Risk of progression of cervical intraepithelial neoplasia grade 2 in human papillomavirus-vaccinated and unvaccinated women: a population-based cohort study.

BACKGROUND: Many countries have implemented active surveillance (ie, leaving the lesion untreated) as an option among younger women with cervical intraepithelial neoplasia grade 2 because regression rates are high and excisional treatment increases the risk for preterm birth in subsequent pregnancies. However, early identification of women at increased risk for progression to cervical intraepithelial neoplasia grade 3 or worse is important to ensure timely treatment. Because women who have received a human papillomavirus vaccine have a lower risk for cervical cancer, they may have a lower risk for progression of untreated cervical intraepithelial neoplasia grade 2 to cervical intraepithelial neoplasia grade 3 or worse. OBJECTIVE: This study aimed to investigate if women who received a human papillomavirus vaccine and who are undergoing active surveillance for cervical intraepithelial neoplasia grade 2 are less likely to progress to cervical intraepithelial neoplasia grade 3 or worse when compared with women who did not receive the vaccine. STUDY DESIGN: We conducted a population-based cohort study in Denmark using data from national health registers. We identified all women aged 18 to 40 years who were undergoing active surveillance for cervical intraepithelial neoplasia grade 2 from January 1, 2007, to December 31, 2020. Women with a previous record of cervical intraepithelial neoplasia grade 2 or worse, hysterectomy, or a loop electrosurgical excision procedure were excluded. Exposure was defined as having received ≥1 dose of a human papillomavirus vaccine at least 1 year before the cervical intraepithelial neoplasia grade 2 diagnosis. We used cumulative incidence functions to estimate the risk for progression to cervical intraepithelial neoplasia grade 3 or worse within 28 months using hysterectomy, emigration, and death as competing events. We used modified Poisson regression to calculate crude and adjusted relative risks of progression during the 28-month surveillance period. Results were stratified by age at vaccination and adjusted for index cytology, disposable income, and educational level. RESULTS: The study population consisted of 7904 women of whom 3867 (48.9%) were vaccinated at least 1 year before a diagnosis of cervical intraepithelial neoplasia grade 2. At the time of cervical intraepithelial neoplasia grade 2 diagnosis, women who were vaccinated were younger (median age, 25 years; interquartile range, 23-27 years) than those who were not (median age, 29 years; interquartile range, 25-33 years). The 28-month cumulative risk for cervical intraepithelial neoplasia grade 3 or worse was significantly lower among women who were vaccinated before the age of 15 years (22.9%; 95% confidence interval, 19.8-26.1) and between the ages of 15 and 20 years (31.5%; 95% confidence interval, 28.8-34.3) when compared with women who were not vaccinated (37.6%; 95% confidence interval, 36.1-39.1). Thus, when compared with women who were not vaccinated, those who were vaccinated before the age of 15 years had a 35% lower risk for progression to cervical intraepithelial neoplasia grade 3 or worse (adjusted relative risk, 0.65; 95% confidence interval, 0.57-0.75), whereas women who were vaccinated between the ages of 15 and 20 years had a 14% lower risk (adjusted relative risk, 0.86; 95% confidence interval, 0.79-0.95). For women who were vaccinated after the age of 20 years, the risk was comparable with that among women who were not vaccinated (adjusted relative risk, 1.02; 95% confidence interval, 0.96-1.09). CONCLUSION: Women who were vaccinated and who were undergoing active surveillance for cervical intraepithelial neoplasia grade 2 had a lower risk for progression to cervical intraepithelial neoplasia grade 3 or worse during 28 months of follow-up when compared with women who were not vaccinated but only if the vaccine was administered by the age of 20 years. These findings may suggest that the human papillomavirus vaccination status can be used for risk stratification in clinical management of cervical intraepithelial neoplasia grade 2.

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.

Reproducibility of colposcopy quality indicators-A survey among members of the European Federation for Colposcopy.

INTRODUCTION: Colposcopy is an important part of the diagnostic work-up of women with an abnormal cervical screening test as it is used to guide the collection of biopsies. Although quality assurance has been used in the evaluation of screening programs, not much is known about quality indicators for the diagnostics and treatment of screen-positive women. Therefore, the European Federation for Colposcopy developed quality indicators aiming to support colposcopy practice across Europe. We performed a survey of colposcopy cases to determine if the quality indicators are understandable, relevant, and reproducible. MATERIAL AND METHODS: We conducted a survey among all members of the European Federation for Colposcopy Quality and Standards Group from November 2022 to March 2023. Members were asked to collect information on a total of 17 quality indicators for 50 women who had been newly referred for colposcopy due to an abnormal screening test between January 1, 2020 to December 31, 2021. Results were reported descriptively. RESULTS: We included data on 609 cases from 12 members across Europe. The majority of the quality indicators were either achieved or within reach of the agreed standard, often due to few countries with outlying data. One quality indicator had very low performance, although stratified results indicated that two countries had different clinical management of the patient type thereby skewing the results. In addition, discrepancies between the number of cases included in each quality indicator raised concerns regarding potential misunderstanding of the quality indicator and its objective. CONCLUSIONS: Quality indicators on colposcopy must be understandable to those collecting data, highlighting the importance of validating quality indicators before data collection.

Agreement on Lesion Presence and Location at Colposcopy.

OBJECTIVES/PURPOSE: The reproducibility and sensitivity of image-based colposcopy is low, but agreement on lesion presence and location remains to be explored. Here, we investigate the interobserver agreement on lesions on colposcopic images by evaluating and comparing marked lesions on digitized colposcopic images between colposcopists. METHODS: Five colposcopists reviewed images from 268 colposcopic examinations. Cases were selected based on histologic diagnosis, i.e., normal/cervical intraepithelial neoplasia (CIN)1 ( n = 50), CIN2 ( n = 50), CIN3 ( n = 100), adenocarcinoma in situ ( n = 53), and cancer ( n = 15). We obtained digitized time-series images every 7-10 seconds from before acetic acid application to 2 minutes after application. Colposcopists were instructed to digitally annotate all areas with acetowhitening or suspect of lesions. To estimate the agreement on lesion presence and location, we assessed the proportion of images with annotations and the proportion of images with overlapping annotated area by at least 4 (4+) colposcopists, respectively. RESULTS: We included images from 241 examinations (1 image from each) with adequate annotations. The proportion with a least 1 lesion annotated by 4+ colposcopists increased by severity of histologic diagnosis. Among the CIN3 cases, 84% had at least 1 lesion annotated by 4+ colposcopists, whereas 54% of normal/CIN1 cases had a lesion annotated. Notably, the proportion was 70% for adenocarcinoma in situ and 71% for cancer. Regarding lesion location, there was no linear association with severity of histologic diagnosis. CONCLUSION: Despite that 80% of the CIN2 and CIN3 cases were annotated by 4+ colposcopists, we did not find increasing agreement on lesion location with histology severity. This underlines the subjective nature of colposcopy.

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.

Infection, recovery and re-infection of farmed mink with SARS-CoV-2.

Mink, on a farm with about 15,000 animals, became infected with SARS-CoV-2. Over 75% of tested animals were positive for SARS-CoV-2 RNA in throat swabs and 100% of tested animals were seropositive. The virus responsible had a deletion of nucleotides encoding residues H69 and V70 within the spike protein gene as well as the A22920T mutation, resulting in the Y453F substitution within this protein, seen previously in mink. The infected mink recovered and after free-testing of 300 mink (a level giving 93% confidence of detecting a 1% prevalence), the animals remained seropositive. During further follow-up studies, after a period of more than 2 months without any virus detection, over 75% of tested animals again scored positive for SARS-CoV-2 RNA. Whole genome sequencing showed that the viruses circulating during this re-infection were most closely related to those identified in the first outbreak on this farm but additional sequence changes had occurred. Animals had much higher levels of anti-SARS-CoV-2 antibodies in serum samples after the second round of infection than at free-testing or during recovery from initial infection, consistent with a boosted immune response. Thus, it was concluded that following recovery from an initial infection, seropositive mink were readily re-infected by SARS-CoV-2.

Risk of cervical intraepithelial neoplasia grade 2 or worse in women aged ≥ 69 referred to colposcopy due to an HPV-positive screening test.

BACKGROUND: Cervical cancer incidence and mortality rates are high in older women in many developed countries, including Denmark. Therefore, Danish women aged 69 and older were invited for one additional human papilloma virus (HPV) based screening test in 2017. Here, we describe the clinical management and detection rate of cervical intraepithelial neoplasia grade 2 or worse (CIN2 +) in screen-positive women referred for colposcopy. METHODS: We conducted an observational study in public gynecology departments in Central Denmark Region, Denmark. Women were eligible for enrolment if they were aged 69 + in 2017, HPV positive on a screening test taken between April 20th, 2017, and December 31st, 2017, and had been referred for direct colposcopy. Data on participants' characteristics, colposcopic findings, and histological outcomes were collected from medical records and the Danish Pathology Databank. We estimated the proportion of women with CIN2 + at the first colposcopy visit and at end of follow up including 95% confidence intervals (CIs). RESULTS: A total of 191 women were included with a median age of 74 years (IQR: 71-78). Most women (74.9%) did not have a fully visible transformation zone at colposcopy. At the first visit 170 women (89.0%) had a histological sample collected, 34 of whom (20.0%, 95% CI 14.3-26.8%) had CIN2 + diagnosed, 19 had CIN3 + , and two had cervical cancer). During follow-up additional CIN2 + were detected resulting in a total of 42 women (24.4%, 95% CI: 18.2-31.5%) being diagnosed with CIN2 + , 25 with CIN3 + , and three with cervical cancer. When restricting to women with paired histologic results (i.e., biopsies and a loop electrosurgical excision procedure (LEEP) specimen), we found that CIN2 + was missed in 17.9% (95% CI 8.9-30.4%) of biopsies compared to the LEEP. CONCLUSION: Our findings suggest a potential risk of underdiagnosis in older postmenopausal women referred to colposcopy. Future studies should explore potential risk-markers for discrimination of women at increased risk of CIN2 + from those at low risk, as this would reduce risk of underdiagnosis and overtreatment.

Clinical course of cervical intraepithelial neoplasia grade 2: a population-based cohort study.

BACKGROUND: Cervical intraepithelial neoplasia grade 2 has historically been the threshold for surgical excision, but because of high regression rates, many countries are transitioning to active surveillance. However, estimates for regression rates are based on small studies with heterogeneous definitions of regression and progression. OBJECTIVE: This study aimed to describe regression and progression rates of cervical intraepithelial neoplasia grade 2 using nationwide healthcare registry data. STUDY DESIGN: This was a nationwide population-based cohort study on women aged 18 to 40 years who had undergone active surveillance for cervical intraepithelial neoplasia grade 2 in Denmark from 1998 to 2020. This study excluded women with a previous record of cervical intraepithelial neoplasia grade 2 or worse or surgical excision. Cumulative incidence functions were used to estimate the rates of regression and progression at 6, 12, 18, and 24 months after diagnosis. In addition, a modified Poisson regression was used to estimate the crude and adjusted relative risks of progression within 24 months stratified by index cytology and age. RESULTS: During the study period, 11,056 women underwent active surveillance, 6767 of whom regressed and 3580 of whom progressed within 24 months. This corresponded to regression rates of 62.9% (95% confidence interval, 61.9-63.8) and progression rates of 33.3% (95% confidence interval, 32.4-34.2) at 24 months of follow-up. Most women regressed (90%) or progressed (90%) within the first 12 months. Women with high-grade index cytology had a higher risk of progression than women with normal index cytology (adjusted relative, 1.58; 95% confidence interval, 1.43-1.76), whereas there was no difference in the risk of progression between women aged 30 and 40 years and women aged 23 to 29 years (adjusted relative risk, 0.98; 95% confidence interval, 0.88-1.10). CONCLUSION: The observed high regression rates of cervical intraepithelial neoplasia grade 2 supported the transition in clinical management from surgical excision to active surveillance, particularly among women with low-grade or normal index cytology.

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.

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.

Risk factors for and pregnancy outcomes after SARS-CoV-2 in pregnancy according to disease severity: A nationwide cohort study with validation of the SARS-CoV-2 diagnosis.

INTRODUCTION: We identified risk factors and outcomes associated with SARS-CoV-2 infection in pregnancy in a universally tested population according to disease severity and validated information on SARS-CoV-2 during pregnancy in national health registers in Denmark. MATERIAL AND METHODS: Cohort study using data from national registers and medical records including all pregnancies between March 1, 2020 and February 28, 2021. We compared women with a validated positive SARS-CoV-2 test during pregnancy with non-infected pregnant women. Risk factors and pregnancy outcomes were assessed by Poisson and Cox regression models and stratified according to disease severity defined by hospital admission status and admission reason (COVID-19 symptoms or other). Using medical record data on actual period of pregnancy, we calculated predictive values of the SARS-CoV-2 diagnosis in pregnancy in the registers. RESULTS: SARS-CoV-2 infection was detected in 1819 (1.6%) of 111 185 pregnancies. Asthma was associated with infection (relative risk [RR] 1.63, 95% confidence interval [CI] 1.28-2.07). Risk factors for severe COVID-19 disease requiring hospital admission were high body mass index (median ratio 1.06, 95% CI 1.04-1.09), asthma (RR 7.47, 95% CI 3.51-15.90) and gestational age at the time of infection (gestational age 28-36 vs < 22: RR 3.53, 95% CI 1.75-7.10). SARS-CoV-2-infected women more frequently had hypertensive disorders in pregnancy (adjusted hazard ratio [aHR] 1.31, 95% CI 1.04-1.64), early pregnancy loss (aHR 1.37, 95% CI 1.00-1.88), preterm delivery before gestational age 28 (aHR 2.31, 95% CI 1.01-5.26), iatrogenically preterm delivery before gestational age 37 (aHR 1.49, 95% CI 1.01-2.19) and small-for-gestational age children (aHR 1.28, 95% CI 1.05-1.54). The associations were stronger among women admitted to hospital for any reason. The validity of the SARS-CoV-2 diagnosis in relation to pregnancy in the registers compared with medical records showed a negative predictive value of 99.9 (95% CI 99.9-100.0) and a positive predictive value of 82.1 (95% CI 80.4-83.7). CONCLUSIONS: Women infected with SARS-CoV-2 during pregnancy were at increased risk of hypertensive disorders in pregnancy, early pregnancy loss, preterm delivery and having children small for gestational age. The validity of Danish national registers was acceptable for identification of SARS-CoV-2 infection during pregnancy.

Understanding cervical cancer after the age of routine screening: Characteristics of cases, treatment, and survival in the United States.

OBJECTIVE: Given that cervical cancer incidence rates do not decline in women >65, there is generally limited screening, and these women have a poor prognosis, it is imperative to better understand this population. We aim to describe the characteristics, treatment, and survival of women >65 diagnosed with cervical cancer. METHODS: SEER-Medicare 2004-2013 data was used to describe 2274 patients >65 diagnosed with cervical cancer. Five-year cancer-specific survival was estimated using the Kaplan-Meier method. Multivariable Poisson and Cox regression analyses identified characteristics associated with treatment and mortality. RESULTS: The median age was 76.1 years, with nearly one-third of cases occurring in women >80 years. Most patients were non-Hispanic White (64.8%), had comorbidity scores ≥ 1 (53.9%) and squamous histology (66.3%). Most women were diagnosed at stage II or higher (62.7%), including nearly one-quarter at Stage IV (23.1%). Nearly 15% of patients were not treated (14.6%). Lack of treatment was associated with oldest age (>80), comorbidity scores ≥3, and stage IV disease. Five-year cancer-specific survival was 50%. Increasing age and stage at diagnosis were significantly associated with lower cancer-specific survival whereas treatment was strongly associated with increased survival. CONCLUSION: Most women >65 with cervical cancer are diagnosed with locally advanced or metastatic disease and many do not receive treatment. Survival is improved with early-stage diagnosis and treatment. These findings, coupled with the fact that women >65 constitute an increasing proportion of the population, highlight the need to re-evaluate screening and treatment practices in this population to detect cervical cancer at earlier stages and increase survival. NOVELTY AND IMPACT STATEMENT: In SEER-Medicare linked data from 2004 to 2013, most women >65 with cervical cancer were diagnosed with locally advanced or metastatic disease. Both receipt of treatment and survival decreased with increasing age. These findings, coupled with the fact that women aged >65 constitute an increasing proportion of the population, highlight the need to re-evaluate screening and treatment practices in older women to detect cervical cancer at earlier stages and increase survival.

Comparison of accuracy and reproducibility of colposcopic impression based on a single image versus a two-minute time series of colposcopic images.

OBJECTIVE: Colposcopy is an important part of cervical screening/management programs. Colposcopic appearance is often classified, for teaching and telemedicine, based on static images that do not reveal the dynamics of acetowhitening. We compared the accuracy and reproducibility of colposcopic impression based on a single image at one minute after application of acetic acid versus a time-series of 17 sequential images over two minutes. METHODS: Approximately 5000 colposcopic examinations conducted with the DYSIS colposcopic system were divided into 10 random sets, each assigned to a separate expert colposcopist. Colposcopists first classified single two-dimensional images at one minute and then a time-series of 17 sequential images as 'normal,' 'indeterminate,' 'high grade,' or 'cancer'. Ratings were compared to histologic diagnoses. Additionally, 5 colposcopists reviewed a subset of 200 single images and 200 time series to estimate intra- and inter-rater reliability. RESULTS: Of 4640 patients with adequate images, only 24.4% were correctly categorized by single image visual assessment (11% of 64 cancers; 31% of 605 CIN3; 22.4% of 558 CIN2; 23.9% of 3412 < CIN2). Individual colposcopist accuracy was low; Youden indices (sensitivity plus specificity minus one) ranged from 0.07 to 0.24. Use of the time-series increased the proportion of images classified as normal, regardless of histology. Intra-rater reliability was substantial (weighted kappa = 0.64); inter-rater reliability was fair ( weighted kappa = 0.26). CONCLUSION: Substantial variation exists in visual assessment of colposcopic images, even when a 17-image time series showing the two-minute process of acetowhitening is presented. We are currently evaluating whether deep-learning image evaluation can assist classification.

Safety of belimumab in adult patients with systemic lupus erythematosus: Results of a large integrated analysis of controlled clinical trial data.

OBJECTIVES: Systemic lupus erythematosus (SLE) is a chronic, autoimmune disease that affects multiple organ systems. Belimumab, a targeted human monoclonal antibody, binds to and inhibits soluble B-lymphocyte stimulator. The safety and efficacy of belimumab has consistently been demonstrated in multiple clinical trials for the treatment of patients with active SLE. Integration of these data provides an additional opportunity to explore the safety of belimumab in a larger and more diverse population. This post hoc pooled analysis of clinical studies evaluated the safety profile of belimumab versus placebo in adults with SLE. METHODS: This was a pooled post hoc analysis of 52-week safety data from one Phase 2 and five Phase 3 belimumab trials in adult patients with SLE. Patients received ≥1 dose of placebo or belimumab (1, 4, or 10 mg/kg intravenous or 200 mg subcutaneous), plus standard therapy. Outcomes included the incidence of adverse events (AEs), serious AEs (SAEs), severe AEs, AEs of special interest (AESI), and mortality. RESULTS: Across 4170 patients (placebo: N = 1355; belimumab: N = 2815), baseline demographics, disease characteristics, and treatment exposure were similar for placebo and belimumab. Most patients (placebo: 76.6%; belimumab: 81.0%) completed the protocol Week 52 visit. Overall, incidence of AEs, SAEs, severe AEs, AESI, and mortality were similar between groups. In both groups, the most commonly reported SAEs by system organ class were infections and infestations (placebo: 5.9%; belimumab: 5.4%) and renal and urinary disorders (placebo: 2.2%; belimumab: 1.7%). Additionally, a greater proportion of patients experienced AESI with belimumab versus placebo for post-infusion/injection systemic reactions (placebo: 8.1%; belimumab: 10.2%). Mortality rates were similar between groups (placebo: 0.4%; belimumab: 0.6%). CONCLUSIONS: These results are consistent with those of the individual studies, BASE, BLISS-LN, and long-term extension studies, making belimumab one of the most studied SLE treatments for safety. Collectively, this evidence continues to support a positive benefit-risk profile of belimumab in the treatment of adult patients with SLE.

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.

Current controversies: Null hypothesis significance testing.

Traditional null hypothesis significance testing (NHST) incorporating the critical level of significance of 0.05 has become the cornerstone of decision-making in health care, and nowhere less so than in obstetric and gynecological research. However, such practice is controversial. In particular, it was never intended for clinical significance to be inferred from statistical significance. The inference of clinical importance based on statistical significance (p < 0.05), and lack of clinical significance otherwise (p ≥ 0.05) represents misunderstanding of the original purpose of NHST. Furthermore, the limitations of NHST-sensitivity to sample size, plus type I and II errors-are frequently ignored. Therefore, decision-making based on NHST has the potential for recurrent false claims about the effectiveness of interventions or importance of exposure to risk factors, or dismissal of important ones. This commentary presents the history behind NHST along with the limitations that modern-day NHST presents, and suggests that a statistics reform regarding NHST be considered.

"I feel reassured, but there is no guarantee." How do women with a future childbearing desire respond to active surveillance of cervical intraepithelial neoplasia grade 2? A qualitative study.

INTRODUCTION: In Denmark, women with a future childbearing desire diagnosed with cervical intraepithelial neoplasia grade 2 (CIN2) are recommended active surveillance instead of excisional treatment. However, we have limited and contradictory knowledge about how active surveillance of CIN2 may affect women emotionally. The aim of this study was to explore thoughts and emotional responses in women undergoing active surveillance of CIN2 and to explore how active surveillance may affect women's future childbearing desire. MATERIAL AND METHODS: This qualitative study was conducted in the gynecological outpatient clinic, the Department of Obstetrics and Gynecology, Gødstrup Hospital, Denmark. Women of childbearing age undergoing active surveillance with colposcopy, biopsy and smear every 6 months due to CIN2 were eligible for enrollment. In-depth semi-structured interviews were conducted. The interviews were audiotaped and transcribed verbatim. A thematic analysis was performed using a phenomenological approach. RESULTS: A total of 20 women were included. All women experienced nervousness and anxiety when they were diagnosed with CIN2 initially. Their main concern was whether they had cancer. Most women carried on with their everyday lives with only minor occasional worries about CIN2, often prompted just before check-up. However, some women were particularly nervous and found the period between check-ups frustrating and challenging. Women did not want to postpone their plans for pregnancy because of CIN2, but experienced the worries and check-ups associated with active surveillance as disruptive elements in their family planning. Women preparing for fertility treatment had their startup unnecessarily delayed due to active surveillance of CIN2, as clinical guidelines were inconsistent across subspecialties. Various factors influenced women's emotional well-being: life circumstances, information needs, and mental and physical discomfort during colposcopic examination. CONCLUSIONS: Women felt that worries and check-ups due to active surveillance of CIN2 were disrupting elements in their family planning, although they did not affect their every-day life. Some women, however, were particularly anxious, demonstrating the importance of including women's experiences and preferences in clinical counseling. The fact that fertility treatment was delayed due inconsistent guidelines across subspecialties, suggests a need for a revision of current guidelines.

Human papillomavirus vaccination in women undergoing excisional treatment for cervical intraepithelial neoplasia and subsequent risk of recurrence: A systematic review and meta-analysis.

INTRODUCTION: In this review and meta-analysis we aimed to investigate whether human papilloma virus (HPV) vaccination administered after excisional treatment of cervical intraepithelial neoplasia (CIN) is associated with a reduced risk of recurrence of CIN grade 2 or worse (CIN2+). MATERIAL AND METHODS: We performed a systematic literature search in three online databases through June 2021. Observational studies and randomized controlled trials (RCTs) were eligible for inclusion if the prophylactic HPV vaccine was administered after excisional treatment for histologically verified CIN. Only English language literature was included. The primary outcome measure was recurrence of CIN2+ after treatment. A meta-analysis was performed using fixed and random-effects models, and results were reported as pooled odds ratios (OR) with 95% confidence intervals (95% CI). Quality assessment was performed using ROB2-tool for RCTs and ROBINS-I for observational studies. The protocol was registered in PROSPERO (CRD42021238257). RESULTS: A total of 1561 studies were identified, of which nine, including 19 971 women, were included. Two studies were RCTs and seven were observational studies. Using the fixed-effect model on the two RCTs, the OR for recurrence of CIN2+ was 0.29 (95% CI 0.16-0.53). Due to considerable heterogeneity in observational studies, the random-effects model was used to estimate pooled OR for CIN2+ recurrence in these studies. Thus, using unadjusted data from observational studies, the OR for CIN2+ recurrence was 0.35 (95% CI 0.18-0.67), whereas when using adjusted data, the OR for CIN2+ recurrence was 0.54 (95% CI 0.21-1.35). However, quality assessment revealed a serious risk of bias for the majority of the studies included. CONCLUSIONS: HPV vaccination post-treatment was associated with a significantly reduced risk of CIN2+ recurrence when using unadjusted estimates from observational studies and RCTs. We found no significant effect of HPV vaccination on risk of CIN2+ recurrence when using the outcome measure from observational studies with the least risk of bias. Large, well-designed randomized placebo-controlled trials are needed to determine whether post-treatment HPV vaccination should be recommended to all women undergoing excisional treatment for CIN.

Evidence of latent HPV infection in older Danish women with a previous history of cervical dysplasia.

INTRODUCTION: Understanding whether human papillomavirus (HPV) may establish latency in the uterine cervix is important. A better understanding of HPV natural history is useful for clinical counseling of women attending screening and to accurately inform health prevention strategies such as screening and HPV vaccination. We evaluated the extent of latent HPV infections in older women with a history of abnormal cytology. MATERIAL AND METHODS: We conducted a cross-sectional study in Aarhus, Denmark, from March 2013 through April 2015. Women were enrolled if they underwent cervical amputation or total hysterectomy because of benign disease. Prior to surgery, women completed a questionnaire and a cervical smear was collected for HPV testing and morphological assessment. For evaluation of latency (i.e., no evidence of active HPV infection, but HPV detected in the tissue), we selected women with a history of abnormal cervical cytology or histology, as these women were considered at increased risk of harboring a latent infection. Cervical tissue underwent extensive HPV testing using the SPF10-DEIA-LipA25 assay. RESULTS: Of 103 women enrolled, 26 were included in this analysis. Median age was 55 years (interquartile range [IQR] 52-65), and most women were postmenopausal and parous. The median number of sexual partners over the lifetime was six (IQR 3-10), and 85% reported no recent new sexual partner. Five women (19.2%) had evidence of active infection at the time of surgery, and 19 underwent latency evaluation. Of these, a latent infection was detected in 11 (57.9%), with HPV16 being the most prevalent type (50%). Nearly 80% (n = 14) of the 18 women with a history of previous low-grade or high-grade cytology with no treatment had an active or latent HPV infection, with latent infections predominating. HPV was detected in two of the six women with a history of high-grade cytology and subsequent excisional treatment, both as latent infections. CONCLUSIONS: HPV can be detected in cervical tissue specimens without any evidence of an active HPV infection, indicative of a latent, immunologically controlled infection. Modeling studies should consider including a latent state in their model when estimating the appropriate age to stop screening and when evaluating the impact of HPV vaccination.