A twenty-first century perspective on concepts of modern epidemiology in Ignaz Philipp Semmelweis' work on puerperal sepsis.

We aimed to review Semmelweis's complete work on puerperal sepsis mortality in maternity wards in relation to exposure to cadavers and chlorine handwashing and other factors from the perspective of modern epidemiological methods. We reviewed Semmelweis' complete work and data as published by von Györy 1905 according to current standards. We paid particular attention to Semmelweis's definition of mortality in and of itself, to concepts of modern epidemiology that were already recognizable in Semmelweis's work, and to bias sources. We did several quantitative bias analyses to address selection bias and information bias from outcome measurement error. Semmelweis addressed biases that have become known to modern epidemiology, such as confounding, selection bias and bias from outcome misclassification. Our bias analysis shows that differential loss to follow-up is an unlikely explanation for his results. Bias due to outcome misclassification would only be relevant if misclassification differed between time periods. Confounding by health status was likely but could not be quantitatively addressed. Semmelweis was aware that cause-specific mortality is a function of incidence and prognosis. He reasoned in potential outcome terms to estimate the reduced number of deaths from an intervention. He advanced a hypothesis of clinic overcrowding as a risk factor for puerperal sepsis mortality that turns out to be wrong. Semmelweis' data provide a great pool for illustrating the logic of scientific discovery by use of the numerical method. The explanatory power of his work was strong and Semmelweis was able to refute several previous causal explanations.