protocol was registered on the International Prospective Register of Systematic Reviews (PROSPERO) (CRD42021222406). Two authors independently screened studies, extracted data, performed the risk-of-bias assessment (Quality Assessment of Diagnostic Accuracy Studies-2), and rated the certainty of the evidence using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology. A meta-analysis of diagnostic test accuracy was performed using a bivariate random-effects model. RESULTS: We included 7 studies: 4 diagnostic cohort studies and 3 randomized clinical trials. The reference standard was conization or hysterectomy. Risk of bias and concern about applicability were high for some of the studies in patient selection and flow and timing. Overall pooled sensitivity was 81% (95% confidence interval, 48-95; 799 women; 7 studies; low quality of evidence) for endocervical brush and 70% (95% confidence interval, 42-89; 761 women; 7 studies; low quality of evidence) for endocervical curettage. Overall pooled specificity was 73% (95% confidence interval, 36-93; 799 women; 7 studies; low quality of evidence) for endocervical brush and 81% (95% confidence interval, 56-94; 761 women; 7 studies; low quality of evidence) for endocervical curettage. The risk ratio for inadequate samples with endocervical curettage compared with endocervical brush was 2.53 (95% confidence interval, 0.58-11.0; P=.215; low-certainty evidence). Two studies reported on patient discomfort; one found less discomfort in the endocervical brush group, and the other found no difference. CONCLUSION: No difference was found between endocervical brush and endocervical curettage in diagnostic accuracy, inadequate sampling rate, and adverse effects based on low-quality of evidence. Variation in the characteristics of women and the resulting diagnostic pathways make the external validity limited.

Performance of HPV E4 and p16INK4a biomarkers in predicting regression of cervical intraepithelial neoplasia grade 2 (CIN2): protocol for a historical cohort study.

INTRODUCTION: Cervical intraepithelial neoplasia grade 2 (CIN2) represents a spectrum of lesions with variable progression and regression. Pathological diagnosis of CIN2 is subjective and poorly reproducible. Accurate diagnosis and identification of different patterns of CIN2 related to outcome are essential to reduce the risks of overtreatment or undertreatment. It is important to explore novel methods for risk stratification of CIN2 to enable targeted treatment of women at high risk of progression or persistent disease and follow-up of women at low risk. The combination of the novel biomarker human papillomavirus (HPV) E4 with p16INK4a targets steps in the transition from a productive oncogenic HPV infection (CIN1) to a transformed lesion (CIN3) within CIN2. Previous cross-sectional studies suggest that HPV E4 combined with p16INK4a may be valuable for risk assessment of CIN2. However, data on HPV E4/p16INK4a as a predictor for CIN2 regression is lacking. METHODS AND ANALYSIS: We will conduct a historical cohort study including 500 women aged 23-40 years with a first CIN2 diagnosis in Aarhus, Denmark during 2000-2010. Women will be eligible if they have undergone active surveillance and have no previous record of hysterectomy, cone biopsy, and CIN2 or worse. Women will be randomly selected through the Danish Pathology Databank. Tissue samples from women included will be sectioned for p16INK4a and HPV E4 immunohistochemical staining in addition to conventional hematoxylin and eosin (H&E) staining. A positive result will be defined as HPV E4 positive. Through the Danish Pathology Databank, we will collect results on all subsequent cervical biopsies. Regression will be used as the primary outcome. ETHICS AND DISSEMINATION: The study has been approved by the Ethical Committee in Central Denmark Region (1-10-72-60-20) and registered at the Faculty of Health, Aarhus University. Results will be published in a peer-reviewed journal and presented at scientific meetings. TRIAL REGISTRATION NUMBER: NCT05049252.

Cervical intraepithelial neoplasia in women with transformation zone type 3: cervical biopsy versus large loop excision.

OBJECTIVE: To compare the proportion of cervical intraepithelial neoplasia grade 2 or higher (CIN2+) in cervical biopsies with that in large loop excision of the transformation zone (LLETZ) specimens in women aged ≥45 years with transformation zone type 3 (TZ3). DESIGN: Multicentre cross-sectional study. SETTING: Three colposcopy clinics in the Central Denmark Region. POPULATION: Women aged ≥45 years referred to colposcopy as a result of a positive human papillomavirus (HPV) test and/or abnormal cytology and with TZ3 at colposcopy. METHODS: Women had multiple biopsies taken and an LLETZ was performed. MAIN OUTCOME MEASURES: Histologically confirmed CIN2+ in biopsies compared with that in LLETZ specimens. RESULTS: Of 166 eligible women at colposcopy, 102 women with paired data from biopsies and LLETZ specimens were included for final analysis. The median age was 67.7 years (IQR 62.6-70.4 years), and most were postmenopausal (94.1%) and had undergone HPV-based screening (81.3%). The CIN2+ detection rate was significantly higher in LLETZ specimens than in biopsies (32.4% vs 14.7%, difference 17.7%, 95% CI 6.3-29.0%), resulting in more than half of CIN2+ cases being missed in biopsies (54.5%, 95% CI 36.4-71.9%). The overall agreement between biopsies and LLETZ was 82.4% (95% CI 73.6-89.2%). CONCLUSIONS: CIN2+ detection is underestimated in women aged ≥45 years with TZ3 if detection relies on the results of biopsies alone. To reduce the risk of underdiagnosis and overtreatment, future studies should explore the use of new biomarkers for risk stratification to improve discrimination between women at increased risk of CIN2+ who need to undergo LLETZ and women who may undergo follow-up.

Adherence to follow-up after the exit cervical cancer screening test at age 60-64: A nationwide register-based study.

BACKGROUND: In Denmark, human papillomavirus (HPV) testing has replaced cytology in primary cervical cancer screening for women aged 60-64; at this age, women are invited for the last (exit) screening test within the national organized program. AIM: We investigated the adherence of these women to the recommended follow-up after a non-negative (positive or inadequate) HPV test and the overall resource use during that follow-up. MATERIALS & METHODS: We included all 2926 women aged 60-64 years with nonnegative HPV screening tests between March 2012 and December 2016. All relevant follow-up tests and procedures were retrieved until the end of 2020 from the highly complete Danish administrative health registers, and the data were linked at the individual level. We determined the extent to which the adherence patterns followed the national recommendations for follow-up and estimated the total numbers of tests and diagnostic procedures utilized during the entire process. RESULTS: In total, only 26% of women had follow-up in accordance with the recommendations; 4% had no follow-up, 46% had insufficient follow-up, and 24% had more follow-up than recommended. We estimated that 17% of women remained in follow-up for longer than 4 years. The average numbers of diagnostic tests and procedures used after positive HPV screening were higher than expected, even among women who had insufficient follow-up, that is, those who received less invasive procedures than recommended, or experienced delays in receiving those procedures. CONCLUSION: To conclude, we found that the patterns of follow-up of women with nonnegative primary HPV screening tests at 60-64 often diverged from the recommendations. Addressing these inconsistencies in follow-up by providing evidence for optimal clinical management should help improve the quality of screening programs and secure an equal and reliable follow-up care service for all women.

Can biopsies be omitted after normal colposcopy in women referred with low-grade cervical cytology? A prospective cohort study.

BACKGROUND: Controversy surrounds whether women with low-risk cytology screening results but a normal colposcopic assessment should have random biopsies taken. The aim of this study was to determine the yield of CIN2+ from one to four cervical biopsies in women with cytology of LSIL or ASCUS and a normal colposcopic impression. METHODS: Between January 2017 and September 2020, women over 18 years old referred for colposcopic examination due to either an abnormal smear (ASCUS+) or follow-up after previous cervical intraepithelial neoplasia (CIN) were invited to participate in the study. All study participants underwent colposcopic examination and had four biopsies taken. The biopsies were analyzed separately. RESULTS: In total, 1327 women with abnormal cervical cancer screening results or attending follow-up after a previous CIN diagnosis were enrolled in the study and examined by colposcopy. Of these, 173 were newly referred with cytology of LSIL or ASCUS and had a normal colposcopic impression and four adequate biopsies. Of these, 22.0% were diagnosed with CIN2+. When combining the results of the four biopsies, we found a 100% relative increase in CIN2+ cases compared to using only one biopsy (from 11.0% to 22.0%, P = 0.006). CONCLUSION: As we found CIN2+ from random cervical biopsies in 22.0% of women with cytology of LSIL or ASCUS who had a normal colposcopic impression, we advocate performing four random cervical biopsies at the squamocolumnar junction in such women. Trial registration NCT04249856, January 31 2020 (retrospectively registered).

Concerns about transmission, changed services and place of birth in the early COVID-19 pandemic: a national survey among Danish pregnant women. The COVIDPregDK study.

BACKGROUND: The outbreak of the COVID-19 pandemic caused great uncertainty about causes, treatment and mortality of the new virus. Constant updates of recommendations and restrictions from national authorities may have caused great concern for pregnant women. Reports suggested an increased number of pregnant women choosing to give birth at home, some even unassisted ('freebirth') due to concerns of transmission in hospital or reduction in birthplace options. During April and May 2020, we aimed to investigate i) the level of concern about coronavirus transmission in Danish pregnant women, ii) the level of concern related to changes in maternity services due to the pandemic, and iii) implications for choice of place of birth. METHODS: We conducted a nationwide cross-sectional online survey study, inviting all registered pregnant women in Denmark (n = 30,009) in April and May 2020. RESULTS: The response rate was 60% (n = 17,995). Concerns of transmission during pregnancy and birth were considerable; 63% worried about getting severely ill whilst pregnant, and 55% worried that virus would be transmitted to their child. Thirtyeight percent worried about contracting the virus at the hospital. The most predominant concern related to changes in maternity services during the pandemic was restrictions on partners' attendance at birth (81%). Especially nulliparous women were concerned about whether cancelled antenatal classes or fewer physical midwifery consultations would affect their ability to give birth or care for their child postpartum.. The proportion of women who considered a home birth was equivalent to pre-pandemic home birth rates in Denmark (3%). During the temporary discontinue of public home birth services, 18% of this group considered a home birth assisted by a private midwife (n = 125), and 6% considered a home birth with no midwifery assistance at all (n = 41). CONCLUSION: Danish pregnant womens' concerns about virus transmission to the unborn child and worries about contracting the virus during hospital appointments were considerable during the early pandemic. Home birth rates may not be affected by the pandemic, but restrictions in home birth services may impose decisions to freebirth for a small proportion of the population.

Perceptions of cervical cancer prevention among a group of ethnic minority women in Denmark-A qualitative study.

BACKGROUND: Cervical cancer screening (CCS) and human papillomavirus vaccination (HPVV) are effective measures against cervical cancer (CC). Attendance in HPVV and CCS provides the greatest protection, while combined non-attendance in HPVV and CCS provides little to no protection. It is hence concerning that some large ethnic minority groups show considerably lower HPVV and CCS attendance than other women-especially women from Middle-Eastern and North African (MENA) countries and Pakistan. Little is, however, known about the reasons for this low combined attendance pattern n. AIM: To explore perceptions of and barriers to HPVV and CCS, among MENA and Pakistani women in Denmark. METHOD: Focus group interviews were conducted. Data was transcribed verbatim, and analysed using systematic text condensation. FINDINGS: Seventeen long-term resident women originating from six major MENA countries and Pakistan were included. Mean age was 36 years. We found that these women, across different age groups and descent, had sparse knowledge and understanding about CC, and their perceived relevance of disease prevention was low. Compared to HPVV, their barriers to CCS were more fixed and often linked to socio-cultural factors such as taboos related to female genitals and sexuality. Moreover, they presented unmet expectations and signs of mistrust in the healthcare system. However, at the end of the interviews, participants became more attentive toward CC prevention, particularly toward HPVV. CONCLUSION: Elements of insufficient knowledge and understanding of CC and its prevention were found among a group of MENA and Pakistani women. Their socio-cultural background further represents a barrier particularly towards CCS. Additionally, negative experiences and unmet expectations lessen their trust in the healthcare system. All of which underlines the need for new tailored CC preventive strategies for this group. Based on our findings we suggest that future studies develop and evaluate interventions aiming to improve HPVV and CCS, including user-involvement.