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.
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.”
Most previous studies of suicide and self-harm risk among persons with ADHD have focused on adolescents and adults. They’ve also tended to be cross-sectional, analyzing data from a population at a specific point in time.
An Australian study team took a different approach, conducting a before-and-after study through the birth cohort of the Longitudinal Study of Australian Children (LSAC), comprising 5,107 children who have been followed up every two years since birth.
The diagnosis of ADHD was based on parents reporting that their child had received a diagnosis of ADHD at or before age ten.
Suicide and self-harm were defined as children’s self-report at age 14 of any thought or attempt of suicide and self-harm respectively over the past year.
The team adjusted for the following confounders: socioeconomic status, birth weight, ADHD medication history, maternal education level, maternal age at birth, experience in bullying victimization at age 12, and depression score based on Short Mood and Feelings Questionnaire (SMFQ).
Of the 5,107 participants, 3,696 had all the valid data required for analysis and were included in the final cohort. Of these, 3.6% were diagnosed with ADHD by age 10.
With diagnosis of ADHD at age 10 and all other factors held constant:
Both depression and exposure to bullying were statistically significant mediators for the relationship. Nevertheless, depression and exposure to bullying each accounted for well under 10% of the overall effect.
Neither socioeconomic status nor maternal factors had any significant mediating effect on outcomes.
Conclusion:
The authors concluded, “This study provides compelling evidence that children diagnosed with ADHD at the age of 10 years face significantly elevated risks of experiencing suicidal thoughts, planning, or attempts, as well as self-harm, by the age of 14 years, which underscores the critical importance of recognizing and addressing these heightened risks in children with ADHD.”
While factors like depression and bullying contribute, ADHD itself remains a key risk factor. Early intervention and strong mental health support are crucial to protecting these children’s well-being.
Noting that “Recent research has demonstrated that some gut bacteria can affect the nervous system,” and speculating that “dysregulation in the gut microbiota may increase the incidence of ADHD by overproducing reactive oxygen and nitrogen species, thereby causing neuroinflammation and oxidative stress”, a Taiwanese study team decided to explore whether early-life use of antibiotics – in the first two years – is associated with increased risk of subsequent diagnosis of ADHD.
Because Taiwan has a single-payer national health insurance system that covers 99.8% of the island’s population, they were able to use the system’s National Health Insurance Research Database (NHIRD) and Maternal and Child Health Database (TMCHD) to include all 1.6 million children born between 2004 and 2012.
Of these, a little over 1.1 million were given antibiotics before turning two years old, and just over 460,000 were not given antibiotics in the same time frame.
The mean follow-up period for records of subsequent ADHD diagnoses was seven years.
The team adjusted for confounding variables: sex, gestational age at birth (weeks), and birth weight (grams) of the children, and age at birth (years), insurance amount (New Taiwan Dollar (TWD)), insurance location, method of delivery, comorbidities, and medication used during pregnancy.
With these adjustments, early-life antibiotics use was associated with a 12% increase in likelihood of being subsequently diagnosed with ADHD.
However, looking at the effects of antibiotics as an undifferentiated grouping turned out to be misleading, because the association was limited to only some classes of antibiotics.
Penicillins were associated with a 22% increase in risk of subsequent ADHD diagnosis, cephalosporins with a 10% increase.
On the other hand, there was absolutely no such association for tetracyclines, macrolides, and quinolones.
The Take-Away:
This study found that children in Taiwan who took certain types of antibiotics before age 2 had a slightly higher risk of developing ADHD later in life. More work is needed to determine if this finding is due to unmeasured confounding before a causal link can be concluded.
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