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Human papillomavirus vaccination history and diagnosis of cervical intraepithelial neoplasia grade ≥2 severe lesions among a cohort of women who underwent colposcopy in Kaiser Permanente Southern California

Open AccessPublished:July 14, 2021DOI:https://doi.org/10.1016/j.ajog.2021.07.006

      Background

      The risk of a high-grade lesion in women undergoing colposcopy following an abnormal screening result may be different by human papillomavirus vaccination status, because women who are vaccinated are presumably less likely to harbor human papillomavirus types 16 and 18.

      Objective

      This study aimed to evaluate whether the risk of high-grade cervical lesion diagnosed through colposcopy is lower in women with human papillomavirus vaccination than in women without vaccination referred to colposcopy based on equal abnormal screening findings.

      Study Design

      Kaiser Permanente Orange County female patients between ages 21 and 38 years were included following an abnormal screening if they had ≥1 colposcopies between July 2017 and August 2018 and had at least 1 pathology diagnosis from the colposcopy visits. Data on demographic characteristics, clinical and sexual histories, and human papillomavirus vaccination were collected using a colposcopy registry smart form and from electronic medical records. Human papillomavirus genotyping was performed for tissues from confirmed cervical intraepithelial neoplasm grade 2+ diagnoses. A multilevel generalized linear model with a logic function was used to evaluate the association between human papillomavirus vaccination history and the outcome of a cervical intraepithelial neoplasm grade 2+ diagnosis and for human papillomavirus type 16- or 18-positive cervical intraepithelial neoplasm grade 2+ as an alternative outcome, adjusting for screening results and potential confounders.

      Results

      Of 730 women included in the study, 170 had a histologic diagnosis of cervical intraepithelial neoplasm grade 2+ (23.2%). Moreover, 68 cases (40.0%) were histologically human papillomavirus type 16 and/or 18 positive. Of the 730 women, 311 (43%) were vaccinated for the human papillomavirus before colposcopy. Most women (206 [66.2%]) with human papillomavirus vaccination received the vaccine between the ages 18 and 26 years. A history of human papillomavirus vaccination overall, before sexual debut, before the age of 18 years, or with complete dosing was not associated with lower odds of a cervical intraepithelial neoplasm grade 2+ diagnosis (odds ratio, 1.07 [95% confidence interval, 0.70–1.64]; odds ratio, 1.11 [95% confidence interval, 0.55–2.24]; odds ratio, 0.96 [95% confidence interval, 0.49–1.91]; and odds ratio, 0.84 [95% confidence interval, 0.53–1.35], respectively, in reference to no vaccination). Human papillomavirus vaccination history was not significantly associated with the odds of a human papillomavirus type 16- or 18-positive cervical intraepithelial neoplasm grade 2+ diagnosis (P=.45). Notably, 8 cases (4.8% of all cervical intraepithelial neoplasm grade 2+ cases) showed a human papillomavirus type 16 on a cervical intraepithelial neoplasm grade 2+ histologic polymerase chain reaction analysis despite reported or documented human papillomavirus vaccination before sexual debut, including 2 cases who started vaccination before the age of 13 years.

      Conclusion

      Our study did not support modifying the colposcopy management guidelines for abnormal screening results for women with human papillomavirus vaccination, especially those vaccinated in the catch-up age range. Our findings on the 8 cases of human papillomavirus 16-positive cervical intraepithelial neoplasm grade 2+ vaccination before sexual debut suggested that lowering the recommended age for human papillomavirus vaccination may have additional benefits for preventing human papillomavirus infection that could occur early in life in some women.

      Key words

      Introduction

      Primary prevention through human papillomavirus (HPV) vaccination before sexual debut, optimally during early adolescence, can be anticipated to reduce the emergence of neoplastic lower genital tract disease later in life.
      • Villa L.L.
      • Costa R.L.
      • Petta C.A.
      • et al.
      High sustained efficacy of a prophylactic quadrivalent human papillomavirus types 6/11/16/18 L1 virus-like particle vaccine through 5 years of follow-up.
      Postvaccination humoral immunity in such ideal cases prevents infection and insinuation of the HPV genome into the host cell, presumably on the transformation zone of the cervix after exposure.
      • Mariani L.
      • Venuti A.
      HPV vaccine: an overview of immune response, clinical protection, and new approaches for the future.
      Women undergoing vaccination would be expected to harbor a lower cervical intraepithelial neoplasia (CIN) lesion rate, leading to a lower rate of screening test abnormalities. This was evident with a highly successful national implementation program in Australia.
      • Patel C.
      • Brotherton J.M.
      • Pillsbury A.
      • et al.
      The impact of 10 years of human papillomavirus (HPV) vaccination in Australia: what additional disease burden will a nonavalent vaccine prevent?.

       Why was this study conducted?

      This study aimed to evaluate whether the likelihood of a cervical intraepithelial neoplasm grade 2+ (CIN2+) diagnosis in women who underwent a colposcopy following an abnormal screening result varies by previous human papillomavirus (HPV) vaccination status.

       Key findings

      HPV vaccination history predominantly in the catch-up age range was not associated with a lower likelihood of having a CIN2+ diagnosis in women who underwent a colposcopy.

       What does this add to what is known?

      Our study did not support an alternative colposcopic management approach for abnormal screening results based on HPV vaccination status.
      Although routine screening continues to be recommended to women with prior HPV vaccination, data used to inform current clinical guidelines on the management of abnormal screening results were derived primarily from studies not accounting for HPV vaccination status.
      • Wright Jr., T.C.
      • Massad L.S.
      • Dunton C.J.
      • et al.
      2006 consensus guidelines for the management of women with abnormal cervical cancer screening tests.
      Although available for 14 years, the history of HPV vaccination has not been used as a risk assessment tool in a triage to colposcopy. However, the protective effect of the vaccine begs the question of whether women vaccinated for HPV with a screening abnormality can be or should be followed or managed differently. Guidelines related to the management of cervical HPV testing and cytology were updated and proliferated in the expert and provider communities that focused on age-stratified risk, with the caveat that there should be equal management of abnormalities based on the equal risk of harboring CIN3, an undisputed invasive cancer precursor.
      • Massad L.S.
      • Einstein M.H.
      • Huh W.K.
      • et al.
      2012 updated consensus guidelines for the management of abnormal cervical cancer screening tests and cancer precursors.
      ,
      • Perkins R.B.
      • Guido R.S.
      • Castle P.E.
      • et al.
      2019 ASCCP risk-based management consensus guidelines for abnormal cervical cancer screening tests and cancer precursors.
      In addition, many believe that CIN2 is worthy of detection in colposcopy and managed either expectantly or actively with excision or ablation.
      American College of Obstetricians-Gynecologists
      ACOG Committee Opinion. Evaluation and management of abnormal cervical cytology and histology in the adolescent. Number 330, April 2006.
      ,
      • Wright Jr., T.C.
      • Cox J.T.
      • Massad L.S.
      • et al.
      2001 consensus guidelines for the management of women with cervical intraepithelial neoplasia.
      However, little is known about whether cytology abnormalities and HPV testing carry the same clinical significance (ie, risk of CIN2+) in light of HPV vaccination status.
      • Demarco M.
      • Lorey T.S.
      • Fetterman B.
      • et al.
      Risks of CIN 2+, CIN 3+, and cancer by cytology and human papillomavirus status: The Foundation of Risk-Based Cervical Screening Guidelines.
      Several studies examining the virulence of different HPV types suggested that the risk of persistence or progression is lower in lesions free of HPV types 16 and 18. Several studies reported that low-grade lesions that harbored HPV16 infection had a considerably higher likelihood of progression than infections by other HPV oncogenic types.
      • Cho H.W.
      • So K.A.
      • Lee J.K.
      • Hong J.H.
      Type-specific persistence or regression of human papillomavirus genotypes in women with cervical intraepithelial neoplasia 1: a prospective cohort study.
      ,
      • Silveira F.A.
      • Almeida G.
      • Furtado Y.L.
      • et al.
      The association of HPV genotype with the regression, persistence or progression of low-grade squamous intraepithelial lesions.
      Others have reported similar findings for HPV16 infection and persistence in high-grade cervical lesions.
      • Gaarenstroom K.N.
      • Melkert P.
      • Walboomers J.M.
      • et al.
      Human papillomavirus DNA and genotypes: prognostic factors for progression of cervical intraepithelial neoplasia.
      In addition, Fischer et al
      • Fischer S.
      • Bettstetter M.
      • Becher A.
      • et al.
      Shift in prevalence of HPV types in cervical cytology specimens in the era of HPV vaccination.
      concluded a shift in the prevalence of HPV types in abnormal cytology specimens in the vaccination era. Specifically, the prevalence of HPV types 16 and 18 seemed to be suppressed in younger women who were vaccine eligible compared with women of older age. These studies presumed the theory that the emergence of high-grade lesions in women with HPV vaccination is primarily driven by nonvaccine HPV subtypes. Taken together, these studies suggested that the risk of histologically diagnosing a high-grade lesion in women with HPV vaccination undergoing colposcopy following an abnormal screening result may be different from women without HPV vaccination, because women who are vaccinated are presumed less likely to be infected by and harbor HPV types 16 and 18.
      Here, we sought to evaluate, among women with abnormal screening results, whether the risk of harboring a high-risk neoplastic precursor, defined by the presence of high-grade lesions discovered during colposcopy, is lower in women who are vaccinated than in women who are not vaccinated given equal abnormal screening finding to inform if women with HPV vaccination may benefit from a different management approach. In addition, we evaluated whether the histologic evidence from such lesions exhibited vaccine HPV genotypes (eg, HPV types 16 and 18 for quadrivalent recombinant HPV vaccine [types 6, 11, 16, and 18]; Gardasil 4; Merck & Co, Kenilworth, NJ), which we anticipated to be a rare event in women who are vaccinated, especially in women vaccinated before sexual debut.

      Materials and Methods

       Study setting and study population

      This study was conducted at the Kaiser Permanente Southern California (KPSC) Orange County Service Area. KPSC is an integrated healthcare organization that provides comprehensive health services to more than 4.5 million members (>1% of the US population) who are broadly representative of the racially and ethnically and socioeconomically diverse residents in Southern California.
      • Koebnick C.
      • Langer-Gould A.M.
      • Gould M.K.
      • et al.
      Sociodemographic characteristics of members of a large, integrated health care system: comparison with US Census Bureau data.
      Women who met the following eligibility criteria were included in the evaluation:
      • 1.
        Women who had at least 1 colposcopy procedure performed at the KPSC Orange County Service Area (Anaheim and Irvine medical centers) between July 2017 (the inception date of the colposcopy registry, a key data source for this study) and August 2018.
      • 2.
        Women who were between the ages 21 and 38 years at the time of the colposcopy. The requirement of a minimum age of 21 years was to include only women eligible for routine cervical cancer screening, whereas the requirement for the maximum age of 38 years was to ensure that women included had been eligible for HPV vaccination sometime before the colposcopy.
      • 3.
        Women who were referred to colposcopy because of abnormal screening results (screening test may be Papanicolaou test only, HPV reflex, or co-test, depending on the woman’s age).
      • 4.
        Women who had at least 1 pathology diagnosis from colposcopic biopsy or curettage or loop excision therapy visits.
      All physicians at the KPSC followed the same standardized KPSC practice guidelines for colposcopy follow-up of abnormal screening results, which mirrored the national US Preventive Services Task Force guidelines. These guidelines do not currently account for HPV vaccination status for determining follow-up. This study was approved by the KPSC Institutional Review Board (IRB). The requirement for informed consent was waived by the KPSC IRB.

       Data collection

      The KPSC HealthConnect electronic medical records (EMRs) contained an outpatient colposcopy registry, which utilized smart forms with easily retrievable data that were completed in real time by the colposcopist. During the study period, 43 experienced staff colposcopists in the KPSC Orange County Medical Center conducted practices consistent with the American Society for Colposcopy and Cervical Pathology guidelines,
      • Fischer S.
      • Bettstetter M.
      • Becher A.
      • et al.
      Shift in prevalence of HPV types in cervical cytology specimens in the era of HPV vaccination.
      capturing data in the registry smart form. The colposcopist queried patients on the following variables and entered the data in the registry smart form: sexual history, vaccination history, cervical screening or treatment history, smoking behavior, among others. In addition, the colposcopist entered information on referral reason or previous diagnosis and treatment, colposcopic appearance, lesion characteristics, and biopsy practice, including devices used. When biopsy results became available, the colposcopist entered the histologic diagnosis in the registry form. The registry was used for quality assurance, IRB-approved research, and case management.
      For HPV vaccination history, the exposure of interest, and cervical cancer screening results that led to the colposcopy, we predominantly relied on data from the KPSC EMR, supplemented by the data acquired by the colposcopists at the point of service from the patient report and entered into the colposcopy registry (eg, for HPV vaccination or screening received outside of the KPSC). In addition, patient’s age, race and ethnicity, and smoking history (at time of colposcopy or the most recent record before colposcopy) were collected from the KPSC EMR.

       Histologic diagnosis confirmation

      The outcome of interest in this study was the histologic diagnosis of CIN2+. Original diagnostic hematoxylin and eosin stain slides of the cervical lesions were retrieved from the KPSC Orange County Pathology Department and were transferred to the study pathologist (J.C.F.) for re-review for confirmation of histologic diagnosis. All cases of a CIN2+ diagnosis were re-reviewed. The study pathologist was blinded from the original histologic diagnosis of the specimens. If multiple biopsies were taken in a colposcopy examination, the highest histologic grade of the biopsies was used. For women with multiple colposcopies performed in the study period, all colposcopy visits (diagnostic biopsy and therapeutic excision) that yielded a piece of histologic evidence were considered, and the highest-grade histologic evidence was used as the “true CIN status” for these women in the analysis. A clinical meaningful discrepancy between the initial histologic diagnosis and this re-review was defined as a discrepancy between normal or CIN1 and CIN2+. Cases with an overread consistent with CIN2 or higher were included. Molecular p16 biomarker testing was run in 60% of CIN2 cases during clinical care, and the results were available during our analysis. When there was a discrepancy between the initial diagnosis and re-review, those cases with positive p16 staining were considered CIN2 and were included in the cohort for analysis.

       Human papillomavirus genotyping of cervical lesions

      Formalin-fixed paraffin-embedded tissue blocks for cervical biopsies were retrieved from the KPSC Orange County Pathology Department and were transferred to the University of Southern California (D.M.D.S.’s laboratory) for the HPV genotyping assay. Briefly, paraffin ribbons were cut and placed into individual microfuge tubes. The microtome blade was cleaned with DNA AWAY (Molecular BioProducts, San Diego, CA) in each tissue block to avoid cross-contamination. For paraffin ribbons, the tissue was deparaffinized in tubes with centrifugation to pellet tissue. Total genomic DNA was isolated using the DNeasy Tissue Kit according to the manufacturer’s instructions (Qiagen, Valencia, CA). DNA was quantified on a NanoDrop spectrophotometer (Thermo Fisher Scientific, Wilmington, DE). Real-time multiplex polymerase chain reaction (PCR) amplification was performed for HPV DNA and human beta-globin housekeeping DNA (for quality control) using the Novaplex II HPV28 Detection assay (Seegene Technologies, Walnut Creek, CA), which enabled the detection and differentiation of target nucleic acids of 19 high-risk HPV types and 9 low-risk HPV types and endogenous control. For quality control, positive and negative controls were included with the assay.

       Statistical analysis

      The distribution of the demographic and clinical characteristics, including the preceding screening Papanicolaou test and HPV results of the study subjects, was calculated using descriptive statistics, overall and by CIN2+ status (ie, ≤CIN1 vs ≥CIN2). Among those with CIN2+, we further divided them into those with positive HPV16 and/or HPV18 (the HPV genotype covered by the HPV vaccine in this study) vs those without HPV16 or HPV18 in their lesions. Differences in demographic and clinical characteristics and HPV vaccination history between outcome groups were compared using the chi-square test and t test for categorical and continuous variables, respectively. The following categorizations of HPV vaccination status were considered: (1) any HPV vaccination vs no vaccination; (2) first vaccination before vs after sexual debut; (3) complete dosing (≥3 doses) vs incomplete dosing (1–2 doses); and (4) by age at first vaccination (<13 vs ≥13 years; <18 vs ≥18 years).
      We performed a bivariate logistic regression (ie, regression with only 1 independent variable and 1 outcome variable) to evaluate the crude associations between having a CIN2+ histologic diagnosis and HPV vaccination (see above), preceding screening test results (negative Papanicolaou test and positive HPV; atypical squamous cells of uncertain significance [regardless of HPV results]; low-grade squamous intraepithelial lesion [regardless of HPV result]; and high-grade squamous intraepithelial, atypical squamous cells cannot rule out high grade, or atypical glandular cells [regardless of HPV results]), age (21–29 years and 30–38 years), race and ethnicity (non-Hispanic White, non-Hispanic Black, Hispanic, Asian or Pacific Islander, and other), smoking status (current, former, and never), parity (0, 1, and ≥2), and age at sexual debut (<18 and ≥18 years). The multilevel generalized linear models accounting for the clustering of the patients within the providers were used to study the associations between HPV vaccination status and having a CIN2+ diagnosis. The variables described above were adjusted in the multivariable models. The analyses were repeated, redefining the outcome as HPV type 16- and 18-positive CIN2+ lesions vs other lesions (ie, ≤CIN1 or non–HPV type 16 and 18 CIN2+). Multiple imputations were used to handle missing data of the covariates (there was no missing value for the outcome variable as those without any histology diagnosis were not included in this study), including those for vaccination status.
      • Rubin D.B.
      Inference and missing data.
      ,
      • Rubin D.B.
      Multiple imputation for nonresponse in surveys.
      In a sensitivity analysis, we performed the regression models excluding those with missing data.
      A small number of women with CIN2+ diagnosis had HPV vaccination initiated before the self-reported sexual debut. The detailed HPV vaccination history, age at sexual debut, and HPV genotype found in the lesion for these women were described. Medical record review was performed for these women to determine if these women had any immunosuppressive conditions or medications that might be immunosuppressive and predispose them to vaccine failure. All statistical analyses were performed using the Statistical Analysis System (version 9.3; SAS Institute Inc, Cary, NC).

      Results

      We identified a total of 1438 women who underwent colposcopy at the KPSC Orange County Medical Center during the study inclusion period. Of those women, 780 were between the ages 21 and 38 years at the time of the colposcopy. A total of 730 women met all the eligibility criteria and were included in the study (Figure). Of the 730 women, 170 (23.3%) had a histologic diagnosis of CIN2 or more severe lesions (97 CIN2 cases, 71 CIN3 cases, and 2 adenocarcinoma in situ cases), and the remaining 560 were considered to have CIN1 or normal histology. Of the 170 CIN2+ cases, 68 (40.0%) were found to harbor HPV type 16 and/or 18 from the PCR assay, and 5 did not have an HPV PCR assay performed (their tissue blocks were not retrieved).
      Figure thumbnail gr1
      FigureStudy population flowchart
      KPSC OC, Kaiser Permanente Southern California Orange County.
      Lonky et al. Human papillomavirus vaccination and risk of cervical dysplasia in women who underwent colposcopy. Am J Obstet Gynecol 2021.
      Table 1 shows the demographic and clinical characteristics of the study population by histology diagnosis and HPV type 16 or 18 status. Approximately 62% of women were aged ≥30 years at colposcopy. The women were racially and ethnically diverse: 38.4% were of Hispanic ethnicity, 19.5% were Asians or Pacific Islanders, 2.7% were non-Hispanic Black, and 31.4% were non-Hispanic White. Most women had a low-grade Papanicolaou test result proceeding with the colposcopy (>90%). Of all study subjects, 42.6% had HPV vaccination (ie, 48.8% among those with known HPV vaccination status), 44.7% did not have HPV vaccination, and 12.7% had unknown HPV vaccination status. Approximately 15% of the HPV vaccination data recorded were based on patient self-reports. Aside from the referral reason, the distribution of other demographic and clinical characteristics did not differ significantly between those with and without a CIN2+ diagnosis (P-value ranged from .15 -.57). Moreover, the demographic and clinical characteristics did not differ between HPV type 16- or 18-positive and HPV type 16- or 18-negative CIN2+ cases (Table 1).
      Table 1Demographic and clinical characteristics of the study women who underwent colposcopy, by highest histologic diagnosis and HPV type 16 or 18 status
      CharacteristicTotal (N=730)≤CIN1 (n=560)≥CIN2 (n=170)P value≥CIN2 with HPV genotype data (Total N=165)≥CIN 2, HPV type 16 or 18 negative (n=97)≥CIN 2, HPV type 16 or 18 positive (n=68)P value
      Age at diagnosis (y)31.0±4.030.9±4.131.2±3.9.1531.2±3.931.0±3.831.5±4.0.98
       21–29279 (38.2)222 (39.6)57 (33.5)56 (33.9)33 (34.0)23 (33.8)
       30–38451 (61.8)338 (60.4)113 (66.5)109 (66.1)64 (66.0)45 (66.2)
      Race and ethnicity.50.39
       Asian or Pacific Islander142 (19.5)105 (18.8)37 (21.8)8 (4.9)6 (6.2)2 (2.9)
       Black20 (2.7)17 (3.0)3 (1.8)37 (22.4)24 (24.7)13 (19.1)
       Hispanic280 (38.4)221 (39.5)59 (34.7)3 (1.8)1 (1.0)2 (2.9)
       White229 (31.4)170 (30.4)59 (34.7)57 (34.6)30 (30.9)27 (39.7)
       Others23 (3.2)20 (3.6)3 (1.8)3 (1.8)3 (3.1)0 (0)
       Missing36 (4.9)27 (4.8)9 (5.3)57 (34.6)33 (34.0)24 (34.6)
      Referral reason<.01.31
       Negative Papanicolaou test and positive HPV test153 (21.0)125 (22.3)28 (16.5)27 (16.4)15 (15.5)12 (17.7)
       ASCUS
      Regardless of HPV result.
      271 (37.1)213 (38.0)58 (34.1)57 (34.6)34 (35.1)23 (33.8)
       LSIL
      Regardless of HPV result.
      249 (34.1)192 (34.3)57 (33.5)56 (33.9)37 (38.1)19 (27.9)
       ASC-H, HSIL or AGC
      Regardless of HPV result.
      57 (7.8)30 (5.4)27 (15.9)25 (15.2)11 (11.3)14 (20.6)
      HPV vaccination.25.26
       No326 (44.7)241 (43.0)85 (50.0)82 (49.7)43 (44.3)39 (57.4)
       Yes311 (42.6)244 (43.6)67 (39.4)66 (40.0)43 (44.3)23 (33.8)
       Missing93 (12.7)75 (13.4)18 (10.6)17 (10.3)11 (11.3)6 (8.8)
      Age at sexual debut (y).57.60
       <18236 (32.3)177 (31.6)59 (34.7)50 (30.3)32 (33.0)18 (26.5)
       ≥18278 (38.1)219 (39.1)59 (34.7)58 (35.2)34 (35.1%)24 (35.3)
       Missing216 (29.6)164 (29.3)52 (30.6)57 (34.6)31 (32.0)26 (38.2)
      Parity.42.20
       0350 (48.0)266 (47.5)84 (49.4)15 (9.1)10 (10.3)5 (7.4)
       1147 (20.1)119 (21.3)28 (16.5)83 (50.3)54 (55.7)29 (42.7)
       ≥2153 (21.0)112 (20.0)41 (24.1)28 (17.0)15 (15.5)13 (19.1)
       Missing80 (11.0)63 (11.3)17 (10.0)39 (23.6)18 (18.6)21 (30.9)
      Smoking status.39.20
       Current42 (5.8)29 (5.2)13 (7.7)2 (1.2)2 (2.1)0 (0)
       Former77 (10.6)62 (11.1)15 (8.8)13 (7.9)7 (7.2)6 (8.8)
       Never590 (80.8)451 (80.5)139 (81.8)135 (81.8)76 (78.4)59 (86.8)
       Missing21 (2.9)18 (3.2)3 (1.8)15 (9.1)12 (12.4)3 (4.4)
      Data are presented as mean±standard deviation or number (percentage), unless otherwise indicated.
      AGC, atypical glandular cells; ASC-H, atypical squamous cells cannot rule out high grade; ASCUS, atypical squamous cells of uncertain significance; CIN, cervical intraepithelial neoplasm; HPV, human papillomavirus; HSIL, high-grade squamous intraepithelial; LSIL, low-grade squamous intraepithelial lesion.
      Lonky et al. Human papillomavirus vaccination and risk of cervical dysplasia in women who underwent colposcopy. Am J Obstet Gynecol 2021.
      a Regardless of HPV result.
      Among the 311 women who underwent HPV vaccination before colposcopy, 289 (93%) were vaccinated after the age of 13 years and 206 (66%) were vaccinated after the age of 18 years. This likely, in part, reflected the fact that at the time of this study, women who had a chance to get vaccinated before the age of 13 years when the vaccine was introduced only just entered the screening age range, representing a minor proportion of the colposcopy cohort. Approximately one-third of the women received the first HPV vaccine before sexual debut. Moreover, 71.4% received complete dosing, and 78.5% received only quadrivalent recombinant HPV vaccine. The characteristics of HPV vaccination among those vaccinated did not differ significantly among those who had CIN2+ vs those who did not (P-value ranged between .06–.79, data not shown) or by HPV type 16 or 18 status among those with CIN2+ (P-value ranged between .23–.87, data not shown) (Table 2).
      Table 2Characteristics of HPV vaccination among women who were vaccinated, by histologic diagnosis and HPV type 16 or 18 status
      CharacteristicTotal (N=311)≤CIN1 (n=244)≥CIN 2 (n=67)Total (N=66)≥CIN 2, HPV type 16 or 18 negative (n=43)≥CIN 2, HPV type 16 or 18 positive (n=23)
      Age vaccinated (y)
       <1311 (3.5)8 (3.3)3 (4.8)3 (5.6)1 (2.3)2 (8.7)
       ≥13289 (92.9)228 (93.4)61 (91.0)60 (90.9)39 (90.7)21 (91.3)
       <1894 (30.2)77 (31.6)17 (25.4)17 (25.8)10 (23.3)7 (30.4)
       ≥18206 (66.2)159 (65.2)47 (70.2)46 (69.7)30 (69.8)16 (69.6)
       Missing11 (3.5)8 (3.3)3 (4.5)3 (4.6)3 (7.0)0 (0)
      Vaccinated before sexual debut age
       No172 (55.3)137 (56.2)35 (52.2)34 (51.5)22 (51.2)12 (52.2)
       Yes86 (27.7)68 (27.9)18 (26.9)18 (27.3)10 (23.3)8 (34.8)
       Missing53 (17.0)39 (16.0)14 (20.9)14 (21.1)11 (25.6)3 (13.0)
      Vaccination dose
       133 (10.6)22 (9.0)11 (16.4)11 (16.7)5 (11.6)6 (26.1)
       239 (12.5)31 (12.7)8 (11.9)8 (12.1)5 (11.6)3 (13.0)
       >3222 (71.4)180 (73.8)42 (62.7)41 (62.1)29 (67.4)12 (52.2)
       Missing11 (3.5)6 (2.5)5 (7.5)5 (7.6)3 (7.0)2 (8.7)
      Vaccination type
       Quadrivalent recombinant244 (78.5)193 (79.1)51 (76.1)50 (75.8)32 (74.4)18 (78.3)
       Quadrivalent recombinant and nonavalent recombinant15 (4.8)14 (5.7)1 (1.5)1 (1.5)1 (2.3)0 (0)
       Nonavalent recombinant26 (8.4)18 (7.4)8 (11.9)8 (12.1)5 (11.6)3 (13.0)
       Missing26 (8.4)19 (7.8)7 (10.5)7 (10.6)5 (11.6)2 (8.7)
      Data are presented as number (percentage).
      CIN, cervical intraepithelial neoplasm; HPV, human papillomavirus.
      Lonky et al. Human papillomavirus vaccination and risk of cervical dysplasia in women who underwent colposcopy. Am J Obstet Gynecol 2021.
      When we examined the association between HPV vaccination history and CIN2+ diagnosis in regression models, HPV vaccination was not associated with lower odds of having a CIN2+ diagnosis (odds ratio [OR] for any HPV vaccination, 1.07; 95% confidence interval [CI], 0.70–1.64), regardless of whether the HPV vaccine was given before or after sexual debut, before or after the age of 18 years, and with or without complete dosing (Table 3). When we examined HPV type 16- or 18-positive CIN2+ as the outcome of interest, HPV vaccination was not statistically significantly associated with the odds of HPV type 16- or 18-positive CIN2+ (P-value=0.45) (Table 4). This lack of association was also observed for HPV vaccination before sexual debut (OR, 1.00; 95% CI, 0.38–2.68), HPV vaccination with complete dosing (OR, 0.54; 95% CI, 0.26–1.12), and HPV vaccination before the age of 18 years (OR, 0.86; 95% CI, 0.30–2.47) (Table 4). A sensitivity analysis that was restricted to those without missing data resulted in similar findings.
      Table 3ORs from logistic regression of having a histologic diagnosis of CIN2+
      HPV vaccinationReferenceCrude OR (95% CI)P valueAdjust OR (95% CI)
      Model adjusted for age, race and ethnicity, smoking status, parity, and referral reason.
      P value
      Any vaccinationNo vaccination0.88 (0.61–1.26).481.07 (0.70–1.64).74
      Before sexual debutNo vaccination0.82 (0.47–1.43).481.11 (0.55–2.24).76
      After sexual debutNo vaccination0.90 (0.60–1.37).641.06 (0.67–1.68).80
      Complete dosing (≥3 doses)No vaccination0.70 (0.47–1.05).080.84 (0.53–1.35).47
      Incomplete dosing (<3 doses)No vaccination1.51 (0.86–2.65).151.75 (0.98–3.13).06
      First dose at the age of <18 yNo vaccination0.73 (0.42–1.27).260.96 (0.49–1.91).92
      First dose at the age of ≥18 yNo vaccination0.95 (0.62–1.43).801.10 (0.70–1.73).68
      CI, confidence interval; CIN, cervical intraepithelial neoplasm; HPV, human papillomavirus; OR, odds ratio.
      Lonky et al. Human papillomavirus vaccination and risk of cervical dysplasia in women who underwent colposcopy. Am J Obstet Gynecol 2021.
      a Model adjusted for age, race and ethnicity, smoking status, parity, and referral reason.
      Table 4ORs from logistic regression of having a histologic diagnosis of CIN2+ that was HPV type 16 or 18 positive
      HPV vaccinationReferenceCrude OR (95% CI)P valueAdjust OR (95% CI)
      Model adjusted for age, race and ethnicity, smoking status, parity, and referral reason.
      P value
      Any vaccinationNo vaccination0.64 (0.38–1.08).100.78 (0.42–1.47).45
      Before sexual debutNo vaccination0.70 (0.31–1.58).401.00 (0.38–2.68)1.00
      After sexual debutNo vaccination0.61 (0.33–1.11).100.72 (0.37–1.42).35
      Complete dosing (≥3 doses)No vaccination0.45 (0.24–0.87).020.54 (0.26–1.12).10
      Incomplete dosing (<3 doses)No vaccination1.25 (0.60–2.63).551.45 (0.65–3.26).37
      First dose at the age of <18 yNo vaccination0.64 (0.27–1.52).310.86 (0.30–2.47).78
      First dose at the age of ≥18 yNo vaccination0.64 (0.36–1.14).130.76 (0.40–1.47).42
      CI, confidence interval; CIN, cervical intraepithelial neoplasm; HPV, human papillomavirus; OR, odds ratio.
      Lonky et al. Human papillomavirus vaccination and risk of cervical dysplasia in women who underwent colposcopy. Am J Obstet Gynecol 2021.
      a Model adjusted for age, race and ethnicity, smoking status, parity, and referral reason.
      Of the 68 CIN2+ cases that were HPV type 16 or 18 positive, 8 (11.8%) had HPV vaccination before sexual debut. We provided the detailed HPV PCR results and HPV vaccination history for these 8 cases in Table 5. All 8 cases only had HPV16, and most cases had additional oncogenic subtypes found alongside HPV16 during PCR analysis. Moreover, 7 of 8 cases were documented to have received the quadrivalent recombinant HPV vaccine. In addition, 2 cases with CIN3 and previous quadrivalent recombinant HPV vaccination had only HPV16 present in the histologic sample, where vaccination occurred between the ages 14 and 15 years. Furthermore, 2 cases reported the first HPV vaccination before the age of 13 years (at ages 9 and 12, respectively). Notably, at least 4 cases had completed 3 doses of HPV vaccine, including the case whose first HPV vaccination was given at the age of 9 years. None of the 8 women was found to have an immunosuppressive condition or was on immunosuppressive medications on medical record review.
      Table 5Characteristics of 8 cases with CIN2+ and vaccinated before sexual debut
      CaseHistologic diagnosisHPV genotype detectedAge at first HPV vaccinationHPV vaccine dose completedAge at sexual debutHPV vaccine type
      1CIN 31614220Quadrivalent recombinant
      2CIN 216,39,40,58,8218326Quadrivalent recombinant
      3CIN 31615Missing20Quadrivalent recombinant
      4CIN 216,39,40,42,5814316Quadrivalent recombinant
      5CIN 216,39,40,42,5816318Quadrivalent recombinant
      6CIN 216,52,58,6612Missing18Quadrivalent recombinant
      7CIN 216,5214315Quadrivalent recombinant
      8CIN 316,31,589319Missing
      CIN, cervical intraepithelial neoplasm; HPV, human papillomavirus.
      Lonky et al. Human papillomavirus vaccination and risk of cervical dysplasia in women who underwent colposcopy. Am J Obstet Gynecol 2021.

      Comment

       Principal findings

      History of HPV vaccination did not identify a population of women with abnormal screening results who were at lower risk of CIN2+. This finding did not support the use of HPV vaccine history to triage women for less intensive management after an abnormal test result. Overall, HPV vaccination history in this cohort of women referred to colposcopy after abnormal screening results was not rare (slightly over 40%). HPV vaccination history was also common (39.4%) among women who received a CIN2+ diagnosis. We did not find a lower likelihood of CIN2+ diagnosis for those who had any HPV vaccination, for those who had HPV before sexual debut, for those who had complete dosing, or for those who were vaccinated before the age of 18 years. Furthermore, HPV vaccination was not associated with the likelihood of HPV type 16- or 18-positive CIN2+. We showed evidence that patients who underwent vaccination did not harbor CIN 2+ solely associated with nonvaccine subtypes. It should be noted that most of the HPV vaccination in our study population was administrated in the catch-up age range, that is, after the age of 13 years, and thus beyond the age recommended for routine HPV vaccination.

       Results

      Our findings were consistent with Kuroki et al,
      • Kuroki L.M.
      • Binder P.S.
      • Powell M.A.
      • Massad L.S.
      • Gao F.
      Self-reported human papillomavirus vaccination does not have an impact on the risk for high-grade cervical intraepithelial neoplasia among women referred for colposcopy.
      who did not observe a an association between self-reported HPV vaccination history and having a CIN2+ diagnosis among women who underwent colposcopy. In contrast, Dorton et al
      • Dorton B.J.
      • Vitonis A.F.
      • Feldman S.
      Comparing cervical cytology and histology among human papillomavirus-vaccinated and -Unvaccinated women in an Academic Colposcopy Clinic.
      and Munro et al
      • Munro A.
      • Gillespie C.
      • Cotton S.
      • et al.
      The impact of human papillomavirus type on colposcopy performance in women offered HPV immunisation in a catch-up vaccine programme: a two-centre observational study.
      reported a lower likelihood of a CIN2+ diagnosis in women with HPV vaccination than in women without HPV vaccination undergoing colposcopy. Both Dorton et al
      • Dorton B.J.
      • Vitonis A.F.
      • Feldman S.
      Comparing cervical cytology and histology among human papillomavirus-vaccinated and -Unvaccinated women in an Academic Colposcopy Clinic.
      and Munro et al
      • Munro A.
      • Gillespie C.
      • Cotton S.
      • et al.
      The impact of human papillomavirus type on colposcopy performance in women offered HPV immunisation in a catch-up vaccine programme: a two-centre observational study.
      only included women at ages 26 years or younger at colposcopy presentation, although most women received HPV vaccination in the catch-up age range. It should be noted that both of these studies did not condition their findings on equal screening results and thus did not directly address whether the risk of high-grade lesions for a given screening result differed by HPV vaccination status. In addition, none of these previous studies had separately evaluated HPV type 16- or 18-positive CIN2+ as an outcome of interest. As such, the difference between study findings may also be because of differences in data source for HPV vaccination (self-report vs medical record review), the distribution of age at vaccination, exposure to oncogenic HPVs before vaccination across study populations, or whether the colposcopists biopsied less or more aggressively for women with and without HPV vaccination history.
      We found 8 women who reported HPV vaccination before sexual debut yet developed HPV type 16- or 18-positive CIN2+, with no evidence of immunosuppression identified. Several potential explanations exist as follows:
      • 1.
        Women may not have provided the accurate age at sexual debut when asked by a physician.
        • Alexander S.C.
        • Fortenberry J.D.
        • Pollak K.I.
        • et al.
        Disclosure of sexual intercourse by teenagers: agreement Between telephone survey responses and annual visit disclosures.
        ,
        • Schroder K.E.
        • Carey M.P.
        • Vanable P.A.
        Methodological challenges in research on sexual risk behavior: II. Accuracy of self-reports.
      • 2.
        Other sexual contact before sexual debut that permitted HPV transmission. In a study of adolescents, 83%, 71%, and 16% of adolescents believed that they were a virgin if they touched genitals, participated in oral sex, or participated in anal sex, respectively.
        • Bersamin M.M.
        • Fisher D.A.
        • Walker S.
        • Hill D.L.
        • Grube J.W.
        Defining virginity and abstinence: adolescents’ interpretations of sexual behaviors.
      • 3.
        Errors in recalling the first HPV vaccination.
        • Stupiansky N.W.
        • Zimet G.D.
        • Cummings T.
        • Fortenberry J.D.
        • Shew M.
        Accuracy of self-reported human papillomavirus vaccine receipt among adolescent girls and their mothers.
        However, HPV vaccination records for 2 patients were entirely based on KPSC EMR, which were highly valid for vaccination history.
      • 4.
        Childhood sexual abuse. In the literature, it has been reported that the prevalence of childhood sexual abuse was between 11% and 17% (contact abuse) for girls in the United States.
        • Townsend C.
        Estimating a child sexual abuse prevalence rate for practitioners: a review of child sexual abuse prevalence studies.
      • 5.
        Other nonsexual transmissions, including skin-to-skin transmission and vertical transmission from mothers to babies.
        • LaCour D.E.
        • Trimble C.
        Human papillomavirus in infants: transmission, prevalence, and persistence.
        To this end, persistent HPV infection has been detected in children who acquired HPV from vertical transmission for years, with 80% of infections by HPV types 16 and 18.
        • Puranen M.
        • Yliskoski M.
        • Saarikoski S.
        • Syrjänen K.
        • Syrjänen S.
        Vertical transmission of human papillomavirus from infected mothers to their newborn babies and persistence of the virus in childhood.
        This observation supported the findings of HPV infection, including HPV types 16 and 18, in sexually inexperienced children, adolescent, and young women in a previous study.
        • Widdice L.E.
        • Brown D.R.
        • Bernstein D.I.
        • et al.
        Prevalence of human papillomavirus infection in young women receiving the first quadrivalent vaccine dose.
        ,
        • Bacopoulou F.
        • Karakitsos P.
        • Kottaridi C.
        • et al.
        Genital HPV in children and adolescents: does sexual activity make a difference?.
        Thus, the chance of high-grade lesions caused by HPV vaccine types should not be dismissed even among women who were properly vaccinated (ie, before the age of 13 years).
      • 6.
        True HPV vaccine failure. However, because HPV vaccine efficacy was nearly 100% in phase 3 clinical trials,
        • Unger E.R.
        • Fajman N.N.
        • Maloney E.M.
        • et al.
        Anogenital human papillomavirus in sexually abused and nonabused children: a multicenter study.
        ,
        • Williams L.M.
        Recall of childhood trauma: a prospective study of women’s memories of child sexual abuse.
        we considered this explanation far less likely than the other potential explanations provided above.
      The considerations discussed here bring to light the multivariate factors that can affect the preventive aim of HPV vaccination.

       Research implications

      It should be noted that our findings should not be applied to the incidence of cervical cancer precursors in a cohort undergoing cancer screening. Our study was conditioned on an already high-risk cohort with abnormal screening test results. HPV vaccines have been shown effective in reducing abnormal screening results, moderate and severe CINs, and cervical cancer on the population level.
      • Kim J.
      • Bell C.
      • Sun M.
      • et al.
      Effect of human papillomavirus vaccination on cervical cancer screening in Alberta.
      ,
      • Lei J.
      • Ploner A.
      • Elfström K.M.
      • et al.
      HPV vaccination and the risk of invasive cervical cancer.
      In fact, our findings of women who were properly vaccinated developing CIN2+ lesions supported the reassessment of lowering the recommended age of HPV vaccine initiation. Additional research is needed to confirm the role of HPV vaccination in the management strategies of abnormal screening results among a larger group of women vaccinated properly before the age of 13 years and to determine the impact of vaccination on long-term risk of progression or recurrence of cervical lesions.

       Strengths and limitations

      Several limitations should be considered when interpreting the study results. First, as described above, several data elements, such as age at sexual debut and HPV vaccination (partially), relied on self-report from patients, inquired and documented by the physician. Although a minority of our evidence, the accuracy of HPV vaccination based on self-report was found to be suboptimal in previous studies.
      • Stupiansky N.W.
      • Zimet G.D.
      • Cummings T.
      • Fortenberry J.D.
      • Shew M.
      Accuracy of self-reported human papillomavirus vaccine receipt among adolescent girls and their mothers.
      Thus, a certain degree of misclassification in vaccination status and age at sexual debut was expected. Furthermore, sexual debut self-reported by patients may not be a reliable indicator for HPV exposure status. Second, most women who were vaccinated received the quadrivalent HPV vaccine; therefore, the study findings may not be generalizable to women who received the nonavalent HPV vaccine. Third, as described earlier, as most women received HPV vaccination in the catch-up age range (which was a meaningful cohort, prevalent throughout the United States in the colposcopy referral population), our findings may not be generalizable to women who received the HPV vaccine before the age of 13 years. Fourth, sample size may be limited, especially in subgroups (eg, those with complete dosing or vaccinated before sexual debut). Thus, larger studies will be needed to confirm our null findings. In addition, we had a small subgroup of non-Hispanic Black patients. However, we did not expect the association between vaccination history and risk of CIN2+ to differ for Black and non-Black women. Fifth, of the 8 women with CIN2+ vaccinated before sexual debut, it was unclear whether it was the vaccine type that caused the lesion (except for the 2 cases who only had HPV16 infection detected). However, the fact that HPV16 infection was detected in these cases was still worth noting. Sixth, given that colposcopy follow-up was not 100% in women with abnormal screening results, it was possible that those vaccinated vs those unvaccinated may have had different adherence to colposcopy. Thus, our study population may not represent all women with abnormal screening results. To our knowledge, the direction of this potential differential adherence behavior by vaccination status has not been previously evaluated. Finally, we did not evaluate and compare the colposcopy and biopsy practices for women with and without vaccination; thus, it was unclear whether previous HPV vaccination might have impacted the biopsy sampling approach (ie, taking more or fewer biopsies for those vaccinated) of the colposcopists. However, our null results were not particularly sensitive to this potential bias, as this potential differential biopsy practice was expected to lead to an artificial protective association between HPV vaccination and risk of CIN2+.
      Despite these limitations, our study has several unique strengths, including the genotyping for all confirmed CIN2+, expert overread, and, in most cases, the p16 biomarker to confirm CIN2+ diagnosis, the availability of age at sexual debut data that were not been evaluated in prior studies, and the inclusion of a racially and ethnically diverse female population who presented at colposcopy clinics in a large community-based practice.

       Conclusions

      Our study did not support the differential colposcopic referral and management approaches for abnormal screening results based on HPV vaccination received in the catch-up age range. In addition, our findings pointed to the likelihood that infections and severe cervical lesions caused by HPV vaccine types may still occur in women vaccinated before their sexual debut.

      Acknowledgments

      The authors thank the patients of Kaiser Permanente for helping us improve care through the use of information collected through our electronic health record systems, the entire KPSC Orange Country Gynecology Colposcopy Service for piloting the colposcopy smart form, and Dr Abby Berenson for her review and helpful comments for the draft of this manuscript.

      References

        • Villa L.L.
        • Costa R.L.
        • Petta C.A.
        • et al.
        High sustained efficacy of a prophylactic quadrivalent human papillomavirus types 6/11/16/18 L1 virus-like particle vaccine through 5 years of follow-up.
        Br J Cancer. 2006; 95: 1459-1466
        • Mariani L.
        • Venuti A.
        HPV vaccine: an overview of immune response, clinical protection, and new approaches for the future.
        J Transl Med. 2010; 8: 105
        • Patel C.
        • Brotherton J.M.
        • Pillsbury A.
        • et al.
        The impact of 10 years of human papillomavirus (HPV) vaccination in Australia: what additional disease burden will a nonavalent vaccine prevent?.
        Euro Surveill. 2018; 23: 1700737
        • Wright Jr., T.C.
        • Massad L.S.
        • Dunton C.J.
        • et al.
        2006 consensus guidelines for the management of women with abnormal cervical cancer screening tests.
        Am J Obstet Gynecol. 2007; 197: 346-355
        • Massad L.S.
        • Einstein M.H.
        • Huh W.K.
        • et al.
        2012 updated consensus guidelines for the management of abnormal cervical cancer screening tests and cancer precursors.
        Obstet Gynecol. 2013; 121: 829-846
        • Perkins R.B.
        • Guido R.S.
        • Castle P.E.
        • et al.
        2019 ASCCP risk-based management consensus guidelines for abnormal cervical cancer screening tests and cancer precursors.
        J Low Genit Tract Dis. 2020; 24: 102-131
        • American College of Obstetricians-Gynecologists
        ACOG Committee Opinion. Evaluation and management of abnormal cervical cytology and histology in the adolescent. Number 330, April 2006.
        Obstet Gynecol. 2006; 107: 963-968
        • Wright Jr., T.C.
        • Cox J.T.
        • Massad L.S.
        • et al.
        2001 consensus guidelines for the management of women with cervical intraepithelial neoplasia.
        Am J Obstet Gynecol. 2003; 189: 295-304
        • Demarco M.
        • Lorey T.S.
        • Fetterman B.
        • et al.
        Risks of CIN 2+, CIN 3+, and cancer by cytology and human papillomavirus status: The Foundation of Risk-Based Cervical Screening Guidelines.
        J Low Genit Tract Dis. 2017; 21: 261-267
        • Cho H.W.
        • So K.A.
        • Lee J.K.
        • Hong J.H.
        Type-specific persistence or regression of human papillomavirus genotypes in women with cervical intraepithelial neoplasia 1: a prospective cohort study.
        Obstet Gynecol Sci. 2015; 58: 40-45
        • Silveira F.A.
        • Almeida G.
        • Furtado Y.L.
        • et al.
        The association of HPV genotype with the regression, persistence or progression of low-grade squamous intraepithelial lesions.
        Exp Mol Pathol. 2015; 99: 702-706
        • Gaarenstroom K.N.
        • Melkert P.
        • Walboomers J.M.
        • et al.
        Human papillomavirus DNA and genotypes: prognostic factors for progression of cervical intraepithelial neoplasia.
        Int J Gynecol Cancer. 1994; 4: 73-78
        • Fischer S.
        • Bettstetter M.
        • Becher A.
        • et al.
        Shift in prevalence of HPV types in cervical cytology specimens in the era of HPV vaccination.
        Oncol Lett. 2016; 12: 601-610
        • Koebnick C.
        • Langer-Gould A.M.
        • Gould M.K.
        • et al.
        Sociodemographic characteristics of members of a large, integrated health care system: comparison with US Census Bureau data.
        Perm J. 2012; 16: 37-41
        • Rubin D.B.
        Inference and missing data.
        Biometrika. 1976; 63: 581-592
        • Rubin D.B.
        Multiple imputation for nonresponse in surveys.
        Wiley, Chichester, England2004
        • Kuroki L.M.
        • Binder P.S.
        • Powell M.A.
        • Massad L.S.
        • Gao F.
        Self-reported human papillomavirus vaccination does not have an impact on the risk for high-grade cervical intraepithelial neoplasia among women referred for colposcopy.
        Am J Obstet Gynecol. 2016; 215: 123-126
        • Dorton B.J.
        • Vitonis A.F.
        • Feldman S.
        Comparing cervical cytology and histology among human papillomavirus-vaccinated and -Unvaccinated women in an Academic Colposcopy Clinic.
        Obstet Gynecol. 2015; 126: 785-791
        • Munro A.
        • Gillespie C.
        • Cotton S.
        • et al.
        The impact of human papillomavirus type on colposcopy performance in women offered HPV immunisation in a catch-up vaccine programme: a two-centre observational study.
        BJOG. 2017; 124: 1394-1401
        • Alexander S.C.
        • Fortenberry J.D.
        • Pollak K.I.
        • et al.
        Disclosure of sexual intercourse by teenagers: agreement Between telephone survey responses and annual visit disclosures.
        Clin Pediatr (Phila). 2015; 54: 529-533
        • Schroder K.E.
        • Carey M.P.
        • Vanable P.A.
        Methodological challenges in research on sexual risk behavior: II. Accuracy of self-reports.
        Ann Behav Med. 2003; 26: 104-123
        • Bersamin M.M.
        • Fisher D.A.
        • Walker S.
        • Hill D.L.
        • Grube J.W.
        Defining virginity and abstinence: adolescents’ interpretations of sexual behaviors.
        J Adolesc Health. 2007; 41: 182-188
        • Stupiansky N.W.
        • Zimet G.D.
        • Cummings T.
        • Fortenberry J.D.
        • Shew M.
        Accuracy of self-reported human papillomavirus vaccine receipt among adolescent girls and their mothers.
        J Adolesc Health. 2012; 50: 103-105
        • Townsend C.
        Estimating a child sexual abuse prevalence rate for practitioners: a review of child sexual abuse prevalence studies.
        Darkness to Light, Charleston, SC2013
        • LaCour D.E.
        • Trimble C.
        Human papillomavirus in infants: transmission, prevalence, and persistence.
        J Pediatr Adolesc Gynecol. 2012; 25: 93-97
        • Puranen M.
        • Yliskoski M.
        • Saarikoski S.
        • Syrjänen K.
        • Syrjänen S.
        Vertical transmission of human papillomavirus from infected mothers to their newborn babies and persistence of the virus in childhood.
        Am J Obstet Gynecol. 1996; 174: 694-699
        • Widdice L.E.
        • Brown D.R.
        • Bernstein D.I.
        • et al.
        Prevalence of human papillomavirus infection in young women receiving the first quadrivalent vaccine dose.
        Arch Pediatr Adolesc Med. 2012; 166: 774-776
        • Bacopoulou F.
        • Karakitsos P.
        • Kottaridi C.
        • et al.
        Genital HPV in children and adolescents: does sexual activity make a difference?.
        J Pediatr Adolesc Gynecol. 2016; 29: 228-233
        • Unger E.R.
        • Fajman N.N.
        • Maloney E.M.
        • et al.
        Anogenital human papillomavirus in sexually abused and nonabused children: a multicenter study.
        Pediatrics. 2011; 128: e658-e665
        • Williams L.M.
        Recall of childhood trauma: a prospective study of women’s memories of child sexual abuse.
        J Consult Clin Psychol. 1994; 62: 1167-1176
        • Kim J.
        • Bell C.
        • Sun M.
        • et al.
        Effect of human papillomavirus vaccination on cervical cancer screening in Alberta.
        CMAJ. 2016; 188: E281-E288
        • Lei J.
        • Ploner A.
        • Elfström K.M.
        • et al.
        HPV vaccination and the risk of invasive cervical cancer.
        N Engl J Med. 2020; 383: 1340-1348