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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.
The Background:
Previous research has suggested that people with ADHD have higher rates of death than those without the condition. Until now, many of those studies lacked the detail needed to untangle why this might be the case. A recent meta-analysis of eight separate studies reported that ADHD roughly doubled the risk of death, and it hinted that factors like socioeconomic status and other mental illnesses might help explain the link.
The Study:
To explore this in more detail, researchers used the US National Health Interview Survey, a nationally representative prospective cohort of just over 52,000 adults. Survey records were linked with the National Death Index, and participants were followed from the date of interview until death or December 31, 2019, whichever came first. The main outcome was death from any cause. With a median follow-up of just under eight years, there were 6,024 deaths recorded.
When the team adjusted their analysis for age, sex, ethnicity, and the year of the survey, having ADHD was associated with a 58% higher risk of death. Controlling further for family income and educational level reduced that increased risk slightly, to 50%.
Controlling for health conditions (like high blood pressure, diabetes, stroke, heart disease, and cancer) and lifestyle factors (smoking, alcohol use, physical activity, and body weight) also reduced the association to about 46%.
By contrast, when the researchers adjusted for two psychiatric conditions (anxiety and depression) commonly found alongside ADHD, the link between ADHD and higher mortality disappeared statistically. In other words, once anxiety and depression were taken into account, ADHD itself was no longer associated with a clearly measurable increase in the risk of death.
What Does This Mean?
The authors conclude that the apparent effect of ADHD on mortality seems to operate largely through accompanying mental illness, and to a lesser extent through lifestyle and physical health problems. They suggest that treating and managing these co-occurring issues (through medications, therapy, and behavioral interventions) might help reduce the risk of premature death in people with ADHD, although they note that further evidence is needed.
The Background:
Dementia is a rapidly growing public health problem affecting more than 50 million people worldwide. Nearly 10 million new cases are diagnosed each year, and that number is expected to almost triple by 2050. The most common form is Alzheimer’s disease, accounting for roughly 60–70% of cases, followed by vascular dementia at around 20%. Other types include dementia with Lewy bodies, Parkinson’s disease dementia, and frontotemporal dementia. While no cure exists, managing modifiable risk factors (such as high blood pressure, smoking, physical inactivity, and poorly controlled diabetes) can delay or slow both the onset and progression of the condition.
Several studies have reported an elevated dementia risk among people with ADHD, and a number of mechanisms may explain this association. These include shared genetic or neurobiological vulnerabilities, reduced cognitive reserve (leaving the brain less resilient to age-related damage), and greater lifetime exposure to other established dementia risk factors.
Earlier reviews explored the possible link between ADHD and dementia, but tended toward a broader scope (incorporating other neurodegenerative disorders or mixing study designs), which introduced substantial variability and precluded quantitative synthesis. The relevant research literature has also expanded considerably since those reviews appeared.
The Study:
This meta-analysis restricted inclusion to case-control and cohort studies, yielding five that met the criteria. One was a case-control study with 400 participants; the other four were cohort studies collectively covering 3.7 million individuals, two retrospective and two prospective.
The Results:
Pooling the four cohort studies, individuals with ADHD showed approximately two-and-a-half times the dementia risk of those without the diagnosis. There was no indication of publication bias.
The Take-Away:
The authors concluded that ADHD is associated with a significantly increased risk of all-cause dementia in later life, while noting that its relationship to specific dementia subtypes remains less clear and warrants attention in future research.
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The Background:
Women with polycystic ovary syndrome (PCOS) themselves show higher rates of ADHD. Because ADHD is partly heritable (meaning genes contribute to the condition), some of the increased ADHD seen in children of mothers with PCOS could come from shared genetic factors. In other words, a mother’s and her child’s increased risk might sometimes reflect common genes rather than an effect of the pregnancy itself.
Beyond genetics, growing evidence points to maternal metabolic problems during pregnancy as another important risk factor for neurodevelopmental outcomes. PCOS is one of these conditions and is considered both potentially modifiable (treatable or manageable) and biologically plausible as a contributor to risk. PCOS affects an estimated 5–10% of women of reproductive age worldwide and is characterized by signs such as hyperandrogenism (higher-than-normal levels of “male” hormones), insulin resistance (poorer ability to use the hormone insulin, which can affect blood sugar and metabolism), and chronic low-grade inflammation.
However, studies to date have not all reached the same conclusions. Some research suggests the association between maternal PCOS and offspring ADHD is stronger for girls, while other studies did not analyze results by child sex. Methodological differences make it harder to draw clear conclusions.
The Study:
It’s important to note that the studies included in this meta-analysis were observational (cohort studies and case-control studies). Observational studies can identify associations (that two things occur together) but cannot prove that one causes the other. A cohort study follows people over time, and a case-control study compares people with a condition to similar people without it.
The pooled results came from six studies that together included almost 1.4 million mother–child pairs and that adjusted for confounders (other factors that might influence the result, such as maternal age or socioeconomic status). After statistical adjustment, children of mothers with PCOS had about 40% greater odds of ADHD than children of mothers without PCOS. The analysis reported no evidence of publication bias (no clear sign that only positive studies were published) and zero heterogeneity (the results were consistent across the studies).
There was no meaningful difference in results between cohort and case-control studies, and the meta-analysis did not find a significant difference in the association when comparing male and female offspring.
The Take-Away:
The research team concluded that this large-scale synthesis found an association between maternal PCOS and higher odds of ADHD and other neuropsychiatric conditions in children. They suggested that children born to mothers with PCOS may benefit from developmental monitoring to identify and address problems early, while emphasizing that causal relationships have not been established. They called for further studies to confirm these findings and to investigate the biological and environmental mechanisms that might explain the association. Indeed, because women with PCOS show higher rates of ADHD than other women, we need genetically informed research designs to see if the reported association is confounded.
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