Cervical cancer mortality trend in Montenegro—1990–2018

Abstract

Introduction

Cervical cancer is the fourth leading cause of cancer-related deaths in women, resulting in an estimated 350,000 deaths worldwide in 2022 [1]. It is the primary cause of cancer-related deaths in 37 countries, particularly in sub-Saharan Africa, Melanesia, South America, and Southeast Asia [1, 2]. In Europe, it ranks eleventh as a cause of death from tumours and second among younger women [3]. The mortality rate of cervical cancer is notably higher in developing countries than in developed ones [4].

Many risk factors associated with the development of cervical cancer can be prevented. These factors include human papillomavirus (HPV) infection, multiple sexual partners, smoking, chlamydia infection, prolonged use of oral contraceptives, young age at the time of first full-term pregnancy, low economic status, and low consumption of fruits and vegetables [3–5]. Human papillomavirus is the most important individual primary cause of cervical cancer development [3].

The burden of cervical cancer can be modified by public health preventive strategies [3, 5–7]. Immunization against HPV is considered the most effective method for primary prevention, and screening programmes for cervical cancer are considered secondary prevention [5–7].

Currently, the World Health Organization (WHO) recommends administering two doses of the vaccine to girls aged 9–13 years as the most effective preventive measure [8, 9]. For women aged 30–49 years, screening methods include visual examination with acetic acid in low-resource settings, Papanicolaou test (cervical cytology) every 3–5 years, or HPV testing every 5 years along with prompt and effective treatment of precancerous lesions [8, 9]. According to the 2020 American Cancer Society guidelines, women should initiate cervical cancer screening at age 25 years and undergo primary HPV testing every 5 years until they reach 65 years of age [10].

The impact of HPV immunization on cervical cancer rates is expected to become evident 20–30 years after the start of the programme, as it takes ∼20 years for the target age group to develop cervical cancer after infection [8]. Any reduction in mortality was likely to be observed 10 years later [11]. The optimal time interval for detecting improvements in terms of incidence and mortality reduction after screening has not yet been established [12, 13]. The wide variety of screening target groups makes research aggravating [13].

In 2018, the WHO Director-General urged global action to eliminate cervical cancer worldwide (≤4 per 100 000 women) through a three-pronged strategy: vaccinating 90% of girls up to 15 years of age, screening 70% of women twice between ages 35 and 45, and treating at least 90% of all precancerous lesions detected during screening [14]. The WHO's global strategy to accelerate the elimination of cervical cancer, launched in 2020, aims for ‘90-70-90 by 2030’, with 194 countries committed to this goal. Vaccination, screening, and treatment are essential for achieving this triple intervention [15, 16]. In 2020, the WHO called on all countries to mobilize resources to expedite the elimination of cervical cancer and address public health concerns [17].

The initial edition of the European guidelines for early detection of cervical cancer was released in 1993 [18]. Following the recommendations of the European Council [19], several Southeast European countries initiated programmes for the early detection of cervical cancer between 2004 and 2013 [20]. Aligned with the global effort to combat this disease, Montenegro implemented the Cervical Cancer Early Detection Programme in 2011 [21], in line with the Strategy for the Prevention and Control of Non-Communicable Diseases [22], the National Program for Cancer Control guidelines [23], and EU recommendations [24] (2003/878/EC) directive dated 02.12.2003 (2003/878/EC). Cervical cancer screening commenced in Montenegro on July 18, 2016, in the municipality of Podgorica. The screening initially targeted women registered with specific gynaecologists in the 30–34 age group. As of February 1, 2018, screening activities have been extended nationwide, and as of February 1, 2019, the target group has been expanded to women between 30 and 42 years of age, who are registered with selected gynaecologists. According to the recommendations of the European [25] and WHO guidelines [26], the primary screening test involves the detection of HPV DNA in cervical smears. Each screening cycle spans 5 years.

The objective of Montenegro's national programme for cervical cancer prevention was to achieve a 50% reduction in cervical cancer mortality among women within 10 years from the programme's inception [22]. It is currently unclear whether this target has been met. Analysing trends can provide valuable insights into epidemiological patterns and help monitor the effectiveness of preventive strategies [27].

This study aimed to assess the mortality trends of cervical cancer in Montenegro from 1990 to 2018 and identify the impact of preventive measures on mortality rates associated with cervical cancer.

Methods

Study population/data sources

The data concerning cervical cancer mortality in Montenegro from 1990 to 2018 were collected. Cervical cancer was identified using the International Classification of Diseases code 180 from the 9th edition and code C53 from the 10th edition [28]. The data sources until 2009 were the State Statistical Office (unpublished data until 1999), and for the period 1999–2009 published in the statistical yearbooks of the Institute for Public Health of Montenegro [29]. For the period after 2009, the data source on causes of death is the Institute for Public Health [30]. Population data were sourced from the Statistical Office of Montenegro. Mortality rates were age-standardized to the World Standard Population [25] for estimating both the overall and age-specific trends.

Statistical analyses

The joinpoint regression model was used to identify significant changes in the linear time trend and find joinpoints if exist. These models also offered insights into the Estimated Annual Percentage Change and the average annual percentage change (AAPC) of cervical cancer mortality rates. Analyses were performed using the Joinpoint Software, version 5.0. 2 May 2023 from the Surveillance Research Program of the US National Cancer Institute [31]. The Grid-search method was chosen for the analysis. The minimum number of observations for points from the end of the series to the first joinpoint was established as 3 and between two joinpoints as 4. The number of joinpoints was set between 0 and 5. The permutation test facilitated the selection of the most fitting joinpoint model with an overall significance level of 0.05 [32]. In addition to the joinpoint regression analysis, both linear and Poisson regressions were applied using Statistical Software for Social Sciences SPSS 26 (IBM Corp., Armonk, NY, USA). Ethical approval and consent were not required for this study as it was based on publicly available data.

Results

In Montenegro, in the period from to 1990–2018, a total of 438 women died of cervical cancer. The average number of deaths per year for the observed period was 15.1, and the average age-standardized rate was 3.4/100 000 inhabitants in Montenegro (Table 1). Cervical cancer ranks 10th among all causes of cancer-related death, and sixth among women. Joinpoint regression revealed a statistically significant increase in rates by an average of 2.6% per year [AAPC (95%CI) = 2.6 (1.3–3.8); P < .001] for the period from to 1990–2018 (Table 1, Fig. 1). Joinpoint regression indicated that the number of cases of death from cervical cancer increased statistically significantly, on average annually by 3.5% [AAPC (95%CI) = 3.5 (2.2–4.7); P < .001] for the overall level (Table 1, Fig. 2); 3.4% [AAPC (95%CI) = 3.4 (1.2–5.6); P = .004] for age group 45–54, 4.2% [AAPC (95%CI) = 4.2 (1.9–6.4); P = .001] for the age group 55–64 and 4.0% [AAPC (95%CI) = 4.0 (1.1–6.9); P = .008] for the age group 75–84 (Table 1). Joinpoint regression did not reveal points in time where there was a significant reversal in the cervical cancer mortality trend.

Figure 1.

Joinpoint regression analysis of cervical cancer mortality rate in Montenegro from 1990 to 2018. APC-Annual Percentage Change, *APC was significantly different from zero P < .05.

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Figure 2.

Joinpoint regression analysis of cervical cancer mortality death cases in Montenegro from 1990 to 2018. APC-annual percentage change, *APC was significantly different from zero P < .05

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Linear regression confirmed similar changes in the movement of rates at the overall level [β (95%CI) = 0.085 (0.042–0.128); P < .001], revealing a statistically significant increase in rates in age groups 45–54 [β (95%CI) = 0.398 (0.164–0.632); P = .002] and 55–64 [β (95% CI) = 0.368 (0.077–0.659); P = .015] (Table 1).

Poisson regression confirmed an increase in the number of deaths at the overall level [β (95%CI) = 0.034 (0.023–0.046); P < .001], age groups 45–54 [β (95%CI) = 0.048 (0.025–0.070); P < .001], 55–64 [β (95%CI) = 0.046 (0.024–0.068); P < .001] and 75–84 [β (95%CI) = 0.054(0.016–0.092); P = .005] (Table 1).

Among the women who died from a malignant tumour of the cervix, the majority were aged 55–64 (28.3%), then aged 45–54 (27.6%) and aged 65–74 (17.4%) (Fig. 3).

Figure 3.

Distribution of cervical cancer mortality by age groups in Montenegro, 1990–2018.

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Discussion

The main finding of this study

This study was the first to examine the trends of mortality from cervical cancer in Montenegro. Over the past 30 years, there has been a notable increase in mortality from this type of cancer. Both the rate and total number of deaths showed an upward trend in Montenegro.

What is already known on this topic

These results do not correspond with global findings, where mortality from cervical cancer is decreasing [4, 32].

Cervical cancer poses a significant health threat in East Asia and southern sub-Saharan Africa, contributing to the highest number of deaths globally [32]. East Africa had the highest mortality rate at 30.0/100 000, followed by West Africa at 23.0/100 000, Central Africa at 21.1/100 000, South Africa at 20.0/100 000, and Melanesia at 19.0/100 000. Asia accounted for the highest number of deaths in 2018, with 168 411 cases, representing 54.1% of the total deaths, whereas Africa had the highest number of countries with high mortality [4]. In 2019, the highest death rates from cervical cancer were reported in Kiribati (39.95/100 000), Lesotho (21.10/100 000), and Guinea (18.27/100 000) [32].

Generally, mortality rates are higher in countries with a lower human development index (HDI) (23.0/100 000) than in those with a very high HDI (2.7/100 000) [4].

In Montenegro, the average death rate is 3.47 per 100 000, which is twice lower than the global rate (6.9 per 100 000) and significantly lower than the highest rates recorded in neighbouring countries such as Romania (8.5) and Serbia (6.7) and higher than the lowest rate recorded in regional countries such as Slovenia 82,2/100,00, Croatia (2.6/100 000), Macedonia (2,4/100 000) [33].

Specifically, in Montenegro, Joinpoint regression analysis showed a statistically significant increase in rates by an average of 2.6% per year from 1990 to 2018. Conversely, at the global level, the rates decreased by an average of −0.96% during the same period. Overall, mortality rates have declined in most parts of the world in recent decades, with the most substantial decreases observed in Central Latin America (–2.52%), tropical Latin America (–1.96%), and Western Europe (–1.82%) [32]. In individual countries, the Maldives recorded the largest decrease in age-adjusted mortality rates from cervical cancer at −4.37%, followed by Singapore at −4.30%, and Taiwan (China) at −3.83%. Conversely, the largest increase in age-standardized mortality rates was observed in Lesotho (3.32%), followed by Zimbabwe (1.80%), and Bulgaria (1.17%) [32].

The cervical cancer mortality rates vary significantly across European countries. Eastern Europe has notably higher mortality rates (6.1/100 000) than Western Europe (2.1/100 000) [3]. Most European countries are experiencing a decline in mortality rates, with steeper decreases in the European Union and Western Europe. However, in countries with lower screening coverage, such as Montenegro, located in the Balkans and Southeastern Europe, cervical cancer remains a significant public health concern [33].

While Montenegro saw an increase in mortality rates (+2.6% from to 1990–2018), most countries in Southeastern Europe have observed a decline in cervical cancer mortality for the similar period (1990–2017). The most significant reductions occurred in Poland (−2.3% from to 1990–2016), the Czech Republic (−2.3% from to 1990–2017), and Slovenia (−2.7% from to 1990–2015). Serbia (−0.4% from to 1998–2016) and Croatia (−0.5% from to 1990–2016) also saw decreases, while Bulgaria (+1.1% from to 1990–2015) and Latvia (+1.7% from to 1990–2015) experienced increases [33].

The mortality rates in Montenegro are on the rise in the 45–54 and 55–64 age groups as well as in the number of cases within the 45–54, 55–64, and 75–84 age groups. Among women who succumbed to cervical cancer, the majority were aged 55–64 (28.3%), followed by those aged 45–54 (27.6%) and 65–74 (17.4%). In Southeast Europe, countries where the mortality from cervical cancer has decreased across all age groups are the Czech Republic, Estonia, Slovenia, Lithuania, Moldova, Macedonia, Serbia, Poland, and Romania. However, in Latvia, cervical cancer mortality has increased across all age groups [33].

The variations in the trends of death both in the world [32] and in Europe and the region [33] are large. HDI and poverty rates have been shown to account for >52% of the global variance in mortality [34]. For every 0.2 unit increase in HDI, the risk of mortality from cervical cancer decreased by 33% [34]. People with low socioeconomic status have poor access to examinations, immunizations, and timely diagnosis and treatment of cervical cancer [4].

It was found that the burden of cervical cancer is positively associated with a higher prevalence of alcohol consumption [4], in addition to the carcinogenic effect of alcohol, the risky behaviour of alcohol consumers after consuming alcohol, reduced health awareness, and poor adherence to health advice and/or the use of preventive health measures services (e.g. condoms, screening, and immunization) [35]. Accordingly, reducing alcohol consumption in disadvantaged groups is recommended to achieve a significant reduction in the burden of cervical cancer [4].

Scientists attribute changes in mortality from cervical cancer to the wide application of primary and secondary prevention measures [36, 37]. Research on the impact of preventive measures on mortality is difficult due to large differences in the distribution of preventive measures as well as in the target groups [17]. These measures are not implemented equally across countries and within them [7]. Although further research is needed to confirm the association with reduced incidence and mortality [17], it has been observed that countries with lower income and higher mortality rates [4] also have lower coverage of primary prevention measures. Less than 30% of low- and middle-income countries have implemented national HPV vaccination programmes, compared with over 80% of high-income countries as of 2020 [7]. Logistics present a significant barrier to HPV vaccination in most low-income and middle-income countries [5, 36].

In Europe, the year of HPV immunization initiation varies. The countries that started immunization the earliest were Belgium, France, and Germany, which implemented universal HPV immunization programmes in 2007 [5, 37].

There was also variability in the year of initiation and population coverage of national screening programs: Denmark (implementation year: 2006, call coverage: 73.7%), Estonia (2006, 77.1%), Finland (1963, 98%), and Italy (1989, 66.8%), Lithuania (2004, 78.3%), the Netherlands (1970, 95.2%), Poland (2006, 97.7%), Sweden (1967, 80.7%), and the UK (1988, 100.8%) [17].

Recent research [17] on the impact of cervical cancer screening programmes in Europe revealed that countries with long-standing, well-established programs and high coverage of the invited target population have experienced a greater reduction in cervical cancer mortality. Specifically, countries that implemented national screening programs before 2009, with coverage of the invited target population exceeding 58%, saw a statistically significant decrease in cervical cancer mortality compared to those with less comprehensive screening coverage during the period 1985–2014. Notably, Great Britain and Hungary saw the greatest decline in mortality [17]. Additional studies support the positive impact of national screening programs [36–38], particularly in countries with high screening coverage and uptake. Screening coverage and mortality rates vary between East Central and Western Europe, with generally lower screening coverage and higher mortality rates in East-Central Europe [3].

Of the countries in the region, only Slovenia exceeded the coverage of 60%, and this country recorded the lowest rates (2.2/100 000) and the largest reduction in mortality (−2.7%, 1990–2015). Slovenia was the only country in the region that surpassed a 60% coverage threshold of 58%. It recorded the lowest rates at 2.2/100 000 and the largest reduction in mortality at −2.7% from 1990 to 2015 [32].

Despite the challenges faced by all low- and middle-income countries, including until recently Montenegro, it is believed that the combination of screening and vaccination will lead to a reduction in mortality [36, 37].

Currently, high hope is placed on protective HPV vaccines. A vaccine, along with well-organized early detection programmes for cervical cancer, may transform this disease into a non-public health issue worldwide [36].

Vaccination against HPV infection started for the first time in Montenegro on 26 September 2022 [39]. Organized colposcopic examinations are conducted consistently in both public health institutions and the private sector at all levels of care in Montenegro. Since its inception, the implementation of the screening programme has encountered several challenges. In Montenegro, low health awareness among women and irregular gynaecological examinations result in missed opportunities for early detection through highly reliable tests [39]. The screening programme lacks legally defined mandatory participation from women, leading to lower coverage percentages due to variances in teams' abilities to motivate female patients. Additionally, the involvement of Health Centre teams in the screening programme, combined with their regular duties, has resulted in longer working hours and a potential lack of motivation to engage with patients, attributed to staff shortages. The two-year suspension of cervical screening due to the coronavirus pandemic has further complicated the achievement of the Programme for Early Detection of Cervical Cancer goal of reducing mortality from this tumour in Montenegro by 50% since the programme's implementation.

To enhance screening uptake, as invitational coverage is a crucial factor in the declining trend in cervical cancer mortality, scientists recommend addressing social and structural barriers to cervical cancer screening with cultural sensitivity [17]. The scientific community emphasizes the importance of prioritizing prevention as an integral part of controlling cervical cancer, along with simultaneously implementing educational campaigns targeting the younger female population [4].

What this study adds

This analysis highlights a growing trend of mortality from cervical cancer in Montenegro, underscoring the need for additional research into the causes of this serious public health concern.

The findings also highlight the need for public health interventions to prevent and manage this disease, particularly among middle-aged women who have experienced a significant increase in mortality rates. Future efforts in Montenegro have to be pointed to the effectiveness of cervical cancer screening.

Limitations of the study

This study has several limitations. The quality of data on the cause of death depends of the quality data presented in Death certificates and appropriate coding. Two doctors were included in coding during the examined period, one before 2009 and the second after this period. Also, we used two different classification systems, ICD 9 and ICD 10. As there is no good infrastructure of mortality statistics, which is a general problem in developing countries, there is the probability of underreporting, accuracy, and completeness of death cases.

Despite the limitation we used the best evidence from national data and the main strength of this study is that it is the first research of cervical cancer mortality trend ever conducted in Montenegro. Data presented in our research might be the basis for father future strategies and preventive activities. We suggested to policymakers to make future decisions related to the control of this tumour according to results and the most burdened and most vulnerable group by mortality.

Author contributions

Mirjana Nedović Vuković: Conception and design; Final approval of the version to be published; Drafting the article or revising it critically for important intellectual content. Marina Jakšić: Drafting the article or revising it critically for important intellectual content. Snežana Barjaktarović Labović, Ljiljana Vučković, and Adrijana Vujović: Drafting the article or revising it critically for important intellectual content.

Conflict of interest: None declared.

Funding

This study was not supported by any sponsor or funder.

Data availability

This was a secondary analysis of publicly available data.

References