August 1, 2024
Lead’s neurotoxicity is well established, and organophosphate pesticides were deliberately developed first as nerve agents in warfare and then as insecticides.
Noting that “Epidemiologic research on chemical exposures associated with the development of ADHD is numerous; however, studies have employed various methods, and, in some cases, have resulted in seemingly conflicting results,” a U.S. study team has performed an updated meta-analysis applying “identical meta-analytic techniques to the literature on the associations between earlier chemical exposures and later ADHD.”
Lead
Meta-analysis of eleven studies reporting dichotomous outcomes with a combined 7,566 participants found children exposed to lead were almost twice as likely to subsequently be diagnosed with ADHD as their unexposed peers.
A second meta-analysis, of thirteen studies reporting continuous outcomes with a total of 1,775 participants, found a small effect size increase in ADHD diagnosis from exposure to lead.
Interestingly, meta-analysis of four studies with a combined 4,360 participants found no association between prenatal lead exposure and subsequent ADHD diagnosis.
On the other hand, meta-analysis of seven studies combining almost five thousand participants reported that cumulative lead exposure more than doubled the likelihood of subsequent ADHD.
In other words, it’s not so much prenatal exposure as exposure after birth that is associated with increased risk.
Organophosphates
Meta-analysis of four studies reporting continuous outcomes with a combined total of 692 persons likewise found a small effect size increase in ADHD diagnosis from exposure to organophosphates.
Mercury
Meta-analysis of six studies reporting continuous outcomes with a combined total of over 17 thousand participants found a tiny effect size increase in ADHD diagnosis from exposure to mercury.
On the other hand, meta-analysis of ten studies reporting dichotomous outcomes with a combined total of over 650,000 persons found no association whatsoever between mercury exposure and subsequent diagnosis of ADHD.
Other exposures
Meta-analysis of five studies involving more than 34,000 participants found no evidence of an association between exposure to anesthesia and ADHD.
Meta-analysis of three studies encompassing 1,739 individuals found no evidence of an association between exposure to cadmium and ADHD.
Meta-analysis of four studies combining more than 2,400 persons found no evidence of an association between exposure to hexachlorobenzene and ADHD.
A pair of meta-analyses, one of three studies reporting dichotomous outcomes including 2,050 participants, the other of nine studies reporting continuous outcomes involving almost three thousand participants, both found no evidence of an association between exposure to polychlorinated biphenyls (PCBs) and ADHD.
There was little variability (heterogeneity) among results reported by individual studies within these meta-analyses, but a serious limitation was the failure to check for publication bias.
The authors concluded, “given our findings related to exposure to mercury, organophosphates, and PCBs, further research may be helpful to better characterize these relationships. Many of our effect sizes were small, which is consistent with the literature indicating that many genetic and environmental factors contribute to ADHD. … Furthermore, our findings support existing regulations of certain chemicals,” and “may inform future regulatory decisions”
Lina V. Dimitrov, Jennifer W. Kaminski, Joseph R. Holbrook, Rebecca H. Bitsko, Michael Yeh, Joseph G. Courtney, Brenna O’Masta, Brion Maher, Audrey Cerles, Katherine McGowan, and Margaret Rush, “A Systematic Review and Meta-analysis of Chemical Exposures and Attention-Deficit/Hyperactivity Disorder in Children,” Prevention Science (2024), 25 (Suppl 2):S225–S248, https://doi.org/10.1007/s11121-023-01601-6.
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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