March 25, 2025

Population Study Finds No Effect of Maternal and Childhood Infection on Subsequent Offspring ADHD

Maternal infections and inflammatory responses during pregnancy have been proposed as risk factors for neurodevelopmental disorders such as ADHD. 

Taiwan has a single-payer health insurance system that covers virtually the entirety of its population. Its Ministry of Health and Welfare maintains the National Health Insurance Research Database (NHIRD), with detailed information on outpatient services, hospitalizations, and medical treatment for nearly 99% of all residents. 

A Taiwanese study team used NHIRD to examine to examine the relationship between maternal hospitalization for infection, and early childhood infection, and subsequent ADHD in offspring. The study cohort originated with all 3,260,879 individuals born between 2001 and 2018. 

The team excluded births from foreign mothers, still births, births with congenital defects, low birth weights, abnormally late births, twins, triplets, and other multiple births, culminating in a final population cohort of 2,885,662 live-born single infants across 1,893,171 families, and 1,864,660 individuals with full siblings from 872,169 families comprising the full sibling cohort. 

Study participants were followed until diagnosis of a neurodevelopmental disorder, their death, or the end of 2021. 

After adjusting for sex, birth year, paternal and maternal ages, birthweight, birth season, parity, delivery method, 1 minute APGAR score (evaluating baby’s appearance, pulse, grimace, activity and respiration at birth), gestational age, pregnancy and delivery complications, parental history of neurodevelopmental disorders, maternal asthma and diabetes, urbanization level of the residential area, and family’s insurance amount, offspring of mothers hospitalized for infections had 14% greater odds of being subsequently diagnosed with ADHD. 

However, in the full sibling cohort of over 1.8 million, this association vanished. That held true for each of the three trimesters of pregnancy. It also held true for bacterial infections. Surprisingly, offspring of mothers hospitalized for viral infections were 24% less likely to be diagnosed with ADHD than their siblings not exposed to maternal viral infection. Because of that, they also had a 6% lower risk overall. 

After the same adjustments, early childhood infection was associated with 16% greater odds of being diagnosed with ADHD. 

Nevertheless, in the full sibling cohort of over 1.8 million, this association again vanished. That held true overall, as well as separately for childhood infections in months 1-6 and months 7-12. The association vanished altogether both for bacterial infections as well as for viral infections. 

The authors concluded, “the results of this nationwide birth cohort study with population and sibling analyses suggest that the association between maternal infection during pregnancy and offspring neurodevelopmental risk is largely due to familial confounding factors.” 

Mei-Chen Lin, Yi-Jiun Pan, Chi-Shin Wu, Chia-Lin Liu, Pei-Chun Chen, Wesley K. Thompson, Chun-Chieh Fan, and Shi-Heng Wang, “Prenatal and early childhood infections requiring hospitalization and risk of neurodevelopmental disorders in offspring: a population-based birth cohort study in Taiwan,” Molecular Psychiatry (2024), https://doi.org/10.1038/s41380-024-02787-z.

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Updates on ADHD and Vitamin D

The Background on ADHD and Vitamin D

In a blog published in the early days of The ADHD Evidence Project, we discussed an Iranian study examining the association between Vitamin D levels and ADHD in children. The meta-analysis combined 13 studies for a total of 10,344 participants. The researchers found that youth with ADHD had "modest but significant" lower serum concentrations of 25-hydroxyvitamin D compared to those without ADHD.

They also identified four prospective studies that compared maternal vitamin D levels with the subsequent development of ADHD symptoms in their children. Two of these used maternal serum levels, and two used umbilical cord serum levels. Together, these studies found that low maternal vitamin D levels were associated with a 40% higher risk of ADHD in their children. 

Ultimately, the researchers noted that this result "should be considered with caution" because it was heavily dependent on one of the prospective studies included in the analysis. We concluded our blog by pointing out that further research, including more longitudinal studies, is needed before clinicians should start recommending vitamin D supplementation to ADHD patients. 

Further Research: 

Since publishing that initial blog, several more studies have been published about this association. 

The World Federation of Societies of Biological Psychiatry (WFSBP) and the Canadian Network for Mood and Anxiety Disorders (CANMAT) convened an international task force involving 31 leading academics and clinicians from 15 countries between 2019 and 2021. Their goal was to provide a definitive, evidence-based report to assist clinicians in making decisions around the recommendation of nutraceuticals and phytoceuticals for major psychiatric disorders.

For ADHD, the guidelines found only weak support for micronutrients and vitamin D in treatment. Overall, the task force concluded that nutraceuticals and phytoceuticals currently offer very limited evidence‑based benefit for ADHD management.

Another study published in 2023 systematically assessed the results of previously published studies to examine the associations between maternal vitamin D levels, measured as circulating 25(OH)D levels in pregnancy or at birth, and later offspring psychiatric outcomes. This study found a clear association between maternal vitamin D deficiency and subsequent offspring ADHD. They concluded, “Future studies with larger sample sizes, longer follow-up periods, and prenatal vitamin D assessed at multiple time points are needed.”  To that, I will add that studies of this issue should use genetically informed designs to avoid confounding.

Conclusion:

Taking into account the updated research on the topic, there does seem to be an association between low prenatal vitamin D levels and the risk of subsequent offspring ADHD, but it is too soon to say it is a causal relationship due to the possibility of confounding. There is no high-quality evidence, however, that supplementing with vitamin D will significantly reduce symptoms in current ADHD patients. 

July 28, 2025

What Metabolites Tell Us About ADHD — And What This Means for Diet and Treatment

New research has uncovered important links between certain blood metabolites and ADHD by using a genetic method called Mendelian randomization. This approach leverages natural genetic differences to help identify which metabolites might actually cause changes in ADHD risk, offering stronger clues than traditional observational studies.

Key Metabolic Pathways Involved:

The study found 42 plasma metabolites with a causal relationship to ADHD. Most fall into two major groups:

  • Amino acid metabolites from protein metabolism, including those related to tyrosine, methionine, cysteine, and taurine.

  • Fatty acids, especially long-chain polyunsaturated fatty acids (PUFAs) like DHA and EPA, important for brain function.

What Does This Mean for Diet and ADHD?

Since many metabolites come from dietary sources like proteins and fats this supports the idea that diet could influence metabolic pathways involved in ADHD. However, because the study focused on genetic influences on metabolite levels, it doesn’t directly prove that dietary changes will have the same effects.

Notable Metabolites:

  • 3-Methoxytyramine sulfate (MTS): linked to dopamine metabolism, higher genetic levels of MTS were associated with a lower risk of ADHD. Dopamine plays a crucial role in attention and behavior.

  • DHA and EPA: Omega-3 fatty acids abundant in the brain; higher levels were linked to reduced ADHD risk, supporting existing research on omega-3 supplements.

  • N-acetylneuraminate: Involved in brain development and immune function, with higher levels linked to increased ADHD risk, though more research is needed to understand this.

Five metabolites showed bidirectional links with ADHD, meaning genetic risk for ADHD also affects their levels which suggests a complex interaction between brain function and metabolism.

Twelve ADHD-related metabolites are targets of existing drugs or supplements, including:

  • Acetylcysteine: an antioxidant used in various treatments.

  • DHA supplements: widely used to support brain and heart health.

What This Study Doesn’t Show

While these findings highlight biological pathways, they don’t prove that changing diet will directly alter ADHD symptoms. Metabolite levels are shaped by genetics plus environment, lifestyle, and health factors, which require further study.

Conclusion: 

This research provides stronger evidence of metabolic pathways involved in ADHD and points to new possibilities for diagnosis and treatment. Future work could explore how diet or drugs might safely adjust these metabolites to help manage ADHD.

While this study strengthens the link between amino acid and fatty acid metabolism and ADHD risk, suggesting that diet could play a role, ultimately more research is still needed before experts could use this research to give specific nutritional advice.

July 21, 2025

Network Meta-analysis Explores Long-term Efficacy of Nonpharmacological Treatments for Improving Inhibitory Control in Children and Adolescents with ADHD

Background Info:

Executive functions include inhibitory control, working memory, and cognitive flexibility. Inhibitory control is the ability to suppress distractions and focus on goals, which is the main deficit in ADHD. 

Children and adolescents with ADHD often have off-task, unrelated thoughts and are easily distracted, limiting their sustained attention. This makes it difficult for them to focus on tasks and leads to impulsive behaviors that affect their daily life, academics, and social interactions. Improving inhibitory control in ADHD children and adolescents is essential. 

Stimulant medications are commonly used to treat ADHD. However, side effects like insomnia, loss of appetite, and headaches may make parents hesitant to use these medications for their children. 

Non-pharmacological treatments like cognitive training, behavior therapy, and physical exercise have gained attention for their lack of side effects. Research shows that some non-pharmacological methods can improve cognitive outcomes significantly, underscoring their potential in treating ADHD. 

Study:

A Chinese research team identified four key gaps in current research on non-pharmacological treatments for inhibitory control in children with ADHD: 

  • Existing meta-analyses seldom differentiate between short-term and long-term interventions.  
  • Most studies focus primarily on short-term effects and neglect evaluation of maintenance effects through follow-up assessments.  
  • New treatment methods, such as meditation and board games, have not been systematically assessed in meta-analyses for their impact on inhibitory control in children and adolescents with ADHD, leaving their effectiveness uncertain.  
  • Traditional meta-analysis does not tell us which intervention is most effective. Without this comparative analysis, it is difficult to rank efficacy. 

The team therefore performed a network meta-analysis of long-term randomized controlled trials (RCTs) to assess and rank the effectiveness of various non-pharmacological treatments on inhibitory control in children and adolescents with ADHD. 

The team included only RCTs relying on professional diagnoses of ADHD, excluding those based only on parent and teacher rating scales.  

The included studies measured inhibitory control using objective neurocognitive tasks, such as the Stroop test and the Go/No-Go test, to reduce potential subjective bias. Studies relying on parent- or teacher-reported questionnaires were excluded. 

Controls either received no intervention or placebo, such as watching running videos and attending history classes. 

Meta-analysis of 16 studies combining 546 participants found large short-term effect size improvements in inhibitory control from physical exercise. But the two studies with a total of 110 participants that performed a follow-up test reported only a small-to-medium effect size improvement. 

For cognitive training, a meta-analysis of fifteen studies totaling 674 participants reported a medium effect size of short-term improvement in inhibitory control. The ten studies with 563 participants that performed a follow-up test found only a small effect size improvement since treatment initiation. 

For behavioral therapy, meta-analysis of six studies encompassing 244 individuals likewise found a medium effect size short-term improvement in inhibitory control. In this case, however two studies combining 91 participants that performed a follow-up test reported that the medium effect size improvement was maintained. 

For neurofeedback, meta-analysis of seven studies encompassing 186 individuals found a small-to-medium effect size short-term improvement in inhibitory control. The only study that performed a follow-up test reported a small effect size improvement since treatment initiation. 

The two studies with a combined 44 individuals exploring board games found no significant improvement in inhibitory control. Likewise, the two studies combining 32 participants that explored meditation found no significant improvement in inhibitory control. 

There was no indication of publication bias. 

Conclusion:

The team concluded, “Existing evidence shows that physical exercise, behavior therapy, cognitive training, and neurofeedback can effectively improve the inhibitory control of children and adolescents with ADHD. However, meditation, EMG feedback, and board games did not significantly affect inhibitory control. Physical exercise has the best effect among all non-pharmacological treatments, but its impact will be weakened after intervention. Behavior therapy and cognitive training had a slightly lower effect, but they have a better maintenance effect.” 

Ultimately, the study results suggest that non-drug treatments can help children and teens with ADHD improve their ability to control their actions and stay focused. Some methods, like physical exercise, work well at first but may fade once the activity stops. Other methods, like behavioral therapy and cognitive training, may take a little longer to show results but can last longer and make a bigger difference over time. Ultimately, and most importantly, because this work did not study the symptoms of ADHD or its real-world impairments, it provides no reason to change current treatment practices for ADHD.

July 16, 2025