Could Childhood ADHD Have Its Roots in Perinatal Autoimmune Disorders?

RESEARCH UPDATE
The importance of maternal mental health for fetal development has been the subject of extensive study.^1,2 Researchers have also investigated the possibility that other perinatal illnesses, like viral or bacterial infections, could increase the risk of a child later developing psychiatric conditions such as schizophrenia.³

Perinatal immunological diseases may have long-term effects, too, especially because the immune system plays a role in brain development.⁴ There is evidence that activation of the maternal immune system during pregnancy—whether by infection, chronic inflammation, or autoimmune disease—is associated with increased risk of neurodevelopmental disorders in the offspring.^5,6 In the case of the latter, maternal autoantibodies may cross the placenta and alter fetal development through epigenetic changes, brain microglial cell activation, and modulation of synapses.⁷

Previous studies have focused on the association between maternal autoimmune disease and autism spectrum disorders, whereas attention-deficit/hyperactivity disorder (ADHD) has been less studied. Only 1 previous study examined the association between any maternal autoimmune disease and ADHD risk in children.⁸ A recent paper, however, set out to investigate the association between any (and specific) maternal autoimmune disease and ADHD in children, and to incorporate those results into a systematic review and meta-analysis on this topic.⁹

Collecting the Data

Using the New South Wales (NSW) Perinatal Data Collection, Nielson and colleagues identified all women with full-term, singleton live births from July 2000 to December 2010. Birth data were linked to all hospital admissions for both mother and child, and pharmaceutical data for the child for treatment of ADHD through registers. A child was considered to have ADHD if they had a stimulant prescription for ADHD and/or a hospital diagnosis of ADHD. Children linked to a first ADHD event before age 3 years were excluded. Children were followed to death or at the end of follow-up in December 2014.

Maternal autoimmune disease was determined based on the mother’s hospitalization records. Children whose mother had at least 1 hospitalization for autoimmune disease were considered exposed. Exposed and nonexposed mothers were propensity matched based on age, country of birth, socioeconomic status, place of residency, parity, smoking during pregnancy, and mental health diagnosis. Cox proportional hazard models were used to examine the association of maternal autoimmune disease and ADHD, adjusting for child sex. Analyses were performed for any maternal autoimmune disease and individual conditions with at least 15 cases of ADHD among exposed children.

The authors also performed a systematic search of MEDLINE, Embase, and Web of Science to identify studies on the association between maternal autoimmune disease and ADHD. Studies were assessed for quality using the Newcastle-Ottawa Quality Assessment Scale. Meta-analyses of any (and specific) maternal autoimmune disease with ADHD in the offspring were performed by calculating random-effects pooled hazard ratios (HRs) and inverse-variance weighting.

In the NSW Perinatal Data Collection, 831,718 mothers and children were included, and 12,767 children (1.5%) were exposed to maternal autoimmune disease. Propensity score matching included a cohort of 12,610 exposed children and 50,440 controls. During follow-up, 1094 male (3.4%) and 332 female (1.1%) children were diagnosed with ADHD. After adjustment, any maternal autoimmune disease (HR, 1.30), type 1 diabetes mellitus (HR, 2.23), psoriasis (HR, 1.66), and rheumatic fever or carditis (HR, 1.75) were associated with increased risk of ADHD, and this association was not moderated by child sex (Figure). When considering mothers diagnosed before or within 180 days of birth (N = 9700), any maternal autoimmune disease (HR, 1.28) and type 1 diabetes mellitus (HR, 1.95) remained significantly associated with ADHD.

Five studies, including the present cohort, were included in the meta-analysis. Two studies estimated the association with any maternal autoimmune disease, and 11 specific conditions were investigated in 2 or more individual studies. In the meta-analyses, any maternal autoimmune disease (HR, 1.20), type 1 diabetes mellitus (HR, 1.53), hyperthyroidism (HR, 1.15), and psoriasis (HR, 1.31) were all associated with increased risk of ADHD.

Study Findings

The authors found an association between any maternal autoimmune disease, type 1 diabetes mellitus, and psoriasis in both the present study and meta-analysis, and an association with hyperthyroidism in the meta-analysis. They noted significant heterogeneity in findings across individual studies, and that nonimmune factors such as glycemic control (in type 1 diabetes) and endocrine aspects of hyperthyroidism may also contribute to associations with ADHD.

Strengths of the present study include the hybrid design, including a large population-based cohort and meta-analysis. Limitations include the lack of outpatient/primary care records for identifying maternal autoimmune disease, absence of data on the clinical status of the mother’s autoimmune disease and associated medications, and absence of data on nonstimulant ADHD medications and severity of ADHD.

The Bottom Line

Maternal autoimmune disease is associated with increased risk of ADHD in offspring, adding evidence that adverse maternal immune function during pregnancy may alter fetal neurodevelopment. Children of affected mothers may benefit from additional follow-up and support for developmental issues.

Dr Miller is a professor in the Department of Psychiatry and Health Behavior, Augusta University, Augusta, Georgia. He is on the editorial board and serves as the schizophrenia section chief for Psychiatric Times^TM. The author reports that he receives research support from Augusta University, the National Institute of Mental Health, the Brain and Behavior Research Foundation, and the Stanley Medical Research Institute.

References

1. Stein A, Pearson RM, Goodman SH, et al. Effects of perinatal mental disorders on the fetus and child. Lancet. 2014;384(9956):1800-1819.

2. Muzik M, Borovska S. Perinatal depression: implications for child mental health. Ment Health Fam Med. 2010;7(4):239-247.

3. Miller B. Maternal infection during pregnancy: increased risk of psychosis in offspring. Psychiatric Times. 2019;36(12):29.

4. Kipnis J. Multifaceted interactions between adaptive immunity and the central nervous system. Science. 2016;353(6301):766-771.

5. Knuesel I, Chicha L, Britschgi M, et al. Maternal immune activation and abnormal brain development across CNS disorders. Nat Rev Neurol. 2014;10(11):643-660.

6. Estes ML, McAllister AK. Maternal immune activation: implications for neuropsychiatric disorders. Science. 2016;353(6301):772-777.

7. Gumusoglu SB, Stevens HE. Maternal inflammation and neurodevelopmental programming: a review of preclinical outcomes and implications for translational psychiatry. Biol Psychiatry. 2019;85(2):107-121.

8. Rising Nielsen P, Eriksen Benros M, Dalsgaard S. Associations between autoimmune diseases and attention-deficit/hyperactivity disorder: a nationwide study. J Am Acad Child Adolesc Psychiatry. 2017;56(3):234-240.e1.

9. Nielsen TC, Nassar N, Shand AW, et al. Association of maternal autoimmune disease with attention-deficit/hyperactivity disorder in children. JAMA Pediatr. 2021;175(3):e205487. ❒