Researchers mapped 569 diagnoses among more than 10 million US siblings to examine how birth order relates to disease risk, according to an Aug. 4 report. The study, published in Nature Health, analyzed inpatient, outpatient, and pharmacy claims from approximately five million two-child families using the Merative MarketScan dataset.
The findings showed that first-born individuals had higher odds of recorded neurodevelopmental and immune-allergic conditions. In contrast, second-born siblings had higher odds of substance abuse and gastrointestinal disorders. The strongest first-born excesses were seen for other/unspecified pervasive developmental disorder code group, tics/Tourette syndrome, and autism. Significant associations were also observed for attention-deficit/hyperactivity disorder (ADHD), food allergies, and allergic rhinitis among first-borns. Second-born participants showed higher odds of conditions such as gastritis and duodenitis.
The researchers conducted both within-family comparisons—using 5.1 million two-child families—and between-family comparisons—using 1.6 million matched pairs from different families matched on several demographic factors. Disease risk was assessed using logistic regression models that adjusted for demographic, parental age, geographical, clinical, and observation-related factors in the between-family analysis; conditional logistic regression stratified by family was used for within-family analysis.
A comprehensive disease atlas was developed to illustrate the directionality of birth-order effects across diseases. Of the diseases analyzed across families with at least 500 cases or sufficient sibling pairs with discordant diagnoses, a total of 150 associations met stringent statistical thresholds accounting for multiple testing.
First-born excesses were particularly pronounced in neuropsychiatric domains but also present in dermatological conditions; respiratory and endocrine/metabolic conditions showed bidirectional associations by birth order status. Second-born excesses were found among digestive disorders as well as circulatory, genitourinary, musculoskeletal, and infectious conditions—though many domain-level shifts weakened when restricting analysis within families.
The study noted limitations including reliance on claims data rather than true incidence rates; potential residual confounding from healthcare-seeking behavior or parental age; age-related differences; calendar-period effects; cohort differences; and restriction to two-child families only. Researchers said future studies should test whether these patterns replicate in larger sibships or more diverse populations before applying findings to family counseling or screening prioritization.
