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June 10, 2025

Meta-analysis Finds Strong Link Between Maternal Smoking During Pregnancy and Increased Risk of ADHD in Children

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.

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Researchers Have Found the First Risk Genes for ADHD

Researchers have found the first risk genes for ADHD

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.

July 4, 2021

Large Sibling Study Finds Genetic Link Between ADHD and Other Disorders

Swedish Countrywide Sibling Population Study Finds Co-occurrence of ADHD with Neurological and Psychiatric Disorders is Largely Due to Genetics

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."

March 16, 2024

ADHD and Acetaminophen use During Pregnancy

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.

March 16, 2021

Nationwide Population Study Reports Increased Risk of Hospitalization for Psychosis or Mania Following Initiation of ADHD Medication

Background:

In Iceland, treatment with ADHD medication can only be initiated by psychiatrists or pediatricians with experience in diagnosing neurodevelopmental disorders. The diagnostic evaluation is most often carried out by a psychologist or psychiatrist, and must be confirmed by a psychiatrist.

Some previous studies have suggested a small but significant increased risk of psychosis or mania associated with ADHD medication, while others have not.

Iceland has a single-payer national healthcare insurance system that tracks virtually its entire population. An Icelandic research team accessed two administrative databases with nationwide coverage – the Icelandic Prescription Medicines Register and the Icelandic Hospital Discharge Register – to explore this relationship among all adults from 2010 through 2022.

They included three categories of ADHD medications prescribed in Iceland: amphetamines, including dexamphetamine and lisdexamphetamine; methylphenidate; and atomoxetine. In Iceland, methylphenidate or atomoxetine must be prescribed and tried first before switching to lisdexamphetamine or dexamphetamine.

Method:

Diagnoses of mania or psychosis recorded in electronic health records were used to identify individuals who were admitted to a psychiatric ward within one year of starting treatment with a specific class of ADHD medication. First-onset psychosis or mania was defined as the emergence of these conditions in individuals with no prior history, diagnosis, or hospitalization for psychosis or mania.

A total of 16,125 adults began using an ADHD medication for the first time during the 13-year study period.

Methylphenidate was the most used ADHD medication among those admitted for psychosis or mania (25 out of 61; 41%), reflecting its status as the most frequently prescribed stimulant during the study period. It was followed by amphetamines (21 out of 61; 34.4%) and atomoxetine (15 out of 61; 24.6%).

Half of those hospitalized had previously received a diagnosis of substance use disorder. One in nine (11%) of those hospitalized acknowledged misuse of the type of ADHD medication they had been prescribed.

Within a year of discharge, 42 out of the 61 patients (68.9%) had been prescribed an ADHD medication again. Among those, one in four (11 out of 42; 26%) were readmitted for psychosis or mania within the following year.

The team noted, “It is concerning that most patients (68.9%) in our study resumed ADHD drug treatment within a year of hospital discharge … However, some studies have reported that the use of psychostimulants or atomoxetine to treat ADHD in individuals with psychotic disorders did not increase the risk of hospitalisation for psychosis if used concurrently with antipsychotic medication or that such use might even reduce this risk.”

Findings:

By comparison with the general population, adults initiating ADHD medications had eight times the relative risk of being admitted for psychosis or mania within the first year.

The absolute risk was low: 0.38% overall for those initiating ADHD medication. Adjusting for the general population risk of hospitalization for first-onset psychosis or mania, more than 300 patients would need to be initiated to ADHD medication to generate one hospital admission for psychosis or mania.

The team conceded, “Confounders of real-life clinical settings, such as non-disclosed ADHD drug abuse or misuse or some degree of substance abuse, may have influenced our findings.”

A further, unmentioned, limitation is that the team did not perform any of the usual adjustments for confounding variables, critically including co-occurring (comorbid) psychiatric disorders known to be common with ADHD, and likely to have a major effect on the relative risk of hospitalization.

Given the very small increase in risk along with the methodological flaws, the team’s suggestion of a “potential causal role of ADHD drugs in the development of first-onset psychosis or mania” is unsubstantiated and speculative. This is especially so given other studies suggesting no increased risk for psychosis due to these medications.

In any event, causation cannot be established through observational studies.

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June 19, 2025

Study Finds Association Between Childhood ADHD and Poor Dental Health

The Spanish National Health Survey tracks health care outcomes through representative samples of the Spanish population.

A Spanish research team used survey data to explore the relationship between ADHD symptoms and dental and gum health in a representative sample of 3,402 Spanish children aged 6 to 14.

While previous studies have found associations between ADHD and poor dental health, they have not fully accounted for such important determinants of poor oral health as socioeconomic status, dental hygiene, or diet.

The team therefore adjusted for sociodemographic factors, lifestyle variables, and oral hygiene behaviors. More specifically, they adjusted for sex, age, social class, parental education, exposure to tobacco smoke, consumption of sweets, consumption of sugary drinks, use of asthma or allergy medication, adequate oral hygiene behavior of children, adherence to regular dental visits, parental adequate oral hygiene behavior, and parental adherence to regular dental visits.

With those adjustments, children with ADHD symptoms had over twice the incidence of dental caries (cavities) as their counterparts without ADHD symptoms.

Tooth extractions and dental restorations also occurred with over 40% greater frequency in children with ADHD symptoms.

Gum bleeding, a sign of gum disease, was more than 60% more common among children with ADHD symptoms than among their non-ADHD peers.

Importantly, excluding children with daily sugar consumption, which left 1,693 children in the sample, made no difference in the outcome for cavities.

Excluding children with poor oral hygiene habits, which left 1,657 children in the sample, those with ADHD had 2.5-fold more caries than their non-ADHD counterparts.

Excluding children of low social class, which left 1,827 children in the sample, those with ADHD had 2.6-fold more caries than their non-ADHD counterparts.

Turning to a different method to address potential confounding factors, the team used nearest-neighbor propensity score matching to create virtual controls. This compared 461 children with ADHD to 461 carefully matched children without ADHD.

This time, children with ADHD symptoms had just under twice the incidence of cavities as their counterparts without ADHD symptoms, but 60% more tooth extractions and about 75% more dental restorations. The difference in gum bleeding became nonsignificant.

Noting that “The increased risk of caries was maintained when the analyses were restricted to middle/high social class families and children with low sugar intake, good oral hygiene behaviors and regular dental visits,” the team concluded, “Children with ADHD symptoms in Spain had worse oral health indicators than those without ADHD symptoms. Our results suggest that the association of ADHD symptoms with caries was independent of socioeconomic level, cariogenic diet, frequency of toothbrushing, and dental visits.”

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June 13, 2025

A Lesson in Correlation Versus Causation : Maternal Smoking and ADHD Risk in Children