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February 17, 2022
Roughly five of every thousand women (0.5%) have epilepsy, a neurological disorder characterized by sudden recurrent episodes of sensory disturbance, loss of consciousness, or convulsions, associated with abnormal electrical activity in the brain. Primary treatment consists of anti-seizure medications (ASMs).
Yet, research has shown that ASMs cross the human placenta. In rodents, ASMs have been shown to lead to abnormal neuronal development, and some research has pointed to the risk of adverse birth outcomes and neurodevelopmental disorders in humans. But samples have been too small for reliable conclusions, and in most cases confounding factors are not addressed.
For a more comprehensive evaluation of risk from ASMs, an international team of researchers examined a nationwide cohort using Swedish national registers that track health outcomes for virtually the entire population.
Using the Medical Birth Register, the National Patient Register, and the Multi-Generation Register, they were able to identify 14,614 children born from 1996-to 2011 to mothers with epilepsy.
Through the prescribed Drug Register, they also examined the first-trimester use of anti-seizure medications (ASMs) by these mothers. The three most frequently used ASMs "frequent enough to yield useful data“ were valproic acid, lamotrigine, and carbamazepine.
The researchers identified ADHD in offspring in one of two ways: ICD-10 (international classification of Diseases, 10th Revision) diagnoses, or filled prescriptions of ADHD medication.
Finally, they consulted the Integrated Database for Labor Market Research and the Education Register to explore potential confounding variables. These included maternal and paternal age at birth, the highest education, cohabitation status, and country of origin. They also included maternal and paternal disposable income in the year of birth and a measure of neighborhood deprivation.
Using the medical registers, they considered parental psychiatric and behavioral problems diagnosed before pregnancy, including bipolar disorder, suicide attempt, schizophrenia diagnosis, substance use disorder, and criminal convictions. They adjusted for inpatient diagnosis of seizures in the year before pregnancy to capture and adjust for indication severity.
Other covariates explored included year of birth, birth order, child sex, maternal-reported smoking during pregnancy, and use of other psychotropic medications.
After fully adjusting for all these confounders, children of mothers who were taking valproic acid were more than 70% more likely to develop ADHD than those of mothers not taking an anti-seizure medicine during pregnancy. The sample size was 699, and the 95% confidence interval stretched from 28% to 138% more likely to develop ADHD.
By contrast, children of mothers who were taking lamotrigine were at absolutely no greater risk(Hazard Ratio = 1) of developing ADHD than those of mothers not taking an anti-seizure medicine during pregnancy.
Finally, children of mothers who were taking carbamazepine were 18% more likely to develop ADHD than those of mothers not taking an anti-seizure medicine during pregnancy, but this result was not statistically significant (the 95% confidence interval ranged from 9% less likely to 52% more likely).
The authors concluded, "The present study did not find support for a causal association between maternal use of lamotrigine in pregnancy and ASD [Autism Spectrum Disorder] and ADHD in children. We observed an elevated risk of ASD and ADHD related to maternal use of valproic acid, while associations with carbamazepine were weak and not statistically significant. Although we could not rule out all potential confounding factors, our findings add to a growing body of evidence that suggests that certain ASMs (i.e., lamotrigine) may be safer than others in pregnancy."
Kelsey K. Wiggs, Martin E. Rickert, Ayesha C. Sujan, Patrick. Quinn, Henrik Larsson, Paul Lichtenstein, A. Sara Oberg, and Brian Onofrio, "Antiseizure medication use during pregnancy and risk of ASD and ADHD in children" Neurology(2020),95:e3232-e3240, published online,https://doi.org/10.1212/WNL.0000000000010993.
Girls are diagnosed with ADHD at less than half the rate of boys, but this gap closes significantly by adulthood. ADHD also looks different in females than in males, with distinct patterns in symptoms, development, functional impairment, economic impact, and long-term outcomes. Despite this, sex differences in how ADHD relates to physical health have been poorly studied.
Prior research has established that both children and adults with ADHD face elevated risk for a range of physical health conditions. But that work has been hampered by small samples, retrospective designs, and limited population coverage.
The Study:
Denmark's single-payer national health system makes it possible to conduct truly population-wide research. This study drew on Danish national registers to follow more than 825,000 individuals, born between 1984 and 1995, from birth through adolescence and into young adulthood, tracking them across 13 categories of physical disease. Only individuals free of a relevant physical diagnosis at birth were included, and ADHD diagnosis was treated as something that could be acquired over time rather than a fixed characteristic.
The Results:
Across both sexes, people diagnosed with ADHD consistently showed higher disease risk than the general population, with cancer being the one notable exception. The absence of a meaningful cancer signal is expected, given that cancer predominantly affects older age groups than those captured in this study.
For most other disease categories (including infectious, endocrine, metabolic, respiratory, digestive, musculoskeletal, and genitourinary diseases), elevated risk emerged in early adolescence. For the remaining categories, elevated risk was present at all ages studied.
The magnitude of these risks was often substantial:
By early adulthood, individuals with ADHD showed at least 20% greater risk across every disease category except cancer, regardless of sex.
Sex Differences Shift With Age
One of the study's more nuanced findings concerns how sex interacts with ADHD diagnosis over time. In the general population, females tend to have higher physical disease risk from the teenage years onward, while males show higher risk in early childhood. ADHD diagnosis disrupted these patterns unevenly, amplifying risk in some groups and age windows more than others.
Perhaps most notably, the transition into young adulthood appeared to reduce the ADHD-associated gap between the sexes for endocrine, nutritional, and metabolic diseases (from a ninefold female-to-male disparity down to roughly 4.5-fold). The authors suggest this may reflect ADHD's influence on sex hormone activity during this developmental period.
Takeaway
This large, population-representative study confirms that an ADHD diagnosis is associated with meaningfully elevated risk across nearly all categories of physical disease, and that this relationship is neither uniform across sexes nor static across the lifespan. The findings underscore the need for sex-sensitive, developmentally informed approaches to the physical healthcare of people with ADHD.
Antidepressants are the primary drug treatment for depressive disorders, which affect 15–20% of pregnant women. They are among the most widely prescribed medications worldwide, and their use has increased in recent decades. Understanding their reproductive safety is critical to support informed, evidence-based prescribing during pregnancy.
A new meta-analysis sheds important light on one of the most debated concerns: whether children born to mothers who took antidepressants during pregnancy face a higher risk of ADHD.
The Study:
Pooling 14 studies covering more than 14 million participants, the analysis found that prenatal antidepressant exposure was associated with a 35% higher rate of ADHD in offspring compared to no exposure. A separate look at SSRIs (the most widely prescribed class of antidepressants, including Prozac and Zoloft) across 11 studies and over four million pregnancies found an even higher apparent risk (44%) after correcting for publication bias. On the surface, these are striking numbers.
Both associations came with an important caveat: enormous variation between individual studies, a statistical red flag suggesting the results may not reflect a true underlying effect. More tellingly, the apparent risk evaporated entirely when researchers applied a more rigorous method — comparing siblings within the same family, where one child was exposed to antidepressants in the womb, and another was not.
This sibling-comparison design is particularly powerful because it automatically controls for factors that run in families: shared genes, household environment, parenting, and socioeconomic conditions. When those influences are held constant, the link between antidepressant exposure and ADHD disappears. The same pattern held for SSRIs specifically.
Two other antidepressant classes, SNRIs (serotonin norepinephrine reuptake inhibitors) and tricyclics, showed no significant association in any analysis.
“Confounding by Indication”:
The probable driver of the initial association is what researchers call confounding by indication. The very condition being treated (depression) is itself a risk factor for ADHD in offspring, independently of any medication. Mothers with more severe depression are also more likely to be prescribed antidepressants, meaning the drug and the underlying illness are difficult to disentangle in standard analyses. Sibling studies cut through this problem cleanly.
The Take-Away:
The authors concluded that the association between antidepressants and ADHD risk was non-significant across all analyses designed to account for these confounding factors. This doesn’t mean antidepressants are without any reproductive considerations, but it does suggest that ADHD risk, at least, is driven by heritable and family-level factors rather than medication exposure itself.
For clinicians and patients weighing the risks of treating or not treating depression during pregnancy, this distinction matters considerably.
Executive functions are the mental processes that allow us to plan, adapt, and follow through. This encompasses working memory, inhibitory control, cognitive flexibility, goal-directed planning, and problem-solving. In people with ADHD, weaknesses in these areas compound the disorder's core symptoms, making it substantially harder to manage complex, real-world demands.
Background:
Medication remains the frontline clinical response. Stimulant medications can meaningfully reduce both executive function deficits and ADHD symptoms, and are often combined with behavioral or psychological therapies for better overall outcomes.
Medication, however, is not entirely without risk of side effects. These risks have spurred interest in new, non-pharmacological alternatives that target the same neural pathways. One of these new therapies is Computerized Cognitive Remediation Therapy (CCRT). This therapy uses digital programs delivered via computer, tablet, or smartphone that train attention, memory, and inhibitory control through structured cognitive exercises. A key feature of many CCRT platforms is adaptive difficulty: tasks adjust in real time to match the child’s current ability, keeping training both challenging and engaging.
The Study:
Despite this promise, the evidence base in younger populations has been limited. This meta-analysis pooled results from randomized controlled trials enrolling participants under 18 who either carried an ADHD diagnosis or scored above the threshold on a validated rating scale. Comparators included no treatment (waitlist), placebo (pharmacological or psychological), or treatment as usual. The primary outcomes (overall executive function and clinical symptom severity) were assessed via questionnaires and neuropsychological testing. Studies including participants with comorbid autism, tic disorders, epilepsy, or other psychiatric conditions were excluded.
The findings were informative, but overall results were mixed. CCRT produced a small but statistically meaningful reduction in inattention symptoms across 13 studies (885 participants), with consistent results across individual trials and no evidence of publication bias. However, it had no detectable effect on hyperactivity and impulsivity (12 studies, 833 participants) or on total ADHD symptom burden (10 studies, 731 participants).
The picture was more encouraging for executive function. Nine studies (500 participants) showed small overall improvements, with specific gains in working memory (454 participants), inhibitory control (428 participants), and planning (6 studies, 335 participants). Emotional control showed no significant change (5 studies, 265 participants), nor did cognitive flexibility (4 studies, 189 participants).
The Take-Away:
Taken together, these results are modest rather than transformative, but context matters. CCRT is low-cost, digitally scalable, and carries negligible side effects. For a population where medication often comes with a significant burden of adverse reactions, even small, reliable improvements in executive function represent a meaningful clinical option.
The evidence positions CCRT not as a replacement for established treatments, but as a practical and well-tolerated addition to the therapeutic toolkit for children and adolescents with ADHD.
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