September 27, 2023
Denmark has a universal health insurance system that requires tracking all health care data in a system of national registries. That makes it possible to explore what's going on in an entire national population, rather than have to rely on sampling a small part of it, and hoping the sampling is reasonably representative.
A team of Danish researchers used the Civil Registration System to identify all single births through 1993 through 2014 and linked those records to corresponding records in the Psychiatric Central Research Register and National Patient Register for the years 2011through 2016. There were 1,397,850 youths in that cohort, of whom 12,844 were diagnosed with ADHD during the study period.
At five years of follow-up after diagnosis, almost three in ten youths with ADHD (29 percent) had registered evidence of sleep problems (including the use of melatonin, which is by prescription only in Denmark). For those with concomitant conduct disorder, almost half (45 percent) had registered evidence of sleep problems.
In the general population, on the other hand, the cumulative risk of sleep problems at five years of follow-up varied from one in a hundred for children followed from age 5 or age 10 to one in forty for those followed from age 15.
After adjusting for the confounding effects of three other neurodevelopmental disorders - autism spectrum disorder, oppositional defiant disorder/conduct disorder, and epilepsy- youths with ADHD were still roughly 23 times more likely to have sleeping problems than were normally developing youths.
The authors cautioned, however, that the low rate of sleep problems in the general population "may indicate that sleeping problems without coexisting neurodevelopmental disorders are generally diagnosed or treated in primary health care (and hence not included in our study)."
A further limitation, they added, is that "we can not exclude the possibility of residual confounding. Thus, it remains unclear whether neurodevelopmental disorder contributes to the sleep problem or whether certain unmeasured characteristics of children with neurodevelopmental disorders may explain the apparent association with sleep problems."
Allan Hvolby, Jakob Christensen, Christiane Gasse, Soren Dalsgaard, Julie Werenberg Dreier, "Cumulative incidence and relative risk of sleep problems among children and adolescents with newly diagnosed neurodevelopmental disorders: A nationwide register-based study," Journal of Sleep Research (2020), https://doi.org/10.1111/jsr.13122.
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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