Maternal Autoimmune Diseases Tied to Higher Risk of ADHD in Offspring

-Future studies should focus on mechanisms underlying this association, says expert

by Zeena Nackerdien PhD, CME Writer, MedPage Today 2021-01-27

Maternal Autoimmune Diseases Tied to Higher Risk of ADHD in Offspring | MedPage Today

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Study Authors: Timothy C. Nielsen, Natasha Nassar, et al.; Søren Dalsgaard

Target Audience and Goal Statement: Pediatricians, obstetrician-gynecologists, rheumatologists

The goal of this study was to examine the association of maternal autoimmune diseases with attention deficit-hyperactivity disorder (ADHD) in children.

Question Addressed:

  • Do maternal autoimmune diseases increase risk of ADHD in children?

Study Synopsis and Perspective:

Autoimmune diseases affect 3%-9% of the world’s population, disproportionately affecting reproductive-age women. Emerging evidence suggests that immune-related cells and proteins may also play a role in brain development and function, and that maternal immune activation increases the risk of neurodevelopmental disorders in children.

Action Points

  • Children whose mothers had an autoimmune disease were more likely to develop attention deficit-hyperactivity disorder (ADHD), according to results of a cohort study and meta-analysis.
  • Note that the study findings suggest possible shared genetic or environmental factors between autoimmune diseases and ADHD.

While such associations have been found for schizophrenia, bipolar disorder, depression, and autism spectrum disorder, fewer studies have examined associations with obsessive-compulsive disorder, tic disorder, and ADHD.

ADHD, which affects an estimated 5% of children globally, is characterized by inattention or hyperactivity-impulsivity, as well as comorbidity with other neurodevelopmental disorders.

Most of the studies reporting an increased risk of ADHD among women with specific autoimmune diseases have been limited by small sample sizes or limited case numbers.

According to results of a cohort study and meta-analysis published in JAMA Pediatrics, children whose mothers had an autoimmune disease were more likely to develop ADHD.

Mothers with an autoimmune disease were 30% more likely to have a child with ADHD (hazard ratio [HR] 1.30, 95% CI 1.15-1.46), reported Timothy Nielsen, MPH, of the University of Sydney in Australia, and colleagues.

Nielsen’s group conducted a systematic review of the literature published before November 2019, along with an analysis of a dataset from New South Wales, Australia, covering all singleton live births that took place from 2000 to 2014. In particular, the group looked for hospitalizations for both mother and child up to 2012, and matched birth data to children’s pharmaceutical information to determine ADHD treatment. Children in the study were followed until 2014.

In total, 831,718 infants were included in the study. Of these, 12,767 were born to mothers with an autoimmune disorder.

Mothers had a mean age of 29, and those with an autoimmune disease were more likely to also have a mental health diagnosis versus their counterparts without an autoimmune disease (23.4% vs 13.3%).

Babies in the autoimmune disease cohort were matched to a control group of over 50,000 infants, for a population of 63,050 infants.

A total of 1,094 male children and 332 female children were diagnosed with ADHD — defined as an authorization or filled prescription for stimulant treatment or a hospital diagnosis of ADHD — during follow-up.

In addition, type 1 diabetes (HR 2.23, 95% CI 1.66-3.00), psoriasis (HR 1.66, 95% CI 1.02-2.70), and rheumatic fever or rheumatic carditis (HR 1.75, 95% CI 1.06-2.89) were all associated with an increased risk of ADHD in offspring.

In a sensitivity analysis restricted to exposed children whose mothers were diagnosed before or within 180 days of birth (n=9,700) and their matched controls (n=38,800), all maternal autoimmune diseases and type 1 diabetes remained associated with ADHD in children.

Restricting the cohort to children with at least 8 years of follow-up did not appreciably change estimates, and there was no evidence of effect modification by child sex.

In a systematic review of six studies (including this one), the researchers found that any autoimmune illness (HR 1.20, 95% CI 1.03-1.38), type 1 diabetes (HR 1.53, 95% CI 1.27-1.85), hyperthyroidism (HR 1.15, 95% CI 1.06-1.26), and psoriasis (HR 1.31, 95% CI 1.10-1.56) were all associated with ADHD.

Nielsen’s group acknowledged that mothers with an autoimmune disorder recorded in this study were likely undercounted, since they did not include patients who received care for autoimmune illnesses in primary care or outpatient settings. They also did not include any data about medications mothers took during pregnancy or disease severity, which may have influenced their results.

Source References: JAMA Pediatrics 2021; DOI: 10.1001/jamapediatrics.2020.5487

Editorial: JAMA Pediatrics 2021; DOI: 10.1001/jamapediatrics.2020.5502

Study Highlights and Explanation of Findings:

In a population-based cohort study and combined systematic review and meta-analysis, it was found that maternal autoimmune diseases were associated with ADHD in children.

« Our study provides justification for future studies that examine the effect of maternal autoimmune diseases, including biomarkers, condition severity, and management in pregnancy and in the periconception period, on neurodevelopmental disorders in children, » the researchers wrote. « It also highlights the importance of high-quality multidisciplinary care for women with autoimmune diseases and their children. »

They called for healthcare providers to discuss reproductive goals with women who have autoimmune diseases and to encourage planning pregnancies when the disease is stable and well managed. The offspring of these women might also benefit from additional follow-up and support for developmental issues.

In an accompanying editorial, Søren Dalsgaard, MD, PhD, of Aarhus University in Denmark, called the results « important » but noted that for the many different autoimmune diseases, varying underlying mechanisms for the associations with disorders of the central nervous system were likely.

Dalsgaard said that there were potential mechanisms outlined in this article, such as shared genetic or environmental factors between autoimmune illness and ADHD, or the « direct effects of maternal autoantibodies or cytokines crossing the placenta and altering the fetal immune response. » But he added that these explanations need further investigation.

« Neither this hybrid article by Nielsen et al. nor the previously published epidemiologic studies give any clear answers as to which mechanisms may explain the association between autoimmune diseases and ADHD, » he wrote. « Still, there is a growing body of evidence for associations between both the overall category and some specific autoimmune diseases and ADHD. »

« Our team is currently working on research into the causal mechanisms that underlie the association between autoimmune disease and ADHD, » Nielsen said in a statement. This may shed light on whether the « severity of disease, symptoms, use of medications or other inflammatory factors modifies this risk of ADHD. »

Reviewed by Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco

Primary Source

JAMA Pediatrics

Source Reference: Nielsen TC, et al « Association of maternal autoimmune disease with attention-deficit/hyperactivity disorder in children » JAMA Pediatr 2021; DOI: 10.1001/jamapediatrics.2020.5487.

Secondary Source

JAMA Pediatrics

Source Reference: Dalsgaard S « More evidence linking autoimmune diseases to attention-deficit/hyperactivity disorder » JAMA Pediatr 2021; DOI: 10.1001/jamapediatrics.2020.5502.

Additional Source

MedPage Today

Source Reference: D’Ambrosio A « Study IDs Puzzling Risk Factor for ADHD » 2021.

ADHD » 2021.