April 13, 2021
In the world of research, it is unusual for a single study to be definitive. A possible exception is a recent report in the highly esteemed Lancet, which concluded that people diagnosed with ADHD were about two times more likely to die early than people without ADHD. The data came from the medical registers of Denmark that include1.92 a million people, of which 32,061 have ADHD. The registers included the times and causes of deaths spanning 32 years.
It is a remarkable resource. We know that people with very severe ADHD are at high risk for substance use disorders and antisocial behaviors. In the Danish study, these disorders also increased the risk for premature death, but the risk was even higher if people with those disorders also had ADHD. ADHD also increased the risk for early death among people without these extra problems. This latter finding points to an ADHD-specific pathway to premature death. What is it? Well, we know that ADHD people are at risk for injuries, traffic accidents, and traumatic brain injury. We don't know for certain why, but two symptom clusters of ADHD, inattention, and impulsivity, would be expected to increase the risk for accidents and injuries. For example, adults who are distracted while driving are clearly at risk for accidents. Accidents accounted for most of the early deaths in the Danish study. But the study also found an increase in natural causes of death due to having ADHD. This may be due to the well-replicated association between ADHD and obesity, or the possibility that ADHD symptoms lead to poor health habits.
In the Danish study, the mean age at diagnosis was 12.3, which means that many of the ADHD people in the study were not treated for many years after the onset of symptoms. The risk for early death increased with the age at diagnosis. This suggests that failing to diagnose and treat ADHD early makes the disorder worse and increases the risk for the types of behaviors that lead to premature death. Will these data change public policy or clinician behavior? I hope so. Perhaps the media will stop trivializing ADHD and accept it as a bona fide disorder in need of early identification and treatment. Policymakers should allocate ADHD people their fair share of healthcare and research resources. For clinicians, early identification and treatment should become the rule rather than the exception.
Talk of premature death will worry parents and patients. That is understandable, but such worries can be alleviated by focusing on two facts: the absolute risk for premature death is low, and this risk can be greatly reduced by seeking and adhering to evidence-based treatments for the disorder.
Dalsgaard, S., Ostergaard, S. D., Leckman, J. F., Mortensen,P. B. & Pedersen, M. G. (2015). Mortality in children, adolescents, andadults with attention deficit hyperactivity disorder: a nationwide cohortstudy. Lancet.
Vaa T. ADHD and relative risk of accidents in road traffic:a meta-analysis. Accident; analysis and prevention.2014; 62: 415-25.
Adeyemo BO,Biederman J, Zafonte R, Kagan E, Spencer TJ, Uchida M, et al. MildTraumatic Brain Injury and ADHD: A Systematic Review of the Literature andMeta-Analysis. J AttenDisord. 2014; 18(7): 576-84.
Cortese S, Faraone SV, Bernardi S, Wang S, Blanco C. Adultattention-deficit hyperactivity disorder and obesity: epidemiological study. BrJ Psychiatry.2013; 203: 24-34.
Spencer TS, Faraone SV, Tarko L, McDermott K, Biederman J.ADHD and Adverse Health Outcomes in Adults: Results from a Large ControlledStudy. 2013.
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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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