Prevalence of Human Papillomavirus Subtypes and Related Cytology in Estonian Cervical Cancer Screening Population in 2021

Abstract

Introduction

Prevalence of high risk human papillomavirus (hrHPV) and its subtypes by sociodemographic factors and the related cytological findings in the Estonian cancer screening population were examined, with the aim to improve cancer prevention.

Methods

This cross-sectional study included all women who participated in the Estonian cervical cancer screening programme from January 1, 2021 to January 31, 2022 and had a valid HPV test result reported to the Estonian Cancer Screening Registry (n = 37 537, aged 30, 35, 40, 45, 50, 55, 60, and 65). Limited sample (N = 18 784) within the total sample consisted of women who used self-sampling (N = 3535) or whose clinician collected sample was analysed using lab methodology that differentiates HPV16, 18, and 45. Data on HPV and cytology results were obtained from the Estonian Cancer Screening Registry, whereas data on education, nationality, and marital status were obtained from the Estonian Population Registry.

Results

hrHPV was detected in the samples of 3307 (8.8%) women, and the prevalence was significantly higher in age groups under 40, in women with lower education, of Estonian nationality, and with no partner. The overall prevalence of HPV16 was 1.8%, ranging from 4.4% in 30-year-old women to 0.9% in 55-year-old women. The proportion of normal cytology was 50% among all hrHPV positive women and 35% in all HPV16 positive women, while it was 47% for HPV16 alone and 24% for HPV16 plus other hrHPV subtypes. The probability of normal cytology was significantly higher in women aged 50 and older compared to women aged 30 and 35 for total hrHPV and HPV16.

Conclusion

All countries should monitor HPV prevalence across different age groups. As different HPV genotypes have a different oncogenic risk profile, extended or complete genotyping would help personalised risk-based screening approaches, with less health care costs, less harms, and a bigger net benefit. In addition, lab methodology should be harmonised.

Plain Language Summary

All countries should regularly monitor HPV prevalence in different groups to make evidence-based decisions for reducing HPV related cancer burden. Monitoring different HPV subtypes across different population groups opens an opportunity for personalised risk-based approaches, with less harms and bigger benefits. In 2021 in Estonia, high-risk human papillomavirus (hrHPV) prevalence among women attending cervical cancer screening was 8.8% (HPV 16 prevalence 1.8%), being higher in younger women, Estonians, women without a partner, and with basic education.

Keywords

human papillomavirus (HPV)cervical cancer screening cytological findings

Introduction

Cervical cancer incidence and mortality in Estonia have been consistently higher than the average for European Union, with the estimated age-standardized (world) rate of 11.7 and 3.8 per 100 000 in 2022, respectively.¹

Organized cervical cancer screening has been in place in Estonia since 2006. Until 2021, the target age group was 30-55 years, primary test was Pap-smear, and women without valid health insurance did not have access to free screening (the proportion of working-age population without health insurance was around 5%). Several problems have been reported regarding Pap-smear based screening, mainly associated with low attendance and poor quality of reporting and follow-up.^2,3 In 2021, several changes were implemented: the primary test is now HPV test followed by liquid-based cytology (LBC), target age group was extended to include women aged 30-65 years and people with no health insurance were included in screening programme. In addition, a randomized pilot study of HPV self-sampling was conducted in the second half of 2021, offering a random sample of women an option to choose between traditional clinic-based screening and self-sampling.⁴

About 99.7% of cervical cancer cases are caused by persistent genital high-risk human papillomavirus (hrHPV) infection.⁵ hrHPV prevalence among the population varies across countries and age-groups.^6-8 Different hrHPV genotypes are related to a different proportion of cervical precancerous lesions.^8,9

Prevalence of hrHPV has an impact on the amount of triage tests and colposcopies needed and thus, on health care costs. Population based hrHPV prevalence is an indicator for HPV related cancer burden⁹ and reflects the effectiveness or ineffectiveness of the population coverage with HPV vaccination.¹⁰ HPV vaccination in Estonia was introduced in 2018 for 12-14-year old girls and extended to include both boys and girls aged 12-18 in 2024.

The aim of this study was to examine the prevalence of hrHPV and its subtypes as well as related cytology in Estonia among women screened in the first year of HPV-based cervical cancer screening. hrHPV prevalence was additionally studied by sociodemographic variables. HPV prevalence by subtype and population group and related cytology among the screening population has not been previously analysed in Estonia. The strength of this study is a large population-based sample covering a wide range of age groups. The results can be used to define risk groups for targeted screening and to improve vaccination coverage.

Methods

Data Collection and Definitions

The main data source for this cross-sectional study was the Estonian Cancer Screening Registry. Population eligible for cervical cancer screening in Estonia in 2021 consisted of all women aged 30, 35, 40, 45, 50, 55, 60 and 65 who were Estonian residents according to the Estonian Population Register and who had not been diagnosed with uterine cancer in previous 5 years (N = 73 786, Figure 1). Sociodemographic data (nationality, marital status, education) were collected from the Estonian Population Register.

Figure 1.

Flowchart of Cervical Cancer Screening Study Population Included in Analysis, Estonia 2021

Women who had not participated in organised cervical screening by August 2021 were randomized into 3 groups: an opt-out group who were sent the sampling kit to their home address; an opt-in group who received a web-link for ordering the sampling kit online, and a control group who had access to conventional screening at the clinic without self-sampling option. Both intervention groups could choose between self-sampling and conventional screening at the clinic.⁴

All women who participated in screening from January 1, 2021 to January 31, 2022 and had a valid HPV test result reported to the Estonian Cancer Screening Registry (N = 37 537) formed the study population. Women with missing HPV test results (N = 19) were excluded.

Thus, the study population in this analysis included women who had the sample taken by a health care provider (N = 34 002) and as well as women who had provided a self-sample (N = 3535).

A sub-group analysis was performed among a limited sample which consisted of women who chose self-sampling or whose HPV test that was collected at the clinic was analysed using lab methodology that differentiates 3 individual HPV subtypes (HPV 16, 18, and 45).

All patient data details have been de-identified. The reporting of this study conforms to STROBE guidelines.¹¹

Based on data reported to the Estonian Cancer Screening Registry, 773 women had done more than 1 HPV test during the eligibility period. For this study, only one HPV test per woman was included: in case of agreement between 2 test results or if the first test was positive, the first HPV result was included. The second HPV result was included for 33 women, whose first result was negative and the second one was positive.

According to Estonian screening guidelines, the laboratories participating in organized screening are required to detect 14 hrHPV subtypes: HPV16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68. Three different HPV sequencing assays were used by laboratories that analysed clinician-collected HPV samples in 2021: Alinity m hrHPV assay, which differentiates 3 individual hrHPV subtypes (HPV16, 18, and 45) and 2 hrHPV subtype groups (group A (HPV31, 33, 52, 58) and group B (HPV35, 39, 51, 56, 59, 66, 68)); Cobas® 4800 System, which differentiates 2 individual hrHPV subtypes (HPV16, 18) and 1 hrHPV subtype group (HPV31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68) and Aptima HPV (Hologic) assay, which differentiates 1 individual hrHPV subtype (HPV16) and 2 hrHPV subtype groups (HPV 18,45 together and HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68).

Self-samples were analysed by 2 laboratories. One of them used Alinity hrHPV assay (see above), another used an in-house method⁴ which determined all subtypes individually plus 2 additional subtypes (HPV53, 82).

For analysing the distribution of subtypes, the categories were as follows: HPV16 alone; HPV16 plus any other hrHPV subtype; HPV18 alone; HPV18 plus any other hrHPV subtype, except H16; HPV45; HPV45 plus any other hrHPV subtype, except HPV16 and HPV18; hrHPV group A alone; hrHPV group A and any other hrHPV subtype, except HPV16, HPV18 and HPV45; hrHPV group B alone; hrHPV group B plus any other hrHPV subtype, except HPV16, HPV18, HPV45 and group A; HPV53 or HPV 82 alone.

Liquid-based cytology (LBC) tests done within 6 months of the positive HPV test were included. Only the first LBC test result following a positive hrHPV test was included in the analysis, unless the first LBC yielded an inadequate result, in which case the next LBC result was included.

LBC results were reported according to the latest Bethesda system. For this study, cytology was grouped into the following categories: (1) negative for intraepithelial lesion or malignancy (NILM); (2) atypical squamous cells of undetermined significance (ASC-US) or low-grade squamous intraepithelial lesion (LSIL); (3) atypical glandular cells (AGC), atypical squamous cells - cannot exclude atypical squamous cells of undetermined significance (ASC-H), high-grade squamous intraepithelial lesion (HSIL) or carcinoma. The category “LBC not available” (N = 288) includes women with results reported as “inadequate” or “unknown” and those with no data on LBC at the ECSR, which means that LBC was either not done or the data did not reach the registry due to data quality reasons.

Age was grouped as 30/35, 40/45, 50/55, 60/65. Region of residence was based on NUTS-3: Northern, Southern, Western, Central and North-Eastern Estonia.^11,12 Nationality was grouped as Estonian or non-Estonian; marital status as married, divorced/widowed or single; education as basic, secondary/vocational or higher. “Unknown” category includes women with no data available from the Population Register.

Statistical Analysis

Total hrHPV prevalence (%) and HPV16 prevalence was examined in the entire study population (N = 37 537). Differences between proportions were tested with chi-squared test.

Analysis of hrHPV subtype prevalence included results from either self-samples or clinician-collected samples analysed using the Alinity m hrHPV assay (limited sample, N = 18 784).

Distribution of hrHPV subtype categories by age group was examined in the limited sample, excluding HPV subtypes 53 and 82, which were only detected in self-samples, to avoid confounding by different proportion of self-samplers in age groups.

The distribution of LBC was described by hrHPV subtype, for total hrHPV and HPV16 in total sample and for other subtypes, in limited sample.

The association of NILM cytology with age was analysed using generalized linear modelling with robust variance and prevalence rate ratios (PRR) with 95% confidence intervals (CI) were calculated separately for total hrHPV, HPV16 (both in total sample) and hrHPV group A and hrHPV group B (in limited sample).

Software used was Stata version 18.

Ethical Approval

This study was approved by the Research Ethics Committee of the University of Tartu (371/T-4, 21.11.2022).

Results

The study population included 37 537 women aged 30 to 65 who participated in cervical cancer screening in Estonia in 2021, 53.3% of whom were below age 50 years. The mean age of women in the main sample was 46.7 years (SD 11.2) and in the limited sample 47.8 years (SD 11.2). Most women were of Estonian nationality (72.3%), nearly half of the women were married or living with a partner (47.6%) and had higher education (45.7%), 9.4% of participants had participated in screening through self-sampling, and more than half (50.4%) were living in Northern Estonia (Table 1).

Table 1.

Characteristics of the Study Population and the Prevalence of Total hrHPV, HPV16 and hrHPV A, B Groups, Estonia 2021

Variable	Total study population^a								Limited sample^a
			hrHPV			HPV16					hrHPV group A^b			hrHPV group B^b
	No.	col%	No.	Row%	P-value^c	No.	Row%	P-value^c	No.	col%	No.	Row%	P-value^c	No.	Row%	P-value^c
Total	37 537		3307	8.8		673	1.8		18 784		438	2.3		659	3.5
Age (years)					<0.001			<0.001					<0.001			<0.001
30	4617	12.3	780	16.9		205	4.4		2019	10.8	103	5.1		110	5.5
35	5278	14.1	630	11.9		121	2.3		2366	12.6	78	3.3		111	4.7
40	5061	13.5	410	8.1		75	1.5		2271	12.1	61	2.7		74	3.3
45	5047	13.4	394	7.8		74	1.5		2423	12.9	49	2.0		79	3.3
50	5170	13.8	333	6.4		55	1.1		2701	14.4	39	1.4		93	3.4
55	4072	10.8	224	5.5		36	0.9		2232	11.9	34	1.5		59	2.6
60	4387	11.7	259	5.9		54	1.2		2547	13.6	33	1.3		67	2.6
65	3905	10.4	277	7.1		53	1.4		2225	11.9	41	1.8		68	3.1
Region of residence					0.060			0.252					0.215			<0.001
Northern Estonia	18 902	50.4	1704	9.0		318	1.7		6775	36.1	177	2.6		283	4.3
Southern Estonia	8241	22.0	754	9.1		169	2.1		6255	33.3	139	2.2		199	3.2
Western Estonia	4482	11.9	363	8.1		88	2.0		2813	15.0	60	2.1		64	2.3
Central Estonia	3251	8.7	283	8.7		58	1.8		1599	8.5	28	1.8		65	4.1
North-Eastern Estonia	2648	7.1	203	7.7		40	1.5		1336	7.1	34	2.5		44	3.3
Unknown	13	0.0	0	-		0	-		6	0.0	0	-		0	-
Nationality					0.001			0.003					0.258			0.529
Estonian	27 141	72.3	2471	9.1		521	1.9		14 230	75.8	320	2.3		507	3.6
Non-Estonian	10 270	27.4	820	8.0		151	1.5		4488	23.9	114	2.5		151	3.4
Unknown	126	0.3	16	12.7		1	0.8		66	0.4	4	6.1		3	4.5
Marital status					<0.001			<0.001					<0.001			<0.001
Married/partner	17 879	47.6	1100	6.2		213	1.2		8948	47.6	136	1.5		236	2.6
Divorced or widowed	7932	21.1	848	10.7		153	1.9		4087	21.8	120	2.9		186	4.6
Single	11 522	30.7	1327	11.5		298	2.6		5652	30.1	177	3.1		233	4.1
Unknown	204	0.5	32	15.7		9	4.4		97	0.5	5	5.2		6	6.2
Educational level					<0.001			<0.001					0.001			0.554
Basic	2510	6.7	308	12.3		81	3.2		1407	7.5	54	3.8		54	3.8
Secondary or vocational	17 399	46.4	1564	9.0		320	1.8		9139	48.7	204	2.2		332	3.6
Higher	17 149	45.7	1412	8.2		265	1.5		7955	42.4	176	2.2		269	3.4
Unknown	479	1.3	23	4.8		7	1.5		283	1.5	4	1.4		6	2.1
Participation					<0.001			<0.001					0.001			<0.001
Clinic	34 002	90.6	2807	8.3		574	1.7		15 249	81.2	327	2.1		463	3.0
Self-sampling	3535	9.4	500	14.1		99	2.8		3535	18.8	111	3.1		198	5.6

^aTotal study population includes all women who participated in cervical cancer screening in 2021 (n = 37 537); limited sample includes women whose clinician collected sample was analysed using the Alinity m hrHPV assay or who used self-sampling (n = 18 784).

^bhrHPV group A includes subtypes 31, 33, 52, 58; group B include subtypes 35, 39, 51, 56, 59, 66, 68.

^cChi-square test, unknown values excluded.

hrHPV was detected in the samples of 3307 (8.8%) women and the prevalence was significantly higher in younger age groups (16.9% in age group 30 and 11.9% in age group 35 compared to the prevalence from 5.5% to 8.1% in the other age groups), in women with lower education (12.3% vs 8.2% among women with higher education), of Estonian nationality (9.1% vs 8.1% among non-Estonians) and with no partner (11.5% vs 6.2% among married women and women living with a partner) (Table 1). The overall prevalence of HPV16 was 1.8%, ranging from 4.4% in 30-year-old women to 0.9% in 55-year-old women. HPV 16 prevalence was higher across the same studied background variables as for total hrHPV.

In the limited sample of 18 784 women among whom HPV 16, 18 and 45 subtypes could be differentiated, the prevalence of different HPV subtypes was as follows: HPV18 0.5%, HPV45 0.5%, hrHPV group A 2.3% and hrHPV group B 3.5%. Table 1 presents the prevalence of hrHPV groups A and B by sociodemographic variables (HPV18 and HPV45 not shown due to small numbers). For group A, differences were seen by age, marital status and education, for group B, by age, region of residence and marital status. Regional differences observed for group B were likely due to the location of the laboratory included in this analysis.

The prevalence total hrHPV as well as subtypes was higher among women who participated in self-sampling, probably due to differences in lab methodology and higher cut-off values for self-collection than in clinician taken samples, also reported in previous studies.¹³

The distribution of HPV subtypes in the limited sample differed across age groups (P < 0.001) (Figure 2). Younger women had a larger proportion of HPV16 combined with other hrHPV genotypes, and hrHPV group A, while older women had a larger proportion of group B.

Figure 2.

Distribution of hrHPV Subtypes by Age Group in the Limited Sample, Estonia 2021

The proportion of NILM was 50% among all hrHPV positive women and 35% in all HPV16 positive women, while it was 47% for HPV16 alone and 24% for HPV16 plus other hrHPV subtypes (Figure 3). The proportion of ASC-H, AGC, HSIL or carcinoma varied from 35% in HPV16 and other hrHPV types and 25% in HPV16 alone (29% in all HPV16 positive) to 4% in HPV45 and 6% in hrHPV group B (Figure 3).

Figure 3.

Liquid-Based Cytology (LBC) Test Results (%) Among hrHPV Positive Women by hrHPV Subtype, Estonia 2021 (Total hrHPV and HPV16 Based on Total Sample, Other Subtypes on Limited Sample)

The proportion of NILM increased with age for total hrHPV and was generally the highest in ages 60/65 with small variations for different subtypes (Table 2). The proportion of ASC-H, AGC, HSIL or carcinoma was higher in ages 30/35 and 40/45 for total hrHPV and HPV16 than in older age groups; for hrHPV group A, it was highest in ages 40/45. Age differences were not significant for hrHPV group B.

Table 2.

Liquid-Based Cytology (LBC) Test Results Among hrHPV Positive Women by hrHPV Subtype and Age, Estonia 2021

hrHPV type^a	Age	No.	NILM (%)	ASC-US or LSIL (%)	ASC-H, AGC, HSIL or carcinoma (%)	P-value^a
Total hrHPV	30/35	1328	43.9	38.8	17.3	<0.001
	40/45	747	45.9	36.4	17.7
	50/55	493	59.0	27.8	13.2
	60/65	451	67.2	19.5	13.3
HPV16	30/35	315	30.2	38.1	31.8	<0.001
	40/45	143	32.2	35.7	32.2
	50/55	83	56.6	24.1	19.3
	60/65	89	55.1	20.2	24.7
hrHPV group A	30/35	154	53.9	29.9	16.2	0.003
	40/45	98	52.0	23.5	24.5
	50/55	57	50.9	28.1	21.1
	60/65	59	81.4	10.2	8.5
hrHPV group B	30/35	200	61.5	33.0	5.5	0.680
	40/45	127	66.1	28.4	5.5
	50/55	129	66.7	27.9	5.4
	60/65	107	71.0	22.4	6.5

^aTotal hrHPV and HPV16 from total sample, hrHPV groups A and B from limited sample.

^bChi-square test.

The probability of LBC result being NILM among hrHPV positive women was significantly higher in women aged 50 and older compared to women aged 30/35 for total hrHPV and HPV16 (Table 3). For hrHPV group A, higher likelihood of NILM was limited to ages 60/65 while no significant differences were seen for hrHPV group B.

Table 3.

Age-Related Prevalence Rate Ratios (PRR) With 95% Confidence Intervals (CI) for LBC Result Being NILM by hrHPV Subtype, Estonia 2021

Age group	Total hrHPV^a		HPV16^a		hrHPV group A^a		hrHPV group B^a
Age group	PRR	95% CI	PRR	95% CI	PRR	95% CI	PRR	95% CI
30/35	1.00		1.00		1.00		1.00
40/45	1.01	0.98-1.05	1.02	0.95-1.09	0.99	0.91-1.07	1.03	0.96-1.10
50/55	1.11	1.07-1.14	1.20	1.11-1.30	0.98	0.89-1.08	1.03	0.97-1.10
60/65	1.16	1.13-1.20	1.19	1.10-1.29	1.18	1.09-1.27	1.06	0.99-1.13

^aTotal hrHPV and HPV16 from total sample, hrHPV groups A and B from limited sample.

Discussion

To date, only a few studies in Estonia have addressed the prevalence of hrHPV, and hrHPV prevalence among the screening population has not been studied earlier. The results of this cross-sectional study showed that the proportion of hrHPV positive women in the Estonian cervical cancer screening programme in 2021 was 8.8%, being higher among younger age-groups, Estonians, single women, and women with basic education.

The overall prevalence of HPV16 was nearly 2%, and more than twice that in 30-year-old women. Cytology was reported normal for 50% of all hrHPV positive women and 35% of HPV16 positive women (47% for HPV16 alone and 24% for HPV combined with other hrHPV subtypes). The proportion of ASC-H, AGC, HSIL or carcinoma was 16% overall and it was several times higher in women with HPV16 combined with other subtypes compared to other subtype combinations. Previous studies have also indicated that having multiple high-risk HPV types increased the probability of abnormal cytological findings.^14,15

The proportion of hrHPV positive women within the screening population in Estonia (8.8%) was similar to that in the Finnish screening population aged 25-65 in 2003-2005 (7.8%)¹⁶¹⁶ as well as in some other countries,^16-18 whereas being lower than in Latvian general population (11.0%),¹⁹ and among Hungarian women aged 25-65 (11.15%).²⁰ These differences in HPV prevalence may be related to differences in population age range. While the prevalence was rather similar in younger age groups, older women in Estonia had slightly higher prevalence of hrHPV than Finnish women (7.1% vs 2.8%, respectively for women aged 65).¹⁶ The 1.8% prevalence of HPV16 was higher than that seen in Finland (0.9%)^16, , but lower than reported in Latvia (3.5%) .¹⁹Such differences may reflect different sexual behaviour. A previous study based on a sample drawn from Estonian Genome Biobank reported similar hrHPV prevalence for young women aged 30-33 (18.7% overall and 4% for HPV16), but higher overall hrHPV prevalence for women aged 57-60 years (10.2%), mainly due to high prevalence of HPV68, while the prevalence of HPV16 was similar to our results.²¹ The higher prevalence in hrHPV among women aged 57-60 in the Biobank group may reflect background differences in this small group.

The overall proportion of normal cytology among hrHPV positive samples was lower in our study compared to Finland (50% vs 62%), mainly on the account of lower proportion of NILM results in younger women. Proportion of NILM results in our study was ranging from 40%–67%, being lower in younger age groups and increasing with age. Similar tendency has been observed previously, eg, Portuguese data presented higher overall prevalence of hrHPV (12.5%), but with significantly higher proportion of NILM results in all age groups (63%–77% ).¹⁴

The effect of socio-economic background factors on HPV prevalence was similar with other reported studies.¹⁶

Results from studies that have analysed hrHPV positivity among women with normal and abnormal cytology results do not reflect the prevalence of hrHPV in the female population, but serve as a valuable source of information for reflecting the carcinogenicity of different HPV genotypes across different populations.^15,22,23

Limitations and Strengths

Several studies have reported HPV prevalence in different cohorts.^24-26 The strength of this study is a large population-based sample covering a wide range of different age groups. Overall participation in the national cervical cancer screening programme in 2021 was 50.9%. with the lowest participation rate of 41.7% in the age group of 65 year and highest participation rates of 55.2%. 54.9% and 54.8% in age groups 50, 40, and 45 years, respectively.²⁷ Before 2021, uptake in organised cervical cancer screening programme in Estonia was 45% in 2018 and 2020 and 48% in 2019.²⁸

The hrHPV prevalence among non-participants in the organised screening might be different than among the participants, and data about prevalence of different hrHPV genotypes among screened women is partly limited due to different lab methodology. In addition, there was a small group of hrHPV positive women whose LBC results were missing, and those who chose self-sampling. The differences in background characteristics of women with self-sampling HPV and women tested at the clinic deserve a separate analysis.

Conclusions

Regular monitoring of HPV prevalence and related cytology among screening population opens an evidence-based possibility to modify screening and vaccination programmes. Targeted interventions based on real-life data may help to improve cancer prevention while reducing health care costs.

Large population-based studies using data from registries are a valuable source of information for further studies and health-policy decisions. Lab methodology has an impact on data being monitored.²⁸ Lab methodology should be harmonised within a small country, and instead of many smaller labs one or 2 central reference labs founded.

As different HPV genotypes have a different oncogenic risk profile, extended or complete genotyping would help personalised risk-based screening approach with less health care costs, less harms and a bigger net benefit. Extended genotyping allows to give a better prediction for patient’s risk for developing precancer and cancer. As our study results indicate, having several hrHPV subtypes increases the probability of worse cytology, and also younger age. In addition to HPV subtypes and age, other factors might play a role in developing cervical cancer, and further research is needed from that aspect.

Prevalence of different HPV genotypes in Estonia shows the huge potential of reducing the HPV related cancer burden with the help of HPV vaccination programme started in 2018.

Footnotes

Acknowledgements

The authors would like to thank all the colleagues in the Estonian Cancer Screening Registry and in labs for data and all women who attended screening in 2021

ORCID iD

Veerus Piret

Ethical Considerations

This study was approved by the Research Ethics Committee of the University of Tartu (371/T-4, 21.11.2022).

Consent to Participate

The study used registry data for which no informed consent is needed.

Author Contributions

PV and KI designed the study, DE obtained the data, DE and KI analysed the data, all authors contributed to data interpretation and drafting the paper.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The study was funded by Estonian Research Council grant PRG2543. The funding body had no role in study design, data collection and analysis, or drafting the paper.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Data Availability Statement

Data can be provided upon request.*

Appendix

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