SARS-CoV-2 infection during pregnancy and perinatal outcomes in Estonia in 2020 and 2021: A register-based study.

INTRODUCTION: Data from different countries show partly controversial impact of SARS-CoV-2 infection on pregnancy outcomes. A nationwide register-based study was conducted in Estonia to assess the impact of SARS-CoV-2 infection at any time during pregnancy on stillbirth, perinatal mortality, Apgar score at 5 minutes, cesarean section rates, rates of preterm birth and preeclampsia. MATERIAL AND METHODS: Data on all newborns and their mothers were obtained from the Estonian Medical Birth Registry, and data on SARS-CoV-2 testing dates, test results and vaccination dates against SARS-CoV-2 from the Estonian Health Information System. Altogether, 26 211 births in 2020 and 2021 in Estonia were included. All analyses were performed per newborn. Odds ratios with 95% confidence intervals (CI) were analyzed for all outcomes, adjusted for mother's place of residence, body mass index, age of mother at delivery and hypertension and for all the aforementioned variables together with mother's vaccination status using data from 2021 when vaccinations against SARS-CoV-2 became available. For studying the effect of a positive SARS-CoV-2 test during pregnancy on preeclampsia, hypertension was omitted from the models to avoid overadjustment. RESULTS: SARS-CoV-2 infection during pregnancy was associated with an increased risk of stillbirth (adjusted odds ratio [aOR] 2.81; 95% CI 1.37-5.74) and perinatal mortality (aOR 2.34; 95% CI 1.20-4.56) but not with a lower Apgar score at 5 minutes, higher risk of cesarean section, preeclampsia or preterm birth. Vaccination slightly decreased the impact of SARS-CoV-2 infection during pregnancy on perinatal mortality. CONCLUSIONS: A positive SARS-CoV-2 test during pregnancy was associated with higher rates of stillbirth and perinatal mortality in Estonia but was not associated with change in preeclampsia, cesarean section or preterm birth rates.

Cesarean section trends from 1992 to 2016 in Estonia and Finland: A registry-based study.

INTRODUCTION: The number of cesarean sections (CSs) has grown steadily, but the underlying factors driving this increase remain unknown. Data from Medical Birth Registries were retrieved to analyze CS trends in Estonia and Finland during the period 1992-2016. MATERIAL AND METHODS: All births in Estonia (n = 356 063) and Finland (n = 1 437 234) were included. The differences between Estonia and Finland in five-year time periods for the total CS rate, and rates in Robson 1, 2, and 5 groups (R1, R2, R5) were analyzed by logistic regression. Total CS rates were adjusted for birthweight, parity, previous CS, gestational age, singleton pregnancy, cephalic position, induction, mother's age. R1; R2; R5 rates were adjusted for birthweight and mother's age. RESULTS: In Estonia, the proportion of CSs increased from 6.5% to 21.0% and in Finland from 15.1% to 16.8% between 1992 and 2016. In 2016, Estonia and Finland remained within the target value with their R1 + 2 (Estonia 18%; Finland 16%) and R5 (Estonia 59%; Finland 42%) values. CONCLUSIONS: Comparing Robson groups in different countries can shed light on divergent CS rates and to improve the quality of perinatal and obstetric care.

Cervical cancer screening history among women diagnosed with cervical cancer in Estonia 2017-18.

BACKGROUND: Despite the national cervical cancer screening programme launched in 2006, Estonia has one of the highest cervical cancer incidence rates in Europe. While the overall coverage of cervical cytology is high, the factors related to cancer screening history prior to cancer diagnosis need to be studied. METHODS: In this study, we aimed to examine the 10-year screening history of women diagnosed with cervical cancer in Estonia in 2017-18, using data collected from laboratory reports from 2007 to 2018. From each report, we extracted information on the date and result of cytology and on the laboratory where the sample was assessed. We analysed these data across cancer histology, the time interval between the last test result and cancer diagnosis and the laboratory type (local or regional). RESULTS: Among 319 women with cervical cancer, 181 (56.7%) did not have any cytology reports available. Among 138 women with at least one cytology, 60% had 1-3, 24% 4-6 and 16% ≥7 tests (mean 3.7) before cancer. In 78% of women, the last test was performed less than 5 years before cancer diagnosis and 62% of these tests did not report any abnormalities. The last cytology results differed significantly between the regional and local laboratories (P = 0.028). CONCLUSION: Women received the cervical cancer diagnosis in Estonia despite having several screening tests 10 years prior to the diagnosis. The proportion of cytology tests without any abnormalities less than 5 years before the diagnosis was worryingly high and needs further investigation together with the difference between laboratory types.

Quality Assessment of Cervical Cytology Practices in Estonia From 2007 to 2018.

BACKGROUND: Cervical cancer incidence and mortality in Estonia are among the highest in Europe, although the overall coverage with cervical cytology is high. This indicates potential issues with the quality of collection and/or laboratory evaluation of cervical cytology. OBJECTIVES: The aim of the retrospective observational study was to assess the quality of cervical cytology specimen collection, evaluation, and reporting using laboratory reports in Estonia. METHODS: The study included women with a cervical cancer diagnosis in 2017-2018. Cervical cytology and histology reports for these women in 2007-2018 were obtained from ten laboratories. We described the quality of cytology specimen collection and reporting of cytology results. Multivariate logistic regression was used to calculate odds ratios (OR) with 95% confidence intervals (CI) to identify factors associated with NILM as the last cervical cytology result within 5 or 2 years before the cervical cancer diagnosis. Also, we calculated cytology-histology correlation (CHC). RESULTS: We identified 503 cytology and 100 histology reports from 138 women. The laboratories differed greatly regarding human resources, work capacity and volume. Differences between local and regional laboratories were observed in reporting specimen adequacy (P < .001). We found that local laboratories had 3 times higher odds (OR = 2.95, 95% CI: 1.05-8.33) of reporting normal results 2 years before cancer diagnosis than regional laboratories. According to the CHC, 58.9% of pairs were in agreement. CONCLUSIONS: The study showed considerable heterogeneity and suboptimal performance of cervical cytology practices in Estonia, particularly at local laboratories. Efforts to improve laboratory quality assurance are crucial.

The potential of breast cancer screening in Europe.

Currently, all European countries offer some form of breast cancer screening. Nevertheless, disparities exist in the status of implementation, attendance and the extent of opportunistic screening. As a result, breast cancer screening has not yet reached its full potential. We examined how many breast cancer deaths could be prevented if all European countries would biennially screen all women aged 50 to 69 for breast cancer. We calculated the number of breast cancer deaths already prevented due to screening as well as the number of breast cancer deaths which could be additionally prevented if the total examination coverage (organised plus opportunistic) would reach 100%. The calculations are based on total examination coverage in women aged 50 to 69, the annual number of breast cancer deaths for women aged 50 to 74 and the maximal possible mortality reduction from breast cancer, assuming similar effectiveness of organised and opportunistic screening. The total examination coverage ranged from 49% (East), 62% (West), 64% (North) to 69% (South). Yearly 21 680 breast cancer deaths have already been prevented due to mammography screening. If all countries would reach 100% examination coverage, 12 434 additional breast cancer deaths could be prevented annually, with the biggest potential in Eastern Europe. With maximum coverage, 23% of their breast cancer deaths could be additionally prevented, while in Western Europe it could be 21%, in Southern Europe 15% and in Northern Europe 9%. Our study illustrates that by further optimising screening coverage, the number of breast cancer deaths in Europe can be lowered substantially.

Cervical cancer screening patterns among HIV-positive women in Estonia: a population-based retrospective cohort study.

BACKGROUND: The World Health Organisation (WHO) calls for the elimination of cervical cancer (CC) as a public health issue. To achieve elimination, efforts must be aligned and accelerated. Women living with HIV (WLWH) have excess risk for developing, and dying from, CC over the general population. Estimates of cervical cancer screening programme coverage in Eastern European countries that have experienced HIV epidemics since the early 2000's are scarce. METHOD: This population-based retrospective study uses a healthcare administrative database and follows cohorts of all WLWH in a ratio of 1:3 randomly matched (age, region) HIV negative women from 2009 to 2018. Annual and longitudinal (over the whole study period) coverage for cervical cancer screening (opportunistic, organised, HIV specific) and adjusted odds ratios (AORs) for longitudinal screening coverage predictors were estimated from 2009 to 2018. RESULTS: Among WLWH and HIV-negative women, the mean annual coverage with opportunistic screening was 61.45 and 65.59%; and organised screening was 20.4 and 28.7%, respectively (both: p < 0.00001). 19.01% (95% CI 18.05-19.97) HIV-negative and 13.9% (95% CI 12.35-15.45) WLWH were longitudinally covered with organised cervical cancer screening. Among WLWH, the mean annual HIV-specific cervical cancer screening coverage was 49.4, and 24.3% were longitudinally covered. Longitudinal coverage with HIV-specific cervical cancer screening was inversely associated with age, hepatitis C virus (HCV) co-infection (AOR 0.754, 95% CI 0.619, 0.916), not having insurance (AOR 0.331, 95% CI 0.264, 0.412), drug abuse (AOR 0.459, 95% CI 0.336, 0.618) and higher among those retained in HIV care (AOR 1.972, 95% CI 1.615, 2.410). Among HIV-negative women, longitudinal coverage with organised cervical cancer screening was inversely associated with residence in the region and higher among older women. CONCLUSIONS: Our results highlight unacceptably low coverage of cervical cancer screening of WLWH in Estonia. There is need for dedicated cervical cancer screening efforts for WLWH considering the high cancer risk and rate in the study population.

NordScreen - an interactive tool for presenting cervical cancer screening indicators in the Nordic countries.

Introduction: Quality assurance and improvement of cancer screening programs require up-to-date monitoring systems and evidence-based indicators. National quality reports exist but the definition and calculation of indicators vary making comparisons between countries difficult. The aim is to stimulate collaborative research and quality improvements in screening through freely available, comparable and regularly updated quality indicators. The project currently includes data on cervical cancer screening but population-based screening programs for breast cancer and colorectal cancer may be included in the future. Material and methods: Through a network of Nordic and Baltic screening managers, population-based individual screening data from each country were converted to standard format in each collaborative center, aggregated by the same R program script and then uploaded to the NordScreen online platform. Registry data included all cervical tests except for Finland where only tests based on invitation are included. Results: The NordScreen collaboration has so far collated standardized indicators based on 32.8 million screening tests from four Nordic countries and Estonia. Interactive comparison of test coverage and distribution of women by number of tests are currently possible online. In 2016, the test coverage within a time interval of 5.5 years in the age group 30-64 year-olds was between 78 and 84% in Iceland, Norway and Sweden whereas 70% in Finland. The application allows users to choose indicator specifications interactively. Conclusions: NordScreen is a pilot model for comparable, reliable and accessible cross-country comparisons of cancer screening. Comparability between countries is enhanced by a uniform data structure and standardized calculations. The comparison of coverage rates to national figures shows that the methods used nationally and in the NordScreen project produce similar results.

A case report and follow-up of the first live birth after heterotopic transplantation of cryopreserved ovarian tissue in Eastern Europe.

BACKGROUND: Ovarian insufficiency is a major concern for long-term cancer survivors. Although semen freezing is well established to preserve male fertility, the possibilities to secure post-cancer female fertility are mostly limited to oocyte or embryo freezing. These methods require time-consuming ovarian stimulation with or without in vitro fertilization (IVF) that evidently delays cancer therapy. Ovarian tissue cryopreservation and subsequent thawed tissue autotransplantation are considered the most promising alternative strategy for restoring the fertility of oncology patients, which has not yet received the full clinical acceptance. Therefore, all successful cases are needed to prove its reliability and safety. CASE PRESENTATION: Here we report a single case in Estonia, where a 28-year-old woman with malignant breast neoplasm had ovarian cortex cryopreserved before commencing gonadotoxic chemo- and radiotherapy. Two years after cancer therapy, the patient underwent heterotopic ovarian tissue transplantation into the lateral pelvic wall. The folliculogenesis was stimulated in the transplanted tissue by exogenous follicle-stimulating hormone and oocytes were collected under ultrasound guidance for IVF and embryo transfer. The healthy boy was born after full-term gestation in 2014, first in Eastern Europe. CONCLUSION: Despite many countries have reported the first implementation of the ovarian tissue freezing and transplantation protocols, the data is still limited on the effectiveness of heterotopic ovarian transplant techniques. Thus, all case reports of heterotopic ovarian tissue transplantation and long-term follow-ups to describe the children's health are valuable source of clinical experience.

Trends in cervical cancer incidence and survival in Estonia from 1995 to 2014.

BACKGROUND: Cervical cancer (CC) incidence in Estonia is the third highest in Europe, even though an organised nation-wide screening program has been in place since 2006. The aim of the study was to analyse the incidence and survival of CC in Estonia, focusing on age, morphology and stage at diagnosis. METHODS: Data from Estonian Cancer Registry were used to analyse age-standardized (world) and age-specific incidence for 1968-2014 rates. Joinpoint regression was used to estimate the annual percentage change (APC) for incidence trends. Age-period-cohort model was used to summarise time trends in terms of cohort and period effects. Relative survival ratios (RSR) were calculated for cases diagnosed in 1995-2014. Union for International Cancer Control version 7 of the TNM classification for malignant tumours was used to categorise stage. RESULTS: The age-standardized incidence of CC increased since 1980s at a rate of 0.8% per year. A significant increase was seen for all age groups except for 70+. The incidence of squamous cell carcinoma mimicked the overall trend, while adenocarcinoma showed increase since mid-1990s (APC 6.7). Age-period-cohort modelling showed strong cohort effects with the lowest risk for birth-cohorts born around 1940 and significantly increasing risks for successive cohorts born thereafter. No period effects were seen. The proportion of stage IV cases increased from 13% in 2005-2009 to 18% in 2010-2014. A significant increase was seen in the overall 5-year RSR from 1995 to 1999 to 2010-2014 (58% vs 66%). In 2010-2014, the 5-year RSRs ranged from 89% in women aged 15-39 to 41% in age group 70+. For stages I to IV, the respective RSRs were 98, 74, 57 and 22%. CONCLUSIONS: The inadequate uptake and insufficient quality of the Pap-smear based screening program has not brought along a decline in the incidence of CC in Estonia. Stage distribution has shifted towards later stages. New approaches are needed to prevent CC in Estonia.

Time Trends in Ovarian Cancer Survival in Estonia by Age and Stage.

OBJECTIVE: The objective of the study was to examine temporal trends in ovarian cancer (OC) survival in Estonia during 1995 to 2009 in relation to age and stage. MATERIALS AND METHODS: Estonian Cancer Registry data on all adult cases of primary OC diagnosed during 1995 to 2009 and followed up for vital status until 2014 were used to estimate relative survival ratios (RSRs). Cohort analysis was used to estimate 1-, 2-, and 5-year RSRs for patients diagnosed in 1995 to 1999, 2000 to 2004, and 2005 to 2009. Analysis was performed by age at diagnosis (<50; 50-59; 60-69; 70+ years) and stage (International Federation of Gynecology and Obstetrics 1988). RESULTS: Among 2296 women included in the study, the age-adjusted 5-year RSR improved from 27% in 1995 to 1999 to 38% in 2005 to 2009. Survival increase of 10% units from 1995 to 1999 to 2005 to 2009 was seen for women aged 50 to 59 and 60 to 69 years. Among younger and older women, the respective changes were smaller. In 1995 to 1999, the difference in survival between the youngest and oldest age groups was 41% units. This decreased over the study period to 37% units. From 1995 to 1999 to 2005 to 2009, the 5-year RSR increased from 82% to 91% for stage I patients; from 48% to 67% for stage II patients; from 25% to 35% for stage III patients; and from 11% to 16% for stage IV patients. CONCLUSIONS: The study showed an improvement of OC survival in Estonia in all age and stage groups, but particularly among younger women and those with early stage disease. Slower progress among older women is of great concern.

Preventable fractions of cervical cancer via effective screening in six Baltic, central, and eastern European countries 2017-40: a population-based study.

BACKGROUND: Cervical cancer incidence remains high in several Baltic, central, and eastern European (BCEE) countries, mainly as a result of a historical absence of effective screening programmes. As a catalyst for action, we aimed to estimate the number of women who could be spared from cervical cancer across six countries in the region during the next 25 years, if effective screening interventions were introduced. METHODS: In this population-based study, we applied age-period-cohort models with spline functions within a Bayesian framework to incidence data from six BCEE countries (Estonia, Latvia, Lithuania, Belarus, Bulgaria, and Russia) to develop projections of the future number of new cases of cervical cancer from 2017 to 2040 based on two future scenarios: continued absence of screening (scenario A) versus the introduction of effective screening from 2017 onwards (scenario B). The timespan of available data varied from 16 years in Bulgaria to 40 years in Estonia. Projected rates up to 2040 were obtained in scenario A by extrapolating cohort-specific trends, a marker of changing risk of human papillomavirus (HPV) infection, assuming a continued absence of effective screening in future years. Scenario B added the effect of gradual introduction of screening in each country, under the assumption period effects would be equivalent to the decreasing trend by calendar year seen in Denmark (our comparator country) since the progressive regional introduction of screening from the late 1960s. FINDINGS: According to scenario A, projected incidence rates will continue to increase substantially in many BCEE countries. Very high age-standardised rates of cervical cancer are predicted in Lithuania, Latvia, Belarus, and Estonia (up to 88 cases per 100 000). According to scenario B, the beneficial effects of effective screening will increase progressively over time, leading to a 50-60% reduction of the projected incidence rates by around 2040, resulting in the prevention of cervical cancer in 1500 women in Estonia and more than 150 000 women in Russia. The immediate launch of effective screening programmes could prevent almost 180 000 new cervical cancer diagnoses in a 25-year period in the six BCEE countries studied. INTERPRETATION: Based on our findings, there is a clear need to begin cervical screening in these six countries as soon as possible to reduce the high and increasing incidence of cervical cancer over the next decades. FUNDING: None.

Hysterectomy types in Estonia are still different from the Nordic countries.

OBJECTIVE: To describe hysterectomy rates in different age groups, indications and proportion of surgery types over time. DESIGN: Nationwide register-based study. SETTING: Estonia. POPULATION: Women who had hysterectomies for benign indications from 2004 to 2011. METHODS: For each case, diagnosis according to ICD-10, type of surgery according to Nordic Medico-Statistical Committee, age, and time of operation were retrieved from the Estonian Health Insurance Fund database. Mid-year female population statistics were obtained from Statistics Estonia. MAIN OUTCOME MEASURES: Rate of hysterectomies per 100 000 women, proportions of different operation types, and main indications for hysterectomies. RESULTS: The total number of hysterectomies was 12 336, with a yearly mean of 1542. The rate of hysterectomies per 100 000 women/year decreased between 2004 and 2011 from 239.1 to 204.9. The proportion of abdominal hysterectomies decreased from 86.0 to 56.1% and the proportion of laparoscopic hysterectomies increased from 6.3 to 34.7%, while the proportion of vaginal hysterectomies remained more or less stable (7.8-9.1%). Most hysterectomies (74.4%) occurred in the age group 35-54 years. The main indications for hysterectomies were leiomyoma (61.5%), female genital prolapse (9.0%) and endometriosis (8.8%). CONCLUSIONS: Population rates and indications for hysterectomies in Estonia were similar to those in most Nordic countries, but the proportion of abdominal hysterectomies was higher and that of vaginal hysterectomy lower. The rates of laparoscopic and vaginal hysterectomies should be increased.

Abortion trends from 1996 to 2011 in Estonia: special emphasis on repeat abortion.

BACKGROUND: The study aimed to describe the overall and age-specific trends of induced abortions from 1996 to 2011 with an emphasis on socio-demographic characteristics and contraceptive use of women having had repeat abortions in Estonia. METHODS: Data were retrieved from the Estonian Medical Birth and Abortion Registry and Statistics Estonia. Total induced abortion numbers, rates, ratios and age-specific rates are presented for 1996-2011. The percentage change in the number of repeat abortions within selected socio-demographic subgroups, contraception use and distribution of induced abortions among Estonians and non-Estonians for the first, second, third, fourth and subsequent abortions were calculated for the periods 1996-2003 and 2004-2011. RESULTS: Observed trends over the 16-year study period indicated a considerable decline in induced abortions with a reduction in abortion rate of 57.1%, which was mainly attributed to younger cohorts. The percentage of women undergoing repeat abortions fell steadily from 63.8% during 1996-2003 to 58.0% during 2004-2011. The percentage of women undergoing repeat abortions significantly decreased over the 16 years within all selected socio-demographic subgroups except among women with low educational attainment and students. Within each time period, a greater percentage of non-Estonians than Estonians underwent repeat abortions and obtained third and subsequent abortions. Most women did not use any contraceptive method prior to their first or subsequent abortion. CONCLUSION: A high percentage of women obtaining repeat abortions reflects a high historical abortion rate. If current trends continue, a rapid decline in repeat abortions may be predicted. To decrease the burden of sexual ill health, routine contraceptive counselling, as standard care in the abortion process, should be seriously addressed with an emphasis on those groups--non-Estonians, women with lower educational attainment, students and women with children--vulnerable with respect to repeat abortion.

Legislative regulation and ethical governance of medical research in different European Union countries.

OBJECTIVE: To obtain information about the similarities and differences in regulating different types of medical research in the European Union (EU). METHODS: Web searches were performed from September 2009 to January 2011. Notes on pre-determined topics were systematically taken down from the web pages. The analysis relied only on documents and reports available on the web, reflecting the situation at the end of 2010. RESULTS: In several countries, regulatory legislation applied only to clinical trials on drugs and medical devices, in other states various types of research were also regulated but by laws different from those concerning trials, and in many countries, some research areas were not controlled by legislation at all. In very few countries was all medical research handled similarly from a legal point of view. The number of research ethics committees (RECs) in a single country varied from one to 264. Their areas of responsibility, working principles and length of time to grant research permission varied as well as the rules for obtaining informed consent from vulnerable groups. In 10 EU countries, there was no appeal mechanism after a negative decision by an REC. The RECs were not accountable to any organisation in five EU countries. CONCLUSIONS: There is a need for a fundamental debate regarding whether and which kinds of changes are needed for the further harmonisation of medical research governance in the EU and how cross-country medical research could be facilitated in the future.

Varying ethics rules in clinical research and routine patient care--research ethics committee chairpersons' views in Finland.

BACKGROUND: To present empirical data on how the variation in regulating clinical research and patient care was perceived in Finland between 2009 and 2012. METHODS: Notes of interviews with 22 research ethics committee (REC) chairpersons were analyzed to identify whether differences in the regulation of clinical research and patient care were addressed. REC chairpersons' opinions on three imaginary cases of clinical research projects challenging current research ethics rules (vignettes) were requested with a questionnaire; 18 of the 22 interviewed chairpersons responded. RESULTS: Based on REC chairpersons' interviews, the differences between care and research regulation were not considered important issues in Finland. In the vignettes, REC chairpersons' assumptions on how their REC would decide varied in regard to allowing research without informed consent, while solutions that are not allowed by current law were even anticipated. Mostly, but not always, the chairpersons' own personal view agreed with their REC. CONCLUSIONS: The distinction between care and research regulation has not been publicly challenged by Finnish RECs, even though it is a challenge when research relevant to health care is carried out. There is a need for debate and changes in laws and practices.

Clinical research in Finland in 2002 and 2007: quantity and type.

BACKGROUND: Regardless of worries over clinical research and various initiatives to overcome problems, few quantitative data on the numbers and type of clinical research exist. This article aims to describe the volume and type of clinical research in 2002 and 2007 in Finland. METHODS: The research law in Finland requires all medical research to be submitted to regional ethics committees (RECs). Data from all new projects in 2002 and 2007 were collected from REC files and the characteristics of clinical projects (76% of all submissions) were analyzed. RESULTS: The number of clinical projects was large, but declining: 794 in 2002 and 762 in 2007. Drug research (mainly trials) represented 29% and 34% of the clinical projects; their total number had not declined, but those without a commercial sponsor had. The number of different principal investigators was large (630 and 581). Most projects were observational, while an experimental design was used in 43% of projects. Multi-center studies were common. In half of the projects, the main funder was health care or was done as unpaid work; 31% had industry funding as the main source. There was a clear difference in the type of research by sponsorship. Industry-funded research was largely drug research, international multi-center studies, with randomized controlled or other experimental design. The findings for the two years were similar, but a university hospital as the main research site became less common between 2002 and 2007. CONCLUSIONS: Clinical research projects were common, but numbers are declining; research was largely funded by health care, with many physicians involved. Drug trials were a minority, even though most research promotion efforts and regulation concerns them.

Results from a blind and a non-blind randomised trial run in parallel: experience from the Estonian Postmenopausal Hormone Therapy (EPHT) Trial.

BACKGROUND: The Estonian Postmenopausal Hormone Therapy (EPHT) Trial assigned 4170 potential participants prior to recruitment to blind or non-blind hormone therapy (HT), with placebo or non-treatment the respective alternatives. Before having to decide on participation, women were told whether they had been randomised to the blind or non-blind trial. Eligible women who were still willing to join the trial were recruited. After recruitment participants in the non-blind trial (N = 1001) received open-label HT or no treatment, participants in the blind trial (N = 777) remained blinded until the end of the trial. The aim of this paper is to analyse the effect of blinding on internal and external validity of trial outcomes. METHODS: Effect of blinding was calculated as the hazard ratio of selected chronic diseases, total mortality and all outcomes. For analysing the effect of blinding on external validity, the hazard ratios from women recruited to the placebo arm and to the non-treatment arm were compared with those not recruited; for analysing the effect of blinding on internal validity, the hazard ratios from the blind trial were compared with those from the non-blind trial. RESULTS: The women recruited to the placebo arm had less cerebrovascular disease events (HR 0.43; 95% CI: 0.26-0.71) and all outcomes combined (HR 0.76; 95% CI: 0.63-0.91) than those who were not recruited. Among women recruited or not recruited to the non-treatment arm, no differences were observed for any of the outcomes studied.Among women recruited to the trial, the risk for coronary heart disease events (HR 0.77; 95% CI: 0.64-0.93), cerebrovascular disease events (HR 0.66; 95%CI: 0.47-0.92), and all outcomes combined (HR 0.82; 95% CI: 0.72-0.94) was smaller among participants in the blind trial than in the non-blind trial. There was no difference between the blind and the non-blind trial for total cancer (HR 0.95; 95% CI: 0.64-1.42), bone fractures (0.93; 95% CI: 0.74-1.16), and total mortality (HR 1.03; 95% CI: 0.53-1.98). CONCLUSIONS: The results from blind and non-blind trials may differ, even if the target population is the same. Blinding may influence both internal and external validity. The effect of blinding may vary for different outcome events. TRIAL REGISTRATION: [ISRCTN35338757].

Variability of bothersome menopausal symptoms over time--a longitudinal analysis using the Estonian postmenopausal hormone therapy trial (EPHT).

BACKGROUND: Very little data are available on the natural course or level of disturbance of vasomotor symptoms among middle-aged women. Using readily collected trial data we studied the persistence of vasomotor symptoms among untreated women. METHODS: In a trial comparing combined hormone therapy to placebo or no treatment (control groups), a cohort of women aged 50-59 at recruitment were followed annually by questionnaires. Women in the control groups (n = 486) were grouped by the number of years followed, with the prevalence and severity of symptoms calculated both cross-sectionally and longitudinally. RESULTS: About two thirds of the women (67%) reported vasomotor symptoms and half (46%) bothersome symptoms at recruitment. In the cross-sectional analysis, their prevalence declined between recruitment and 1-year follow-up (32% bothersome symptoms) and 2-year follow-up (27%). Thereafter it remained about the same level. In the longitudinal analysis, there was a notable variation in the prevalence of disturbing vasomotor symptoms over time, time entering the study and the compliance to the surveys. In the two groups having most follow-up times, the proportion of women with bothersome symptoms first increased and then decreased. CONCLUSIONS: There was a notable variability in the development of disturbing vasomotor symptoms over time in a selected group of women aged 50-59. Population-based follow-up studies of untreated women would be useful to estimate the symptom burden.

Effect of Pap-smear and sociodemographic factors on cervical cancer risk in Estonia: A population-based case-control study.

BACKGROUND: Like many Eastern-European countries, Estonia struggles with ineffective cervical cancer (CC) screening. Despite a long-term organised screening programme and high overall Pap-smear coverage, CC incidence and mortality remain very high. The aim of the study was to examine the reasons for high CC incidence in Estonia by analysing the effect of Pap-smears and sociodemographic factors on CC risk. METHODS: In this population-based case-control study, women aged ≥ 25 years with an in situ/invasive CC diagnosed in Estonia in 2011-2017 were defined as cases. Using a density sampling scheme, controls were randomly selected from general population. To estimate CC risk associated with having no Pap-smears during seven years before diagnosis (cases) or index date (controls), place of residence, interruption in health insurance, and several sociodemographic factors, multivariate logistic regression was used to calculate odds ratios (OR) with 95% confidence intervals (CI). Individual-level data from three population-based registries were used. RESULTS: Among 1439 cases and 4317 controls, proportion of women with no Pap-smears was 53% and 35%, respectively. Women with no Pap-smears were at higher risk for CC (OR=2.35; 95% CI: 1.85-2.98). CC risk was increased among women who were younger, living in more remote regions, lower-educated, or divorced/widowed. Interruption in health insurance was associated with a 23% risk increase. Regional differences in CC risk were observed among screened women. CONCLUSION: To reduce the risk of CC in Estonia, efforts are necessary to increase screening coverage among high-risk women and ensure the quality of CC screening programme. Screening approaches and communication should be tailored to the needs of different population groups. Further studies are warranted to identify the reasons for regional differences in CC risk.