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Background:

Infertility affects about one in six couples worldwide. To address this, medical experts have developed Assisted Reproductive Technologies (ART), including In Vitro Fertilization (IVF) with or without Intra-Cytoplasmic Sperm Injection (ICSI).

Some research suggests that children conceived through ART might have higher rates of intellectual disabilities, cerebral palsy, cancer, and neurological issues compared to children conceived naturally. However, studies looking at a possible link between ART and ADHD have produced mixed and conflicting results.

Until now, there hasn’t been a meta-analysis examining the connection between ART and ADHD. A South Korean research team has conducted the first systematic review and meta-analysis on this topic. Their final analysis included eight studies with a total of over ten million participants, comprising six cohort studies and two cross-sectional studies.

Method:

The research focused on two types of studies:

1. Cohort Studies: These follow two groups (one exposed to ART and one not exposed) over time to see if a specific outcome, like ADHD, occurs.
2. Cross-Sectional Studies: These compare the prevalence of ADHD at a single point in time between those exposed to ART and those who weren’t.

Both types of studies are observational, meaning they don’t involve controlled experiments and can be influenced by confounding factors.  So they can document interesting associations, not causality.  The studie were mostly large-scale national studies and used clinical ADHD diagnoses.

Key Findings:

• Cohort Studies: Meta-analysis of six cohort studies, involving nearly 8 million participants, found no link between ART and ADHD. However, there was high variability (heterogeneity) in the results from individual studies.
• Cross-Sectional Studies: Meta-analysis of two cross-sectional studies, covering over 2.3 million participants, also found no link between ART and ADHD. Heterogeneity was moderate.
• Adjustment for Confounding: A separate analysis of three studies that adjusted for confounding factors (like socioeconomic status or parental health) involved more than 7.5 million participants. It found a very small association, with ART-conceived children being 8% more likely to develop ADHD. There was no variability among these studies.

Conclusion:

The researchers concluded that while there may be a small association between ART and ADHD, the effect is minimal, and the results are influenced by differences in study designs. They advised interpreting these findings with caution, noting, “The limited effect size and inherent heterogeneity underscore the need for cautious interpretation.”

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Attention Deficit Hyperactivity Disorder (ADHD) is a prevalent neurodevelopmental disorder that significantly impacts children’s academic performance, social interactions, and overall quality of life (QoL). While medication is the standard treatment, it often comes with side effects and may not always provide sufficient benefits. A new systematic review and meta-analysis aims to investigate whether physical activity can offer a viable and effective alternative or complement to medication.

About the Study
This protocol, developed in line with the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA) guidelines, focuses on randomized clinical trials involving children and adolescents (ages 3–18) diagnosed with ADHD or hyperkinetic disorder. The study's goal is to evaluate the effects of physical activity on:

• Quality of life (QoL)
• Executive functions
• ADHD symptoms
• Functional impairments

Unlike earlier reviews, which often included non-randomized trials or imposed limits on activity types, this analysis takes a more robust and inclusive approach. It is the first of its kind to examine QoL as an outcome while also incorporating trial sequential analysis—a method to assess evidence strength over time.

Why Physical Activity?
Physical activity is believed to impact the same brain systems targeted by ADHD medications, particularly the catecholaminergic system. This overlap suggests that exercise could play a key role in managing symptoms, potentially reducing reliance on medication or enhancing its effects.

Methodology Highlights

• The review will adhere to principles outlined in the Cochrane Handbook for Systematic Reviews of Interventions.
• It incorporates the latest research and focuses on randomized trials to ensure high-quality evidence.
• No restrictions are placed on the frequency or intensity of physical activity interventions, making the findings broadly applicable.

Significance and Dissemination
The results of this systematic review will provide critical insights into how physical activity could improve outcomes for children and adolescents with ADHD. It is also notable as the first review in this field to prioritize quality of life—a crucial, often-overlooked measure of treatment success.

The findings will be published in peer-reviewed journals and presented at relevant conferences to inform clinicians, educators, and families.

Conclusion
As concerns about the limitations of ADHD medication grow, exploring alternatives like physical activity becomes increasingly important. This systematic review has the potential to shape future treatment strategies, offering children with ADHD a chance for better symptom management and a higher quality of life.

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Background 

ADHD (Attention-Deficit/Hyperactivity Disorder) is one of the most studied neurodevelopmental conditions, with many clinical trials evaluating the effectiveness and safety of various medications. These trials, known as randomized controlled trials (RCTs), are considered the gold standard for assessing treatments. However, strict eligibility criteria often exclude many real-world patients, raising questions about whether the findings from these trials apply to everyday clinical settings.

Our latest study sheds light on this issue, revealing just how many individuals with ADHD might be excluded from RCTs and the impact this exclusion has on their treatment outcomes. 

Method

Researchers used Swedish national registries to analyze data from 189,699 individuals diagnosed with ADHD who started medication between 2007 and 2019. They applied exclusion criteria from 164 international RCTs to identify who would have been considered ineligible for these trials in order to determine the proportion of individuals with ADHD who would not meet the eligibility criteria for RCTs.  

Key Findings

Many Patients Are Ineligible for Clinical Trials:

• Over half (53%) of the study population would have been ineligible for ADHD medication trials.
• Adults were most likely to be excluded (74%), followed by adolescents (35%) and children (21%).

Ineligible Patients Face Unique Challenges:

• Treatment Switching: Ineligible individuals were more likely to switch medications within the first year (14% higher likelihood compared to eligible patients).
• Medication Discontinuation: They were slightly less likely to stop taking their medication during the first year.

Higher Risk of Adverse Outcomes:

• Ineligible patients experienced significantly higher rates of psychiatric hospitalizations and health issues such as depression, anxiety, and substance use disorders. For instance:
  • Psychiatric hospitalizations: Nearly 10 times more likely.
  • Specialist visits for substance use disorders: About 15 times more likely.
  • Anxiety-related visits: Over 11 times more likely.

What This Means

These findings highlight a major gap between the controlled environments of clinical trials and the realities faced by individuals with ADHD in everyday life. While RCTs provide valuable insights, their restrictive criteria often exclude patients with more complex health profiles or co-existing conditions. This limits the generalisability of trial results, meaning that treatment guidelines based solely on RCTs may not fully address the needs of all patients.

Conclusion

This study demonstrated that a significant proportion of individuals with ADHD, particularly adults, do not meet the eligibility criteria for standard RCTs. These results emphasize the importance of bridging the gap between research settings and real-world applications. By recognizing and addressing the limitations of RCTs, we can work towards more equitable and effective ADHD treatment strategies for everyone.

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Background:

Our understanding of Attention-deficit/hyperactivity disorder (ADHD) has grown and evolved considerably since it first appeared in the DSM-II as “Hyperkinetic Reaction of Childhood.”  This study aimed to find the disorder’s placement within the modern psychopathology classification systems like the Hierarchical Taxonomy Of Psychopathology (HiTOP). 

The HiTOP model aims to address limitations of traditional classification systems for mental illness, such as the DSM-5 and ICD-10, by organizing psychopathology according to evidence from research on observable patterns of mental health problems.. Is ADHD best categorized under externalizing conditions, neurodevelopmental disorders, or something else entirely? A recent study by Zheyue Peng, Kasey Stanton, Beatriz Dominguez-Alvarez, and Ashley L. Watts takes a closer look at this question using a symptom-focused approach.

The Study:

Traditionally, ADHD has been associated with externalizing behaviors, such as impulsivity and hyperactivity, or with neurodevelopmental traits, like cognitive delays. However, this study challenges the idea of placing ADHD into a single category. Instead, it maps ADHD symptoms across three major psychopathology spectra: externalizing, neurodevelopmental, and internalizing.

The findings reveal that ADHD symptoms don’t fit neatly into one box. For example, symptoms like impulsivity, poor school performance, and low perseverance were strongly associated with externalizing behaviors. On the other hand, cognitive disengagement (e.g., daydreaming, blank staring) and immaturity were closely linked to neurodevelopmental challenges. Interestingly, cognitive disengagement also showed ties to internalizing symptoms, such as anxiety or depression.

This research underscores the complexity of ADHD. Rather than treating ADHD as a single, unitary construct, the study advocates for a symptom-based approach to better understand and treat individuals. By acknowledging that ADHD symptoms relate to multiple psychopathology spectra, clinicians and researchers can move toward more nuanced classification systems and targeted interventions.

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Conclusion: 

Ultimately, this study highlights the need for modern systems to move beyond rigid categories and adopt a more flexible, symptom-focused framework for understanding ADHD’s place in psychopathology.

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Background:

Exposure to heavy metals like lead, arsenic, mercury, cadmium, and manganese is known to harm developing nervous systems. However, past studies on whether heavy metals specifically increase the risk of ADHD have shown mixed results.

A research team from China (Gu et al., 2024) reviewed medical studies and conducted meta-analyses to better understand this issue.

Methods:

The team included studies on children and teens, focusing on cohort studies, case-control studies, and cross-sectional studies. They only used articles written in English and required validated biomonitoring (like blood tests) to measure heavy metal exposure. ADHD diagnoses had to come from clinical evaluations.

To be included, studies had to report effect sizes such as odds ratios and relative risks with confidence intervals. The team focused on comparisons between groups with high, low, or no exposure, which made it harder to analyze dose-response relationships.

They also evaluated the quality of each study. All cohort studies were rated high-quality. Of the 15 case-control studies, 6 were high-quality, and 9 were moderate-quality. Among cross-sectional studies, only 2 were high-quality, and the rest were moderate-quality.

Key Findings:

1. Lead Exposure and ADHD:some text
   • A meta-analysis of 22 studies with over 20,000 participants found that early exposure to lead was linked to about twice the odds of an ADHD diagnosis compared to unexposed children.
   • However, results varied widely among studies, and signs of publication bias were detected. After adjusting for this bias, the increased odds dropped to about 50%.
   • A dose-response relationship was found:some text
     • Blood lead levels of 2.5 µg/dL increased ADHD risk by 1.8 times.
     • Levels of 5 µg/dL increased the risk 2.5 times.
     • Levels of 7.5 µg/dL increased the risk 2.75 times.
     • Levels of 10 µg/dL tripled the risk.
2. Other Metals:some text
   • No significant links were found between ADHD and exposure to arsenic, mercury, cadmium, or manganese. Fewer studies were available for these metals, and participant numbers were much smaller:some text
     • Arsenic exposure: 25% higher odds of ADHD (4 studies, 3,116 participants).
     • Mercury exposure: 25% higher odds (6 studies, 2,916 participants).
     • Cadmium exposure: 25% higher odds (5 studies, 2,419 participants).
     • Manganese exposure: 45% higher odds (6 studies, 1,664 participants).
3. Austrian Study: An Austrian team (Rosenauer et al., 2024) also conducted a meta-analysis on lead exposure and ADHD. They included 14 studies with over 7,600 participants and found:some text
   • Lead exposure increased the odds of ADHD by about 25%.
   • Studies focusing on higher lead levels found a 43% increased risk, supporting a dose-response relationship.
   • Study results were consistent, with no signs of publication bias.

Conclusion:

There was no evidence linking ADHD to other heavy metals like arsenic, mercury, cadmium, or manganese.  Both meta-analyses suggest that lead exposure is associated with the risk for ADHD.  However, because these studies cannot rule out other explanations, one cannot conclude that lead exposure causes ADHD.  For example, other work shows that people with ADHD are likely to have lower incomes than those without ADHD.  

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The Background:

Caffeine and its primary breakdown compounds – paraxanthine, theophylline, and theobromine (also the primary alkaloid in chocolate) – readily cross the placenta and tend to linger due to the underdevelopment of fetal caffeine metabolizing enzymes.

Could accumulating caffeine metabolites harm the developing fetal brain? Studies to date have come to contradictory conclusions, some finding an association, others finding none.

Norway has a national single-payer health insurance system with a national health registry comprehensively tracking virtually all residents.

The Methods:

An international study team used Norways’s registry, and its Mother, Father, and Child Cohort Study (MoBa) to explore the relationship between maternal and paternal coffee consumption and offspring neurodevelopmental difficulties (ND), including symptoms of ADHD as determined from validated rating scales, using 58,964 mother-child pairs and 22,576 father-child pairs, covering the decade 1999-2008.

Unadjusted results indicated a strong association between maternal coffee consumption before and during pregnancy with offspring ADHD, but none with paternal coffee consumption. Superficially, that might seem like compelling evidence.

Yet after adjusting for education, income, smoking, and alcohol, “previously significant effects attenuated towards zero and some associations switched from being positive to negative.”

Then, after further adjusting for genetic confounding, ADHD symptoms at 1.5 years, 3 years, 5 years (on both of two different rating scales), and 8 years (including separate measures of inattention and hyperactivity symptoms) all became indistinguishable between offspring from mothers consuming coffee during pregnancy and offspring of mothers abstaining from coffee during pregnancy. 

Conclusion:

The team concluded, “This study applied several conventional and genetic epidemiological approaches to investigate the potential relationship between maternal coffee consumption during pregnancy and offspring NDs [neurodevelopmental difficulties]. When considering the results of the conventional and genetic epidemiological analyses, as well as the broader literature, we conclude that there is little evidence that maternal coffee consumption during pregnancy is strongly causally related to offspring NDs.”

More specifically, the team found no evidence of any causal relationship with offspring ADHD. 

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There has been consistent evidence of an association between ADHD and subjectively reported sleep problems even in patients not medicated for the disorder. There have also been studies using wrist-worn actigraphy (a wrist watch-like device that measures gross motor activity) and sleep lab-based polysomnography that measure objective sleep parameters. 

What has been missing are large population-based cohort studies to explore the prevalence rates of different sleep disorders and medical prescriptions in ADHD. 

Methods Used: 

Sweden has a single-payer health insurance system and a series of national population registers that track virtually its entire population. Using the Swedish Total Population Register, a local research team created a cohort of all 6,470,658 persons born between 1945 and 2008. They linked this to the Swedish National Patient Register, which includes inpatient hospitalizations from 1975 to 2013, and outpatient specialist diagnoses from 2001 to 2013, to identify diagnoses of sleep disorders. They also linked to the Prescribed Drug Register, covering 2005 to 2013, to identify prescriptions for sleep medications. 

Summary of Findings: 

Overall, persons with ADHD were eight times more likely to be diagnosed with any sleep disorder relative to normally developing peers. Broken down by age, adolescents with ADHD were 16 times more likely to receive such diagnoses, young adults (18-30) twelve times more likely, children and mid-age adults (31-45) eight times more likely, and older adults six times more likely. 

Broken down by specific sleep disorder diagnoses, relative to normally developing peers, persons with ADHD were: 

• Five times more likely to have sleep terrors and seven times more likely to have nightmares. 

• Six times more likely to sleepwalk. 

• Seven times more likely to have restless leg syndrome. 

• Sixteen times more likely to have insomnia. 

• Nineteen times more likely to have disorders of sleep/wake schedule (circadian rhythms). 

• Twenty times more likely to have hypersomnia (excessive sleeping). 

• Over seventy times more likely to exhibit narcolepsy (daytime sleepiness) and cataplexy (sudden loss of muscle tone leading to collapse). 

As for sleep medication, relative to normally developing peers, persons with ADHD were: 

• Seven times more likely to be prescribed the hypnotic zolpidem (Ambien). 

• Eight times more likely to be prescribed the hypnotic zopiclone or the antihistamine propriomazine. 

• Ten times more likely to be prescribed the sedative and hypnotic zaleplon (Sonata). 

• Fourteen times more likely to be prescribed any sleep medication. 

• 37 times more likely to be prescribed melatonin, the body’s natural sleep-inducing hormone, which is a prescription medication in Europe. 

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Conclusion: 

The team concluded, “Our findings also suggest that greater clinical attention should be directed towards addressing sleep problems in individuals with ADHD. This entails implementing proactive measures through sleep education programmes and providing both pharmacological and non-pharmacological approaches such as cognitive behavioural therapy and parental sleep training.” 

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Congenital cleft lip and palate (CCLP) are birth defects associated with genetic and environmental factors. The latter include heavy maternal consumption of alcohol and fetal exposure to retinoid drugs derived from vitamin A. 

Methods:

Taiwan has an island-wide single-payer health insurance system that reaches over 99% of the population. To explore the relationship between CCLP and various psychiatric disorders including ADHD, a Taiwanese study team used the island’s National Health Insurance Research Database to identify all 1,158 children and adolescents with CCLP during a ten-year period. They matched them ten-to-one with 11,580 age and sex-paired controls without CCLP. 

Summary of Results:

Further adjusting for demographic data (income, residence) and family history of major psychiatric disorders, children and adolescents with CCLP were more than seven times more likely to be diagnosed with ADHD during the follow-up period than controls. Patients with both cleft palate and cleft lip were more than nine times more likely to be subsequently diagnosed with ADHD than controls. 

Patients with CCLP were also six times more likely to be diagnosed with autism spectrum disorder and more than seven times as likely to be diagnosed with schizophrenia as non-CCLP controls. They were also more likely to be diagnosed with bipolar disorder or major depressive disorder, but these results did not reach statistical significance. 

Conclusion:

This study highlights a significant association between congenital cleft lip and palate (CCLP) and an increased risk of developing ADHD, with CCLP patients being more than seven times as likely to be diagnosed with the disorder. Additionally, CCLP was linked to a higher prevalence of other psychiatric conditions, including autism spectrum disorder and schizophrenia. These findings underscore the importance of monitoring mental health in individuals with CCLP and call for further research into the risk factors connecting these birth defects with psychiatric disorders.

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Overview

Attention is a critical determinant of academic achievement, influencing domains such as language, literacy, and mathematics. To explore whether physical activity can improve attention in children with ADHD, an international team conducted a meta-analysis of peer-reviewed studies. The goal was to evaluate the impact of various physical activity regimens on attention-related outcomes in this population.

Methods

The researchers performed a comprehensive search of the medical literature to identify studies examining the effects of physical activity on attention in schoolchildren with ADHD. They included 10 studies with a total of 474 participants in their meta-analysis. The studies evaluated two main types of physical activity:

• Mentally engaging physical activities
• Aerobic exercise

Additionally, they examined variations based on the frequency, duration, and type of control groups used in the studies. To assess consistency, they also analyzed heterogeneity (variability of outcomes) and checked for potential publication bias.

Summary

Key findings from the meta-analysis include:

1. Effectiveness of Mentally Engaging Activities:some text
   • Seven studies (168 participants) involving mentally engaging physical activities showed large reductions in attention problems.
   • Heterogeneity was significantly reduced for these studies.
2. Effectiveness of Aerobic Exercise:some text
   • Three studies (306 participants) using aerobic exercise alone found no improvements in attention.
3. Impact of Control Groups:some text
   • Studies with no intervention as a control group (4 studies, 81 participants) reported large improvements in attention problems.
   • Those comparing physical activity with other interventions (6 studies, 393 participants) found only small improvements.
4. Frequency and Duration:some text
   • Duration of physical activity made little difference. Studies with sessions of an hour or more had slightly better outcomes, but the difference was not significant.
   • Surprisingly, lower frequency was more effective:some text
     • One to two sessions per week (7 studies, 162 participants) led to large reductions in attention problems.
     • Three or more sessions per week (3 studies, 312 participants) showed no improvement.

Conclusion

The authors concluded that mentally engaging exercise is more effective than aerobic exercise in improving attention problems in schoolchildren with ADHD. Furthermore, higher frequency and longer duration of physical activity do not necessarily yield better outcomes.

This research underscores the importance of tailoring physical activity interventions to emphasize cognitive engagement over intensity or duration. By refining strategies, educators and parents can better support children with ADHD in achieving academic success.   But take note:  given the results from controlled studies, it seems clear that if there is a positive effect of exercise, it is very small so should not replace standard treatments for ADHD.  

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