BackgroundReproductive events are associated with important physiologic changes, yet little is known about how reproductive factors influence long-term health in women. Our objective was to assess the relation of reproductive characteristics with all-cause and cause-specific mortality risk.MethodsThe analysis was performed within the European Investigation into Cancer and Nutrition prospective cohort study, which enrolled >500,000 women and men from 1992 to 2000, who were residing in a given town/geographic area in 10 European countries. The current analysis included 322,972 eligible women aged 25–70 years with 99 % complete follow-up for vital status. We assessed reproductive characteristics reported at the study baseline including parity, age at the first birth, breastfeeding, infertility, oral contraceptive use, age at menarche and menopause, total ovulatory years, and history of oophorectomy/hysterectomy. Hazard ratios (HRs) and 95 % confidence intervals (CIs) for mortality were determined using Cox proportional hazards regression models adjusted for menopausal status, body mass index, physical activity, education level, and smoking status/intensity and duration.ResultsDuring a mean follow-up of 12.9 years, 14,383 deaths occurred. The HR (95 % CI) for risk of all-cause mortality was lower in parous versus nulliparous women (0.80; 0.76–0.84), in women who had ever versus never breastfed (0.92; 0.87–0.97), in ever versus never users of oral contraceptives (among non-smokers; 0.90; 0.86–0.95), and in women reporting a later age at menarche (≥15 years versus <12; 0.90; 0.85–0.96; P for trend = 0.038).ConclusionsChildbirth, breastfeeding, oral contraceptive use, and a later age at menarche were associated with better health outcomes. These findings may contribute to the development of improved strategies to promote better long-term health in women.Electronic supplementary materialThe online version of this article (doi:10.1186/s12916-015-0484-3) contains supplementary material, which is available to authorized users.

Long‐term weight gain (i.e., weight gain since age 20) has been related to higher risk of postmenopausal breast cancer, but a lower risk of premenopausal breast cancer. The effect of weight change in middle adulthood is unclear. We investigated the association between weight change in middle adulthood (i.e., women aged 40–50 years) and the risk of breast cancer before and after the age of 50. We included female participants of the European Prospective Investigation into Cancer and Nutrition cohort, with information on anthropometric measures at recruitment and after a median follow‐up of 4.3 years. Annual weight change was categorized using quintiles taking quintile 2 and 3 as the reference category (−0.44 to 0.36 kg/year). Multivariable Cox proportional hazards regression analysis was used to examine the association. 205,723 women were included and 4,663 incident breast cancer cases were diagnosed during a median follow‐up of 7.5 years (from second weight assessment onward). High weight gain (Q5: 0.83–4.98 kg/year) was related to a slightly, but significantly higher breast cancer risk (HRQ5_versus_Q2/3: 1.09, 95% CI: 1.01−1.18). The association was more pronounced for breast cancer diagnosed before or at age 50 (HRQ5_versus_Q2/3: 1.37, 95% CI: 1.02−1.85). Weight loss was not associated with breast cancer risk. There was no evidence for heterogeneity by hormone receptor status. In conclusion, high weight gain in middle adulthood increases the risk of breast cancer. The association seems to be more pronounced for breast cancer diagnosed before or at age 50. Our results illustrate the importance of avoiding weight gain in middle adulthood.

We have recently identified the promoter that positions the initiation (cap) site for RNA encoding the Epstein-Barr virus (EBV) determined nuclear antigen 2 (EBNA2) in transfected COS-1 cells. The cells were transfected with recombinant vectors that contained the BamHI WYH region of the EBV genome. In order to delineate regulatory DNA sequences required for the expression of EBNA2 the 5' flanking region of the gene was linked to reporter genes in expression vectors and transfected into EBV genome-negative lymphoid DG75 cells. We demonstrate that several cis-acting elements contribute to a transcriptional enhancer activity found in the region between nucleotides-553 and -86 relative to the cap site. The enhancer was active in lymphoid DG75 cells but not in HeLa cells and stimulated transcription also from the heterologous thymidine kinase (TK) and beta-globin promoters. Nuclear extracts of lymphoid cells contained protein factors that bound to the enhancer. The in vitro introduction of a mutation in the enhancer sequence that substantially reduced the transcription stimulatory activity concurrently blocked the binding of one of the factors.