574155 research-article2015
SJP0010.1177/1403494815574155B.B. Sander et al.Cervical cancer preventive measures
Scandinavian Journal of Public Health, 1–8
Original Article
Mothers’ and their daughters’ use of preventive measures against cervical cancer
Bente Braad Sander1, Miguel Vázquez-Prada1, Matejka Rebolj1, Palle Valentiner-Branth2 & Elsebeth Lynge1 1Department of Public Health, University of Copenhagen, Denmark, and 2Department of Epidemiology, Statens Serum Institut, Ørestads, Denmark
Abstract Aims: Vaccination against human papillomavirus (HPV) and screening are complementary preventive measures against cervical cancer. In Denmark, screening and vaccination are free of charge for the women. In total, 75% of women are screened and about 90% of girls are vaccinated with at least one dose. Our aim was to determine whether, in Denmark, daughters of unscreened mothers are less likely to be vaccinated against HPV than are daughters of screened mothers. Methods: We used population-based data from the Danish Patient Register, Health Service Registration, Pathology Data Bank, and Civil Registration System. Individual-level data on screening, vaccination, and vital status until 31 December 2010 were retrieved. Daughters were linked to their mothers through the link provided in the Civil Registration System. The study population included 149,147 girls born in 1993–1997 and their mothers. We calculated birth cohort-specific relative risks (RRs) of non-initiation of HPV vaccination in daughters depending on their mothers’ screening status. Results: In total, 8% of girls did not receive any vaccination, and 35% of their mothers were unscreened. Among the 92% of girls receiving at least one vaccine dose, 14% of mothers were unscreened. The birth cohort-specific RRs of non-initiation of vaccination given an unscreened mother varied between 2.16 (95% CI: 2.00–2.33) and 2.83 (95% CI: 2.63–3.05). Conclusions: The observed association between screening and vaccination suggest that it will be difficult to increase the vaccination coverage by, for example, counselling at the mother’s cervical screening appointment. Other measures to increase the coverage with vaccination will be important. Key Words: Cervical cancer, screening, vaccination, human papillomavirus, coverage, birth cohort
Introduction Without prevention, cervical cancer was an important public health disease, with a cumulative life-time background risk of over 3% [1]. At present, the incidence rate of cervical cancer in Denmark is around 10 per 100,000 age-standardized rate by World Standard Population (ASW) [2], and cervical cancer is more frequent among women of low socio-economic status [3]. Cervical screening and human papilloma virus (HPV) vaccination are now complementary and effective cervical cancer prevention strategies. Several foreign studies observed that the daughters of unscreened
mothers were more likely than the daughters of screened mothers to remain unvaccinated [4–10]. In Denmark, screening coverage of women aged 23–65 years has been relatively high, around 75% [11], and so has been the vaccination coverage of girls that today are aged 15–21, at around 90% for the first dose [12]. Furthermore, screening and vaccination have been free of charge, suggesting a low threshold for mothers to get screened and to have their daughters vaccinated. Nevertheless, screening attendance is lower among women with low education and an infrequent use of
Correspondence: Bente Braad Sander, Department of Public Health, University of Copenhagen, Øster Farimagsgade 5, DK-1014 Copenhagen, Denmark. E-mail: [email protected] (Accepted 27 January 2015) © 2015 the Nordic Societies of Public Health DOI: 10.1177/1403494815574155
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2 B.B. Sander et al. other health care services [13]. The parents’ lower education level and their lower income were associated with a lower coverage of HPV vaccination [14]. This suggests that high risk of cervical cancer and non-participation in cervical cancer prevention may be clustered in certain families. Therefore, the aim of this nationwide register-based study was to investigate whether also in Denmark, the daughter’s vaccination status was dependent on the mother’s screening status. Material and methods In Denmark, an organized program offering free quadrivalent HPV vaccination, administered in general practice (GP), started on 1 October 2008, targeting catch-up cohorts of 13–15-year-old girls (born 1993–1995). This offer ended on 31 December 2010 [15]. On 1 January 2009, HPV vaccination of 12-yearold girls (born in 1996 or later) was introduced as part of the general tax-financed childhood vaccination program [16]. In this analysis, we studied five birth cohorts: the three catch-up cohorts and the two first cohorts of the routine program. The official coverage estimate for the third dose for both programs was around 80% [12]. Personal invitations were sent to all five cohorts, possibly one reason behind the high coverage [16,17]. Screening started at a regional level in the 1960s, and was extended over the entire country in the coming decades [16]. The presently recommended screening interval is 3 years (for 23–49-year-old women) or 5 years (for 50–65-year-old women) [16]. The coverage was 75% in 2012 [11]. Data sources Vaccination data were retrieved from two registers. The first was the National Health Service Register (NHSR, started in 1990) [18] covering doses administered by GPs as part of the organized vaccination program. Although there is some underreporting [19], it is probably quite complete since it is used for financial reimbursements. Codes 8328, 8329, and 8330 were used for the first, second, and third dose, respectively. The second data source was the Danish National Prescription Registry (DNPR). This register documents doses purchased through prescriptions in community pharmacies. The Anatomical Therapeutic Chemical codes used to identify HPV vaccinations were J07BM02 and J07BM01. There should be hardly any overlap of the same dose in the two registers, since they cover different financing situations. For the two data sources combined, we observed illogical/erroneous registrations for 8% of girls (e.g., for the NHSR, no registration of dose 1,
two for dose 2, and one for dose 3, or for the DNPR, a person purchasing more than three doses). Excluding the 8% of girls changed the results only marginally (data not reported). Some unregistered vaccine doses were purchased by medical professionals and administered to self-paying patients. Using information on the official HPV vaccination sales statistics [20], we subtracted the registered doses, and estimated that for all age groups combined around 30%, 10%, and 15% of doses were not registered in 2008, 2009, and 2010, respectively. The unregistered doses were probably not frequent, particularly for the younger cohorts, as parents are unlikely to pay for a service otherwise provided free of charge. However, mothers with a higher socioeconomic status (who have higher screening participation rates compared to the general population [13]) may more often have paid for their (older) daughters’ vaccination before the start of the free program. Such a situation would mean that the calculated RRs are slightly underestimated. Some girls have, furthermore, received unregistered vaccine doses through HPV vaccination trials, but only a few of them were from the birth cohorts included in our analysis. Screening information was obtained from three registers, the NHSR (since 1990 covering all samples taken or evaluated in primary care [18]), the National Patient Register (a hospital discharge register started in 1977 that partially covers cytology samples from hospitals [21]), and the National Danish Pathology Data Bank (started in the 1970s, over the time covering an increasing proportion of samples taken in primary practice and hospitals [22]). The combined screening data have been virtually complete since 1990, although diagnoses were not registered completely throughout the whole period. Hysterectomized mothers were included in the analysis, but this proportion was low in the studied age groups (unpublished data). Information from the Danish Civil Registration System [23] (CRS, started in 1968) was used to define birth cohorts, link mothers and daughters, and to obtain information on the women’s vital status and migrations. All data were linked using the unique personal identification (CPR) numbers assigned to all Danish residents, and retrieved from the beginning of the registration until 31 December 2010. The populations and the linkage between mothers and daughters All girls born in 1993–1997 were selected for the study if they had lived in Denmark during the entire period from 20 September 2006 (when the first HPV vaccine was granted a marketing authorization in the European Union) to 31 December 2010 (Figure 1). Presence was defined as a continuous residence registered in the
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Family use of cervical cancer preventive measures 3
Figure 1. Flowchart of the study population.
CRS, with registration absences not longer than a day. Daughters were coupled to their mothers through a linkage between the girl’s and her mother’s CPR numbers, which was virtually complete for cohorts born after 1960. The mothers should have lived in Denmark continuously (with up to 1-day registration absences) in the period of 4 years before the daughter’s first date of (pseudo) vaccination so that the screening behaviour could be accounted for. This period was chosen based on the 3-year screening interval, allowing for delay in participation. For 8% of mothers aged ⩾50 years at their daughters’ first vaccination date, a 6-year period was assessed based on the 5-year screening
interval recommended for this age group from 2007 onwards. To ensure independent observations, we excluded younger siblings; twins were excluded by chance. The final number of mother–daughter pairs used in the main analysis was thus 149,147. Inclusion of siblings had no significant effect on the results (data not presented). Statistical analysis The date of vaccination with the first dose was defined as the first registered date of any vaccination dose, the date of vaccination with the second dose as the
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4 B.B. Sander et al. second registered date, and likewise for the third dose. For unvaccinated girls, pseudo-dates were defined as the average dates of the first, second, or third vaccination dates among the vaccinated girls in the same birth cohort. We focused on vaccination initiation (having received ⩾1 vaccination dose). As a separate analysis, we also analysed completion of vaccination (three doses) among girls who had initiated the vaccination (N=113,639). We assessed the mother’s screening history (cervical cytology, histology, or HPV testing) 4 or 6 years before the date of her daughter’s first (pseudo-) vaccination. In a separate analysis including only screened mothers, we investigated the effect of having previously experienced screen-detected abnormalities (defined as abnormal cytology or biopsy ⩽10 years before the daughter’s first vaccination). For the same analysis, we further restricted the study population by including only mothers who lived in Denmark from January 1, 1995, onwards, resulting in 122,447 mother–daughter pairs. Inadequate cytology was included in the definition of abnormality because it may have led to anxiety and concern similar to those in women receiving abnormal cytology test results [24]. We calculated crude RRs of non-vaccination in daughters of unscreened mothers as compared with daughters of screened mothers (RR=(unvaccinated daughters of unscreened mothers/all daughters of unscreened mothers)/(unvaccinated daughters of screened mothers/all daughters of screened mothers)). Similar formulae were used for the other reported combinations of exposure and outcome variables. All RRs are calculated by 1-year birth cohort due to differences in the eligibility for vaccination. Calculations were performed using R version 3.0.1. The 95% confidence intervals (CIs) of RRs were calculated assuming that their logarithms were approximately normally distributed. Results About 90% of the daughters initiated HPV vaccination, although this differed slightly by birth cohort (Table I). The mothers’ screening coverage was about 84% for daughters of all birth cohorts. Among unscreened mothers, 15% (=689/4680 for birth cohort 1995) to 21% (859/4141 for birth cohort 1996) of daughters did not initiate vaccination, whereas for screened mothers this was 5% (=1355/25,983 for birth cohort 1995) to 9% (=2024/21,718 for birth cohort 1997). Consequently, the risk of daughters not initiating vaccination among unscreened mothers was significantly increased compared with that of daughters of screened mothers. The RRs were 2.45 (95% CI: 2.28–2.63), 2.64 (95%
CI: 2.43–2.86), 2.82 (95% CI: 2.59–3.08), 2.83 (95% CI: 2.63–3.05), and 2.16 (95% CI: 2.00–2.33), for birth cohorts 1993, 1994, 1995, 1996, and 1997, respectively (Table II). Daughters who initiated HPV vaccination were significantly less likely to receive all three doses if their mothers were unscreened. The RRs of not completing vaccination comparing unscreened to screened mothers varied by birth cohort between 1.44 (95% CI: 1.35–1.53 for birth cohorts 1993 and 1994) and 1.51 (95% CI: 1.42– 1.61 for birth cohort 1996, Table III). Vaccination initiation did not depend on whether the mother had previous abnormal screening tests (Table IV). Discussion General findings Daughters of unscreened mothers had more than double the risk of remaining unvaccinated against HPV compared with daughters of screened mothers. Moreover, even if the daughters of unscreened mothers initiated the vaccination process by receiving at least one dose of the vaccine, they were still more likely than the daughters of screened mothers to not complete the recommended vaccination schedule with three vaccine doses. On the other hand, mothers with abnormal screening results were just as likely to have their daughters vaccinated as mothers with normal screening results. Our finding was in line with other studies [4,7], and implied that the link between a daughter’s vaccination and her mother’s screening participation is perhaps not a result of a mother’s fear of cancer but rather a (familial) clustering of health prevention behaviour [10,13]. With the high coverage of vaccination as seen for example in Denmark, mathematical studies have suggested a certain, although not large, reduction in HPV prevalence also among unvaccinated females through the process of herd immunity [25,26]. A recent study from Australia, a country with a similarly high HPV vaccination coverage, observed a reduction in HPV prevalence among unvaccinated women using routine data [27]. Nevertheless, it will remain important for girls to participate in both programs because vaccination does not cover all carcinogenic HPV types. Comparison with other studies Other European studies also found an association between the mothers’ screening and their daughters’ vaccination statuses, but the strength thereof varied. Unlike our study, which calculated RRs, these studies calculated odds ratios (ORs) for participation (OR=(vaccinated daughters of screened mothers/
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Family use of cervical cancer preventive measures 5 Table I. Average age at human papillomavirus vaccination and vaccination coverage for daughters, and average age at cervical screening and screening coverage rate for mothers included in the study, by the daughters’ birth cohort, N=149,147. Birth cohorts Daughters Average age in years (IQR) at first vaccination dose (vaccination initiation) Average age in years (IQR) at second vaccination dose Average age in years (IQR) at third vaccination dose (vaccination completion) Coverage, first dose (vaccination initiation)a Coverage, second dosea Coverage, third dose (vaccination completion)a Mothers Average age in years (IQR) at daughter’s first vaccination dose (vaccination initiation) Screening coverage in the last 4/6 years
1993
1994
1995
1996
1997
15.4 (15.1–15.7)
14.4 (14.2–14.7)
13.5 (13.3–13.8)
12.8 (12.5–13.1)
12.3 (12.1–12.5)
15.6 (15.3–15.9)
14.6 (14.4–14.9)
13.7 (13.5–14.0)
13.0 (12.7–13.3)
12.5 (12.3–12.8)
15.9 (15.6–16.2)
15.0 (14.8–15.3)
14.1 (13.9–14.4)
13.3 (13.0–13.6)
12.8 (12.6–13.0)
90.9%
93.1%
93.3%
90.6%
89.0%
86.9% 75.3%
89.8% 79.1%
90.0% 79.6%
86.1% 73.5%
83.1% 67.8%
44.2 (41.1–47.2)
43.5 (40.4–46.5)
42.7 (39.5–45.8)
42.1 (38.7–45.2)
41.7 (38.3–44.8)
83.8%
84.1%
84.7%
84.8%
84.6%
IQR, inter-quartile range. aThe coverage rates differ from the official reported coverage rates [12] owing to definition differences for the 8% of daughters with errors in vaccination registration. Table II. Association between cervical cancer screening use among mothers and the initiation of human papillomavirus vaccination among daughters, N=149,147. Birth cohort
1993 1994 1995 1996 1997
Mother’s screening coverage
N (%)
All Not Screened Screened All Not Screened Screened All Not Screened Screened All Not Screened Screened All Not Screened Screened
32,426 (100%) 5252 (16.2%) 27,174 (83.8%) 33,071 (100%) 5253 (15.9%) 27,818 (84.1%) 30,663 (100%) 4680 (15.3%) 25,983 (84.7%) 27,330 (100%) 4141 (15.2%) 23,189 (84.8%) 25,657 (100%) 3939 (15.4%) 21,718 (84.6%)
Daughter’s HPV vaccine initiation No, N (%)
Yes, N (%)
RRa unvaccinated (95% CI)
2957 (9.1%) 950 (2.9%) 2007 (6.2%) 2292 (6.9%) 762 (2.3%) 1530 (4.6%) 2044 (6.7%) 689 (2.2%) 1355 (4.4%) 2558 (9.4%) 859 (3.1%) 1699 (6.2%) 2816 (11.0%) 792 (3.1%) 2024 (7.9%)
29,469 (90.9%) 4302 (13.3%) 25,167 (77.6%) 30,779 (93.1%) 4491 (13.6%) 26,288 (79.5%) 28,619 (93.3%) 3991 (13.0%) 24,628 (80.3%) 24,772 (90.6%) 3282 (12.0%) 21,490 (78.6%) 22,841 (89.0%) 3147 (12.3%) 19,694 (76.8%)
2.45 (2.28–2.63) 1 (reference) 2.64 (2.43–2.86) 1 (reference) 2.82 (2.59–3.08) 1 (reference) 2.83 (2.63–3.05) 1 (reference) 2.16 (2.00–2.33) 1 (reference)
aRR=(unvaccinated
daughters of unscreened mothers/all daughters of unscreened mothers)/(unvaccinated daughters of screened mothers/ all daughters of screened mothers).
unvaccinated daughters of screened mothers)/(vaccinated daughters of unscreened mothers/unvaccinated daughters of unscreened mothers)). Adjusted ORs in a Dutch study by Steens et al. [8] was 1.40 (95% CI: 1.38–1.43). Vaccination coverage was 58% ([8]; Anneke Steens, personal communication, 9 March 2014). A study from the north-west of England by Spencer et al. [7] found a stronger association for both the routine and the
catch-up programs, adjusted ORs 3.7 (95% CI: 3.2–4.1) and 3.6 (95% CI: 3.2–4.1), respectively, with the vaccination coverage of 76% in the routine program and 82% in the catch-up cohorts. In a Flemish study by Lefevere et al. [5], where 54% of daughters were vaccinated, ORs for mothers with 1, 2, or ⩾3 smears in a 3-year period, compared with no smears, were 4.5 (95% CI: 3.5–5.9), 9.2 (95% CI: 7.9–11.2), and 16.0 (95% CI: 12.1–21.2),
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6 B.B. Sander et al. Table III. Association between cervical cancer screening participation among mothers and non-completion of human papillomavirus vaccination schedule among daughters who initiated vaccination, N=113,639. Birth cohorta
1993 1994 1995 1996
Mother’s screening participation
All Not Screened Screened All Not screened Screened All Not screened Screened All Not screened Screened
N (%)
Non-completion of the vaccination schedule among daughters who initiated vaccination
29,469 (100%) 4302 (14.6%) 25,167 (85.4%) 30,779 (100%) 4491 (14.6%) 26,288 (85.4%) 28,619 (100%) 3991 (13.9%) 24,628 (86.1%) 24,772 (100%) 3282 (13.2%) 21,490 (86.8%)
Non-completers, N (%)
Completers, N (%)
RRb (95% CI)
5046 (17.1%) 996 (3.4%) 4050 (13.7%) 4605 (15.0%) 908 (3.0%) 3697 (12.0%) 4217 (14.7%) 801 (2.8%) 3416 (11.9%) 4673 (18.9%) 876 (3.5%) 3797 (15.3%)
24,423 (82.9%) 3306 (11.2%) 21,117 (71.7%) 26,174 (85.0%) 3583 (11.6%) 22,591 (73.4%) 24,402 (85.3%) 3190 (11.1%) 21,212 (74.1%) 20,099 (81.1%) 2406 (9.7%) 17,693 (71.4%)
1.44 (1.35–1.53) 1 (reference) 1.44 (1.35–1.53) 1 (reference) 1.45 (1.35–1.55) 1 (reference) 1.51 (1.42–1.61) 1 (reference)
aCalculations
for vaccination completion were left out for vaccinated girls in the birth cohort of 1997 (N= 22,814) since those girls were still eligible for vaccination for up to two years after December 31 2010. bRR=(daughters of unscreened mothers not completing vaccination /all daughters of unscreened mothers who initiated the vaccination)/ (daughters of screened mothers not completing vaccination/all daughters of screened mothers who initiated the vaccination). Table IV. Association between abnormal screening test results among screened mothers and initiation of human papillomavirus vaccination among their daughters, N=122,447. Birth cohort
1993 1994 1995 1996 1997
Mother’s screening test outcomea
N (%)
All Not Abnormal Abnormal All Not Abnormal Abnormal All Not Abnormal Abnormal All Not Abnormal Abnormal All Not Abnormal Abnormal
26,547 (100%) 21,465 (80.9%) 5082 (19.1%) 27,159 (100%) 21,894 (80.6%) 5265 (19.4%) 25,330 (100%) 20,336 (80.3%) 4994 (19.7%) 22,484(100%) 18,056 (80.3%) 4428 (19.7%) 20,927 (100%) 16,839 (80.5%) 4088 (19.5%)
Daughter’s HPV vaccine initiation No, N (%)
Yes, N (%)
RRb unvaccinated (95% CI)
1945 (7.3%) 1583 (6.0%) 362 (1.4%) 1490 (5.5%) 1223 (4.5%) 267 (1.0%) 1305 (5.2%) 1061 (4.2%) 244 (1.0%) 1631 (7.3%) 1338 (6.0%) 293 (1.3%) 1914 (9.1%) 1544 (7.4%) 370 (1.8%)
24,602 (92.7%) 19,882 (74.9%) 4720 (17.8%) 25,669 (94.5%) 20,671 (76.1%) 4998 (18.4%) 24,025 (94.8%) 19,275 (76.1%) 4750 (18.8%) 20,853 (92.7%) 16,718 (74.4%) 4135 (18.4%) 19,013 (90.9%) 15,295 (73.1%) 3718 (17.8%)
1 (reference) 0.97 (0.87–1.08) 1 (reference) 0.91 (0.80–1.03) 1 (reference) 0.94 (0.82–1.07) 1 (reference) 0.89 (0.79–1.01) 1 (reference) 0.99 (0.89–1.10)
aAssessed
for 10 years before her daughter’s first vaccination. daughters of mothers who had an abnormal screening test/all daughters of mothers who had an abnormal screening test)/(unvaccinated daughters of mothers who did not have an abnormal screening test/all daughters of mothers who did not have an abnormal screening test).
bRR=(unvaccinated
respectively (Eva Lefevere, personal communication, 22 May 2014). A similarly high OR, 6.2 (95% CI: 1.5–25.8), was found in a small French study by Lutringer-Magnin et al. [6] undertaken at GP level, where 68% of daughters were vaccinated. Also studies from the USA found positive associations, but the strength thereof tended to be weaker, possibly due to the lower vaccination coverage [4,9,10]. To compare these results with our study, we calculated crude RRs of non-initiation of vaccination for
unscreened compared with screened mothers, as described in the Methods ([5–8]; Eva Lefevere personal communication, 22 November 2013; Anneke Steens personal communication, 9 March 2014). The following estimates were found for the RRs (with the screening exposure as defined in the studies): 1.22 (95% CI: 1.21–1.23) for the Netherlands, 1.33 (95% CI: 1.32–1.35) for Flanders, 1.40 (95% CI: 0.93–2.12) for France, and 1.51 (95% CI: 1.45–1.57) for the UK (the routine program). All these were lower than the
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Family use of cervical cancer preventive measures 7 RRs for Denmark (Table II), though the RRs tended to increase with vaccination and screening coverage rates. The more selected the unscreened groups were, the stronger the mother–daughter associations became. Weaknesses of the analysis Data on socioeconomic and health care characteristics were not available for this study, and all RRs were unadjusted. However, lack of adjustment probably cannot explain our findings. A comparison of crude and adjusted ORs from previous studies suggested only a very small impact of adjustments [4,7–10]. Furthermore, in a Danish study on predictors of nonparticipation in cervical screening the differences between crude and adjusted ORs were also small [13]. The 1996 and 1997 birth cohorts were eligible for free vaccination until turning 15 years (in 2011 and 2012, respectively) [15], but we could only assess their vaccination status until the end of 2010. For the 1996 cohort, the official vaccination coverage by December 31, 2010, was 86% for the first and 79% for the third dose [15], whereas by mid-November 2012, the coverage rates were 87% and 81%, respectively [12]. For the 1997 cohort, the official coverage by December 31, 2010, was 86% for the first and 70% for the third dose [15], whereas by mid-November 2012, the coverage rates were 90% and 82%, respectively [12]. Consequently, we could not reliably assess the relationship between the mother’s screening status and her daughter’s vaccination completion for the 1997 cohort; this cohort was thus excluded from the calculation in Table III. Recently, it was also decided to reoffer the 1993–1997 birth cohorts free vaccination in 2014 and 2015, and vaccination is now free up until age 18 years for all birth cohorts Furthermore, unvaccinated girls included in the study could decide at an older age to pay for vaccination themselves, but at that age the effectiveness of vaccination would be lower than when vaccination is delivered before the sexual debut, which is the situation covered by our data. For 1813 daughters, the mother could not be identified through the mother–daughter linkage in the CRS (Figure 1). This could be due to immigration. Foreign women less frequently participate in cervical cancer screening [13]. From the CRS data, we could infer that 1744 (96%) of the 1813 girls may have indeed been immigrants, defined as having the first CRS record from a date that was more than 1 month later than the date of birth. Using the same definition, 15,447 (10%) of all girls in our study population were likely immigrants. Thereby, immigrant girls who could not be linked to their mothers constituted only 11% (=1744/15,447) of all immigrant girls.
Strengths of the analysis Our large study was population based, from a region for which similar data have not yet been reported. To our knowledge, no previous study included data for an entire country. The risk of selection bias was probably very low as 99% of eligible daughters could be linked to a mother, and the main reason why linking was not possible was immigration. Of all immigrants, the majority could still be linked to a mother. The two other main reasons for an exclusion of mother–daughter pairs were mothers with more than one daughter in the assessed birth cohort and daughters who had not lived in Denmark continuously throughout the study period, reasons probably associated with only a low risk of selection bias. We could link daughters to mothers directly. In previous larger studies, mothers were identified (mostly) based on a shared home address and a predefined age difference with the daughters [7,8], household numbers and age [5], or records of family members and age difference [4,10].With our method, we addressed the correlation between two persons registered officially as the mother and her daughter. On the other hand, we could not be certain that the two actually had contact. Perspectives The observed association between screening and vaccination suggests that it will be difficult to increase the vaccination coverage by, for example, counselling at the mother’s cervical screening appointment [28]. Instead, text messages have been proposed to remind parents that their daughter is due for vaccination [29]. Although invitations for their daughters’ vaccination have so far been sent to parents in Denmark [16], a study showed that GPs contacting parents by phone or letter significantly increased the likelihood of subsequent vaccination among initially unvaccinated girls [30]. Correspondingly, it has been decided that from May 2014 onwards reminders will be sent to parents of children aged 2, 6.5, and 14 years who have not received all recommended childhood vaccinations. In conclusion, despite screening and vaccination being offered free of charge in Denmark, a daughter’s HPV vaccination status was dependent on her mother’s screening status. Coverage with both preventive services shows potential room for improvement. Research ethics In Denmark, notification to the Danish Data Inspection Agency serves as ethical approval of register-based research projects in which no contact is
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8 B.B. Sander et al. made to patients, their relatives or treating physicians. The project has notification number 201041-5594. Conflict of interest Elsebeth Lynge and Matejka Rebolj have been involved in comparative studies of new-generation HPV tests, involving collaboration with Roche, Genomica, Qiagen, Hologic/Gen-Probe, BD, and Rovers. Elsebeth Lynge served as unpaid scientific advisor to Gen-Probe and Norchip, and Matejka Rebolj and her employer have received honoraria for lectures from Qiagen. Concerning the present paper, there was no collaboration with, or support from any of the companies. Funding Bente Braad Sander held a PhD scholarship from the Danish Research and Innovation Agency, and received a grant from Aase and Ejnar Danielsens Foundation. Matejka Rebolj was supported by a grant from the Danish Strategic Research Council. References [1] Barken SS, Rebolj M, Andersen ES, et al. Frequency of cervical intraepithelial neoplasia treatment in a well-screened population. Int J Cancer 2012,130:2438–44. [2] Engholm G, Ferlay J, Christensen N, et al. NORDCAN, http://www.ancr.nu (2014, accessed 14 May 2014]. [3] Jensen KE, Hannibal CG, Nielsen A, et al. Social inequality and incidence of and survival from cancer of the female genital organs in a population-based study in Denmark, 1994–2003. Eur J Cancer 2008;44:2003–17. [4] Chao C, Slezak JM, Coleman KJ, et al. Papanicolaou screening behavior in mothers and human papillomavirus vaccine uptake in adolescent girls. Am J Public Health 2009;99:1137–42. [5] Lefevere E, Hens N, Theeten H, et al. Like mother, like daughter? Mother’s history of cervical cancer screening and daughter’s Human Papillomavirus vaccine uptake in Flanders (Belgium). Vaccine 2011;29:8390–6. [6] Lutringer-Magnin D, Cropet C, Barone G, et al. HPV vaccination among French girls and women aged 14–23 years and the relationship with their mothers’ uptake of Pap smear screening: A study in general practice. Vaccine 2013;31:5243–9. [7] Spencer Nee Pilkington AM, Brabin L, et al. Mothers’ screening histories influence daughters’ vaccination uptake: An analysis of linked cervical screening and human papillomavirus vaccination in the North West of England. Eur J Cancer 2013;49:1264–72. [8] Steens A, Wielders CC, Bogaards JA, et al. Association between human papillomavirus vaccine uptake and cervical cancer screening in the Netherlands: Implications for future impact on prevention. Int J Cancer 2013;132:932–43. [9] Monnat SM and Wallington SF. Is there an association between maternal pap test use and adolescent human papillomavirus vaccination? J Adolesc Health 2013;52:212–8. [10] Markovitz AR, Song JY, Paustian ML, et al. Association between maternal preventive care utilization and adolescent vaccination: It’s not just about Pap testing. J Pediatr Adolesc Gynecol 2014;27:29–36.
[11] Dansk Kvalitetsdatabase for Livmoderhalskræftscreening, Årsrapport DKLS 2012. Yearly report of the Danish database for quality in cervical cancer screening, DKLS 2012, https://www.sundhed.dk/content/cms/80/1880_dkls%C3%A5rsrapport-2012.pdf (2012, accessed 14 May 2014) [in Danish]. [12] Statens serum institut. EPI-NEWS HPV Vaccina tion – Coverage 2012, http://www.ssi.dk/English/News/ (2013, EPI-NEWS/2013/No%2020%20-%202013.aspx accessed 14 May 2014). [13] Kristensson JH, Sander BB, von Euler-Chelpin M, et al. Predictors of non-participation in cervical screening in Denmark. Cancer Epidemiol 2014;38:174–80. [14] Baldur-Felskov B, Dehlendorff C, Munk C, et al. Early impact of human papillomavirus vaccination on cervical neoplasia: Nationwide follow-up of young Danish women. J Natl Cancer Inst 2014;106. [15] Statens Serum Institut. EPI-NEWS HPV vaccination, coverage 2010 (http://www.ssi.dk/English/News/EPINEWS/2011/No%2018%20-%202011.aspx (2011, 10 May 2014). [16] Sander BB, Rebolj M, Valentiner-Branth P and Lynge E. Introduction of human papillomavirus vaccination in Nordic countries. Vaccine 2012;30:1425–33. [17] Poulsen S. Keys to the success of HPV vaccination in Denmark, http://www.hpvtoday.com/revista3031/vaccines-corner.html (2014, 14 January 2015). [18] Andersen JS, Olivarius Nde F and Krasnik A. The Danish National Health Service Register. Scand J Public Health 2011;39(Suppl):34–7. [19] Wojcik OP, Simonsen J, Molbak K, et al. Validation of the 5-year tetanus, diphtheria, pertussis and polio booster vaccination in the Danish childhood vaccination database. Vaccine 2013;31:955–9. [20] Med Stat. Statens Serum Institut, http://www.medstat.dk/en (accessed 14 May 2014). [21] Lynge E, Sandegaard JL and Rebolj M. The Danish National Patient Register. Scand J Public Health 2011;39(Suppl):30–3. [22] Bjerregaard B and Larsen OB. The Danish Pathology Register. Scand J Public Health 2011;39(Suppl):72–4. [23] Pedersen CB. The Danish Civil Registration System. Scand J Public Health 2011;39(Suppl):22–5. [24] French DP, Maissi E and Marteau TM. The psychological costs of inadequate cervical smear test results: Three-month follow-up. Psychooncology 2006;15:498–508. [25] Regan DG, Philp DJ, Hocking JS, et al. Modelling the population-level impact of vaccination on the transmission of human papillomavirus type 16 in Australia. Sex Health 2007;4:147–63. [26] Vanska S, Auranen K, Leino T, et al. Impact of vaccination on 14 high-risk HPV type infections: A mathematical modelling approach. PLoS One 2013;8. e72088 [27] Tabrizi SN, Brotherton JM, Kaldor JM, et al. Assessment of herd immunity and cross-protection after a human papillomavirus vaccination programme in Australia: A repeat cross-sectional study. Lancet Infect Dis 2014;14: 958–66 [28] Carlos RC, Dempsey AF, Resnicow K, et al. Feasibility of using maternal cancer screening visits to identify adolescent girls eligible for human papillomavirus vaccination. J Womens Health (Larchmt) 2010;19:2271–5. [29] Kharbanda EO, Stockwell MS, Fox HW, et al. Text message reminders to promote human papillomavirus vaccination. Vaccine 2011;29:2537–41. [30] Hohwu L and Bro F. Tilslutningen til HPV-vaccination kan øges ved henvendelse fra almen praksis til ikkevaccinerede piger [Contact from general practitioners to unvaccinated girls can increase HPV vaccination consent]. Ugeskr Laeger 2012;174:942–5.
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SJP0010.1177/1403494815574155B.B. Sander et al.Cervical cancer preventive measures
Scandinavian Journal of Public Health, 1–8
Original Article
Mothers’ and their daughters’ use of preventive measures against cervical cancer
Bente Braad Sander1, Miguel Vázquez-Prada1, Matejka Rebolj1, Palle Valentiner-Branth2 & Elsebeth Lynge1 1Department of Public Health, University of Copenhagen, Denmark, and 2Department of Epidemiology, Statens Serum Institut, Ørestads, Denmark
Abstract Aims: Vaccination against human papillomavirus (HPV) and screening are complementary preventive measures against cervical cancer. In Denmark, screening and vaccination are free of charge for the women. In total, 75% of women are screened and about 90% of girls are vaccinated with at least one dose. Our aim was to determine whether, in Denmark, daughters of unscreened mothers are less likely to be vaccinated against HPV than are daughters of screened mothers. Methods: We used population-based data from the Danish Patient Register, Health Service Registration, Pathology Data Bank, and Civil Registration System. Individual-level data on screening, vaccination, and vital status until 31 December 2010 were retrieved. Daughters were linked to their mothers through the link provided in the Civil Registration System. The study population included 149,147 girls born in 1993–1997 and their mothers. We calculated birth cohort-specific relative risks (RRs) of non-initiation of HPV vaccination in daughters depending on their mothers’ screening status. Results: In total, 8% of girls did not receive any vaccination, and 35% of their mothers were unscreened. Among the 92% of girls receiving at least one vaccine dose, 14% of mothers were unscreened. The birth cohort-specific RRs of non-initiation of vaccination given an unscreened mother varied between 2.16 (95% CI: 2.00–2.33) and 2.83 (95% CI: 2.63–3.05). Conclusions: The observed association between screening and vaccination suggest that it will be difficult to increase the vaccination coverage by, for example, counselling at the mother’s cervical screening appointment. Other measures to increase the coverage with vaccination will be important. Key Words: Cervical cancer, screening, vaccination, human papillomavirus, coverage, birth cohort
Introduction Without prevention, cervical cancer was an important public health disease, with a cumulative life-time background risk of over 3% [1]. At present, the incidence rate of cervical cancer in Denmark is around 10 per 100,000 age-standardized rate by World Standard Population (ASW) [2], and cervical cancer is more frequent among women of low socio-economic status [3]. Cervical screening and human papilloma virus (HPV) vaccination are now complementary and effective cervical cancer prevention strategies. Several foreign studies observed that the daughters of unscreened
mothers were more likely than the daughters of screened mothers to remain unvaccinated [4–10]. In Denmark, screening coverage of women aged 23–65 years has been relatively high, around 75% [11], and so has been the vaccination coverage of girls that today are aged 15–21, at around 90% for the first dose [12]. Furthermore, screening and vaccination have been free of charge, suggesting a low threshold for mothers to get screened and to have their daughters vaccinated. Nevertheless, screening attendance is lower among women with low education and an infrequent use of
Correspondence: Bente Braad Sander, Department of Public Health, University of Copenhagen, Øster Farimagsgade 5, DK-1014 Copenhagen, Denmark. E-mail: [email protected] (Accepted 27 January 2015) © 2015 the Nordic Societies of Public Health DOI: 10.1177/1403494815574155
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2 B.B. Sander et al. other health care services [13]. The parents’ lower education level and their lower income were associated with a lower coverage of HPV vaccination [14]. This suggests that high risk of cervical cancer and non-participation in cervical cancer prevention may be clustered in certain families. Therefore, the aim of this nationwide register-based study was to investigate whether also in Denmark, the daughter’s vaccination status was dependent on the mother’s screening status. Material and methods In Denmark, an organized program offering free quadrivalent HPV vaccination, administered in general practice (GP), started on 1 October 2008, targeting catch-up cohorts of 13–15-year-old girls (born 1993–1995). This offer ended on 31 December 2010 [15]. On 1 January 2009, HPV vaccination of 12-yearold girls (born in 1996 or later) was introduced as part of the general tax-financed childhood vaccination program [16]. In this analysis, we studied five birth cohorts: the three catch-up cohorts and the two first cohorts of the routine program. The official coverage estimate for the third dose for both programs was around 80% [12]. Personal invitations were sent to all five cohorts, possibly one reason behind the high coverage [16,17]. Screening started at a regional level in the 1960s, and was extended over the entire country in the coming decades [16]. The presently recommended screening interval is 3 years (for 23–49-year-old women) or 5 years (for 50–65-year-old women) [16]. The coverage was 75% in 2012 [11]. Data sources Vaccination data were retrieved from two registers. The first was the National Health Service Register (NHSR, started in 1990) [18] covering doses administered by GPs as part of the organized vaccination program. Although there is some underreporting [19], it is probably quite complete since it is used for financial reimbursements. Codes 8328, 8329, and 8330 were used for the first, second, and third dose, respectively. The second data source was the Danish National Prescription Registry (DNPR). This register documents doses purchased through prescriptions in community pharmacies. The Anatomical Therapeutic Chemical codes used to identify HPV vaccinations were J07BM02 and J07BM01. There should be hardly any overlap of the same dose in the two registers, since they cover different financing situations. For the two data sources combined, we observed illogical/erroneous registrations for 8% of girls (e.g., for the NHSR, no registration of dose 1,
two for dose 2, and one for dose 3, or for the DNPR, a person purchasing more than three doses). Excluding the 8% of girls changed the results only marginally (data not reported). Some unregistered vaccine doses were purchased by medical professionals and administered to self-paying patients. Using information on the official HPV vaccination sales statistics [20], we subtracted the registered doses, and estimated that for all age groups combined around 30%, 10%, and 15% of doses were not registered in 2008, 2009, and 2010, respectively. The unregistered doses were probably not frequent, particularly for the younger cohorts, as parents are unlikely to pay for a service otherwise provided free of charge. However, mothers with a higher socioeconomic status (who have higher screening participation rates compared to the general population [13]) may more often have paid for their (older) daughters’ vaccination before the start of the free program. Such a situation would mean that the calculated RRs are slightly underestimated. Some girls have, furthermore, received unregistered vaccine doses through HPV vaccination trials, but only a few of them were from the birth cohorts included in our analysis. Screening information was obtained from three registers, the NHSR (since 1990 covering all samples taken or evaluated in primary care [18]), the National Patient Register (a hospital discharge register started in 1977 that partially covers cytology samples from hospitals [21]), and the National Danish Pathology Data Bank (started in the 1970s, over the time covering an increasing proportion of samples taken in primary practice and hospitals [22]). The combined screening data have been virtually complete since 1990, although diagnoses were not registered completely throughout the whole period. Hysterectomized mothers were included in the analysis, but this proportion was low in the studied age groups (unpublished data). Information from the Danish Civil Registration System [23] (CRS, started in 1968) was used to define birth cohorts, link mothers and daughters, and to obtain information on the women’s vital status and migrations. All data were linked using the unique personal identification (CPR) numbers assigned to all Danish residents, and retrieved from the beginning of the registration until 31 December 2010. The populations and the linkage between mothers and daughters All girls born in 1993–1997 were selected for the study if they had lived in Denmark during the entire period from 20 September 2006 (when the first HPV vaccine was granted a marketing authorization in the European Union) to 31 December 2010 (Figure 1). Presence was defined as a continuous residence registered in the
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Family use of cervical cancer preventive measures 3
Figure 1. Flowchart of the study population.
CRS, with registration absences not longer than a day. Daughters were coupled to their mothers through a linkage between the girl’s and her mother’s CPR numbers, which was virtually complete for cohorts born after 1960. The mothers should have lived in Denmark continuously (with up to 1-day registration absences) in the period of 4 years before the daughter’s first date of (pseudo) vaccination so that the screening behaviour could be accounted for. This period was chosen based on the 3-year screening interval, allowing for delay in participation. For 8% of mothers aged ⩾50 years at their daughters’ first vaccination date, a 6-year period was assessed based on the 5-year screening
interval recommended for this age group from 2007 onwards. To ensure independent observations, we excluded younger siblings; twins were excluded by chance. The final number of mother–daughter pairs used in the main analysis was thus 149,147. Inclusion of siblings had no significant effect on the results (data not presented). Statistical analysis The date of vaccination with the first dose was defined as the first registered date of any vaccination dose, the date of vaccination with the second dose as the
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4 B.B. Sander et al. second registered date, and likewise for the third dose. For unvaccinated girls, pseudo-dates were defined as the average dates of the first, second, or third vaccination dates among the vaccinated girls in the same birth cohort. We focused on vaccination initiation (having received ⩾1 vaccination dose). As a separate analysis, we also analysed completion of vaccination (three doses) among girls who had initiated the vaccination (N=113,639). We assessed the mother’s screening history (cervical cytology, histology, or HPV testing) 4 or 6 years before the date of her daughter’s first (pseudo-) vaccination. In a separate analysis including only screened mothers, we investigated the effect of having previously experienced screen-detected abnormalities (defined as abnormal cytology or biopsy ⩽10 years before the daughter’s first vaccination). For the same analysis, we further restricted the study population by including only mothers who lived in Denmark from January 1, 1995, onwards, resulting in 122,447 mother–daughter pairs. Inadequate cytology was included in the definition of abnormality because it may have led to anxiety and concern similar to those in women receiving abnormal cytology test results [24]. We calculated crude RRs of non-vaccination in daughters of unscreened mothers as compared with daughters of screened mothers (RR=(unvaccinated daughters of unscreened mothers/all daughters of unscreened mothers)/(unvaccinated daughters of screened mothers/all daughters of screened mothers)). Similar formulae were used for the other reported combinations of exposure and outcome variables. All RRs are calculated by 1-year birth cohort due to differences in the eligibility for vaccination. Calculations were performed using R version 3.0.1. The 95% confidence intervals (CIs) of RRs were calculated assuming that their logarithms were approximately normally distributed. Results About 90% of the daughters initiated HPV vaccination, although this differed slightly by birth cohort (Table I). The mothers’ screening coverage was about 84% for daughters of all birth cohorts. Among unscreened mothers, 15% (=689/4680 for birth cohort 1995) to 21% (859/4141 for birth cohort 1996) of daughters did not initiate vaccination, whereas for screened mothers this was 5% (=1355/25,983 for birth cohort 1995) to 9% (=2024/21,718 for birth cohort 1997). Consequently, the risk of daughters not initiating vaccination among unscreened mothers was significantly increased compared with that of daughters of screened mothers. The RRs were 2.45 (95% CI: 2.28–2.63), 2.64 (95%
CI: 2.43–2.86), 2.82 (95% CI: 2.59–3.08), 2.83 (95% CI: 2.63–3.05), and 2.16 (95% CI: 2.00–2.33), for birth cohorts 1993, 1994, 1995, 1996, and 1997, respectively (Table II). Daughters who initiated HPV vaccination were significantly less likely to receive all three doses if their mothers were unscreened. The RRs of not completing vaccination comparing unscreened to screened mothers varied by birth cohort between 1.44 (95% CI: 1.35–1.53 for birth cohorts 1993 and 1994) and 1.51 (95% CI: 1.42– 1.61 for birth cohort 1996, Table III). Vaccination initiation did not depend on whether the mother had previous abnormal screening tests (Table IV). Discussion General findings Daughters of unscreened mothers had more than double the risk of remaining unvaccinated against HPV compared with daughters of screened mothers. Moreover, even if the daughters of unscreened mothers initiated the vaccination process by receiving at least one dose of the vaccine, they were still more likely than the daughters of screened mothers to not complete the recommended vaccination schedule with three vaccine doses. On the other hand, mothers with abnormal screening results were just as likely to have their daughters vaccinated as mothers with normal screening results. Our finding was in line with other studies [4,7], and implied that the link between a daughter’s vaccination and her mother’s screening participation is perhaps not a result of a mother’s fear of cancer but rather a (familial) clustering of health prevention behaviour [10,13]. With the high coverage of vaccination as seen for example in Denmark, mathematical studies have suggested a certain, although not large, reduction in HPV prevalence also among unvaccinated females through the process of herd immunity [25,26]. A recent study from Australia, a country with a similarly high HPV vaccination coverage, observed a reduction in HPV prevalence among unvaccinated women using routine data [27]. Nevertheless, it will remain important for girls to participate in both programs because vaccination does not cover all carcinogenic HPV types. Comparison with other studies Other European studies also found an association between the mothers’ screening and their daughters’ vaccination statuses, but the strength thereof varied. Unlike our study, which calculated RRs, these studies calculated odds ratios (ORs) for participation (OR=(vaccinated daughters of screened mothers/
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Family use of cervical cancer preventive measures 5 Table I. Average age at human papillomavirus vaccination and vaccination coverage for daughters, and average age at cervical screening and screening coverage rate for mothers included in the study, by the daughters’ birth cohort, N=149,147. Birth cohorts Daughters Average age in years (IQR) at first vaccination dose (vaccination initiation) Average age in years (IQR) at second vaccination dose Average age in years (IQR) at third vaccination dose (vaccination completion) Coverage, first dose (vaccination initiation)a Coverage, second dosea Coverage, third dose (vaccination completion)a Mothers Average age in years (IQR) at daughter’s first vaccination dose (vaccination initiation) Screening coverage in the last 4/6 years
1993
1994
1995
1996
1997
15.4 (15.1–15.7)
14.4 (14.2–14.7)
13.5 (13.3–13.8)
12.8 (12.5–13.1)
12.3 (12.1–12.5)
15.6 (15.3–15.9)
14.6 (14.4–14.9)
13.7 (13.5–14.0)
13.0 (12.7–13.3)
12.5 (12.3–12.8)
15.9 (15.6–16.2)
15.0 (14.8–15.3)
14.1 (13.9–14.4)
13.3 (13.0–13.6)
12.8 (12.6–13.0)
90.9%
93.1%
93.3%
90.6%
89.0%
86.9% 75.3%
89.8% 79.1%
90.0% 79.6%
86.1% 73.5%
83.1% 67.8%
44.2 (41.1–47.2)
43.5 (40.4–46.5)
42.7 (39.5–45.8)
42.1 (38.7–45.2)
41.7 (38.3–44.8)
83.8%
84.1%
84.7%
84.8%
84.6%
IQR, inter-quartile range. aThe coverage rates differ from the official reported coverage rates [12] owing to definition differences for the 8% of daughters with errors in vaccination registration. Table II. Association between cervical cancer screening use among mothers and the initiation of human papillomavirus vaccination among daughters, N=149,147. Birth cohort
1993 1994 1995 1996 1997
Mother’s screening coverage
N (%)
All Not Screened Screened All Not Screened Screened All Not Screened Screened All Not Screened Screened All Not Screened Screened
32,426 (100%) 5252 (16.2%) 27,174 (83.8%) 33,071 (100%) 5253 (15.9%) 27,818 (84.1%) 30,663 (100%) 4680 (15.3%) 25,983 (84.7%) 27,330 (100%) 4141 (15.2%) 23,189 (84.8%) 25,657 (100%) 3939 (15.4%) 21,718 (84.6%)
Daughter’s HPV vaccine initiation No, N (%)
Yes, N (%)
RRa unvaccinated (95% CI)
2957 (9.1%) 950 (2.9%) 2007 (6.2%) 2292 (6.9%) 762 (2.3%) 1530 (4.6%) 2044 (6.7%) 689 (2.2%) 1355 (4.4%) 2558 (9.4%) 859 (3.1%) 1699 (6.2%) 2816 (11.0%) 792 (3.1%) 2024 (7.9%)
29,469 (90.9%) 4302 (13.3%) 25,167 (77.6%) 30,779 (93.1%) 4491 (13.6%) 26,288 (79.5%) 28,619 (93.3%) 3991 (13.0%) 24,628 (80.3%) 24,772 (90.6%) 3282 (12.0%) 21,490 (78.6%) 22,841 (89.0%) 3147 (12.3%) 19,694 (76.8%)
2.45 (2.28–2.63) 1 (reference) 2.64 (2.43–2.86) 1 (reference) 2.82 (2.59–3.08) 1 (reference) 2.83 (2.63–3.05) 1 (reference) 2.16 (2.00–2.33) 1 (reference)
aRR=(unvaccinated
daughters of unscreened mothers/all daughters of unscreened mothers)/(unvaccinated daughters of screened mothers/ all daughters of screened mothers).
unvaccinated daughters of screened mothers)/(vaccinated daughters of unscreened mothers/unvaccinated daughters of unscreened mothers)). Adjusted ORs in a Dutch study by Steens et al. [8] was 1.40 (95% CI: 1.38–1.43). Vaccination coverage was 58% ([8]; Anneke Steens, personal communication, 9 March 2014). A study from the north-west of England by Spencer et al. [7] found a stronger association for both the routine and the
catch-up programs, adjusted ORs 3.7 (95% CI: 3.2–4.1) and 3.6 (95% CI: 3.2–4.1), respectively, with the vaccination coverage of 76% in the routine program and 82% in the catch-up cohorts. In a Flemish study by Lefevere et al. [5], where 54% of daughters were vaccinated, ORs for mothers with 1, 2, or ⩾3 smears in a 3-year period, compared with no smears, were 4.5 (95% CI: 3.5–5.9), 9.2 (95% CI: 7.9–11.2), and 16.0 (95% CI: 12.1–21.2),
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6 B.B. Sander et al. Table III. Association between cervical cancer screening participation among mothers and non-completion of human papillomavirus vaccination schedule among daughters who initiated vaccination, N=113,639. Birth cohorta
1993 1994 1995 1996
Mother’s screening participation
All Not Screened Screened All Not screened Screened All Not screened Screened All Not screened Screened
N (%)
Non-completion of the vaccination schedule among daughters who initiated vaccination
29,469 (100%) 4302 (14.6%) 25,167 (85.4%) 30,779 (100%) 4491 (14.6%) 26,288 (85.4%) 28,619 (100%) 3991 (13.9%) 24,628 (86.1%) 24,772 (100%) 3282 (13.2%) 21,490 (86.8%)
Non-completers, N (%)
Completers, N (%)
RRb (95% CI)
5046 (17.1%) 996 (3.4%) 4050 (13.7%) 4605 (15.0%) 908 (3.0%) 3697 (12.0%) 4217 (14.7%) 801 (2.8%) 3416 (11.9%) 4673 (18.9%) 876 (3.5%) 3797 (15.3%)
24,423 (82.9%) 3306 (11.2%) 21,117 (71.7%) 26,174 (85.0%) 3583 (11.6%) 22,591 (73.4%) 24,402 (85.3%) 3190 (11.1%) 21,212 (74.1%) 20,099 (81.1%) 2406 (9.7%) 17,693 (71.4%)
1.44 (1.35–1.53) 1 (reference) 1.44 (1.35–1.53) 1 (reference) 1.45 (1.35–1.55) 1 (reference) 1.51 (1.42–1.61) 1 (reference)
aCalculations
for vaccination completion were left out for vaccinated girls in the birth cohort of 1997 (N= 22,814) since those girls were still eligible for vaccination for up to two years after December 31 2010. bRR=(daughters of unscreened mothers not completing vaccination /all daughters of unscreened mothers who initiated the vaccination)/ (daughters of screened mothers not completing vaccination/all daughters of screened mothers who initiated the vaccination). Table IV. Association between abnormal screening test results among screened mothers and initiation of human papillomavirus vaccination among their daughters, N=122,447. Birth cohort
1993 1994 1995 1996 1997
Mother’s screening test outcomea
N (%)
All Not Abnormal Abnormal All Not Abnormal Abnormal All Not Abnormal Abnormal All Not Abnormal Abnormal All Not Abnormal Abnormal
26,547 (100%) 21,465 (80.9%) 5082 (19.1%) 27,159 (100%) 21,894 (80.6%) 5265 (19.4%) 25,330 (100%) 20,336 (80.3%) 4994 (19.7%) 22,484(100%) 18,056 (80.3%) 4428 (19.7%) 20,927 (100%) 16,839 (80.5%) 4088 (19.5%)
Daughter’s HPV vaccine initiation No, N (%)
Yes, N (%)
RRb unvaccinated (95% CI)
1945 (7.3%) 1583 (6.0%) 362 (1.4%) 1490 (5.5%) 1223 (4.5%) 267 (1.0%) 1305 (5.2%) 1061 (4.2%) 244 (1.0%) 1631 (7.3%) 1338 (6.0%) 293 (1.3%) 1914 (9.1%) 1544 (7.4%) 370 (1.8%)
24,602 (92.7%) 19,882 (74.9%) 4720 (17.8%) 25,669 (94.5%) 20,671 (76.1%) 4998 (18.4%) 24,025 (94.8%) 19,275 (76.1%) 4750 (18.8%) 20,853 (92.7%) 16,718 (74.4%) 4135 (18.4%) 19,013 (90.9%) 15,295 (73.1%) 3718 (17.8%)
1 (reference) 0.97 (0.87–1.08) 1 (reference) 0.91 (0.80–1.03) 1 (reference) 0.94 (0.82–1.07) 1 (reference) 0.89 (0.79–1.01) 1 (reference) 0.99 (0.89–1.10)
aAssessed
for 10 years before her daughter’s first vaccination. daughters of mothers who had an abnormal screening test/all daughters of mothers who had an abnormal screening test)/(unvaccinated daughters of mothers who did not have an abnormal screening test/all daughters of mothers who did not have an abnormal screening test).
bRR=(unvaccinated
respectively (Eva Lefevere, personal communication, 22 May 2014). A similarly high OR, 6.2 (95% CI: 1.5–25.8), was found in a small French study by Lutringer-Magnin et al. [6] undertaken at GP level, where 68% of daughters were vaccinated. Also studies from the USA found positive associations, but the strength thereof tended to be weaker, possibly due to the lower vaccination coverage [4,9,10]. To compare these results with our study, we calculated crude RRs of non-initiation of vaccination for
unscreened compared with screened mothers, as described in the Methods ([5–8]; Eva Lefevere personal communication, 22 November 2013; Anneke Steens personal communication, 9 March 2014). The following estimates were found for the RRs (with the screening exposure as defined in the studies): 1.22 (95% CI: 1.21–1.23) for the Netherlands, 1.33 (95% CI: 1.32–1.35) for Flanders, 1.40 (95% CI: 0.93–2.12) for France, and 1.51 (95% CI: 1.45–1.57) for the UK (the routine program). All these were lower than the
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Family use of cervical cancer preventive measures 7 RRs for Denmark (Table II), though the RRs tended to increase with vaccination and screening coverage rates. The more selected the unscreened groups were, the stronger the mother–daughter associations became. Weaknesses of the analysis Data on socioeconomic and health care characteristics were not available for this study, and all RRs were unadjusted. However, lack of adjustment probably cannot explain our findings. A comparison of crude and adjusted ORs from previous studies suggested only a very small impact of adjustments [4,7–10]. Furthermore, in a Danish study on predictors of nonparticipation in cervical screening the differences between crude and adjusted ORs were also small [13]. The 1996 and 1997 birth cohorts were eligible for free vaccination until turning 15 years (in 2011 and 2012, respectively) [15], but we could only assess their vaccination status until the end of 2010. For the 1996 cohort, the official vaccination coverage by December 31, 2010, was 86% for the first and 79% for the third dose [15], whereas by mid-November 2012, the coverage rates were 87% and 81%, respectively [12]. For the 1997 cohort, the official coverage by December 31, 2010, was 86% for the first and 70% for the third dose [15], whereas by mid-November 2012, the coverage rates were 90% and 82%, respectively [12]. Consequently, we could not reliably assess the relationship between the mother’s screening status and her daughter’s vaccination completion for the 1997 cohort; this cohort was thus excluded from the calculation in Table III. Recently, it was also decided to reoffer the 1993–1997 birth cohorts free vaccination in 2014 and 2015, and vaccination is now free up until age 18 years for all birth cohorts Furthermore, unvaccinated girls included in the study could decide at an older age to pay for vaccination themselves, but at that age the effectiveness of vaccination would be lower than when vaccination is delivered before the sexual debut, which is the situation covered by our data. For 1813 daughters, the mother could not be identified through the mother–daughter linkage in the CRS (Figure 1). This could be due to immigration. Foreign women less frequently participate in cervical cancer screening [13]. From the CRS data, we could infer that 1744 (96%) of the 1813 girls may have indeed been immigrants, defined as having the first CRS record from a date that was more than 1 month later than the date of birth. Using the same definition, 15,447 (10%) of all girls in our study population were likely immigrants. Thereby, immigrant girls who could not be linked to their mothers constituted only 11% (=1744/15,447) of all immigrant girls.
Strengths of the analysis Our large study was population based, from a region for which similar data have not yet been reported. To our knowledge, no previous study included data for an entire country. The risk of selection bias was probably very low as 99% of eligible daughters could be linked to a mother, and the main reason why linking was not possible was immigration. Of all immigrants, the majority could still be linked to a mother. The two other main reasons for an exclusion of mother–daughter pairs were mothers with more than one daughter in the assessed birth cohort and daughters who had not lived in Denmark continuously throughout the study period, reasons probably associated with only a low risk of selection bias. We could link daughters to mothers directly. In previous larger studies, mothers were identified (mostly) based on a shared home address and a predefined age difference with the daughters [7,8], household numbers and age [5], or records of family members and age difference [4,10].With our method, we addressed the correlation between two persons registered officially as the mother and her daughter. On the other hand, we could not be certain that the two actually had contact. Perspectives The observed association between screening and vaccination suggests that it will be difficult to increase the vaccination coverage by, for example, counselling at the mother’s cervical screening appointment [28]. Instead, text messages have been proposed to remind parents that their daughter is due for vaccination [29]. Although invitations for their daughters’ vaccination have so far been sent to parents in Denmark [16], a study showed that GPs contacting parents by phone or letter significantly increased the likelihood of subsequent vaccination among initially unvaccinated girls [30]. Correspondingly, it has been decided that from May 2014 onwards reminders will be sent to parents of children aged 2, 6.5, and 14 years who have not received all recommended childhood vaccinations. In conclusion, despite screening and vaccination being offered free of charge in Denmark, a daughter’s HPV vaccination status was dependent on her mother’s screening status. Coverage with both preventive services shows potential room for improvement. Research ethics In Denmark, notification to the Danish Data Inspection Agency serves as ethical approval of register-based research projects in which no contact is
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8 B.B. Sander et al. made to patients, their relatives or treating physicians. The project has notification number 201041-5594. Conflict of interest Elsebeth Lynge and Matejka Rebolj have been involved in comparative studies of new-generation HPV tests, involving collaboration with Roche, Genomica, Qiagen, Hologic/Gen-Probe, BD, and Rovers. Elsebeth Lynge served as unpaid scientific advisor to Gen-Probe and Norchip, and Matejka Rebolj and her employer have received honoraria for lectures from Qiagen. Concerning the present paper, there was no collaboration with, or support from any of the companies. Funding Bente Braad Sander held a PhD scholarship from the Danish Research and Innovation Agency, and received a grant from Aase and Ejnar Danielsens Foundation. Matejka Rebolj was supported by a grant from the Danish Strategic Research Council. References [1] Barken SS, Rebolj M, Andersen ES, et al. Frequency of cervical intraepithelial neoplasia treatment in a well-screened population. Int J Cancer 2012,130:2438–44. [2] Engholm G, Ferlay J, Christensen N, et al. NORDCAN, http://www.ancr.nu (2014, accessed 14 May 2014]. [3] Jensen KE, Hannibal CG, Nielsen A, et al. Social inequality and incidence of and survival from cancer of the female genital organs in a population-based study in Denmark, 1994–2003. Eur J Cancer 2008;44:2003–17. [4] Chao C, Slezak JM, Coleman KJ, et al. Papanicolaou screening behavior in mothers and human papillomavirus vaccine uptake in adolescent girls. Am J Public Health 2009;99:1137–42. [5] Lefevere E, Hens N, Theeten H, et al. Like mother, like daughter? Mother’s history of cervical cancer screening and daughter’s Human Papillomavirus vaccine uptake in Flanders (Belgium). Vaccine 2011;29:8390–6. [6] Lutringer-Magnin D, Cropet C, Barone G, et al. HPV vaccination among French girls and women aged 14–23 years and the relationship with their mothers’ uptake of Pap smear screening: A study in general practice. Vaccine 2013;31:5243–9. [7] Spencer Nee Pilkington AM, Brabin L, et al. Mothers’ screening histories influence daughters’ vaccination uptake: An analysis of linked cervical screening and human papillomavirus vaccination in the North West of England. Eur J Cancer 2013;49:1264–72. [8] Steens A, Wielders CC, Bogaards JA, et al. Association between human papillomavirus vaccine uptake and cervical cancer screening in the Netherlands: Implications for future impact on prevention. Int J Cancer 2013;132:932–43. [9] Monnat SM and Wallington SF. Is there an association between maternal pap test use and adolescent human papillomavirus vaccination? J Adolesc Health 2013;52:212–8. [10] Markovitz AR, Song JY, Paustian ML, et al. Association between maternal preventive care utilization and adolescent vaccination: It’s not just about Pap testing. J Pediatr Adolesc Gynecol 2014;27:29–36.
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