Would the number of new cases of hereditary angioedema decrease due to declining fertility rates?

Hereditary angioedema (HAE) is a rare, potentially life-threatening disorder caused by autosomal dominant mutations in the SERPING1 gene, leading to deficiency or dysfunction of C1 esterase inhibitor. Recent estimates of global HAE prevalence are 1.22 per 100,000 individuals. With total fertility rates (TFRs) decreasing worldwide, several developed countries are now well below the population replacement rate in an "ultra-low fertility" group. With the decrease in fertility, how rare diseases are approached should be re-examined. In this letter, we describe how continued and sustained declines in total fertility rate and population may influence the future number of new HAE cases. We also address disease-specific factors that may further influence future case count, including reproductive hesitancy related to autosomal dominant inheritance, estrogen-associated exacerbation of angioedema attacks, and potential fertility effects of complement dysregulation. These demographic considerations are relevant to clinicians, researchers, and pharmaceutical companies involved in HAE care. Better characterizing population changes in the context of reduced fertility rates may help inform long-term clinical planning and the development of novel therapies for HAE and other rare diseases.