Cervical cancer screening improvements with self- sampling during the COVID-19 pandemic

BackgroundAt the onset of the COVID-19 pandemic cervical screening in the capital region of Sweden was cancelled for several months. A series of measures to preserve and improve the cervical screening under the circumstances were instituted, including a switch to screening with HPV self-sampling to enable screening in compliance with social distancing recommendations.MethodsWe describe the major changes implemented, which were i) nationwide implementation of HPV screening ii) switch to primary self-sampling instead of clinician sampling iii) implementation of HPV screening in all screening ages and iv) combined HPV vaccination and HPV screening in the cervical screening program.ResultsA temporary government regulation allowed primary self-sampling with HPV screening in all ages. In the Stockholm region, 330,000 self-sampling kits were sent to the home address of screening-eligible women, instead of an invitation to clinician sampling. A dramatic increase in population test coverage was seen (from 75% to 85% in just one year). In addition, a national campaign for faster elimination of cervical cancer with concomitant screening and vaccination for women in ages 23- 28 was launched.ConclusionsThe COVID-19 pandemic necessitated major changes in the cervical cancer preventive strategies, where it can already be concluded that the strategy with organised primary self-sampling for HPV has resulted in a major improvement of population test-coverage.FundingFunded by the Swedish Association 44 of Local Authorities and Regions, the Swedish Cancer Society, the European Unions Horizon 2020 Research and Innovation Program, the Swedish government and the Stockholm county.


Introduction
Prior to the COVID-19 pandemic outbreak in spring 2020, the Swedish cervical cancer prevention efforts consisted of invitations for screening at maternity clinics at an interval of 3-7 years.The National Board of Health and Welfare decided in 2015 that screening of 30-70year-old women should primarily be performed with an HPV-test and screening of 23-29year-old women with cytology (1).However, 5 years later when surveyed during the autumn of the pandemic, 5/21 regions in Sweden had still not implemented the national program (https://cancercentrum.se/samverkan/vara-uppdrag/prevention-och-tidigupptackt/gynekologisk-cellprovskontroll/vardprogram/status-for-inforandet/).Self-sampling targeting long-term non-attenders as a method to increase population coverage was recommended but was rarely used (2).There was school-based vaccination of both girls and boys (with high population coverage) (3) but no consideration of strategies for an even faster strategy to eliminate cervical cancer by concomitant screening and vaccination of young women (4).Although HPV-testing has been shown to have higher sensitivity in all age groups and higher specificity for women aged 30 or older compared to cytology-based screening, it was previously not recommended below 30 years of age largely because of the high prevalence of HPV infections, most of which will be cleared without causing cellular lesions or cancer, leading to overdiagnosis and overtreatment (5)(6)(7).However, an increasing proportion of young women that are entering the screening program have been vaccinated, resulting in lower HPV prevalences and lower predictive values of screening (8).Cellular abnormalities among young, vaccinated women are still seen, but typically contain only nonprogressive HPV types (9).
In April of 2020 all non-emergency health care was stopped in the capital region of Sweden because of a severe COVID-19 outbreak.Consequently 192,000 cervical cancer screening invitations with appointments were cancelled.In June the same year, the screening programme was allowed to restart but the midwife clinics could not be used for screening as usual, to avoid crowding.The Swedish National Board of Health and Welfare enacted a temporary regulation that allowed for self-sampling instead of clinician-based sampling.It is well known that when self-samples are analyzed using an HPV-assay based on polymerase chain reaction, the sensitivity is not inferior to samples taken by medically trained staff (10) and that self-sampling can be used to increase population coverage of screening, with improved attendance among under-screened and hard-to-reach women (11,12).

Study population and data collection
The data in this report derives from publicly available data on new Swedish regulations and strategies used during the pandemic (major official websites www.socialstyrelsen.seand www.regeringen.se).Results on population coverage and number of screening invitations/self-sampling kits sent are derived from the website of the Swedish National Cervical Screening Registry of Sweden (www.nkcx.se).The registry collects all data on cervical screenings and invitations in Sweden and compares the data to the population registry to calculate the population coverage of screening (13). .

Results
The number of cervical screening invitations sent per month in the Stockholm region during 2019 and 2020 is shown in figure 1.The formal decision to cancel all screening was effective April-June 2020, during which time there was a severe COVID-19 outbreak in the Stockholm region (14).When screening was re-initiated in the second half of 2020, only a limited number of invitations was allowed per screening station in order to avoid crowding (Figure 1).
Women invited for their first cervical screen and women due for follow-up were invited to clinician sampling.Clinician-based sampling was also recommended for women who were pregnant when they received their invitation to self-sampling.In March 2021, the screening program launched primary self-sampling as the prime screening modality.Self-sampling kits were mailed to all eligible women (direct send instead of invitation to maternity care clinicno requirement of having to order the kit).A detailed description of the self-sampling kits and their use can be found in Elfström et al. (15).
The organised screening program is based on first generating a list of eligible women who i) are resident in the catchment area (in this case the greater Stockholm region, with about 2 million resident inhabitants) ii) did not take a cervical test during the recommended agespecific screening interval (3 years 23-49 years of age, 7 years 50-70 years of age).This is assessed by importing of files with tests performed from all laboratories (both public and private) in the region and comparing the sampling dates and the personal identification numbers with the population registry of resident women iii) checking that they did not opt out of the screening program.This is not common, but out of the 732,276 resident women in the eligible target ages, 2,655 women (0,4%) had opted out of the program.In the switch that was implemented in February 2021, the previous policy of sending an invitation letter with an appointment time for cervical screening at a local Maternity Care clinic was replaced by sending of a self-sampling kit (including instructions and a pre-paid return envelope).During .2021, approximately 320,000 self-sampling kits were mailed.There was an increase in the population coverage of the cervical screening program, from 66% to 70% (Table 1).The improvement was particularly strong among women younger than 50 years of age and the population test coverage levels approached the test coverage levels in the year before the Covid19 outbreak when the program was cancelled (Table 1).
As self-sampling can not be used for cytology, only for HPV testing, the need to use selfsampling promoted a change to more widespread use of HPV testing.Although HPV testing had been mandated from age 30 and upwards already in 2015, in 2020 there were still 5 counties that did not use it.This changed and since autumn 2021 all counties in Sweden now use primary HPV screening.In the age groups below 30, HPV screening had not previously been recommended because of concerns about over-screening in an age where HPV infections were common.However, HPV prevalences are dropping because of vaccination and the emergency interim guidelines had now allowed HPV screening in all ages.
After the pandemic, permanent regulations were issued that came into effect on 2022-07-01.
These allow choice between primary self-sampling or sampling by a clinician and have also changed the age for HPV screening to be mandated between 23-70 years of age.In other words, the changes that were required because of the pandemic have resulted in that huge and permanent improvements could be implemented.

Launch of an even faster cervical cancer elimination campaign
The EVEN FASTER concept for rapid cervical cancer elimination is based on concomitant HPV vaccination and HPV screening targeting the age groups where the HPV infection is spread (have a reproductive rate >1) (4).HPV vaccination without concomitant testing is most effective among subjects before sexual debut, as they are HPV negative and the vaccine does not prevent infections that have already occurred (15).However, among women after sexual .debut who test HPV negative, the vaccine is equally effective as among subjects before sexual debut (16).By concomitant vaccination and HPV screening, HPV negative women will reap the full benefit of protection by vaccination and the HPV-positive women can be followed up as usual in the screening program (and are thus also protected against cervical cancer).
Although the first version of the concept of concomitant screening was published 7 years ago (17), there had been no consideration of whether to actually implement it.
After the acute phase of the epidemic, the setting changed.There was a large screening deficit and multiple strategies were needed in order to ensure that it could be managed without adverse effects for the women.Also, very effective mass vaccination campaigns against COVID-19 had been successfully launched and the switch to self-sampling resulted in that Maternity Care Clinics were interested in advancing their offer for in-person visits by providing both vaccination and screening to women coming for their first screening visit.
It is expected that if there is a strong reduction in the circulation of cancer-causing HPVtypes, the screening and follow-up efforts can be concentrated to those few women who still test positive for oncogenic HPV types thus greatly improving the ability to cope with the screening deficit and enabling Sweden to faster reach the WHO target of elimination of cervical cancer. .

Discussion
A large COVID-19 outbreak in the Stockholm region necessitated concentration of health care to emergency care and cancer screening was cancelled.We describe that the major measures taken to mitigate the screening deficit (organized primary self-sampling and an even faster campaign with concomitant screening and vaccination) resulted in several important and lasting improvements of the cervical cancer prevention program in Sweden.
The roll-out of primary self-sampling was done in the context of routine screening which means that decisions were made consecutively and the program was adapted as needed to meet the changing dynamics of the pandemic.Therefore, this analysis of the response was completed post-hoc.Given that Sweden has a comprehensive registry of all invitations (including mailing of self-sampling materials) and all cervical tests performed in the country, it was possible to perform a detailed description and evaluation of the switch retrospectively.
The national even faster campaign with concomitant screening and vaccination was launched as a formal Phase IV trial with the protocol registered at clinicaltrials.govwhere everyone interested can read the details.
In the US there was a 94% reduction of cervical cancer screenings during the initial phase of the pandemic compared to the same period the previous years, and although the screening has partially recovered since then, the cervical cancer screening rates are still 10% below prepandemic levels (18).Likewise, in England a 43-91% drop per month of received screening samples was observed during the period April to June 2020 and by April 2021 there was still 6,4% fewer samples than expected (19).Thus, although there was a prompt re-initiation of screening through re-opening of screening services and catch-up screening during the period following the initial phase of the pandemic, the impact of the disruption was significant.This contrasts with our findings where the disruption was used as an opportunity to advance the .program, with lasting improvements already materializing as a greatly improved screening coverage, lower costs of sample taking and increased use of HPV vaccines.
Self-sampling in cervical screening is well known to improve participation among women who seldom or never attended screening (20).The most likely explanation for the large increase in population coverage seen is that the sending of self-sampling kits resulted in improved attendance in particular among previously non-attending women.
As the cancellation of non-emergency healthcare also involved cancelling of follow-up and treatment of newly-detected screen-positive women, it has been speculated that a rise in cervical cancer would result (19,21).We could, however, not see any such effect, probably because non-emergency healthcare was allowed again in June 2020 after a less than 3 months disruption.
In summary, the major COVID-19 outbreak necessitated several emergency changes to the cervical screening program.These have resulted in several major and lasting improvements of the cervical cancer prevention strategy that are likely to promote an accelerated eliminate of HPV and cervical cancer.The funding agencies have had no role in the design, execution, or interpretation of the study or in the decision to submit for publication.

Competing interests
None of the authors have any competing interests to declare.   .
The work of the Swedish National Cervical Screening registry was supported by the Swedish Association of Local Authorities and Regions and the Swedish Cancer Society (20 1199 UsF 02 H).Miriam Elfström and Joakim Dillner are supported by the European Union's Horizon 2020 Research and Innovation Program, RISCC under grant agreement No. 847845.The Swedish even faster campaign is supported by the Swedish government and by the Stockholm county.

FiguresFigure 1 .
Figures Figure 1.Number of invitations to cervical cancer screening in Stockholm by month and year.