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There are large variations in the incidence of Type I (insulin-dependent) diabetes mellitus within Europe, ranging from 3.2 cases per 100 000 person-years in the Republic of Macedonia to more than 40 new cases per 100 000 person-years in Finland. This variation could be caused by differences in the distribution of genetic susceptibility markers, by differences in the distribution of environmental disease determinants or by a combination of both. To assess how much genes contribute to this variation, we correlated the level of incidence of Type I diabetes with the prevalence in the general population of genetic susceptibility and protective markers encoded by the human leukocyte antigen (HLA)-DQ loci. Positive association was found for the combined group of genotypes associated with Type I diabetes risk (p < 0.001). The whole positive effect was, however, accounted for by the HLA-DQ2/DQ8 (DQA1*0501-DQB1*0201/DQA1*0301-DQ-B1*0302) and HLA-DQ4/DQ8 (DQA1*0401-DQB1*0402/DQA1*0301-DQB1*0302) genotypes (p < 0.001 and p < 0.004, respectively). No correlation was found between incidence of Type I diabetes and population prevalence of genotypes not encoding for aspartate on position 57 on the HLA-DQ β chain. It was not possible to detect any negative correlation between Type I diabetes incidence and the prevalence of HLA-genotypes conferring protection against Type I diabetes in a population (HLA-DQA1*0102-DQB1*0602/X). The results suggest that a substantial part of the transnational variation in the incidence of childhood-onset Type I diabetes in Europe is explained by variations between populations in the distribution of particular DQ genotypes which confer a high risk of Type I diabetes in the general population. [Diabetologia (2001) 44 [Suppl 3]: B 51–B 59] [ABSTRACT FROM AUTHOR]

: BACKGROUND It is plausible that a couples ability to achieve the desired number of children is limited by biological fertility, especially if childbearing is postponed. Family size has declined and semen quality may have deteriorated in much of Europe, although studies have found an increase rather than a decrease in couple fertility. : METHODS Using four high-quality European datasets, we took the reported time to pregnancy (TTP) as the predictor variable; births reported as following contraceptive failure were an additional category. The outcome variable was final or near-final family size. Potential confounders were maternal age when unprotected sex began prior to the first birth, and maternal smoking. Desired family size was available in only one of the datasets. : RESULTS Couples with a TTP of at least 12 months tended to have smaller families, with odds ratios for the risk of not having a second child approximately 1.8, and for the risk of not having a third child approximately 1.6. Below 12 months no association was observed. Findings were generally consistent across datasets. There was also a more than 2-fold risk of not achieving the desired family size if TTP was 12 months or more for the first child. : CONCLUSIONS Within the limits of the available data quality, family size appears to be predicted by biological fertility, even after adjustment for maternal age, if the woman was at least 20 years old when the couples first attempt at conception started. The contribution of behavioural factors to this result also needs to be investigated. [ABSTRACT FROM AUTHOR]

We investigated trends in biological fertility in a comprehensive analysis of 5 major European data sets with data on time to pregnancy (TTP) and proportion of contraceptive failures. In particular, we distinguished a period effect from a birth cohort effect (lifelong tendency) in both sexes. Attempts at conception not resulting in birth were excluded. We analyzed data on pregnancies occurring in 9,247 couples between 1953 and 1993 and performed sensitivity analyses to check the robustness of findings. Separate analyses of each time effect showed an increasing fertility trend. Mutually adjusted analyses demonstrated that this rise was visible as a male cohort effect for both TTP and contraceptive failure. On the other hand, the female birth cohort effect showed a slight fall in the first half of the study period for both TTP and contraceptive failure. As a period effect, fertility remained generally stable, the slight trends in TTP and contraceptive failure being in opposite directions, likely indicating an artifact. The rising trend accords with most previous evidence. The increasing trend in male fertility does not contradict the previously reported semen quality deterioration, the effects of which are calculated to be small. The declining female fertility accords with a falling dizygotic twinning rate during the same period.

Epidemiologic studies have shown an increased risk of breast cancer following hormone replacement therapy (HRT). The aim of this study was to investigate whether different treatment regimens or the androgenecity of progestins influence the risk of breast cancer differently. The Danish Nurse Cohort was established in 1993, where all female nurses aged 45 years and above received a mailed questionnaire (n = 23,178). A total of 19,898 women returned the questionnaire (86%). The questionnaire included information on HRT types and regimens, reproductive history and lifestyle-related factors. Breast cancer cases were ascertained using nationwide registries. The follow-up ended on 31 December 1999. Women with former cancer diagnoses, women with missing information on HRT, surgical menopause, premenopausal, as well as hysterectomized women were excluded, leaving 10,874 for analyses. Statistical analyses were performed using Cox proportional hazards model. A total of 244 women developed breast cancer during follow-up. After adjustment for confounding factors, an increased risk of breast cancer was found for the current use of estrogen only (RR = 1.96; 95% CI = 1.16-3.35), for the combined use of estrogen and progestin (RR = 2.70; 95% CI = 1.96-3.73) and for current users of tibolone (RR = 4.27; 95% CI = 1.74-10.51) compared to the never use of HRT. In current users of combined HRT with testosterone-like progestins, the continuous combined regimens were associated with a statistically significant higher risk of breast cancer than the cyclical combined regimens (RR = 4.16, 95% CI = 2.56-6.75, and RR = 1.94, 95% CI = 1.26-3.00, respectively). An increased risk of breast cancer was noted with longer durations of use for the continuous combined regimens (p for trend = 0.048). The European traditional HRT regimens were associated with an increased risk of breast cancer. The highest risk was found for the use of continuous combined estrogen and progestin., (Copyright 2004 Wiley-Liss, Inc.)

Between 1996 and 1999, the authors invited all young men from five European countries who were undergoing compulsory medical examination for possible military service to participate in a study on male reproductive health. The participation rate was 19% in two cities in Denmark (n = 889), 17% in Oslo, Norway (n = 221), 13% in Turku, Finland (n = 313), 14% in Kaunas, Lithuania (n = 157), and 19% in Tartu, Estonia (n = 190). Each man provided a semen sample, was examined by a physician, and, in collaboration with his mother, completed a questionnaire about general and reproductive health, current smoking habits, and exposure to smoking in utero. After adjustment for confounding factors, men exposed to smoking in utero had a reduction in sperm concentration of 20.1% (95% confidence interval (CI): 6.8, 33.5) and a reduction in total sperm count of 24.5% (95% CI: 9.5, 39.5) in comparison with unexposed men. Percentages of motile and morphologically normal sperm cells were 1.85 (95% CI: 0.46, 3.23) and 0.64 (95% CI: -0.02, 1.30) percentage points lower, respectively, among men exposed in utero, and exposed men had a 1.15-ml (95% CI: 0.66, 1.64) smaller testis size. The associations were present when data from the study centers were analyzed separately (though not in Lithuania, where only 1% of mothers smoked during pregnancy), although the strength of the association varied. Maternal smoking may have long-term implications for the reproductive health of the offspring. This is another good reason to advise pregnant women to avoid smoking.

Background: In fertile populations, little is known about the association between semen parameters and time to pregnancy (TTP)., Methods: Pregnant women from Copenhagen, Edinburgh, Paris and Turku who conceived without medical intervention were asked for their TTP (942 couples), and their partners provided a semen sample. The proportion of morphologically normal sperm and the multiple anomalies index (MAI, ratio of the total number of anomalies to the number of abnormal sperm) were centrally estimated. We estimated rate ratios for the occurrence of a pregnancy by a discrete survival model, adjusted for sexual activity and female factors affecting fecundity., Results: Increasing sperm concentration influenced TTP up to 55 x 10(6)/ml. The proportion of morphologically normal sperm influenced TTP up to 39% according to David's criteria, and this association held among the subjects with a sperm concentration >55 x 10(6)/ml. For strict criteria, the threshold value was 19% normal sperm. An increase of 0.5 in MAI was associated with an adjusted rate ratio for the occurrence of a pregnancy of 0.68 (95% confidence interval: 0.54-0.85)., Conclusions: These results highlight the importance of sperm morphology parameters and indicate that the effect of proportion of normal sperm on TTP may be independent of sperm concentration.

Recent reports have indicated a decrease in semen quality of men in some countries, and suggested regional differences. A study was undertaken of semen samples from 1082 fertile men from four European cities (Copenhagen, Denmark; Paris, France; Edinburgh, Scotland; and Turku, Finland). Semen analysis was standardized, inter-laboratory differences in assessment of sperm concentration were evaluated, and morphology assessment centralized. Lowest sperm concentrations and total counts were detected for Danish men, followed by French and Scottish men. Finnish men had the highest sperm counts. Men from Edinburgh had the highest proportion of motile spermatozoa, followed by men from Turku, Copenhagen and Paris. Only the differences between Paris/Edinburgh and Paris/Turku were statistically significant (P < 0.003 and P < 0.002 respectively). No significant differences in morphology were detected. A general seasonal variation in sperm concentration (summer 70% of winter) and total sperm count (summer 72% of winter) was detected. Semen quality of a 'standardized' man (30 years old, fertile, ejaculation abstinence of 96 h) were estimated. Typically, sperm concentrations (x 10(6)/ml) for winter/summer were: Turku 132/93; Edinburgh 119/84; Paris 103/73; and Copenhagen 98/69. These differences in semen quality may indicate different environmental exposures or lifestyle changes in the four populations. However, it remains to be seen whether such changes can account for these differences. These data may also serve as a reference point for future studies on time trends in semen quality in Europe.

The retrospective study based on pregnancy samples is the most commonly used method for studying time to pregnancy. Using a simple Monte Carlo simulation, this note focuses on a particular selection bias problem associated with this design: even if each woman's fecundity decreases with age, estimation of the effect of age may show the opposite trend. We recommend exercising increased caution in interpreting findings from pregnancy-based time-to-pregnancy studies.

The aim of this study was to examine the effect of malotilate on survival in patients with alcoholic liver disease and to determine prognostic variables for survival. Four hundred and seven patients with alcoholic liver diseases, from seven European liver units, entered a randomized placebo-controlled, double-blind trial: 140 patients received malotilate 1500 mg/day, 133 patients received 750 mg/day, and 134 patients received placebo. The patients were included in the study over a period of 3 1/2 years, and the study was closed 1 year after the entry of the last patient. Eighty-four patients died (35, 19, 30 patients in groups 1500 mg/day, 750 mg/day, and placebo, respectively). Survival was slightly better in the 750 mg/day group than in the two other treatment groups, when tested by conventional log-rank tests (p = 0.06). However, a treatment effect was supported by a highly significant (p = 0.006) non-proportionality of the death intensity in patients receiving 750 mg/day against those receiving either 1500 mg/day or placebo. Prognostic variables for survival were evaluated using the multiple Cox regression analysis of clinical and laboratory variables and with or without liver histology variables, as determined at entry into the study. The analysis was stratified for the three treatment regimens. In the analysis including liver histology variables, independent significant prognostic variables were: years of high alcohol intake, prothrombin index, alkaline phosphatases, creatinine, immunoglobulin M, white blood cell count, and liver cell steatosis. In the analysis without liver histology variables, prognostic variables were: years of high alcohol intake, prothrombin index, alkaline phosphatases, creatinine, and immunoglobulin M.

"Occupational mortality and morbidity is usually studied via standardized mortality (or morbidity) ratios, with little attention to the basic fit of the implicit underlying proportional hazards model. This paper presents a case study on unemployment and mortality, based on the complete Danish male population aged 20-64 years at the 1970 census. The effect of unemployment on the age-specific mortality rate is intermediate between additive and multiplicative and was fitted well by an additive effect on the square root of the mortality. The paper discusses and illustrates whether finer stratification or random residual variation ('frailty') is to be preferred for obtaining a statistically satisfactory fit.", (excerpt)