Offspring of Mothers With Primary Immunodeficiencies at an Increased Risk of Psychiatric Disorders

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The same risk was not found for offspring of fathers with primary immunodeficiencies.

A new analysis shows offspring of mothers with primary immunodeficiencies are at an increased risk of several psychiatric disorders, including anxiety and depression, as well as suicidal behavior1.

A team, led by Josef Isung, MD, PhD, Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, assessed the association of maternal and paternal primary immunodeficiencies with psychiatric disorders and suicidal behavior in offspring.

“Maternal immune activation (MIA) leading to altered neurodevelopment in utero is a hypothesized risk factor for psychiatric outcomes in offspring,” the authors wrote. “Primary antibody immunodeficiencies constitute a unique natural experiment to test the MIA hypothesis of mental disorders.”

A Large Cohort

In the study, the investigators examined the data of 4.3 million offspring of parents with and without primary immunodeficiencies in Sweden between 1973-2013 from the Swedish nationwide health and administrative registers. The team exclude parent-offspring pairs where both parents had a history of primary immunodeficiencies, as well as offspring with their own immunodeficiencies and autoimmune diseases.

The investigators identified lifetime records of 10 psychiatric disorders and suicidal behave or, including suicide attempts and death by suicide, among offspring. The covariates included sex, birth year, parent psychopathology, suicide attempts, and autoimmune diseases.

The team fitted Poisson regression models separately for mothers and fathers to estimate incidence rate ratios (IRRs) and 95% confidence intervals (CI) for the risk of psychiatric disorders and suicidal behavior outcomes in offspring with primary immunodeficiencies parents (n = 7270; 0.17%) compared to unexposed mothers or fathers (n = 4.2 million).

The Risk

Using the fully adjusted models, the investigators found offspring of mothers with primary immunodeficiencies had an increased risk of any psychiatric disorders. On the other hand, offspring of fathers with primary immunodeficiencies had no risk (IRR, 1.17; 95% CI, 1.10-1.25 compared to IRR, 1.10; 95% CI, 0.94-1.14; P <.001).

The results also show an increased risk of suicidal behavior among offspring of mothers with primary immunodeficiencies, but similarly did not find the same risk in the offspring of fathers with primary immunodeficiencies (IRR, 1.20; 95% CI, 1.06-1.36 vs IRR, 1.10; 95% CI, 0.91-1.34; P = .01).

Specifically in the cohort of offspring of mothers with primary immunodeficiencies, the risk of developing any psychiatric disorder was significantly higher if the mothers had 6 of the 10 individual disorders. The IRR ranged 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.

Moreover, the offspring of mothers with both primary immunodeficiencies and autoimmune diseases were at the highest risk of any psychiatric disorder (IRR, 1.24; 95% CI, 1.11-1.38) and suicidal behavior (IRR, 1.44; 95% CI, 1.17-1.78).

“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,” the authors wrote. “These findings align with the MIA hypothesis of mental disorders, but the precise mechanisms remain to be elucidated.”


Isung J, Isomura K, Williams K, et al. Association of Primary Immunodeficiencies in Parents With Psychiatric Disorders and Suicidal Behavior in Their Offspring. JAMA Psychiatry. Published online February 01, 2023. doi:10.1001/jamapsychiatry.2022.4786