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February 5, 2024
Organophosphate pesticides were originally developed as nerve agents for chemical warfare, then used in lower doses as insecticides.
Their neurotoxicity raises the possibility of effects on development of the nervous system at lower doses, including psychiatric disorders.
Previous studies have found mixed results for any association with ADHD.
Norway has a single-payer health insurance system that covers virtually the entire population, facilitating nationwide population studies.
A primarily Norwegian study team used the Norwegian Mother, Father, and Child Cohort Study, a prospective population-based cohort that enrolled participants between 1999 and 2008 to explore possible associations. The study invited all 227,702 pregnant mothers to enroll, of which 112,908 (41%) actually enrolled.
Children were eligible for the present study if they were born after 2002, did not have Down’s syndrome or cerebral palsy, had available maternal biospecimens, were the result of a singleton pregnancy, and lived near Oslo (the location of the clinic). That left a sample of 24,035.
The team used the Norwegian Patient Registry (NPR) to identify diagnosed cases of ADHD.
From the final eligible population, the team randomly selected 552 mother-child pairs to represent the exposure distribution in the population of pregnancies that gave rise to the cases of ADHD.
At about 17 weeks into pregnancy, maternal spot urine samples were collected at the mother’s first ultrasound appointment. These samples were then tested for concentrations of organophosphate metabolites (breakdown chemicals).
Adjustments were made for a variety of possible confounding variables: season, birth year, maternal education, vegetable intake, fruit intake, maternal self-reported ADHD, financial status, other organophosphorus pesticides, and sex.
Comparing higher versus lower maternal exposures to organophosphates, no significant differences emerged in rates of ADHD diagnosis among offspring.
Amber M. Hall, Jake E. Thistle, Cherrel K. Manley, Kyle R. Roell, Amanda M. Ramos, Gro D. Villanger, Ted Reichborn-Kjennerud, Pål Zeiner, Enrique Cequier, Amrit K. Sakhi, Cathrine Thomsen, Heidi Aase, and Stephanie M. Engel, “Organophosphorus Pesticide Exposure at 17 Weeks’ Gestation and Odds of Offspring Attention-Deficit/Hyperactivity Disorder Diagnosis in the Norwegian Mother, Father, and Child Cohort Study,” International Journal of Environmental Research and Public Health (2022) 19, 16851, https://doi.org/10.3390/ijerph192416851.
The Background:
Meta-analyses have previously suggested a link between maternal thyroid dysfunction and neurodevelopmental disorders (NDDs) in children, though some studies report no significant difference. Overweight and obesity are more common in children and adolescents with NDDs. Hypothyroidism is often associated with obesity, which may result from reduced energy expenditure or disrupted hormone signaling affecting growth and appetite. These hormone-related parameters could potentially serve as biomarkers for NDDs; however, research findings on these indicators vary.
The Study:
A Chinese research group recently released a meta-analysis examining the relationship between neurodevelopmental disorders (NDDs) and hormone levels – including thyroid, growth, and appetite hormones – in children and adolescents.
The analysis included peer-reviewed studies that compared hormone levels – such as thyroid hormones (FT3, FT4, TT3, TT4, TSH, TPO-Ab, or TG-Ab), growth hormones (IGF-1 or IGFBP-3), and appetite-related hormones (leptin, ghrelin, or adiponectin) – in children and adolescents with NDDs like ADHD, against matched healthy controls. To be included, NDD cases had to be first-diagnosis and medication-free, or have stopped medication before testing. Hormone measurements needed to come from blood, urine, or cerebrospinal fluid samples, and all studies were required to provide both means and standard deviations for these measurements.
Meta-analysis of nine studies encompassing over 5,700 participants reported a medium effect size increase in free triiodothyronine (FT3) in children and adolescents with ADHD relative to healthy controls. There was no indication of publication bias, but variation between individual study outcomes (heterogeneity) was very high. Further analysis showed FT3 was only significantly elevated in the predominantly inattentive form of ADHD (three studies), again with medium effect size, but not in the hyperactive/impulsive and combined forms.
Meta-analysis of two studies combining more than 4,800 participants found a small effect size increase in thyroid peroxidase antibody (TPO-Ab) in children and adolescents with ADHD relative to healthy controls. In this case, the two studies had consistent results. Because only two studies were involved, there was no way to evaluate publication bias.
The remaining thyroid hormone meta-analyses, involving 6 to 18 studies and over 5,000 participants in each instance, found no significant differences in levels between children and adolescents with ADHD and healthy controls.
Meta-analyses of six studies with 317 participants and two studies with 192 participants found no significant differences in growth hormone levels between children and adolescents with ADHD and healthy controls.
Finally, meta-analyses of nine studies with 333 participants, five studies with 311 participants, and three studies with 143 participants found no significant differences in appetite-related hormone levels between children and adolescents with ADHD and healthy controls.
The Conclusion:
The team concluded that FT3 and TPO-Ab might be useful biomarkers for predicting ADHD in youth. However, since FT3 was only linked to inattentive ADHD, and TPO-Ab’s evidence came from just two studies with small effects, this conclusion may overstate the meta-analysis results.
Our Take-Away:
Overall, this meta-analysis found only limited evidence that hormone differences are linked to ADHD. One thyroid hormone (FT3) was higher in children with ADHD—mainly in the inattentive presentation—but the findings varied widely across studies. Another marker, TPO-Ab, showed a small increase, but this came from only two studies, making the result less certain. For all other thyroid, growth, and appetite-related hormones, the researchers found no meaningful differences between children with ADHD and those without. While FT3 and TPO-Ab may be worth exploring in future research, the current evidence is not strong enough to consider them reliable biomarkers.
Background:
Recent progress in reproductive medicine has increased the number of children conceived via assisted reproductive techniques (ART). These include:
Although ART helps with infertility, there are concerns about its long-term effects on offspring, especially regarding neurodevelopment. Factors such as hormonal treatments, gamete manipulation, altered embryonic environments, as well as parental age and infertility, may influence brain development and raise the risk of neurodevelopmental and mental health disorders.
With previous studies finding conflicting results on a possible association between ART and increased risk of mental health disorders, an Indian research team has just published a new meta-analysis exploring this topic.
The Study:
Studies were eligible if they were observational (cohort, case-control, or cross-sectional), reported confounder-adjusted effect sizes for ADHD, and were published in English in peer-reviewed journals.
A meta-analysis of eight studies encompassing nearly twelve million individuals indicated a 7% higher prevalence of ADHD in offspring conceived via IVF/ICSI compared to those conceived naturally. The heterogeneity among studies was minimal, and no evidence of publication bias was observed.
The study’s 95% confidence interval ranged from 4% to 10%. Further analysis of five studies comprising almost nine million participants that distinguished outcomes by sex revealed that the increase in ADHD risk among female offspring was not statistically significant. In contrast, the elevated risk in male offspring persisted, though it was marginally significant, with the lower bound of the confidence limit at only 1%.
Results:
A meta-analysis of three studies (1.4 million participants) found a 13% higher rate of ADHD in children conceived via ovulation induction/intrauterine insemination (OI/IUI) compared to natural conception. The effect size, though doubled, remains small. Minimal heterogeneity and no publication bias were observed.
The team concluded, “The review found a small but statistically significant moderate certainty evidence of an increased risk of ADHD in those conceived through ART, compared to spontaneous conception. The magnitude of observed risk is small and is reassuring for parents and clinicians.”
Our Take-Away:
Overall, the meta-analysis points to a small, but measurable increase in ADHD diagnoses among children conceived through ART, but the effect sizes are modest and supported by moderate-certainty evidence. And we must always keep in mind that the researchers who wrote the original articles could not correct for all possible confounds. These findings suggest that while reproductive technologies may introduce slight variation in neurodevelopmental outcomes, the effects are small and uncertain. For families and clinicians, the results are generally reassuring: ART remains a safe and effective avenue to parenthood, and the results of this study should not be viewed as a prohibitive concern. Thoughtful developmental monitoring and open, evidence-based counseling can help ensure that ART-conceived children receive support that caters to their individual needs.
The Background:
Myopia is a growing global health concern linked to conditions like macular degeneration, glaucoma, and retinal detachment. Its prevalence has surged in recent decades; by 2050, an estimated 5 billion people will have myopia. The increase is especially marked in Asia – a survey in Taiwan reports that 84% of students aged 15 to 18 are myopic, with 24% severely affected.
Dopamine is an important neurotransmitter in the retina, involved in eye development, visual signaling, and refractive changes. The dopamine hypothesis, suggesting that retinal dopamine release helps prevent myopia, has emerged as a leading theory of myopia control.
Most studies show ADHD is highly heritable, often involving dopamine system genes. ADHD is strongly associated with dopaminergic abnormalities, especially in dopamine transporter function and release dynamics.
Medications for ADHD, like methylphenidate, atomoxetine, and clonidine, help regulate dopamine to reduce symptoms.
The Study:
Given dopamine’s critical involvement in both ADHD and myopia, a Taiwanese research team hypothesized that medications for ADHD that influence dopaminergic pathways may have a significant effect on myopia risk.
To evaluate this hypothesis, the team conducted a nationwide cohort study using data from Taiwan’s National Health Insurance (NHI) program, which covers 99% of the nation’s 23 million residents and provides access to comprehensive eye care and screenings. Taiwan requires visual acuity screenings beginning at age four, with annual examinations for school-aged children to promote the early detection of visual anomalies such as myopia.
Furthermore, ADHD medication and diagnosis are tracked through compulsory diagnostic codes. This permits an accurate assessment of the effects of dopaminergic medications on myopia risk.
Propensity score allocation using a multivariable logistic regression model was applied to reduce bias from confounding influences, pairing cohorts based on similar scores.
The Results:
Comparing 133,945 individuals with ADHD with an equal number without ADHD, untreated ADHD was associated with a 22% greater risk of myopia.
However, after adjusting for covariates (gender, age, insured premium, comorbidities, location, and urbanization level), the ADHD cohort receiving medication treatment showed a 39% decreased risk of myopia relative to the untreated ADHD cohort.
Narrowing this further to the ADHD cohort receiving dopaminergic medications reduced the risk of myopia by more than half (52%) relative to the untreated ADHD cohort.
Treatment with two dopaminergic medications reduced the risk by well over two-thirds (72%) relative to the untreated ADHD cohort.
There were no significant differences between methylphenidate, atomoxetine, and clonidine. Each reduced risk by about 50%.
The team did not directly compare the ADHD cohort receiving dopaminergic medications with the non-ADHD cohort. But if there were 122 cases of myopia in the ADHD cohort for every 100 cases in the non-ADHD cohort, and dopaminergic medications halved the cases in the ADHD cohort to about 60, that would represent a roughly 40% reduction in myopia risk relative to the non-ADHD cohort.
The team concluded, “our research indicates that pharmacologically treated ADHD children have a reduced risk of myopia. Conversely, untreated ADHD children are at a heightened risk relative to those without ADHD. Moreover, the cumulative effects of ADHD medications were found to notably decrease myopia incidence, emphasizing the protective influence of dopaminergic modulation in these interventions.”
The Take-Away:
Children with untreated ADHD are more likely to develop myopia, but those receiving dopaminergic medications had a substantially lower risk. The findings suggest that ADHD medications may help protect against myopia by boosting dopamine signaling. More research is needed before firmly drawing this conclusion, but this research could open the door to new approaches for preventing myopia in at-risk children.
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