A novel human papillomavirus and host DNA methylation score and detection of cervical adenocarcinoma.

BACKGROUND: The widespread introduction of Pap testing in the 1960s was followed by substantial reductions in the incidence of cervical squamous cell cancer (SCC). However, the incidence of cervical adenocarcinoma (ADC) did not decrease, likely because of low Pap test sensitivity for ADC and adenocarcinoma in situ (AIS). This study assessed a novel human papillomavirus (HPV) and host DNA Methylation Score for AIS and ADC screening. METHODS: We measured methylation levels at CpG sites in the L2/L1 open reading frames of HPV16, HPV18, and HPV45-as well as 2 human loci, DCC and HS3ST2. Specifically, we tested exfoliated cervicovaginal cells from women in the HPV Persistence and Progression (PaP) cohort who were positive for 1 of HPV16, 18, or 45, including: 1) 176 with AIS/ADC, 2) 353 with cervical intraepithelial neoplasia-3 (CIN3) or SCC, and 3) controls who either cleared (HPV-Clearers; n = 579) or had persistent HPV16, 18, or 45 infection (HPV-Persisters; n = 292). CpG site-specific methylation percentages were measured using our reported next-generation methods. The Methylation Score was the average methylation percentage across all 35 CpG sites tested. RESULTS: Each individual CpG site had higher methylation percentages in exfoliated cervicovaginal cells collected from patients with AIS/ADC, and as well as those with CIN3/SCC, relative to either control group (weakest P = .004). The Methylation Score for AIS/ADC had a sensitivity of 74% and specificity of 89%. The multivariate odds ratio (OR) between the Methylation Score (4th vs 1st quartile) for AIS/ADC was ORq4-q1 = 49.01 (PBenjamini-Hochberg = 4.64E-12), using HPV-Clearers as controls. CIN3/SCC had similar, albeit weaker, associations with the Methylation Score. CONCLUSIONS: HPV16/18/45-infected women with Methylation Scores in the highest quartile had very high odds of AIS/ADC, suggesting they may warrant careful histologic evaluation of the cervical transition zone (eg, conization or loop electrosurgical excision procedure [LEEP]).

Fetal heart rate patterns and the incidence of adverse events after oral misoprostol administration for cervical ripening among low-risk pregnancies.

OBJECTIVE: Though misoprostol is commonly used for inpatient cervical ripening, its use in outpatient settings has been limited by safety concerns. This study was conducted to assess the association between early fetal heart tracing (FHT) and maternal tocodynamometry patterns and the incidence of adverse fetal and pregnancy outcomes after the administration of oral misoprostol for cervical ripening. METHODS: We conducted a retrospective cohort study of 9908 low-risk patients at ≥37 weeks gestation who received oral misoprostol for cervical ripening prior to rupture of membranes between 01/01/2012 and 12/31/2017 at Kaiser Permanente Northern California hospitals as inpatients. We excluded patients who received a different agent for cervical ripening or had any need for additional inpatient monitoring, including hypertensive disorders of pregnancy, diabetes, or intrauterine growth restriction. Abnormal FHT, abnormal uterine activity, and adverse pregnancy or fetal-related events documented in the electronic health record in the four hours after administration of the first and second doses of misoprostol were assessed using descriptive statistics. RESULTS: We found that 0.9% of patients experienced tachysystole after the first dose of misoprostol (0.6% without decelerations; 0.3% with decelerations). The incidence of variable decelerations only and other FHT abnormalities (i.e. bradycardia, late or prolonged decelerations, or absent or minimal variability) in the first hour after misoprostol administration were 7.1% and 6.7% respectively, and diminished over time. The need for tocolytic use was 0.2% in the first hour and declined over time to 0.03% in the fourth hour after the first dose. Urgent cesarean delivery occurred in 0.1% of patients after receiving the first dose of misoprostol. Patients who did not experience variable, prolonged, or late decelerations in the first hour after the initial misoprostol dose were less likely to have such FHT abnormalities in the subsequent three hours compared to patients who had other FHT abnormalities (11.8% among patients with no FHT abnormalities vs. 43.7% among patients with other FHT abnormalities; p <.001). The overall trends in outcomes over time were similar after the second dose of misoprostol. CONCLUSION: The risk of short-term adverse outcomes associated with misoprostol is low among relatively low-risk patients. FHT abnormalities occurred in up to 32% of patients in the first four hours of monitoring post-misoprostol. Patients with no FHT abnormalities in the first hour after receiving misoprostol had a low risk of developing adverse outcomes and FHT abnormalities on continued monitoring, while patients with any type of deceleration in the first hour were at higher risk of adverse outcomes and FHT abnormalities. Our data may inform the development of protocols for cervical ripening that allow reduced monitoring for a subset of low-risk patients, however, more research is needed to validate findings and develop clinical protocols.

Labor Induction Outcomes with Outpatient Misoprostol for Cervical Ripening among Low-Risk Women.

OBJECTIVE: In 2012, two Kaiser Permanente Northern California (KPNC) hospitals began offering outpatient cervical ripening with oral misoprostol under a study protocol. We evaluated inpatient time from admission to delivery and adverse maternal and neonatal outcomes associated with outpatient use of misoprostol for cervical ripening among low-risk women with term pregnancies. STUDY DESIGN: We conducted a retrospective cohort study comparing three groups: women who received misoprostol (1) outpatient, under a study protocol; (2) inpatient, at the study sites; and (3) inpatient, at all KPNC hospitals. Data were obtained from between 2012 and 2017. The primary outcome was time from inpatient admission to delivery. Secondarily, we evaluated maternal and neonatal outcomes, including the duration and maximum rate of oxytocin administered, rate of cesarean delivery, incidence of chorioamnionitis and blood transfusion, Apgar scores, and neonatal intensive care unit admissions. Demographic and clinical characteristics and outcomes of the outpatient group were compared with both inpatient misoprostol groups using the appropriate statistical test. Variables included in the regression analysis were either statistically significant in the bivariate analyses or have been reported in the literature to be potential confounders: maternal age at admission, race/ethnicity, body mass index, cervical dilation at initial misoprostol, and parity. RESULTS: We analyzed data from 10,253 patients: (1) 345 outpatients, under a study protocol; (2) 1,374 inpatients, at the study sites; and (3) 9,908 inpatients, at all the Kaiser hospitals. Women in the outpatient group were more likely to be white than both inpatient groups (63.3 vs. 56.3% at study sites and 47.1% in all hospitals, p = 0.002 and <0.001, respectively); other demographics were clinically comparable. Most women undergoing labor induction were nulliparous; however, a greater proportion in the outpatient group were nulliparous compared with inpatient groups (70.8 vs. 61.8% and 64.3%, p = 0.002 and 0.01). On inpatient admission for delivery, women who received outpatient misoprostol were more likely to have a cervical dilation of ≥3 cm (39.8 vs. 12.5% at study sites and 9.7% at all KPNC hospitals, p < 0.001 for both). The outpatient group had a shorter mean time between admission and delivery (23.6 vs. 29.4 at study sites and 29.8 hours at all KPNC, p < 0.001 for both). The adjusted estimated mean difference between the outpatient and inpatient group at all the Kaiser hospitals in time from admission to delivery was -6.48 hours (p < 0.001), and the adjusted estimated mean difference in cervical dilation on admission was +1.02 cm (p < 0.001). There was no difference in cesarean delivery rates between groups. The rate of chorioamnionitis in the outpatient group was higher compared with inpatients at all hospitals (17.7 vs. 10.6%, p < 0.001), but similar when compared with the inpatients at the study sites (17.7 vs. 15.4%, p = 0.29). CONCLUSION: Outpatient use of misoprostol for cervical ripening under the study protocol was associated with reduced inpatient time from admission to delivery compared with inpatient misoprostol. Although there was a higher rate of chorioamnionitis among outpatients under the study protocol compared with inpatients at all hospitals, there was no difference when compared with inpatients at the study sites. There was no difference in rates of cesarean delivery or maternal or neonatal complications with outpatient misoprostol. KEY POINTS: · Outpatient misoprostol patients had 6.46 fewer hours from admission to delivery compared with inpatients at all hospitals.. · There was no difference in the rate of cesareans between the outpatient versus inpatient misoprostol groups.. · Other maternal and neonatal complications were low and comparable among outpatients and inpatients who received misoprostol; this study was not large enough to assess rare safety outcomes..

Contribution of Etiologic Cofactors to CIN3+ Risk Among Women With Human Papillomavirus-Positive Screening Test Results.

OBJECTIVE: The US screening and management guidelines for cervical cancer are based on the absolute risk of precancer estimated from large clinical cohorts and trials. Given the widespread transition toward screening with human papillomavirus (HPV) testing, it is important to assess which additional factors to include in clinical risk assessment to optimize management of HPV-infected women. MATERIALS AND METHODS: We analyzed data from HPV-infected women, ages 30-65 years, in the National Cancer Institute-Kaiser Permanente Northern California Persistence and Progression study. We estimated the influence of HPV risk group, cytology result, and selected cofactors on immediate risk of cervical intraepithelial neoplasia grade 3 or higher (CIN 3+) among 16,094 HPV-positive women. Cofactors considered included, age, race/ethnicity, income, smoking, and hormonal contraceptive use. RESULTS: Human papillomavirus risk group and cytology test result were strongly correlated with CIN 3+ risk. After considering cytology and HPV risk group, other cofactors (age, race/ethnicity, income, smoking, and hormonal contraceptive use) had minimal impact on CIN 3+ risk and did not change recommended management based on accepted risk thresholds. We had insufficient data to assess the impact of long-duration heavy smoking, parity, history of sexually transmitted infection, or immunosuppression. CONCLUSIONS: In our study at the Kaiser Permanente Northern California, the risk of CIN 3+ was determined mainly by HPV risk group and cytology results, with other cofactors having limited impact in adjusted analyses. This supports the use of HPV and cytology results in risk-based management guidelines.

Variation in Vaginal Hysterectomy Rates in an Integrated Healthcare System.

STUDY OBJECTIVE: To describe trends in minimally invasive hysterectomy (MIH) and assess patient, surgical, and provider characteristics associated with differences in vaginal versus laparoscopic rates within an integrated healthcare system. DESIGN: A retrospective cohort study. SETTING: Kaiser Permanente Northern California from 2008 to 2018. PATIENTS: Patients who underwent MIH for benign conditions excluding uterine prolapse and incontinence surgeries. INTERVENTIONS: Hysterectomies. MEASUREMENTS AND MAIN RESULTS: A total of 27518 hysterectomies were performed for benign indications. Of these, the proportion of MIH increased from 29.1% (2008) to 96.7% (2018) (p <.001). The proportion of vaginal hysterectomies (VHs) of all hysterectomies did not change significantly over the study period (p = .07); however, the proportion of VH among MIH cases decreased from a high of 50.6% in 2008 to 13.2% in 2018 (p <.001). VH rates were lower in obese and morbidly obese patients (p <.001 and p = .02, respectively) and in women with uterine weights >250 g (p <.001). The differences persisted after controlling for patient demographic, clinical, and surgery characteristics. Low surgical volume was inversely associated with VH (adjusted relative risk, 7.19; 95% confidence interval, 6.62-7.81; p <.001). VH rates ranged from 11.5% to 27.8% across service areas (hospitals). Service area remained a significant predictor of VH after controlling for patient (including body mass index and uterine weight) and surgery-related characteristics. Postoperative hospital stay decreased from 33.8 ± 16.4 hours (2008) to 6.1 ± 12.2 (2018) for VH. Operative time was shorter for VH than laparoscopic hysterectomies (LHs) (1.7 vs 2.5 hours; p <.001). Overall operative/perioperative complications were low and not significantly different (VH vs LH). CONCLUSION: As the proportion of MIH increased, LH became the preferred route despite similar rates of postoperative stay and intraoperative complications and shorter operative time for VH compared with LH. Service area and provider volume were independent predictors of MIH route, suggesting that training and evidence-based guidelines for route selection may help preserve VH rates.

Pharmacists' knowledge, perspectives, and experiences with mifepristone dispensing for medication abortion.

BACKGROUND: The U.S. Food and Drug Administration (FDA) restricts dispensing of mifepristone for medication abortion to certified health care providers at clinical facilities, thus prohibiting pharmacist dispensing. Allowing mifepristone dispensing by pharmacists could improve access to medication abortion. OBJECTIVE: To assess the feasibility of pharmacists dispensing mifepristone to patients who have undergone evaluation for eligibility and counseling for medication abortion by a clinician. METHODS: Before providing a study training on medication abortion, we administered baseline surveys to pharmacists who participated in a multisite mifepristone-dispensing intervention. The survey assessed medication abortion knowledge-using a 15-item score-and perceptions about the benefits and challenges of the model. We administered follow-up surveys in the study's final month that also assessed the pharmacists' satisfaction and experiences with mifepristone dispensing. To investigate the association of the study intervention with the pharmacists' knowledge, perceptions, and experiences dispensing mifepristone, we conducted multivariable linear regression analyses using generalized estimating equation models, accounting for clustering by individual. RESULTS: Among the 72 pharmacists invited from 6 pharmacies, 47 (65%) completed the baseline surveys, and 56 (78%) received training. At the study's end (mean 18 months later), 43 of the 56 pharmacists who received training (77%) completed the follow-up surveys. At follow-up, 36 (83%) respondents were very or somewhat satisfied with mifepristone dispensing, and 24 (56%) reported experiencing no challenges dispensing mifepristone. Four (6%) of the 72 pharmacists invited objected to participating in mifepristone dispensing. In regression analyses, average knowledge scores, perceived ease of implementation, and level of support for the pharmacist-dispensing model were higher at follow-up (P < 0.001). CONCLUSION: Most pharmacists were willing to be trained, dispensed mifepristone with few challenges when given the opportunity, were satisfied with the model, and had higher knowledge levels at follow-up. Our findings support removal of FDA's restriction on pharmacist dispensing of mifepristone.

Medication Abortion With Pharmacist Dispensing of Mifepristone.

OBJECTIVE: To estimate effectiveness and acceptability of medication abortion with mifepristone dispensed by pharmacists. METHODS: We conducted a prospective cohort study at eight clinical sites and pharmacies in California and Washington State from July 2018 to March 2020. Pharmacists at participating pharmacies underwent a 1-hour training on medication abortion. We approached patients who had already been evaluated, counseled, and consented for medication abortion per standard of care. Patients interested in study participation gave consent, and the clinician electronically sent a prescription to the pharmacy for mifepristone 200 mg orally, followed 24-48 hours later by misoprostol 800 micrograms buccally. Participants were sent web-based surveys about their experience and outcomes on days 2 and 14 after enrollment and had routine follow-up with study sites. We extracted demographic and clinical data, including abortion outcome and adverse events, from medical records. We performed multivariable logistic regression to assess the association of pharmacy experience and other covariates with satisfaction. RESULTS: We enrolled 266 participants and obtained clinical outcome information for 262 (98.5%), of whom two reported not taking either medication. Of the 260 participants with abortion outcome information, 252 (96.9%) and 237 (91.2%) completed day 2 and 14 surveys, respectively. Complete medication abortion (primary outcome) occurred for 243 participants (93.5%, 95% CI 89.7-96.1%). Four participants (1.5%, 95% CI 0.4-3.9%) had an adverse event, none of which was serious or related to pharmacist dispensing. In the day 2 survey, 91.3% (95% CI 87.1-94.4%) of participants reported satisfaction with the pharmacy experience. In the day 14 survey, 84.4% (95% CI 79.1-88.8%) reported satisfaction with the medication abortion experience. Those reporting being very satisfied with the pharmacy experience had higher odds of reporting overall satisfaction with medication abortion (adjusted odds ratio 2.96, 95% CI 1.38-6.32). CONCLUSION: Pharmacist dispensing of mifepristone for medication abortion is effective and acceptable to patients, with a low prevalence of adverse events. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT03320057.

A study of type-specific HPV natural history and implications for contemporary cervical cancer screening programs.

BACKGROUND: HPV testing is replacing cytology for cervical cancer screening because of greater sensitivity and superior reassurance following negative tests for the dozen HPV genotypes that cause cervical cancer. Management of women testing positive is unresolved. The need for identification of individual HPV genotypes for clinical use is debated. Also, it is unclear how long to observe persistent infections when precancer is not initially found. METHODS: In the longitudinal NCI-Kaiser Permanente Northern California Persistence and Progression (PaP) Study, we observed the clinical outcomes (clearance, progression to CIN3+, or persistence without progression) of 11,573 HPV-positive women aged 30-65 yielding 14,158 type-specific infections. FINDINGS: Risks of CIN3+ progression differed substantially by type, with HPV16 conveying uniquely elevated risk (26% of infections with seven-year CIN3+ risk of 22%). The other carcinogenic HPV types fell into 3 distinct seven-year CIN3+ risk groups: HPV18, 45 (13% of infections, risks >5%, with known elevated cancer risk); HPV31, 33, 35, 52, 58 (39%, risks >5%); and HPV39, 51, 56, 59, 68 (23%, risks <5%). In the absence of progression, HPV clearance rates were similar by type, with 80% of infections no longer detected within three years; persistence to seven years without progression was uncommon. The predictive value of abnormal cytology was most evident for prevalent CIN3+, but less evident in follow-up. A woman's age did not modify risk; rather it was the duration of persistence that was important. INTERPRETATION: HPV type and persistence are the major predictors of progression to CIN3+; at a minimum, distinguishing HPV16 is clinically important. Dividing the other HPV types into three risk-groups is worth considering.

A Study of Partial Human Papillomavirus Genotyping in Support of the 2019 ASCCP Risk-Based Management Consensus Guidelines.

INTRODUCTION: The 2019 ASCCP Risk-Based Management Consensus Guidelines include recommendations for partial human papillomavirus (HPV) genotyping in management of abnormal cervical cancer screening results. The guidelines are based on matching estimates of cervical intraepithelial neoplasia (CIN) 3+ risk to consensus clinical action thresholds. In support of the guidelines, this analysis addresses the risks predicted by individual identification of HPV 16 and HPV 18. METHODS: Risk estimates were drawn from a subset of women in the Kaiser Permanente Northern California screening program, whose residual cervical specimens were HPV typed as part of the HPV Persistence and Progression study. We calculated risk of CIN 3+ to assess how identification of HPV 16, HPV 18, or 12 other "high-risk" HPV types would influence recommended clinical management of new abnormal screening results, taking into account current cytologic results and recent screening history. Immediate and/or 5-year risks of CIN 3+ were matched to clinical actions identified in the guidelines. RESULTS: Identification of HPV 16 at the first visit including HPV testing elevated immediate risk of diagnosing CIN 3+ sufficiently to mandate colposcopic referral even when cytology was Negative for Intraepithelial Lesions or Malignancy and to support a preference for treatment of cytologic high-grade squamous intraepithelial lesion. HPV 18 less clearly elevated CIN 3+ risk. CONCLUSIONS: Identification of HPV 16 clearly mandated consideration in clinical management of new abnormal screening results. HPV 18 positivity must be considered as a special situation because of established disproportionate risk of invasive cancer. More detailed genotyping and use beyond initial management will be considered in guideline updates.

Automated Cervical Screening and Triage, Based on HPV Testing and Computer-Interpreted Cytology.

Background: State-of-the-art cervical cancer prevention includes human papillomavirus (HPV) vaccination among adolescents and screening/treatment of cervical precancer (CIN3/AIS and, less strictly, CIN2) among adults. HPV testing provides sensitive detection of precancer but, to reduce overtreatment, secondary "triage" is needed to predict women at highest risk. Those with the highest-risk HPV types or abnormal cytology are commonly referred to colposcopy; however, expert cytology services are critically lacking in many regions. Methods: To permit completely automatable cervical screening/triage, we designed and validated a novel triage method, a cytologic risk score algorithm based on computer-scanned liquid-based slide features (FocalPoint, BD, Burlington, NC). We compared it with abnormal cytology in predicting precancer among 1839 women testing HPV positive (HC2, Qiagen, Germantown, MD) in 2010 at Kaiser Permanente Northern California (KPNC). Precancer outcomes were ascertained by record linkage. As additional validation, we compared the algorithm prospectively with cytology results among 243 807 women screened at KPNC (2016-2017). All statistical tests were two-sided. Results: Among HPV-positive women, the algorithm matched the triage performance of abnormal cytology. Combined with HPV16/18/45 typing (Onclarity, BD, Sparks, MD), the automatable strategy referred 91.7% of HPV-positive CIN3/AIS cases to immediate colposcopy while deferring 38.4% of all HPV-positive women to one-year retesting (compared with 89.1% and 37.4%, respectively, for typing and cytology triage). In the 2016-2017 validation, the predicted risk scores strongly correlated with cytology (P < .001). Conclusions: High-quality cervical screening and triage performance is achievable using this completely automated approach. Automated technology could permit extension of high-quality cervical screening/triage coverage to currently underserved regions.

Validation of a Human Papillomavirus (HPV) DNA Cervical Screening Test That Provides Expanded HPV Typing.

As cervical cancer screening shifts from cytology to human papillomavirus (HPV) testing, a major question is the clinical value of identifying individual HPV types. We aimed to validate Onclarity (Becton Dickinson Diagnostics, Sparks, MD), a nine-channel HPV test recently approved by the FDA, by assessing (i) the association of Onclarity types/channels with precancer/cancer; (ii) HPV type/channel agreement between the results of Onclarity and cobas (Roche Molecular Systems, Pleasanton, CA), another FDA-approved test; and (iii) Onclarity typing for all types/channels compared to typing results from a research assay (linear array [LA]; Roche). We compared Onclarity to histopathology, cobas, and LA. We tested a stratified random sample (n = 9,701) of discarded routine clinical specimens that had tested positive by Hybrid Capture 2 (HC2; Qiagen, Germantown, MD). A subset had already been tested by cobas and LA (n = 1,965). Cervical histopathology was ascertained from electronic health records. Hierarchical Onclarity channels showed a significant linear association with histological severity. Onclarity and cobas had excellent agreement on partial typing of HPV16, HPV18, and the other 12 types as a pool (sample-weighted kappa value of 0.83); cobas was slightly more sensitive for HPV18 and slightly less sensitive for the pooled high-risk types. Typing by Onclarity showed excellent agreement with types and groups of types identified by LA (kappa values from 0.80 for HPV39/68/35 to 0.97 for HPV16). Onclarity typing results corresponded well to histopathology and to an already validated HPV DNA test and could provide additional clinical typing if such discrimination is determined to be clinically desirable.

Human Papillomavirus DNA Methylation as a Biomarker for Cervical Precancer: Consistency across 12 Genotypes and Potential Impact on Management of HPV-Positive Women.

Purpose: Human papillomavirus (HPV) DNA methylation testing is a promising triage option for women testing HPV positive during cervical cancer screening. However, the extent to which methylation indicates precancer for all 12 carcinogenic HPV types has not been evaluated.Experimental Design: In this nested case-control study, we tested up to 30 cases of precancer [cervical intraepithelial neoplasia grade 3 (CIN3)/adenocarcinoma in situ (AIS)] and 30 normal controls for each carcinogenic type (single infections with 16/18/31/33/35/39/45/51/52/56/58/59). Next-generation bisulfite sequencing was performed on CpG sites within the L1 and L2 genes. We calculated differences in methylation, ORs, and AUC. Using a fixed sensitivity of 80%, we evaluated the specificity and the risk of CIN3/AIS for best performing CpG sites, and compared the performance of an explorative multi-type methylation assay with current triage strategies.Results: Methylation was positively associated with CIN3/AIS across all 12 types. AUCs for the top sites ranged from 0.71 (HPV51 and HPV56) to 0.86 (HPV18). A combined 12-type methylation assay had the highest Youden index (0.46), compared with cytology (0.31) and a 5-type methylation assay, including only previously described types (0.26). The 12-type methylation assay had higher sensitivity (80% vs. 76.6%) and lower test positivity compared with cytology (38.5% vs. 48.7%). The risk of CIN3/AIS was highest for methylation positives and lowest for cytology or HPV16/18 positives.Conclusions: HPV DNA methylation is a general phenomenon marking the transition from HPV infection to precancer for all 12 carcinogenic types. Development of a combined multitype methylation assay may serve as a triage test for HPV-positive women. Clin Cancer Res; 24(9); 2194-202. ©2018 AACR.

Epidemiologic Evidence That Excess Body Weight Increases Risk of Cervical Cancer by Decreased Detection of Precancer.

Purpose Obesity has been inconsistently linked to increased cervical cancer incidence and mortality; however, the effect of obesity on cervical screening has not been explored. We investigated the hypothesis that increased body mass might decrease detection of cervical precancer and increase risk of cervical cancer even in women undergoing state-of-the-art screening. Methods We conducted a retrospective cohort study of 944,227 women age 30 to 64 years who underwent cytology and human papillomavirus DNA testing (ie, cotesting) at Kaiser Permanente Northern California (January 2003 to December 2015). Body mass index was categorized as normal/underweight (< 25 kg/m2), overweight (25 to < 30 kg/m2), or obese (≥ 30 kg/m2). We estimated 5-year cumulative risks of cervical precancer and cancer by category of body mass index using logistic Weibull survival models. Results We observed lower risk of cervical precancer (n = 4,489) and higher risk of cervical cancer (n = 490) with increasing body mass index. Specifically, obese women had the lowest 5-year risk of precancer (0.51%; 95% CI, 0.48% to 0.54% v 0.73%; 95% CI, 0.70% to 0.76% in normal/underweight women; P trend < .001). In contrast, obese women had the highest 5-year risk of cancer (0.083%; 95% CI, 0.072% to 0.096% v 0.056%; 95% CI, 0.048% to 0.066% in normal/underweight women; P trend < .001). Results were consistent in subgroups defined by age (30 to 49 v 50 to 64 years), human papillomavirus status (positive v negative), and histologic subtype (glandular v squamous). Approximately 20% of cervical cancers could be attributed to overweight or obesity in the women in our study who underwent routine cervical screening. Conclusion In this large, screened population, overweight and obese women had an increased risk of cervical cancer, likely because of underdiagnosis of cervical precancer. Improvements in equipment and/or technique to assure adequate sampling and visualization of women with elevated body mass might reduce cervical cancer incidence.

Assessment of a New Lower-Cost Real-Time PCR Assay for Detection of High-Risk Human Papillomavirus: Useful for Cervical Screening in Limited-Resource Settings?

Inexpensive and easy-to-perform human papillomavirus (HPV) tests are needed for primary cervical cancer screening in lower-resource regions. In a convenience sample of 516 residual exfoliative cervical specimens from the Kaiser Permanente Northern California and U.S. National Cancer Institute Persistence and Progression Study, we assessed the agreement and clinical performance of a simple, inexpensive real-time PCR assay for the detection of 13 carcinogenic HPV types (the H13 assay; Hybribio, Hong Kong) that is marketed in limited-resource settings compared to previous testing by the Hybrid Capture 2 assay (HC2; Qiagen, Germantown, MD) and the Onclarity assay (BD Diagnostics, Sparks, MD). The test set was chosen to include many HPV-positive specimens. The reference standard was a combination of HC2 and Onclarity results for HPV detection and histologic diagnosis of controls (less than cervical intraepithelial neoplasia grade 2 [

Over-the-Counter Access to Oral Contraceptives for Adolescents.

Oral contraceptives (OCs) are used by millions of women in the U.S. The requirement to obtain OCs by prescription from a clinician may serve as a barrier to contraceptive initiation and continuation for women, in particular adolescents. Over-the-counter (OTC) availability would reduce this barrier and could further reduce unintended pregnancy rates. This review explores the scientific issues and regulatory processes involved in switching OCs to OTC status for minor adolescents. We review: (1) the regulatory criteria for switching a drug to OTC status; (2) risk of pregnancy and safety during use of OCs including combined oral contraceptives and progestin-only pills for adolescents; (3) the ability of adolescents to use OCs consistently and correctly; (4) OTC access to OCs and potential effect on sexual risk behaviors; and (5) the potential for reduced opportunities for clinicians to counsel and provide recommended reproductive health care to adolescents. We find strong scientific rationale for including adolescents in any regulatory change to switch OCs to OTC status. OCs are safe and highly effective among adolescents; contraindications are rarer among adolescents compared to adult women. Ready access to OCs, condoms, and emergency contraception increases their use without increasing sexual risk behaviors.

A cohort study of cervical screening using partial HPV typing and cytology triage.

HPV testing is more sensitive than cytology for cervical screening. However, to incorporate HPV tests into screening, risk-stratification ("triage") of HPV-positive women is needed to avoid excessive colposcopy and overtreatment. We prospectively evaluated combinations of partial HPV typing (Onclarity, BD) and cytology triage, and explored whether management could be simplified, based on grouping combinations yielding similar 3-year or 18-month CIN3+ risks. We typed ∼9,000 archived specimens, taken at enrollment (2007-2011) into the NCI-Kaiser Permanente Northern California (KPNC) HPV Persistence and Progression (PaP) cohort. Stratified sampling, with reweighting in the statistical analysis, permitted risk estimation of HPV/cytology combinations for the 700,000+-woman KPNC screening population. Based on 3-year CIN3+ risks, Onclarity results could be combined into five groups (HPV16, else HPV18/45, else HPV31/33/58/52, else HPV51/35/39/68/56/66/68, else HPV negative); cytology results fell into three risk groups ("high-grade," ASC-US/LSIL, NILM). For the resultant 15 HPV group-cytology combinations, 3-year CIN3+ risks ranged 1,000-fold from 60.6% to 0.06%. To guide management, we compared the risks to established "benchmark" risk/management thresholds in this same population (e.g., LSIL predicted 3-year CIN3+ risk of 5.8% in the screening population, providing the benchmark for colposcopic referral). By benchmarking to 3-year risk thresholds (supplemented by 18-month estimates), the widely varying risk strata could be condensed into four action bands (very high risk of CIN3+ mandating consideration of cone biopsy if colposcopy did not find precancer; moderate risk justifying colposcopy; low risk managed by intensified follow-up to permit HPV "clearance"; and very low risk permitting routine screening.) Overall, the results support primary HPV testing, with management of HPV-positive women using partial HPV typing and cytology.

A study of HPV typing for the management of HPV-positive ASC-US cervical cytologic results.

BACKGROUND: In US cervical screening, immediate colposcopy is recommended for women with HPV-positive ASC-US (equivocal) cytology. We evaluated whether partial typing by Onclarity™ (BD) might identify HPV-positive women with low enough CIN3+ risk to permit 1-year follow-up instead. METHODS: The NCI-Kaiser Permanente Northern California Persistence and Progression cohort includes a subset of 13,890 women aged 21+ with HC2 (Qiagen)-positive ASC-US at enrollment; current median follow-up is 3.0years. Using stratified random sampling, we typed 2079 archived enrollment specimens including 329 women subsequently diagnosed with CIN3+, 563 with CIN2, and 1187 with

Development of a brief questionnaire to assess contraceptive intent.

OBJECTIVE: We sought to develop and validate an instrument that can enable providers to identify young women who may be at risk of contraceptive non-adherence. METHODS: Item response theory based methods were used to evaluate the psychometric properties of the Contraceptive Intent Questionnaire, a 15-item self-administered questionnaire, based on theory and prior qualitative and quantitative research. The questionnaire was administered to 200 women aged 15-24 years who were initiating contraceptives. We assessed item fit to the item response model, internal consistency, internal structure validity, and differential item functioning. RESULTS: All items fit a one-dimensional model. The separation reliability coefficient was 0.73. Participants' overall scores covered the full range of the scale (0-15), and items appropriately matched the range of participants' contraceptive intent. Items met the criteria for internal structure validity and most items functioned similarly between groups of women. CONCLUSION: The Contraceptive Intent Questionnaire appears to be a reliable and valid tool. Future testing is needed to assess predictive ability and clinical utility. PRACTICE IMPLICATIONS: The Contraceptive Intent Questionnaire may serve as a valid tool to help providers identify women who may have problems with contraceptive adherence, as well as to pinpoint areas in which counseling may be directed.