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June 10, 2025
This new meta-analysis confirms what other meta-analysis have already shown, i.e, that there exists in the population an association between maternal smoking during pregnancy and ADHD in their offspring. But reader beware, association does not mean causation.
The team identified 55 studies with quantitative data suitable for meta-analysis, including 11 case-control, 13 cross-sectional, and 31 retrospective/prospective cohort studies.
Altogether they combined more than four million persons in countries spanning six continents, including the United States, Finland, Sweden, Brazil, the Netherlands, Japan, the UK, Spain, China, Australia, New Zealand, Norway, Canada, France, Sweden, South Korea, Turkey, Romania, Bulgaria, Lithuania, Germany, Denmark, Egypt, and India.
Meta-analysis of all 55 studies found that offspring of mothers who smoked tobacco during pregnancy were about 70% more likely to develop ADHD than offspring of mothers who did not smoke during pregnancy.
Because variation in outcomes across studies was very high, the team performed subgroup analyses to explore potential sources of this heterogeneity.
Comparing study designs, cohort studies reported roughly 50% greater odds of ADHD among children of mothers who smoked during pregnancy, whereas case-control studies reported roughly 70% greater odds and cross-sectional studies 2.3-fold greater odds.
Studies using the most reliable method of determining ADHD – clinical interview/professional diagnosis – reported 90% greater odds, contrasting with 66% through medical records/databases and 58% through self-report by child/parent or through teacher report.
Good quality studies reported roughly 75% greater odds.
Studies with sample sizes above two thousand similarly found 70% greater odds.
There was no sign of publication bias using the more commonly used Egger’s test, but a marginal indication of publication bias using Begg’s test. Performing a standard correction reduced the effect size, indicating that the offspring of mothers who smoked tobacco during pregnancy were over 50% more likely to develop ADHD than the offspring of mothers who did not smoke during pregnancy.
The team concluded, “This systematic review and meta-analysis of 55 studies, encompassing over four million participants, provides compelling evidence that maternal tobacco smoking during pregnancy significantly increases the odds of ADHD in children … These findings underscore the critical need for public health interventions aimed at reducing tobacco smoking during pregnancy.”
However, we disagree with this conclusion; The authors ignore substantial evidence showing that maternal smoking during pregnancy is confounded by maternal ADHD. These mothers transmit ADHD via genetics, not via their smoking. This study should be seen not as "...[further evidence that smoking during pregnancy causes ADHD.] ", but as a lesson in how easy it can be to see correlation as causation.
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Mahdi Mohammadian, Lusine G. Khachatryan, Filipp V. Vadiyan, Mostafa Maleki, Fatemeh Fatahian, and Abdollah Mohammadian-Hafshejani, “The association between maternal tobacco smoking during pregnancy and the risk of attention-deficit/hyperactivity disorder (ADHD) in offspring: A systematic review and meta-analysis,” PLOS ONE (2025), 20(2): e0317112, https://doi.org/10.1371/journal.pone.0317112.
Our genes are very important for the development of mental disorders-including ADHD, where genetic factors capture up to 75% of the risk. Until now, the search for these genes had yet to deliver clear results. In the 1990s, many of us were searching for genes that increased the risk for ADHD because we know from twin studies that ADHD had a robust genetic component. Because I realized that solving this problem required many DNA samples from people with and without ADHD, I created the ADHD Molecular Genetics Network, funded by the US NIMH. We later joined forces with the Psychiatric Genomics Consortium (PTC) and the Danish psych group, which had access to many samples.
The result is a study of over 20,000 people with ADHD and 35,000 who do not suffer from it - finding twelve locations (loci) where people with a particular genetic variant have an increased risk of ADHD compared to those who do not have the variant. The results of the study have just been published in the scientific journal Nature Genetics, https://www.nature.com/articles/s41588-018-0269-7.
These genetic discoveries provide new insights into the biology behind developing ADHD. For example, some genes have significance for how brain cells communicate with each other, while others are important for cognitive functions such as language and learning.
Our study used the genome-wide association study (GWAS)methodology because it allowed us to discover genetic loci anywhere on the genome. The method assays DNA variants throughout the genome and determines which variants are more common among ADHDvs. control participants. It also allowed for the discovery of loci having very small effects. That feature was essential because prior work suggested that, except for very rare cases, ADHD risk loci would individually have small effects.
The main findings are:
A) we found 12 loci on the genome that we can be certain harbor DNA risk variants for ADHD. None of these loci were traditional candidate genes' for ADHD, i.e., genes involved in regulating neurotransmission systems that are affected by ADHD medications. Instead, these genes seem to be involved in the development of brain circuits.
B) we found a significant polygenic etiology in our data, which means that there must be many loci(perhaps thousands) having variants that increase the risk for ADHD. We will need to collect a much larger sample to find out which specific loci are involved;
We also compared the new results with those from a genetic study of continuous measures of ADHD symptoms in the general population. We found that the same genetic variants that give rise to an ADHD diagnosis also affect inattention and impulsivity in the general population. This supports prior clinical research suggesting that, like hypertension and hypercholesteremia, ADHD is a continuous trait in the population. These genetic data now show that the genetic susceptibility to ADHD is also a quantitative trait comprised of many, perhaps thousands, of DNA variants
The study also examined the genetic overlap with other disorders and traits in analyses that ask the questions: Do genetic risk variants for ADHD increase or decrease the likelihood a person will express other traits and disorders. These analyses found a strong negative genetic correlation between ADHD and education. This tells us that many of the genetic variants which increase the risk for ADHD also make it more likely that a person will perform poorly in educational settings. The study also found a positive correlation between ADHD and obesity, increased BMI, and type-2 diabetes, which is to say that variants that increase the risk of ADHD also increase the risk of overweight and type-2 diabetes in the population. This work has laid the foundation for future work that will clarify how genetic risks combine with environmental risks to cause ADHD. When the pieces of that puzzle come together, researchers will be able to improve the diagnosis and treatment of ADHD.
A Swedish-Danish-Dutch team used the Swedish Medical Birth Register to identify the almost 1.7 million individuals born in the country between 1980 and 1995. Then, using the Multi-Generation Register, they identified 341,066 pairs of full siblings and 46,142 pairs of maternal half-siblings, totaling 774,416 individuals.
The team used the National Patient Register to identify diagnoses of ADHD, as well as neurodevelopmental disorders (autism spectrum disorder, developmental disorders, intellectual disability, motor disorders), externalizing psychiatric disorders (oppositional defiant and related disorders, alcohol misuse, drug misuse), and internalizing psychiatric disorders (depression, anxiety disorder, phobias, stress disorders, obsessive-compulsive disorder).
The team found that ADHD was strongly correlated with general psychopathology overall (r =0.67), as well as with the neurodevelopmental (r = 0.75), externalizing (r =0.67), and internalizing (r = 0.67) sub factors.
To tease out the effects of heredity, shared environment, and non-shared environment, a multivariate correlation model was used. Genetic variables were estimated by fixing them to correlate between siblings at their expected average gene sharing (0.5for full siblings, 0.25 for half-siblings). Non-genetic environmental components shared by siblings (such as growing up in the same family) were estimated by fixing them to correlate at 1 across full and half-siblings. Finally, non-shared environmental variables were estimated by fixing them to correlate at zero across all siblings.
This model estimated the heritability of the general psychopathology factor at 49%, with the contribution of the shared environment at 7 percent and the non-shared environment at 44%. After adjusting for the general psychopathology factor, ADHD showed a significant and moderately strong phenotypic correlation with the neurodevelopmental-specific factor (r = 0.43), and a significantly smaller correlation with the externalizing-specific factor (r = 0.25).
For phenotypic correlation between ADHD and the general psychopathology factor, genetics explained 52% of the total correlation, the non-shared environment 39%, and the shared familial environment only 9%. For the phenotypic correlation between ADHD and the neurodevelopmental-specific factor, genetics explained the entire correlation because the other two factors had competing effects that canceled each other out. For the phenotypic correlation between ADHD and the externalizing-specific factor, genetics explained 23% of the correlation, shared environment 22%, and non-shared environment 55%.
The authors concluded that "ADHD is more phenotypically and genetically linked to neurodevelopmental disorders than to externalizing and internalizing disorders, after accounting for a general psychopathology factor. ... After accounting for the general psychopathology factor, the correlation between ADHD and the neurodevelopmental-specific factor remained moderately strong, and was largely genetic in origin, suggesting substantial unique sharing of biological mechanisms among disorders. In contrast, the correlation between ADHD and the externalizing-specific factor was much smaller and was largely explained by-shared environmental effects. Lastly, the correlation between ADHD and the internalizing subfactor was almost entirely explained by the general psychopathology factor. This finding suggests that the comorbidity of ADHD and internalizing disorders are largely due to shared genetic effects and non-shared environmental influences that have effects on general psychopathology."
A recent CNN report, http://tinyurl.com/yannlfd6, highlighted a paper published in Pediatrics, which reported that pregnant women who use acetaminophen during pregnancy put their unborn child at two-fold increased risk for attention deficit hyperactivity disorder (ADHD). In that study, acetaminophen use during pregnancy was common; nearly half of women surveyed used the painkiller during pregnancy. Other studies have reported similar associations of acetaminophen, also known as paracetamol with ADHD or with other problems in childhood (e.g., https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5300094/, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4177119/, https://www.ncbi.nlm.nih.gov/pubmed/24566677, https://www.ncbi.nlm.nih.gov/pubmed/24163279). Given these prior findings, it seems unlikely that the new report is a chance finding. But does it make any biological sense? One answer to that question came from an epigenetic study. Such studies figure out if assaults from the environment change the genetic code. One epigenetic study found that prenatal exposure changes the fetal genome via a process called methylation. Such genomic changes could increase the risk for ADHD (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5540511/). Because all of these studies are observational studies, one cannot assert with certainty that there is a causal link between acetaminophen use during pregnancy.
The observed association could be due to some unmeasured third factor. Although the researchers did a respectable job ruling out some third factors, we must acknowledge some uncertainty in the finding. That said, what should pregnant women do if they need acetaminophen. I suggest you bring this information to your physician and ask if there is a suitable alternative.
Background:
Despite recommendations for combined pharmacological and behavioral treatment in childhood ADHD, caregivers may avoid these options due to concerns about side effects or the stigma that still surrounds stimulant medications. Alternatives like psychosocial interventions and environmental changes are limited by questionable effectiveness for many patients. Increasingly, patients and caregivers are seeking other therapies, such as neuromodulation – particularly transcranial direct current stimulation (tDCS).
tDCS seeks to enhance neurocognitive function by modulating cognitive control circuits with low-intensity scalp currents. There is also evidence that tDCS can induce neuroplasticity. However, results for ADHD symptom improvement in children and adolescents are inconsistent.
The Method:
To examine the evidence more rigorously, a Taiwanese research team conducted a systematic search focusing exclusively on randomized controlled trials (RCTs) that tested tDCS in children and adolescents diagnosed with ADHD. They included only studies that used sham-tDCS as a control condition – an essential design feature that prevents participants from knowing whether they received the active treatment, thereby controlling for placebo effects.
The Results:
Meta-analysis of five studies combining 141 participants found no improvement in ADHD symptoms for tDCS over sham-TDCS. That held true for both the right and left prefrontal cortex. There was no sign of publication bias, nor of variation (heterogeneity) in outcomes among the RCTs.
Meta-analysis of six studies totaling 171 participants likewise found no improvement in inattention symptoms, hyperactivity symptoms, or impulsivity symptoms for tDCS over sham-TDCS. Again, this held true for both the right and left prefrontal cortex, and there was no sign of either publication bias or heterogeneity.
Most of the RCTs also performed follow-ups roughly a month after treatment, on the theory that induced neuroplasticity could lead to later improvements.
Meta-analysis of four RCTs combining 118 participants found no significant improvement in ADHD symptoms for tDCS over sham-TDCS at follow-up. This held true for both the right and left prefrontal cortex, with no sign of either publication bias or heterogeneity.
Meta-analysis of five studies totaling 148 participants likewise found no improvement in inattention symptoms or hyperactivity symptoms for tDCS over sham-TDCS at follow-up. AS before, this was true for both the right and left prefrontal cortex, with no sign of either publication bias or heterogeneity.
The only positive results came from meta-analysis of the same five studies, which reported a medium effect size improvement in impulsivity symptoms at follow-up. Closer examination showed no improvement from stimulation of the right prefrontal cortex, but a large effect size improvement from stimulation of the left prefrontal cortex.
Interpretation:
It is important to note that the one positive result was from three RCTs combining only 90 children and adolescents, a small sample size. Moreover, when only one of sixteen combinations yields a positive outcome, that begins to look like p-hacking for a positive result.
In research, scientists use something called a “p-value” to determine if their findings are real or just due to chance. A p-value below 0.05 (or 5%) is considered “statistically significant,” meaning there's less than a 5% chance the result happened by pure luck.
When testing twenty outcomes by this standard, one would expect one to test positive by chance even if there is no underlying association. In this case, one in 16 comes awfully close to that.
To be sure, the research team straightforwardly reported all sixteen outcomes, but offered an arguably over-positive spin in their conclusion: “Our study only showed tDCS-associated impulsivity improvement in children/adolescents with ADHD during follow-ups and anode placement on the left PFC. ... our findings based on a limited number of available trials warrant further verification from large-scale clinical investigations.”
Children and adolescents with ADHD tend to be less active and more sedentary than their typically developing peers. This is concerning, since physical activity benefits mental, physical, and social development. For youth with ADHD, being active can improve symptoms like inattention, working memory, and inhibitory control.
A major barrier to physical activity for children and adolescents with ADHD is limited motor competence. This stems from challenges in developing basic motor skills and more complex abilities needed for sports and advanced movements.
Difficulties in developing fundamental movement skills – such as locomotor (running, jumping), object-control (throwing, catching), and stability skills (balancing, turning) – can reduce motor competence and limit physical activity. These basic movements are learned and refined with practice and age, not innate abilities.
To date, research on the link between ADHD and motor competence has remained inconclusive. This systematic review and meta-analysis by a Spanish research team therefore aimed to determine whether children and adolescents with ADHD differ in motor competence from those with typical development (TD).
Studies had to include children and adolescents diagnosed with ADHD. They had to involve a full motor assessment battery, not just one test, and present motor competence data for both ADHD and TD groups.
The team excluded studies involving participants with other neurodevelopmental disorders or cognitive impairments, unless separate data for the ADHD subgroup were reported.
Meta-analysis of six studies combining 323 children and adolescents found that typically developing individuals were twelve times more likely to score in the 5th percentile of the Movement Assessment Battery for Children as their peers diagnosed with ADHD. They were also three times more likely to score in the 15th percentile (five studies, 289 participants). Results were consistent across the studies (low heterogeneity). All included studies were randomized.
Meta-analysis of five studies totaling 198 participants using the Test of Gross Motor Development reported significant deficits in both locomotor skills and object control skills among children and adolescents diagnosed with ADHD relative to their typically developing peers. In this case, however, results were inconsistent across studies (very high heterogeneity), and one of the studies was unrandomized. Because the team published only unstandardized mean differences, there was no indication of effect sizes.
Meta-analysis of two studies encompassing 164 participants using the Bruininks-Oseretsky Test of Motor Proficiency similarly yielded significant deficits among children and adolescents diagnosed with ADHD relative to their typically developing peers, but in this case with low heterogeneity. Notably, one of the two studies was not randomized.
Moreover, the team made no assessment of publication bias.
The team concluded, “The findings of this review indicate that children and adolescents with ADHD show significantly lower levels of motor competence compared to their TD peers. This trend was evident across a range of validated assessment tools, including the MABC, BOT, TGMD, and other standardized test batteries. Future research should aim to reduce methodological heterogeneity and further investigate the influence of factors such as ADHD subtypes and comorbid conditions on motor development trajectories.”
However, without a publication bias assessment, reliance on unrandomized studies in two of the tests, no indication of effect size in the same two tests, and small sample sizes, these results are at best suggestive, and will require further research to confirm.
Executive function impairment is a key feature of ADHD, with its severity linked to the intensity of ADHD symptoms. Executive function involves managing complex cognitive tasks for organized behavior and includes three main areas: inhibitory control (suppressing impulsive actions), working memory (holding information briefly), and cognitive flexibility (switching between different mental tasks). Improving executive functions is a critical objective in the treatment of ADHD.
Amphetamines and methylphenidate are commonly used to treat ADHD, but can cause side effects like reduced appetite, sleep problems, nausea, and headaches. Long-term use may also lead to stunted growth and cardiovascular issues. This encourages the search for non-invasive methods to enhance executive function in children with ADHD.
Neurological techniques like neurofeedback and transcranial stimulation are increasingly used to treat children with neurodevelopmental disorders. Neurofeedback is the most adopted method; it is noninvasive and aims to improve brain function by providing real-time feedback on brainwave activity so participants can self-regulate targeted brain regions.
The systematic search and meta-analysis examined children and adolescents aged 6–18 with ADHD. It included randomized and non-randomized controlled trials, as well as quasi-experimental studies that reported statistical data such as participant numbers, means, and standard deviations. Studies were required to use validated measures of executive function, including neurocognitive tasks or questionnaires. They also had to have control groups.
A meta-analysis of ten studies (539 participants) found a small-to-medium improvement in inhibitory control after neurofeedback training, with no publication bias and minimal study heterogeneity*. Long-term treatment (over 21 hours) showed benefits, while short-term treatment did not. However, publication bias was present in the long-term treatment studies and was not addressed.
A meta-analysis of seven studies with 370 children and adolescents found a small-to-medium improvement in working memory after neurofeedback, with no publication bias overall but high heterogeneity. A dose-response effect was observed: treatments over 21 hours showed benefits, while shorter ones did not. However, publication bias was present in the long-term treatment studies and was not addressed.
The study team also looked at sustained effects six months to a year after conclusion of training. Meta-analysis of two studies totaling 131 participants found a sustained small-to-medium improvement in inhibitory control, with negligible heterogeneity. Meta-analysis of three studies combining 182 participants found a sustained medium improvement in working memory, with moderate heterogeneity and no sign of publication bias.
The team concluded, “NFT is an effective intervention for improving executive function in children with ADHD, specifically inhibitory control and working memory. This approach demonstrates a more pronounced impact on working memory when extended beyond 1000 min [sic], with inhibitory control following closely behind. Furthermore, the evidence suggests that NFT may have sustained effects on both working memory and inhibitory control. Given the relatively small number of studies assessing long-term effects and the potential for publication bias, further research is necessary to confirm these effects.”
Moreover, because 1) RCTs are the gold standard, and the meta-analyses combined RCTs with non-RCTs, and 2) data from neurocognitive tasks was combined with data from more subjective and less accurate questionnaires, these meta-analysis results should be interpreted with further caution.
*Heterogeneity refers to the rate of variation between individual study outcomes. High heterogeneity means that there was substantial variation in the results. When a meta-anaylysis has high heterogeneity, it suggests that the studies differ significantly in their populations, methods, interventions, or outcomes, making the combined result much less reliable.
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