Colposcopy non-attendance following an abnormal cervical cancer screening result: a prospective population-based cohort study

The data stem from randomly recruited participants from the general population (n = 2,627) who were screened within the randomised trial and prospective cohort MARZY study, described previously [27, 28]. Briefly, women eligible from the general population (aged 30 to 65 years, with no history of hysterectomy or CC and not pregnant) were screened by office-based gynaecologists at study baseline (R1, 2005–2007) with routine Pap smear, plus an additional MARZY study swab (liquid-based cytology, ThinPrep, Cytyc/Hologic including subsequent HPV testing, Hybrid Capture®2). HPV co-testing was investigated [27]. Participants were administered a questionnaire (Q1) relating to sociodemographic and other factors.

Positive screening results were defined as atypical squamous cells of undetermined significance or worse (ASC-US+) or high-risk HPV positive (hrHPV). Screen-positives were contacted by postal letter, which included HPV information and referred to the study colposcopy clinic (University Medical Center, Mainz; Fig. 1). These letters contained additional information on HPV infection and explained the colposcopy procedure in simple terms. Active telephone recall efforts were carried out by female study personnel to improve colposcopy attendance rates among women who did not arrange an appointment at the study clinic within 3 months of referral. Personnel also interviewed non-attendees for their reasons on non-attendance.

Screening was conducted again 3 years later (R2, 2008–2010) among women who participated in R1 and were still eligible (no hysterectomy or CC diagnoses since R1 and not pregnant). Lifestyle exposures such as smoking status were updated in a second questionnaire (Q2). Active recalls were again conducted by female study personnel if screen-positive participants had not attended colposcopy within 3 months following referral to the designated study clinic (University Medical Center, Mainz and St. Vincenz and Elisabeth Hospital, Mainz).

After R2 concluded (2010), an additional questionnaire with HPV-related questions (Q3) was administered to all hrHPV positive women, investigating perception and communication of HPV results, and HPV knowledge. As the MARZY screenings were conducted with a 3-year interval but routine Pap screenings were offered opportunistically and annually in the study region, any screenings conducted outside the study between the two MARZY rounds were retrospectively documented.

We classified colposcopy attendance status using medical records from the designated colposcopy clinics. The primary outcome was non-attendance after referral to colposcopy within a 4 month time-frame, calculated as number of non-attendees among all referrals. This definition is based on the study referral threshold (ASC-US+ or hrHPV or both positive). At the time of study conduct, the 2008 European guidelines suggested colposcopies be conducted following ASC-US+ and hrHPV positive results [9]. The German CCS guideline in effect at the time advised women with low-grade squamous intraepithelial lesions or worse (LSIL+) who were also hrHPV positive to undergo colposcopy [29]. Attendance was estimated for both thresholds (ASC-US+ and hrHPV positive; LSIL+ and hrHPV positive).

Sociodemographic variables obtained included age, region of residency, nationality, highest education level attained (lower secondary; upper secondary and further), employment situation, net monthly household income (low income ≤ 1500€; higher income > 1500€), marital status, parity (≤ 2 children; ≥ 3 children) and health insurance status. Smoking status, oral contraception use and hormone replacement therapy (HRT) were dichotomised (ever vs. never). Self-reported frequency of CCS attendance was grouped (regularly every 1–2 years; irregularly every 3 years or less or never). Screen-positive was defined as ASC-US+ only, hrHPV only or both ASC-US+ and hrHPV positive, and also LSIL+ only or both LSIL and hrHPV positive.

At the time of the Q3 survey, no validated HPV knowledge scale was available for use but the questionnaire items were based on extensive review of the qualitative body of evidence published. Perceived experience during and after the screening examination and concerns about infectivity or impact on sexual relationships were based on the Psychosocial Effects of Abnormal PAP Smears Questionnaire (PEAPS-Q) [30] and Cervical Dysplasia Distress Questionnaire (CDDQ) [31]. The items of interest were sub-categorised by 5-point Likert scale or binary “yes/no” answers as (i) Perception: negative screening experience (dichotomised), degree of negative reaction and understanding regarding the positive hrHPV result such as anxiety or insecurity, and (ii) HPV knowledge: as determined by the ability to identify at least 2 areas of HPV infection (virus, persistence consequences, vaccination; dichotomised), level of HPV understanding (none to good), and prior HPV knowledge to the study. Communication (iii) that occurred between the gynaecologists and participant (dichotomised), comprehensiveness of the counselling (dedicated time, provided background information and support), trust in the physician and discussion of result between the participant and friends or family members were also analysed. Concerns (iv) regarding cancer, infertility and infectivity were captured.

Any screen-positives leading to a referral at either round between 2005 and 2010 were included. If women were referred at both rounds, we designated questionnaire and interview data from the first referral only for regression analyses. All variables of interest were analysed using R (version 4.0.5, R Foundation for Statistical Computing, Vienna, Austria). Potential associations between attendance and individual factors were examined by univariable regression modelling and collinearity between variables were assessed. For multivariable regression, we applied multiple imputation methods to obtain model averaged estimates for missing data and computed bootstrap resampled 95% confidence intervals (CI; bootstraps = 500) using the MAMI package for R [32]. Missing data in regression models were treated as available case analyses and the adjusted odds ratios (aOR) controlled for all available confounders (age, region of residency, nationality, highest education level attained, employment situation, income, marital status, parity, smoking status, OC use, HRT use, screening frequency, screening result and insurance status), as these were previously reported to be associated with attendance [3, 10, 13‐23]. Education, employment and screening result were dichotomised for regression. Non-attendee interview responses from both rounds were described together. In the case where women were non-attendees at both rounds, we designated the interview data from the first interview only. We also descriptively assessed the longitudinal outcomes (screening results, colposcopy attendance) of R1 referrals who did not attend colposcopy then but who were screened again at R2.

Informed consent was provided by all study participants prior to screening at study baseline. The MARZY study was approved by the ethical committee of the state of Rhineland-Palatinate (Landesärztekammer Rheinland-Pfalz: 837.438.03 (4100)) and the state government data protection office.

Of 2,627 women screened at R1, 228 (8.7%) were screen-positive, 222 (8.5%) were referred to colposcopy while 6 were not invited due to pre-planned hysterectomy elsewhere (Fig. 1). Initially, 106 of these 222 screen-positive women did not attend colposcopy within 3 months following referral. With active recall efforts, 96 could be reached and 28 (29.2%) attended afterwards. One woman who was not reached by telephone eventually attended colposcopy. Finally, 145 women (65.3%) attended colposcopy within 4 months, while 77 (34.7%) did not.

At R2, 2,093 (79.7%) women were screened at a median of 2.7 years later. Of the 107 screen-positive women referred to colposcopy, 32 initially did not attend after referral and 28 were reached via active recall (Fig. 1). Ten (31.3%) women were motivated to attend. Finally, 23 (21.5%) were non-attendees and 84 attended colposcopy (78.5%; Additional file 1: Table S1).

Twenty-one women were referred at both rounds where half were referred due to only hrHPV positive results (Additional file 1: Table S2). A total of 222 women (R1) and 86 women (R2) were referred to colposcopy (n = 308) in the entire study.

Overall, among 308 total referrals, attendance was recorded in 219 (71.1%) women and non-attendance in 89 (28.9%). Mean age in both groups were similar: 45.8 years (SD = 9.1) and 45.7 years (SD = 10.1) respectively. Among both ASC-US+ and hrHPV co-test positives, 9 (19.6%) did not attend (Fig. 2A). Among LSIL+ and hrHPV positives, 6 (17.1%) did not attend colposcopy (Fig. 2B). Approximately half of only cytology-positives attended colposcopy; the majority had ASC-US (Additional file 1: Table S3). By R2, 32 women had positive routine Pap results detected between study rounds. Non-attendance rates were similar (~ 20%) after excluding these cases (Additional file 1: Figure S1).

Compared to younger women (30–39 years), 40–49 year old women were more likely to attend colposcopy (75% vs. 69%; aOR = 1.55, 95% CI 1.02, 4.96) (Table 1). Women who resided in the urban area were less likely to attend, albeit not statistically significant (65% vs. 76%; aOR = 0.63, 95% CI 0.30, 1.00). Among women from low income households, 87% were attendees while 68% of the women from higher income households (net monthly income >1500€) attended colposcopy. Women with higher household income or who had birthed ≥ 3 children were 67% (aOR = 0.33, 95% CI 0.11, 0.92) and 68% (aOR = 0.32, 95% CI 0.10, 0.86) less likely to attend colposcopy respectively. Smoking status, oral contraceptive use and HRT were not significantly associated with attendance. Sixty percent who attended screening irregularly (every 3 years or less) or not at all, attended colposcopy versus 73% of regular participants. A positive hrHPV screening result increased likelihood of attending by threefold (aOR = 3.04, 95% CI 1.49, 7.22; Table 1).

Overall, 83 respondents provided reasons on non-compliance (response rate R1: 68/77 (88.3%); R2: 18/23 (78.3%) (Fig. 3). Over half indicated lack of time (56%), almost half (48%) mentioned barriers such as long travel time, travel cost, childcare challenges and 29% cited lack of choice of colposcopy clinic (Fig. 3A). A fifth of the women reported to have forgotten the appointment, while 15–16% feared the procedure itself or the outcome of the examination (Fig. 3A).

Forty-four percent mentioned that their office-based gynaecologist who conducted screening advised against colposcopy at the study clinic (Fig. 3B). Thirty-six percent of these women resided in the urban region, 40% were aged 40–49 years, 8% had a positive co-test at the guideline threshold LSIL+ , 12% reported irregular or no screening history and 80% reported having a repeat test since the MARZY screening round (Figs. 3B.1–B.5). Among 9 co-test screen-positives (ASC-US+ and hrHPV positive) who did not attend at either round (Table 1), only one cited the advice of the screening gynaecologist as the main reason for non-attendance; the remainder reported other barriers or concerns (Additional file 1: Table S4).

Among women who reported negative experiences during screening, 78% attended colposcopy compared to 87% of attendees who did not report a negative screening experience and 78% who reported moderate to high levels of negative reaction to their HPV result attended compared to 84% of attendees with little to no negative reaction (Table 2). Likelihood of attending colposcopy was lowered if screening was associated with a negative experience (OR = 0.49, 95% CI 0.21, 1.09) or reaction (OR = 0.64, 95% CI 0.27, 1.41), but not statistically significant. Approximately 79% of women reporting to have HPV knowledge attended compared to 82% with no HPV knowledge. Better levels of HPV knowledge were markedly lower among attendees (75%) than those reporting poor or no HPV knowledge who also attended colposcopy (82%). Level of understanding of the HPV result was not significantly associated with attendance (OR = 1.15, 95% CI 0.42, 2.82).

For communication, 85% of attendees reported direct communication of the HPV result by their gynaecologist compared to 76% of colposcopy attendees who were not directly informed by the gynaecologist. Direct communication increased the likelihood of attending but was not statistically significant (OR = 1.34, 95% CI 0.39, 5.03). Higher proportions of attendees also reported comprehensive counselling (83% vs. 80%), and discussed their result with a friend or family member (84% vs. 74%) than those who did not report these discussions. Eighty-five percent of women who reported lack of trust in their gynaecologist went to colposcopy compared to 81% who reported trust. Approximately 77% of all hrHPV positive women who responded in Q3 were concerned about cancer.

At baseline R1, 77 referrals to colposcopy at R1 did not attend. Of these, 44 were lost to follow-up and not subsequently screened at R2. Respectively, baseline data and retrospective documentation of outcomes among these women indicated that 25 women (57%) were at least hrHPV positive (hrHPV positive only or both ASC-US+ and hrHPV positive) and a total of 4 women were scheduled to later undergo hysterectomies outside of the study (Additional file 1: Table S5). Three of the 4 women who underwent hysterectomies had a positive screening result within routine screening after R1 of MARZY.

Among the 33 referrals who did not attend colposcopy at R1 and were re-screened at R2, the majority (92%) were screened routinely between study rounds with negative screening results (Table 3). Only 2 non-attendees from R1 were screen-positive upon routine screening after study baseline. At R2, 4 women (12%) were hrHPV positive only, 2 (6%) were co-test positive to both cytology and hrHPV, while 27 (82%) were screen-negative. Among the 6 women referred again to colposcopy at R2, 5 (83%) did not attend, despite all 5 having a hrHPV positive result detected at R2 screening. Two of these women also had a concurrent cytological abnormality and via retrospective data linkage, it was found that they later underwent hysterectomies due to severe cervical intraepithelial neoplasia or worse (CIN3+ ; Additional file 1: Table S6).

Characteristics of the non-attendees who presented again at R2 show that 67% were women aged 50 years and above and 61% resided in an urban area (Additional file 1: Table S7). Twenty-one percent had 3 or more children and 28% did not attend screening regularly. Sixty-four percent of non-attendees from R1 reported no time as a reason for non-attendance at R1 and 50% reported a barrier. Among the 5 referrals who did not attend colposcopy at either R1 or R2, common reasons were lack of time, concerns and obstacles to arranging the appointment (Additional file 1: Table S6).

We defined non-attendees as screen-positive to either cytology or HPV testing, rather than both cytology and HPV test positive. This may overestimate non-attendance as many who are screen-positive to one test only would normally undergo repeat Pap smear 3, 6 or 12 months later according to the guidelines in effect at the time in Germany [29]. However after restricting non-attendance to positive co-test results (ASC-US+ or LSIL+ and hrHPV positive), we found similar attendance rates. The sample size may have also restricted our analyses, particularly for the HPV-related items in Q3. However, only 18% of hrHPV positive cases were Q3 non-respondents. Additional assessment between Q3 respondents and non-respondents revealed some differences in nationality and socioeconomic status (Additional file 1: Table S8). These differences highlight potential external validity limitations of our results to un(der)screened women. Some non-attendees whom were unreachable may have sought colposcopy elsewhere, but the numbers are small.