Associations were also found for total and decaffeinated coffee consumption and higher risk of rheumatoid arthritis, 74 75 but neither reached significance. Finally, for one extra cup a day, significance was reached for beneficial associations with 11 outcomes and harmful associations with three. High versus low intake of decaffeinated coffee was also associated with lower all cause mortality, with summary estimates indicating largest benefit at three cups a day 0. Eight out of 18 studies 19 20 21 22 23 24 25 26 27 that tested for non-linearity for the association with one extra cup a day found significant evidence for this. Similarly, decaffeinated coffee seemed to have negligible effect on the lipid profile. Galarraga and Boffetta examined the possible confounding by smoking in two ways in their recent meta-analysis 47 of coffee consumption and risk of lung cancer. After adjustment for smoking, consumption in pregnancy seems to be associated with harmful outcomes related to low birth weight, 82 preterm birth, 83 and pregnancy loss. For randomised controlled trials, coffee has been given as an intervention for only short durations and limited to a small number of outcomes, including blood pressure, lipid profiles, and one trial in pregnancy. The conclusion of benefit associated with coffee consumption was supported by significant associations with lower risk for the generic outcomes of all cause mortality, 28 cardiovascular mortality, 28 and total cancer. The increases in cholesterol concentration were mitigated with filtered coffee, with a marginal rise in concentration mean difference 0. These results suggest that sex might be a significant effect modifier in the association between coffee and risk of fracture. High versus low coffee consumption was associated with a lower risk of prostate cancer, 39 endometrial cancer, 40 melanoma, 41 oral cancer, 39 leukaemia, 38 non-melanoma skin cancer, 42 and liver cancer. In type 2 diabetes, despite significant non-linearity, relative risk reduced sequentially from one through to six cups a day. There were also harmful associations between consumption and congenital malformations, though these did not reach significance. Coffee and caffeine have also been linked to oestrogen metabolism in premenopausal women 99 and increased concentrations of sex hormone binding globulin SHBG in observational research of postmenopausal women. Firstly, they performed the meta-analysis in those who had never smoked and detected no harmful association. It has been shown to contribute a large proportion of daily intake of dietary antioxidant, greater than tea, fruit, and vegetables.