The rising trend of childlessness in Western European countries, particularly Finland and Sweden, has spurred significant research into the underlying social, economic, and structural factors. In Finland, for example, childlessness among women aged 40 has increased from 14% to 22%, and for men from 22% to 32% since the 1970s. These increases are attributed to several factors, including increased access to contraception, increased opportunities for women in education and the workforce, and work-life balance challenges. While the 'incomplete gender revolution' has provided women with greater career opportunities, it has often presented them with a difficult choice between career and parenthood, leading to delayed or forgone childbearing. Similar challenges for men, including job insecurity and a shift in societal norms, have also contributed to increased childlessness. While voluntary childlessness accounts for a small percentage (estimated around 5% in Europe), the majority of childless individuals are considered involuntarily childless. This involuntary childlessness has implications for mental and physical health, potentially leading to relationship dissolution, low self-esteem, isolation, depression, and negative impacts on career opportunities. While extensive research exists on the social and economic determinants of childlessness, the impact of diseases remains understudied, particularly concerning involuntary childlessness. This study aims to bridge this gap by conducting a comprehensive analysis of the association between early-life diseases and lifetime childlessness in a large population.

Previous research has primarily focused on specific diseases' impact on childlessness, mostly in women. Studies have examined the link between reproductive biology-related diseases like recurrent miscarriage, polycystic ovary syndrome, and endometriosis, and childlessness. The relationship between infertility and inflammatory bowel disease (IBD) has also been extensively investigated, with studies showing that up to one-third of individuals with IBD choose to remain childfree, often due to a lack of knowledge about pregnancy-related IBD issues or increased risk of adverse pregnancy outcomes. Similar research has explored the association between multiple sclerosis and childlessness, linking it to relationship instability, fear of genetic transmission, and treatment discontinuation. While fecundity in patients with major psychiatric disorders and genetic liability for schizophrenia has been studied, research regarding men's experiences remains limited, often confined to highly selective samples from infertility clinics. Existing research suffers from several limitations: it primarily examined individual diseases in isolation, lacking a systematic assessment of multiple diseases' combined impact; it often neglected sex-specific associations due to differing reproductive patterns and disease prevalence/severity; and it used limited time horizons and methodological tools to control for confounding familial factors. This study addresses these limitations.

This study leveraged high-quality nationwide population registers from Finland and Sweden, encompassing individuals born between 1956 and 1973 (men born between 1956 and 1968; women born between 1956 and 1973). The study followed these individuals to the end of their reproductive lifespan (age 45 for women and age 50 for men) in 2018. The study population included over 2.5 million individuals (1,425,640 women and 1,119,380 men). Researchers utilized a disease-agnostic family-based approach using nationwide registers to associate sociodemographic and reproductive information with 414 disease diagnoses across 16 categories. The primary outcome was childlessness (no live-born children by the end of the reproductive lifespan), and the secondary outcome was singlehood (no registered partner by age 45 for women and age 50 for men). The main analysis employed a matched-pair case-control design, using same-sex sibling pairs discordant for childlessness (71,524 full-sister and 77,622 full-brother pairs). Within each pair, a childless sibling was matched with a sibling with children (closest in birth order). Disease diagnoses were considered only if they occurred before the first birth of the sibling with children. Conditional logistic regression was used to analyze the associations between disease diagnoses and childlessness, adjusting for birth year. The analysis further explored sex-specific effects, age-at-onset effects, and the mediating role of singlehood and education. Several sensitivity analyses were performed, including a population-based matched case-control design, an analysis restricted to individuals alive at the end of follow-up, a Cox proportional hazards model, and analyses adjusting for education level. The meta-analysis was performed to combine findings from both countries.

The study found significant associations between early-life diseases and childlessness in both men and women. Mental-behavioral disorders were strongly associated with childlessness, particularly in men (OR = 3.2, 95% CI [2.6–4.0]). Congenital anomalies and endocrine-nutritional-metabolic disorders showed strong associations with childlessness, especially in women (OR = 3.1, 95% CI [2.6–3.7]). Specific diseases within these categories showed particularly strong associations: mild intellectual disability (men: OR = 21.7, 95% CI [10.8–43.5]), cerebral palsy (women: OR = 13.4, 95% CI [7.9–22.7]), and obesity (men: OR = 2.7, 95% CI [2.0–3.6]). The study also identified new associations between inflammatory and autoimmune diseases and childlessness. Sex-specific effects were observed, with mental-behavioral disorders like schizophrenia and alcohol intoxication showing stronger associations in men, whereas type 1 diabetes and congenital anomalies had stronger associations in women. Age-at-onset of disease also impacted the strength of the association, with the strongest associations occurring between 21-25 years old for women and 26-30 years old for men. Singlehood played a significant mediating role in the association between diseases and childlessness, accounting for 29.3% (median) of the effect in women and 37.9% in men. Several diseases retained strong associations with childlessness even among partnered individuals, including obesity and type 1 diabetes. Sensitivity analyses using population-based designs yielded similar results, although some associations were stronger in the population-based analysis. The study also found that childless individuals are more similar to their siblings with one child than those with more children regarding risk for childlessness-associated early-life diseases.

This study provides strong evidence for a link between early-life diseases and lifetime childlessness, highlighting the complexity of factors contributing to this phenomenon. The findings extend beyond previous research by considering a broad range of diseases and accounting for sex-specific differences and the mediating role of singlehood and education. The significant associations found between mental-behavioral disorders and childlessness in men suggest the importance of considering mental health in fertility research. The strong associations observed with congenital anomalies and endocrine-nutritional-metabolic disorders in women underscore the impact of physical health on reproductive outcomes. The identification of new associations with inflammatory and autoimmune diseases opens up avenues for future research. The mediating role of singlehood highlights the social and relational context surrounding fertility, emphasizing the need for a holistic understanding that goes beyond individual health factors. While this study primarily identifies associations, not causal relationships, it provides valuable insights into potential mechanisms contributing to involuntary childlessness and can inform the development of public health interventions.

This comprehensive study using nationwide registers from Finland and Sweden revealed robust associations between early-life diseases and lifetime childlessness. The findings demonstrate significant sex-specific effects, highlight the mediating role of singlehood and education, and identify new associations with inflammatory and autoimmune diseases. This research underscores the need for a multi-faceted approach to understanding childlessness, considering both individual health and social factors. Future research should investigate the causal pathways involved, explore potential interventions targeting involuntary childlessness, and replicate these findings in diverse populations.

Several limitations should be considered when interpreting the results. The reliance on secondary and tertiary health care data may lead to underreporting of less severe diseases. The use of harmonized ICD codes across different versions might affect the accuracy of disease classification. The study population is limited to individuals born between 1956 and 1973, potentially limiting the generalizability of findings to more recent cohorts. The study could not definitively distinguish between voluntary and involuntary childlessness due to a lack of data on reproductive intentions. Assortative mating and residual confounding factors could influence the interpretation of results. The use of only individuals with same-sex full siblings might also introduce selection bias.