Reference population
When women start using HC, some will within days, weeks, or months experience mood deterioration or even depression due to that use, and will, therefore, stop using these products. These former users are at an increased risk of depression – not due to their former use of HC, but that use was the first test to reveal their mental sensitivity. In addition, during the study period some users of HC will develop mood deterioration without getting a prescription of anti-depressants or a depression diagnosis, e.g., those seeking psychological therapy, and will stop using HC. Both of these groups of previous users will be at an increased risk of depression and use of antidepressants. By including those women in the reference group of non-users, will underestimate the risk of depression development in current users.
In pharmacoepidemiology it is default practice to compare exposed women with non-exposed women. For rare outcomes it doesn’t make any difference whether non-exposed or never exposed are used as reference population. But with a frequent outcome, such as depression development, it makes a huge difference, which was illustrated in study 1, where the risk of depression with use of oral contraceptives changed from 23% increased risk to 70% increased risk with change in reference group from non-users to never-users. In study 3 the risk of depression with HC use changed from 1% increased risk to 29% increased risk with the same change in reference group.