December 11, 2021
Taiwan has a single-payer healthcare system that covers virtually every inhabitant (99.5%). That makes it relatively easy to track healthcare issues using its comprehensive National Health Insurance Research Database.
This database maintains a subset, the Longitudinal Health Insurance Database (LHID), consisting of a million persons, with no significant differences in sex, age, or healthcare use from the parent database.
A Taiwanese research team used the LHID to identify 114,486 individuals diagnosed with ADHD from 1997 to 2013. It then compared their motor vehicle (including motorcycles, which are extremely common in Taiwan) crash patterns with 338,261 normally developing controls from the same database.
Adjusting for sex, age, and psychiatric comorbidities, persons with ADHD were about a fifth (19%)more likely to be in traffic crashes. Breaking it down further by sex, women with ADHD were no more likely to be in crashes, but men with ADHD were about a quarter (24%) more likely than their healthy counterparts.
Since the database also tracks pharmaceutical prescriptions, the team also looked into the effect of methylphenidate (MPH), the medication that is the first-line treatment for ADHD under Taiwanese guidelines, and the only approved stimulant. Atomoxetine, a non-stimulant, is used where MPH is either ineffective or not indicated for any other reason and is only used in 4% of all cases.
Of the 114,486 persons diagnosed with ADHD, 89,826 used MPH, and 24,660 did not.
Compared with persons with ADHD who were not on methylphenidate, those with ADHD who were on MPH for 180 days (roughly half a year) or less had 77% fewer accidents, and those on MPH for over 180 days had 93% fewer accidents. This strong dose-response relationship is suggestive of a causal relationship, with MPH perhaps reducing impulsive behavior, particularly among young men with ADHD.
The team also conducted within-person analyses, comparing times when persons with ADHD were taking MPH with periods when they were not. These showed no effect within 30 days of use, rising to a 65%reduction in crashes within 60 to 90 days of use, which was barely outside the 95% confidence interval (p = .07), very likely because of "the extremely low incidence of transport accidence (i.e. 0.6%)enlarged the confidence interval."
The authors concluded, "All registration medical claim data came from the nationally-representative sample of NHI, minimizing the selection and recall bias. By excluding transport accidents before ADHD diagnosis, we have precluded the reverse association between ADHD and road traffic accidents as much as possible. The advantage of the between-subjects comparison was that we were able to examine the MPH effect in different dose groups. However, confounding by indication cannot be eliminated. For example, those with a severe degree of ADHD symptoms, an exhibition of risky behaviors, or comorbid with other psychiatric illnesses were more likely to be prescribed medication. Hence, we also performed within-subject comparisons to adjust for time-invariant factors."
Transport safety thus offers another compelling reason to treat ADHD symptoms. Methylphenidate in particular seems to be especially effective in reducing traffic fatalities and injuries.
Yi-Chun Liu, Vincent Chin-Hung Chen, Yao-Hsu Yang, Yi-LungChe, and Michael Gossop, "Association of psychiatric comorbidities with the risk of transport accidents in ADHD and MPH," Epidemiology and PsychiatricSciences30 (2021), e14, 1-9,https://doi.org/10.1017/S2045796021000032.
A 2021 consensus statement by an international group of scientists and clinicians (Bauer et al.) recommended that pregnant individuals “forego [acetaminophen] unless its use is medically indicated,” due to the potential risk of developmental disorders such as autism and attention-deficit/hyperactivity disorder (ADHD).
A mostly Swedish research team, collaborating with a U.S. researcher, nevertheless noted that previous studies have been limited by:
Sweden has a single-payer health insurance system that includes virtually its entire population, and national registers that enable tracking the health history of mothers and their children, including their children’s siblings.
The team used the Swedish registers to identify the roughly two-and-a-half million children born in Sweden from mid-1995 through 2019. They were also able to identify all siblings to be able to control for otherwise unmeasured familial and genetic confounding.
Almost 186,000 of these children were exposed to acetaminophen during pregnancy.
After adjusting for available known confounders, including (but not limited to) child sex and birthdate, mother’s age and medical history, use of any other painkillers, use of any psychoactive medications, country of birth, residential region, smoking status, highest household education, and disposable income, children exposed to acetaminophen during pregnancy were 7% more likely to be diagnosed with ADHD subsequently than those who were not exposed.
However, roughly the same results were found for other painkillers, including aspirin, non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs), opioids, and antimigraine medication. High doses of acetaminophen did not produce any stronger association with subsequent ADHD than low dosage.
Moreover, when confining results to siblings – 8,526 children who were exposed versus 87,679 who were unexposed – the association between acetaminophen use during pregnancy and subsequent offspring ADHD vanished altogether (and, again, at every dose level). The associations similarly vanished with every other painkiller medication.
The Swedish team concluded, “Acetaminophen use during pregnancy was not associated with children’s risk of autism, ADHD, or intellectual disability in sibling control analyses. This suggests that associations observed in models without sibling control may have been attributable to confounding.”
Antipsychotic medications are used to treat a variety of psychiatric disorders, including schizophrenia, bipolar disorder, sleeping problems, major depression, and severe anxiety.
Untreated maternal mental illness is associated with poor health outcomes for both mothers and their offspring. On the other hand, one must guard against any potential direct harms of medications on development – including neurological development – of the fetus.
Because prenatal use of antipsychotics is infrequent, previous observational studies have suffered from small sample sizes that have not enabled precise and reliable assessment of risk. The clinical decision about whether to continue antipsychotic treatment in patients who become pregnant has therefore remained inconclusive.
In search of more reliable guidance, an international study team conducted a systematic search of the peer-reviewed medical literature to perform the first meta-analysis on this topic.
They evaluated study quality and only included studies rated “good” or better.
Identification of ADHD was determined by clinical diagnosis.
Meta-analysis of four studies encompassing over eight million participants found a slight association. Children exposed to maternal antipsychotics during pregnancy were 11% more likely to be diagnosed with ADHD subsequently.
But even in observational studies with millions of participants, such associations – especially when slight to begin with – could be due to unmeasured confounders.
The team therefore compared children with gestational exposure to siblings from the same mother who were not exposed, to address shared genetic and social factors at the family level.
Meta-analysis of two population-based sibling-matched studies with a combined total of over 4.6 million participants in Denmark, Norway, Sweden, Finland, Iceland, and Hong Kong found no significant association between gestational exposure to antipsychotic medications and subsequent diagnosis of ADHD.
The team concluded, “Our systematic review and meta-analysis of observational studies indicates that the heightened risks of ADHD and ASD observed in children gestationally exposed to antipsychotics appear to be attributable to maternal characteristics, rather than having a causal relation to the antipsychotic itself.”
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 a 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.
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.”
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