Clinical Context

Prevalence of autoimmune diseases exceeds 5%, and these diseases carry a high morbidity burden. Most autoimmune diseases are more common in women of reproductive age. Animal studies suggest that maternal immune activation can trigger changes in brain morphology, abnormal neurotransmitter activity, and behavioral deficits in offspring, implicating intrauterine exposure to immunologic insults in the pathophysiology of mental disorders.

Empirical evidence suggests links between certain maternal autoimmune diseases, including type 1 diabetes and rheumatoid arthritis, and specific mental disorders in offspring, including autism spectrum disorder and attention-deficit/hyperactivity disorder (ADHD).

Study Synopsis and Perspective

Mental disorders were significantly more likely in children whose mothers had 1 of 5 common autoimmune diseases, a new study has found.

Previous research has linked both maternal and paternal autoimmune diseases and specific mental disorders, such as ADHD, but most of these studies focused on specific conditions in relatively small populations. The new study included data on more than 2 million births, making it one of the largest efforts to date to examine the association, according to the researchers, whose findings were published in JAMA Network Open.

Previous evidence of the possible association between certain maternal autoimmune diseases and mental disorders in offspring has been "scattered and limited," which "hampered an overall understanding" of the link, Fei Li, MD, the corresponding author of the study, told Medscape Medical News.

Dr Li, from Shanghai Jiao Tong University School of Medicine, in China, and colleagues reviewed data from a Danish registry cohort of singleton births with up to 38 years of follow-up. They explored associations between a range of maternal autoimmune diseases diagnosed before childbirth and the risks for mental disorders in children in early childhood through young adulthood.

The study population included 2,254,234 births and 38,916,359 person-years. Data on mental health were collected from the Psychiatric Central Research Register and the country's National Patient Register. The median age of the children at the time of assessment was 16.7 years; approximately half were male.

A total of 50,863 children (2.26%) were born to mothers who had been diagnosed with autoimmune diseases before childbirth. During the follow-up period, 5460 children of mothers with autoimmune diseases and 303,092 children of mothers without autoimmune diseases were diagnosed with a mental disorder (10.73% vs 13.76%), according to the researchers.

The risk of being diagnosed with a mental disorder was significantly higher among children of mothers with any autoimmune disease (hazard ratio [HR], 1.16), with an incidence of 9.38 vs 7.91 per 1000 person-years, the researchers report.

The increased risk persisted when the results were classified by organ system, including connective tissue (HR, 1.24), endocrine (HR, 1.19), gastrointestinal (HR, 1.11), blood (HR, 1.10), nervous (HR, 1.17), and skin (HR, 1.19) systems.

The 5 autoimmune diseases in mothers that were most commonly associated mental health disorders in children were type 1 diabetes, rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, and psoriasis vulgaris.

The greatest risk for children of mothers with any autoimmune disease was observed for organic conditions such as delirium (HR, 1.54), followed by obsessive-compulsive disorder (HR, 1.42), schizophrenia (HR, 1.35), and mood problems (HR, 1.12).

Children of mothers with any autoimmune disorder also had a significantly increased risk for childhood autism (HR, 1.21), intellectual disability (HR, 1.19), and ADHD (HR, 1.19).

The results add to evidence that activation of the maternal immune system may drive changes in the brain and behavioral problems, which has been observed in animal studies, the researchers write.

Potential underlying mechanisms in need of more exploration include genetic risk factors, maternal transmission of autoantibodies to the fetus during pregnancy, and the increased risk for obstetric complications, such as preterm birth, for women with autoimmune disorders that could affect mental development in children, the authors add.

The study findings were limited by several factors, including the lack of data on the potential exacerbation of autoimmune disease activity during pregnancy and its effect on the fetus, the researchers note. Other limitations included potential detection bias, lack of data on mental disorders in adulthood, and potential changes in diagnostic criteria during the long study period.

The results were strengthened by the use of a population-based registry, the large sample size, and the ability to consider a range of confounders, the researchers say.

"This study could help acquire a comprehensive compilation of the associations between maternal autoimmune disorders diagnosed before childbirth and offspring's mental disorders from childhood through early adulthood," Dr Li told Medscape Medical News.

For clinicians, Dr Li said, the findings suggest that the offspring of mothers with autoimmune diseases may benefit from long-term surveillance for mental health disorders.

"Further studies should provide more evidence on the detailed associations of specific maternal autoimmune diseases with a full spectrum of mental disorders in offspring, and more research on underlying mechanisms is needed as well," she said.

M. Susan Jay, MD, an adjunct professor of pediatrics at the Medical College of Wisconsin, Milwaukee, said that previous efforts to examine the association between maternal autoimmunity were hampered by study design, small samples, and self-report of disease history--problems the new research avoids.

The large patient population allowed for detailed subgroup analysis of different conditions and outcomes. Another advantage was the availability of sociodemographic and clinical information, which allowed for the elimination of confounding factors, said Dr Jay, who was not involved in the research.

"It would be prudent to follow children of mothers with autoimmune disorders before or during pregnancy for mental health issues, and if identified clinically, to offer psychological and developmental behavioral support options," Dr Jay added.

The authors have reported no relevant financial relationships.

JAMA Netw Open. April 15, 2022.^[1]

Clinical Implications

• Prenatal exposure to most autoimmune diseases was associated with modestly increased risks for overall and type-specific mental disorders in offspring.
• If these findings are confirmed in future studies, they may have important implications for early screening and appropriate intervention for children at high risk for mental disorders.
• Implications for the Health Care Team: Offspring of mothers with autoimmune diseases may benefit from long-term surveillance for a wide spectrum of mental disorders.

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