Trends in all-cause mortality among people with diagnosed diabetes in high-income settings: a multicountry analysis of aggregate data.

BACKGROUND: Population-level trends in mortality among people with diabetes are inadequately described. We aimed to examine the magnitude and trends in excess all-cause mortality in people with diabetes. METHODS: In this retrospective, multicountry analysis, we collected aggregate data from 19 data sources in 16 high-income countries or jurisdictions (in six data sources in Asia, eight in Europe, one from Australia, and four from North America) for the period from Jan 1, 1995, to Dec 31, 2016, (or a subset of this period) on all-cause mortality in people with diagnosed total or type 2 diabetes. We collected data from administrative sources, health insurance records, registries, and a health survey. We estimated excess mortality using the standardised mortality ratio (SMR). FINDINGS: In our dataset, there were approximately 21 million deaths during 0·5 billion person-years of follow-up among people with diagnosed diabetes. 17 of 19 data sources showed decreases in the age-standardised and sex-standardised mortality in people with diabetes, among which the annual percentage change in mortality ranged from -0·5% (95% CI -0·7 to -0·3) in Hungary to -4·2% (-4·3 to -4·1) in Hong Kong. The largest decreases in mortality were observed in east and southeast Asia, with a change of -4·2% (95% CI -4·3 to -4·1) in Hong Kong, -4·0% (-4·8 to -3·2) in South Korea, -3·5% (-4·0 to -3·0) in Taiwan, and -3·6% (-4·2 to -2·9) in Singapore. The annual estimated change in SMR between people with and without diabetes ranged from -3·0% (95% CI -3·0 to -2·9; US Medicare) to 1·6% (1·4 to 1·7; Lombardy, Italy). Among the 17 data sources with decreasing mortality among people with diabetes, we found a significant SMR increase in five data sources, no significant SMR change in four data sources, and a significant SMR decrease in eight data sources. INTERPRETATION: All-cause mortality in diabetes has decreased in most of the high-income countries we assessed. In eight of 19 data sources analysed, mortality decreased more rapidly in people with diabetes than in those without diabetes. Further longevity gains will require continued improvement in prevention and management of diabetes. FUNDING: US Centers for Disease Control and Prevention, Diabetes Australia Research Program, and Victoria State Government Operational Infrastructure Support Program.

Incidence of HPV-related Anogenital Intraepithelial Neoplasia and Cancer in Men With Diabetes Compared With the General Population.

BACKGROUND: Diabetes may increase risk of human papillomavirus (HPV)-related precancer and cancer. We estimated incidence of penile and anal high-grade intraepithelial neoplasia (hgPeIN, hgAIN) and squamous cell carcinoma (SCC) in men with diabetes compared with the entire Danish male population without diabetes. METHODS: In this registry-based cohort study, we included all men born 1916-2001 and residing in Denmark (n = 2,528,756). From nationwide registries, we retrieved individual-level information on diabetes, educational level, and diagnoses of hgPeIN, hgAIN, penile SCC, and anal SCC. We used Poisson regression models to estimate incidence of hgPeIN, hgAIN, penile SCC, and anal SCC as a function of diabetes status, attained age, calendar period, and education. We estimated incidence rate ratios (IRRs) of each outcome in men with diabetes compared with nondiabetic men, both for diabetes overall and separately for type 1 (T1D) and type 2 diabetes (T2D). RESULTS: Men with diabetes had increased incidence rate of penile SCC compared with nondiabetic men (IRR = 1.5, 95% CI = 1.2, 1.9). We saw similar trends for anal SCC, hgPeIN, and hgAIN. The combined incidence rate of penile and anal SCC was increased in men with T2D (IRR = 1.5, 95% CI = 1.3, 1.8), but not with T1D (IRR = 0.53, 95% CI = 0.20, 1.4) compared with men without diabetes. CONCLUSION: The incidence of penile and anal high-grade intraepithelial neoplasia and SCC in men with diabetes was increased compared with men without diabetes. For penile and anal SCCs, this was primarily due to an increased risk in men with T2D.

Incidence of human papillomavirus-related anogenital precancer and cancer in women with diabetes: A nationwide registry-based cohort study.

In this register-based cohort study, we estimated the incidence of human papillomavirus (HPV)-related anogenital precancer and cancer in women with diabetes compared with women without diabetes. We followed all women living in Denmark born 1916 to 2001 (n = 2 508 321) for individual-level information on diabetes (Type 1 or 2 [T1D or T2D]), diagnoses of cervical, vaginal, vulvar and anal intraepithelial neoplasia Grade 2 or 3 (IN2/3) and cancer and other covariates from nationwide registries. We used Poisson regression to model the incidence rates of anogenital IN2/3 and cancer as a function of diabetes status, age, HPV vaccination, education, calendar year, and cervical cancer screening status. Incidence rate ratios (IRRs) were estimated for diabetes overall, and separately for T1D and T2D, compared with women without diabetes. Women with diabetes had higher rates of vulvar IN2/3 (IRR = 1.63; 95% confidence interval [CI]: 1.41-1.88), vulvar cancer (IRR = 1.61; 95% CI: 1.36-1.91) and vaginal cancer (IRR = 1.79; 95% CI: 1.27-1.91) than women without diabetes. Similar patterns were observed for anal IN2/3, anal cancer and cervical cancer, although not statistically significant. In contrast, women with diabetes had lower rates of cervical IN2/3 (IRR = 0.74; 95% CI: 0.69-0.79) than women without diabetes. Patterns were generally similar in women with T1D and T2D, although cancer rates were higher in women with T2D. In conclusion, the incidence of most anogenital precancers and cancers were increased in women with diabetes. However, women with diabetes had lower incidence of cervical precancer. Our findings could be explained by biological mechanisms and/or behavioral factors, such as smoking and less frequent cervical screening participation.

Effect of duration and burden of microvascular complications on mortality rate in type 1 diabetes: an observational clinical cohort study.

AIMS/HYPOTHESIS: The role of burden and duration of multiple microvascular complications on mortality rate has not been explored in detail in type 1 diabetes. Taking complication burden and time-updated duration into account we aimed to quantify mortality rate in individuals with and without microvascular complications. METHODS: This observational clinical cohort included 3828 individuals with type 1 diabetes attending the Steno Diabetes Center Copenhagen in 2001-2013. We used information on mortality and detailed clinical measures of microvascular complications from electronic patient records. Poisson models were used to model mortality rates according to complication burden. RESULTS: During 26,665 person-years of follow-up, 503 deaths occurred. Compared with individuals without microvascular complications, the mortality rate ratio was 2.20 (95% CI 1.79, 2.69) for individuals with diabetic kidney disease, 1.72 (95% CI 1.39, 2.12) for individuals with neuropathy and 1.02 (95% CI 0.77, 1.37) for individuals with retinopathy, all adjusted for calendar time (year/month/day), age, duration of diabetes, sex, HbA1c, LDL-cholesterol, BMI, smoking status, systolic blood pressure, use of antihypertensive and lipid-lowering medication, and cardiovascular disease status. In individuals with two complications or more, the risk of mortality did not exceed the combined risk from each individual complication. Mortality rate ratios increased immediately after diagnosis of neuropathy and diabetic kidney disease. Mortality rate ratios were independent of the duration of neuropathy and retinopathy, while the mortality rate associated with diabetic kidney disease reached a stable level after approximately 3 years. CONCLUSIONS/INTERPRETATION: Neuropathy and diabetic kidney disease are strong and independent risk markers of mortality in type 1 diabetes, whereas no evidence of higher mortality rate was found for retinopathy. We found no indication that the mortality risk with multiple complications exceeds the risk conferred by each complication separately. The duration spent with microvascular complications had only a marginal effect on mortality.

Incidence of diabetic eye disease among migrants: A cohort study of 100,000 adults with diabetes in Denmark.

AIMS: To examine the incidence rates of any and referable diabetic retinopathy (DR) among migrants in Denmark. METHODS: Nationwide clinical data on diabetes patients followed since 2005 were analysed. Patients were classified according to country of origin into six groups: Denmark, other Europe, Sub Saharan Africa, Middle East/North Africa, Asia, and America/Oceania. A total of 93,780 or 110,897 patients without any (including unspecific diagnoses) or referable (proliferative) DR at baseline were analyzed. We estimated event rates and hazard ratios (HRs) for incidence of any and referable DR according to country of origin. RESULTS: After an average follow-up of 3.59 years 6727 had incident any DR and 4747 patients had referable DR. Compared to people of Danish origin, migrants from the Middle East/North Africa and Asia had a higher risk of any and referable DR after adjustment for age, sex, body mass index, smoking status, types and duration of diabetes, clinic type (general practice vs outpatient clinic), HbA1c, blood pressure and lipid levels. The associations remained significant after further adjustment for frequency of eye screening. CONCLUSIONS: Migrants from the Middle East/North Africa and Asia were at increased risk of developing any and referable DR compared to native Danes, and these differences were not fully explained by differences in underlying clinical, diabetic and cardiometabolic risk factors.

Development of Microvascular Complications and Effect of Concurrent Risk Factors in Type 1 Diabetes: A Multistate Model From an Observational Clinical Cohort Study.

OBJECTIVE: Type 1 diabetes is a complex disease, and development of multiple complications over time can be analyzed only with advanced statistical methods. This study describes the development of microvascular complications and explores the effect of complication burden and important concurrent risk factors by applying a multistate model. RESEARCH DESIGN AND METHODS: We used a clinical cohort at the Steno Diabetes Center Copenhagen to study the development of diabetic kidney disease, retinopathy, and neuropathy. We extracted information from electronic patient records and estimated incidence rates of complications by concurrent complication burden. We explored the extent to which concurrent complications modify the effect of selected risk factors on the development of microvascular complications. RESULTS: We included 3,586 individuals. Incidence rate ratios in individuals with two previous complications were 3.2 (95% CI 2.3-4.5) for diabetic kidney disease, 2.1 (1.5-3.1) for retinopathy, and 1.7 (1.2-2.4) for neuropathy compared with individuals without complications. The models included diabetes duration; calendar time and age as timescales; and sex, HbA1c, lipid-lowering and antihypertensive treatment, systolic blood pressure, BMI, estimated glomerular filtration rate (eGFR), cardiovascular disease (CVD), LDL cholesterol, insulin dose (units/kg/day), and smoking status as covariates. Effects of HbA1c, diabetes duration, systolic blood pressure, BMI, eGFR, and LDL cholesterol where not modified by concurrent complication burden, whereas the effect of sex and CVD were. CONCLUSIONS: The risk of microvascular complications highly depends on the concurrent complication burden and risk factor profile in individuals with type 1 diabetes. The results emphasize attention to risk factors, regardless of existing number of complications, to prevent development of further microvascular complications.

Impact of age at diagnosis and duration of type 2 diabetes on mortality in Australia 1997-2011.

AIMS/HYPOTHESIS: Current evidence suggests that type 2 diabetes may have a greater impact on those with earlier diagnosis (longer duration of disease), but data are limited. We examined the effect of age at diagnosis of type 2 diabetes on the risk of all-cause and cause-specific mortality over 15 years. METHODS: The data of 743,709 Australians with type 2 diabetes who were registered on the National Diabetes Services Scheme (NDSS) between 1997 and 2011 were examined. Mortality data were derived by linking the NDSS to the National Death Index. All-cause mortality and mortality due to cardiovascular disease (CVD), cancer and all other causes were identified. Poisson regression was used to model mortality rates by sex, current age, age at diagnosis, diabetes duration and calendar time. RESULTS: The median age at registration on the NDSS was 60.2 years (interquartile range [IQR] 50.9-69.5) and the median follow-up was 7.2 years (IQR 3.4-11.3). The median age at diagnosis was 58.6 years (IQR 49.4-67.9). A total of 115,363 deaths occurred during 7.20 million person-years of follow-up. During the first 1.8 years after diabetes diagnosis, rates of all-cause and cancer mortality declined and CVD mortality was constant. All mortality rates increased exponentially with age. An earlier diagnosis of type 2 diabetes (longer duration of disease) was associated with a higher risk of all-cause mortality, primarily driven by CVD mortality. A 10 year earlier diagnosis (equivalent to 10 years' longer duration of diabetes) was associated with a 1.2-1.3 times increased risk of all-cause mortality and about 1.6 times increased risk of CVD mortality. The effects were similar in men and women. For mortality due to cancer (all cancers and colorectal and lung cancers), we found that earlier diagnosis of type 2 diabetes was associated with lower mortality compared with diagnosis at an older age. CONCLUSIONS/INTERPRETATION: Our findings suggest that younger-onset type 2 diabetes increases mortality risk, and that this is mainly through earlier CVD mortality. Efforts to delay the onset of type 2 diabetes might, therefore, reduce mortality.

Long-term patterns of adherence to medication therapy among patients with type 2 diabetes mellitus in Denmark: The importance of initiation.

AIMS: Poor adherence to medication therapy among type 2 diabetes patients is a clinical challenge. We aimed to determine which factors are associated with the three phases of long-term adherence to medication: initiation, implementation and discontinuation in a register-based study. METHODS: Adherence to six medicine groups (metformin, sulfonylureas, acetylsalicylic acid, thiazide diuretics, renin angiotensin system inhibitors, and statins) were analysed among 5,232 patients with type 2 diabetes at a tertiary referral hospital during 1998-2009. Rate-ratios of initiation of treatment, recurrent gaps in supply of medication, and discontinuation of treatment were analysed using Poisson regression. RESULTS: Poor initiation rather than poor implementation or discontinuation was the main contributor to medication nonadherence. Polypharmacy was a risk factor for slower initiation of treatment for all six medicine groups (rate ratio ranging 0.79 95%CI [0.72-0.87] to 0.89 95%CI [0.82-0.96] per already prescribed medicine), but once patients were in treatment, polypharmacy was not associated with recurrence of gaps in supply of medication, and polypharmacy was associated with lower risk of discontinuation (rate ratio ranging 0.93 95%CI [0.86-1.00] to 0.96 95%CI [0.93-0.99] per prescribed medicine). Other identified risk factors for slow initiation, poor implementation, and discontinuation were diabetes duration, younger age, and Turkish/Pakistani origin. DISCUSSION: This study showed that a risk factor does not necessarily have the same association with all three elements of adherence (initiation, implementation and discontinuation), and that efforts supporting patients introduced to more complex drug combinations should be prioritized.

Cancer incidence in persons with type 1 diabetes: a five-country study of 9,000 cancers in type 1 diabetic individuals.

AIMS/HYPOTHESIS: An excess cancer incidence of 20-25% has been identified among persons with diabetes, most of whom have type 2 diabetes. We aimed to describe the association between type 1 diabetes and cancer incidence. METHODS: Persons with type 1 diabetes were identified from five nationwide diabetes registers: Australia (2000-2008), Denmark (1995-2014), Finland (1972-2012), Scotland (1995-2012) and Sweden (1987-2012). Linkage to national cancer registries provided the numbers of incident cancers in people with type 1 diabetes and in the general population. We used Poisson models with adjustment for age and date of follow up to estimate hazard ratios for total and site-specific cancers. RESULTS: A total of 9,149 cancers occurred among persons with type 1 diabetes in 3.9 million person-years. The median age at cancer diagnosis was 51.1 years (interquartile range 43.5-59.5). The hazard ratios (HRs) (95% CIs) associated with type 1 diabetes for all cancers combined were 1.01 (0.98, 1.04) among men and 1.07 (1.04, 1.10) among women. HRs were increased for cancer of the stomach (men, HR 1.23 [1.04, 1.46]; women, HR 1.78 [1.49, 2.13]), liver (men, HR 2.00 [1.67, 2.40]; women, HR 1.55 [1.14, 2.10]), pancreas (men, HR 1.53 [1.30, 1.79]; women, HR 1.25 [1.02,1.53]), endometrium (HR 1.42 [1.27, 1.58]) and kidney (men, HR 1.30 [1.12, 1.49]; women, HR 1.47 [1.23, 1.77]). Reduced HRs were found for cancer of the prostate (HR 0.56 [0.51, 0.61]) and breast (HR 0.90 [0.85, 0.94]). HRs declined with increasing diabetes duration. CONCLUSION: Type 1 diabetes was associated with differences in the risk of several common cancers; the strength of these associations varied with the duration of diabetes.

Abdominal Fat Distribution and Cardiovascular Risk in Men and Women With Different Levels of Glucose Tolerance.

CONTEXT: Regional fat distribution rather than overall obesity has been recognized as important to understanding the link between obesity and cardiovascular disease. OBJECTIVE: We examined the associations of abdominal visceral adipose tissue (VAT) and abdominal subcutaneous adipose tissue (SAT) with cardiovascular risk factors in a Caucasian population of men and women with normal glucose tolerance, prediabetes, or screen-detected diabetes. DESIGN, SETTING, AND PARTICIPANTS: The study was based on cross-sectional analysis of data from 1412 adults age 45-80 years. VAT and SAT were assessed by ultrasound. The associations of VAT and SAT with blood pressure and lipids were examined by linear regression analysis adjusted for age, sex, smoking, alcohol, physical activity, glucose tolerance status (GTS), medication use, and body mass index. Effect modification by GTS and sex was examined, and stratified analyses performed. RESULTS: Independent of SAT and overall obesity, VAT was associated with higher triglyceride and lower high-density lipoprotein (HDL) cholesterol levels in both men and women and additionally associated with higher total cholesterol in men. SAT was independently associated with higher total cholesterol and low-density lipoprotein cholesterol levels in both sexes, and SAT was additionally associated with higher triglyceride and lower HDL cholesterol levels in women and with higher blood pressure in participants with diabetes. CONCLUSION: Both abdominal VAT and SAT are independent of overall obesity associated with cardiovascular risk in a population of men and women at low to high risk of diabetes or with screen-detected diabetes.

Improved prognosis of diabetic nephropathy in type 1 diabetes.

The natural history of diabetic nephropathy offered an average survival of only 5-7 years. During the past decades, multiple changes in therapy and lifestyle have occurred. The prognosis of diabetic nephropathy after implementing stricter control of blood pressure (including increased use of long-term renin-angiotensin system inhibition), lipids, and glycemia, along with less smoking and other lifestyle and treatment advancements, is inadequately analyzed. To clarify this, we studied 497 patients with type 1 diabetes and diabetic nephropathy at the Steno Diabetes Center and compared them with previous data, obtained using identical criteria at our hospital. The glomerular filtration rate, measured yearly by 51Cr-EDTA plasma clearance, was a mean of 71 ml/min per 1.73 m2 at baseline. The mean glomerular filtration rate decline was significantly reduced by 19% (95% confidence interval 5-34) from previously 4.0 to 3.3 ml/min per 1.73 m2/year. During a median follow-up of 9.1 years, 29% of participants doubled their plasma creatinine or developed end-stage renal disease. Mortality risk was similar to our prior study (hazard ratio 1.05 (0.76-1.43). However, after age adjustment, as both diabetes and nephropathy onset occurred later in life, mortality was reduced by 30%. Risk factors for decline in glomerular filtration rate, death, and other renal end points were generally in agreement with prior studies. Thus, with current treatment of nephropathy in type 1 diabetes, the prognosis and loss of renal function has improved along with better control of modifiable risk factors.

The epidemiology of diabetes and cancer.

The literature on cancer occurrence in persons with diabetes has almost invariably been concerned with relative measures. In this paper, we briefly review this, but the aim is to quantify the absolute occurrence of diabetes and cancer in the population in order to give a fuller picture, which also includes the competing mortality risk. Overall, we find that some 35 % of the population will have a diagnosis of diabetes in their lifetime, 44 % a diagnosis of cancer, and about 15 % will have both diagnoses. The impact of differing mortality between persons with and without diabetes is illustrated by the fact that a person without diabetes at age 50 has a smaller lifetime risk of cancer than a person aged 50 with diabetes. Thus, the differences in cancer occurrence between persons with and without diabetes are of quantitatively smaller importance than the differences in mortality.

Mortality after cancer among patients with diabetes mellitus: effect of diabetes duration and treatment.

AIMS/HYPOTHESIS: The prognostic role of different diabetes treatment types has not been studied in detail. We compared mortality rates among cancer patients with and without diabetes, accounting for diabetes treatment and diabetes duration. METHODS: This register-based study included all cancer patients diagnosed in Denmark during 1995-2009. The patients were classified into four groups according to diabetes status at the time of cancer diagnosis: no diabetes, diabetes without medication, diabetes with only oral hypoglycaemic agent (OHA) or diabetes with insulin treatment. Poisson models were used to examine the association between pre-existing diabetes in cancer patients and mortality relative to the non-diabetic cancer population. RESULTS: Among 426,129 patients with incident cancer, we identified 42,205 patients with diabetes prior to cancer diagnosis. Overall, cancer patients with diabetes had higher mortality rates than non-diabetic cancer patients, highest among OHA- or insulin-treated patients. For all cancers combined and diabetes duration of 2 years at cancer diagnosis, insulin-treated patients experienced the highest mortality rate ratios starting from 3.7 (95% CI 2.7, 5.1) for men and 4.4 (3.1, 6.5) for women 1 year after cancer diagnosis, increasing to 5 (3.5, 7.0) for men and 6.5 (4.2, 9.3) for women 9 years after cancer diagnosis. CONCLUSIONS/INTERPRETATION: Our study provides strong evidence that cancer patients with pre-existing diabetes experience higher mortality than cancer patients without diabetes. The higher mortality seen among cancer patients treated with OHAs or insulin is in accordance with the existing evidence that more intensive diabetes treatment reflects a larger degree of comorbidity at the time of cancer diagnosis, and hence poorer survival.

Multiple time scales in multi-state models.

In multi-state models, it has been the tradition to model all transition intensities on one time scale, usually the time since entry into the study ('clock-forward' approach). The effect of time since an intermediate event has been accommodated either by changing the time scale to time since entry to the new state ('clock-back' approach) or by including the time at entry to the new state as a covariate. In this paper, we argue that the choice of time scale for the various transitions in a multi-state model should be dealt with as an empirical question, as also the question of whether a single time scale is sufficient. We illustrate that these questions are best addressed by using parametric models for the transition rates, as opposed to the traditional Cox-model-based approaches. Specific advantages are that dependence of failure rates on multiple time scales can be made explicit and described in informative graphical displays. Using a single common time scale for all transitions greatly facilitates computations of probabilities of being in a particular state at a given time, because the machinery from the theory of Markov chains can be applied. However, a realistic model for transition rates is preferable, especially when the focus is not on prediction of final outcomes from start but on the analysis of instantaneous risk or on dynamic prediction. We illustrate the various approaches using a data set from stem cell transplant in leukemia and provide supplementary online material in R.

Register-based studies of diabetes.

INTRODUCTION: During the last decade, a number of population-based diabetes registers have emerged which have enhanced the population-based epidemiology of diabetes. The aim of this paper is to review research based on Danish diabetes registers and to compare with similar research in Finland, Sweden, Scotland, and Canada. RESEARCH TOPICS: The pattern with the highest prevalences in ages around 75 years is consistent between studies based on different registers, and so is the finding that incidence rates of diabetes are higher among females than males only in ages 20-40. Diabetes registers have been and is increasingly being used to study and particularly quantify links with cardiovascular disease and with cancer. Recently, available medication profiles of diabetes patients have been used as well to further elucidate these links. CONCLUSION: Diabetes registers are valuable sources of data for description of the trends in occurrence, development, and mortality of diabetes. However, it requires careful application of modern statistical methods since effects of calendar time, age, and duration of diabetes all have to be taken into account when reporting results.

Incidence trends of adenocarcinoma of the cervix in 13 European countries.

Rapid increases in cervical adenocarcinoma incidence have been observed in Western countries in recent decades. Postulated explanations include an increasing specificity of subtype-the capability to diagnose the disease, an inability of cytologic screening to reduce adenocarcinoma, and heterogeneity in cofactors related to persistent human papillomavirus infection. This study examines the possible contribution of these factors in relation with trends observed in Europe. Age-period-cohort models were fitted to cervical adenocarcinoma incidence trends in women ages <75 in 13 European countries. Age-adjusted adenocarcinoma incidence rates increased throughout Europe, the rate of increase ranging from around 0.5% per annum in Denmark, Sweden, and Switzerland to >/=3% in Finland, Slovakia, and Slovenia. The increases first affected generations born in the early 1930s through the mid-1940s, with risk invariably higher in women born in the mid-1960s relative to those born 20 years earlier. The magnitude of this risk ratio varied considerably from around 7 in Slovenia to almost unity in France. Declines in period-specific risk were observed in United Kingdom, Denmark, and Sweden, primarily among women ages >30. Whereas increasing specificity of subtype with time may be responsible for some of the increases in several countries, the changing distribution and prevalence of persistent infection with high-risk human papillomavirus types, alongside an inability to detect cervical adenocarcinoma within screening programs, would accord with the temporal profile observed in Europe. The homogeneity of trends in adenocarcinoma and squamous cell carcinoma in birth cohort is consistent with the notion that they share a similar etiology irrespective of the differential capability of screen detection. Screening may have had at least some impact in reducing cervical adenocarcinoma incidence in several countries during the 1990s.

Early childhood risk factors associated with type 1 diabetes--is gender important?

BACKGROUND: The incidence of childhood diabetes is increasing in Denmark as in the rest of the world. The aim of this investigation was to study intrauterine and early childhood risk factors for insulin dependent diabetes mellitus, and to evaluate gender differences in the effect of these. METHODS/MATERIAL: A number of 602 diabetic cases aged 0-14 years diagnosed 1996-1999 were identified from the Danish register of childhood diabetes. A total of 1490 non-diabetic healthy children matched by gender and date of birth were randomly selected from the Danish population register. In addition a combination of national register data and questionnaire data was used. RESULTS: High parental age, neonatal infections and pre-eclampsia were associated with type 1 diabetes in boys, whereas being preterm was associated with an increased risk in girls. An increased risk was associated with a family history of diabetes and amniocentesis, while a decreased risk was associated with increasing birth order and maternal smoking. In a multiple logistic regression analysis, the following risk factors were significantly associated with case-control status: maternal smoking (OR: 0.6(0.4-0.9)), neonatal infection in boys (OR: 5.5(1.4-21.8)), neonatal infection in girls (OR: 0.6(0.1-3.0)), amniocentesis (OR: 1.6(1.0-2.6)), preschool siblings (OR: 0.8(0.6-1.0)), introduction of cow's milk after the age of 3 months (OR: 0.7(0.4-0.9)) and a 1st degree family member with diabetes (OR: 9.1(95% CI:5.2-16)). CONCLUSION: The study showed associations between several risk factors and childhood diabetes, for some risk factors the odds ratio in boys were different from the odds ratio in girls.