Abstract
IMPORTANCE: Maternal immune activation (MIA) leading to altered neurodevelopment in utero is a hypothesized risk factor for psychiatric outcomes in offspring. Primary antibody immunodeficiencies (PIDs) constitute a unique natural experiment to test the MIA hypothesis of mental disorders. OBJECTIVE: To assess the association of maternal and paternal PIDs with psychiatric disorders and suicidal behavior in offspring. DESIGN, SETTING, AND PARTICIPANTS: Cohort study of 4 294 169 offspring of parents with and without PIDs living in Sweden at any time between 1973 and 2013. Data were extracted from Swedish nationwide health and administrative registers and were analyzed from May 5 to September 30, 2022. All individuals with diagnoses of PIDs identified between 1973 and 2013 from the National Patient Register were included. Offspring were included if born before 2003. Parent-offspring pairs in which both parents had a history of PIDs were excluded. EXPOSURES: Lifetime records of parental PIDs according to the International Classification of Diseases, Eighth Revision (ICD-8); International Classification of Diseases, Ninth Revision (ICD-9); and International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) diagnostic codes. MAIN OUTCOMES AND MEASURES: Lifetime records of 10 psychiatric disorders and suicidal behavior identified using ICD-8, ICD-9, and ICD-10 diagnostic codes, including suicide attempts and death by suicide, among offspring. Covariates included sex, birth year, parental psychopathology, suicide attempts, and autoimmune diseases. Additional analyses excluded offspring with their own PIDs and autoimmune diseases. Poisson regression models were fitted separately for mothers and fathers to estimate incidence rate ratios (IRRs) and 95% CIs for the risk of psychiatric and suicidal behavior outcomes in the offspring of PID-exposed vs PID-unexposed mothers or fathers. RESULTS: The cohort included 4 294 169 offspring (2 207 651 males [51.4%]) and 3 954 937 parents (1 987 972 females [50.3%]). A total of 7270 offspring (0.17%) had parents with PIDs, and 4 286 899 offspring had parents without PIDs. In fully adjusted models, offspring of mothers with PIDs had an increased risk of any psychiatric disorder, while no such risks were observed in offspring of fathers with PIDs (IRR, 1.17; 95% CI, 1.10-1.25 vs IRR, 1.03; 95% CI, 0.94-1.14; P < .001). Likewise, an increased risk of suicidal behavior was observed among offspring of mothers with PIDs but not offspring of fathers with PIDs (IRR, 1.20; 95% CI, 1.06-1.36 vs IRR, 1.10; 95% CI, 0.91-1.34; P = .01). For the offspring of mothers with PIDs, the risk of developing any psychiatric disorder was significantly higher for those with mothers with 6 of 10 individual disorders, with IRRs ranging from 1.15 (95% CI, 1.04-1.26) for anxiety and stress-related disorders and 1.15 (95% CI, 1.03-1.30) for substance use disorders to 1.71 (95% CI, 1.37-2.14) for bipolar disorders. Offspring of mothers with both PIDs and autoimmune diseases had the highest risk for any psychiatric disorder (IRR, 1.24; 95% CI, 1.11-1.38) and suicidal behavior (IRR, 1.44; 95% CI, 1.17-1.78). CONCLUSIONS AND RELEVANCE: Findings of this cohort study suggest that maternal, but not paternal, PIDs were associated with a statistically significant increased risk of psychiatric disorders and suicidal behavior in the offspring, particularly when PIDs co-occur with autoimmune diseases. These findings align with the MIA hypothesis of mental disorders, but the precise mechanisms remain to be elucidated.