The relationship of major diseases with childlessness: a sibling matched case-control and population register study in Finland and Sweden
Authors: Liu Aoxing , Akimova Evelina T , Ding Xuejie , Jukarainen Sakari , Vartiainen Pekka , Kiiskinen Tuomo , Kuitunen Sara , Havulinna Aki S , Gissler Mika , Lombardi Stefano , Fall Tove , Mills Melinda C , Ganna Andrea 
Published: April 2022

SummaryBackgroundApproximately 20% of men and 15% of women remain childless at the end of their reproductive lifespan, with childlessness increasing over time, yet we lack a comprehensive understanding of the role and relative importance of diseases associated with childlessness, particularly among men.MethodsWe examined all individuals born in Finland (n=1,035,928) and Sweden (n=1,509,092) between 1956 and 1968 (men) or 1956 and 1973 (women) and followed them up until the end of 2018. Socio-demographic, health, and reproductive information was obtained from nationwide registers. We assessed the association of 414 diseases across 16 categories with having no children by age 45 (women) and 50 (men) using a matched pair case-control design based on 71,524 pairs of full-sisters and 77,622 full-brothers who were discordant for childlessness as well as a population-based approach.FindingsMental-behavioral, congenital anomalies, and endocrine-nutritional-metabolic disorders had the strongest associations with childlessness. Novel associations were discovered with inflammatory (eg. myocarditis) and autoimmune diseases (eg. juvenile idiopathic arthritis). Mental-behavioral disorders had stronger associations amongst men, particularly for schizophrenia and acute alcohol intoxication, while congenital anomalies, obesity-related diseases such as diabetes, and inflammatory diseases had stronger associations amongst women. Associations were dependent on the age at onset of the disease, with the strongest association observed earlier in women (21-25 years old) than men (26-30 years old). For most diseases, the association with childlessness was mediated by singlehood, especially in men. Some diseases, however, remained associated with childlessness among partnered individuals, including some mood- and endocrine-nutritional-metabolic disorders. All results can be explored in an interactive online dashboard.InterpretationWe provide evidence that disease burden across multiple domains is associated with childlessness, identifying modifiable mental-behavioral disorders and novel autoimmune and inflammatory diseases. Evidence can be used for targeted health interventions to counter decreasing fertility, reproductive health, involuntary childlessness, and shrinking populations.FundingEuropean Research Council (835079, 945733) and The Leverhulme Trust.Research in ContextEvidence before this studyThe majority of research on infertility and childlessness has focused on socio-environmental factors, diseases related to reproduction, and examined predominantly women. Diseases are often considered separately, without a yardstick of their relative importance, and rarely examined within an entire population.Added value of this studyThis is the first large-scale population study examining the association of 414 diseases across 16 broad categories with remaining childless, examining the entire reproductive and disease histories of 2.5 million men and women.Implications of all the available evidenceOur study provides evidence that childlessness is associated with multiple diseases that are potentially modifiable with targeted public health interventions, particularly mental-behavioral disorders such as alcohol dependence in men or endocrine-nutritional-metabolic disorders linked to obesity and diabetes. Our broader approach revealed hitherto unknown links of childlessness with autoimmune (eg. juvenile idiopathic arthritis, multiple sclerosis, systemic lupus erythematosus) and inflammatory diseases (eg. myocarditis), warranting future studies examining the mechanisms underlying these associations.