Screening for the prevention and early detection of cervical cancer: systematic reviews to inform an update to recommendations by the Canadian Task Force on Preventive Health Care

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To inform updated recommendations by the Canadian Task Force on Preventive Health Care (task force) on screening in primary care for the prevention and early detection of cervical cancer in individuals with a cervix who are 15 years or older who have been sexually active and have no symptoms of cervical cancer. We systematically reviewed evidence from Very High Development Index countries of: screening effectiveness (focusing on ages to start and stop) and comparative effectiveness (strategies and intervals); comparative test accuracy; informed individuals’ values and preferences, and effectiveness of interventions to improve screening rates among the under/never screened. Two existing systematic reviews provided evidence regarding adverse pregnancy outcomes associated with the conservative management of cervical intraepithelial neoplasia (CIN). Methods. We searched three databases (Medline, Embase, and Cochrane Central) for effectiveness and accuracy questions; Medline, Scopus, and EconLit for patient preferences [to Sept/Oct 2023 for screening effects and preferences and March 2019 for accuracy and interventions to increase uptake]) and reference lists of included studies and relevant systematic reviews. Two reviewers independently screened studies and assessed risk of bias. Most data were extracted by one reviewer with verification by another; outcome data for screening effectiveness were extracted in duplicate. We performed meta-analysis where possible. Absolute effects were expressed as events among 10,000 individuals. Two reviewers appraised the certainty of evidence using GRADE. The task force determined thresholds for their certainty assessments about comparative effectiveness. Results . We included 112 studies across questions (22 on ages to start and stop screening, 17 on comparative effectiveness, 10 on comparative accuracy, 23 on patient preferences, and 44 on interventions to increase uptake). When reviewing evidence to help inform ages to start and stop screening, only observational studies on cytology screening were identified. There was very low certainty evidence for the effects in individuals 20-24, 25-29 and 30-34 years of age to prevent invasive cervical cancer (ICC) or mortality (all-cause and cervical-cancer specific). For individuals 60-69 years of age, screening with cytology is probably (moderate certainty) associated with reduced ICC (≥ 9 fewer per 10,000) and cervical-cancer mortality (≥ 0.19 to 0.29 fewer) over 10-15 years of follow-up among those who had no screening, abnormal, or inadequate screening in their 50s. A reduction for these outcomes among those 60-69 years who were adequately screened during their 50s is less certain. For persons aged 70-79 years, screening with cytology reduced ICC with low certainty for those with no, abnormal, or inadequate screening histories. Evidence for ICC for those adequately screened and on mortality overall was very uncertain. Very low certainty evidence was found for reduction in ICC and cervical-cancer mortality for cytology screening every 3 years versus 3-to-5 years. Across 10 groups of comparisons between screening strategies (e.g., initial testing with cytology vs. high-risk human papillomavirus [hrHPV], different triage methods, different populations), we are very uncertain about any differential impacts on all-cause and cervical-cancer mortality and on overdiagnosis. i) Compared with cytology alone, hrHPV alone may (low certainty) make little-to-no difference for 25-59 year-olds for incidence of CIN 3+ (hrHPV detecting 30 more CIN 2+ per 10,000) but is probably associated with more (possibly ≥ 600 per 10,000) referrals for colposcopy and false positives for CIN 2+ and CIN 3+ for those aged 25-29 years. ii) hrHPV with triage to cytology versus cytology alone may reduce incidence of ICC (e.g., 24 more CIN 3+ detections) for those aged 29-69 years, though when adding a recall phase (with additional testing beyond the initial triage) there are probably more harms for 25-29 year-olds. iii) The comparison of hrHPV with cytology triage versus cytology with hrHPV triage was divided into subgroups based on whether there was a recall stage. The hrHPV strategy probably reduces incidence of ICC (46 and 32 more CIN 3+ detected with and without using recalls) without added harm for those aged 30-59 years. For those aged 25-29 years, adding recall may reduce incidence of CIN3+ (via 271 more CIN2+ cases detected) but also considerably increase harms (≥ 800 false positives); evidence for ICC incidence was uncertain. One round of hrHPV with cytology triage versus two rounds of cytology with hrHPV triage (over 4 years), both strategies including recall, may make little-to-no difference in incidence of CIN 2 or 3+ for those 30-69 years, and probably leads to similar effect on harms. Evidence for incidence of ICC was of very low certainty. iv) The effects on incidence of ICC are uncertain from adding partial genotyping to these hrHPV and cytology triage strategies; for those aged 30-59 years there may be little-to-no difference in incidence of CIN3+ and is probably no difference in harms. v) When comparing hrHPV with cytology triage of negative tests versus cytology with hrHPV triage, both arms having recall, low certainty evidence found reduced incidence of ICC (36.0 more CIN3+ detected) from the hrHPV strategy arm and little-to-no difference between strategies for incidence of CIN3+, with moderate certainty evidence that the hrHPV strategy results in more referrals to colposcopies and false positives (about 600 per 10,000). From studies only enrolling those aged 30-59 years, vi.b) there was moderate certainty of little-to-no difference in false positives between hrHPV self-sampling with cytology triage compared with hrHPV clinician-sampling with cytology triage, with low certainty of little-to-no impact on incidence of CIN 3+; vii) evidence was low certainty for little-to-no difference in CIN 2+ detection and in false positives for hrHPV self- versus clinician-sampling, each with triage to repeat hrHPV testing at 3-6 months; and vi,b and viii-x) evidence was of very low certainty evidence across all reported outcomes (detection of CIN 2+ and 3+ and false positives) from studies comparing effects of hrHPV self-sampling among populations who were non-responders or underscreened. From comparative accuracy studies, adding cytology triage to hrHPV testing alone (via self-or clinician sampling), or replacing the hrHPV test with one allowing partial genotyping with or without cytology triage, reduces the number of false positives (high certainty; > 300 fewer per 10,000 screened). There is probably little-to-no difference in false positives between hrHPV with partial genotyping (types 16/18) and hrHPV with cytology triage. hrHPV with partial genotyping (types 16/18) versus cytology alone may increase specificity (reducing false positives) at the expense of sensitivity, though the number of missed cases may be very small (e.g., up to 9 fewer cases of CIN3+ detected). There was little-to-no difference in sensitivity and specificity between cytology alone and hrHPV with partial genotyping (types 16/18) with triage to cytology on non-16/18 types (moderate certainty). Cytology with hrHPV triage versus cytology alone may make little-to-no difference for sensitivity or specificity for CIN 3+ detection. In relation to adverse pregnancy outcome from treatment, findings from two existing systematic reviews of observational studies found very low certainty evidence about whether conservative management of CIN 2/3 is associated with total miscarriage rates, second trimester miscarriage, preterm birth (≥ 37 weeks’ gestation), low birth weight (< 2500 g), or cervical cerclage. Despite findings that would lead to very small increases in some outcomes among the entire screening population, the evidence was considered indirect for current practices that use a more cautionary approach to treatment particularly for CIN2 in individuals prioritizing a reproductive future. Findings from studies on patient preferences via measurement of the disutility (i.e., impact on participant’s quality of life, values ranging between 0 [no impact] and 1 [similar to death]) of having one of the outcomes indicated that ICC (disutility of 0.11) may be at least twice as important as CIN 2/3 (0.05), and that both cervical cancer and CIN 2/3 are probably much more important than false positives that did not cause any disutility. Other studies on patient preferences about cytology screening indicated, with low certainty, that a large majority of individuals eligible for and informed about screening may weigh the benefits as more important than the harms of screening using cytology, but think it is important to provide information on benefits and harms for decision making. Findings from a single study suggested that some individuals <25 years may have intentions to screen even when informed that screening does not reduce cancer diagnoses or deaths for their age group and leads to overdiagnosis. Five types of interventions to improve screening rates for under/never-screened individuals were reviewed. All were found with moderate or high certainty to improve screening rates : written contact (relative risk [RR] 1.50, 95% CI 1.22 to 1.84; 619 more per 10,000, 95% CI 273 to 1041; 16 trials, N=138,880); personal contact (RR 1.50, 95% CI 1.07 to 2.11; 797 more, 95% CI 1116 to 1770; 7 trials, N=17,034); composite interventions (usually mixture of written and personal contact; RR 1.73, 95% CI 1.33 to 2.27; 1351 more, 95% CI 610 to 2350; 8 trials, N=17,738); universal mail-out of HPV self-sampling kit (RR 2.56, 95% CI 2.10 to 3.12; 1534 more, 95% CI 1082 to 2085; 22 trials, N=211,031); and opt-in to receive a HPV self-sampling kit (RR 1.56, 95% CI 1.19 to 2.03; 727 more, 95% CI 247 to 1338; 11 trials, N=71,433). Conclusions Screening for prevention or early detection of cervical cancer with cytology has been employed for decades and is probably effective for otherwise healthy persons with a cervix at least into their 60s. Whether to screen individuals younger than 35 years old using cytology was uncertain based on the need to rely on observational evidence without consistent reporting across age groups. Screening during one’s 60s and 70s may have less effect for those adequately screened in their 50s. The effects of screening with cytology every 5 years versus 3 years are uncertain. The evidence provided very low certainty about any differential impacts between various screening strategies on mortality and overdiagnosis outcomes. Compared with cytology alone or cytology with hrHPV triage, there was evidence of a small benefit from reducing ICC from using hrHPV with cytology triage though findings were most robust for those aged 30-59 years. Any additional benefit from adding recall is not clear especially for those 25-29 years where it probably adds substantial harm. Screening using hrHPV with triage to cytology every 4 years may lead to similar detection of cancer precursors as would cytology with hrHPV triage conducted every 2 years, though the effects compared with cytology alone were not examined. Further, it is uncertain what the effects are on the incidence of ICC from adding partial genotyping to the triage strategies for those aged 30-59 years. For those aged 30-59 years, moderate certainty evidence found little-to-no difference in false positives between hrHPV self-sampling with cytology triage compared with hrHPV clinician-sampling with cytology triage, and low certainty that there may be little-to-no impact on incidence of CIN 3+. The comparative effectiveness studies did not examine all relevant comparisons and thus comparative accuracy data may help provide suggestions of possible alternative strategies with similar sensitivity and similar or higher specificity. Most of the studies on screening effects were undertaken in populations either in which HPV vaccination had not been implemented or carried out in a period when vaccination rates were low. For under- or never-screened individuals, the offer of self-sampling kits for hrHPV testing may improve screening rates with similar test accuracy, but it is uncertain if findings apply when triage to cytology is used because of the need for adequate cervical cells and likely a clinic visit. ICC and CIN2/3 probably make an important impact on one’s quality of life, whereas a false positive result when using cytology alone does not; whether the disutility of a false positive result applies to hrHPV testing is unknown. There was low certainty evidence that informed individuals eligible for screening think the benefits outweigh the harms from screening. Choices for screening strategies apart from cytology alone may result largely from contextual considerations such as access, acceptability, resources and costs. Systematic review registration . Not registered. Cervical cancer screening accuracy patient preferences systematic review meta-analysis guideline Figures Figure 1 BACKGROUND Burden and natural history of disease In 2023, cervical cancer was projected to be the 20th most commonly diagnosed cancer among Canadian females (based on sex assigned at birth) ( 1 ) (4th most common among 15–44 year-olds), with an annual age-standardized incidence of 8 per 100,000 and a lifetime probability of 0.7%. Estimates of cervical cancer incidence among trans men and non-binary people assigned female at birth are lacking. The incidence rate of cervical cancer has been increasing by 3.7% each year since 2015, though its mortality rate has declined annually by 0.8% since 2006 ( 1 ). The median age at diagnosis of Canadians with cervical cancer is 47 years, with those at highest risk in their early forties (16.6 cases/100,000) ( 2 ). Data from 2017 show that most cervical cancers in Canada were diagnosed at an early stage of disease (Stage I, 54%) and at an average age of 45 years, while 10% were diagnosed with advanced (Stage IV) disease occurring more commonly in older individuals (57 years) ( 3 ). Five-year net survival from cervical cancer in Canada is about 74% ( 1 ) and is impacted by stage at diagnosis, with survival substantially improved in early stage disease (Stage I, 93% versus Stage IVA, 15%) ( 4 ). Persistent infection with human papillomavirus (HPV) is necessary but not sufficient for the development of cervical cancer ( 5 ). Other important co-factors include immunosuppression, smoking, and high parity/number of vaginal deliveries ( 6 ). HPV is a sexually transmitted and usually transient infection that is relatively common among sexually active individuals ( 7 ). Over their lifetime, most females (> 80%) and males (> 90%) will be infected with HPV, with the majority being infected before the age of 45 years ( 8 ). Among 200 known HPV types ( 9 ), 12 (types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59) have been designated as high-risk (hrHPV) by the International Agency for Research on Cancer Working Group due to their strong oncogenic potential ( 10 ). In Canada, types 16 and 18 account for about 74% of cervical cancer cases (48% and 26%, respectively) ( 11 ). Among Canadian studies, prevalence rates for having any oncogenic HPV strain in unvaccinated females among general screening (i.e., not high-risk) populations ranged between 3% and 47% ( 12 ). Pooled rates for the three most common strains ( 16 , 18 and 52 ) were 8.6%, 3.3% and 2.5%, respectively. The highest rates of HPV infection of any type in Canada (> 20–47%, across several age groups) were found among people living in Nunavut and among Inuit females. Approximately 90% of HPV infections resolve on their own within 2 years ( 9 ). Persistent infection, however, can result in slow and progressive changes to the cervix that may lead to the development of cancer over years ( 7 , 13 , 14 ). As with HPV infection, if left untreated, many cervical lesions will regress or remain unchanged ( Supplemental file i contains different cytological reporting systems used to describe changes to cervical squamous cells identified during sampling). In individuals with moderate dysplasia or cervical intraepithelial neoplasia grade 2 (CIN 2) about 50% (95% CI, 43–57%) of lesions regress to normal or to CIN 1 without treatment within two years; 18% (95% CI, 12–39%) of lesions will progress to CIN 3 or to invasive cervical cancer (ICC); and 32% (95% CI, 23–42%) of lesions will remain unchanged ( 15 ). Individuals identified with CIN 3 (corresponding to severe dysplasia), have a 25 to 30% risk of progression to ICC over a 30-year period ( 16 , 17 ). Based on data from HPV incidence and progression, about 1 in 200 unscreened individuals with a cervix may develop cervical cancer over a period of 30 years ( 18 ) ( Supplemental file i ). Prevention The causal relationship between HPV infection and cervical cancer, along with the typically slow progression from HPV infection to pre-cancerous lesions to cancer and availability of effective treatment, make cervical cancer particularly amenable to prevention efforts like vaccination and/or screening. Two HPV vaccines are currently authorized for use in Canada; bivalent (Cervarix™ or HPV2) and nine-valent (Gardasil 9® or HPV9) ( 19 ). All vaccines protect against HPV types 16 and 18 ( 20 ) while the Gardasil 9® vaccine protects against seven additional oncogenic HPV types ( 6 , 11 , 31 , 33 , 45 , 52 , and 58 ). All Canadian jurisdictions have publicly funded school-based HPV vaccination programs, mostly for children in grades 6 or 7 (12 to 13 years) offered on a 2- or 3-dose schedule ( 21 ). Programs for girls were mostly implemented in 2007 or 2008, whereas for boys the programs started in 2015–2017; all programs currently offer Gardasil 9® with the exception of Quebec that also uses Cervarix. Available data on 2015–2019 provincial/territorial coverage rates show that among girls, immunization uptake for the final dose ranges from 57–91% with 9 of 11 province and territory rates exceeding 70%; among boys, the immunization uptake for the final dose ranges from 58–91% ( 21 ). Based on these numbers, in 2023 approximately 70% of 13 to 27-year-old females may be considered fully vaccinated. Substantial herd effects are expected from these immunization rates ( 22 ). Screening for cervical cancer can be done using cytology (i.e., cervical cells collected with a Papanicolaou [Pap] test) alone, high-risk HPV (hrHPV) testing alone, co-testing (simultaneous cytology and hrHPV testing), or triaging a positive result from an initial screening test to additional testing (i.e., cytology followed by triaging positive results to receive hrHPV testing, or hrHPV testing with triage to cytology). The term “primary” is often used to describe the first test but is also used when a test is used alone so we have avoided using this term and specify if the test was used alone or with triage in all cases. Unlike the Pap test, HPV samples can be self-collected, although concerns have been raised about the concordance between self- and clinician-collected samples ( 23 ). When used alone HPV tests are more sensitive than cytology (i.e., identifying more cancers and fewer false negatives), but they may have lower specificity resulting in more false positive findings and potentially unnecessary follow-up interventions and treatments (e.g., colposcopies, biopsies) ( 24 ). A single sample taken by a clinician of the endocervix can be used for both Pap and HPV testing, whereas HPV tests do not require cells of the endocervix, so sampling, especially via self-sampling, may not obtain sufficient endocervical cells and thus not provide an adequate sample for cytology. Currently in Canada, screening for cervical cancer is mostly implemented through province-wide screening programs, with various recruitment methods including letters of invitation, recall lists sent to primary care providers, and telephone calls to eligible individuals ( 25 ). Some provinces and the territories rely on opportunistic, rather than programmatic, approaches that may miss people not regularly seeking healthcare. Until recently, all screening relied on cytology for the first test with five provinces and two territories using triage to HPV testing for individuals (mostly for those ≥ 30 years) with an abnormal cytology result ( 26 ). Several provinces and territories have plans to implement HPV as the first test ( 27 ) and in early 2024 British Columbia announced its new province-wide hrHPV self-screening option. In 2017, 74% of Canadian females aged 25 to 69 years reported receiving a Pap test in the past 3 years ( 28 ). However, certain populations (e.g., individuals in rural or remote communities, Indigenous populations, individuals with low socioeconomic status, new immigrants, and transgender persons) remain under-screened ( 27 , 29 ). To address disparities, several provinces have applied strategies to improve cervical cancer screening rates among under-screened populations. Strategies include incorporating culturally-appropriate screening approaches, providing education and support to health care providers, and trialing mobile testing units and mailed self-sampling HPV kits to homes ( 25 ). In 2020, the World Health Assembly adopted the Global Strategy for Cervical Cancer Elimination worldwide ( 30 ), which Canada has committed to achieving. In collaboration with national stakeholders and experts, the Canadian Partnership Against Cancer has set goals in line with those of the World Health Organization to eliminate cervical cancer (i.e., age-standardized rate of < 4 per 100,000 vs. 2016 rate of 6.6 per 100,000) by 2040, using the aims of improving HPV immunization rates (90% of 17-year-olds fully vaccinated by 2025), implementing screening with HPV alone by 2030 (using oncogenic HPV 16/18 testing and offering self-sampling especially where there are access barriers), and improving follow-up of abnormal screening results ( 31 ). Individual patients may make different choices for screening based on their unique values and preferences ( 32 ). Screening preferences are associated with the relative importance/value people place on expected or experienced outcomes ( 33 ). Preference data can be sought directly through comparing the disutilities of different health states, measured on scale of 0 (no disutility) to 1 (similar to death) and a value of about 0.04 is considered important among the Canadian public ( 34 )). A utility measures the impact of the outcomes on one’s health-related quality of life and can be measured using generic multi-attribute utility instruments such as the EuroQoL 5-Dimensions (EQ-5D) or via direct choice-based utility elicitation methods such as standard gamble (SG) or time tradeoff (TTO) (i.e., determining what people would be willing to risk or give up to avoid living in that health state). Other preference-based data, such as trade-offs between outcomes, also directly capture preferences. Indirectly, the relative importance of benefits versus harms overall can be inferred from attitudes, intentions, and behaviors towards screening among informed patients provided with estimates of the magnitudes of benefit(s) and harm(s). Findings on outcome preferences can then be considered as patient input when balancing the effect estimates on benefits and harms reported by empirical evidence on the clinical effectiveness of screening programs. Despite the anticipated benefits from cervical cancer screening, including reduced cancer incidence and mortality through the early detection and treatment of pre-cancerous lesions, potential harms exist, including physical or psychosocial consequences from repeated testing as well as frequent follow-up testing and invasive diagnostic procedures (e.g., biopsy, colposcopy), unnecessary treatment of false-positive results, and psychological harms associated with positive tests ( 35 ). As many pre-cancerous lesions would have never become clinically apparent and some unrecognized (thus untreated) cancers would not have led to morbidity or mortality over an individual’s lifetime, overdiagnosis of pre-cancerous (and to a smaller extent of cancerous lesions) is of concern for patients and providers. Overdiagnosis can lead to unnecessary testing and treatment and the harms associated with these procedures. Purpose of review In 2013 the Canadian Task Force on Preventive Health Care (the task force) recommended that females aged 25 to 29 (weak recommendation) and 30 to 69 (strong recommendation) years be screened every 3 years with Pap testing; females aged 24 years and younger not be routinely screened (weak recommendation); and females aged 70 years or older, who have undergone adequate screening, not be screened (weak recommendation) ( 36 ). At the time of these recommendations, evidence to inform ages to start and stop screening, along with optimal screening intervals, was sparse and limited to epidemiologic data, particularly for females aged 25 to 29 and 70 or older. Further, these recommendations were limited to cytological screening for cervical cancer since the task force judged that there was insufficient evidence to make recommendations on the use of hrHPV testing. Since the 2013 Canadian guideline, international guidelines (including those for Australia, the United Kingdom, the Netherlands, and the United States) have provided recommendations for hrHPV testing alone or with triage to cytology ( 35 , 37 – 39 ). Also, new studies have been published that are likely to improve our understanding of screening in primary care settings for cervical cancer. Thus, we undertook several systematic reviews to inform an update of the 2013 task force guideline with a focus on the effectiveness (benefits and harms) and comparative effectiveness of various cervical cancer screening strategies; the comparative accuracy of various screening tests or strategies (e.g., cytology versus HPV, single test versus adding triages); values and preferences for potential outcomes from cervical cancer screening; and the effectiveness of interventions aimed at improving screening uptake rates in under-screened and never-screened individuals. METHODS This review was undertaken on behalf of the task force following a pre-defined peer- and stakeholder (n = 17) reviewed protocol ( 18 ) and is reported in accordance with current standards ( 40 ). During protocol development, a working group was formed consisting of task force members, with input from clinical experts and scientific support from the Global Health and Guidelines Division at the Public Health Agency of Canada (see Acknowledgements). The working group contributed to the development of the key questions (KQs) and PICOTS (population, intervention(s) or exposure(s), comparator (s), outcomes, timing, setting, and study design) elements. Task force members made the final decisions with regard to the KQs and PICOTS. The task force and organizational stakeholders (n = x [currently underway]) reviewed a draft of this manuscript, and all comments were taken into consideration. The protocol has details for all methods, and we focus here on key processes and any changes from the protocol. Key Questions The task force determined the following KQs to be of interest: KQ 1 What are the effectiveness (benefits and harms) and comparative effectiveness of different screening strategies for cervical cancer? KQ 1a Do the effectiveness and comparative effectiveness of different screening strategies for cervical cancer screening differ by age or by other population subgroups? KQ 2 What is the comparative accuracy of screening tests for cervical cancer? KQ 2a Does the comparative accuracy of screening tests differ by age or by HPV vaccination status? KQ 3 What are the adverse pregnancy outcomes associated with conservative management of CIN? KQ 4 What is the relative importance individuals place on the potential outcomes from screening for cervical cancer? KQ 5 What is the effectiveness of primary care-based interventions to increase rates of cervical cancer screening for under- and never screened individuals? The main purpose for KQs 2 and 3 was to fill in gaps for outcomes (false-positive results in KQ2 and treatment harms in KQ3) not reported by the studies eligible for KQ1. KQ2 evidence may also provide information about the comparative accuracy of screening strategies using cytology and/or HPV tests not studied in KQ1 to help determine if these may be appropriate to use in practice in the absence of KQ1 evidence (e.g., very similar sensitivity and specificity). Eligibility Criteria Table 1 shows the final PICOTS elements for KQs 1, 2, 4, and 5. For KQ3 the review team relied on two high-quality Cochrane reviews as described in the protocol ( 18 ). Key questions 1 and 2 The population of interest for KQs 1 and 2 were individuals with a cervix who were 15 years or older who have been sexually active, and have no symptoms of cervical cancer. We were also interested in findings by age group and among specific populations (KQs 1a and 2a); the working group amended the protocol to add interest in subgroups of individuals with differing screening results in their 50s or 60s, for studies reporting effects of those in their 60s or 70s. Interventions of interest for KQ1 were any screening strategy using hrHPV or cytology with subsequent follow-up of abnormal tests, except for co-testing of all participants with both HPV and cytology, which was not considered cost-effective by the working group as well as other stakeholders in Canada ( 41 ) and is not currently under consideration in Canada ( 31 ). KQ2 exposures included hrHPV testing with HPV nucleic acid tests alone, or hrHPV testing with HPV nucleic acid tests followed by some form of triage either with cytology or another hrHPV test. After the protocol was developed, we added exposure to cytology with triage to hrHPV or to partial genotyping hrHPV as eligible for KQ2 because these strategies are currently being used in some provinces (e.g., Quebec, New Brunswick and Alberta) ( 26 ). Comparisons of interest for KQ1 were no routine screening (effectiveness) and any screening strategy that differed by one or more of the following (comparative effectiveness): screening test strategy, screening interval (i.e., 3 vs. 5 years), universal versus targeted screening, method of sample collection, or follow up protocol for abnormal screening results. For KQ2, comparisons were cytology, alone or with triage to hrHPV testing, hrHPV testing followed by different forms of triage, and hrHPV testing using different methods of sample collection. Table 1 lists exclusion criteria for both KQs, which included urine and point-of-care tests. The reference standard for KQ2 was colposcopy with histological inspection of cervical tissue applied to all patients or all screen-test positive patients and a subset (e.g., random 10%) of screen-negative patients. For each comparison in KQ1, randomized controlled trials (RCTs) were prioritized, with nonrandomized studies only included where RCTs were lacking. After initial study selection identified dozens of observational (KQ1 for cytology versus no screening, where no eligible RCTs were identified) and accuracy studies (KQ2) reporting on comparisons considered of little interest to Canadian decision making (e.g., age groups within middle age, hrHPV versus cytology plus repeat cytology triage, hrHPV with partial genotyping [types 16/18] versus hrHPV with partial genotyping [type 16]), the task force working group members provided input to focus the evidence for these KQs. For the effectiveness portion of KQ1 (cytology vs. no routine screening), a decision was made to focus on studies helping to inform KQ1a, more specifically on ages to begin (20 vs. 25 vs. 30 years) and stop (60 vs. ≥70 years) screening. Further, for the comparative effects of different screening strategies in KQ1 the focus for the observational evidence was changed to only compare screening intervals. The revisions also limited data to outcomes rated critical by the task force (see next paragraph). The review team charted out all possible comparisons reported in the eligible KQ2 studies (n = 32) and used working group input again to focus the eligibility. As a result, comparisons that were examined in RCTs for KQ1 and reported on false positives were not examined further in KQ2, with the exception of subgroup data based on age. Before reviewing any data, task force members and clinical experts determined the importance placed on proposed outcomes for the guideline by rating their value for clinical decision-making according to methods of Grading of Recommendations Assessment, Development and Evaluation (GRADE) ( 42 ). Critical outcomes (rated at 7 or above on 9-point scale) pertaining to the effectiveness and comparative effectiveness of screening included: incidence of ICC, cervical cancer mortality, all-cause mortality, incidence of CIN 2 and CIN 3, and overdiagnosis of CIN 2, CIN 3, and ICC. We defined incidence as the documentation of a cervical abnormality (CIN and ICC) during follow-up (e.g., cancer registries and testing in a subsequent round) that was not detected in the previous round. Ideally, all people that did not have the outcome of interest at the previous round would be followed for the outcome, though we included data from study samples where there was exclusion of those with abnormal results (e.g., CIN 1 and/or 2) from follow-up. Lesions detected during a subsequent round that we have defined as “incident” could include false-negative screens from the previous screening round. Final important outcomes (rated 4–6) for inclusion were: the number and rate of colposcopies and biopsies (or referral rates), adverse pregnancy-related outcomes from conservative management of CIN, and the false-positives for detecting CIN 2, CIN 3, and ICC. We considered false-positives to be the proportion of those screened where the cervical screening test was positive (according to the screening strategy used in the individual studies, recognizing that definitions of test positivity differ across studies) and led to diagnostic follow-up testing (i.e., colposcopy with or without biopsy), but were not confirmed as CIN 2, CIN 3, or more severe disease. The protocol was amended to add a false positive outcome related to those referred to either diagnostic follow-up testing (colposcopy) or to further (“recall”/”intensive”) screening within the same round of screening. Further, given the scarcity of data for incidence of CIN 3 and ICC, the task force decided to consider detection rates of CIN 2/2 + and CIN 3/3 + during screening as surrogates (indirect outcomes/markers) for incidence of CIN 3/3 + and ICC, respectively. The classification of each outcome as a benefit or harm was considered after evaluating the evidence, based on the direction of effect and considering the selected thresholds (see section Assessing Certainty in the Body of Evidence ). KQ2 focused on measures of diagnostic test accuracy (e.g., number of false positives, and sensitivity and specificity for detecting high-grade cervical lesions or cervical cancer). For KQs 1 and 2, studies had to be published on or after 1995, in English or French, and undertaken in Very High Human Development Index Countries ( 43 ). Key question 4 KQ4 synthesized evidence of the relative importance that individuals place on the outcomes from cervical cancer screening ( 44 , 45 ), including all critical and important outcomes defined for KQ 1 ( Table 1 ). This KQ included patients and individuals from the general public age 15 years or older with a cervix, or who have had their cervix removed as part of treatment for cervical cancer. Included exposures were experience with an outcome (“heath state”) related to screening or exposure to clinical scenarios or information about outcomes and/or estimates of effect on outcome risks from screening. In the absence of participants having experience or exposure to scenarios, authors could solicit probability trade-offs or ratings of different outcomes. Comparators were different critical outcomes or groups of outcomes (benefits vs. harms), healthy state without the outcome or no comparison (if reporting health-state utilities), and no or another intervention (e.g., no screening, another screening strategy). Outcomes and study designs for KQ4 were included in a hierarchal manner where we would use qualitative study findings only in the absence of quantitative measures (i.e., health-state utilities [valuation of the impact of the health state on one’s health-related quality of life using a scale of 0 (death) to 1 (perfect health)], ratings/rankings, acceptability of screening based on information on the magnitude of benefits and risks). Key question 5 KQ5 focused on interventions for improving screening rates in under-or never-screened persons with a cervix (i.e., individuals who would meet the criteria for cervical cancer screening but who had never attended or who were considered under-screened, as defined by study authors). Moreover, we pre-specified four priority populations of interest; Indigenous peoples, immigrants, rural communities, and those with low socioeconomic status. We included any intervention amenable to a primary care setting that targeted individuals or primary care providers to increase uptake of screening (e.g., reminders, education, counselling), including mail-out or opt-in HPV self-sampling. RCTs were prioritized over nonrandomized studies. For KQs 4 and 5, to include studies that reflect current preferences, practices and outreach strategies, studies had to be published in 2000 or later, in English or French, and undertaken in Very High Human Development Index Countries ( 43 ). Literature Search and Study Selection Details of the search approaches are included in Table 1 . During protocol development, our research librarian undertook a comprehensive search for relevant systematic reviews, published between 2014 and March 2019, to identify reviews that may be eligible for using as is (i.e., no changes to methods apart from possible contextualization to Canada for assessment of evidence certainty or otherwise), updating (i.e., adding more recent studies but otherwise following the authors’ methodology), or integrating (i.e., used for locating primary studies to a particular date with a search update and otherwise use of de novo methods). This process identified two reviews for use as is for KQ3 ( 46 , 47 ) and three reviews to integrate into KQs 2 (with a search date of 2016) and 5 (search dates of 2008)( 23 , 48 , 49 ). Initial contact with the authors of the reviews for KQ3 indicated that these reviews were planned to be updated by the completion of our reviews. No reviews were eligible for use or integration for KQs 1 and 4. We did not update searches from the review informing the 2013 task force guideline because that review did not include the incidence of CIN as an outcome and thus we may have missed studies. The searches (see Supplemental file i ) were developed and finalized by our research librarian after peer review, and initially run on August 5-6th, 2020. We later updated the searches for KQ1 (September 18, 2023) and KQ4 (October 23, 2023); we did not update searches for KQs 2 or 5 because (for KQ2) the evidence was not anticipated to weigh into the recommendations very much and (for KQ5) because we had moderate or high certainty of the evidence which was not anticipated to change by adding more studies. Following pre-specified criteria, two reviewers independently screened studies for eligibility in two stages; by title and abstract using DistillerSR (Evidence Partners, Ottawa, Canada) followed by full text review of records marked as “include” or “unsure” by either reviewer during title/abstract screening. Excluded records were screened by a second reviewer to confirm exclusion. Studies were included at the full text level if independent reviewers agreed on inclusion, with arbitration by a third reviewer as needed. Reasons for exclusion at full text were recorded and are reported in the Supplemental file ii . Data Extraction and Analysis One reviewer extracted data for each KQ into standard forms in Excel v. 2016 (Microsoft Corporation, Redmond, Washington) using pre-defined items ( 18 ). A second reviewer verified extracted data for accuracy and completeness, except for outcome data for KQ1 that were extracted in duplicate by two reviewers, and disagreements were resolved by consensus or a third reviewer. As described above, we charted major study characteristics, but not results, of nonrandomized studies for KQ1 and all studies in KQ2 to allow for further input on eligibility from the task force. Though we had anticipated the possibility of building efficiencies by using data extracted by other review authors, we ended up doing all data extraction anew. Key question 1: Effectiveness and comparative effectiveness The measure of effect was the relative risk (RR) or odds ratio (OR) with 95% confidence intervals (CIs); ORs were used for observational studies to allow for use of reported adjusted ORs reported in case-control studies) and Peto ORs were used for trial data on effectiveness because of the relatively rare events. These were calculated in Review Manager version 5.3 (The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, Denmark) from crude events reported in the studies, unless adjusted estimates (as preferred) were reported in nonrandomized studies. For RCTs, we had planned to use an intention-to-screen analysis whereby the analysis included all individuals randomized, but in several RCTs people were randomized before their eligibility was assessed or they consented, and there was no attempt to collect data on the number randomized. Instead, we used the number enrolled in the study, which was in most cases those who undertook screening (not a true ITT). Where appropriate, we pooled studies reporting on similar outcome-comparisons using suitable random effect models. For observational data, we pooled using the inverse variance approach to enable incorporation of adjusted ORs. Data from RCTs and controlled clinical trials were pooled separately from observational studies, and cohort studies separately from case-control studies. For KQ1a, screening ages were categorized into 5-year age groups for individuals under 35 years of age for age to start screening and 10-year age categories from 60 years and older for age to stop screening. For case-control studies, screening age was estimated from age of diagnosis and interval since last screen (e.g., 3 or 5 years or pre-invasive period [as defined by studies]). Age to start and stop screening compared screening within an age group with no screening. As per clinical expert input, if studies included participants who had undergone screening 5 or more years before the index date for the study, these individuals were included within the no screening group for our analysis. We included data from studies when the age categories were similar but not identical to ours (i.e., the age range in a study could be wider than ours). In these cases, standard errors from individual studies were weighted to adjust confidence intervals to approximate the proportion of participant data that was relevant to the age category of interest. Weighting was applied to data from studies that included participants with more than 1 year outside of an age category of interest. For this analysis, assumptions were made that screened participants and effects were equally distributed across the age range of the study sample. Some studies were more dramatically out of the age category of interest when using 5-year age groups versus the 10-year categories. We rated down for indirectness when grading this evidence if a majority of studies required weighting. Screening interval data focused on comparing screening intervals of 3 and 5 years (or similar) across all available age groups in a study. When possible, we calculated the ORs for comparing 3-yearly screening with 5-yearly screening as the reference. However, in studies where the reference was no screening and we were not able to adjust the reference to 5-yearly screening, we calculated the ratio of 3-yearly screening versus no screening and 5-yearly screening versus no screening and entered that ratio into our analysis. For all analyses on the comparative effectiveness of screening, we conducted stratified analyses using within-study data by age categories (20–24/25–29/30–59/60–69/70–79 years), and (for screening intervals) between studies based on whether the country/region used opportunistic or programmatic screening. For overdiagnosis, we relied on authors’ calculations and synthesized the data descriptively. Key question 2: Comparative accuracy We populated 2 x 2 tables with the true positives, false positives, true negatives and false negatives for each screening test used in each study, as well as reported sensitivities and specificities. We considered pooling, as described in the protocol, but no comparison had more than three studies. Instead, we compared and contrasted study findings, relying mostly on the largest and best conducted studies ( 50 ), to judge whether (for specificity and sensitivity) the strategies differed (and in what direction), or (for false positives) whether the difference exceeded a threshold of 3% (300 per 10,000) as determined to be of minimal importance by input from the working group (see below and Supplement i ). Key question 4: Relative importance of potential outcomes from screening We focused on data providing the disutility (i.e., impact on one’s health-related quality of life) of each health state. Disutility is the difference/reduction between the utility/value of being in an ‘average/healthy’ general population (eligible for cervical cancer screening) and that from having each of the relevant health states (e.g., utility of general population minus utility of cervical cancer = disutility from cervical cancer). When studies had data for a population we considered reasonably applicable to the general population (e.g., control group, group receiving negative results from smears), we used the data and considered this a direct measure for calculating the disutility of the other health state(s) reported by the study. For studies that did not have a relevant comparison group, we used a weighted estimate from data in other studies for the utility of the general population; the calculated disutility in these cases is considered indirect because of the use of between-study information. When comparing this weighted average of the general population utility score when using the EQ-5D within the included studies, we obtained very similar findings to the Alberta Population Norms ( 51 ). Data from use of the EQ-5D index measure was the focus (‘primary analysis’) since it was the most commonly reported measure, had the most data in comparison with a general population comparison, and is a commonly used tool in the health economic literature. This measure was used to provide the best estimates of the disutility of each health state. For our outcomes about the rank-order/relative importance across the different health states (e.g., CIN 2 vs. ICC), we used these EQ-5D disutilities together with those estimated from the other measurement tools (e.g., time trade off [TTO], standard gamble [SG]) based on the assumption that without the health state the utility is 1 (perfect health). For studies not reporting on health-state utilities, we undertook a narrative synthesis given the likely heterogeneity in study designs, exposures, comparisons, and outcomes reported across studies ( 52 ). Key question 5: Effectiveness and comparative effectiveness of interventions to increase screening rates After charting the study characteristics, we grouped interventions into five categories: written contact, personal contact, composite interventions (generally written and personal contact), universal mail-out HPV self-samples, and opt-in HPV self-samples (participants need to request the sample kit). The measure of effect was the RR with 95% CIs, calculated in Review Manager version 5.3 (The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, Denmark) from raw data reported in the studies. Data were pooled using a Dersimonian Laird random effects model ( 53 ). Aside from pre-specified populations of interest (Indigenous peoples, immigrant groups, rural populations, low socioeconomic status populations), our charting identified multiple additional variables that differed across studies and may have contributed to heterogeneity in magnitude of effect and thus led to specific sub-group analyses: follow-up duration (< 6 months vs. ≥ 6 months), under-screened definition (3 years), setting (organized [i.e., health system-based reminders] or opportunistic [i.e., during visits with clinicians]), intervention intensity (varied by comparison), and risk of bias rating (high vs. low or unclear). We included all participants randomized in the denominator for analyses for all included studies, even though this number in some cases included people who were not eligible upon closer examination. For trials that included multiple intervention arms or multiple eligible control groups for one of our analyses, we divided the arms to avoid double-counting in analysis ( 54 ). Cluster trial data were adjusted to ensure comparability with parallel trial data using an intra-cluster correlation coefficient from a representative trial ( 55 ) and calculating a design effect that was then applied to both the sample size and the number of events in each of the treatment and control groups ( 56 ). The pooled RR for each outcome-comparison was transformed to an absolute risk difference (ARD) by multiplying the RR with the median control event rate ( 57 ). Dealing with Missing Data and Assessment of Reporting Biases We used all available information (i.e., associated publications, protocols) we could locate to collect data for each study. When the individual studies did not report data required for synthesis, we contacted the corresponding author via e-mail to inquire about the availability of the data. We contacted authors twice, two weeks apart, before ceasing attempted contact if we did not receive a response. For KQ4, if studies were missing a measure of variance, we used the variance from a comparator within the study; if no variance was reported within the study we used the largest measure of variance in studies using the same utility instrument to evaluate the same health state (eligible for pooling with the study). We attempted to limit missing studies by employing comprehensive searches (including grey literature) and by contacting authors for reports of unpublished studies. When meta-analyses of trials contained at least eight studies of varying size, we tested for small study bias visually by inspecting funnel plots for asymmetry and statistically via the Egger’s test ( 58 ). Risk of Bias Assessments Two reviewers independently assessed risk of bias for each included study and reached consensus. This was done at the outcome level, where risk of bias could differ by outcome. If consensus could not be reached, a third reviewer provided arbitration. Standardized study design-specific tools were used to assess risk of bias for each included study. Trials, diagnostic accuracy studies, clinical utility/preference-based, and cohort and case-control studies were rated with the Cochrane ROB tool (version 2011), QUADAS-C tool, GRADE guidance, and Newcastle-Ottawa Scale, respectively ( 44 , 59 – 61 ). In KQ1, for non- and quasi-randomized trials and for RCTs where people were randomized before their eligibility was assessed and less than 90% of those randomized were enrolled in the study, we considered random sequence generation to be at unclear (vs. high) risk of bias if there was demonstration of similarity between arms in enrollment rates and several baseline characteristics; otherwise this domain was rated as having high risk of bias. Risk of bias assessments contributed to grading the certainty of the evidence across studies for each KQ and outcome. Assessing Certainty in the Body of Evidence We used GRADE methods ( 62 ) to assess the certainty of evidence for all outcomes. For KQ3, where we used existing systematic reviews ( 46 , 47 ), we reviewed the rationale for the certainty of evidence appraisals and undertook amendments as suitable. In cases where studies of interventions or accuracy could not be pooled in meta-analysis, we used GRADE guidance for rating the certainty of evidence in the absence of a single estimate of effect ( 63 ). Two reviewers independently assessed the certainty of evidence for each outcome and agreed on the final assessments. A third reviewer arbitrated as needed. The certainty of the evidence (very low, low, moderate, or high) was usually based on five considerations: study limitations (risk of bias), inconsistency of results (or lack of consistency if only a single study was available or contributed a large majority of the data), indirectness of evidence (e.g., use of detection outcomes for assessing incidence), imprecision, and publication (small study) bias ( 64 – 69 ). For KQs of intervention effects (KQs 1 and 5), findings from controlled trials began at high certainty ( 70 ), whereas observational studies began at low certainty with the added possibility for upgrading (e.g., for large effects) ( 71 ). For KQ2 on diagnostic accuracy and KQ4 on patient preferences, all studies began at high certainty because we chose as eligible the most suitable study designs for these questions ( 72 , 73 ). For KQ4, we adhered to GRADE methods for assessing the certainty of evidence in the importance of outcomes or values and preferences ( 45 , 74 ). For the main outcomes reported in the trials for KQ1 on the comparative effectiveness (also for application to false positives in KQ2), and with the working group blinded to results of each analysis, thresholds were created for what (using point estimates) would be considered to mean little-to-no difference , to obtain a target for our certainty assessments ( 75 ). Using data on the natural progression of cervical lesions, survival rates for ICC, assumptions that results from single rounds of screening could be additive across at least 3–4 rounds at the population level, and a desired effectiveness of a 20% reduction in ICC (i.e., reducing cumulative incidence over many years from 5 per 1,000 to 4 per 1,000), the following thresholds for a single round of screening were decided based on consensus: false positives and related outcomes (e.g., referrals for colposcopy, biopsies): 3% (300 fewer/more per 10,000 screened); CIN 2/2+ (incidence or detection): 1% (100 fewer per 10,000 screened); CIN 3/3+ (incidence or detection): 0.1% (10 fewer per 10,000 screened); ICC (incidence or detection): 0.03% (3 fewer per 10,000 screened); mortality: 0.02% (2 fewer per 10,000 screened). There was no reliance on statistical significance when making conclusions. When interpreting our assessments, they relate to whether the effects met or exceeded the threshold but not whether we have the same certainty in the point estimate. Supplemental file i has more details about our certainty assessments. We adopted standard GRADE wording to describe our findings, using the word ‘may’ together with the direction of effect to describe findings of low certainty; ‘probably’ for those of moderate certainty, and ‘is’ for high certainty ( 76 ). When our certainty in the evidence was very low, we describe the evidence only as ‘very uncertain’ without any associated direction or data. RESULTS Figure 1 describes the flow of literature. 27,848 unique citations underwent title/abstract screening, and 1,799 underwent full-text review, after which we included 112 studies reported in 121 papers across KQs 1, 2, 4 and 5. Citations excluded at full-text review, with reasons, are included in Supplemental file ii . Key Question 1 and 1a: Effectiveness and Comparative Effectiveness No RCTs comparing screening versus no screening were eligible for this review. The review conducted for the previous task force guideline included one RCT from India ( 77 ), which compared cytology versus no screening, but this was no longer eligible in view of the new criterion of only including studies from countries with a Very High Development Index. Ages to start and stop screening and use of 3- versus 5-year intervals Study characteristics Twenty-two observational studies, reported in 24 papers, informed the effectiveness of cytology screening and comparative effects of 3- versus 5-yearly cytology screening intervals ( Supplemental file 1a has study characteristics, risk of bias assessments and all evidence sets). Some studies were used for both questions. There were no studies focusing on hrHPV screening. The associated publications included populations that overlapped substantially with the primary publication but either focused on a different outcome ( 78 , 79 ) or contained data on age subgroups for comparing intervals (but with a smaller sample than the primary paper reporting across all ages) ( 80 , 81 ). In one case, two studies by the same authors were considered different studies because, though there was some overlap in populations, the studies were used for different comparisons (screening interval ( 82 ) and age to stop ( 83 )). We included seven studies in eight publications ( 78 , 79 , 84 – 89 ) to inform age to start screening, 10 studies in 11 publications that addressed age to stop screening ( 79 , 82 – 86 , 90 – 95 ), and 10 studies in 12 publications on screening at different intervals ( 78 – 80 , 82 , 84 , 96 – 102 ). Studies were typically done in Europe and North America with a single study conducted in Japan ( 103 ). In nine studies (10 publications), screening was undertaken within an organized program ( 80 – 83 , 86 , 88 , 89 , 100 , 103 – 105 ); seven studies relied on opportunistic screening ( 78 , 79 , 85 , 92 , 95 , 97 , 99 ); and the remainder had organized screening running parallel to opportunistic screening ( 84 , 87 , 90 , 91 , 93 , 94 ). Sixteen studies (18 publications) used a case-control design with a median of 790 cases of ICC (range number of cases 39 to 5,047) ( 78 – 85 , 87 , 88 , 90 , 92 , 95 , 97 , 99 , 103 , 105 ) and six were cohort studies ( 86 , 89 , 91 , 94 ) with a median sample size of 545,934 (range of sample sizes 2,081 to 2,621,802). Very few studies reported on participant characteristics of interest, such as HPV vaccination status, race/ethnicity, or socioeconomic status. Of note, all studies were carried out before HPV vaccination was implemented, or done in periods when HPV vaccinate rates were very low. In terms of risk of bias, most studies did not demonstrate significant concerns for most variables with the exception of lack of adjustment or controlling for potential confounders other than age in 13 (59%) studies, which was considered an important source of bias. In most cases, the risk of bias was not considered serious such that we did not rate down during the assessments of certainty, which already started at low due to the inability of observational studies to control for unmeasured confounding. Findings Six studies reported the effect of cytology screening at age 20 to 34 years on the incidence of ICC ( 79 , 84 – 88 ). None reported on individuals aged under 20 years of age. Based on pooling five case-control studies and considering findings from the cohort study, we rated the evidence to be of very low certainty for all age groups included to inform age to start cervical cancer screening (20–24, 25–29, and 30–34 years) ( Supplemental file 1a) . Several studies reported on ages that did not closely align with the 5-year age categories of interest, warranting rating down for indirectness. Further, there was high heterogeneity among the case-control studies and between estimates from the case-control and cohort studies; for example, pooled data from case-control studies favoured no screening in 20 to 24 and 25 to 29-year-olds, whereas the large cohort study (sample over 2 million but not reported by age) favoured screening in both of these age categories. Similarly, data from one high risk-of-bias cohort study (n = 353,045) ( 89 ) and one small (n = 1,483) case-control study ( 78 ) provided very low certainty evidence for all age groups about the effect of cervical cancer screening on subsequent all-cause and cervical-cancer specific mortality, respectively. In separate pooled analyses of six case-control studies ( 79 , 83 – 85 , 90 , 92 ) (N = 16,909) and two cohort studies (n = 569,132 ( 91 ); number not reported for the age group ( 86 )) screening between the ages of 60–69 years was associated with lower incident ICC compared with not screening (pooled OR 0.46, 95% CI 0.34 to 0.62; pooled RR 0.54, 95% CI 0.46 to 0.62, respectively). Based on a cumulative rate for ICC in participants not screened (n = 360,093) in their early 60s in a national Swedish cohort ( 91 ) of about 20 ICC cases per 10,000 individuals over 10–15 years, the absolute reduction would be estimated at 9 fewer ICC per 10,000 over 10–15 years (i.e., similar to our threshold of 3 fewer per 10,000 after one of about three possible screening rounds). Two case-control studies ( 79 , 90 ) that provided data using 5-year increments found associations with reduced ICC for both 60–64 and 65-69-year-olds. When exploring our other subpopulations, two studies examined the effect on ICC incidence of cytology screening versus no screening at age 60–65 years depending on their screening results in their 50s ( 83 , 91 ). First, one case-control study (n = 12,708) from the UK ( 83 ) found reductions over 25 years of 43 per 10,000 from screening among those who had an abnormal screen during their 50s and 49 cases if they had not been screened during their 50s. Smaller reductions were observed among those who had “irregularly screened” (i.e., no abnormal tests aged 50-59y and a negative test between aged 50-54y but not 55-59y, or aged 55-59y but not 50-54y; 12.9 fewer, 95% CI 6.5 to 19.3) or “adequately” screened (i.e., only normal tests, with one in each 5-year period; 6.3 fewer, 95% CI 0.3 to 12.3). Second and similarly, a large Swedish cohort study (n = 569,132) ( 91 ) following individuals up to 24 years (mean 10.9) reported that screening versus no screening at age 61–65 benefitted those who had not been screened (33 fewer per 10,000) or had abnormal results (60–70 fewer per 10,000) in their 50s, but had less effect for those who had inadequately (5.4 fewer per 10,000, 95% CI 14.2 fewer to 3.4 more; aHR 0.82, 95% CI 0.56 to 1.22) or adequately (2.8 fewer per 10,000 [7.8 fewer to 2.2 more]; aHR 0.90 [0.69 to 1.17]) (similar definitions as in the UK study) screened. For reduction in ICC among those aged 60–69 years, we rated the certainty of evidence as moderate (rating up for large effect) for a reduction among those with no, abnormal, or inadequate screening in their 50s, and low (with some imprecision especially in the larger study) for a reduction among those adequately screened during their 50s. For mortality from cervical cancer among those aged 60–69 years, benefit was shown in analyses of three case-control studies ( 78 , 93 , 95 ) (pooled OR 0.50, 95% CI 0.37 to 0.67, N = 2,582) and one cohort study ( 94 ) (RR 0.23, 95% CI 0.10 to 0.51, n = 59,065). Based on data in Finland for cervical-cancer mortality rates over about 10 years among those not invited to screen at age 65 (n = 486,869; 0.38 per 10,000) ( 94 ), the absolute risk reduction may be between 0.19 and 0.29 fewer deaths per 10,000 screened. Considering the variation in effects for incidence of ICC from studies looking at effects among subpopulations based on screening results in their 50s, we rated the certainty of evidence as moderate (rated up for large effect) for a reduction in cervical-cancer mortality among those with no, abnormal, or inadequate screening in their 50s, and low (due to indirectness of the overall findings to this population) for a reduction among those adequately screened during their 50s. For persons aged 70–79 years, the effect of screening for cervical cancer on incident ICC, though appearing to be of benefit, was less certain than for those 60–69 years in pooled analysis of three case-control studies (OR 0.44, 95% CI 0.33 to 0.57, N = 4,258) ( 84 , 85 , 92 ). The analysis relied mainly (97% weight) on one study ( 92 ). We did not find a good estimate for the rate of ICC in unscreened individuals in their 70s who had been screened during their 60s, as a basis for estimating absolute effects. It was judged that the varying effects for those in their 60s for ICC, based on screening results in their 50s, would translate to this age group. The certainty was rated as low for a reduction in ICC incidence for those aged 70–79 with no, abnormal, or inadequate screening in their 50s and very low for those adequately screened during their 50s. Only one small case-control study ( 95 ) reported the effect of screening in one’s 70s on cervical cancer mortality, leading to inconclusive findings related to imprecision, lack of consistency and (for those adequately screened in their 50s) indirectness. Eight case-control (N = 20,862) and two cohort (N = approximately 174,000) studies contributed to data on the effect of cytology screening by intervals less than 3.5 years versus 3.5 to 5.5 years on incident ICC across age groups and provided inconsistent and thus very low certainty evidence ( 79 , 80 , 82 , 84 , 97 , 99 , 100 , 103 – 105 ). Analyses stratified by 5-year age groups and by setting/type of screening program did not explain the heterogeneity ( Supplemental file 1a ). One case-control study (n = 11,447) ( 78 ) found a significant effect for reducing the risk of death from cervical cancer when screening at an interval of ≤ 3 years compared with 3–5 years, but findings were of very low certainty for lack of consistency especially when there was inconsistency demonstrated for the incidence outcome. Scarce data were reported for other specific populations of interest and were limited to cytology screening. In one US case-control study (n = 11,404) of persons with a cervix aged 65 years or older, race (White vs. non-white) was not associated with the (beneficial) effect of screening (p = 0.243 for interaction) when adjusted for median income by zip code and potential impact of hysterectomy ( 92 ). A large (n = 2,621,802) cohort study that adjusted results for age, there was no difference in the (beneficial) effect of screening 23 to 50-year-olds on incidence of ICC based on immigrant status (Swedish-born vs. birth outside Sweden) ( 86 ). No data were presented for trans or nonbinary individuals. Comparative effectiveness between screening strategies Study characteristics We included 16 trials (14 RCTs ( 106 – 119 ) and 2 quasi-RCTs (i.e., using odd-even date of birth or personal identification number) ( 120 , 121 )), one observational study ( 122 ) and four associated papers ( 123 – 126 ) that addressed the comparative effectiveness of different screening strategies ( Table 2 ; Supplemental file 1b ). Most studies were conducted in the setting of organized screening programs in Europe and in addition, one trial each was done in Canada ( 127 – 129 ), Hong Kong ( 130 ), and Australia ( 131 ). Fifteen trials only reported on one screening round (number enrolled ranging from 667 ( 118 ) to 201,038 ( 120 )), because any second rounds of screening used the same method in each group compared. One RCT (HPV Focal; n = 22,588) provided data for one round as well as the comparison between two rounds of screening with cytology with triage to hrHPV (over 4 years) and one round of screening with hrHPV with triage to cytology ( 112 ). As previously mentioned, the data from these studies were collected on those who undertook screening; some trials had very low (5–52%) ( 106 , 109 , 110 , 113 , 116 , 117 , 120 , 121 ) rates of enrollment among those allocated. Most trials included participants across age groups, typically ranging from individuals in their 20s and 30s to those in their 60s. Two trials ( 109 , 132 ) only included older participants (aged 50–60 and 56–60 years). Length of follow-up for incidence outcomes ranged from 18 months to 5 years. Outcomes in pre-specified populations and data for subgroup analyses were limited with five trials ( 113 , 117 – 119 , 133 ) enrolling persons with a cervix who were underscreened and seven trials ( 106 , 115 , 120 , 121 , 123 , 127 – 129 , 131 , 134 , 135 ) presenting data by age subgroups. Four trials ( 117 , 118 , 127 – 129 , 136 ) were not considered at high risk of bias for any included outcome. Six trials were at high risk of bias for inadequate sequence generation ( 106 , 109 , 110 , 116 , 120 , 121 ). Blinding of participants (performance bias) and outcome assessors was unclear in most trials, though blinding of participants was not thought to be of major concern in these studies of comparative effectiveness. The domain of incomplete outcome data, from attrition after the screening test, was at high risk of bias across multiple outcomes in one trial ( 116 ) and for the incidence outcomes in two others ( 108 , 126 ) ( Supplemental file 1b ). Two trials ( 107 , 111 ) were at risk of missing data for the incidence outcomes because they were not actively ascertained for all participants (only using data linkage or safety reporting), thus some events particularly for CIN 2 and CIN 3 could have been missed. Methods for detecting incident cases varied, and included cytology (conventional or liquid-based), hrHPV and liquid-based cytology co-testing, data linkage, safety monitoring (i.e., reported as an adverse event), and a combination of these approaches. Outcomes that included cases of ICC (incidence of CIN 2+, CIN 3 + and ICC) but did not use data linkage to find clinically detected cases were considered indirect. Further indirectness came from studies where people with CIN 2 or 3 detected during screening were not followed to find any cases that progressed. The large (n = 1,262,510) observational study from England was only included for the incidence of ICC outcome (via second round screening and cancer registries) not reported by a trial for one comparison; the groups were differentiated by changes in laboratories in some regions to implement hrHPV screening with triage to cytology but the authors noted differences between groups in socioeconomic status which was not accounted for in the analysis. Table 2 describes the strategies in each study in detail. Based on descriptions of the interventions and clinical input from the working group, we classified the trials to examine 10 major comparisons ( Box 1 ), with some evaluated by only one RCT. In a few cases (e.g., Comparisons 1 and 10, 2 and 8, 6a and 6b), the screening strategies were quite similar but differences in the populations (general population vs. under/never-screened) were thought to differentiate them enough to separate for analysis. Further, in two cases (Comparisons 2 and 3) there were differences between trials within the same major comparison with respect to whether there was additional follow-up (e.g., at 6–12 months) beyond the main triage testing at baseline during each round of screening. For this, we created subgroup comparisons for screening “without recall” and “with recall” in each round. Two trials provided data for more than one major comparison or subgroup. The Norwegian HPV Pilot trial (n = 157,447) ( 121 ), primarily comparing hrHPV with cytology triage versus cytology with hrHPV triage (with recall; Comparison 3b), also provided data for Comparison 2a of hrHPV with cytology triage versus cytology alone (without recall) because the hrHPV triage results in the cytology arm were not acted upon until the recall phase, to check for persistence, and positive results from cytology alone were referred to colposcopy at baseline (allowing for detection and false positive outcomes from this perspective). Likewise, the HPV Focal RCT ( 112 ) provided data for some outcomes in Comparisons 3a, b, (n = 22,588) and c (n = 16,374). In comparisons including more than one trial, there were sometimes differences between trials in the threshold used for referral to colposcopy after cytology and in the screening methods used at the recall stage (Box 1 ). There were no comparisons between cytology alone and either cytology with hrHPV triage or hrHPV with partial genotyping (with or without triage). Findings Supplementary file 1b contains the full evidence sets for each outcome-comparison. We did not rate down for indirectness in our certainty assessments when considering the trials focused on adherence to screening, versus being invited to screen, though in some cases the risk of bias was high when RCTs enrolled many fewer participants than randomized and did not demonstrate comparable baseline characteristics between arms. For all comparisons, we are very uncertain about any impacts on all-cause and cervical-cancer mortality and for overdiagnosis. No trial reported on cervical-cancer mortality, and only one trial (COMPASS; n = 2,987) ( 107 ) in Comparison 4 reported on all-cause mortality at short follow-up (18 months) duration and with imprecision. For overdiagnosis, an associated paper ( 123 ) to the FINNISH RCT ( 111 ) in Comparison 2 used results from the trial for 5-year follow-up after one round from the screening (including prevalent and incident cancers) strategies together with historical population-based data for an estimated incidence of cancer without screening over 5 years (Finland in 1958–1962; incidence 17 per 100,000 person-years). In this study, overdiagnosis was defined as the risk of CIN 3 cases that would not have progressed to invasive disease by the next screen (5 years later) using the period prevalence of CIN 3 lesions diagnosed at the screen and during the following screening interval minus the rate of prevented cancers (squamous cell cancer) within the same screening round (the rate assuming no screening minus the rate of interval cancers found in the trial). Estimates of overdiagnosis of non-progressive CIN3 + were presented for hrHPV with cytology triage (cases overdiagnosed 39.6 per 1,000 person-years, 95% CI 31.3 to 48.9) and from cytology alone (20.3 per 1,000 person-years, 95% CI 13.6 to 27.9). The evidence was rated to have very low certainty, from data that was considered observational (this started at low certainty), at risk of bias, and indirect from the use of historical incidence data for the no screening comparator. Results for other outcomes are presented here by groupings of comparisons. Comparisons 1 through 4 : Table 3 contains the summary of findings from these comparisons that were considered most relevant for decision-making about which strategies to recommend. In each comparison, the certainty was assessed separately for each major age group reported across the studies (25–29, 30–59, and 60–69 years); if the study(ies) reporting on a comparison did not include any participants in the age group (e.g., 60–69 year-olds in Comparison 1) we report the certainty as very low. Only three trials provided data comparing strategies using clinician-sampled hrHPV versus cytology alone (Comparisons 1 and 2), which was considered the major comparator of interest. The NTCC Phase II RCT in Italy (Comparison 1) compared hrHPV screening alone with cytology alone (≥ ASCUS to colposcopy in most centres) at nine screening centres ( 115 ). Low certainty evidence suggested little-to-no difference for 25–59 years-olds between strategies for incidence of CIN 2 and CIN 3+ (latter using detection of CIN 2 + as a surrogate) and very low certainty was found for incidence of CIN 3 and ICC (using CIN 3 + detection). Though results were statistically significant for higher detection of CIN 2 + and 3 + with hrHPV screening alone, the point estimate and its 95% CI for CIN 2+ (30.2 more) did not exceed our threshold of 100 more per 10,000 for indicating greater than little-to-no difference, and the 95% CIs (across all ages and within age groups) were imprecise for CIN 3 + detection meeting its threshold of 10 more per 10,000. There was moderate certainty evidence for at least some harm (≥ 300 per 10,000) from referrals to colposcopy for 25–59 years-olds (possibly considerably more for those 25–29 years), and from biopsies and false positives for CIN 2 + and CIN 3 + for those aged 25–29 years. The Finnish RCT (n = 132,194; ages 25 to 65 years) ( 111 ) and Norwegian HPV Screening Pilot trial (n = 157,447; ages 34 to 69 years) ( 121 ) contributed to data for Comparison 2a, of hrHPV with triage to cytology versus cytology alone, without recalls. Data from the recall stage in both trials were not used for detection or false positive outcomes, whereas data on case detection during the recall (“intensive screening”) phase in the Finnish RCT contributed to incidence outcomes for this comparison. Using detection data for CIN 3+, findings suggested that there may be fewer incident cases of ICC from hrHPV with triage to cytology across age groups (low certainty). Across age groups, there was low certainty evidence of little-to-no difference for incidence of CIN 2 and CIN 3+ (using detection of CIN 2+) and moderate certainty of little-to-no difference in referrals to colposcopy and in false positives for CIN 2+, CIN 3+, and ICC. For Comparison 2b adding recall, where only the Finnish RCT contributed data, there was still low certainty for little-to-difference for CIN 2 or CIN3 + incidence across age groups, but only evidence of reduced ICC incidence (via CIN3 + detection) for the group of 25–29 year-olds because of imprecise findings for the older ages. It is unclear if adding a recall phase (including all HPV positives) in this main comparison increases the potential benefit from the hrHPV strategy, and this would need to be considered in light of moderate certainty evidence showing harm from false positives to recall which may be at least twice our threshold (possibly 800–900 more per 10,000). The Canadian HPV Focal RCT ( 112 , 124 ) (25–65 years) contributed to Comparisons 3a, b, and c, whereas data from two other studies contributed to each of Comparisons 3a and b. Two trials from Sweden, using the exact same comparison but non-overlapping populations with differing ages (Swedish HPV Trial 30–64 years, n = 201,028 ( 120 ) and Stockholm-Gotlund 56–60 years, n = 14,763 ( 110 )) provided data for detection, referrals to colposcopy and false positive outcomes for Comparison 3a, because they did not include recall in their screening strategy. Data by age group for detection of CIN 3 + and ICC for the larger Swedish trial were obtained from the authors. For Comparison 3b, the Norwegian HPV Screening Pilot trial ( 121 ) contributed data for detection, referrals to colposcopy and false positive outcomes and the English HPV screening observational study ( 122 , 125 ) was used for incidence of ICC (not reported by the trials). For incidence outcomes other than ICC, the HPV Focal RCT was the only contributor of data. For Comparison 3b, data for incidence after recall during round one used cases detected during round two in the cytology arm as well as the 48-month exit co-testing for both arms. For Comparison 3a, we assessed evidence as moderate certainty for an association between the hrHPV strategy and reduced ICC incidence, via CIN 3 + detection, for the age group of 30–59 year-olds; results were imprecise for 25–29 year-olds and of low certainty for little-to-no difference for 60–69 year-olds. For those aged 30–69 years there was low certainty for little-to-no difference between strategies for detection of ICC and incidence of CIN 3+, via CIN2 + detection (for 25–29 year-olds the data was either not reported or very low certainty). For those 30–69 years, there was moderate certainty evidence for little-to-no difference between strategies for the reported harm outcomes; for the 25–29 year age group we rated the certainty down further for indirectness because this age group contributed < 1% of the total sample for the outcome. For Comparison 3b, findings appeared similar to Comparison 3a for the 30–59 year (moderate certainty of some reduction in ICC without increased harm) and 60–69 year (low certainty for little-to-no benefit) age groups. For the younger ages, adding the recall appears to add an advantage from the hrHPV strategy for detecting CIN2+, though while noticeably increasing harm from more referrals to colposcopy and false positives. One contributing factor may have been that in the hrHPV strategy in the HPV Focal RCT (only trial with 25–29 year-olds) those persistent for HPV at recall were sent for colposcopy even if they had normal (< ASCUS) cytology results, whereas in the cytology strategy arm only those with ≥ ASCUS were sent to recall. The findings from direct evidence on incidence of ICC and CIN 3 + during follow-up were of very low certainty; apart from lack of consistency from use of one study for each of these outcomes, for ICC the observational study was at high risk of bias and for CIN 3 + there was very serious indirectness from the 48-month exit round in the HPV Focal RCT failing to include those with CIN 2 or 3 during baseline screening and from lack of data linkage to capture clinically detected cases (incidence outcomes were not a primary aim for these trials). For Comparison 3c, using data across all ages from the HPV Focal RCT findings were of little-to-no difference for incidence of CIN 2, CIN 2 + and CIN3+ (via CIN2 + detection) for those aged 30–69 and for incidence of CIN 2 for those 25–29 years. Little-to-no difference was found for referrals to colposcopy and false positives for CIN 2 + and 3+, with moderate certainty for 30–69 year-olds and low certainty for 25–29 year-olds. Evidence for incidence of ICC via detection of CIN3 + was rated as very low certainty due to lack of consistency, indirectness, and imprecision. One small RCT (n = 2,987) ( 107 ) contributed to Comparison 4, where hrHPV testing used partial genotyping in both arms of hrHPV with cytology triage (though referral to colposcopy for types 16/18 and for type 45 with ≥ HSIL) and cytology with hrHPV triage (referral to colposcopy for HPV types 16/28 with ≥ ASCUS). Up to two recalls 12 months apart were advised for some individuals (e.g., with ASCUS or LSIL and negative hrHPV results). There was low certainty evidence of little-to-no difference between strategies for incidence of CIN3+ (from more detection of CIN2+) for those aged 30–59 years. Findings for the other age groups and other benefit outcomes across all ages were of very low certainty, often from added imprecision (e.g., n = 629 in 25–29 year age group) or indirectness from needing to rely on data from those aged 30–64 for findings among 60–69 year-olds. For referrals to colposcopy and false positives for CIN2+, CIN3 + and ICC, there was little-to-no differences with moderate certainty for the 30–59 year-olds and low certainty for the other age groups. Comparisons 5, 6a, and 7 These comparisons had at least one outcome with low or higher certainty evidence and Supplementary file 1b has all data sets. In Comparison 5, an RCT from Hong Kong ( 108 ) compared hrHPV with cytology triage of negative tests versus cytology with hrHPV triage, both arms having recall. The certainty for all outcomes was very low for age groups 25–29 and 60–69 years because the trial only enrolled those 30–60 years. Low certainty evidence found reduced incidence in the hrHPV strategy arm of ICC via more detection of CIN3+ (36.0 more per 10,000, 95% CI 14.3 to 71.0 more) and little-to-no difference between arms for incidence of CIN3 + via CIN 2 + detection (51.9 more per 10,000, 95% CI 23.4 to 93.7 more). There was moderate certainty evidence that the hrHPV strategy resulted in more referrals to colposcopies and false positives (about 600 per 10,000). In Comparison 6a, the IMPROVE RCT from The Netherlands (n = 13,799) examined self- versus clinician- sampling for hrHPV within arms using the same methods for triage to cytology ( 114 ). The certainty for all outcomes was very low for age groups 25–29 and 60–69 years because the trial only enrolled those aged 29–61 years. There was low certainty evidence of little-to-no difference between arms for CIN 2 + detection (1.5 fewer per 10,000 in self-sampling arm, 95% CI 36.5 fewer to 44.9 more) and very low certainty evidence for CIN 3 + and ICC detection, both of which had imprecision though there were a higher number of CIN 3 + cases detected in the self-sampling arm. There was moderate certainty evidence of little-to-no difference between arms in referrals and number of colposcopies (57 fewer from self-sampling) and for false positives for CIN 2+, CIN 3 + and ICC (range 54 to 81 fewer). No incidence data was reported. Two RCTs from Sweden (Uppsala I [50–60 year-olds] & II [30–60 year-olds]; N = 11,414) ( 106 , 109 ) compared hrHPV self- and clinician-sampling where individuals with positive tests in both arms had repeat testing with the same method 3–6 months later and those persistent for hrHPV were referred to colposcopy (Comparison 7). There was low certainty evidence of little-to-no difference between arms for CIN 2 + detection (32.5 fewer per 10,000 in self-sampling arm, 95% CI 65.3 fewer to 12.7 more) and very low certainty evidence for CIN 3 + detection because of imprecision. There was low certainty evidence of little-to-no difference between arms in referrals and number of colposcopies (20 more from self-sampling) and for false positives for CIN 2 + and CIN 3+ (49 and 35 more, respectively). One of the RCTs ( 109 ) enrolling 65% of the total sample in this comparison included only participants aged 50 years or older, so this age group was overrepresented in the analysis and we rated down for indirectness to the age range of interest (30–59 years). Comparisons 6b and 8–10 . Five small RCTs (range n analyzed = 164 to 2,845) reported on the comparative effects involving hrHPV self-sampling in one or more arms among populations who were either non-responders or underscreened ( Box 1 ) ( 113 , 116 – 119 ). In all but one ( 118 ) reporting on Comparison 9, the number of enrolled participants was far below (5.4%-13%) the number randomized and all RCTs were rated at high risk of bias. Very low certainty evidence was found for all reported outcomes (colposcopy, detection of CIN 2 + and 3 + and false positives) in these comparisons ( Supplementary file 1b ). Four of these RCTs were also included in KQ5 on interventions to increase screening uptake ( 113 , 116 – 118 ). Key Question 2: Comparative Accuracy Ten studies in 11 papers were included for KQ2 ( 137 – 147 ). Several studies included in other similar reviews we screened for eligibility ( 41 , 48 ) were excluded either because they reported on comparisons excluded in this review (either per protocol or post hoc as per Methods), were conducted in countries without a Very High Development Index, or did not apply the reference standard in at least a sample of the test negative population. Characteristics and risk of bias assessment of included studies, and all evidence sets are presented in Supplemental file 2 . The median patient age was 40.0 years (range of means 23.0 to 45.8) with sample sizes ranging from 247 to 256,648 participants. Studies were generally from countries with organized screening, including two studies in Greece ( 137 , 140 ), three from the United States ( 138 , 139 , 141 ), and one from each of Canada ( 144 ), Germany ( 143 ), France ( 145 ), South Korea ( 146 ), and England ( 147 ). Only one study, conducted in Germany ( 142 ), was in an area with largely opportunistic screening. Only three studies reported that HPV vaccination had been implemented, with proportions of the study populations vaccinated ranging from 0.1–4.0% ( 137 , 140 , 141 ). All studies were rated as having unclear risk of bias due to lack of reporting on items for one or more domains. Thresholds for a positive HPV screening test were generally not reported, but where reported the threshold was either 1.0 relative light unit (5,000 or more HPV DNA copies) ( 138 ) or 1.0 pg/ml ( 144 , 145 , 147 ). Findings for cytology are for the ≥ ASCUS threshold unless otherwise stated. Lastly, findings apply to CIN 2 and CIN 3 unless otherwise stated. False positives The main purpose of this review was to examine false-positives from screening strategies used in KQ1 RCTs, when false positives were not reported in the RCT (i.e., for ICC from hrHPV alone versus cytology alone) or had very low certainty evidence. Additionally, we focused on comparisons between strategies not examined in the RCTs (e.g., hrHPV with cytology triage versus hrHPV, cytology with hrHPV triage versus cytology alone) to give some indication of where replacements/alternatives could possibly be used. Table 4 summarizes the findings for the comparative false positives between screening strategies. A conclusion of little-to-no difference indicates that there was less than 3% (300 per 10,000) fewer or more false positives with the first versus the second strategy. Our evidence found that self- versus clinician sampling of hrHPV alone probably makes little-to-no difference in false positives. Compared with hrHPV testing alone (via self-or clinician sampling), adding cytology triage or replacing the hrHPV test with one allowing partial genotyping with or without cytology triage, reduces the number of false positives. Though we did not rate our certainty in the magnitude of difference beyond the threshold of 3%, there appears to be a large reduction in false positives from adding cytology triage or genotyping to HPV alone (range 500 to almost 3,000 fewer per 10,000). There is probably little-to-no difference in false positives for CIN 2 + or CIN 3 + between hrHPV with partial genotyping (types 16/18) alone and hrHPV with cytology triage. Adding cytology for the non-16/18 types after using partial genotyping probably increases false positives. Results from replacing cytology alone with hrHPV tests with partial genotyping (types 16/18) alone led to varying results based on the cytology threshold; when compared to cytological detection of ≥ ASCUS, there may be fewer false positives (which remain fewer if adding on cytology for non-16/18 types), whereas for cytological detection of ≥ LSIL there was little-to-no difference, and for atypical squamous cells – cannot exclude HSIL (≥ ASCH+) and ≥ HSIL the false positives probably increase when cytology is replaced by hrHPV. Adding hrHPV triage (with or without partial genotyping for types 16/18) to positive cytology may reduce false positives compared with cytology alone. Findings within different age groups were in the same direction of effect for hrHPV alone versus cytology alone and for hrHPV with partial genotyping (types 16/18) alone versus hrHPV alone or cytology alone. Sensitivity and specificity All results and certainty assessments for sensitivity and specificity are included in Supplemental file 2 . As expected, in a majority of cases there is a trade-off between sensitivity and specificity and as such attempts to increase specificity (to reduce false positives) often lead to lower sensitivity (i.e., some number of missed cases). Assuming prevalence rates for CIN 2 + of 1.4% and CIN 3 + of 0.6%, as aggregated across the included studies, the reduction in sensitivity and thus number of missed cases varied across comparisons. For example, adding cytology triage (≥ ASCUS) to hrHPV alone may increase specificity to a large degree (with possibly 3000 per 10,000 fewer false positives) but at the expense of missing some CIN 2+ (55 to 65 per 10,000; 2 studies, N = 38,113) and CIN 3+ (23 per 10,000; 1 study, n = 34,254) cases. Similar findings were found with replacing hrHPV alone with hrHPV with partial genotyping (types 16/18) alone (range 713 to 2943 fewer false positives but 58 to 73 fewer CIN 2 + and 12 to 33 fewer CIN3 + cases detected per 10,000; 3 studies, N = 41,018), whereas replacing cytology (≥ ASCUS) alone with hrHPV with partial genotyping (types 16/18) alone appears to have less impact (range 70 to 1830 false positives and up to 21 fewer CIN 2 + and 9 fewer CIN3 + cases detected per 10,000; 3 studies, N = 41,018). With hrHPV alone, self-sampling probably has lower sensitivity than, and similar specificity to, clinician sampling for detecting CIN 2 + or CIN2/3 (3 studies, N = 2,832); the number of missed cases may be small (13 to 27 missed cases per 10,000). Cytology (≥ ASCUS) with hrHPV triage with partial genotyping for types 16/18 versus cytology alone may increase specificity without impacting sensitivity (CIN 2 + and CIN 3+; 1 study, n = 2,905). In two comparisons there was little-to-no difference between strategies in sensitivity or specificity for CIN 3 + detection, such that replacing one with the other may make little impact: hrHPV with partial genotyping (types 16/18) alone versus hrHPV with cytology triage (≥ ASCUS) (1 study, n = 34,254; low [sensitivity] and moderate [specificity] certainty); cytology (≥ ASCUS) with hrHPV triage versus cytology (≥ ASCUS) alone (1 study, n = 2,905; low certainty). There is probably (moderate certainty) an increase in both sensitivity and specificity for the first strategy in two comparisons: hrHPV with partial genotyping (types 16/18) with triage to cytology on non-16/18 types (≥ ASCUS) versus hrHPV with cytology triage (≥ ASCUS) (for CIN 3+; 1 study, n = 34,254); hrHPV with partial genotyping (types 16/18) with triage to cytology on non-16/18 types (≥ ASCUS) versus cytology (≥ ASCUS) alone (CIN 2+; 2 studies, N = 38,113 and CIN 3+; 1 study, n = 34,254). Few studies reported on accuracy of ICC detection. One study (n = 2,905) found that hrHPV with partial genotyping [types 16/18] increased sensitivity and reduced specificity for ICC compared with cytology alone (various thresholds). Most findings for CIN 2 + and CIN 3 + were similar for 20 to 29 and ≥ 30-year-olds. Compared with cytology alone, hrHPV with partial genotyping 16/18 alone may decrease sensitivity for CIN 2 + in 20 to 29-year-olds, but increase sensitivity in ≥ 30-year-olds, both having low certainty. Key Question 3: Pregnancy Harms of Conservative Management of CIN Two Cochrane reviews ( 46 , 47 ) synthesized evidence about adverse pregnancy outcomes following excisional or ablative management of CIN (all grades and both squamous and glandular intra-epithelial neoplasia). One reported on early pregnancy outcomes ( 47 ), while the other focused on late obstetrical outcomes ( 46 ), and the latter also expanded the exposure of interest to early (stage IA1) cervical cancer. Both reviews examined outcomes among individuals treated for lesions compared with an untreated reference population (i.e., untreated females from the general population, internal controls of pregnancies in the same individual before treatment, or individuals with disease that did not receive treatment). All included studies were observational in design, thereby limiting certainty in the evidence (certainty started at low). Despite this, the authors rated most studies as good quality and did not rate down the certainty further for additional study limitations, indirectness or imprecision. Supplemental file 3 presents the summary of findings tables. Early pregnancy outcomes There may be little-to-no difference in total miscarriage rates between individuals treated for CIN and those not treated (RR 1.04, 95% CI 0.90 to 1.21; ARD 1 more, 95% CI 3 fewer to 6 more per 1000; 10 studies, N = 39,504; low certainty evidence). The authors’ meta-analysis found that, across all studies, CIN treatment was associated with increased risk of second trimester (12 to 24 weeks’ gestation) miscarriage versus no treatment (RR 2.60, 95% CI 1.45 to 4.67; ARD 6 more, 95% CI 2 to 14 more per 1000; 8 studies, N = 2,182,268). Based on input from the working group, current clinical practice for the management of CIN 2 has become much more conservative (e.g., avoiding excisional procedures, more surveillance due to better knowledge about their frequent regression) in recent years for those ≤ 25 years old or prioritizing reproductive futures ( 148 , 149 ). Because of this, we rated down the certainty to very low from indirectness of the types of management provided in the studies (most conducted pre-2010) compared with current practice. Other priority outcomes in early pregnancy (i.e., cerclage and cervical insufficiency) were not addressed in the studies. Late obstetrical outcomes Meta-analysis of 59 studies found that preterm birth (< 37 weeks) rates were higher among individuals who have been treated for CIN or early cervical cancer compared with those who were not treated (RR 1.75, 95% CI 1.57 to 1.96; ARD 41 more, 95% CI 31 to 52 more per 1000; N = 5,242,917). Risk for preterm birth progressively increased with increasing cone depth among persons treated for CIN or early cervical cancer by excisional procedures versus untreated controls (from RR of 1.54 for depth ≤ 10 to 12 mm to RR of 4.91 for depth ≥ 20 mm). Other treatment factors that increased the risk for prematurity included multiple treatments versus single, excision rather than ablation management, and more radical treatment techniques. Because of clinical input that the management strategies in these studies would usually be more aggressive than used in current practice, we rated the certainty as very low from indirectness. Risk for low birth weight (< 2500 g) was also shown to be higher among individuals treated for CIN or early cervical cancer versus those who were not treated (RR 1.81, 95% CI 1.58 to 2.07; ARD 29 more, 95% CI 21 to 39 more per 1000; 30 studies, N = 1,348,206), though this evidence was also rated down for indirectness to current practice. For both preterm birth and low birth weight, the review authors rated down the evidence for inconsistency; we did not rate down for this factor because a majority of study results were in the same direction of effect even if their magnitudes differed. Lastly, higher rates of cervical cerclage in later pregnancy were found for treated persons compared with untreated controls (RR 14.29, 95% CI 2.85 to 71.65; ARD 15.9 more, 95% CI 2.2 to 84.4 per 1,000; 8 studies, N = 141,300), but again the certainty was very low. Key Question 4: Relative Importance of Potential Outcomes from Screening Twenty-three observational studies were included for this key question. Nineteen studies measured health state utility values ( 150 – 168 ) and four measured preferences using other methods ( 169 – 172 ). Across all studies, participant median age was 39.9 years (range of means 18.9 to 53.4) and the median sample size was 342 (range of sample sizes 36 to 146,336,855). Eleven studies were from Europe ( 151 , 155 – 157 , 159 – 161 , 167 , 170 – 172 ), four from Australia ( 152 , 164 , 166 , 169 ), and four from the United States ( 153 , 154 , 158 , 165 ). One study was included from each of Canada ( 150 ), Japan ( 162 ), South Korea ( 163 ), and Thailand ( 168 ). Twelve studies measured utilities with the EQ-5D (and other instruments in some cases) whereas seven only measured utilities with another instrument. The main issues in risk of bias were low study recruitment rates and failure to perform appropriate analysis to adjust for confounding. Fifteen of the 23 studies recruited less than 50% of eligible subjects or lacked information in this domain. Additionally, 13 of the 19 studies estimating utility scores did not perform appropriate analysis to adjust for confounding. Characteristics of included studies, risk of bias assessments and summary of findings tables are presented in Supplemental file 4 . Disutilities A weighted average of EQ-5D utilities of the general public was calculated among five of the included studies for use as an indirect comparison to calculate estimates of disutilities in studies that lacked a control group. The resulting utility of the general public was 0.86 (95% CI 0.82 to 0.90), which was similar to that of estimates obtained in a Canadian population ( 173 ). We rated this estimate as having high certainty. Using the EQ-5D instrument, the disutility from cervical cancer is probably 0.11, more than one year after initiating treatment ( 155 , 160 , 162 , 165 , 168 ). Some within-study evidence suggests that the disutility may be considerably higher immediately after diagnosis or during treatment and/or with more disease severity. EQ-5D disutility from CIN 3 is very uncertain, but for CIN 2/3 it may be about 0.05 after (18 to 20 months) treatment (low certainty), with insufficient data from after a diagnosis to postulate whether disutility would significantly differ ( 160 – 162 ). Additionally, there was high certainty of little-to-no disutility from having a false positive result after cytology screening, mainly in comparison with those screening with normal results ( 150 , 156 , 157 , 159 , 167 ). When using these data together with findings from utility measurement using other tools, cervical cancer may be at least twice as important as CIN 2/3, and both cervical cancer and CIN 2/3 are probably much more important than false positives. The relative utilities across outcomes from data within studies ( 160 , 161 ) that compared different health states using EQ-5D and TTO aligned with these findings, whereas the SG technique in one study ( 162 ) found quite similar utilities for ICC, CIN 3 and CIN 2. Other data on preferences : For the studies reporting on non-utility data, we did not undertake a narrative synthesis as planned ( 52 ) because the four studies differed in their methodology and/or populations substantially ( Supplemental file 4) . All studies focused on preferences related to cytology screening. One quantitative study (n = 248) ( 170 ) among those aged 30–60 years eligible for the Dutch screening program directly assessed the importance of benefits versus harms from screening to inform screening decisions via an online survey using a 7-point Likert scale for ratings and a ranking system. We judged that the data provided portrayed a relatively high net benefit from screening over 30 years: ICC incidence (8 vs. 25 per 100,000) and mortality (2 vs. 8 per 100,000) versus false positives (1,000 among 100,000) and overdiagnosis (descriptive without numerical data). On the Likert scale the benefits were rated higher than harms (5.09 and 5.37 vs. 4.88 and 4.65, respectively), and when ranking the outcomes the benefits were ranked first and second. Some variability existed between participants (e.g., SDs 1.79 and 1.75 for ratings for ICC incidence and false positives), but results did not differ by age. The evidence was of low certainty that a large majority of individuals aged 30–60 years may weigh the benefits as more important than the harms of screening for cervical cancer using cytology, but think it is important to provide information on benefits and harms for decision making. Three other studies inferred preferences between the benefits and harms based on data on intentions or attitudes about screening ( 169 , 172 ) or a willingness-to-pay (WTP) experiment ( 171 ). One study (n = 161; 12% previously screened) ( 169 ) in Australia provided university students (range 17–24 years) with information on outcomes (stating no benefit in ICC incidence or mortality) using two decision aids that both detailed several harms but differed in whether they explained overdiagnosis (1,600 of 100,000 will have pre-cancers treated that may have resolved). Intentions (3.2 ± 1.3 and 3.0 ± 1.3 on 5-point Likert scale) and attitudes (31.1 ± 8.8 and 32.8 ± 8.2 on scale with range 6–42 with higher indicating more positive attitude) did not differ between the two decision aids. This study found that some individuals < 25 years may have intentions to screen even when informed that screening does not reduce cancer diagnoses or deaths for their age group (low certainty). Two other studies examined intentions to screen (n = 283) and WTP (n = 1,524) amongst regular screeners within the UK using comparisons between factual information and controls. Authors of the WTP study cite literature verifying the validity of WTP for screening in the UK. Both studies provided data on a large reduction in ICC incidence (e.g., 1 in 100,000 screened vs. 10 in 100,000 unscreened) and focused on false positives (e.g., 10% each year, one indicating 50% over 7 rounds) without any information on overdiagnosis of precancers. Although intentions and WTP reduced in intervention versus control groups, they remained quite high (79% vs. 88% and mean WTP 128£ vs. 175 £). Findings indicated that across all ages that may be eligible for screening, a large majority of individuals may weigh the benefits as greater than the harms from screening for cervical cancer. Due to risk of bias and indirectness from relying on inferences about the relative importance of outcomes based on intentions/WTP for screening which may relate to other factors, we rated the certainty of evidence as low. Key Question 5: Effectiveness and Comparative Effectiveness of Interventions to Increase Screening Rates There were 44 RCTs in 46 publications included for this key question. One RCT ( 119 ) included in KQ1 from our search update (a search update was not conducted for KQ5) also relates to this question but was not included in the synthesis; findings were very similar to those reported here for the effects of opt-in and universal HPV sampling kits. Characteristics of included trials are presented in Supplemental file 5 . Trials included a range of participant ages (range from 20 to 74 years) and were typically undertaken in organized screening settings with outcome ascertainment based on register or medical record data of having performed cervical cancer screening either through cytology or HPV testing. Sample sizes ranged from 88 to 90,247 participants. Of 46 publications, most were from Europe ( 55 , 113 , 116 – 118 , 174 – 197 ), seven were from the United States ( 198 – 204 ), four from Canada ( 205 – 208 ), three from Australia ( 209 – 211 ), two from Japan ( 212 , 213 ), and a single study from Malaysia ( 214 ). One trial in HIV-positive individuals with a cervix ( 199 ) was excluded from the meta-analyses and is described qualitatively due to a difference in population, intervention, and usual care compared with other studies. Five trials were considered at high risk of bias ( 113 , 174 , 181 , 205 , 214 ). Two trials considered high risk of bias had issues with random sequence generation ( 113 , 205 ), and baseline imbalances; and in single trials there was lack of allocation concealment ( 181 ), incomplete outcome reporting ( 174 ), and lack of blinding in a subjective/self-reported outcome assessment ( 214 ). The remaining trials were rated as having unclear risk of bias due to lack of reporting across multiple domains. Thus, no trial was considered at low risk of bias. Five main analyses with large sample sizes were undertaken based on grouping similar interventions together; written contact (RR 1.50, 95% CI 1.22 to 1.84; ARD 619 fewer per 10,000, 95% CI 273 to 1041; 16 trials, N = 138,880), personal contact (RR 1.50, 95% CI 1.07 to 2.11; ARD 797, 95% CI 1116 to 1770; 7 trials, N = 17,034), composite interventions (RR 1.73, 95% CI 1.33 to 2.27; ARD 1351, 95% CI 610 to 2350; 8 trials, N = 17,738), universal mail-out HPV (RR 2.56, 95% CI 2.10 to 3.12; ARD 1534, 95% CI 1082 to 2085; 22 trials, N = 211,031), and opt-in HPV self-samples (RR 1.56, 95% CI: 1.19 to 2.03; ARD 727, 95% CI 247 to 1338; 11 trials, N = 71,433). All interventions improved cervical cancer screening rates among persons with a cervix who were never or under-screened. The largest effects appear to be from mailing HPV self-sampling kits to all eligible persons, with about 15% more people screened. There was high heterogeneity in magnitude (not direction) of effect within four of the five main analyses, but none of the pre-specified subgroup analyses reduced heterogeneity ( Supplemental file 5 ). For the fifth analysis which indicated inconsistency in direction of effect, subgroup analysis indicated that the effectiveness of a strategy of opt-in HPV self-samples may be most applicable when the screening test is requested, obtained and returned via one’s home versus requiring an in-person contact (10 trials, N = 61,908: RR 1.61, 95% CI 1.19 to 2.18 vs. 1 RCT n = 9,525: RR 1.00, 95% CI 0.90 to 1.12, respectively). Examination of funnel plots and Egger’s tests (all p values > .05) did not indicate issues with small study effects. Using the GRADE approach and considering only direction of effect, the certainty of the evidence was rated high for all comparisons aside from opt-in HPV self-sampling, which was rated moderate certainty due to the concerns with inconsistency. Pre-specified between-study analyses exploring the effect of population characteristics (i.e., SES, immigrant, and indigenous status, and rural/remote communities) were not done due to a paucity of data; most trials did not report these characteristics. Further, screening rates by pre-specified populations within trials were not commonly reported. Generally, the magnitude of effects differed to some degree between populations but the interventions remained effective across groups with one exception: one universal mail-out trial in Italy showed improved screening uptake only in urban centers ( 183 ) ( Supplemental file 5 ). DISCUSSION Summary of principal findings for screening Screening for prevention and early detection of cervical cancer has previously been found to be effective when using cytology and findings across all ages examined in studies. This review focused on trying to better define screening intervals, which ages to start and stop screening, and what screening strategy(ies) to use based on the effects on the critical outcomes of incidence, mortality, and overdiagnosis. To inform ages to start and stop screening and screening intervals, there were no eligible trials and all observational studies (which stared at low certainty evidence) focused on cytology screening. For age to start screening, we found very low certainty evidence, largely based on inconsistent results across studies and indirectness of the categorical age data, for risk of ICC and mortality from cervical cancer in persons with a cervix aged 20 to 24, 25 to 29, and 30 to 34 years. For age to stop, there was moderate certainty evidence (from rating up for large effect) that screening is probably associated with a lower risk of ICC (e.g., at least 9 fewer cases per 10,000 screened) and cervical-cancer mortality (at least 0.19 to 0.29 fewer deaths per 10,000) over 10 years among those aged 60–69 years who had no screen, an abnormal screen, or inadequate screening in their 50s. For those aged 60–69 years who were adequately screened in their 50s (i.e., only negative screening results at least twice about 5 years apart), the reduction in ICC was smaller so the evidence was rated at low certainty. A reduced risk for ICC among 70 to 79-year-olds was found but with low or very low (for those adequately screened previously) certainty, and data were limited for associations with cervical-cancer mortality in this age category. Based on the existing evidence, we are very uncertain about whether the effects on the incidence of ICC or cervical-cancer or all-cause mortality differ between cytology screening intervals of 3 years or under versus 3 to 5 years. There were no eligible trials to inform about any strategy involving hrHPV testing versus no screening. For comparative effectiveness between different screening strategies, this review found 10 major comparisons examined in trials. All but one of the trials reported on one randomized screening round (i.e., any subsequent testing method was similar across groups and used for incidence data), with a maximum follow-up of 5 years (18 months to 5 years) for incidence of CINs and ICC. All of the trials only enrolled and thus reported outcomes for acceptors of screening so the effects at a population level from an invitation/offer to screen to individuals are less certain. There was very low certainty for all-cause mortality from one trial, no data on cervical-cancer mortality, and very low certainty evidence about overdiagnosis from one observational analysis by authors of one trial. Few trials reported directly on the incidence of CIN or ICC (and if so most evidence was of very low certainty), and a post hoc decision was made to analyze detection rates of CIN 2 + and CIN 3 + as surrogates for incidence of CIN 3 + and ICC, respectively, but for which we rated down our certainty for indirectness. In comparison with cytology alone, where only three trials provided data for screening using hrHPV alone or hrHPV with triage to cytology, very-low certainty evidence was found across most critical benefit outcomes though hrHPV with triage to cytology may reduce incidence of ICC from detecting more cases of CIN3+. There was moderate certainty that hrHPV alone considerably increased false positives for those aged 25–29 years, whereas hrHPV with cytology triage probably does not unless a recall phase (additional testing after the initial triage within every round) is added. Data from four trials provided evidence that hrHPV with cytology triage versus cytology with hrHPV triage probably reduces incidence of ICC to some degree for those aged 30–59 years, without adding harm. For those aged 25–29 years, when recalls are used there may be a reduction in CIN3 + incidence (via more detection of CIN2+) at the expense of an increase in referrals to colposcopy and false positives (possibly exceeding 900 per 10,000 for CIN 2 + diagnosis). Findings from one trial comparing two rounds of cytology with hrHPV triage (over 4 years) and one round of hrHPV with cytology triage (both including recall stages) suggested that one round of hrHPV testing every four years may make little-to-no difference in incidence of CIN 2 or 3+, and probably has similar rates of harms as do two rounds of cytology with hrHPV triage. Evidence for incidence of ICC was of very low certainty. From one small trial, it is uncertain what the effects are on incidence of ICC from adding partial genotyping to these triage strategies for those aged 30–59 years; there may be little-to-no difference in incidence of CIN3 + may and probably no difference in harms. Effects on all benefit outcomes from adding partial genotyping were of very low certainty for those aged 25–29 and 60–69 years due to small samples in these age categories. For those aged 30–59 years, one RCT provided moderate certainty of little-to-no difference in false positives between hrHPV self-sampling with cytology triage compared with hrHPV clinician-sampling with cytology triage, and low certainty that there may be little-to-no impact on incidence of CIN 3+. Two RCTs enrolling people 30–60 and 50–60 years compared hrHPV self- and clinician-sampling each with triage to repeat the hrHPV testing at 3–6 months, with evidence of low certainty for little-to-no difference in CIN 2 + detection, and low certainty for little-to-no difference for false positives. Five small RCTs reported on the comparative effects involving hrHPV self-sampling in one or more arms among populations who were either non-responders or underscreened. Very low certainty evidence was found for all reported outcomes (detection of CIN 2 + and 3 + and false positives) in these comparisons. Findings from indirect evidence on comparative test accuracy and treatment harms Though the focus of the recommendations will be on screening, questions on comparative accuracy of different screening strategies and adverse pregnancy outcomes from conservative management of CIN were included to provide additional information. For example, if recommendations were made about a screening strategy shown effective in an RCT eligible for KQ1 there may be the ability to also recommend a different strategy—such as one easier to administer—having similar accuracy but not examined in the trial setting (Table 4 findings from accuracy studies and Supplemental file 2). Further, we expected to have little if any data from the screening RCTs on the adverse pregnancy outcomes from conservative management of CIN, such that this data from treatment studies would help fill this evidence gap, albeit indirectly. For comparative accuracy, we focused on studies from Very High Development Index countries, that also made efforts to minimize verification bias by giving a sample of screen negative participants the reference standard. The criteria led to relatively high certainty in our evidence due to lack of concerns over directness and, generally, lower risk of bias. The main finding when looking at false positives was that compared with hrHPV testing alone (via self-or clinician sampling), adding cytology triage or replacing the hrHPV test with one allowing partial genotyping with or without cytology triage, reduces the number of false positives. There is probably little-to-no difference in false positives between hrHPV with partial genotyping (types 16/18) alone and hrHPV with cytology triage. Further, adding hrHPV triage (with or without partial genotyping for types 16/18) to positive cytology may reduce false positives compared with cytology alone. Findings within different age groups were in the same direction of effect for hrHPV alone versus cytology alone and for hrHPV with partial genotyping (types 16/18) alone versus hrHPV or cytology alone. There is often a trade-off between sensitivity and specificity. If the goal is to reduce harms (false positives and the associated follow-up tests and sequelae) by increasing specificity, minimal loss in sensitivity would be the aim as appears to occur when replacing cytology alone (threshold ASCUS+) with either cytology with triage to hrHPV with partial genotyping (little-to-no difference in sensitivity for CIN 2 + or 3+) or hrHPV with partial genotyping (types 16/18) alone (up to 21 fewer CIN 2 + and 9 fewer CIN3 + cases detected per 10,000; 3 studies, N = 41,018). Better yet, we found moderate certainty for increasing both sensitivity and specificity from using hrHPV with partial genotyping (types 16/18) with triage to cytology on non-16/18 types (ASCUS+) versus cytology alone (ASCUS+). The ability to make triage to cytology after hrHPV testing feasible may rely on there being the availability of performing (reflex) cytology testing on an hrHPV sample, to avoid the need for individuals to attend a clinic for another test, or even for one test if using mailed hrHPV self-sampling kits to maximize access or acceptability. Reflex cytology from hrHPV self-sampling would need also to rely on there being sufficient collection of cervical epithelial cells which may be unlikely. Though self-sampling for hrHPV alone probably has lower sensitivity and similar specificity compared with clinician sampling for detecting CIN 2 + or CIN2/3, the number of missed cases may be small (13 to 27 missed cases per 10,000) and this method of testing may have a role if it can increase coverage in the under- and never-screened. One caveat is that we did not find any eligible studies comparing self- versus clinician-sampling for hrHPV with partial genotyping to know if findings are similar to those for hrHPV alone. From findings of two existing systematic reviews of observational studies, there is low certainty that conservative management of CIN 2/3 may make little-to-no difference for total miscarriage rates, but very low certainty about whether there are associations with rates of second trimester miscarriage, preterm birth (≥ 37 weeks’ gestation), low birth weight (< 2500 g), or cervical cerclage due to the indirect nature of the treatment approaches in most of the studies compared with current practice that has become more conservative especially for younger people. Even if there were some certainty of harm, the magnitude of effects would be expected to be very small when considering a screening population where only a portion is treated for CIN 2/3 and at reproductive age. For example, if applying the absolute effects from treatment (60 events per 10,000 treated) to an estimate (on average across the trials showing benefit for more detection and with rates cut in half to capture those at reproductive age) of 15 more cases of CIN3 + per 10,000, there may be at most 0.1 more second trimester miscarriages per 10,000 screened. Patient preferences The disutilities of ICC and CIN 2 + were estimated at 0.11 and 0.05, respectively. Though there may not be high confidence that the disutility from having cancer is more than twice that from a CIN 2 + diagnosis and management, there is evidence to support that there is an important difference between the health states based on reported minimally important differences in disutility of 0.06 to 0.16 and 0.037 to 0.056 for cancer and general populations, respectively, with use of the EQ-5D measurement tool ( 34 , 215 ). We found high certainty evidence that there is little to no disutility from a false positive result when screening with cytology, but any reduction in disutility from fewer ICC occurring in screening still needs to be weighed against that from a portion of CIN 2/3 cases that may be overdiagnosed. Further, because the findings for a false positive were specific to use of cytology screening, we are less certain about the degree of relative importance between ICC/CIN 2 + and false positives in hrHPV screening. Perceptions by some individuals of negative consequences of an HPV infection, including stigmatization and possible relationship distress ( 216 ), could create some disutility from a false positive result if the negative perceptions actually impact one’s overall quality of life. Other studies on patient preferences about cytology screening indicated, with low certainty, that a large majority of individuals eligible for screening may weigh the benefits as more important than the harms of screening for cervical cancer using cytology, but think it is important to provide information on benefits and harms for decision making. One study suggested that some individuals < 25 years may have intentions to screen even when informed that screening does not reduce cancer diagnoses or deaths for their age group and leads to overdiagnosis. Increasing participation rates for under-never-screened populations Our review on interventions to increase screening rates among under- or never-screened individuals found high certainty that various interventions could be successful. The effects from providing mailed-out self-sampling hrHPV kits appear to be greater than for less resource-intensive interventions including written and in-person reminders or promotional education. Though mailing out kits may have upfront costs, there will likely be fewer visits to primary care providers needed. However, the downstream effects on subsequent management of results was not examined to understand the full implications. Although self- versus clinician sampled tests may be somewhat less sensitive, if able to achieve any versus no screening for these populations there may be benefit for their use. To successfully apply any of the interventions, the ability to target the under-screened populations would be necessary, as would some assurance of successful follow-up procedures whether there be some manner of in-person visit or reflex cytology on the HPV test sample, if collection of enough cervical cells could be relied upon. Comparisons with other reviews The previous review conducted for the task force included an RCT from India that found that a single lifetime cytology screening test significantly decreased the risk of mortality from and incidence of advanced cervical cancer compared to no screening (mortality: RR 0.65, 95% CI 0.47 to 0.90; incidence: RR 0.56, 95% CI 0.42 to 0.75). Although our review only included studies from countries with a Very High Development Index, its focus on screening ages and intervals differed from the overall effectiveness of cytology screening in the previous review because the task force was not challenging the strength or direction of the previous recommendation for cytology-based screening. Our review closely examined effects of screening in discrete age categories in attempts to further elucidate ages to start and stop screening as well as the frequency of screening. Several more recent studies were captured for this evaluation. Unlike some other reviews on the comparative effectiveness of screening, we did not include studies using co-testing where all participants received hrHPV and cytology screening at the same time. Authors of a meta-analysis of four European trials, NTCC and three others using co-testing (POBASCAM, Swedescreen, ARTISTIC) concluded that “HPV-based” versus cytology alone led to a 60–70% greater protection against ICC (cumulative incidences of 4.6 per 100,000 [95% CI 1.1 to 12.1] and 8.7 per 100,000 [3.3 to 18.6] at 3.5 and 5.5 years, respectively, in HPV-based versus 15.4 per 100,000 [7.9 to 27.0] and 36.0 per 100,000 [23.2 to 53.5] with cytology) ( 217 ). The absolute risk reduction of 29 fewer per 100,000 at 5.5 years approaches the threshold used for an important effect in this review (3 fewer per 10,000) but co-testing is not currently considered a cost-effective approach in Canada. Our review eligibility also differs in this regard from those undertaken for the United States Preventive Services Task Force ( 24 ). Other major organizations have also used analyses of these studies to support hrHPV screening ( 218 ). One systematic review also found lower sensitivity for self-sampling versus clinician-sampling when using commonly used signal-amplification tests (e.g., Hybrid Capture II), but additionally found lower specificity for these tests whereas our review did not find a difference ( 219 ). This variation may partially be explained by the inclusion criteria (e.g., included countries) which resulted in significantly fewer but more applicable studies included for our review. This review as well as another found that self-sampling polymerase chain reaction (PCR) tests were more sensitive than those using signal amplification ( 23 ); our review did not have this feature of the test as a specific variable for subgroup analysis, nor did we include enough studies for each comparison to make valid conclusions in this respect. Another earlier review comparing accuracy of hrHPV to cytology tests had similar conclusions to this review, that although differences in sensitivity between tests could be interpreted as large, absolute differences in missed diagnoses were often small ( 220 ). Small differences in specificity can result in fairly large absolute differences in false positives. Other reviews have examined utility values of cervical cancer screening health states. Similar to our review, findings of group estimating disutilities of the screening process and diagnostic workup stage indicated disutilities of near zero when studies employed the EQ-5D tool ( 221 ). Authors of another review reported heterogeneity among findings of health state utilities across several timepoints before and after screening, which may have been related to their use of both EQ-5D index and VAS scores (known to differ) as well as samples of patients as well as the general public ( 222 ). Improved rates of screening uptake using mail-out HPV kits were also reported in a systematic review that included individuals in the general population, not limited to non-responders to regular screening ( 223 ). Opt-in HPV self-sampling, in which eligible persons had to request a kit, was less consistently effective for increasing screening uptake in our review and in two prior reviews ( 48 , 223 ). This differential finding from acquisition of HPV self-samples implies that characteristics specific to mail-out samples may be more acceptable to recipients than opt-in options (e.g., convenience, kit acts as a reminder). In support of this theory, a Canadian Health Technology Assessment ( 23 ) found that logistical inconvenience was one barrier to participation in cervical cancer screening in Canada and countries with comparable health care (e.g., US, Australia) and a study in Geneva (Switzerland) ( 224 ) reported that practical considerations (e.g., lack of time) were the most cited reasons for non-participation in cervical cancer screening programs. Moreover, one Canadian trial ( 208 ) in a rural setting, which explored the acceptability of HPV self-sampling, found that about 43% of respondents assigned to the HPV self-sample arm reported that they would not have been screened for cervical cancer if they had not received the testing kit at home, with the majority (almost 90%) of those who performed HPV self-testing agreeing that HPV self-testing was acceptable and that they would use it in future (90%) and recommend it to a friend or family member (88%). Although the acceptance of self-sampling kits may be high, if screening completion required triage to cytology the overall uptake may be lower as may follow-up of positive tests which requires in-person visit(s). Notably in some of the trials in our review ( 176 , 182 , 189 ), some individuals who received an HPV-self sample kit in the mail completed a Pap smear in clinic, rather than sending back the sample, suggesting the presence of a “nudge” effect in these participants. Limitations of the evidence Although the studies included in this review were generally of high quality there are limitations in their findings for various other reasons. The data in several of the observational studies used to examine ages to start and stop screening were not closely aligned with the 5-year age categories of interest for this review, such that this evidence was rated down for indirectness of the population because of the need to assume that the effects would be similar in often wider age ranges than we analyzed. No RCTs have been conducted comparing cytology alone to hrHPV with partial genotyping with or without triage to cytology. Using comparative accuracy data to fill this gap may be problematic since the accuracy of the tests is one of several considerations for measuring effectiveness of screening. Trials on other comparisons of effectiveness of screening approaches mainly included one round of screening such that effects from longer-term screening are not known. The enrolled participants were also those attending for their screening visit (acceptors of screening) and as such the effects of offers to screening at a population level are unclear. Reporting of HPV vaccination status was poor across observational studies and trials of screening effectiveness, though many were conducted in time periods where very few participants would have been vaccinated. Scarce data was reported for specific populations apart from age. The need to use indirect evidence about detection rates to infer what might happen to the downstream health states (e.g., CIN 3 + detection for assessing incidence of ICC) limited the certainty in the evidence. The lack of certainty about effects on overdiagnosis to weigh against reductions in cancer incidence is concerning. Based on epidemiological data, if 82% of CIN 2 lesions either regress to normal/CIN 1 or remain unchanged and if only 30% of CIN 3 progress to cancer ( 15 – 17 ) there could be considerable psychosocial harm from labelling and/or physical harm from treatment of a lesion that would never have been identified without screening. We did not locate any preference studies that used methods to generate trade-offs between the benefit and harm outcomes, to understand what the maximum acceptable number of harms may be to prevent one case of ICC. Strengths and limitations of the review We comprehensively reviewed evidence related to the benefits and harms of screening and of different screening strategies for the prevention of cervical cancer by first considering direct evidence from studies on screening, and supplementing this by reviews on the comparative accuracy of screening tests and strategies and on the harms of treatment of CIN. We also reviewed evidence on patient preferences to assist with judgements about the balance of benefits with harms. We assessed our certainty in all outcomes to enable decision-making based on various factors that influence conclusions. Findings are likely not highly applicable to settings considering co-testing using hrHPV and cytology because trials examining this screening strategy were not eligible for this review. We implemented rigorous searches to locate all potentially relevant studies; though our eligibility was limited to English and French language studies our criteria of using studies from Very High Development Index countries raises confidence that we did not miss any influential studies. Some of the decision for eligibility (e.g., limiting studies on screening versus no screening to ages to start and stop screening and screening intervals; comparisons of interest for KQ2 on accuracy) and analysis (e.g., subgroups for assessing heterogeneity in KQ5 on interventions to increase uptake; thresholds for use when assessing certainty of outcomes in KQs 1 and 2) were made after the protocol was developed, but all decisions were made prior to the task force being aware of study findings. The evidence used in the reviews we summarized for KQ3 on harms from management of CIN is likely not completely up to date. We had anticipated that these reviews would be updated during the period of our review but this did not occur. Assessing findings from more recent studies, if they exist and have large samples and good quality, using contemporary treatment approaches may be useful. In KQ4 on outcome valuation, our search was limited to health states encountered during a program for screening for cervical cancer and thus no studies on the disutility from the harms from treatment of CIN (e.g., preterm birth) were found. Research gaps Trials of more than one randomized screening round with enough unselected participants and long-term follow-up to examine the comparative effects of different strategies on incidence of ICC, mortality rates, and overdiagnosis are needed. More research is needed once prevalence of hrHPV reduces due to vaccination; this will help determine if vaccination as a preventive strategy is sufficient to reduce or replace screening at some point. Due to a larger risk-to-benefit ratio, there is still uncertainty about the effects of screening all individuals under 30 to 35 years of age, particularly if using a test with lower specificity. Prospective controlled trials comparing different ages to stop screening, different intervals of screening, and examining the effects for various subpopulations are also needed. Conclusions Screening for prevention or early detection of cervical cancer with cytology has been employed for decades and is probably effective for otherwise healthy persons with a cervix at least into their 60s. Whether to screen individuals younger than 35 years old using cytology is uncertain based on need to rely on observational evidence without consistent reporting across these age groups. Screening during ones 60s and 70s may have less effect for those adequately screened in their 50s. The effects of screening with cytology every 5 years versus 3 years are uncertain. The evidence provided very low certainty about any differential impacts between various screening strategies on mortality and overdiagnosis outcomes and comparative effectiveness was mostly limited to one round of screening among those attending screening. Compared with cytology alone or cytology with hrHPV triage, there was evidence of a small benefit from reducing ICC from using hrHPV with cytology triage though findings were most robust for those aged 30–59 years. Any additional benefit from adding recall is not clear especially for those 25–29 years where it probably adds substantial harm. There is some indication that screening using hrHPV with triage to cytology every 4 years may lead to similar detection of cancer precursors as would cytology with hrHPV triage conducted every 2 years, though the effects compared with cytology testing alone were not examined. Further, it is uncertain what the effects are on incidence of ICC from adding partial genotyping to the triage strategies for those aged 30–59 years. For those aged 30–59 years, moderate certainty evidence found little-to-no difference in false positives between hrHPV self-sampling with cytology triage compared with hrHPV clinician-sampling with cytology triage, and low certainty that there may be little-to-no impact on incidence of CIN 3+. The comparative effectiveness studies did not examine all relevant comparisons and thus comparative accuracy data may help provide suggestions of possible alternative strategies with similar sensitivity and specificity. Most of the studies on screening effects were undertaken in populations either in which HPV vaccination had not been implemented or carried out in a period when vaccination rates were low. For under- or never-screened individuals, self-sampled hrHPV tests may improve screening rates with similar test accuracy, but it is uncertain if findings apply when triage to cytology is used because of the need for adequate cervical cells and likely a clinic visit. ICC and CIN2/3 probably make an important impact on one’s quality of life, whereas a false positive result when using cytology alone does not; whether the disutility of a false positive result applies to hrHPV testing is unknown. There was low certainty evidence that informed individuals eligible for screening think the benefits outweigh the harms from screening. Choices for screening strategies apart from cytology alone may result largely from contextual considerations such as access, acceptability, resources and costs. Declarations Ethics approval and consent to participate. Not applicable. Consent for publication. Not applicable. Availability of data and materials. The data generated during this study are available within the manuscript or its supplementary files. Competing interests. AG is an employee of the Canadian Agency for Drugs and Technologies in Health (CADTH). The current work was unrelated to her employment and CADTH had no role in the funding, design, or oversight of the work. The remaining authors declare that they have no competing interests. Funding. This review was conducted for the Public Health Agency of Canada (PHAC). The contents of this manuscript do not necessarily represent the views of the Government of Canada. Dr. Hartling is supported by a Canada Research Chair in Knowledge Synthesis and Translation. The funding body had no role in the design of the study, nor the collection, analysis, and interpretation of data. Contributions of the authors. JP contributed to the conception and design of the work, provided methodological expertise at all phases, participated in certainty of evidence appraisals, assisted with drafting the manuscript, and is the guarantor of the review. AG contributed to the conception and design of the work, screened studies for inclusion (all KQs), extracted and verified data (KQs 1, 2 and 5), and participated in risk of bias (KQs 1, 2 and 5) and certainty assessments (KQ1). BZ extracted and verified data (KQ 1 and 5); participated in risk of bias, data analysis, and certainty assessments (KQs 1 and 5), and drafted portions of the manuscript. SG screened citations (all KQs), extracted and verified data (KQs 1, 2 and 4); participated in risk of bias, data analysis, and certainty assessments (KQs 1, 2 and 4), and drafted portions of the manuscript. SS screened studies (all KQs) and participated in data extraction and risk of bias assessments (KQs 1 and 5). BV provided statistical input for KQs 1, 2 and 5. LH contributed to the conception and design of the work, and provided methodological input at all phases. All authors have reviewed drafts of the manuscript for important intellectual content and approve of the version of the manuscript as submitted. Acknowledgments. We thank previous and current Task Force members serving on this topic’s Working Group (Donna Reynolds, Guylène Thériault, Brett D Thombs, Nathalie Slavtcheva, Richard Henry) and the clinical experts (Julian Little, Catherine Popadiuk, Dirk van Niekerk) for helping to interpret the findings and for reviewing drafts of the manuscript. We would like to acknowledge current or past Task Force members who were not in the Working Group: Ahmed Abou-Setta, Eddy Lang, Scott Klarenbach, Ashraf Sefin, Gail Macartney, Henry Siu, Jennifer Flemming, Kate Miller, Keith Todd, and Patricia Li who reviewed a draft of this manuscript. 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Catarino RR, Vassilakos PP, Royannez D, II, Guillot CC, Alzuphar SS, Fehlmann AA, et al. Barriers to cervical cancer screening in Geneva (DEPIST Study). J. 2016;20(2):135-8. Tables Tables 1-4 are available in the Supplementary Files section. Box Box. Classification of Screening Strategies Considered in Comparative Effectiveness Studies 1: hrHPV alone vs. cytology alone (≥ASCUS to colposcopy): 1 RCT (NTCC Phase II/Ronco 2008); n=49,196 2a: hrHPV with cytology triage (≥LSIL or ≥ASCUS to colposcopy) vs. cytology alone (≥LSIL or >LSIL to colposcopy); without recall: 1 RCT (Finnish/Leinonen 2012) & 1 quasi-RCT (Norwegian HPV Screening Pilot/Nygard 2022); N=289,641 2b: hrHPV with cytology triage (≥LSIL to colposcopy) vs. cytology alone (≥LSIL to colposcopy); with recall of ≥ASCUS and HPV + vs. ≥ASCUS using same screening at 12-24 months: 1 RCT (Finnish/Leinonen 2012); n=132,194 3a: hrHPV with cytology triage (≥ASCUS to colposcopy) vs. cytology (≥LSIL or ≥HSIL to colposcopy) with hrHPV triage (HPV + with ≥ASCUS to colposcopy); without recall: 2 RCTs (HPV Focal/Olgilvie 2017 & Stockholm-Gotlund/Lamin 2017) and 1 quasi-RCT (Swedish HPV Trial/Elfstrom 2021); N=226,132 3b: hrHPV with cytology triage vs. cytology with hrHPV triage (as for 3a); with recall of HPV + with <ASCUS (hrHPV arm) vs. HPV - with ≥ASCUS (cytology arm) at 6-12 months for co-testing/hrHPV testing/hrHPV with cytology triage (hrHPV arm) or cytology/co-testing/none (cytology arm): 1 RCT (HPV Focal/Olgilvie 2017) & 1 quasi-RCT (Norwegian HPV Screening Pilot/Nygard 2022); N=182,541 and 1 observational study used for data on incidence of ICC (English HPV Screening Pilot/Rebolj 2022); n=1,171,192 3c: One round of hrHPV with cytology triage (≥ASCUS to colposcopy) vs. two rounds of cytology with hrHPV triage (≥LSIL and HPV+ with ≥ASCUS to colposcopy); with recall to co-testing (hrHPV arm; HPV + or ≥ASCUS to colposcopy) or cytology (cytology arm; ≥ASCUS to colposcopy): 1 RCT (HPV Focal/Olgilvie 2017); n=18,948 4: hrHPV with partial genotyping (types 16/18 direct to colposcopy) and cytology triage of hrHPV type 45 (hrHPV type 45 + with ≥HSIL to colposcopy) vs. cytology (≥HSIL direct to colposcopy) with hrHPV with partial genotyping triage (hrHPV type 16/18 with ≥ASCUS to colposcopy); with recall of ≤LSIL vs. hrHPV type 45 + for hrHPV testing at 12 (hrHPV + to colposcopy) and again (if hrHPV - ) at 24 months: 1 RCT (COMPASS/Canfell 2017); n=2,987 5: hrHPV (hrHPV + direct to colposcopy) with cytology triage of negative tests (≥LSIL to colposcopy) vs. cytology (≥LSIL to colposcopy) with hrHPV triage (ASCUS and hrHPV + to colposcopy); with recall of ASCUS vs. hrHPV - to co-testing at 12 months with ≥ASCUS or hrHPV + to colposcopy: 1 RCT (Chan 2020); n=15,833 6a: hrHPV via self-sampling with cytology triage vs. clinician-sampled hrHPV with cytology triage (hrHPV + and ≥ASCUS to colposcopy); with recall of <ASCUS to cytology at 6 months: 1 RCT (IMPROVE/Polman 2019); n=13,799 6b: hrHPV via self-sampling with cytology triage vs. clinician-sampled hrHPV with cytology triage (hrHPV types 16/18 and ≥ASCUS or hrHPV other types and ≥HSIL to colposcopy); with recall of <ASCUS to hrHPV testing at 12 or 24 months (underscreened population): 1 RCT (Aasbo 2022); n=963 7: hrHPV via self-sampling with triage to repeat self-sampling vs. clinician-sampled hrHPV with triage to repeat clinician-sampled hrHPV (persistent hrHPV to colposcopy): 2 RCTs (Uppsala I/Gustavsson 2019 & Uppsala II/Aarnio 2021); N=11,414 8: hrHPV via self-sampling with cytology triage vs. cytology alone (in both ≥ASCUS to colposcopy) (underscreened): 2 RCTs (ARCADES Phase I/Piana 2011 & ARCADES Phase II/Sancho-Garnier 2013); N=2,845 9: hrHPV via self-sampling (hrHPV types 16/18 direct to colposcopy) with cytology triage (hrHPV other types and ≥ASCUS to colposcopy) vs. cytology (≥LSIL to colposcopy) with hrHPV triage (≥ASCUS and hrPV to colposcopy) (underscreened): 1 RCT (Vivano 2017); n=618 10: hrHPV via self-sampling alone (offered cytology but hrHPV + could go to colposcopy) vs. cytology alone (≥ASCUS to colposcopy) (underscreened): 1 RCT (Westminster/Szarewski 2011); n=164 Supplementary Files PRISMA2020checklist.docx SupplementaryFile1aKQ1ageandintervals.docx Supplementary file 1a. Evidence for Key Question 1 on ages to start/stop screening and screening intervals SupplementaryFile1bKQ1comparativeeffectiveness.docx Supplementary file 1b. Evidence for Key Question 1 on comparative effectiveness of screening strategies Supplementaryfile2comparativeaccuracy.docx Supplementary file 2. Evidence for Key Question 2 on comparative accuracy Supplementaryfile3treatmentharms.docx Supplementary file 3. Evidence for Key Question 3 on adverse pregnancy outcomes associated with conservative management of CIN Supplementaryfile4patientpreferences.docx Supplementary file 4. Evidence for Key Question 4 on relative importance of the outcomes SupplementaryFile5increasinguptake.docx Supplementary file 5. Evidence for Key Question 5 on effectiveness of primary care-based interventions screening uptake of under/never screened individuals Supplementaryfileiadditionalmethods.docx Supplementary file i. Additional background and methods SupplementaryfileiiExcludedstudies.xlsx Supplementary file ii. Excluded studies Tables.docx Cite Share Download PDF Status: Published Journal Publication published 28 Oct, 2025 Read the published version in Systematic Reviews → Version 1 posted Editorial decision: Minor revision 04 Oct, 2024 Reviewers agreed at journal 09 Jul, 2024 Reviewers invited by journal 09 Jul, 2024 Editor assigned by journal 03 Jul, 2024 First submitted to journal 02 Jul, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4677378","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":324947036,"identity":"6f53e74d-450f-408b-99b5-6d6c31dfa019","order_by":0,"name":"Jennifer Pillay","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA50lEQVRIiWNgGAWjYBACxgbGxgMPGBjkGBiY24jW0nAggYHBGMgEaTEgThtIS2ID0VqYZzcDbak5nL7h+MG2Bx/3/JFnYD/8AL/D5hwEajl2OHfDmcR2wxnPDAwbeNLwW8U4IxGohQ2o5UBimzTPAQPGBgkCroNo+Xc43eD8wzbpPwcM7Bsk2D8Q1pLYdjjB4AbQFoYDBokNEjwEbAH5JbEv3XDmjYfthj0HjJPbeHIK8GoxnN3+8MGHb9byfOeTjz34cUDOtp/9+Ab8WmaAqWaECBte9UAgLwGm6gipGwWjYBSMgpEMAAMaVGdxyEjKAAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0001-6086-7229","institution":"University of Alberta","correspondingAuthor":true,"prefix":"","firstName":"Jennifer","middleName":"","lastName":"Pillay","suffix":""},{"id":324947037,"identity":"88e719fc-c6f3-4007-a0e3-b52c90f79b77","order_by":1,"name":"Allison Gates","email":"","orcid":"","institution":"University of Alberta","correspondingAuthor":false,"prefix":"","firstName":"Allison","middleName":"","lastName":"Gates","suffix":""},{"id":324947038,"identity":"c16e7a5b-4795-434e-ade3-b4afd114ae5d","order_by":2,"name":"Samantha Guitard","email":"","orcid":"","institution":"University of Alberta","correspondingAuthor":false,"prefix":"","firstName":"Samantha","middleName":"","lastName":"Guitard","suffix":""},{"id":324947039,"identity":"ea2419d5-2f35-479a-b715-68994a954e0a","order_by":3,"name":"Bernadette Zakher","email":"","orcid":"","institution":"University of Alberta","correspondingAuthor":false,"prefix":"","firstName":"Bernadette","middleName":"","lastName":"Zakher","suffix":""},{"id":324947040,"identity":"b957f546-0904-4684-aadb-6638b7c9d778","order_by":4,"name":"Shannon Sim","email":"","orcid":"","institution":"University of Alberta","correspondingAuthor":false,"prefix":"","firstName":"Shannon","middleName":"","lastName":"Sim","suffix":""},{"id":324947041,"identity":"f4f25315-1cd6-42d2-9a79-24b223a05263","order_by":5,"name":"Benjamin Vandermeer","email":"","orcid":"","institution":"University of Alberta","correspondingAuthor":false,"prefix":"","firstName":"Benjamin","middleName":"","lastName":"Vandermeer","suffix":""},{"id":324947042,"identity":"bba97e44-ebde-41e4-94e6-ece6409e789b","order_by":6,"name":"Lisa Hartling","email":"","orcid":"","institution":"University of Alberta","correspondingAuthor":false,"prefix":"","firstName":"Lisa","middleName":"","lastName":"Hartling","suffix":""}],"badges":[],"createdAt":"2024-07-03 03:48:00","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4677378/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4677378/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s13643-025-02866-4","type":"published","date":"2025-10-28T15:58:02+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":62157060,"identity":"a24c97fb-1030-4ea2-aaab-d857c56e7578","added_by":"auto","created_at":"2024-08-09 21:14:51","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":145413,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFlow of literature\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-4677378/v1/470a1a8fd0567efe42ff8deb.png"},{"id":95041393,"identity":"62fe2d19-4025-4f8b-b470-012be297c21d","added_by":"auto","created_at":"2025-11-03 16:11:27","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2275590,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4677378/v1/cacd04bb-a5e7-4220-8abe-460459a8ad1a.pdf"},{"id":62155865,"identity":"0872f1fd-82c1-4f08-abb9-5bef809fa935","added_by":"auto","created_at":"2024-08-09 21:06:51","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":27838,"visible":true,"origin":"","legend":"","description":"","filename":"PRISMA2020checklist.docx","url":"https://assets-eu.researchsquare.com/files/rs-4677378/v1/71f22c03c04860ae3e4dcd79.docx"},{"id":62157061,"identity":"636be0da-cbad-4d99-996c-24e866b6eeff","added_by":"auto","created_at":"2024-08-09 21:14:51","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":370883,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSupplementary file 1a. Evidence for Key Question 1 on ages to start/stop screening and screening intervals\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"SupplementaryFile1aKQ1ageandintervals.docx","url":"https://assets-eu.researchsquare.com/files/rs-4677378/v1/d1e42ce7628afdec976e75a1.docx"},{"id":62155869,"identity":"76f1c288-ee41-40e9-89bd-3def48be148c","added_by":"auto","created_at":"2024-08-09 21:06:51","extension":"docx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":2414416,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSupplementary file 1b.\u003c/strong\u003e \u003cstrong\u003eEvidence for Key Question 1 on comparative effectiveness of screening strategies\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"SupplementaryFile1bKQ1comparativeeffectiveness.docx","url":"https://assets-eu.researchsquare.com/files/rs-4677378/v1/2659b3bb309d7fe9c6f8cec2.docx"},{"id":62155873,"identity":"3fe0b359-450d-4826-a877-534530bab92a","added_by":"auto","created_at":"2024-08-09 21:06:51","extension":"docx","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":263605,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSupplementary file 2. Evidence for Key Question 2 on comparative accuracy\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"Supplementaryfile2comparativeaccuracy.docx","url":"https://assets-eu.researchsquare.com/files/rs-4677378/v1/c5cc7e081bc3fbef309e511e.docx"},{"id":62155867,"identity":"6cbe685b-08e8-4543-9a55-66606de023ee","added_by":"auto","created_at":"2024-08-09 21:06:51","extension":"docx","order_by":5,"title":"","display":"","copyAsset":false,"role":"supplement","size":20990,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSupplementary file 3. Evidence for Key Question 3 on adverse pregnancy outcomes associated with conservative management of CIN\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"Supplementaryfile3treatmentharms.docx","url":"https://assets-eu.researchsquare.com/files/rs-4677378/v1/7234a21a83b3d1720d155ed3.docx"},{"id":62155872,"identity":"b711240e-0d34-4c73-8327-47cc5e504390","added_by":"auto","created_at":"2024-08-09 21:06:51","extension":"docx","order_by":6,"title":"","display":"","copyAsset":false,"role":"supplement","size":155458,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSupplementary file 4.\u003c/strong\u003e \u003cstrong\u003eEvidence for Key Question 4 on relative importance of the outcomes\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"Supplementaryfile4patientpreferences.docx","url":"https://assets-eu.researchsquare.com/files/rs-4677378/v1/1f3e06ce9964d127d6f52450.docx"},{"id":62157738,"identity":"8516a8fc-16fb-4195-9d53-6e6c3a017d6e","added_by":"auto","created_at":"2024-08-09 21:22:51","extension":"docx","order_by":7,"title":"","display":"","copyAsset":false,"role":"supplement","size":528576,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSupplementary file 5.\u003c/strong\u003e \u003cstrong\u003eEvidence for Key Question 5 on effectiveness of primary care-based interventions screening uptake of under/never screened individuals\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"SupplementaryFile5increasinguptake.docx","url":"https://assets-eu.researchsquare.com/files/rs-4677378/v1/9767fe799b98e595614503f1.docx"},{"id":62157737,"identity":"52bbc30d-4e1b-4494-a9a1-cd9755be0b68","added_by":"auto","created_at":"2024-08-09 21:22:51","extension":"docx","order_by":8,"title":"","display":"","copyAsset":false,"role":"supplement","size":109510,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSupplementary file i. Additional background and methods\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"Supplementaryfileiadditionalmethods.docx","url":"https://assets-eu.researchsquare.com/files/rs-4677378/v1/4be15bf1288d190793950ae3.docx"},{"id":62157064,"identity":"a485c5b7-a8ac-49bd-8351-a2ea94e4f4f4","added_by":"auto","created_at":"2024-08-09 21:14:51","extension":"xlsx","order_by":9,"title":"","display":"","copyAsset":false,"role":"supplement","size":201116,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSupplementary file ii. Excluded studies\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"SupplementaryfileiiExcludedstudies.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-4677378/v1/3286acf1882386dfe3840c28.xlsx"},{"id":62157062,"identity":"e23f7283-6642-4beb-8fe8-f533d56b53e1","added_by":"auto","created_at":"2024-08-09 21:14:51","extension":"docx","order_by":10,"title":"","display":"","copyAsset":false,"role":"supplement","size":75737,"visible":true,"origin":"","legend":"","description":"","filename":"Tables.docx","url":"https://assets-eu.researchsquare.com/files/rs-4677378/v1/a9989169c85e152f8c3a6991.docx"}],"financialInterests":"","formattedTitle":"Screening for the prevention and early detection of cervical cancer: systematic reviews to inform an update to recommendations by the Canadian Task Force on Preventive Health Care","fulltext":[{"header":"BACKGROUND","content":"\u003cdiv id=\"Sec2\" class=\"Section2\"\u003e \u003ch2\u003eBurden and natural history of disease\u003c/h2\u003e \u003cp\u003eIn 2023, cervical cancer was projected to be the 20th most commonly diagnosed cancer among Canadian females (based on sex assigned at birth) (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) (4th most common among 15\u0026ndash;44 year-olds), with an annual age-standardized incidence of 8 per 100,000 and a lifetime probability of 0.7%. Estimates of cervical cancer incidence among trans men and non-binary people assigned female at birth are lacking. The incidence rate of cervical cancer has been increasing by 3.7% each year since 2015, though its mortality rate has declined annually by 0.8% since 2006 (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). The median age at diagnosis of Canadians with cervical cancer is 47 years, with those at highest risk in their early forties (16.6 cases/100,000) (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). Data from 2017 show that most cervical cancers in Canada were diagnosed at an early stage of disease (Stage I, 54%) and at an average age of 45 years, while 10% were diagnosed with advanced (Stage IV) disease occurring more commonly in older individuals (57 years) (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). Five-year net survival from cervical cancer in Canada is about 74% (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) and is impacted by stage at diagnosis, with survival substantially improved in early stage disease (Stage I, 93% versus Stage IVA, 15%) (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003cp\u003ePersistent infection with human papillomavirus (HPV) is necessary but not sufficient for the development of cervical cancer (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). Other important co-factors include immunosuppression, smoking, and high parity/number of vaginal deliveries (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). HPV is a sexually transmitted and usually transient infection that is relatively common among sexually active individuals (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). Over their lifetime, most females (\u0026gt;\u0026thinsp;80%) and males (\u0026gt;\u0026thinsp;90%) will be infected with HPV, with the majority being infected before the age of 45 years (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). Among 200 known HPV types (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e), 12 (types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59) have been designated as high-risk (hrHPV) by the International Agency for Research on Cancer Working Group due to their strong oncogenic potential (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). In Canada, types 16 and 18 account for about 74% of cervical cancer cases (48% and 26%, respectively) (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). Among Canadian studies, prevalence rates for having any oncogenic HPV strain in unvaccinated females among general screening (i.e., not high-risk) populations ranged between 3% and 47% (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). Pooled rates for the three most common strains (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e and \u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e) were 8.6%, 3.3% and 2.5%, respectively. The highest rates of HPV infection of any type in Canada (\u0026gt;\u0026thinsp;20\u0026ndash;47%, across several age groups) were found among people living in Nunavut and among Inuit females. Approximately 90% of HPV infections resolve on their own within 2 years (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). Persistent infection, however, can result in slow and progressive changes to the cervix that may lead to the development of cancer over years (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eAs with HPV infection, if left untreated, many cervical lesions will regress or remain unchanged (\u003cb\u003eSupplemental file i\u003c/b\u003e contains different cytological reporting systems used to describe changes to cervical squamous cells identified during sampling). In individuals with moderate dysplasia or cervical intraepithelial neoplasia grade 2 (CIN 2) about 50% (95% CI, 43\u0026ndash;57%) of lesions regress to normal or to CIN 1 without treatment within two years; 18% (95% CI, 12\u0026ndash;39%) of lesions will progress to CIN 3 or to invasive cervical cancer (ICC); and 32% (95% CI, 23\u0026ndash;42%) of lesions will remain unchanged (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). Individuals identified with CIN 3 (corresponding to severe dysplasia), have a 25 to 30% risk of progression to ICC over a 30-year period (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). Based on data from HPV incidence and progression, about 1 in 200 unscreened individuals with a cervix may develop cervical cancer over a period of 30 years (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e) (\u003cb\u003eSupplemental file i\u003c/b\u003e).\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003ePrevention\u003c/h3\u003e\n\u003cp\u003eThe causal relationship between HPV infection and cervical cancer, along with the typically slow progression from HPV infection to pre-cancerous lesions to cancer and availability of effective treatment, make cervical cancer particularly amenable to prevention efforts like vaccination and/or screening. Two HPV vaccines are currently authorized for use in Canada; bivalent (Cervarix\u0026trade; or HPV2) and nine-valent (Gardasil 9\u0026reg; or HPV9) (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). All vaccines protect against HPV types 16 and 18 (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e) while the Gardasil 9\u0026reg; vaccine protects against seven additional oncogenic HPV types (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e, \u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e, and \u003cspan citationid=\"CR58\" class=\"CitationRef\"\u003e58\u003c/span\u003e). All Canadian jurisdictions have publicly funded school-based HPV vaccination programs, mostly for children in grades 6 or 7 (12 to 13 years) offered on a 2- or 3-dose schedule (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e). Programs for girls were mostly implemented in 2007 or 2008, whereas for boys the programs started in 2015\u0026ndash;2017; all programs currently offer Gardasil 9\u0026reg; with the exception of Quebec that also uses Cervarix. Available data on 2015\u0026ndash;2019 provincial/territorial coverage rates show that among girls, immunization uptake for the final dose ranges from 57\u0026ndash;91% with 9 of 11 province and territory rates exceeding 70%; among boys, the immunization uptake for the final dose ranges from 58\u0026ndash;91% (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e). Based on these numbers, in 2023 approximately 70% of 13 to 27-year-old females may be considered fully vaccinated. Substantial herd effects are expected from these immunization rates (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eScreening for cervical cancer can be done using cytology (i.e., cervical cells collected with a Papanicolaou [Pap] test) alone, high-risk HPV (hrHPV) testing alone, co-testing (simultaneous cytology and hrHPV testing), or triaging a positive result from an initial screening test to additional testing (i.e., cytology followed by triaging positive results to receive hrHPV testing, or hrHPV testing with triage to cytology). The term \u0026ldquo;primary\u0026rdquo; is often used to describe the first test but is also used when a test is used alone so we have avoided using this term and specify if the test was used alone or with triage in all cases. Unlike the Pap test, HPV samples can be self-collected, although concerns have been raised about the concordance between self- and clinician-collected samples (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e). When used alone HPV tests are more sensitive than cytology (i.e., identifying more cancers and fewer false negatives), but they may have lower specificity resulting in more false positive findings and potentially unnecessary follow-up interventions and treatments (e.g., colposcopies, biopsies) (\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e). A single sample taken by a clinician of the endocervix can be used for both Pap and HPV testing, whereas HPV tests do not require cells of the endocervix, so sampling, especially via self-sampling, may not obtain sufficient endocervical cells and thus not provide an adequate sample for cytology.\u003c/p\u003e \u003cp\u003eCurrently in Canada, screening for cervical cancer is mostly implemented through province-wide screening programs, with various recruitment methods including letters of invitation, recall lists sent to primary care providers, and telephone calls to eligible individuals (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e). Some provinces and the territories rely on opportunistic, rather than programmatic, approaches that may miss people not regularly seeking healthcare. Until recently, all screening relied on cytology for the first test with five provinces and two territories using triage to HPV testing for individuals (mostly for those\u0026thinsp;\u0026ge;\u0026thinsp;30 years) with an abnormal cytology result (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e). Several provinces and territories have plans to implement HPV as the first test (\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e) and in early 2024 British Columbia announced its new province-wide hrHPV self-screening option. In 2017, 74% of Canadian females aged 25 to 69 years reported receiving a Pap test in the past 3 years (\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e). However, certain populations (e.g., individuals in rural or remote communities, Indigenous populations, individuals with low socioeconomic status, new immigrants, and transgender persons) remain under-screened (\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e). To address disparities, several provinces have applied strategies to improve cervical cancer screening rates among under-screened populations. Strategies include incorporating culturally-appropriate screening approaches, providing education and support to health care providers, and trialing mobile testing units and mailed self-sampling HPV kits to homes (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e). In 2020, the World Health Assembly adopted the Global Strategy for Cervical Cancer Elimination worldwide (\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e), which Canada has committed to achieving. In collaboration with national stakeholders and experts, the Canadian Partnership Against Cancer has set goals in line with those of the World Health Organization to eliminate cervical cancer (i.e., age-standardized rate of \u0026lt;\u0026thinsp;4 per 100,000 vs. 2016 rate of 6.6 per 100,000) by 2040, using the aims of improving HPV immunization rates (90% of 17-year-olds fully vaccinated by 2025), implementing screening with HPV alone by 2030 (using oncogenic HPV 16/18 testing and offering self-sampling especially where there are access barriers), and improving follow-up of abnormal screening results (\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIndividual patients may make different choices for screening based on their unique values and preferences (\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e). Screening preferences are associated with the relative importance/value people place on expected or experienced outcomes (\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e). Preference data can be sought directly through comparing the disutilities of different health states, measured on scale of 0 (no disutility) to 1 (similar to death) and a value of about 0.04 is considered important among the Canadian public (\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e)). A utility measures the impact of the outcomes on one\u0026rsquo;s health-related quality of life and can be measured using generic multi-attribute utility instruments such as the EuroQoL 5-Dimensions (EQ-5D) or via direct choice-based utility elicitation methods such as standard gamble (SG) or time tradeoff (TTO) (i.e., determining what people would be willing to risk or give up to avoid living in that health state). Other preference-based data, such as trade-offs between outcomes, also directly capture preferences. Indirectly, the relative importance of benefits versus harms overall can be inferred from attitudes, intentions, and behaviors towards screening among informed patients provided with estimates of the magnitudes of benefit(s) and harm(s). Findings on outcome preferences can then be considered as patient input when balancing the effect estimates on benefits and harms reported by empirical evidence on the clinical effectiveness of screening programs.\u003c/p\u003e \u003cp\u003eDespite the anticipated benefits from cervical cancer screening, including reduced cancer incidence and mortality through the early detection and treatment of pre-cancerous lesions, potential harms exist, including physical or psychosocial consequences from repeated testing as well as frequent follow-up testing and invasive diagnostic procedures (e.g., biopsy, colposcopy), unnecessary treatment of false-positive results, and psychological harms associated with positive tests (\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e). As many pre-cancerous lesions would have never become clinically apparent and some unrecognized (thus untreated) cancers would not have led to morbidity or mortality over an individual\u0026rsquo;s lifetime, overdiagnosis of pre-cancerous (and to a smaller extent of cancerous lesions) is of concern for patients and providers. Overdiagnosis can lead to unnecessary testing and treatment and the harms associated with these procedures.\u003c/p\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003ePurpose of review\u003c/h2\u003e \u003cp\u003eIn 2013 the Canadian Task Force on Preventive Health Care (the task force) recommended that females aged 25 to 29 (weak recommendation) and 30 to 69 (strong recommendation) years be screened every 3 years with Pap testing; females aged 24 years and younger not be routinely screened (weak recommendation); and females aged 70 years or older, who have undergone adequate screening, not be screened (weak recommendation) (\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e). At the time of these recommendations, evidence to inform ages to start and stop screening, along with optimal screening intervals, was sparse and limited to epidemiologic data, particularly for females aged 25 to 29 and 70 or older. Further, these recommendations were limited to cytological screening for cervical cancer since the task force judged that there was insufficient evidence to make recommendations on the use of hrHPV testing. Since the 2013 Canadian guideline, international guidelines (including those for Australia, the United Kingdom, the Netherlands, and the United States) have provided recommendations for hrHPV testing alone or with triage to cytology (\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e, \u003cspan additionalcitationids=\"CR38\" citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e). Also, new studies have been published that are likely to improve our understanding of screening in primary care settings for cervical cancer. Thus, we undertook several systematic reviews to inform an update of the 2013 task force guideline with a focus on the effectiveness (benefits and harms) and comparative effectiveness of various cervical cancer screening strategies; the comparative accuracy of various screening tests or strategies (e.g., cytology versus HPV, single test versus adding triages); values and preferences for potential outcomes from cervical cancer screening; and the effectiveness of interventions aimed at improving screening uptake rates in under-screened and never-screened individuals.\u003c/p\u003e \u003c/div\u003e"},{"header":"METHODS","content":"\u003cp\u003eThis review was undertaken on behalf of the task force following a pre-defined peer- and stakeholder (n\u0026thinsp;=\u0026thinsp;17) reviewed protocol (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e) and is reported in accordance with current standards (\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e). During protocol development, a working group was formed consisting of task force members, with input from clinical experts and scientific support from the Global Health and Guidelines Division at the Public Health Agency of Canada (see Acknowledgements). The working group contributed to the development of the key questions (KQs) and PICOTS (population, intervention(s) or exposure(s), comparator (s), outcomes, timing, setting, and study design) elements. Task force members made the final decisions with regard to the KQs and PICOTS. The task force and organizational stakeholders (n\u0026thinsp;=\u0026thinsp;x [currently underway]) reviewed a draft of this manuscript, and all comments were taken into consideration. The protocol has details for all methods, and we focus here on key processes and any changes from the protocol.\u003c/p\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eKey Questions\u003c/h2\u003e \u003cp\u003eThe task force determined the following KQs to be of interest:\u003c/p\u003e \u003cp\u003e \u003cstrong\u003eKQ 1\u003c/strong\u003e \u003cp\u003eWhat are the effectiveness (benefits and harms) and comparative effectiveness of different screening strategies for cervical cancer?\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eKQ 1a\u003c/strong\u003e \u003cp\u003eDo the effectiveness and comparative effectiveness of different screening strategies for cervical cancer screening differ by age or by other population subgroups?\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eKQ 2\u003c/strong\u003e \u003cp\u003eWhat is the comparative accuracy of screening tests for cervical cancer?\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eKQ 2a\u003c/strong\u003e \u003cp\u003eDoes the comparative accuracy of screening tests differ by age or by HPV vaccination status?\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eKQ 3\u003c/strong\u003e \u003cp\u003eWhat are the adverse pregnancy outcomes associated with conservative management of CIN?\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eKQ 4\u003c/strong\u003e \u003cp\u003eWhat is the relative importance individuals place on the potential outcomes from screening for cervical cancer?\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eKQ 5\u003c/strong\u003e \u003cp\u003eWhat is the effectiveness of primary care-based interventions to increase rates of cervical cancer screening for under- and never screened individuals?\u003c/p\u003e \u003c/p\u003e \u003cp\u003eThe main purpose for KQs 2 and 3 was to fill in gaps for outcomes (false-positive results in KQ2 and treatment harms in KQ3) not reported by the studies eligible for KQ1. KQ2 evidence may also provide information about the comparative accuracy of screening strategies using cytology and/or HPV tests not studied in KQ1 to help determine if these may be appropriate to use in practice in the absence of KQ1 evidence (e.g., very similar sensitivity and specificity).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eEligibility Criteria\u003c/h2\u003e \u003cp\u003e\u003cb\u003eTable\u0026nbsp;1\u003c/b\u003e shows the final PICOTS elements for KQs 1, 2, 4, and 5. For KQ3 the review team relied on two high-quality Cochrane reviews as described in the protocol (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eKey questions 1 and 2\u003c/h2\u003e \u003cp\u003eThe population of interest for KQs 1 and 2 were individuals with a cervix who were 15 years or older who have been sexually active, and have no symptoms of cervical cancer. We were also interested in findings by age group and among specific populations (KQs 1a and 2a); the working group amended the protocol to add interest in subgroups of individuals with differing screening results in their 50s or 60s, for studies reporting effects of those in their 60s or 70s. Interventions of interest for KQ1 were any screening strategy using hrHPV or cytology with subsequent follow-up of abnormal tests, except for co-testing of all participants with both HPV and cytology, which was not considered cost-effective by the working group as well as other stakeholders in Canada (\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e) and is not currently under consideration in Canada (\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e). KQ2 exposures included hrHPV testing with HPV nucleic acid tests alone, or hrHPV testing with HPV nucleic acid tests followed by some form of triage either with cytology or another hrHPV test. After the protocol was developed, we added exposure to cytology with triage to hrHPV or to partial genotyping hrHPV as eligible for KQ2 because these strategies are currently being used in some provinces (e.g., Quebec, New Brunswick and Alberta) (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eComparisons of interest for KQ1 were no routine screening (effectiveness) and any screening strategy that differed by one or more of the following (comparative effectiveness): screening test strategy, screening interval (i.e., 3 vs. 5 years), universal versus targeted screening, method of sample collection, or follow up protocol for abnormal screening results. For KQ2, comparisons were cytology, alone or with triage to hrHPV testing, hrHPV testing followed by different forms of triage, and hrHPV testing using different methods of sample collection. \u003cb\u003eTable\u0026nbsp;1\u003c/b\u003e lists exclusion criteria for both KQs, which included urine and point-of-care tests. The reference standard for KQ2 was colposcopy with histological inspection of cervical tissue applied to all patients or all screen-test positive patients and a subset (e.g., random 10%) of screen-negative patients.\u003c/p\u003e \u003cp\u003eFor each comparison in KQ1, randomized controlled trials (RCTs) were prioritized, with nonrandomized studies only included where RCTs were lacking. After initial study selection identified dozens of observational (KQ1 for cytology versus no screening, where no eligible RCTs were identified) and accuracy studies (KQ2) reporting on comparisons considered of little interest to Canadian decision making (e.g., age groups within middle age, hrHPV versus cytology plus repeat cytology triage, hrHPV with partial genotyping [types 16/18] versus hrHPV with partial genotyping [type 16]), the task force working group members provided input to focus the evidence for these KQs. For the effectiveness portion of KQ1 (cytology vs. no routine screening), a decision was made to focus on studies helping to inform KQ1a, more specifically on ages to begin (20 vs. 25 vs. 30 years) and stop (60 vs. \u0026ge;70 years) screening. Further, for the comparative effects of different screening strategies in KQ1 the focus for the observational evidence was changed to only compare screening intervals. The revisions also limited data to outcomes rated critical by the task force (see next paragraph). The review team charted out all possible comparisons reported in the eligible KQ2 studies (n\u0026thinsp;=\u0026thinsp;32) and used working group input again to focus the eligibility. As a result, comparisons that were examined in RCTs for KQ1 and reported on false positives were not examined further in KQ2, with the exception of subgroup data based on age.\u003c/p\u003e \u003cp\u003eBefore reviewing any data, task force members and clinical experts determined the importance placed on proposed outcomes for the guideline by rating their value for clinical decision-making according to methods of Grading of Recommendations Assessment, Development and Evaluation (GRADE) (\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e). Critical outcomes (rated at 7 or above on 9-point scale) pertaining to the effectiveness and comparative effectiveness of screening included: incidence of ICC, cervical cancer mortality, all-cause mortality, incidence of CIN 2 and CIN 3, and overdiagnosis of CIN 2, CIN 3, and ICC. We defined incidence as the documentation of a cervical abnormality (CIN and ICC) during follow-up (e.g., cancer registries and testing in a subsequent round) that was not detected in the previous round. Ideally, all people that did not have the outcome of interest at the previous round would be followed for the outcome, though we included data from study samples where there was exclusion of those with abnormal results (e.g., CIN 1 and/or 2) from follow-up. Lesions detected during a subsequent round that we have defined as \u0026ldquo;incident\u0026rdquo; could include false-negative screens from the previous screening round. Final important outcomes (rated 4\u0026ndash;6) for inclusion were: the number and rate of colposcopies and biopsies (or referral rates), adverse pregnancy-related outcomes from conservative management of CIN, and the false-positives for detecting CIN 2, CIN 3, and ICC. We considered false-positives to be the proportion of those screened where the cervical screening test was positive (according to the screening strategy used in the individual studies, recognizing that definitions of test positivity differ across studies) and led to diagnostic follow-up testing (i.e., colposcopy with or without biopsy), but were not confirmed as CIN 2, CIN 3, or more severe disease. The protocol was amended to add a false positive outcome related to those referred to either diagnostic follow-up testing (colposcopy) or to further (\u0026ldquo;recall\u0026rdquo;/\u0026rdquo;intensive\u0026rdquo;) screening within the same round of screening. Further, given the scarcity of data for incidence of CIN 3 and ICC, the task force decided to consider detection rates of CIN 2/2\u0026thinsp;+\u0026thinsp;and CIN 3/3\u0026thinsp;+\u0026thinsp;during screening as surrogates (indirect outcomes/markers) for incidence of CIN 3/3\u0026thinsp;+\u0026thinsp;and ICC, respectively. The classification of each outcome as a benefit or harm was considered after evaluating the evidence, based on the direction of effect and considering the selected thresholds (see section \u003cspan refid=\"Sec19\" class=\"InternalRef\"\u003eAssessing Certainty in the Body of Evidence\u003c/span\u003e). KQ2 focused on measures of diagnostic test accuracy (e.g., number of false positives, and sensitivity and specificity for detecting high-grade cervical lesions or cervical cancer).\u003c/p\u003e \u003cp\u003eFor KQs 1 and 2, studies had to be published on or after 1995, in English or French, and undertaken in Very High Human Development Index Countries (\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eKey question 4\u003c/h2\u003e \u003cp\u003eKQ4 synthesized evidence of the relative importance that individuals place on the outcomes from cervical cancer screening (\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e, \u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e), including all critical and important outcomes defined for KQ 1 (\u003cb\u003eTable\u0026nbsp;1\u003c/b\u003e). This KQ included patients and individuals from the general public age 15 years or older with a cervix, or who have had their cervix removed as part of treatment for cervical cancer. Included exposures were experience with an outcome (\u0026ldquo;heath state\u0026rdquo;) related to screening or exposure to clinical scenarios or information about outcomes and/or estimates of effect on outcome risks from screening. In the absence of participants having experience or exposure to scenarios, authors could solicit probability trade-offs or ratings of different outcomes. Comparators were different critical outcomes or groups of outcomes (benefits vs. harms), healthy state without the outcome or no comparison (if reporting health-state utilities), and no or another intervention (e.g., no screening, another screening strategy). Outcomes and study designs for KQ4 were included in a hierarchal manner where we would use qualitative study findings only in the absence of quantitative measures (i.e., health-state utilities [valuation of the impact of the health state on one\u0026rsquo;s health-related quality of life using a scale of 0 (death) to 1 (perfect health)], ratings/rankings, acceptability of screening based on information on the magnitude of benefits and risks).\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eKey question 5\u003c/h3\u003e\n\u003cp\u003eKQ5 focused on interventions for improving screening rates in under-or never-screened persons with a cervix (i.e., individuals who would meet the criteria for cervical cancer screening but who had never attended or who were considered under-screened, as defined by study authors). Moreover, we pre-specified four priority populations of interest; Indigenous peoples, immigrants, rural communities, and those with low socioeconomic status. We included any intervention amenable to a primary care setting that targeted individuals or primary care providers to increase uptake of screening (e.g., reminders, education, counselling), including mail-out or opt-in HPV self-sampling. RCTs were prioritized over nonrandomized studies.\u003c/p\u003e \u003cp\u003eFor KQs 4 and 5, to include studies that reflect current preferences, practices and outreach strategies, studies had to be published in 2000 or later, in English or French, and undertaken in Very High Human Development Index Countries (\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e).\u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eLiterature Search and Study Selection\u003c/h2\u003e \u003cp\u003eDetails of the search approaches are included in \u003cb\u003eTable\u0026nbsp;1\u003c/b\u003e. During protocol development, our research librarian undertook a comprehensive search for relevant systematic reviews, published between 2014 and March 2019, to identify reviews that may be eligible for using \u003cem\u003eas is\u003c/em\u003e (i.e., no changes to methods apart from possible contextualization to Canada for assessment of evidence certainty or otherwise), updating (i.e., adding more recent studies but otherwise following the authors\u0026rsquo; methodology), or integrating (i.e., used for locating primary studies to a particular date with a search update and otherwise use of de novo methods). This process identified two reviews for use as is for KQ3 (\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e, \u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e) and three reviews to integrate into KQs 2 (with a search date of 2016) and 5 (search dates of 2008)(\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e, \u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e). Initial contact with the authors of the reviews for KQ3 indicated that these reviews were planned to be updated by the completion of our reviews. No reviews were eligible for use or integration for KQs 1 and 4. We did not update searches from the review informing the 2013 task force guideline because that review did not include the incidence of CIN as an outcome and thus we may have missed studies. The searches (see \u003cb\u003eSupplemental file i\u003c/b\u003e) were developed and finalized by our research librarian after peer review, and initially run on August 5-6th, 2020. We later updated the searches for KQ1 (September 18, 2023) and KQ4 (October 23, 2023); we did not update searches for KQs 2 or 5 because (for KQ2) the evidence was not anticipated to weigh into the recommendations very much and (for KQ5) because we had moderate or high certainty of the evidence which was not anticipated to change by adding more studies.\u003c/p\u003e \u003cp\u003e Following pre-specified criteria, two reviewers independently screened studies for eligibility in two stages; by title and abstract using DistillerSR (Evidence Partners, Ottawa, Canada) followed by full text review of records marked as \u0026ldquo;include\u0026rdquo; or \u0026ldquo;unsure\u0026rdquo; by either reviewer during title/abstract screening. Excluded records were screened by a second reviewer to confirm exclusion. Studies were included at the full text level if independent reviewers agreed on inclusion, with arbitration by a third reviewer as needed. Reasons for exclusion at full text were recorded and are reported in the \u003cb\u003eSupplemental file ii\u003c/b\u003e.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eData Extraction and Analysis\u003c/h2\u003e \u003cp\u003eOne reviewer extracted data for each KQ into standard forms in Excel v. 2016 (Microsoft Corporation, Redmond, Washington) using pre-defined items (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). A second reviewer verified extracted data for accuracy and completeness, except for outcome data for KQ1 that were extracted in duplicate by two reviewers, and disagreements were resolved by consensus or a third reviewer. As described above, we charted major study characteristics, but not results, of nonrandomized studies for KQ1 and all studies in KQ2 to allow for further input on eligibility from the task force. Though we had anticipated the possibility of building efficiencies by using data extracted by other review authors, we ended up doing all data extraction anew.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eKey question 1: Effectiveness and comparative effectiveness\u003c/h2\u003e \u003cp\u003eThe measure of effect was the relative risk (RR) or odds ratio (OR) with 95% confidence intervals (CIs); ORs were used for observational studies to allow for use of reported adjusted ORs reported in case-control studies) and Peto ORs were used for trial data on effectiveness because of the relatively rare events. These were calculated in Review Manager version 5.3 (The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, Denmark) from crude events reported in the studies, unless adjusted estimates (as preferred) were reported in nonrandomized studies. For RCTs, we had planned to use an intention-to-screen analysis whereby the analysis included all individuals randomized, but in several RCTs people were randomized before their eligibility was assessed or they consented, and there was no attempt to collect data on the number randomized. Instead, we used the number enrolled in the study, which was in most cases those who undertook screening (not a true ITT).\u003c/p\u003e \u003cp\u003eWhere appropriate, we pooled studies reporting on similar outcome-comparisons using suitable random effect models. For observational data, we pooled using the inverse variance approach to enable incorporation of adjusted ORs. Data from RCTs and controlled clinical trials were pooled separately from observational studies, and cohort studies separately from case-control studies.\u003c/p\u003e \u003cp\u003eFor KQ1a, screening ages were categorized into 5-year age groups for individuals under 35 years of age for age to start screening and 10-year age categories from 60 years and older for age to stop screening. For case-control studies, screening age was estimated from age of diagnosis and interval since last screen (e.g., 3 or 5 years or pre-invasive period [as defined by studies]). Age to start and stop screening compared screening within an age group with no screening. As per clinical expert input, if studies included participants who had undergone screening 5 or more years before the index date for the study, these individuals were included within the no screening group for our analysis. We included data from studies when the age categories were similar but not identical to ours (i.e., the age range in a study could be wider than ours). In these cases, standard errors from individual studies were weighted to adjust confidence intervals to approximate the proportion of participant data that was relevant to the age category of interest. Weighting was applied to data from studies that included participants with more than 1 year outside of an age category of interest. For this analysis, assumptions were made that screened participants and effects were equally distributed across the age range of the study sample. Some studies were more dramatically out of the age category of interest when using 5-year age groups versus the 10-year categories. We rated down for indirectness when grading this evidence if a majority of studies required weighting.\u003c/p\u003e \u003cp\u003eScreening interval data focused on comparing screening intervals of 3 and 5 years (or similar) across all available age groups in a study. When possible, we calculated the ORs for comparing 3-yearly screening with 5-yearly screening as the reference. However, in studies where the reference was no screening and we were not able to adjust the reference to 5-yearly screening, we calculated the ratio of 3-yearly screening versus no screening and 5-yearly screening versus no screening and entered that ratio into our analysis.\u003c/p\u003e \u003cp\u003eFor all analyses on the comparative effectiveness of screening, we conducted stratified analyses using within-study data by age categories (20\u0026ndash;24/25\u0026ndash;29/30\u0026ndash;59/60\u0026ndash;69/70\u0026ndash;79 years), and (for screening intervals) between studies based on whether the country/region used opportunistic or programmatic screening.\u003c/p\u003e \u003cp\u003eFor overdiagnosis, we relied on authors\u0026rsquo; calculations and synthesized the data descriptively.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eKey question 2: Comparative accuracy\u003c/h2\u003e \u003cp\u003eWe populated 2 x 2 tables with the true positives, false positives, true negatives and false negatives for each screening test used in each study, as well as reported sensitivities and specificities. We considered pooling, as described in the protocol, but no comparison had more than three studies. Instead, we compared and contrasted study findings, relying mostly on the largest and best conducted studies (\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e), to judge whether (for specificity and sensitivity) the strategies differed (and in what direction), or (for false positives) whether the difference exceeded a threshold of 3% (300 per 10,000) as determined to be of minimal importance by input from the working group (see below and \u003cb\u003eSupplement i\u003c/b\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eKey question 4: Relative importance of potential outcomes from screening\u003c/h2\u003e \u003cp\u003eWe focused on data providing the disutility (i.e., impact on one\u0026rsquo;s health-related quality of life) of each health state. Disutility is the difference/reduction between the utility/value of being in an \u0026lsquo;average/healthy\u0026rsquo; general population (eligible for cervical cancer screening) and that from having each of the relevant health states (e.g., utility of general population minus utility of cervical cancer\u0026thinsp;=\u0026thinsp;disutility from cervical cancer). When studies had data for a population we considered reasonably applicable to the general population (e.g., control group, group receiving negative results from smears), we used the data and considered this a direct measure for calculating the disutility of the other health state(s) reported by the study. For studies that did not have a relevant comparison group, we used a weighted estimate from data in other studies for the utility of the general population; the calculated disutility in these cases is considered indirect because of the use of between-study information. When comparing this weighted average of the general population utility score when using the EQ-5D within the included studies, we obtained very similar findings to the Alberta Population Norms (\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eData from use of the EQ-5D index measure was the focus (\u0026lsquo;primary analysis\u0026rsquo;) since it was the most commonly reported measure, had the most data in comparison with a general population comparison, and is a commonly used tool in the health economic literature. This measure was used to provide the best estimates of the disutility of each health state. For our outcomes about the rank-order/relative importance across the different health states (e.g., CIN 2 vs. ICC), we used these EQ-5D disutilities together with those estimated from the other measurement tools (e.g., time trade off [TTO], standard gamble [SG]) based on the assumption that without the health state the utility is 1 (perfect health).\u003c/p\u003e \u003cp\u003eFor studies not reporting on health-state utilities, we undertook a narrative synthesis given the likely heterogeneity in study designs, exposures, comparisons, and outcomes reported across studies (\u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003eKey question 5: Effectiveness and comparative effectiveness of interventions to increase screening rates\u003c/h2\u003e \u003cp\u003eAfter charting the study characteristics, we grouped interventions into five categories: written contact, personal contact, composite interventions (generally written and personal contact), universal mail-out HPV self-samples, and opt-in HPV self-samples (participants need to request the sample kit). The measure of effect was the RR with 95% CIs, calculated in Review Manager version 5.3 (The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, Denmark) from raw data reported in the studies. Data were pooled using a Dersimonian Laird random effects model (\u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e). Aside from pre-specified populations of interest (Indigenous peoples, immigrant groups, rural populations, low socioeconomic status populations), our charting identified multiple additional variables that differed across studies and may have contributed to heterogeneity in magnitude of effect and thus led to specific sub-group analyses: follow-up duration (\u0026lt;\u0026thinsp;6 months vs. \u0026ge; 6 months), under-screened definition (\u0026lt;\u0026thinsp;3 years vs. \u0026gt;3 years), setting (organized [i.e., health system-based reminders] or opportunistic [i.e., during visits with clinicians]), intervention intensity (varied by comparison), and risk of bias rating (high vs. low or unclear).\u003c/p\u003e \u003cp\u003e We included all participants randomized in the denominator for analyses for all included studies, even though this number in some cases included people who were not eligible upon closer examination. For trials that included multiple intervention arms or multiple eligible control groups for one of our analyses, we divided the arms to avoid double-counting in analysis (\u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e). Cluster trial data were adjusted to ensure comparability with parallel trial data using an intra-cluster correlation coefficient from a representative trial (\u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e) and calculating a design effect that was then applied to both the sample size and the number of events in each of the treatment and control groups (\u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e). The pooled RR for each outcome-comparison was transformed to an absolute risk difference (ARD) by multiplying the RR with the median control event rate (\u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e57\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003eDealing with Missing Data and Assessment of Reporting Biases\u003c/h2\u003e \u003cp\u003eWe used all available information (i.e., associated publications, protocols) we could locate to collect data for each study. When the individual studies did not report data required for synthesis, we contacted the corresponding author via e-mail to inquire about the availability of the data. We contacted authors twice, two weeks apart, before ceasing attempted contact if we did not receive a response. For KQ4, if studies were missing a measure of variance, we used the variance from a comparator within the study; if no variance was reported within the study we used the largest measure of variance in studies using the same utility instrument to evaluate the same health state (eligible for pooling with the study). We attempted to limit missing studies by employing comprehensive searches (including grey literature) and by contacting authors for reports of unpublished studies. When meta-analyses of trials contained at least eight studies of varying size, we tested for small study bias visually by inspecting funnel plots for asymmetry and statistically via the Egger\u0026rsquo;s test (\u003cspan citationid=\"CR58\" class=\"CitationRef\"\u003e58\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec18\" class=\"Section2\"\u003e \u003ch2\u003eRisk of Bias Assessments\u003c/h2\u003e \u003cp\u003eTwo reviewers independently assessed risk of bias for each included study and reached consensus. This was done at the outcome level, where risk of bias could differ by outcome. If consensus could not be reached, a third reviewer provided arbitration. Standardized study design-specific tools were used to assess risk of bias for each included study. Trials, diagnostic accuracy studies, clinical utility/preference-based, and cohort and case-control studies were rated with the Cochrane ROB tool (version 2011), QUADAS-C tool, GRADE guidance, and Newcastle-Ottawa Scale, respectively (\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e, \u003cspan additionalcitationids=\"CR60\" citationid=\"CR59\" class=\"CitationRef\"\u003e59\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR61\" class=\"CitationRef\"\u003e61\u003c/span\u003e). In KQ1, for non- and quasi-randomized trials and for RCTs where people were randomized before their eligibility was assessed and less than 90% of those randomized were enrolled in the study, we considered random sequence generation to be at unclear (vs. high) risk of bias if there was demonstration of similarity between arms in enrollment rates and several baseline characteristics; otherwise this domain was rated as having high risk of bias. Risk of bias assessments contributed to grading the certainty of the evidence across studies for each KQ and outcome.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec19\" class=\"Section2\"\u003e \u003ch2\u003eAssessing Certainty in the Body of Evidence\u003c/h2\u003e \u003cp\u003eWe used GRADE methods (\u003cspan citationid=\"CR62\" class=\"CitationRef\"\u003e62\u003c/span\u003e) to assess the certainty of evidence for all outcomes. For KQ3, where we used existing systematic reviews (\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e, \u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e), we reviewed the rationale for the certainty of evidence appraisals and undertook amendments as suitable. In cases where studies of interventions or accuracy could not be pooled in meta-analysis, we used GRADE guidance for rating the certainty of evidence in the absence of a single estimate of effect (\u003cspan citationid=\"CR63\" class=\"CitationRef\"\u003e63\u003c/span\u003e). Two reviewers independently assessed the certainty of evidence for each outcome and agreed on the final assessments. A third reviewer arbitrated as needed.\u003c/p\u003e \u003cp\u003eThe certainty of the evidence (very low, low, moderate, or high) was usually based on five considerations: study limitations (risk of bias), inconsistency of results (or lack of consistency if only a single study was available or contributed a large majority of the data), indirectness of evidence (e.g., use of detection outcomes for assessing incidence), imprecision, and publication (small study) bias (\u003cspan additionalcitationids=\"CR65 CR66 CR67 CR68\" citationid=\"CR64\" class=\"CitationRef\"\u003e64\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR69\" class=\"CitationRef\"\u003e69\u003c/span\u003e). For KQs of intervention effects (KQs 1 and 5), findings from controlled trials began at high certainty (\u003cspan citationid=\"CR70\" class=\"CitationRef\"\u003e70\u003c/span\u003e), whereas observational studies began at low certainty with the added possibility for upgrading (e.g., for large effects) (\u003cspan citationid=\"CR71\" class=\"CitationRef\"\u003e71\u003c/span\u003e). For KQ2 on diagnostic accuracy and KQ4 on patient preferences, all studies began at high certainty because we chose as eligible the most suitable study designs for these questions (\u003cspan citationid=\"CR72\" class=\"CitationRef\"\u003e72\u003c/span\u003e, \u003cspan citationid=\"CR73\" class=\"CitationRef\"\u003e73\u003c/span\u003e). For KQ4, we adhered to GRADE methods for assessing the certainty of evidence in the importance of outcomes or values and preferences (\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e, \u003cspan citationid=\"CR74\" class=\"CitationRef\"\u003e74\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eFor the main outcomes reported in the trials for KQ1 on the comparative effectiveness (also for application to false positives in KQ2), and with the working group blinded to results of each analysis, thresholds were created for what (using point estimates) would be considered to mean \u003cem\u003elittle-to-no difference\u003c/em\u003e, to obtain a target for our certainty assessments (\u003cspan citationid=\"CR75\" class=\"CitationRef\"\u003e75\u003c/span\u003e). Using data on the natural progression of cervical lesions, survival rates for ICC, assumptions that results from single rounds of screening could be additive across at least 3\u0026ndash;4 rounds at the population level, and a desired effectiveness of a 20% reduction in ICC (i.e., reducing cumulative incidence over many years from 5 per 1,000 to 4 per 1,000), the following thresholds for a single round of screening were decided based on consensus: false positives and related outcomes (e.g., referrals for colposcopy, biopsies): 3% (300 fewer/more per 10,000 screened); CIN 2/2+ (incidence or detection): 1% (100 fewer per 10,000 screened); CIN 3/3+ (incidence or detection): 0.1% (10 fewer per 10,000 screened); ICC (incidence or detection): 0.03% (3 fewer per 10,000 screened); mortality: 0.02% (2 fewer per 10,000 screened). There was no reliance on statistical significance when making conclusions. When interpreting our assessments, they relate to whether the effects met or exceeded the threshold but not whether we have the same certainty in the point estimate. \u003cb\u003eSupplemental file i\u003c/b\u003e has more details about our certainty assessments.\u003c/p\u003e \u003cp\u003eWe adopted standard GRADE wording to describe our findings, using the word \u0026lsquo;may\u0026rsquo; together with the direction of effect to describe findings of low certainty; \u0026lsquo;probably\u0026rsquo; for those of moderate certainty, and \u0026lsquo;is\u0026rsquo; for high certainty (\u003cspan citationid=\"CR76\" class=\"CitationRef\"\u003e76\u003c/span\u003e). When our certainty in the evidence was very low, we describe the evidence only as \u0026lsquo;very uncertain\u0026rsquo; without any associated direction or data.\u003c/p\u003e \u003c/div\u003e"},{"header":"RESULTS","content":"\u003cp\u003e \u003cb\u003eFigure 1\u003c/b\u003e describes the flow of literature. 27,848 unique citations underwent title/abstract screening, and 1,799 underwent full-text review, after which we included 112 studies reported in 121 papers across KQs 1, 2, 4 and 5. Citations excluded at full-text review, with reasons, are included in \u003cb\u003eSupplemental file ii\u003c/b\u003e.\u003c/p\u003e \u003cdiv id=\"Sec21\" class=\"Section2\"\u003e \u003ch2\u003eKey Question 1 and 1a: Effectiveness and Comparative Effectiveness\u003c/h2\u003e \u003cp\u003eNo RCTs comparing screening versus no screening were eligible for this review. The review conducted for the previous task force guideline included one RCT from India (\u003cspan citationid=\"CR77\" class=\"CitationRef\"\u003e77\u003c/span\u003e), which compared cytology versus no screening, but this was no longer eligible in view of the new criterion of only including studies from countries with a Very High Development Index.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec22\" class=\"Section2\"\u003e \u003ch2\u003eAges to start and stop screening and use of 3- versus 5-year intervals\u003c/h2\u003e \u003cdiv id=\"Sec23\" class=\"Section3\"\u003e \u003ch2\u003eStudy characteristics\u003c/h2\u003e \u003cp\u003eTwenty-two observational studies, reported in 24 papers, informed the effectiveness of cytology screening and comparative effects of 3- versus 5-yearly cytology screening intervals (\u003cb\u003eSupplemental file 1a\u003c/b\u003e has study characteristics, risk of bias assessments and all evidence sets). Some studies were used for both questions. There were no studies focusing on hrHPV screening. The associated publications included populations that overlapped substantially with the primary publication but either focused on a different outcome (\u003cspan citationid=\"CR78\" class=\"CitationRef\"\u003e78\u003c/span\u003e, \u003cspan citationid=\"CR79\" class=\"CitationRef\"\u003e79\u003c/span\u003e) or contained data on age subgroups for comparing intervals (but with a smaller sample than the primary paper reporting across all ages) (\u003cspan citationid=\"CR80\" class=\"CitationRef\"\u003e80\u003c/span\u003e, \u003cspan citationid=\"CR81\" class=\"CitationRef\"\u003e81\u003c/span\u003e). In one case, two studies by the same authors were considered different studies because, though there was some overlap in populations, the studies were used for different comparisons (screening interval (\u003cspan citationid=\"CR82\" class=\"CitationRef\"\u003e82\u003c/span\u003e) and age to stop (\u003cspan citationid=\"CR83\" class=\"CitationRef\"\u003e83\u003c/span\u003e)). We included seven studies in eight publications (\u003cspan citationid=\"CR78\" class=\"CitationRef\"\u003e78\u003c/span\u003e, \u003cspan citationid=\"CR79\" class=\"CitationRef\"\u003e79\u003c/span\u003e, \u003cspan additionalcitationids=\"CR85 CR86 CR87 CR88\" citationid=\"CR84\" class=\"CitationRef\"\u003e84\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR89\" class=\"CitationRef\"\u003e89\u003c/span\u003e) to inform age to start screening, 10 studies in 11 publications that addressed age to stop screening (\u003cspan citationid=\"CR79\" class=\"CitationRef\"\u003e79\u003c/span\u003e, \u003cspan additionalcitationids=\"CR83 CR84 CR85\" citationid=\"CR82\" class=\"CitationRef\"\u003e82\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR86\" class=\"CitationRef\"\u003e86\u003c/span\u003e, \u003cspan additionalcitationids=\"CR91 CR92 CR93 CR94\" citationid=\"CR90\" class=\"CitationRef\"\u003e90\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR95\" class=\"CitationRef\"\u003e95\u003c/span\u003e), and 10 studies in 12 publications on screening at different intervals (\u003cspan additionalcitationids=\"CR79\" citationid=\"CR78\" class=\"CitationRef\"\u003e78\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR80\" class=\"CitationRef\"\u003e80\u003c/span\u003e, \u003cspan citationid=\"CR82\" class=\"CitationRef\"\u003e82\u003c/span\u003e, \u003cspan citationid=\"CR84\" class=\"CitationRef\"\u003e84\u003c/span\u003e, \u003cspan additionalcitationids=\"CR97 CR98 CR99 CR100 CR101\" citationid=\"CR96\" class=\"CitationRef\"\u003e96\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR102\" class=\"CitationRef\"\u003e102\u003c/span\u003e). Studies were typically done in Europe and North America with a single study conducted in Japan (\u003cspan citationid=\"CR103\" class=\"CitationRef\"\u003e103\u003c/span\u003e). In nine studies (10 publications), screening was undertaken within an organized program (\u003cspan additionalcitationids=\"CR81 CR82\" citationid=\"CR80\" class=\"CitationRef\"\u003e80\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR83\" class=\"CitationRef\"\u003e83\u003c/span\u003e, \u003cspan citationid=\"CR86\" class=\"CitationRef\"\u003e86\u003c/span\u003e, \u003cspan citationid=\"CR88\" class=\"CitationRef\"\u003e88\u003c/span\u003e, \u003cspan citationid=\"CR89\" class=\"CitationRef\"\u003e89\u003c/span\u003e, \u003cspan citationid=\"CR100\" class=\"CitationRef\"\u003e100\u003c/span\u003e, \u003cspan additionalcitationids=\"CR104\" citationid=\"CR103\" class=\"CitationRef\"\u003e103\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR105\" class=\"CitationRef\"\u003e105\u003c/span\u003e); seven studies relied on opportunistic screening (\u003cspan citationid=\"CR78\" class=\"CitationRef\"\u003e78\u003c/span\u003e, \u003cspan citationid=\"CR79\" class=\"CitationRef\"\u003e79\u003c/span\u003e, \u003cspan citationid=\"CR85\" class=\"CitationRef\"\u003e85\u003c/span\u003e, \u003cspan citationid=\"CR92\" class=\"CitationRef\"\u003e92\u003c/span\u003e, \u003cspan citationid=\"CR95\" class=\"CitationRef\"\u003e95\u003c/span\u003e, \u003cspan citationid=\"CR97\" class=\"CitationRef\"\u003e97\u003c/span\u003e, \u003cspan citationid=\"CR99\" class=\"CitationRef\"\u003e99\u003c/span\u003e); and the remainder had organized screening running parallel to opportunistic screening (\u003cspan citationid=\"CR84\" class=\"CitationRef\"\u003e84\u003c/span\u003e, \u003cspan citationid=\"CR87\" class=\"CitationRef\"\u003e87\u003c/span\u003e, \u003cspan citationid=\"CR90\" class=\"CitationRef\"\u003e90\u003c/span\u003e, \u003cspan citationid=\"CR91\" class=\"CitationRef\"\u003e91\u003c/span\u003e, \u003cspan citationid=\"CR93\" class=\"CitationRef\"\u003e93\u003c/span\u003e, \u003cspan citationid=\"CR94\" class=\"CitationRef\"\u003e94\u003c/span\u003e). Sixteen studies (18 publications) used a case-control design with a median of 790 cases of ICC (range number of cases 39 to 5,047) (\u003cspan additionalcitationids=\"CR79 CR80 CR81 CR82 CR83 CR84\" citationid=\"CR78\" class=\"CitationRef\"\u003e78\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR85\" class=\"CitationRef\"\u003e85\u003c/span\u003e, \u003cspan citationid=\"CR87\" class=\"CitationRef\"\u003e87\u003c/span\u003e, \u003cspan citationid=\"CR88\" class=\"CitationRef\"\u003e88\u003c/span\u003e, \u003cspan citationid=\"CR90\" class=\"CitationRef\"\u003e90\u003c/span\u003e, \u003cspan citationid=\"CR92\" class=\"CitationRef\"\u003e92\u003c/span\u003e, \u003cspan citationid=\"CR95\" class=\"CitationRef\"\u003e95\u003c/span\u003e, \u003cspan citationid=\"CR97\" class=\"CitationRef\"\u003e97\u003c/span\u003e, \u003cspan citationid=\"CR99\" class=\"CitationRef\"\u003e99\u003c/span\u003e, \u003cspan citationid=\"CR103\" class=\"CitationRef\"\u003e103\u003c/span\u003e, \u003cspan citationid=\"CR105\" class=\"CitationRef\"\u003e105\u003c/span\u003e) and six were cohort studies (\u003cspan citationid=\"CR86\" class=\"CitationRef\"\u003e86\u003c/span\u003e, \u003cspan citationid=\"CR89\" class=\"CitationRef\"\u003e89\u003c/span\u003e, \u003cspan citationid=\"CR91\" class=\"CitationRef\"\u003e91\u003c/span\u003e, \u003cspan citationid=\"CR94\" class=\"CitationRef\"\u003e94\u003c/span\u003e) with a median sample size of 545,934 (range of sample sizes 2,081 to 2,621,802). Very few studies reported on participant characteristics of interest, such as HPV vaccination status, race/ethnicity, or socioeconomic status. Of note, all studies were carried out before HPV vaccination was implemented, or done in periods when HPV vaccinate rates were very low. In terms of risk of bias, most studies did not demonstrate significant concerns for most variables with the exception of lack of adjustment or controlling for potential confounders other than age in 13 (59%) studies, which was considered an important source of bias. In most cases, the risk of bias was not considered serious such that we did not rate down during the assessments of certainty, which already started at low due to the inability of observational studies to control for unmeasured confounding.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec24\" class=\"Section2\"\u003e \u003ch2\u003eFindings\u003c/h2\u003e \u003cp\u003eSix studies reported the effect of cytology screening at age 20 to 34 years on the incidence of ICC (\u003cspan citationid=\"CR79\" class=\"CitationRef\"\u003e79\u003c/span\u003e, \u003cspan additionalcitationids=\"CR85 CR86 CR87\" citationid=\"CR84\" class=\"CitationRef\"\u003e84\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR88\" class=\"CitationRef\"\u003e88\u003c/span\u003e). None reported on individuals aged under 20 years of age. Based on pooling five case-control studies and considering findings from the cohort study, we rated the evidence to be of very low certainty for all age groups included to inform age to start cervical cancer screening (20\u0026ndash;24, 25\u0026ndash;29, and 30\u0026ndash;34 years) (\u003cb\u003eSupplemental file 1a)\u003c/b\u003e. Several studies reported on ages that did not closely align with the 5-year age categories of interest, warranting rating down for indirectness. Further, there was high heterogeneity among the case-control studies and between estimates from the case-control and cohort studies; for example, pooled data from case-control studies favoured no screening in 20 to 24 and 25 to 29-year-olds, whereas the large cohort study (sample over 2\u0026nbsp;million but not reported by age) favoured screening in both of these age categories. Similarly, data from one high risk-of-bias cohort study (n\u0026thinsp;=\u0026thinsp;353,045) (\u003cspan citationid=\"CR89\" class=\"CitationRef\"\u003e89\u003c/span\u003e) and one small (n\u0026thinsp;=\u0026thinsp;1,483) case-control study (\u003cspan citationid=\"CR78\" class=\"CitationRef\"\u003e78\u003c/span\u003e) provided very low certainty evidence for all age groups about the effect of cervical cancer screening on subsequent all-cause and cervical-cancer specific mortality, respectively.\u003c/p\u003e \u003cp\u003eIn separate pooled analyses of six case-control studies (\u003cspan citationid=\"CR79\" class=\"CitationRef\"\u003e79\u003c/span\u003e, \u003cspan additionalcitationids=\"CR84\" citationid=\"CR83\" class=\"CitationRef\"\u003e83\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR85\" class=\"CitationRef\"\u003e85\u003c/span\u003e, \u003cspan citationid=\"CR90\" class=\"CitationRef\"\u003e90\u003c/span\u003e, \u003cspan citationid=\"CR92\" class=\"CitationRef\"\u003e92\u003c/span\u003e) (N\u0026thinsp;=\u0026thinsp;16,909) and two cohort studies (n\u0026thinsp;=\u0026thinsp;569,132 (\u003cspan citationid=\"CR91\" class=\"CitationRef\"\u003e91\u003c/span\u003e); number not reported for the age group (\u003cspan citationid=\"CR86\" class=\"CitationRef\"\u003e86\u003c/span\u003e)) screening between the ages of 60\u0026ndash;69 years was associated with lower incident ICC compared with not screening (pooled OR 0.46, 95% CI 0.34 to 0.62; pooled RR 0.54, 95% CI 0.46 to 0.62, respectively). Based on a cumulative rate for ICC in participants not screened (n\u0026thinsp;=\u0026thinsp;360,093) in their early 60s in a national Swedish cohort (\u003cspan citationid=\"CR91\" class=\"CitationRef\"\u003e91\u003c/span\u003e) of about 20 ICC cases per 10,000 individuals over 10\u0026ndash;15 years, the absolute reduction would be estimated at 9 fewer ICC per 10,000 over 10\u0026ndash;15 years (i.e., similar to our threshold of 3 fewer per 10,000 after one of about three possible screening rounds). Two case-control studies (\u003cspan citationid=\"CR79\" class=\"CitationRef\"\u003e79\u003c/span\u003e, \u003cspan citationid=\"CR90\" class=\"CitationRef\"\u003e90\u003c/span\u003e) that provided data using 5-year increments found associations with reduced ICC for both 60\u0026ndash;64 and 65-69-year-olds. When exploring our other subpopulations, two studies examined the effect on ICC incidence of cytology screening versus no screening at age 60\u0026ndash;65 years depending on their screening results in their 50s (\u003cspan citationid=\"CR83\" class=\"CitationRef\"\u003e83\u003c/span\u003e, \u003cspan citationid=\"CR91\" class=\"CitationRef\"\u003e91\u003c/span\u003e). First, one case-control study (n\u0026thinsp;=\u0026thinsp;12,708) from the UK (\u003cspan citationid=\"CR83\" class=\"CitationRef\"\u003e83\u003c/span\u003e) found reductions over 25 years of 43 per 10,000 from screening among those who had an abnormal screen during their 50s and 49 cases if they had not been screened during their 50s. Smaller reductions were observed among those who had \u0026ldquo;irregularly screened\u0026rdquo; (i.e., no abnormal tests aged 50-59y and a negative test between aged 50-54y but not 55-59y, or aged 55-59y but not 50-54y; 12.9 fewer, 95% CI 6.5 to 19.3) or \u0026ldquo;adequately\u0026rdquo; screened (i.e., only normal tests, with one in each 5-year period; 6.3 fewer, 95% CI 0.3 to 12.3). Second and similarly, a large Swedish cohort study (n\u0026thinsp;=\u0026thinsp;569,132) (\u003cspan citationid=\"CR91\" class=\"CitationRef\"\u003e91\u003c/span\u003e) following individuals up to 24 years (mean 10.9) reported that screening versus no screening at age 61\u0026ndash;65 benefitted those who had not been screened (33 fewer per 10,000) or had abnormal results (60\u0026ndash;70 fewer per 10,000) in their 50s, but had less effect for those who had inadequately (5.4 fewer per 10,000, 95% CI 14.2 fewer to 3.4 more; aHR 0.82, 95% CI 0.56 to 1.22) or adequately (2.8 fewer per 10,000 [7.8 fewer to 2.2 more]; aHR 0.90 [0.69 to 1.17]) (similar definitions as in the UK study) screened. For reduction in ICC among those aged 60\u0026ndash;69 years, we rated the certainty of evidence as moderate (rating up for large effect) for a reduction among those with no, abnormal, or inadequate screening in their 50s, and low (with some imprecision especially in the larger study) for a reduction among those adequately screened during their 50s.\u003c/p\u003e \u003cp\u003eFor mortality from cervical cancer among those aged 60\u0026ndash;69 years, benefit was shown in analyses of three case-control studies (\u003cspan citationid=\"CR78\" class=\"CitationRef\"\u003e78\u003c/span\u003e, \u003cspan citationid=\"CR93\" class=\"CitationRef\"\u003e93\u003c/span\u003e, \u003cspan citationid=\"CR95\" class=\"CitationRef\"\u003e95\u003c/span\u003e) (pooled OR 0.50, 95% CI 0.37 to 0.67, N\u0026thinsp;=\u0026thinsp;2,582) and one cohort study (\u003cspan citationid=\"CR94\" class=\"CitationRef\"\u003e94\u003c/span\u003e) (RR 0.23, 95% CI 0.10 to 0.51, n\u0026thinsp;=\u0026thinsp;59,065). Based on data in Finland for cervical-cancer mortality rates over about 10 years among those not invited to screen at age 65 (n\u0026thinsp;=\u0026thinsp;486,869; 0.38 per 10,000) (\u003cspan citationid=\"CR94\" class=\"CitationRef\"\u003e94\u003c/span\u003e), the absolute risk reduction may be between 0.19 and 0.29 fewer deaths per 10,000 screened. Considering the variation in effects for incidence of ICC from studies looking at effects among subpopulations based on screening results in their 50s, we rated the certainty of evidence as moderate (rated up for large effect) for a reduction in cervical-cancer mortality among those with no, abnormal, or inadequate screening in their 50s, and low (due to indirectness of the overall findings to this population) for a reduction among those adequately screened during their 50s.\u003c/p\u003e \u003cp\u003eFor persons aged 70\u0026ndash;79 years, the effect of screening for cervical cancer on incident ICC, though appearing to be of benefit, was less certain than for those 60\u0026ndash;69 years in pooled analysis of three case-control studies (OR 0.44, 95% CI 0.33 to 0.57, N\u0026thinsp;=\u0026thinsp;4,258) (\u003cspan citationid=\"CR84\" class=\"CitationRef\"\u003e84\u003c/span\u003e, \u003cspan citationid=\"CR85\" class=\"CitationRef\"\u003e85\u003c/span\u003e, \u003cspan citationid=\"CR92\" class=\"CitationRef\"\u003e92\u003c/span\u003e). The analysis relied mainly (97% weight) on one study (\u003cspan citationid=\"CR92\" class=\"CitationRef\"\u003e92\u003c/span\u003e). We did not find a good estimate for the rate of ICC in unscreened individuals in their 70s who had been screened during their 60s, as a basis for estimating absolute effects. It was judged that the varying effects for those in their 60s for ICC, based on screening results in their 50s, would translate to this age group. The certainty was rated as low for a reduction in ICC incidence for those aged 70\u0026ndash;79 with no, abnormal, or inadequate screening in their 50s and very low for those adequately screened during their 50s. Only one small case-control study (\u003cspan citationid=\"CR95\" class=\"CitationRef\"\u003e95\u003c/span\u003e) reported the effect of screening in one\u0026rsquo;s 70s on cervical cancer mortality, leading to inconclusive findings related to imprecision, lack of consistency and (for those adequately screened in their 50s) indirectness.\u003c/p\u003e \u003cp\u003eEight case-control (N\u0026thinsp;=\u0026thinsp;20,862) and two cohort (N\u0026thinsp;=\u0026thinsp;approximately 174,000) studies contributed to data on the effect of cytology screening by intervals less than 3.5 years versus 3.5 to 5.5 years on incident ICC across age groups and provided inconsistent and thus very low certainty evidence (\u003cspan citationid=\"CR79\" class=\"CitationRef\"\u003e79\u003c/span\u003e, \u003cspan citationid=\"CR80\" class=\"CitationRef\"\u003e80\u003c/span\u003e, \u003cspan citationid=\"CR82\" class=\"CitationRef\"\u003e82\u003c/span\u003e, \u003cspan citationid=\"CR84\" class=\"CitationRef\"\u003e84\u003c/span\u003e, \u003cspan citationid=\"CR97\" class=\"CitationRef\"\u003e97\u003c/span\u003e, \u003cspan citationid=\"CR99\" class=\"CitationRef\"\u003e99\u003c/span\u003e, \u003cspan citationid=\"CR100\" class=\"CitationRef\"\u003e100\u003c/span\u003e, \u003cspan additionalcitationids=\"CR104\" citationid=\"CR103\" class=\"CitationRef\"\u003e103\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR105\" class=\"CitationRef\"\u003e105\u003c/span\u003e). Analyses stratified by 5-year age groups and by setting/type of screening program did not explain the heterogeneity (\u003cb\u003eSupplemental file 1a\u003c/b\u003e). One case-control study (n\u0026thinsp;=\u0026thinsp;11,447) (\u003cspan citationid=\"CR78\" class=\"CitationRef\"\u003e78\u003c/span\u003e) found a significant effect for reducing the risk of death from cervical cancer when screening at an interval of \u0026le;\u0026thinsp;3 years compared with 3\u0026ndash;5 years, but findings were of very low certainty for lack of consistency especially when there was inconsistency demonstrated for the incidence outcome.\u003c/p\u003e \u003cp\u003eScarce data were reported for other specific populations of interest and were limited to cytology screening. In one US case-control study (n\u0026thinsp;=\u0026thinsp;11,404) of persons with a cervix aged 65 years or older, race (White vs. non-white) was not associated with the (beneficial) effect of screening (p\u0026thinsp;=\u0026thinsp;0.243 for interaction) when adjusted for median income by zip code and potential impact of hysterectomy (\u003cspan citationid=\"CR92\" class=\"CitationRef\"\u003e92\u003c/span\u003e). A large (n\u0026thinsp;=\u0026thinsp;2,621,802) cohort study that adjusted results for age, there was no difference in the (beneficial) effect of screening 23 to 50-year-olds on incidence of ICC based on immigrant status (Swedish-born vs. birth outside Sweden) (\u003cspan citationid=\"CR86\" class=\"CitationRef\"\u003e86\u003c/span\u003e). No data were presented for trans or nonbinary individuals.\u003c/p\u003e \u003cdiv id=\"Sec25\" class=\"Section3\"\u003e \u003ch2\u003eComparative effectiveness between screening strategies\u003c/h2\u003e \u003cdiv id=\"Sec26\" class=\"Section4\"\u003e \u003ch2\u003eStudy characteristics\u003c/h2\u003e \u003cp\u003eWe included 16 trials (14 RCTs (\u003cspan additionalcitationids=\"CR107 CR108 CR109 CR110 CR111 CR112 CR113 CR114 CR115 CR116 CR117 CR118\" citationid=\"CR106\" class=\"CitationRef\"\u003e106\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR119\" class=\"CitationRef\"\u003e119\u003c/span\u003e) and 2 quasi-RCTs (i.e., using odd-even date of birth or personal identification number) (\u003cspan citationid=\"CR120\" class=\"CitationRef\"\u003e120\u003c/span\u003e, \u003cspan citationid=\"CR121\" class=\"CitationRef\"\u003e121\u003c/span\u003e)), one observational study (\u003cspan citationid=\"CR122\" class=\"CitationRef\"\u003e122\u003c/span\u003e) and four associated papers (\u003cspan additionalcitationids=\"CR124 CR125\" citationid=\"CR123\" class=\"CitationRef\"\u003e123\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR126\" class=\"CitationRef\"\u003e126\u003c/span\u003e) that addressed the comparative effectiveness of different screening strategies (\u003cb\u003eTable\u0026nbsp;2\u003c/b\u003e; \u003cb\u003eSupplemental file 1b\u003c/b\u003e). Most studies were conducted in the setting of organized screening programs in Europe and in addition, one trial each was done in Canada (\u003cspan additionalcitationids=\"CR128\" citationid=\"CR127\" class=\"CitationRef\"\u003e127\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR129\" class=\"CitationRef\"\u003e129\u003c/span\u003e), Hong Kong (\u003cspan citationid=\"CR130\" class=\"CitationRef\"\u003e130\u003c/span\u003e), and Australia (\u003cspan citationid=\"CR131\" class=\"CitationRef\"\u003e131\u003c/span\u003e). Fifteen trials only reported on one screening round (number enrolled ranging from 667 (\u003cspan citationid=\"CR118\" class=\"CitationRef\"\u003e118\u003c/span\u003e) to 201,038 (\u003cspan citationid=\"CR120\" class=\"CitationRef\"\u003e120\u003c/span\u003e)), because any second rounds of screening used the same method in each group compared. One RCT (HPV Focal; n\u0026thinsp;=\u0026thinsp;22,588) provided data for one round as well as the comparison between two rounds of screening with cytology with triage to hrHPV (over 4 years) and one round of screening with hrHPV with triage to cytology (\u003cspan citationid=\"CR112\" class=\"CitationRef\"\u003e112\u003c/span\u003e). As previously mentioned, the data from these studies were collected on those who undertook screening; some trials had very low (5\u0026ndash;52%) (\u003cspan citationid=\"CR106\" class=\"CitationRef\"\u003e106\u003c/span\u003e, \u003cspan citationid=\"CR109\" class=\"CitationRef\"\u003e109\u003c/span\u003e, \u003cspan citationid=\"CR110\" class=\"CitationRef\"\u003e110\u003c/span\u003e, \u003cspan citationid=\"CR113\" class=\"CitationRef\"\u003e113\u003c/span\u003e, \u003cspan citationid=\"CR116\" class=\"CitationRef\"\u003e116\u003c/span\u003e, \u003cspan citationid=\"CR117\" class=\"CitationRef\"\u003e117\u003c/span\u003e, \u003cspan citationid=\"CR120\" class=\"CitationRef\"\u003e120\u003c/span\u003e, \u003cspan citationid=\"CR121\" class=\"CitationRef\"\u003e121\u003c/span\u003e) rates of enrollment among those allocated. Most trials included participants across age groups, typically ranging from individuals in their 20s and 30s to those in their 60s. Two trials (\u003cspan citationid=\"CR109\" class=\"CitationRef\"\u003e109\u003c/span\u003e, \u003cspan citationid=\"CR132\" class=\"CitationRef\"\u003e132\u003c/span\u003e) only included older participants (aged 50\u0026ndash;60 and 56\u0026ndash;60 years). Length of follow-up for incidence outcomes ranged from 18 months to 5 years. Outcomes in pre-specified populations and data for subgroup analyses were limited with five trials (\u003cspan citationid=\"CR113\" class=\"CitationRef\"\u003e113\u003c/span\u003e, \u003cspan additionalcitationids=\"CR118\" citationid=\"CR117\" class=\"CitationRef\"\u003e117\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR119\" class=\"CitationRef\"\u003e119\u003c/span\u003e, \u003cspan citationid=\"CR133\" class=\"CitationRef\"\u003e133\u003c/span\u003e) enrolling persons with a cervix who were underscreened and seven trials (\u003cspan citationid=\"CR106\" class=\"CitationRef\"\u003e106\u003c/span\u003e, \u003cspan citationid=\"CR115\" class=\"CitationRef\"\u003e115\u003c/span\u003e, \u003cspan citationid=\"CR120\" class=\"CitationRef\"\u003e120\u003c/span\u003e, \u003cspan citationid=\"CR121\" class=\"CitationRef\"\u003e121\u003c/span\u003e, \u003cspan citationid=\"CR123\" class=\"CitationRef\"\u003e123\u003c/span\u003e, \u003cspan additionalcitationids=\"CR128\" citationid=\"CR127\" class=\"CitationRef\"\u003e127\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR129\" class=\"CitationRef\"\u003e129\u003c/span\u003e, \u003cspan citationid=\"CR131\" class=\"CitationRef\"\u003e131\u003c/span\u003e, \u003cspan citationid=\"CR134\" class=\"CitationRef\"\u003e134\u003c/span\u003e, \u003cspan citationid=\"CR135\" class=\"CitationRef\"\u003e135\u003c/span\u003e) presenting data by age subgroups.\u003c/p\u003e \u003cp\u003eFour trials (\u003cspan citationid=\"CR117\" class=\"CitationRef\"\u003e117\u003c/span\u003e, \u003cspan citationid=\"CR118\" class=\"CitationRef\"\u003e118\u003c/span\u003e, \u003cspan additionalcitationids=\"CR128\" citationid=\"CR127\" class=\"CitationRef\"\u003e127\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR129\" class=\"CitationRef\"\u003e129\u003c/span\u003e, \u003cspan citationid=\"CR136\" class=\"CitationRef\"\u003e136\u003c/span\u003e) were not considered at high risk of bias for any included outcome. Six trials were at high risk of bias for inadequate sequence generation (\u003cspan citationid=\"CR106\" class=\"CitationRef\"\u003e106\u003c/span\u003e, \u003cspan citationid=\"CR109\" class=\"CitationRef\"\u003e109\u003c/span\u003e, \u003cspan citationid=\"CR110\" class=\"CitationRef\"\u003e110\u003c/span\u003e, \u003cspan citationid=\"CR116\" class=\"CitationRef\"\u003e116\u003c/span\u003e, \u003cspan citationid=\"CR120\" class=\"CitationRef\"\u003e120\u003c/span\u003e, \u003cspan citationid=\"CR121\" class=\"CitationRef\"\u003e121\u003c/span\u003e). Blinding of participants (performance bias) and outcome assessors was unclear in most trials, though blinding of participants was not thought to be of major concern in these studies of comparative effectiveness. The domain of incomplete outcome data, from attrition after the screening test, was at high risk of bias across multiple outcomes in one trial (\u003cspan citationid=\"CR116\" class=\"CitationRef\"\u003e116\u003c/span\u003e) and for the incidence outcomes in two others (\u003cspan citationid=\"CR108\" class=\"CitationRef\"\u003e108\u003c/span\u003e, \u003cspan citationid=\"CR126\" class=\"CitationRef\"\u003e126\u003c/span\u003e) (\u003cb\u003eSupplemental file 1b\u003c/b\u003e). Two trials (\u003cspan citationid=\"CR107\" class=\"CitationRef\"\u003e107\u003c/span\u003e, \u003cspan citationid=\"CR111\" class=\"CitationRef\"\u003e111\u003c/span\u003e) were at risk of missing data for the incidence outcomes because they were not actively ascertained for all participants (only using data linkage or safety reporting), thus some events particularly for CIN 2 and CIN 3 could have been missed.\u003c/p\u003e \u003cp\u003eMethods for detecting incident cases varied, and included cytology (conventional or liquid-based), hrHPV and liquid-based cytology co-testing, data linkage, safety monitoring (i.e., reported as an adverse event), and a combination of these approaches. Outcomes that included cases of ICC (incidence of CIN 2+, CIN 3\u0026thinsp;+\u0026thinsp;and ICC) but did not use data linkage to find clinically detected cases were considered indirect. Further indirectness came from studies where people with CIN 2 or 3 detected during screening were not followed to find any cases that progressed. The large (n\u0026thinsp;=\u0026thinsp;1,262,510) observational study from England was only included for the incidence of ICC outcome (via second round screening and cancer registries) not reported by a trial for one comparison; the groups were differentiated by changes in laboratories in some regions to implement hrHPV screening with triage to cytology but the authors noted differences between groups in socioeconomic status which was not accounted for in the analysis.\u003c/p\u003e \u003cp\u003e \u003cb\u003eTable\u0026nbsp;2\u003c/b\u003e describes the strategies in each study in detail. Based on descriptions of the interventions and clinical input from the working group, we classified the trials to examine 10 major comparisons (\u003cb\u003eBox 1\u003c/b\u003e), with some evaluated by only one RCT. In a few cases (e.g., Comparisons 1 and 10, 2 and 8, 6a and 6b), the screening strategies were quite similar but differences in the populations (general population vs. under/never-screened) were thought to differentiate them enough to separate for analysis. Further, in two cases (Comparisons 2 and 3) there were differences between trials within the same major comparison with respect to whether there was additional follow-up (e.g., at 6\u0026ndash;12 months) beyond the main triage testing at baseline during each round of screening. For this, we created subgroup comparisons for screening \u0026ldquo;without recall\u0026rdquo; and \u0026ldquo;with recall\u0026rdquo; in each round. Two trials provided data for more than one major comparison or subgroup. The Norwegian HPV Pilot trial (n\u0026thinsp;=\u0026thinsp;157,447) (\u003cspan citationid=\"CR121\" class=\"CitationRef\"\u003e121\u003c/span\u003e), primarily comparing hrHPV with cytology triage versus cytology with hrHPV triage (with recall; Comparison 3b), also provided data for Comparison 2a of hrHPV with cytology triage versus cytology alone (without recall) because the hrHPV triage results in the cytology arm were not acted upon until the recall phase, to check for persistence, and positive results from cytology alone were referred to colposcopy at baseline (allowing for detection and false positive outcomes from this perspective). Likewise, the HPV Focal RCT (\u003cspan citationid=\"CR112\" class=\"CitationRef\"\u003e112\u003c/span\u003e) provided data for some outcomes in Comparisons 3a, b, (n\u0026thinsp;=\u0026thinsp;22,588) and c (n\u0026thinsp;=\u0026thinsp;16,374). In comparisons including more than one trial, there were sometimes differences between trials in the threshold used for referral to colposcopy after cytology and in the screening methods used at the recall stage \u003cb\u003e(Box 1\u003c/b\u003e). There were no comparisons between cytology alone and either cytology with hrHPV triage or hrHPV with partial genotyping (with or without triage).\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec27\" class=\"Section3\"\u003e \u003ch2\u003eFindings\u003c/h2\u003e \u003cp\u003e \u003cb\u003eSupplementary file 1b\u003c/b\u003e contains the full evidence sets for each outcome-comparison. We did not rate down for indirectness in our certainty assessments when considering the trials focused on adherence to screening, versus being invited to screen, though in some cases the risk of bias was high when RCTs enrolled many fewer participants than randomized and did not demonstrate comparable baseline characteristics between arms.\u003c/p\u003e \u003cp\u003eFor all comparisons, we are very uncertain about any impacts on all-cause and cervical-cancer mortality and for overdiagnosis. No trial reported on cervical-cancer mortality, and only one trial (COMPASS; n\u0026thinsp;=\u0026thinsp;2,987) (\u003cspan citationid=\"CR107\" class=\"CitationRef\"\u003e107\u003c/span\u003e) in Comparison 4 reported on all-cause mortality at short follow-up (18 months) duration and with imprecision. For overdiagnosis, an associated paper (\u003cspan citationid=\"CR123\" class=\"CitationRef\"\u003e123\u003c/span\u003e) to the FINNISH RCT (\u003cspan citationid=\"CR111\" class=\"CitationRef\"\u003e111\u003c/span\u003e) in Comparison 2 used results from the trial for 5-year follow-up after one round from the screening (including prevalent and incident cancers) strategies together with historical population-based data for an estimated incidence of cancer without screening over 5 years (Finland in 1958\u0026ndash;1962; incidence 17 per 100,000 person-years). In this study, overdiagnosis was defined as the risk of CIN 3 cases that would not have progressed to invasive disease by the next screen (5 years later) using the period prevalence of CIN 3 lesions diagnosed at the screen and during the following screening interval minus the rate of prevented cancers (squamous cell cancer) within the same screening round (the rate assuming no screening minus the rate of interval cancers found in the trial). Estimates of overdiagnosis of non-progressive CIN3\u0026thinsp;+\u0026thinsp;were presented for hrHPV with cytology triage (cases overdiagnosed 39.6 per 1,000 person-years, 95% CI 31.3 to 48.9) and from cytology alone (20.3 per 1,000 person-years, 95% CI 13.6 to 27.9). The evidence was rated to have very low certainty, from data that was considered observational (this started at low certainty), at risk of bias, and indirect from the use of historical incidence data for the no screening comparator. Results for other outcomes are presented here by groupings of comparisons.\u003c/p\u003e \u003cp\u003e \u003cb\u003eComparisons 1 through 4\u003c/b\u003e: \u003cb\u003eTable\u0026nbsp;3\u003c/b\u003e contains the summary of findings from these comparisons that were considered most relevant for decision-making about which strategies to recommend. In each comparison, the certainty was assessed separately for each major age group reported across the studies (25\u0026ndash;29, 30\u0026ndash;59, and 60\u0026ndash;69 years); if the study(ies) reporting on a comparison did not include any participants in the age group (e.g., 60\u0026ndash;69 year-olds in Comparison 1) we report the certainty as very low.\u003c/p\u003e \u003cp\u003eOnly three trials provided data comparing strategies using clinician-sampled hrHPV versus cytology alone (Comparisons 1 and 2), which was considered the major comparator of interest. The NTCC Phase II RCT in Italy (Comparison 1) compared hrHPV screening alone with cytology alone (\u0026ge;\u0026thinsp;ASCUS to colposcopy in most centres) at nine screening centres (\u003cspan citationid=\"CR115\" class=\"CitationRef\"\u003e115\u003c/span\u003e). Low certainty evidence suggested little-to-no difference for 25\u0026ndash;59 years-olds between strategies for incidence of CIN 2 and CIN 3+ (latter using detection of CIN 2\u0026thinsp;+\u0026thinsp;as a surrogate) and very low certainty was found for incidence of CIN 3 and ICC (using CIN 3\u0026thinsp;+\u0026thinsp;detection). Though results were statistically significant for higher detection of CIN 2\u0026thinsp;+\u0026thinsp;and 3\u0026thinsp;+\u0026thinsp;with hrHPV screening alone, the point estimate and its 95% CI for CIN 2+ (30.2 more) did not exceed our threshold of 100 more per 10,000 for indicating greater than little-to-no difference, and the 95% CIs (across all ages and within age groups) were imprecise for CIN 3\u0026thinsp;+\u0026thinsp;detection meeting its threshold of 10 more per 10,000. There was moderate certainty evidence for at least some harm (\u0026ge;\u0026thinsp;300 per 10,000) from referrals to colposcopy for 25\u0026ndash;59 years-olds (possibly considerably more for those 25\u0026ndash;29 years), and from biopsies and false positives for CIN 2\u0026thinsp;+\u0026thinsp;and CIN 3\u0026thinsp;+\u0026thinsp;for those aged 25\u0026ndash;29 years.\u003c/p\u003e \u003cp\u003eThe Finnish RCT (n\u0026thinsp;=\u0026thinsp;132,194; ages 25 to 65 years) (\u003cspan citationid=\"CR111\" class=\"CitationRef\"\u003e111\u003c/span\u003e) and Norwegian HPV Screening Pilot trial (n\u0026thinsp;=\u0026thinsp;157,447; ages 34 to 69 years) (\u003cspan citationid=\"CR121\" class=\"CitationRef\"\u003e121\u003c/span\u003e) contributed to data for Comparison 2a, of hrHPV with triage to cytology versus cytology alone, without recalls. Data from the recall stage in both trials were not used for detection or false positive outcomes, whereas data on case detection during the recall (\u0026ldquo;intensive screening\u0026rdquo;) phase in the Finnish RCT contributed to incidence outcomes for this comparison. Using detection data for CIN 3+, findings suggested that there may be fewer incident cases of ICC from hrHPV with triage to cytology across age groups (low certainty). Across age groups, there was low certainty evidence of little-to-no difference for incidence of CIN 2 and CIN 3+ (using detection of CIN 2+) and moderate certainty of little-to-no difference in referrals to colposcopy and in false positives for CIN 2+, CIN 3+, and ICC. For Comparison 2b adding recall, where only the Finnish RCT contributed data, there was still low certainty for little-to-difference for CIN 2 or CIN3\u0026thinsp;+\u0026thinsp;incidence across age groups, but only evidence of reduced ICC incidence (via CIN3\u0026thinsp;+\u0026thinsp;detection) for the group of 25\u0026ndash;29 year-olds because of imprecise findings for the older ages. It is unclear if adding a recall phase (including all HPV positives) in this main comparison increases the potential benefit from the hrHPV strategy, and this would need to be considered in light of moderate certainty evidence showing harm from false positives to recall which may be at least twice our threshold (possibly 800\u0026ndash;900 more per 10,000).\u003c/p\u003e \u003cp\u003eThe Canadian HPV Focal RCT (\u003cspan citationid=\"CR112\" class=\"CitationRef\"\u003e112\u003c/span\u003e, \u003cspan citationid=\"CR124\" class=\"CitationRef\"\u003e124\u003c/span\u003e) (25\u0026ndash;65 years) contributed to Comparisons 3a, b, and c, whereas data from two other studies contributed to each of Comparisons 3a and b. Two trials from Sweden, using the exact same comparison but non-overlapping populations with differing ages (Swedish HPV Trial 30\u0026ndash;64 years, n\u0026thinsp;=\u0026thinsp;201,028 (\u003cspan citationid=\"CR120\" class=\"CitationRef\"\u003e120\u003c/span\u003e) and Stockholm-Gotlund 56\u0026ndash;60 years, n\u0026thinsp;=\u0026thinsp;14,763 (\u003cspan citationid=\"CR110\" class=\"CitationRef\"\u003e110\u003c/span\u003e)) provided data for detection, referrals to colposcopy and false positive outcomes for Comparison 3a, because they did not include recall in their screening strategy. Data by age group for detection of CIN 3\u0026thinsp;+\u0026thinsp;and ICC for the larger Swedish trial were obtained from the authors. For Comparison 3b, the Norwegian HPV Screening Pilot trial (\u003cspan citationid=\"CR121\" class=\"CitationRef\"\u003e121\u003c/span\u003e) contributed data for detection, referrals to colposcopy and false positive outcomes and the English HPV screening observational study (\u003cspan citationid=\"CR122\" class=\"CitationRef\"\u003e122\u003c/span\u003e, \u003cspan citationid=\"CR125\" class=\"CitationRef\"\u003e125\u003c/span\u003e) was used for incidence of ICC (not reported by the trials). For incidence outcomes other than ICC, the HPV Focal RCT was the only contributor of data. For Comparison 3b, data for incidence after recall during round one used cases detected during round two in the cytology arm as well as the 48-month exit co-testing for both arms.\u003c/p\u003e \u003cp\u003eFor Comparison 3a, we assessed evidence as moderate certainty for an association between the hrHPV strategy and reduced ICC incidence, via CIN 3\u0026thinsp;+\u0026thinsp;detection, for the age group of 30\u0026ndash;59 year-olds; results were imprecise for 25\u0026ndash;29 year-olds and of low certainty for little-to-no difference for 60\u0026ndash;69 year-olds. For those aged 30\u0026ndash;69 years there was low certainty for little-to-no difference between strategies for detection of ICC and incidence of CIN 3+, via CIN2\u0026thinsp;+\u0026thinsp;detection (for 25\u0026ndash;29 year-olds the data was either not reported or very low certainty). For those 30\u0026ndash;69 years, there was moderate certainty evidence for little-to-no difference between strategies for the reported harm outcomes; for the 25\u0026ndash;29 year age group we rated the certainty down further for indirectness because this age group contributed\u0026thinsp;\u0026lt;\u0026thinsp;1% of the total sample for the outcome.\u003c/p\u003e \u003cp\u003eFor Comparison 3b, findings appeared similar to Comparison 3a for the 30\u0026ndash;59 year (moderate certainty of some reduction in ICC without increased harm) and 60\u0026ndash;69 year (low certainty for little-to-no benefit) age groups. For the younger ages, adding the recall appears to add an advantage from the hrHPV strategy for detecting CIN2+, though while noticeably increasing harm from more referrals to colposcopy and false positives. One contributing factor may have been that in the hrHPV strategy in the HPV Focal RCT (only trial with 25\u0026ndash;29 year-olds) those persistent for HPV at recall were sent for colposcopy even if they had normal (\u0026lt;\u0026thinsp;ASCUS) cytology results, whereas in the cytology strategy arm only those with \u0026ge;\u0026thinsp;ASCUS were sent to recall. The findings from direct evidence on incidence of ICC and CIN 3\u0026thinsp;+\u0026thinsp;during follow-up were of very low certainty; apart from lack of consistency from use of one study for each of these outcomes, for ICC the observational study was at high risk of bias and for CIN 3\u0026thinsp;+\u0026thinsp;there was very serious indirectness from the 48-month exit round in the HPV Focal RCT failing to include those with CIN 2 or 3 during baseline screening and from lack of data linkage to capture clinically detected cases (incidence outcomes were not a primary aim for these trials).\u003c/p\u003e \u003cp\u003eFor Comparison 3c, using data across all ages from the HPV Focal RCT findings were of little-to-no difference for incidence of CIN 2, CIN 2\u0026thinsp;+\u0026thinsp;and CIN3+ (via CIN2\u0026thinsp;+\u0026thinsp;detection) for those aged 30\u0026ndash;69 and for incidence of CIN 2 for those 25\u0026ndash;29 years. Little-to-no difference was found for referrals to colposcopy and false positives for CIN 2\u0026thinsp;+\u0026thinsp;and 3+, with moderate certainty for 30\u0026ndash;69 year-olds and low certainty for 25\u0026ndash;29 year-olds. Evidence for incidence of ICC via detection of CIN3\u0026thinsp;+\u0026thinsp;was rated as very low certainty due to lack of consistency, indirectness, and imprecision.\u003c/p\u003e \u003cp\u003eOne small RCT (n\u0026thinsp;=\u0026thinsp;2,987) (\u003cspan citationid=\"CR107\" class=\"CitationRef\"\u003e107\u003c/span\u003e) contributed to Comparison 4, where hrHPV testing used partial genotyping in both arms of hrHPV with cytology triage (though referral to colposcopy for types 16/18 and for type 45 with \u0026ge;\u0026thinsp;HSIL) and cytology with hrHPV triage (referral to colposcopy for HPV types 16/28 with \u0026ge;\u0026thinsp;ASCUS). Up to two recalls 12 months apart were advised for some individuals (e.g., with ASCUS or LSIL and negative hrHPV results). There was low certainty evidence of little-to-no difference between strategies for incidence of CIN3+ (from more detection of CIN2+) for those aged 30\u0026ndash;59 years. Findings for the other age groups and other benefit outcomes across all ages were of very low certainty, often from added imprecision (e.g., n\u0026thinsp;=\u0026thinsp;629 in 25\u0026ndash;29 year age group) or indirectness from needing to rely on data from those aged 30\u0026ndash;64 for findings among 60\u0026ndash;69 year-olds. For referrals to colposcopy and false positives for CIN2+, CIN3\u0026thinsp;+\u0026thinsp;and ICC, there was little-to-no differences with moderate certainty for the 30\u0026ndash;59 year-olds and low certainty for the other age groups.\u003c/p\u003e \u003cp\u003e \u003cstrong\u003eComparisons 5, 6a, and 7\u003c/strong\u003e \u003cp\u003eThese comparisons had at least one outcome with low or higher certainty evidence and \u003cb\u003eSupplementary file 1b\u003c/b\u003e has all data sets.\u003c/p\u003e \u003c/p\u003e \u003cp\u003eIn Comparison 5, an RCT from Hong Kong (\u003cspan citationid=\"CR108\" class=\"CitationRef\"\u003e108\u003c/span\u003e) compared hrHPV with cytology triage of \u003cem\u003enegative\u003c/em\u003e tests versus cytology with hrHPV triage, both arms having recall. The certainty for all outcomes was very low for age groups 25\u0026ndash;29 and 60\u0026ndash;69 years because the trial only enrolled those 30\u0026ndash;60 years. Low certainty evidence found reduced incidence in the hrHPV strategy arm of ICC via more detection of CIN3+ (36.0 more per 10,000, 95% CI 14.3 to 71.0 more) and little-to-no difference between arms for incidence of CIN3\u0026thinsp;+\u0026thinsp;via CIN 2\u0026thinsp;+\u0026thinsp;detection (51.9 more per 10,000, 95% CI 23.4 to 93.7 more). There was moderate certainty evidence that the hrHPV strategy resulted in more referrals to colposcopies and false positives (about 600 per 10,000).\u003c/p\u003e \u003cp\u003eIn Comparison 6a, the IMPROVE RCT from The Netherlands (n\u0026thinsp;=\u0026thinsp;13,799) examined self- versus clinician- sampling for hrHPV within arms using the same methods for triage to cytology (\u003cspan citationid=\"CR114\" class=\"CitationRef\"\u003e114\u003c/span\u003e). The certainty for all outcomes was very low for age groups 25\u0026ndash;29 and 60\u0026ndash;69 years because the trial only enrolled those aged 29\u0026ndash;61 years. There was low certainty evidence of little-to-no difference between arms for CIN 2\u0026thinsp;+\u0026thinsp;detection (1.5 fewer per 10,000 in self-sampling arm, 95% CI 36.5 fewer to 44.9 more) and very low certainty evidence for CIN 3\u0026thinsp;+\u0026thinsp;and ICC detection, both of which had imprecision though there were a higher number of CIN 3\u0026thinsp;+\u0026thinsp;cases detected in the self-sampling arm. There was moderate certainty evidence of little-to-no difference between arms in referrals and number of colposcopies (57 fewer from self-sampling) and for false positives for CIN 2+, CIN 3\u0026thinsp;+\u0026thinsp;and ICC (range 54 to 81 fewer). No incidence data was reported.\u003c/p\u003e \u003cp\u003eTwo RCTs from Sweden (Uppsala I [50\u0026ndash;60 year-olds] \u0026amp; II [30\u0026ndash;60 year-olds]; N\u0026thinsp;=\u0026thinsp;11,414) (\u003cspan citationid=\"CR106\" class=\"CitationRef\"\u003e106\u003c/span\u003e, \u003cspan citationid=\"CR109\" class=\"CitationRef\"\u003e109\u003c/span\u003e) compared hrHPV self- and clinician-sampling where individuals with positive tests in both arms had repeat testing with the same method 3\u0026ndash;6 months later and those persistent for hrHPV were referred to colposcopy (Comparison 7). There was low certainty evidence of little-to-no difference between arms for CIN 2\u0026thinsp;+\u0026thinsp;detection (32.5 fewer per 10,000 in self-sampling arm, 95% CI 65.3 fewer to 12.7 more) and very low certainty evidence for CIN 3\u0026thinsp;+\u0026thinsp;detection because of imprecision. There was low certainty evidence of little-to-no difference between arms in referrals and number of colposcopies (20 more from self-sampling) and for false positives for CIN 2\u0026thinsp;+\u0026thinsp;and CIN 3+ (49 and 35 more, respectively). One of the RCTs (\u003cspan citationid=\"CR109\" class=\"CitationRef\"\u003e109\u003c/span\u003e) enrolling 65% of the total sample in this comparison included only participants aged 50 years or older, so this age group was overrepresented in the analysis and we rated down for indirectness to the age range of interest (30\u0026ndash;59 years).\u003c/p\u003e \u003cp\u003e \u003cb\u003eComparisons 6b and 8\u0026ndash;10\u003c/b\u003e. Five small RCTs (range n analyzed\u0026thinsp;=\u0026thinsp;164 to 2,845) reported on the comparative effects involving hrHPV self-sampling in one or more arms among populations who were either non-responders or underscreened (\u003cb\u003eBox 1\u003c/b\u003e) (\u003cspan citationid=\"CR113\" class=\"CitationRef\"\u003e113\u003c/span\u003e, \u003cspan additionalcitationids=\"CR117 CR118\" citationid=\"CR116\" class=\"CitationRef\"\u003e116\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR119\" class=\"CitationRef\"\u003e119\u003c/span\u003e). In all but one (\u003cspan citationid=\"CR118\" class=\"CitationRef\"\u003e118\u003c/span\u003e) reporting on Comparison 9, the number of enrolled participants was far below (5.4%-13%) the number randomized and all RCTs were rated at high risk of bias. Very low certainty evidence was found for all reported outcomes (colposcopy, detection of CIN 2\u0026thinsp;+\u0026thinsp;and 3\u0026thinsp;+\u0026thinsp;and false positives) in these comparisons (\u003cb\u003eSupplementary file 1b\u003c/b\u003e). Four of these RCTs were also included in KQ5 on interventions to increase screening uptake (\u003cspan citationid=\"CR113\" class=\"CitationRef\"\u003e113\u003c/span\u003e, \u003cspan additionalcitationids=\"CR117\" citationid=\"CR116\" class=\"CitationRef\"\u003e116\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR118\" class=\"CitationRef\"\u003e118\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec28\" class=\"Section2\"\u003e \u003ch2\u003eKey Question 2: Comparative Accuracy\u003c/h2\u003e \u003cp\u003eTen studies in 11 papers were included for KQ2 (\u003cspan additionalcitationids=\"CR138 CR139 CR140 CR141 CR142 CR143 CR144 CR145 CR146\" citationid=\"CR137\" class=\"CitationRef\"\u003e137\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR147\" class=\"CitationRef\"\u003e147\u003c/span\u003e). Several studies included in other similar reviews we screened for eligibility (\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e, \u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e) were excluded either because they reported on comparisons excluded in this review (either per protocol or post hoc as per Methods), were conducted in countries without a Very High Development Index, or did not apply the reference standard in at least a sample of the test negative population. Characteristics and risk of bias assessment of included studies, and all evidence sets are presented in \u003cb\u003eSupplemental file 2\u003c/b\u003e.\u003c/p\u003e \u003cp\u003eThe median patient age was 40.0 years (range of means 23.0 to 45.8) with sample sizes ranging from 247 to 256,648 participants. Studies were generally from countries with organized screening, including two studies in Greece (\u003cspan citationid=\"CR137\" class=\"CitationRef\"\u003e137\u003c/span\u003e, \u003cspan citationid=\"CR140\" class=\"CitationRef\"\u003e140\u003c/span\u003e), three from the United States (\u003cspan citationid=\"CR138\" class=\"CitationRef\"\u003e138\u003c/span\u003e, \u003cspan citationid=\"CR139\" class=\"CitationRef\"\u003e139\u003c/span\u003e, \u003cspan citationid=\"CR141\" class=\"CitationRef\"\u003e141\u003c/span\u003e), and one from each of Canada (\u003cspan citationid=\"CR144\" class=\"CitationRef\"\u003e144\u003c/span\u003e), Germany (\u003cspan citationid=\"CR143\" class=\"CitationRef\"\u003e143\u003c/span\u003e), France (\u003cspan citationid=\"CR145\" class=\"CitationRef\"\u003e145\u003c/span\u003e), South Korea (\u003cspan citationid=\"CR146\" class=\"CitationRef\"\u003e146\u003c/span\u003e), and England (\u003cspan citationid=\"CR147\" class=\"CitationRef\"\u003e147\u003c/span\u003e). Only one study, conducted in Germany (\u003cspan citationid=\"CR142\" class=\"CitationRef\"\u003e142\u003c/span\u003e), was in an area with largely opportunistic screening. Only three studies reported that HPV vaccination had been implemented, with proportions of the study populations vaccinated ranging from 0.1\u0026ndash;4.0% (\u003cspan citationid=\"CR137\" class=\"CitationRef\"\u003e137\u003c/span\u003e, \u003cspan citationid=\"CR140\" class=\"CitationRef\"\u003e140\u003c/span\u003e, \u003cspan citationid=\"CR141\" class=\"CitationRef\"\u003e141\u003c/span\u003e). All studies were rated as having unclear risk of bias due to lack of reporting on items for one or more domains. Thresholds for a positive HPV screening test were generally not reported, but where reported the threshold was either 1.0 relative light unit (5,000 or more HPV DNA copies) (\u003cspan citationid=\"CR138\" class=\"CitationRef\"\u003e138\u003c/span\u003e) or 1.0 pg/ml (\u003cspan citationid=\"CR144\" class=\"CitationRef\"\u003e144\u003c/span\u003e, \u003cspan citationid=\"CR145\" class=\"CitationRef\"\u003e145\u003c/span\u003e, \u003cspan citationid=\"CR147\" class=\"CitationRef\"\u003e147\u003c/span\u003e). Findings for cytology are for the \u0026ge;\u0026thinsp;ASCUS threshold unless otherwise stated. Lastly, findings apply to CIN 2 and CIN 3 unless otherwise stated.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec29\" class=\"Section2\"\u003e \u003ch2\u003eFalse positives\u003c/h2\u003e \u003cp\u003eThe main purpose of this review was to examine false-positives from screening strategies used in KQ1 RCTs, when false positives were not reported in the RCT (i.e., for ICC from hrHPV alone versus cytology alone) or had very low certainty evidence. Additionally, we focused on comparisons between strategies not examined in the RCTs (e.g., hrHPV with cytology triage versus hrHPV, cytology with hrHPV triage versus cytology alone) to give some indication of where replacements/alternatives could possibly be used. \u003cb\u003eTable\u0026nbsp;4\u003c/b\u003e summarizes the findings for the comparative false positives between screening strategies. A conclusion of little-to-no difference indicates that there was less than 3% (300 per 10,000) fewer or more false positives with the first versus the second strategy.\u003c/p\u003e \u003cp\u003eOur evidence found that self- versus clinician sampling of hrHPV alone probably makes little-to-no difference in false positives.\u003c/p\u003e \u003cp\u003eCompared with hrHPV testing alone (via self-or clinician sampling), adding cytology triage or replacing the hrHPV test with one allowing partial genotyping with or without cytology triage, reduces the number of false positives. Though we did not rate our certainty in the magnitude of difference beyond the threshold of 3%, there appears to be a large reduction in false positives from adding cytology triage or genotyping to HPV alone (range 500 to almost 3,000 fewer per 10,000). There is probably little-to-no difference in false positives for CIN 2\u0026thinsp;+\u0026thinsp;or CIN 3\u0026thinsp;+\u0026thinsp;between hrHPV with partial genotyping (types 16/18) alone and hrHPV with cytology triage. Adding cytology for the non-16/18 types after using partial genotyping probably increases false positives.\u003c/p\u003e \u003cp\u003eResults from replacing cytology alone with hrHPV tests with partial genotyping (types 16/18) alone led to varying results based on the cytology threshold; when compared to cytological detection of \u0026ge;\u0026thinsp;ASCUS, there may be fewer false positives (which remain fewer if adding on cytology for non-16/18 types), whereas for cytological detection of \u0026ge;\u0026thinsp;LSIL there was little-to-no difference, and for atypical squamous cells \u0026ndash; cannot exclude HSIL (\u0026ge;\u0026thinsp;ASCH+) and \u0026ge;\u0026thinsp;HSIL the false positives probably increase when cytology is replaced by hrHPV. Adding hrHPV triage (with or without partial genotyping for types 16/18) to positive cytology may reduce false positives compared with cytology alone.\u003c/p\u003e \u003cp\u003eFindings within different age groups were in the same direction of effect for hrHPV alone versus cytology alone and for hrHPV with partial genotyping (types 16/18) alone versus hrHPV alone or cytology alone.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eSensitivity and specificity\u003c/h3\u003e\n\u003cp\u003eAll results and certainty assessments for sensitivity and specificity are included in \u003cb\u003eSupplemental file 2\u003c/b\u003e. As expected, in a majority of cases there is a trade-off between sensitivity and specificity and as such attempts to increase specificity (to reduce false positives) often lead to lower sensitivity (i.e., some number of missed cases). Assuming prevalence rates for CIN 2\u0026thinsp;+\u0026thinsp;of 1.4% and CIN 3\u0026thinsp;+\u0026thinsp;of 0.6%, as aggregated across the included studies, the reduction in sensitivity and thus number of missed cases varied across comparisons. For example, adding cytology triage (\u0026ge;\u0026thinsp;ASCUS) to hrHPV alone may increase specificity to a large degree (with possibly 3000 per 10,000 fewer false positives) but at the expense of missing some CIN 2+ (55 to 65 per 10,000; 2 studies, N\u0026thinsp;=\u0026thinsp;38,113) and CIN 3+ (23 per 10,000; 1 study, n\u0026thinsp;=\u0026thinsp;34,254) cases. Similar findings were found with replacing hrHPV alone with hrHPV with partial genotyping (types 16/18) alone (range 713 to 2943 fewer false positives but 58 to 73 fewer CIN 2\u0026thinsp;+\u0026thinsp;and 12 to 33 fewer CIN3\u0026thinsp;+\u0026thinsp;cases detected per 10,000; 3 studies, N\u0026thinsp;=\u0026thinsp;41,018), whereas replacing cytology (\u0026ge;\u0026thinsp;ASCUS) alone with hrHPV with partial genotyping (types 16/18) alone appears to have less impact (range 70 to 1830 false positives and up to 21 fewer CIN 2\u0026thinsp;+\u0026thinsp;and 9 fewer CIN3\u0026thinsp;+\u0026thinsp;cases detected per 10,000; 3 studies, N\u0026thinsp;=\u0026thinsp;41,018).\u003c/p\u003e \u003cp\u003eWith hrHPV alone, self-sampling probably has lower sensitivity than, and similar specificity to, clinician sampling for detecting CIN 2\u0026thinsp;+\u0026thinsp;or CIN2/3 (3 studies, N\u0026thinsp;=\u0026thinsp;2,832); the number of missed cases may be small (13 to 27 missed cases per 10,000). Cytology (\u0026ge;\u0026thinsp;ASCUS) with hrHPV triage with partial genotyping for types 16/18 versus cytology alone may increase specificity without impacting sensitivity (CIN 2\u0026thinsp;+\u0026thinsp;and CIN 3+; 1 study, n\u0026thinsp;=\u0026thinsp;2,905). In two comparisons there was little-to-no difference between strategies in sensitivity or specificity for CIN 3\u0026thinsp;+\u0026thinsp;detection, such that replacing one with the other may make little impact:\u003c/p\u003e \u003cp\u003e \u003col style=\"list-style-type:lower-roman;\"\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003ehrHPV with partial genotyping (types 16/18) alone versus hrHPV with cytology triage (\u0026ge;\u0026thinsp;ASCUS) (1 study, n\u0026thinsp;=\u0026thinsp;34,254; low [sensitivity] and moderate [specificity] certainty);\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003ecytology (\u0026ge;\u0026thinsp;ASCUS) with hrHPV triage versus cytology (\u0026ge;\u0026thinsp;ASCUS) alone (1 study, n\u0026thinsp;=\u0026thinsp;2,905; low certainty).\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003c/ol\u003e \u003c/p\u003e \u003cp\u003eThere is probably (moderate certainty) an increase in both sensitivity and specificity for the first strategy in two comparisons:\u003c/p\u003e \u003cp\u003e \u003col style=\"list-style-type:lower-roman;\"\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003ehrHPV with partial genotyping (types 16/18) with triage to cytology on non-16/18 types (\u0026ge;\u0026thinsp;ASCUS) versus hrHPV with cytology triage (\u0026ge;\u0026thinsp;ASCUS) (for CIN 3+; 1 study, n\u0026thinsp;=\u0026thinsp;34,254);\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003ehrHPV with partial genotyping (types 16/18) with triage to cytology on non-16/18 types (\u0026ge;\u0026thinsp;ASCUS) versus cytology (\u0026ge;\u0026thinsp;ASCUS) alone (CIN 2+; 2 studies, N\u0026thinsp;=\u0026thinsp;38,113 and CIN 3+; 1 study, n\u0026thinsp;=\u0026thinsp;34,254).\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003c/ol\u003e \u003c/p\u003e \u003cp\u003eFew studies reported on accuracy of ICC detection. One study (n\u0026thinsp;=\u0026thinsp;2,905) found that hrHPV with partial genotyping [types 16/18] increased sensitivity and reduced specificity for ICC compared with cytology alone (various thresholds). Most findings for CIN 2\u0026thinsp;+\u0026thinsp;and CIN 3\u0026thinsp;+\u0026thinsp;were similar for 20 to 29 and \u0026ge;\u0026thinsp;30-year-olds. Compared with cytology alone, hrHPV with partial genotyping 16/18 alone may decrease sensitivity for CIN 2\u0026thinsp;+\u0026thinsp;in 20 to 29-year-olds, but increase sensitivity in \u0026ge;\u0026thinsp;30-year-olds, both having low certainty.\u003c/p\u003e \u003cdiv id=\"Sec31\" class=\"Section2\"\u003e \u003ch2\u003eKey Question 3: Pregnancy Harms of Conservative Management of CIN\u003c/h2\u003e \u003cp\u003eTwo Cochrane reviews (\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e, \u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e) synthesized evidence about adverse pregnancy outcomes following excisional or ablative management of CIN (all grades and both squamous and glandular intra-epithelial neoplasia). One reported on early pregnancy outcomes (\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e), while the other focused on late obstetrical outcomes (\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e), and the latter also expanded the exposure of interest to early (stage IA1) cervical cancer. Both reviews examined outcomes among individuals treated for lesions compared with an untreated reference population (i.e., untreated females from the general population, internal controls of pregnancies in the same individual before treatment, or individuals with disease that did not receive treatment). All included studies were observational in design, thereby limiting certainty in the evidence (certainty started at low). Despite this, the authors rated most studies as good quality and did not rate down the certainty further for additional study limitations, indirectness or imprecision. \u003cb\u003eSupplemental file 3\u003c/b\u003e presents the summary of findings tables.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec32\" class=\"Section2\"\u003e \u003ch2\u003eEarly pregnancy outcomes\u003c/h2\u003e \u003cp\u003eThere may be little-to-no difference in total miscarriage rates between individuals treated for CIN and those not treated (RR 1.04, 95% CI 0.90 to 1.21; ARD 1 more, 95% CI 3 fewer to 6 more per 1000; 10 studies, N\u0026thinsp;=\u0026thinsp;39,504; low certainty evidence). The authors\u0026rsquo; meta-analysis found that, across all studies, CIN treatment was associated with increased risk of second trimester (12 to 24 weeks\u0026rsquo; gestation) miscarriage versus no treatment (RR 2.60, 95% CI 1.45 to 4.67; ARD 6 more, 95% CI 2 to 14 more per 1000; 8 studies, N\u0026thinsp;=\u0026thinsp;2,182,268). Based on input from the working group, current clinical practice for the management of CIN 2 has become much more conservative (e.g., avoiding excisional procedures, more surveillance due to better knowledge about their frequent regression) in recent years for those\u0026thinsp;\u0026le;\u0026thinsp;25 years old or prioritizing reproductive futures (\u003cspan citationid=\"CR148\" class=\"CitationRef\"\u003e148\u003c/span\u003e, \u003cspan citationid=\"CR149\" class=\"CitationRef\"\u003e149\u003c/span\u003e). Because of this, we rated down the certainty to very low from indirectness of the types of management provided in the studies (most conducted pre-2010) compared with current practice. Other priority outcomes in early pregnancy (i.e., cerclage and cervical insufficiency) were not addressed in the studies.\u003c/p\u003e \u003cdiv id=\"Sec33\" class=\"Section3\"\u003e \u003ch2\u003eLate obstetrical outcomes\u003c/h2\u003e \u003cp\u003eMeta-analysis of 59 studies found that preterm birth (\u0026lt;\u0026thinsp;37 weeks) rates were higher among individuals who have been treated for CIN or early cervical cancer compared with those who were not treated (RR 1.75, 95% CI 1.57 to 1.96; ARD 41 more, 95% CI 31 to 52 more per 1000; N\u0026thinsp;=\u0026thinsp;5,242,917). Risk for preterm birth progressively increased with increasing cone depth among persons treated for CIN or early cervical cancer by excisional procedures versus untreated controls (from RR of 1.54 for depth\u0026thinsp;\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026le;\u003c/span\u003e\u0026thinsp;10 to 12 mm to RR of 4.91 for depth\u0026thinsp;\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026ge;\u003c/span\u003e\u0026thinsp;20 mm). Other treatment factors that increased the risk for prematurity included multiple treatments versus single, excision rather than ablation management, and more radical treatment techniques. Because of clinical input that the management strategies in these studies would usually be more aggressive than used in current practice, we rated the certainty as very low from indirectness. Risk for low birth weight (\u0026lt;\u0026thinsp;2500 g) was also shown to be higher among individuals treated for CIN or early cervical cancer versus those who were not treated (RR 1.81, 95% CI 1.58 to 2.07; ARD 29 more, 95% CI 21 to 39 more per 1000; 30 studies, N\u0026thinsp;=\u0026thinsp;1,348,206), though this evidence was also rated down for indirectness to current practice. For both preterm birth and low birth weight, the review authors rated down the evidence for inconsistency; we did not rate down for this factor because a majority of study results were in the same direction of effect even if their magnitudes differed. Lastly, higher rates of cervical cerclage in later pregnancy were found for treated persons compared with untreated controls (RR 14.29, 95% CI 2.85 to 71.65; ARD 15.9 more, 95% CI 2.2 to 84.4 per 1,000; 8 studies, N\u0026thinsp;=\u0026thinsp;141,300), but again the certainty was very low.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec34\" class=\"Section3\"\u003e \u003ch2\u003eKey Question 4: Relative Importance of Potential Outcomes from Screening\u003c/h2\u003e \u003cp\u003eTwenty-three observational studies were included for this key question. Nineteen studies measured health state utility values (\u003cspan additionalcitationids=\"CR151 CR152 CR153 CR154 CR155 CR156 CR157 CR158 CR159 CR160 CR161 CR162 CR163 CR164 CR165 CR166 CR167\" citationid=\"CR150\" class=\"CitationRef\"\u003e150\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR168\" class=\"CitationRef\"\u003e168\u003c/span\u003e) and four measured preferences using other methods (\u003cspan additionalcitationids=\"CR170 CR171\" citationid=\"CR169\" class=\"CitationRef\"\u003e169\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR172\" class=\"CitationRef\"\u003e172\u003c/span\u003e). Across all studies, participant median age was 39.9 years (range of means 18.9 to 53.4) and the median sample size was 342 (range of sample sizes 36 to 146,336,855). Eleven studies were from Europe (\u003cspan citationid=\"CR151\" class=\"CitationRef\"\u003e151\u003c/span\u003e, \u003cspan additionalcitationids=\"CR156\" citationid=\"CR155\" class=\"CitationRef\"\u003e155\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR157\" class=\"CitationRef\"\u003e157\u003c/span\u003e, \u003cspan additionalcitationids=\"CR160\" citationid=\"CR159\" class=\"CitationRef\"\u003e159\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR161\" class=\"CitationRef\"\u003e161\u003c/span\u003e, \u003cspan citationid=\"CR167\" class=\"CitationRef\"\u003e167\u003c/span\u003e, \u003cspan additionalcitationids=\"CR171\" citationid=\"CR170\" class=\"CitationRef\"\u003e170\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR172\" class=\"CitationRef\"\u003e172\u003c/span\u003e), four from Australia (\u003cspan citationid=\"CR152\" class=\"CitationRef\"\u003e152\u003c/span\u003e, \u003cspan citationid=\"CR164\" class=\"CitationRef\"\u003e164\u003c/span\u003e, \u003cspan citationid=\"CR166\" class=\"CitationRef\"\u003e166\u003c/span\u003e, \u003cspan citationid=\"CR169\" class=\"CitationRef\"\u003e169\u003c/span\u003e), and four from the United States (\u003cspan citationid=\"CR153\" class=\"CitationRef\"\u003e153\u003c/span\u003e, \u003cspan citationid=\"CR154\" class=\"CitationRef\"\u003e154\u003c/span\u003e, \u003cspan citationid=\"CR158\" class=\"CitationRef\"\u003e158\u003c/span\u003e, \u003cspan citationid=\"CR165\" class=\"CitationRef\"\u003e165\u003c/span\u003e). One study was included from each of Canada (\u003cspan citationid=\"CR150\" class=\"CitationRef\"\u003e150\u003c/span\u003e), Japan (\u003cspan citationid=\"CR162\" class=\"CitationRef\"\u003e162\u003c/span\u003e), South Korea (\u003cspan citationid=\"CR163\" class=\"CitationRef\"\u003e163\u003c/span\u003e), and Thailand (\u003cspan citationid=\"CR168\" class=\"CitationRef\"\u003e168\u003c/span\u003e). Twelve studies measured utilities with the EQ-5D (and other instruments in some cases) whereas seven only measured utilities with another instrument. The main issues in risk of bias were low study recruitment rates and failure to perform appropriate analysis to adjust for confounding. Fifteen of the 23 studies recruited less than 50% of eligible subjects or lacked information in this domain. Additionally, 13 of the 19 studies estimating utility scores did not perform appropriate analysis to adjust for confounding. Characteristics of included studies, risk of bias assessments and summary of findings tables are presented in \u003cb\u003eSupplemental file 4\u003c/b\u003e.\u003c/p\u003e \u003cp\u003e \u003cstrong\u003eDisutilities\u003c/strong\u003e \u003cp\u003eA weighted average of EQ-5D utilities of the general public was calculated among five of the included studies for use as an indirect comparison to calculate estimates of disutilities in studies that lacked a control group. The resulting utility of the general public was 0.86 (95% CI 0.82 to 0.90), which was similar to that of estimates obtained in a Canadian population (\u003cspan citationid=\"CR173\" class=\"CitationRef\"\u003e173\u003c/span\u003e). We rated this estimate as having high certainty.\u003c/p\u003e \u003c/p\u003e \u003cp\u003eUsing the EQ-5D instrument, the disutility from cervical cancer is probably 0.11, more than one year after initiating treatment (\u003cspan citationid=\"CR155\" class=\"CitationRef\"\u003e155\u003c/span\u003e, \u003cspan citationid=\"CR160\" class=\"CitationRef\"\u003e160\u003c/span\u003e, \u003cspan citationid=\"CR162\" class=\"CitationRef\"\u003e162\u003c/span\u003e, \u003cspan citationid=\"CR165\" class=\"CitationRef\"\u003e165\u003c/span\u003e, \u003cspan citationid=\"CR168\" class=\"CitationRef\"\u003e168\u003c/span\u003e). Some within-study evidence suggests that the disutility may be considerably higher immediately after diagnosis or during treatment and/or with more disease severity. EQ-5D disutility from CIN 3 is very uncertain, but for CIN 2/3 it may be about 0.05 after (18 to 20 months) treatment (low certainty), with insufficient data from after a diagnosis to postulate whether disutility would significantly differ (\u003cspan additionalcitationids=\"CR161\" citationid=\"CR160\" class=\"CitationRef\"\u003e160\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR162\" class=\"CitationRef\"\u003e162\u003c/span\u003e). Additionally, there was high certainty of little-to-no disutility from having a false positive result after cytology screening, mainly in comparison with those screening with normal results (\u003cspan citationid=\"CR150\" class=\"CitationRef\"\u003e150\u003c/span\u003e, \u003cspan citationid=\"CR156\" class=\"CitationRef\"\u003e156\u003c/span\u003e, \u003cspan citationid=\"CR157\" class=\"CitationRef\"\u003e157\u003c/span\u003e, \u003cspan citationid=\"CR159\" class=\"CitationRef\"\u003e159\u003c/span\u003e, \u003cspan citationid=\"CR167\" class=\"CitationRef\"\u003e167\u003c/span\u003e). When using these data together with findings from utility measurement using other tools, cervical cancer may be at least twice as important as CIN 2/3, and both cervical cancer and CIN 2/3 are probably much more important than false positives. The relative utilities across outcomes from data within studies (\u003cspan citationid=\"CR160\" class=\"CitationRef\"\u003e160\u003c/span\u003e, \u003cspan citationid=\"CR161\" class=\"CitationRef\"\u003e161\u003c/span\u003e) that compared different health states using EQ-5D and TTO aligned with these findings, whereas the SG technique in one study (\u003cspan citationid=\"CR162\" class=\"CitationRef\"\u003e162\u003c/span\u003e) found quite similar utilities for ICC, CIN 3 and CIN 2.\u003c/p\u003e \u003cp\u003e \u003cb\u003eOther data on preferences\u003c/b\u003e: For the studies reporting on non-utility data, we did not undertake a narrative synthesis as planned (\u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e) because the four studies differed in their methodology and/or populations substantially (\u003cb\u003eSupplemental file 4)\u003c/b\u003e. All studies focused on preferences related to cytology screening. One quantitative study (n\u0026thinsp;=\u0026thinsp;248) (\u003cspan citationid=\"CR170\" class=\"CitationRef\"\u003e170\u003c/span\u003e) among those aged 30\u0026ndash;60 years eligible for the Dutch screening program directly assessed the importance of benefits versus harms from screening to inform screening decisions via an online survey using a 7-point Likert scale for ratings and a ranking system. We judged that the data provided portrayed a relatively high net benefit from screening over 30 years: ICC incidence (8 vs. 25 per 100,000) and mortality (2 vs. 8 per 100,000) versus false positives (1,000 among 100,000) and overdiagnosis (descriptive without numerical data). On the Likert scale the benefits were rated higher than harms (5.09 and 5.37 vs. 4.88 and 4.65, respectively), and when ranking the outcomes the benefits were ranked first and second. Some variability existed between participants (e.g., SDs 1.79 and 1.75 for ratings for ICC incidence and false positives), but results did not differ by age. The evidence was of low certainty that a large majority of individuals aged 30\u0026ndash;60 years may weigh the benefits as more important than the harms of screening for cervical cancer using cytology, but think it is important to provide information on benefits and harms for decision making.\u003c/p\u003e \u003cp\u003eThree other studies inferred preferences between the benefits and harms based on data on intentions or attitudes about screening (\u003cspan citationid=\"CR169\" class=\"CitationRef\"\u003e169\u003c/span\u003e, \u003cspan citationid=\"CR172\" class=\"CitationRef\"\u003e172\u003c/span\u003e) or a willingness-to-pay (WTP) experiment (\u003cspan citationid=\"CR171\" class=\"CitationRef\"\u003e171\u003c/span\u003e). One study (n\u0026thinsp;=\u0026thinsp;161; 12% previously screened) (\u003cspan citationid=\"CR169\" class=\"CitationRef\"\u003e169\u003c/span\u003e) in Australia provided university students (range 17\u0026ndash;24 years) with information on outcomes (stating no benefit in ICC incidence or mortality) using two decision aids that both detailed several harms but differed in whether they explained overdiagnosis (1,600 of 100,000 will have pre-cancers treated that may have resolved). Intentions (3.2\u0026thinsp;\u0026plusmn;\u0026thinsp;1.3 and 3.0\u0026thinsp;\u0026plusmn;\u0026thinsp;1.3 on 5-point Likert scale) and attitudes (31.1\u0026thinsp;\u0026plusmn;\u0026thinsp;8.8 and 32.8\u0026thinsp;\u0026plusmn;\u0026thinsp;8.2 on scale with range 6\u0026ndash;42 with higher indicating more positive attitude) did not differ between the two decision aids. This study found that some individuals\u0026thinsp;\u0026lt;\u0026thinsp;25 years may have intentions to screen even when informed that screening does not reduce cancer diagnoses or deaths for their age group (low certainty). Two other studies examined intentions to screen (n\u0026thinsp;=\u0026thinsp;283) and WTP (n\u0026thinsp;=\u0026thinsp;1,524) amongst regular screeners within the UK using comparisons between factual information and controls. Authors of the WTP study cite literature verifying the validity of WTP for screening in the UK. Both studies provided data on a large reduction in ICC incidence (e.g., 1 in 100,000 screened vs. 10 in 100,000 unscreened) and focused on false positives (e.g., 10% each year, one indicating 50% over 7 rounds) without any information on overdiagnosis of precancers. Although intentions and WTP reduced in intervention versus control groups, they remained quite high (79% vs. 88% and mean WTP 128\u0026pound; vs. 175 \u0026pound;). Findings indicated that across all ages that may be eligible for screening, a large majority of individuals may weigh the benefits as greater than the harms from screening for cervical cancer. Due to risk of bias and indirectness from relying on inferences about the relative importance of outcomes based on intentions/WTP for screening which may relate to other factors, we rated the certainty of evidence as low.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e\n\u003ch3\u003eKey Question 5: Effectiveness and Comparative Effectiveness of Interventions to Increase Screening Rates\u003c/h3\u003e\n\u003cp\u003eThere were 44 RCTs in 46 publications included for this key question. One RCT (\u003cspan citationid=\"CR119\" class=\"CitationRef\"\u003e119\u003c/span\u003e) included in KQ1 from our search update (a search update was not conducted for KQ5) also relates to this question but was not included in the synthesis; findings were very similar to those reported here for the effects of opt-in and universal HPV sampling kits. Characteristics of included trials are presented in \u003cb\u003eSupplemental file 5\u003c/b\u003e. Trials included a range of participant ages (range from 20 to 74 years) and were typically undertaken in organized screening settings with outcome ascertainment based on register or medical record data of having performed cervical cancer screening either through cytology or HPV testing. Sample sizes ranged from 88 to 90,247 participants. Of 46 publications, most were from Europe (\u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e, \u003cspan citationid=\"CR113\" class=\"CitationRef\"\u003e113\u003c/span\u003e, \u003cspan additionalcitationids=\"CR117\" citationid=\"CR116\" class=\"CitationRef\"\u003e116\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR118\" class=\"CitationRef\"\u003e118\u003c/span\u003e, \u003cspan additionalcitationids=\"CR175 CR176 CR177 CR178 CR179 CR180 CR181 CR182 CR183 CR184 CR185 CR186 CR187 CR188 CR189 CR190 CR191 CR192 CR193 CR194 CR195 CR196\" citationid=\"CR174\" class=\"CitationRef\"\u003e174\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR197\" class=\"CitationRef\"\u003e197\u003c/span\u003e), seven were from the United States (\u003cspan additionalcitationids=\"CR199 CR200 CR201 CR202 CR203\" citationid=\"CR198\" class=\"CitationRef\"\u003e198\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR204\" class=\"CitationRef\"\u003e204\u003c/span\u003e), four from Canada (\u003cspan additionalcitationids=\"CR206 CR207\" citationid=\"CR205\" class=\"CitationRef\"\u003e205\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR208\" class=\"CitationRef\"\u003e208\u003c/span\u003e), three from Australia (\u003cspan additionalcitationids=\"CR210\" citationid=\"CR209\" class=\"CitationRef\"\u003e209\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR211\" class=\"CitationRef\"\u003e211\u003c/span\u003e), two from Japan (\u003cspan citationid=\"CR212\" class=\"CitationRef\"\u003e212\u003c/span\u003e, \u003cspan citationid=\"CR213\" class=\"CitationRef\"\u003e213\u003c/span\u003e), and a single study from Malaysia (\u003cspan citationid=\"CR214\" class=\"CitationRef\"\u003e214\u003c/span\u003e). One trial in HIV-positive individuals with a cervix (\u003cspan citationid=\"CR199\" class=\"CitationRef\"\u003e199\u003c/span\u003e) was excluded from the meta-analyses and is described qualitatively due to a difference in population, intervention, and usual care compared with other studies. Five trials were considered at high risk of bias (\u003cspan citationid=\"CR113\" class=\"CitationRef\"\u003e113\u003c/span\u003e, \u003cspan citationid=\"CR174\" class=\"CitationRef\"\u003e174\u003c/span\u003e, \u003cspan citationid=\"CR181\" class=\"CitationRef\"\u003e181\u003c/span\u003e, \u003cspan citationid=\"CR205\" class=\"CitationRef\"\u003e205\u003c/span\u003e, \u003cspan citationid=\"CR214\" class=\"CitationRef\"\u003e214\u003c/span\u003e). Two trials considered high risk of bias had issues with random sequence generation (\u003cspan citationid=\"CR113\" class=\"CitationRef\"\u003e113\u003c/span\u003e, \u003cspan citationid=\"CR205\" class=\"CitationRef\"\u003e205\u003c/span\u003e), and baseline imbalances; and in single trials there was lack of allocation concealment (\u003cspan citationid=\"CR181\" class=\"CitationRef\"\u003e181\u003c/span\u003e), incomplete outcome reporting (\u003cspan citationid=\"CR174\" class=\"CitationRef\"\u003e174\u003c/span\u003e), and lack of blinding in a subjective/self-reported outcome assessment (\u003cspan citationid=\"CR214\" class=\"CitationRef\"\u003e214\u003c/span\u003e). The remaining trials were rated as having unclear risk of bias due to lack of reporting across multiple domains. Thus, no trial was considered at low risk of bias.\u003c/p\u003e \u003cp\u003eFive main analyses with large sample sizes were undertaken based on grouping similar interventions together; written contact (RR 1.50, 95% CI 1.22 to 1.84; ARD 619 fewer per 10,000, 95% CI 273 to 1041; 16 trials, N\u0026thinsp;=\u0026thinsp;138,880), personal contact (RR 1.50, 95% CI 1.07 to 2.11; ARD 797, 95% CI 1116 to 1770; 7 trials, N\u0026thinsp;=\u0026thinsp;17,034), composite interventions (RR 1.73, 95% CI 1.33 to 2.27; ARD 1351, 95% CI 610 to 2350; 8 trials, N\u0026thinsp;=\u0026thinsp;17,738), universal mail-out HPV (RR 2.56, 95% CI 2.10 to 3.12; ARD 1534, 95% CI 1082 to 2085; 22 trials, N\u0026thinsp;=\u0026thinsp;211,031), and opt-in HPV self-samples (RR 1.56, 95% CI: 1.19 to 2.03; ARD 727, 95% CI 247 to 1338; 11 trials, N\u0026thinsp;=\u0026thinsp;71,433). All interventions improved cervical cancer screening rates among persons with a cervix who were never or under-screened. The largest effects appear to be from mailing HPV self-sampling kits to all eligible persons, with about 15% more people screened. There was high heterogeneity in magnitude (not direction) of effect within four of the five main analyses, but none of the pre-specified subgroup analyses reduced heterogeneity (\u003cb\u003eSupplemental file 5\u003c/b\u003e). For the fifth analysis which indicated inconsistency in direction of effect, subgroup analysis indicated that the effectiveness of a strategy of opt-in HPV self-samples may be most applicable when the screening test is requested, obtained and returned via one\u0026rsquo;s home versus requiring an in-person contact (10 trials, N\u0026thinsp;=\u0026thinsp;61,908: RR 1.61, 95% CI 1.19 to 2.18 vs. 1 RCT n\u0026thinsp;=\u0026thinsp;9,525: RR 1.00, 95% CI 0.90 to 1.12, respectively). Examination of funnel plots and Egger\u0026rsquo;s tests (all p values\u0026thinsp;\u0026gt;\u0026thinsp;.05) did not indicate issues with small study effects. Using the GRADE approach and considering only direction of effect, the certainty of the evidence was rated high for all comparisons aside from opt-in HPV self-sampling, which was rated moderate certainty due to the concerns with inconsistency.\u003c/p\u003e \u003cp\u003ePre-specified between-study analyses exploring the effect of population characteristics (i.e., SES, immigrant, and indigenous status, and rural/remote communities) were not done due to a paucity of data; most trials did not report these characteristics. Further, screening rates by pre-specified populations within trials were not commonly reported. Generally, the magnitude of effects differed to some degree between populations but the interventions remained effective across groups with one exception: one universal mail-out trial in Italy showed improved screening uptake only in urban centers (\u003cspan citationid=\"CR183\" class=\"CitationRef\"\u003e183\u003c/span\u003e) (\u003cb\u003eSupplemental file 5\u003c/b\u003e).\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cdiv id=\"Sec37\" class=\"Section2\"\u003e \u003ch2\u003eSummary of principal findings for screening\u003c/h2\u003e \u003cp\u003eScreening for prevention and early detection of cervical cancer has previously been found to be effective when using cytology and findings across all ages examined in studies. This review focused on trying to better define screening intervals, which ages to start and stop screening, and what screening strategy(ies) to use based on the effects on the critical outcomes of incidence, mortality, and overdiagnosis. To inform ages to start and stop screening and screening intervals, there were no eligible trials and all observational studies (which stared at low certainty evidence) focused on cytology screening. For age to start screening, we found very low certainty evidence, largely based on inconsistent results across studies and indirectness of the categorical age data, for risk of ICC and mortality from cervical cancer in persons with a cervix aged 20 to 24, 25 to 29, and 30 to 34 years. For age to stop, there was moderate certainty evidence (from rating up for large effect) that screening is probably associated with a lower risk of ICC (e.g., at least 9 fewer cases per 10,000 screened) and cervical-cancer mortality (at least 0.19 to 0.29 fewer deaths per 10,000) over 10 years among those aged 60\u0026ndash;69 years who had no screen, an abnormal screen, or inadequate screening in their 50s. For those aged 60\u0026ndash;69 years who were adequately screened in their 50s (i.e., only negative screening results at least twice about 5 years apart), the reduction in ICC was smaller so the evidence was rated at low certainty. A reduced risk for ICC among 70 to 79-year-olds was found but with low or very low (for those adequately screened previously) certainty, and data were limited for associations with cervical-cancer mortality in this age category. Based on the existing evidence, we are very uncertain about whether the effects on the incidence of ICC or cervical-cancer or all-cause mortality differ between cytology screening intervals of 3 years or under versus 3 to 5 years.\u003c/p\u003e \u003cp\u003eThere were no eligible trials to inform about any strategy involving hrHPV testing versus no screening. For comparative effectiveness between different screening strategies, this review found 10 major comparisons examined in trials. All but one of the trials reported on one randomized screening round (i.e., any subsequent testing method was similar across groups and used for incidence data), with a maximum follow-up of 5 years (18 months to 5 years) for incidence of CINs and ICC. All of the trials only enrolled and thus reported outcomes for acceptors of screening so the effects at a population level from an invitation/offer to screen to individuals are less certain. There was very low certainty for all-cause mortality from one trial, no data on cervical-cancer mortality, and very low certainty evidence about overdiagnosis from one observational analysis by authors of one trial. Few trials reported directly on the incidence of CIN or ICC (and if so most evidence was of very low certainty), and a post hoc decision was made to analyze detection rates of CIN 2\u0026thinsp;+\u0026thinsp;and CIN 3\u0026thinsp;+\u0026thinsp;as surrogates for incidence of CIN 3\u0026thinsp;+\u0026thinsp;and ICC, respectively, but for which we rated down our certainty for indirectness.\u003c/p\u003e \u003cp\u003eIn comparison with cytology alone, where only three trials provided data for screening using hrHPV alone or hrHPV with triage to cytology, very-low certainty evidence was found across most critical benefit outcomes though hrHPV with triage to cytology may reduce incidence of ICC from detecting more cases of CIN3+. There was moderate certainty that hrHPV alone considerably increased false positives for those aged 25\u0026ndash;29 years, whereas hrHPV with cytology triage probably does not unless a recall phase (additional testing after the initial triage within every round) is added. Data from four trials provided evidence that hrHPV with cytology triage versus cytology with hrHPV triage probably reduces incidence of ICC to some degree for those aged 30\u0026ndash;59 years, without adding harm. For those aged 25\u0026ndash;29 years, when recalls are used there may be a reduction in CIN3\u0026thinsp;+\u0026thinsp;incidence (via more detection of CIN2+) at the expense of an increase in referrals to colposcopy and false positives (possibly exceeding 900 per 10,000 for CIN 2\u0026thinsp;+\u0026thinsp;diagnosis). Findings from one trial comparing two rounds of cytology with hrHPV triage (over 4 years) and one round of hrHPV with cytology triage (both including recall stages) suggested that one round of hrHPV testing every four years may make little-to-no difference in incidence of CIN 2 or 3+, and probably has similar rates of harms as do two rounds of cytology with hrHPV triage. Evidence for incidence of ICC was of very low certainty. From one small trial, it is uncertain what the effects are on incidence of ICC from adding partial genotyping to these triage strategies for those aged 30\u0026ndash;59 years; there may be little-to-no difference in incidence of CIN3\u0026thinsp;+\u0026thinsp;may and probably no difference in harms. Effects on all benefit outcomes from adding partial genotyping were of very low certainty for those aged 25\u0026ndash;29 and 60\u0026ndash;69 years due to small samples in these age categories. For those aged 30\u0026ndash;59 years, one RCT provided moderate certainty of little-to-no difference in false positives between hrHPV self-sampling with cytology triage compared with hrHPV clinician-sampling with cytology triage, and low certainty that there may be little-to-no impact on incidence of CIN 3+. Two RCTs enrolling people 30\u0026ndash;60 and 50\u0026ndash;60 years compared hrHPV self- and clinician-sampling each with triage to repeat the hrHPV testing at 3\u0026ndash;6 months, with evidence of low certainty for little-to-no difference in CIN 2\u0026thinsp;+\u0026thinsp;detection, and low certainty for little-to-no difference for false positives. Five small RCTs reported on the comparative effects involving hrHPV self-sampling in one or more arms among populations who were either non-responders or underscreened. Very low certainty evidence was found for all reported outcomes (detection of CIN 2\u0026thinsp;+\u0026thinsp;and 3\u0026thinsp;+\u0026thinsp;and false positives) in these comparisons.\u003c/p\u003e \u003cdiv id=\"Sec38\" class=\"Section3\"\u003e \u003ch2\u003eFindings from indirect evidence on comparative test accuracy and treatment harms\u003c/h2\u003e \u003cp\u003eThough the focus of the recommendations will be on screening, questions on comparative accuracy of different screening strategies and adverse pregnancy outcomes from conservative management of CIN were included to provide additional information. For example, if recommendations were made about a screening strategy shown effective in an RCT eligible for KQ1 there may be the ability to also recommend a different strategy\u0026mdash;such as one easier to administer\u0026mdash;having similar accuracy but not examined in the trial setting (Table\u0026nbsp;4 findings from accuracy studies and Supplemental file 2). Further, we expected to have little if any data from the screening RCTs on the adverse pregnancy outcomes from conservative management of CIN, such that this data from treatment studies would help fill this evidence gap, albeit indirectly.\u003c/p\u003e \u003cp\u003eFor comparative accuracy, we focused on studies from Very High Development Index countries, that also made efforts to minimize verification bias by giving a sample of screen negative participants the reference standard. The criteria led to relatively high certainty in our evidence due to lack of concerns over directness and, generally, lower risk of bias. The main finding when looking at false positives was that compared with hrHPV testing alone (via self-or clinician sampling), adding cytology triage or replacing the hrHPV test with one allowing partial genotyping with or without cytology triage, reduces the number of false positives. There is probably little-to-no difference in false positives between hrHPV with partial genotyping (types 16/18) alone and hrHPV with cytology triage. Further, adding hrHPV triage (with or without partial genotyping for types 16/18) to positive cytology may reduce false positives compared with cytology alone. Findings within different age groups were in the same direction of effect for hrHPV alone versus cytology alone and for hrHPV with partial genotyping (types 16/18) alone versus hrHPV or cytology alone.\u003c/p\u003e \u003cp\u003eThere is often a trade-off between sensitivity and specificity. If the goal is to reduce harms (false positives and the associated follow-up tests and sequelae) by increasing specificity, minimal loss in sensitivity would be the aim as appears to occur when replacing cytology alone (threshold ASCUS+) with either cytology with triage to hrHPV with partial genotyping (little-to-no difference in sensitivity for CIN 2\u0026thinsp;+\u0026thinsp;or 3+) or hrHPV with partial genotyping (types 16/18) alone (up to 21 fewer CIN 2\u0026thinsp;+\u0026thinsp;and 9 fewer CIN3\u0026thinsp;+\u0026thinsp;cases detected per 10,000; 3 studies, N\u0026thinsp;=\u0026thinsp;41,018). Better yet, we found moderate certainty for increasing both sensitivity and specificity from using hrHPV with partial genotyping (types 16/18) with triage to cytology on non-16/18 types (ASCUS+) versus cytology alone (ASCUS+).\u003c/p\u003e \u003cp\u003eThe ability to make triage to cytology after hrHPV testing feasible may rely on there being the availability of performing (reflex) cytology testing on an hrHPV sample, to avoid the need for individuals to attend a clinic for another test, or even for one test if using mailed hrHPV self-sampling kits to maximize access or acceptability. Reflex cytology from hrHPV self-sampling would need also to rely on there being sufficient collection of cervical epithelial cells which may be unlikely. Though self-sampling for hrHPV alone probably has lower sensitivity and similar specificity compared with clinician sampling for detecting CIN 2\u0026thinsp;+\u0026thinsp;or CIN2/3, the number of missed cases may be small (13 to 27 missed cases per 10,000) and this method of testing may have a role if it can increase coverage in the under- and never-screened. One caveat is that we did not find any eligible studies comparing self- versus clinician-sampling for hrHPV with partial genotyping to know if findings are similar to those for hrHPV alone.\u003c/p\u003e \u003cp\u003eFrom findings of two existing systematic reviews of observational studies, there is low certainty that conservative management of CIN 2/3 may make little-to-no difference for total miscarriage rates, but very low certainty about whether there are associations with rates of second trimester miscarriage, preterm birth (\u0026ge;\u0026thinsp;37 weeks\u0026rsquo; gestation), low birth weight (\u0026lt;\u0026thinsp;2500 g), or cervical cerclage due to the indirect nature of the treatment approaches in most of the studies compared with current practice that has become more conservative especially for younger people. Even if there were some certainty of harm, the magnitude of effects would be expected to be very small when considering a screening population where only a portion is treated for CIN 2/3 and at reproductive age. For example, if applying the absolute effects from treatment (60 events per 10,000 treated) to an estimate (on average across the trials showing benefit for more detection and with rates cut in half to capture those at reproductive age) of 15 more cases of CIN3\u0026thinsp;+\u0026thinsp;per 10,000, there may be at most 0.1 more second trimester miscarriages per 10,000 screened.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec39\" class=\"Section2\"\u003e \u003ch2\u003ePatient preferences\u003c/h2\u003e \u003cp\u003eThe disutilities of ICC and CIN 2\u0026thinsp;+\u0026thinsp;were estimated at 0.11 and 0.05, respectively. Though there may not be high confidence that the disutility from having cancer is more than twice that from a CIN 2\u0026thinsp;+\u0026thinsp;diagnosis and management, there is evidence to support that there is an important difference between the health states based on reported minimally important differences in disutility of 0.06 to 0.16 and 0.037 to 0.056 for cancer and general populations, respectively, with use of the EQ-5D measurement tool (\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan citationid=\"CR215\" class=\"CitationRef\"\u003e215\u003c/span\u003e). We found high certainty evidence that there is little to no disutility from a false positive result when screening with cytology, but any reduction in disutility from fewer ICC occurring in screening still needs to be weighed against that from a portion of CIN 2/3 cases that may be overdiagnosed. Further, because the findings for a false positive were specific to use of cytology screening, we are less certain about the degree of relative importance between ICC/CIN 2\u0026thinsp;+\u0026thinsp;and false positives in hrHPV screening. Perceptions by some individuals of negative consequences of an HPV infection, including stigmatization and possible relationship distress (\u003cspan citationid=\"CR216\" class=\"CitationRef\"\u003e216\u003c/span\u003e), could create some disutility from a false positive result if the negative perceptions actually impact one\u0026rsquo;s overall quality of life. Other studies on patient preferences about cytology screening indicated, with low certainty, that a large majority of individuals eligible for screening may weigh the benefits as more important than the harms of screening for cervical cancer using cytology, but think it is important to provide information on benefits and harms for decision making. One study suggested that some individuals\u0026thinsp;\u0026lt;\u0026thinsp;25 years may have intentions to screen even when informed that screening does not reduce cancer diagnoses or deaths for their age group and leads to overdiagnosis.\u003c/p\u003e \u003cdiv id=\"Sec40\" class=\"Section3\"\u003e \u003ch2\u003eIncreasing participation rates for under-never-screened populations\u003c/h2\u003e \u003cp\u003eOur review on interventions to increase screening rates among under- or never-screened individuals found high certainty that various interventions could be successful. The effects from providing mailed-out self-sampling hrHPV kits appear to be greater than for less resource-intensive interventions including written and in-person reminders or promotional education. Though mailing out kits may have upfront costs, there will likely be fewer visits to primary care providers needed. However, the downstream effects on subsequent management of results was not examined to understand the full implications. Although self- versus clinician sampled tests may be somewhat less sensitive, if able to achieve any versus no screening for these populations there may be benefit for their use. To successfully apply any of the interventions, the ability to target the under-screened populations would be necessary, as would some assurance of successful follow-up procedures whether there be some manner of in-person visit or reflex cytology on the HPV test sample, if collection of enough cervical cells could be relied upon.\u003c/p\u003e \u003cp\u003e \u003cb\u003eComparisons with other reviews\u003c/b\u003e \u003c/p\u003e \u003cp\u003eThe previous review conducted for the task force included an RCT from India that found that a single lifetime cytology screening test significantly decreased the risk of mortality from and incidence of advanced cervical cancer compared to no screening (mortality: RR 0.65, 95% CI 0.47 to 0.90; incidence: RR 0.56, 95% CI 0.42 to 0.75). Although our review only included studies from countries with a Very High Development Index, its focus on screening ages and intervals differed from the overall effectiveness of cytology screening in the previous review because the task force was not challenging the strength or direction of the previous recommendation for cytology-based screening. Our review closely examined effects of screening in discrete age categories in attempts to further elucidate ages to start and stop screening as well as the frequency of screening. Several more recent studies were captured for this evaluation.\u003c/p\u003e \u003cp\u003eUnlike some other reviews on the comparative effectiveness of screening, we did not include studies using co-testing where all participants received hrHPV and cytology screening at the same time. Authors of a meta-analysis of four European trials, NTCC and three others using co-testing (POBASCAM, Swedescreen, ARTISTIC) concluded that \u0026ldquo;HPV-based\u0026rdquo; versus cytology alone led to a 60\u0026ndash;70% greater protection against ICC (cumulative incidences of 4.6 per 100,000 [95% CI 1.1 to 12.1] and 8.7 per 100,000 [3.3 to 18.6] at 3.5 and 5.5 years, respectively, in HPV-based versus 15.4 per 100,000 [7.9 to 27.0] and 36.0 per 100,000 [23.2 to 53.5] with cytology) (\u003cspan citationid=\"CR217\" class=\"CitationRef\"\u003e217\u003c/span\u003e). The absolute risk reduction of 29 fewer per 100,000 at 5.5 years approaches the threshold used for an important effect in this review (3 fewer per 10,000) but co-testing is not currently considered a cost-effective approach in Canada. Our review eligibility also differs in this regard from those undertaken for the United States Preventive Services Task Force (\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e). Other major organizations have also used analyses of these studies to support hrHPV screening (\u003cspan citationid=\"CR218\" class=\"CitationRef\"\u003e218\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eOne systematic review also found lower sensitivity for self-sampling versus clinician-sampling when using commonly used signal-amplification tests (e.g., Hybrid Capture II), but additionally found lower specificity for these tests whereas our review did not find a difference (\u003cspan citationid=\"CR219\" class=\"CitationRef\"\u003e219\u003c/span\u003e). This variation may partially be explained by the inclusion criteria (e.g., included countries) which resulted in significantly fewer but more applicable studies included for our review. This review as well as another found that self-sampling polymerase chain reaction (PCR) tests were more sensitive than those using signal amplification (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e); our review did not have this feature of the test as a specific variable for subgroup analysis, nor did we include enough studies for each comparison to make valid conclusions in this respect. Another earlier review comparing accuracy of hrHPV to cytology tests had similar conclusions to this review, that although differences in sensitivity between tests could be interpreted as large, absolute differences in missed diagnoses were often small (\u003cspan citationid=\"CR220\" class=\"CitationRef\"\u003e220\u003c/span\u003e). Small differences in specificity can result in fairly large absolute differences in false positives.\u003c/p\u003e \u003cp\u003e Other reviews have examined utility values of cervical cancer screening health states. Similar to our review, findings of group estimating disutilities of the screening process and diagnostic workup stage indicated disutilities of near zero when studies employed the EQ-5D tool (\u003cspan citationid=\"CR221\" class=\"CitationRef\"\u003e221\u003c/span\u003e). Authors of another review reported heterogeneity among findings of health state utilities across several timepoints before and after screening, which may have been related to their use of both EQ-5D index and VAS scores (known to differ) as well as samples of patients as well as the general public (\u003cspan citationid=\"CR222\" class=\"CitationRef\"\u003e222\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eImproved rates of screening uptake using mail-out HPV kits were also reported in a systematic review that included individuals in the general population, not limited to non-responders to regular screening (\u003cspan citationid=\"CR223\" class=\"CitationRef\"\u003e223\u003c/span\u003e). Opt-in HPV self-sampling, in which eligible persons had to request a kit, was less consistently effective for increasing screening uptake in our review and in two prior reviews (\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e, \u003cspan citationid=\"CR223\" class=\"CitationRef\"\u003e223\u003c/span\u003e). This differential finding from acquisition of HPV self-samples implies that characteristics specific to mail-out samples may be more acceptable to recipients than opt-in options (e.g., convenience, kit acts as a reminder). In support of this theory, a Canadian Health Technology Assessment (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e) found that logistical inconvenience was one barrier to participation in cervical cancer screening in Canada and countries with comparable health care (e.g., US, Australia) and a study in Geneva (Switzerland) (\u003cspan citationid=\"CR224\" class=\"CitationRef\"\u003e224\u003c/span\u003e) reported that practical considerations (e.g., lack of time) were the most cited reasons for non-participation in cervical cancer screening programs. Moreover, one Canadian trial (\u003cspan citationid=\"CR208\" class=\"CitationRef\"\u003e208\u003c/span\u003e) in a rural setting, which explored the acceptability of HPV self-sampling, found that about 43% of respondents assigned to the HPV self-sample arm reported that they would not have been screened for cervical cancer if they had not received the testing kit at home, with the majority (almost 90%) of those who performed HPV self-testing agreeing that HPV self-testing was acceptable and that they would use it in future (90%) and recommend it to a friend or family member (88%). Although the acceptance of self-sampling kits may be high, if screening completion required triage to cytology the overall uptake may be lower as may follow-up of positive tests which requires in-person visit(s). Notably in some of the trials in our review (\u003cspan citationid=\"CR176\" class=\"CitationRef\"\u003e176\u003c/span\u003e, \u003cspan citationid=\"CR182\" class=\"CitationRef\"\u003e182\u003c/span\u003e, \u003cspan citationid=\"CR189\" class=\"CitationRef\"\u003e189\u003c/span\u003e), some individuals who received an HPV-self sample kit in the mail completed a Pap smear in clinic, rather than sending back the sample, suggesting the presence of a \u0026ldquo;nudge\u0026rdquo; effect in these participants.\u003c/p\u003e \u003cp\u003e \u003cb\u003eLimitations of the evidence\u003c/b\u003e \u003c/p\u003e \u003cp\u003eAlthough the studies included in this review were generally of high quality there are limitations in their findings for various other reasons. The data in several of the observational studies used to examine ages to start and stop screening were not closely aligned with the 5-year age categories of interest for this review, such that this evidence was rated down for indirectness of the population because of the need to assume that the effects would be similar in often wider age ranges than we analyzed. No RCTs have been conducted comparing cytology alone to hrHPV with partial genotyping with or without triage to cytology. Using comparative accuracy data to fill this gap may be problematic since the accuracy of the tests is one of several considerations for measuring effectiveness of screening. Trials on other comparisons of effectiveness of screening approaches mainly included one round of screening such that effects from longer-term screening are not known. The enrolled participants were also those attending for their screening visit (acceptors of screening) and as such the effects of offers to screening at a population level are unclear. Reporting of HPV vaccination status was poor across observational studies and trials of screening effectiveness, though many were conducted in time periods where very few participants would have been vaccinated. Scarce data was reported for specific populations apart from age. The need to use indirect evidence about detection rates to infer what might happen to the downstream health states (e.g., CIN 3\u0026thinsp;+\u0026thinsp;detection for assessing incidence of ICC) limited the certainty in the evidence. The lack of certainty about effects on overdiagnosis to weigh against reductions in cancer incidence is concerning. Based on epidemiological data, if 82% of CIN 2 lesions either regress to normal/CIN 1 or remain unchanged and if only 30% of CIN 3 progress to cancer (\u003cspan additionalcitationids=\"CR16\" citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e) there could be considerable psychosocial harm from labelling and/or physical harm from treatment of a lesion that would never have been identified without screening. We did not locate any preference studies that used methods to generate trade-offs between the benefit and harm outcomes, to understand what the maximum acceptable number of harms may be to prevent one case of ICC.\u003c/p\u003e \u003cp\u003e \u003cb\u003eStrengths and limitations of the review\u003c/b\u003e \u003c/p\u003e \u003cp\u003e We comprehensively reviewed evidence related to the benefits and harms of screening and of different screening strategies for the prevention of cervical cancer by first considering direct evidence from studies on screening, and supplementing this by reviews on the comparative accuracy of screening tests and strategies and on the harms of treatment of CIN. We also reviewed evidence on patient preferences to assist with judgements about the balance of benefits with harms. We assessed our certainty in all outcomes to enable decision-making based on various factors that influence conclusions. Findings are likely not highly applicable to settings considering co-testing using hrHPV and cytology because trials examining this screening strategy were not eligible for this review. We implemented rigorous searches to locate all potentially relevant studies; though our eligibility was limited to English and French language studies our criteria of using studies from Very High Development Index countries raises confidence that we did not miss any influential studies. Some of the decision for eligibility (e.g., limiting studies on screening versus no screening to ages to start and stop screening and screening intervals; comparisons of interest for KQ2 on accuracy) and analysis (e.g., subgroups for assessing heterogeneity in KQ5 on interventions to increase uptake; thresholds for use when assessing certainty of outcomes in KQs 1 and 2) were made after the protocol was developed, but all decisions were made prior to the task force being aware of study findings. The evidence used in the reviews we summarized for KQ3 on harms from management of CIN is likely not completely up to date. We had anticipated that these reviews would be updated during the period of our review but this did not occur. Assessing findings from more recent studies, if they exist and have large samples and good quality, using contemporary treatment approaches may be useful. In KQ4 on outcome valuation, our search was limited to health states encountered during a program for screening for cervical cancer and thus no studies on the disutility from the harms from treatment of CIN (e.g., preterm birth) were found.\u003c/p\u003e \u003cp\u003e \u003cb\u003eResearch gaps\u003c/b\u003e \u003c/p\u003e \u003cp\u003eTrials of more than one randomized screening round with enough unselected participants and long-term follow-up to examine the comparative effects of different strategies on incidence of ICC, mortality rates, and overdiagnosis are needed. More research is needed once prevalence of hrHPV reduces due to vaccination; this will help determine if vaccination as a preventive strategy is sufficient to reduce or replace screening at some point. Due to a larger risk-to-benefit ratio, there is still uncertainty about the effects of screening all individuals under 30 to 35 years of age, particularly if using a test with lower specificity. Prospective controlled trials comparing different ages to stop screening, different intervals of screening, and examining the effects for various subpopulations are also needed.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Conclusions","content":"\u003cp\u003eScreening for prevention or early detection of cervical cancer with cytology has been employed for decades and is probably effective for otherwise healthy persons with a cervix at least into their 60s. Whether to screen individuals younger than 35 years old using cytology is uncertain based on need to rely on observational evidence without consistent reporting across these age groups. Screening during ones 60s and 70s may have less effect for those adequately screened in their 50s. The effects of screening with cytology every 5 years versus 3 years are uncertain. The evidence provided very low certainty about any differential impacts between various screening strategies on mortality and overdiagnosis outcomes and comparative effectiveness was mostly limited to one round of screening among those attending screening. Compared with cytology alone or cytology with hrHPV triage, there was evidence of a small benefit from reducing ICC from using hrHPV with cytology triage though findings were most robust for those aged 30\u0026ndash;59 years. Any additional benefit from adding recall is not clear especially for those 25\u0026ndash;29 years where it probably adds substantial harm. There is some indication that screening using hrHPV with triage to cytology every 4 years may lead to similar detection of cancer precursors as would cytology with hrHPV triage conducted every 2 years, though the effects compared with cytology testing alone were not examined. Further, it is uncertain what the effects are on incidence of ICC from adding partial genotyping to the triage strategies for those aged 30\u0026ndash;59 years. For those aged 30\u0026ndash;59 years, moderate certainty evidence found little-to-no difference in false positives between hrHPV self-sampling with cytology triage compared with hrHPV clinician-sampling with cytology triage, and low certainty that there may be little-to-no impact on incidence of CIN 3+. The comparative effectiveness studies did not examine all relevant comparisons and thus comparative accuracy data may help provide suggestions of possible alternative strategies with similar sensitivity and specificity. Most of the studies on screening effects were undertaken in populations either in which HPV vaccination had not been implemented or carried out in a period when vaccination rates were low. For under- or never-screened individuals, self-sampled hrHPV tests may improve screening rates with similar test accuracy, but it is uncertain if findings apply when triage to cytology is used because of the need for adequate cervical cells and likely a clinic visit. ICC and CIN2/3 probably make an important impact on one\u0026rsquo;s quality of life, whereas a false positive result when using cytology alone does not; whether the disutility of a false positive result applies to hrHPV testing is unknown. There was low certainty evidence that informed individuals eligible for screening think the benefits outweigh the harms from screening. Choices for screening strategies apart from cytology alone may result largely from contextual considerations such as access, acceptability, resources and costs.\u003c/p\u003e "},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate.\u0026nbsp;\u003c/strong\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication.\u0026nbsp;\u003c/strong\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials.\u0026nbsp;\u003c/strong\u003eThe data generated during this study are available within the manuscript or its supplementary files.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests.\u0026nbsp;\u003c/strong\u003eAG is an employee of the Canadian Agency for Drugs and Technologies in Health (CADTH). The current work was unrelated to her employment and CADTH had no role in the funding, design, or oversight of the work.\u0026nbsp;The remaining authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding.\u0026nbsp;\u003c/strong\u003eThis review was conducted for the Public Health Agency of Canada (PHAC). The contents of this manuscript do not necessarily represent the views of the Government of Canada.\u0026nbsp;Dr. Hartling is supported by a Canada Research Chair in Knowledge Synthesis and Translation. The funding body had no role in the design of the study, nor the collection, analysis, and interpretation of data.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eContributions of the authors. JP\u003c/strong\u003e contributed to the conception and design of the work, provided methodological expertise at all phases, participated in certainty of evidence appraisals, assisted with drafting the manuscript, and is the guarantor of the review. \u003cstrong\u003eAG\u003c/strong\u003e contributed to the conception and design of the work, screened studies for inclusion (all KQs), extracted and verified data (KQs 1, 2 and 5), and participated in risk of bias (KQs 1, 2 and 5) and certainty assessments (KQ1).\u003cstrong\u003e\u0026nbsp;BZ\u0026nbsp;\u003c/strong\u003eextracted and verified data (KQ 1 and 5); participated in risk of bias, data analysis, and certainty assessments (KQs 1 and 5), and drafted portions of the manuscript. \u003cstrong\u003eSG\u003c/strong\u003e screened citations (all KQs), extracted and verified data (KQs 1, 2 and 4); participated in risk of bias, data analysis, and certainty assessments (KQs 1, 2 and 4), and drafted portions of the manuscript. \u003cstrong\u003eSS\u003c/strong\u003e screened studies (all KQs) and participated in data extraction and risk of bias assessments (KQs 1 and 5). \u003cstrong\u003eBV\u003c/strong\u003e provided statistical input for KQs 1, 2 and 5. \u003cstrong\u003eLH\u003c/strong\u003e contributed to the conception and design of the work, and provided methodological input at all phases. All authors have reviewed drafts of the manuscript for important intellectual content and approve of the version of the manuscript as submitted.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments.\u0026nbsp;\u003c/strong\u003eWe thank previous and current Task Force members serving on this topic\u0026rsquo;s Working Group (Donna Reynolds, Guyl\u0026egrave;ne Th\u0026eacute;riault, Brett D Thombs, Nathalie Slavtcheva, Richard Henry) and the clinical experts (Julian Little, Catherine Popadiuk, Dirk van Niekerk) for helping to interpret the findings and for reviewing drafts of the manuscript. We would like to acknowledge current or past Task Force members who were not in the Working Group: Ahmed Abou-Setta, Eddy Lang, Scott Klarenbach, Ashraf Sefin, Gail Macartney, Henry Siu, Jennifer Flemming, Kate Miller, Keith Todd, and Patricia Li who reviewed a draft of this manuscript. We thank information specialists Diana Keto-Lambert for developing the search strategy, Tara Landry for peer reviewing the search strategy, and Maria Tan for running the search updates. \u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eCanadian Cancer Statistics Advisory Committee in collaboration with the Canadian Cancer Society, Statistics Canada and the Public Health Agency of Canada. Canadian Cancer Statistics 2023. Toronto, ON: Candian Cancer Society. 2023. Available from: https://cdn.cancer.ca/-/media/files/research/cancer-statistics/2023-statistics/2023_pdf_en.pdf. Accessed 7 July 2024.\u003c/li\u003e\n\u003cli\u003eNavaneelan T. Trends in the incidence and mortality of female reproductive system cancers. Health at a Glance. Statistics Canada Catologue no 82-624-X. 2015. https://www150.statcan.gc.ca/n1/pub/82-624-x/2015001/article/14095-eng.htm . Accessed 7 July 2024\u003c/li\u003e\n\u003cli\u003eStatistics Canada. 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BMJ Sex Reprod Health. 2022;48(4):295-306.\u003c/li\u003e\n\u003cli\u003eRonco G, Dillner J, Elfstr\u0026ouml;m KM, Tunesi S, Snijders PJ, Arbyn M, et al. Efficacy of HPV-based screening for prevention of invasive cervical cancer: follow-up of four European randomised controlled trials. Lancet. 2014;383(9916):524-32.\u003c/li\u003e\n\u003cli\u003eInternational Agency for Research on Cancer. Volume 18: Cervical Cancer Screening. 2022. In: IARC Handbooks of Cancer Prevention [Internet]. France: IARC. Available from: https://publications.iarc.fr/Book-And-Report-Series/Iarc-Handbooks-Of-Cancer-Prevention/Cervical-Cancer-Screening-2022 . Accessed 7 July 2024.\u003c/li\u003e\n\u003cli\u003eArbyn M, Castle PE, Schiffman M, Wentzensen N, Heckman-Stoddard B, Sahasrabuddhe VV. Meta-analysis of agreement/concordance statistics in studies comparing self- vs clinician-collected samples for HPV testing in cervical cancer screening. 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BMJ Glob. 2019;4(3):e001351.\u003c/li\u003e\n\u003cli\u003eCatarino RR, Vassilakos PP, Royannez D, II, Guillot CC, Alzuphar SS, Fehlmann AA, et al. Barriers to cervical cancer screening in Geneva (DEPIST Study). J. 2016;20(2):135-8.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1-4 are available in the Supplementary Files section.\u003c/p\u003e"},{"header":"Box","content":"\u003ctable\u003e\n \u003ctbody\u003e\u003ctr\u003e\u003ctd\u003e\u003cp\u003e\u003cstrong\u003eBox. Classification of Screening Strategies Considered in Comparative Effectiveness Studies \u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e1: \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;hrHPV alone vs. cytology alone (\u0026ge;ASCUS to colposcopy): 1 RCT (NTCC Phase II/Ronco 2008); n=49,196\u003c/p\u003e\n\u003cp\u003e2a: \u0026nbsp; \u0026nbsp; \u0026nbsp;hrHPV with cytology triage (\u0026ge;LSIL or \u0026ge;ASCUS to colposcopy) vs. cytology alone (\u0026ge;LSIL or \u0026gt;LSIL to colposcopy); without recall: 1 RCT (Finnish/Leinonen 2012) \u0026amp; 1 quasi-RCT (Norwegian HPV Screening Pilot/Nygard 2022); N=289,641\u003c/p\u003e\n\u003cp\u003e2b: \u0026nbsp; \u0026nbsp; \u0026nbsp;hrHPV with cytology triage (\u0026ge;LSIL to colposcopy) vs. cytology alone (\u0026ge;LSIL to colposcopy); with recall of \u0026ge;ASCUS and HPV\u003csup\u003e+\u003c/sup\u003e vs. \u0026ge;ASCUS using same screening at 12-24 months: 1 RCT (Finnish/Leinonen 2012); n=132,194\u003c/p\u003e\n\u003cp\u003e3a: \u0026nbsp; \u0026nbsp; \u0026nbsp;hrHPV with cytology triage (\u0026ge;ASCUS to colposcopy) vs. cytology (\u0026ge;LSIL or \u0026ge;HSIL to colposcopy) with hrHPV triage (HPV\u003csup\u003e+\u003c/sup\u003e with \u0026ge;ASCUS to colposcopy); without recall: 2 RCTs (HPV Focal/Olgilvie 2017 \u0026amp; Stockholm-Gotlund/Lamin 2017) and 1 quasi-RCT (Swedish HPV Trial/Elfstrom 2021); N=226,132\u003c/p\u003e\n\u003cp\u003e3b:\u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;hrHPV with cytology triage vs. cytology with hrHPV triage (as for 3a); with recall of HPV\u003csup\u003e+\u003c/sup\u003e with \u0026lt;ASCUS (hrHPV arm) vs. HPV\u003csup\u003e-\u003c/sup\u003e with \u0026ge;ASCUS (cytology arm) at 6-12 months for co-testing/hrHPV testing/hrHPV with cytology triage (hrHPV arm) or cytology/co-testing/none (cytology arm): 1 RCT (HPV Focal/Olgilvie 2017) \u0026amp; 1 quasi-RCT (Norwegian HPV Screening Pilot/Nygard 2022); N=182,541 and 1 observational study used for data on incidence of ICC (English HPV Screening Pilot/Rebolj 2022); n=1,171,192\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e3c: \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;One round of hrHPV with cytology triage (\u0026ge;ASCUS to colposcopy) vs. two rounds of cytology with hrHPV triage (\u0026ge;LSIL and HPV+ with \u0026ge;ASCUS to colposcopy); with recall to co-testing (hrHPV arm; HPV\u003csup\u003e+\u003c/sup\u003e or \u0026ge;ASCUS to colposcopy) or cytology (cytology arm; \u0026ge;ASCUS to colposcopy): 1 RCT (HPV Focal/Olgilvie 2017); n=18,948\u003c/p\u003e\n\u003cp\u003e4: \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;hrHPV with partial genotyping (types 16/18 direct to colposcopy) and cytology triage of hrHPV type 45 (hrHPV type 45\u003csup\u003e+\u003c/sup\u003e with \u0026ge;HSIL to colposcopy) vs. cytology (\u0026ge;HSIL direct to colposcopy) with hrHPV with partial genotyping triage (hrHPV type 16/18 with \u0026ge;ASCUS to colposcopy); with recall of \u0026le;LSIL vs. hrHPV type 45\u003csup\u003e+\u0026nbsp;\u003c/sup\u003efor hrHPV testing at 12 (hrHPV\u003csup\u003e+\u0026nbsp;\u003c/sup\u003eto colposcopy)\u003csup\u003e\u0026nbsp;\u003c/sup\u003eand again (if hrHPV\u003csup\u003e-\u003c/sup\u003e)\u003csup\u003e\u0026nbsp;\u003c/sup\u003eat 24 months: 1 RCT (COMPASS/Canfell 2017); n=2,987\u003c/p\u003e\n\u003cp\u003e5: \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;hrHPV (hrHPV\u003csup\u003e+\u003c/sup\u003e direct to colposcopy) with cytology triage of \u003cem\u003enegative\u003c/em\u003e tests (\u0026ge;LSIL to colposcopy) vs. cytology (\u0026ge;LSIL to colposcopy) with hrHPV triage (ASCUS and hrHPV\u003csup\u003e+\u003c/sup\u003e to colposcopy); with recall of ASCUS vs. hrHPV\u003csup\u003e-\u003c/sup\u003e to\u003csup\u003e\u0026nbsp;\u003c/sup\u003eco-testing at 12 months with \u0026ge;ASCUS or hrHPV\u003csup\u003e+\u003c/sup\u003e to colposcopy: 1 RCT (Chan 2020); n=15,833\u003c/p\u003e\n\u003cp\u003e6a: \u0026nbsp; \u0026nbsp; \u0026nbsp;hrHPV via self-sampling with cytology triage vs. clinician-sampled hrHPV with cytology triage (hrHPV\u003csup\u003e+\u0026nbsp;\u003c/sup\u003eand \u0026ge;ASCUS to colposcopy); with recall of \u0026lt;ASCUS to cytology at 6 months: 1 RCT (IMPROVE/Polman 2019); n=13,799\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e6b: \u0026nbsp; \u0026nbsp; \u0026nbsp;hrHPV via self-sampling with cytology triage vs. clinician-sampled hrHPV with cytology triage (hrHPV types 16/18 and \u0026ge;ASCUS or hrHPV other types and \u0026ge;HSIL to colposcopy); with recall of \u0026lt;ASCUS to hrHPV testing at 12 or 24 months (underscreened population): 1 RCT (Aasbo 2022); n=963\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e7: \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;hrHPV via self-sampling with triage to repeat self-sampling vs. clinician-sampled hrHPV with triage to repeat clinician-sampled hrHPV (persistent hrHPV to colposcopy): 2 RCTs (Uppsala I/Gustavsson 2019 \u0026amp; Uppsala II/Aarnio 2021); N=11,414\u003c/p\u003e\n\u003cp\u003e8: \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;hrHPV via self-sampling with cytology triage vs. cytology alone (in both \u0026ge;ASCUS to colposcopy) (underscreened): 2 RCTs (ARCADES Phase I/Piana 2011 \u0026amp; ARCADES Phase II/Sancho-Garnier 2013); N=2,845\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e9: \u0026nbsp;\u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;hrHPV via self-sampling (hrHPV types 16/18 direct to colposcopy) with cytology triage (hrHPV other types and\u0026nbsp;\u0026ge;ASCUS to colposcopy) vs. cytology (\u0026ge;LSIL to colposcopy) with hrHPV triage (\u0026ge;ASCUS and hrPV to colposcopy) (underscreened): 1 RCT (Vivano 2017); n=618 \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e10:\u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;hrHPV via self-sampling alone (offered cytology but hrHPV\u003csup\u003e+\u0026nbsp;\u003c/sup\u003ecould go to colposcopy) vs. cytology alone (\u0026ge;ASCUS to colposcopy) (underscreened): 1 RCT (Westminster/Szarewski 2011); n=164\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\n\u003c/table\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"systematic-reviews","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"sysr","sideBox":"Learn more about [Systematic Reviews](http://systematicreviewsjournal.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/sysr/default.aspx","title":"Systematic Reviews","twitterHandle":"@MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Cervical cancer, screening, accuracy, patient preferences, systematic review, meta-analysis, guideline","lastPublishedDoi":"10.21203/rs.3.rs-4677378/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4677378/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003ePurpose. \u003c/strong\u003eTo inform updated recommendations by the Canadian Task Force on Preventive Health Care (task force) on screening in primary care for the prevention and early detection of cervical cancer in individuals with a cervix who are 15 years or older who have been sexually active and have no symptoms of cervical cancer. We systematically reviewed evidence from Very High Development Index countries of: screening effectiveness (focusing on ages to start and stop) and comparative effectiveness (strategies and intervals); comparative test accuracy; informed individuals’ values and preferences, and effectiveness of interventions to improve screening rates among the under/never screened. Two existing systematic reviews provided evidence regarding adverse pregnancy outcomes associated with the conservative management of cervical intraepithelial neoplasia (CIN).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods. \u003c/strong\u003eWe searched three databases (Medline, Embase, and Cochrane Central) for effectiveness and accuracy questions; Medline, Scopus, and EconLit for patient preferences [to Sept/Oct 2023 for screening effects and preferences and March 2019 for accuracy and interventions to increase uptake]) and reference lists of included studies and relevant systematic reviews. Two reviewers independently screened studies and assessed risk of bias. Most data were extracted by one reviewer with verification by another; outcome data for screening effectiveness were extracted in duplicate. We performed meta-analysis where possible. Absolute effects were expressed as events among 10,000 individuals. Two reviewers appraised the certainty of evidence using GRADE. The task force determined thresholds for their certainty assessments about comparative effectiveness.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e. We included 112 studies across questions (22 on ages to start and stop screening, 17 on comparative effectiveness, 10 on comparative accuracy, 23 on patient preferences, and 44 on interventions to increase uptake).\u003c/p\u003e\n\u003cp\u003eWhen reviewing evidence to help inform ages to start and stop screening, only observational studies on cytology screening were identified. There was very low certainty evidence for the effects in individuals 20-24, 25-29 and 30-34 years of age to prevent invasive cervical cancer (ICC) or mortality (all-cause and cervical-cancer specific). For individuals 60-69 years of age, screening with cytology is probably (moderate certainty) associated with reduced ICC (≥ 9 fewer per 10,000) and cervical-cancer mortality (≥ 0.19 to 0.29 fewer) over 10-15 years of follow-up among those who had no screening, abnormal, or inadequate screening in their 50s. A reduction for these outcomes among those 60-69 years who were adequately screened during their 50s is less certain. For persons aged 70-79 years, screening with cytology reduced ICC with low certainty for those with no, abnormal, or inadequate screening histories. Evidence for ICC for those adequately screened and on mortality overall was very uncertain. Very low certainty evidence was found for reduction in ICC and cervical-cancer mortality for cytology screening every 3 years versus 3-to-5 years.\u003c/p\u003e\n\u003cp\u003eAcross 10 groups of comparisons between screening strategies (e.g., initial testing with cytology vs. high-risk human papillomavirus [hrHPV], different triage methods, different populations), we are very uncertain about any differential impacts on all-cause and cervical-cancer mortality and on overdiagnosis. i) Compared with cytology alone, hrHPV alone may (low certainty) make little-to-no difference for 25-59 year-olds for incidence of CIN 3+ (hrHPV detecting 30 more CIN 2+ per 10,000) but is probably associated with more (possibly ≥ 600 per 10,000) referrals for colposcopy and false positives for CIN 2+ and CIN 3+ for those aged 25-29 years. ii) hrHPV with triage to cytology versus cytology alone may reduce incidence of ICC (e.g., 24 more CIN 3+ detections) for those aged 29-69 years, though when adding a recall phase (with additional testing beyond the initial triage) there are probably more harms for 25-29 year-olds. iii) The comparison of hrHPV with cytology triage versus cytology with hrHPV triage was divided into subgroups based on whether there was a recall stage. The hrHPV strategy probably reduces incidence of ICC (46 and 32 more CIN 3+ detected with and without using recalls) without added harm for those aged 30-59 years. For those aged 25-29 years, adding recall may reduce incidence of CIN3+ (via 271 more CIN2+ cases detected) but also considerably increase harms (≥ 800 false positives); evidence for ICC incidence was uncertain. One round of hrHPV with cytology triage versus two rounds of cytology with hrHPV triage (over 4 years), both strategies including recall, may make little-to-no difference in incidence of CIN 2 or 3+ for those 30-69 years, and probably leads to similar effect on harms. Evidence for incidence of ICC was of very low certainty. iv) The effects on incidence of ICC are uncertain from adding partial genotyping to these hrHPV and cytology triage strategies; for those aged 30-59 years there may be little-to-no difference in incidence of CIN3+ and is probably no difference in harms. v) When comparing hrHPV with cytology triage of \u003cem\u003enegative\u003c/em\u003e tests versus cytology with hrHPV triage, both arms having recall, low certainty evidence found reduced incidence of ICC (36.0 more CIN3+ detected) from the hrHPV strategy arm and little-to-no difference between strategies for incidence of CIN3+, with moderate certainty evidence that the hrHPV strategy results in more referrals to colposcopies and false positives (about 600 per 10,000). From studies only enrolling those aged 30-59 years, vi.b) there was moderate certainty of little-to-no difference in false positives between hrHPV self-sampling with cytology triage compared with hrHPV clinician-sampling with cytology triage, with low certainty of little-to-no impact on incidence of CIN 3+; vii) evidence was low certainty for little-to-no difference in CIN 2+ detection and in false positives for hrHPV self- versus clinician-sampling, each with triage to repeat hrHPV testing at 3-6 months; and vi,b and viii-x) evidence was of very low certainty evidence across all reported outcomes (detection of CIN 2+ and 3+ and false positives) from studies comparing effects of hrHPV self-sampling among populations who were non-responders or underscreened.\u003c/p\u003e\n\u003cp\u003eFrom comparative accuracy studies, adding cytology triage to hrHPV testing alone (via self-or clinician sampling), or replacing the hrHPV test with one allowing partial genotyping with or without cytology triage, reduces the number of false positives (high certainty; \u0026gt; 300 fewer per 10,000 screened). There is probably little-to-no difference in false positives between hrHPV with partial genotyping (types 16/18) and hrHPV with cytology triage. hrHPV with partial genotyping (types 16/18) versus cytology alone may increase specificity (reducing false positives) at the expense of sensitivity, though the number of missed cases may be very small (e.g., up to 9 fewer cases of CIN3+ detected). There was little-to-no difference in sensitivity and specificity between cytology alone and hrHPV with partial genotyping (types 16/18) with triage to cytology on non-16/18 types (moderate certainty). Cytology with hrHPV triage versus cytology alone may make little-to-no difference for sensitivity or specificity for CIN 3+ detection.\u003c/p\u003e\n\u003cp\u003eIn relation to adverse pregnancy outcome from treatment, findings from two existing systematic reviews of observational studies found very low certainty evidence about whether conservative management of CIN 2/3 is associated with total miscarriage rates, second trimester miscarriage, preterm birth (≥ 37 weeks’ gestation), low birth weight (\u0026lt; 2500 g), or cervical cerclage. Despite findings that would lead to very small increases in some outcomes among the entire screening population, the evidence was considered indirect for current practices that use a more cautionary approach to treatment particularly for CIN2 in individuals prioritizing a reproductive future.\u003c/p\u003e\n\u003cp\u003eFindings from studies on patient preferences via measurement of the disutility (i.e., impact on participant’s quality of life, values ranging between 0 [no impact] and 1 [similar to death]) of having one of the outcomes indicated that ICC (disutility of 0.11) may be at least twice as important as CIN 2/3 (0.05), and that both cervical cancer and CIN 2/3 are probably much more important than false positives that did not cause any disutility. Other studies on patient preferences about cytology screening indicated, with low certainty, that a large majority of individuals eligible for and informed about screening may weigh the benefits as more important than the harms of screening using cytology, but think it is important to provide information on benefits and harms for decision making. Findings from a single study suggested that some individuals \u0026lt;25 years may have intentions to screen even when informed that screening does not reduce cancer diagnoses or deaths for their age group and leads to overdiagnosis.\u003c/p\u003e\n\u003cp\u003eFive types of interventions to improve screening rates for under/never-screened individuals were reviewed. All were found with moderate or high certainty to improve screening rates : written contact (relative risk [RR] 1.50, 95% CI 1.22 to 1.84; 619 more per 10,000, 95% CI 273 to 1041; 16 trials, N=138,880); personal contact (RR 1.50, 95% CI 1.07 to 2.11; 797 more, 95% CI 1116 to 1770; 7 trials, N=17,034); composite interventions (usually mixture of written and personal contact; RR 1.73, 95% CI 1.33 to 2.27; 1351 more, 95% CI 610 to 2350; 8 trials, N=17,738); universal mail-out of HPV self-sampling kit (RR 2.56, 95% CI 2.10 to 3.12; 1534 more, 95% CI 1082 to 2085; 22 trials, N=211,031); and opt-in to receive a HPV self-sampling kit (RR 1.56, 95% CI 1.19 to 2.03; 727 more, 95% CI 247 to 1338; 11 trials, N=71,433).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eScreening for prevention or early detection of cervical cancer with cytology has been employed for decades and is probably effective for otherwise healthy persons with a cervix at least into their 60s. Whether to screen individuals younger than 35 years old using cytology was uncertain based on the need to rely on observational evidence without consistent reporting across age groups. Screening during one’s 60s and 70s may have less effect for those adequately screened in their 50s. The effects of screening with cytology every 5 years versus 3 years are uncertain. The evidence provided very low certainty about any differential impacts between various screening strategies on mortality and overdiagnosis outcomes. Compared with cytology alone or cytology with hrHPV triage, there was evidence of a small benefit from reducing ICC from using hrHPV with cytology triage though findings were most robust for those aged 30-59 years. Any additional benefit from adding recall is not clear especially for those 25-29 years where it probably adds substantial harm. Screening using hrHPV with triage to cytology every 4 years may lead to similar detection of cancer precursors as would cytology with hrHPV triage conducted every 2 years, though the effects compared with cytology alone were not examined. Further, it is uncertain what the effects are on the incidence of ICC from adding partial genotyping to the triage strategies for those aged 30-59 years. For those aged 30-59 years, moderate certainty evidence found little-to-no difference in false positives between hrHPV self-sampling with cytology triage compared with hrHPV clinician-sampling with cytology triage, and low certainty that there may be little-to-no impact on incidence of CIN 3+. The comparative effectiveness studies did not examine all relevant comparisons and thus comparative accuracy data may help provide suggestions of possible alternative strategies with similar sensitivity and similar or higher specificity. Most of the studies on screening effects were undertaken in populations either in which HPV vaccination had not been implemented or carried out in a period when vaccination rates were low. For under- or never-screened individuals, the offer of self-sampling kits for hrHPV testing may improve screening rates with similar test accuracy, but it is uncertain if findings apply when triage to cytology is used because of the need for adequate cervical cells and likely a clinic visit. ICC and CIN2/3 probably make an important impact on one’s quality of life, whereas a false positive result when using cytology alone does not; whether the disutility of a false positive result applies to hrHPV testing is unknown. There was low certainty evidence that informed individuals eligible for screening think the benefits outweigh the harms from screening. Choices for screening strategies apart from cytology alone may result largely from contextual considerations such as access, acceptability, resources and costs.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSystematic review registration\u003c/strong\u003e. 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