January 24, 2022
Proper development of the gut biota is important for the health of the brain and nervous system. It has been hypothesized that disturbances of gut bacteria by antibiotics could contribute to the development of neurodevelopmental disorders, including ADHD.
In the case of ADHD, studies to date have produced conflicting results. To tease out any familial confounding reflecting shared environment and genetics, a joint Dutch-Swedish team of researchers further tested the hypothesis through 7- to 12-year-old twins in the Netherlands Twin Register (25,781 twins) and 9-year-old twins in the Swedish Twin Registry (7,946 twins).
ADHD symptoms in the Netherlands cohort were derived from mothers' answers to the short Conners' Parental Rating Scale-Revised. For the Swedish cohort, ADHD was determined through the International Classification of Diseases codes for ADHD in the cross-linked National Patient Register.
Exposure to antibiotics during the first two years of childhood was determined by parent reports for the Netherlands twin cohort, and by prescription claims for antibiotics in the Swedish twin cohort.
Covariates were explored in both twin cohorts including educational attainment of parents, gender of the infant, birth weight, delivery mode, and asthma. Breastfeeding was also explored in the Dutch cohort.
In the unmatched analysis, comparing children with ADHD with non-related children without ADHD, early-life antibiotic use was associated with a significant 8% greater odds of ADHD in the Netherlands cohort and a significant 14% greater odds of ADHD in the Swedish cohort.
However, when limiting the analysis to matched monozygotic twins, the association disappeared altogether in both the Dutch and Swedish cohorts. Pooling both cohorts resulted in the same outcome. In all three cases, the odds flipped into a mildly negative association, but with no statistical significance.
Using higher cutoff values for ADHD symptoms made no difference.
The authors concluded, "In this large co-twin study performed in two countries, early-life antibiotic use was associated with increased risk of ADHD and ASD, but the results suggest that the association disappeared when controlled for shared familial environment and genetics, indicating that this association may be susceptible to confounding. Our results indicate that there is no association between ADHD and ASD diagnoses and early antibiotic use when environmental and genetic family factors are taken into account."
Elise M A Slob, Bronwyn K Brew, Susanne J H Vijverberg,Talitha Dijs, Catharina E M van Beijsterveldt, Gerard H Koppelman, MeikeBartels, Conor V Dolan, Henrik Larsson, Sebastian Lundstrom, Paul Lichtenstein,Tong Gong, Anke H Maitland-van der Zee, Aletta D Kraneveld, Catarina Almqvist,Dorret I Boomsma, "Early-life antibiotic use and risk of attention-deficit hyperactivity disorder and autism spectrum disorder: results of a discordant twin study," International Journal of Epidemiology(2020),https://doi.org/10.1093/ije/dyaa168.
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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