3. Physical ADHD risk factors

Author: Ulrich Brennecke
Review: Dipl.-Psych. Waldemar Zdero

Stressful physical or psychological childhood experiences can be a contributory cause of ADHD.

For infants:
Bottle feeding increases the risk of ADHD, while breastfeeding reduces the risk. Crying babies, feeding and sleeping problems in infants, subependymal pseudocysts and antihistamines in the first years of life increase the risk of ADHD.

For infants and children:
Exposure to passive smoking, air pollution (especially particulate matter and nitrogen oxides) and various pollutants such as lead, manganese or phthalates is associated with an increased risk of ADHD.
Surgical procedures under anesthesia, neurodermatitis, bacterial infections, concussions are just as ADHD risk factors as stressful psychological childhood experiences such as trauma, chronic stress or growing up in a home.
Poor bonding behavior of the mother or parents in childhood, stress of the mother in childhood or mental health problems of the parents increase the risk of ADHD in children, as do low socio-economic status, a low level of education or unemployment of the parents.
Earlier school entry and the young age of a child within a class are further risk factors.

During puberty:
A high level of stress during puberty is considered a risk factor for the persistence of ADHD into adulthood.

The % values indicate how much higher the ADHD risk increase correlates with the respective factor. The figures do not indicate that the respective factor is a causal factor.

• 3.1. Newborns, infants
  • 3.1.1. Screaming children (up to + 1181 %)
    • 3.1.1.1. Increased risk of ADHD in crying children
    • 3.1.1.2. Factors that increase the risk of crying children
  • 3.1.2. Febrile convulsions in premature babies (+ 540 %)
  • 3.1.3. Bottle feeding increases (up to +200%), breastfeeding reduces ADHD risk (-23% to -74%)
  • 3.1.4. First-born status (+ 31 to + 100 %)
  • 3.1.5. Type of complementary food (wheat + 8 %, rice - 26 %)
  • 3.1.6. Feeding problems with infants
  • 3.1.7. Sleep problems in infants
  • 3.1.8. Subependymal pseudocysts
  • 3.1.9. Valproate
  • 3.1.10. D-3 insufficiency in the first 12 months
  • 3.1.11. Uncontrolled metabolic decompensation
• 3.2. Children
  • 3.2.1. Infectious diseases
    • 3.2.1.1. Infections in the first year of life (+ 16 %)
    • 3.2.1.2. Bacterial infections (up to + 593 %)
      • 3.2.1.2.1. Bacterial meningitis (meningitis) (+ 40 % to + 180 %)
      • 3.2.1.2.2. Antibiotics in the first years of life (up to + 33 %)
    • 3.2.1.3. Viral infections
  • 3.2.2. Craniosynostosis (+ 500 %)
  • 3.2.3. Epilepsy (+ 470 %)
  • 3.2.4. Metals
    • 3.2.4.1. Copper (up to + 1,546 % (?))
    • 3.2.4.2. Lead (+ 160 % to + 310 %)
    • 3.2.4.3. Cadmium (+ 269 % ?)
    • 3.2.4.4. Manganese (+ 163 % to + 257 %)
    • 3.2.4.5. Antimony (up to + 204 %)
    • 3.2.4.6. Mercury (up to + 168 %)
    • 3.2.4.7. Arsenic (+ 53 %)
    • 3.2.4.8. Zinc
  • 3.2.5. Chemicals
    • 3.2.5.1. Phthalates (+ 212% for girls to + 254% for boys)
    • 3.2.5.2. Perfluorooctane sulfonate (PFOS) (+ 77 %)
    • 3.2.5.3. β-Hexachlorocyclohexane (β-HCH) (+ 75 %)
    • 3.2.5.4. Chlorinated kerosenes (+ 57 % / quartile)
    • 3.2.5.5. Polychlorinated biphenyls (PCBs)
  • 3.2.6. Gastroesophageal reflux (+ 248 %)
  • 3.2.7. Passive smoking - smokers in the environment in the first years of life (+ 42 % to + 170 %)
  • 3.2.8. D-3 insufficiency (+ 157 %)
  • 3.2.9. Air pollution in childhood
    • 3.2.9.1. Particulate matter
      • 3.2.9.1.1. Particulate matter PM10 (up to + 288 %)
      • 3.2.9.1.2. Particulate matter PM2.5 (up to + 82 %)
      • 3.2.9.1.3. Ultrafine dust 23nm
      • 3.2.9.1.4. Pathways of particulate matter on ADHD
    • 3.2.9.2. Nitrogen oxides: nitrogen oxide (NO), nitrogen dioxide (NO2) (up to + 110 %)
    • 3.2.9.3. Nitrous oxide (laughing gas)
    • 3.2.9.4. Ozone
  • 3.2.10. Hyperthyroidism / hyperthyroidism (+ 70 %)
  • 3.2.11. Concussions and traumatic brain injuries (+ 68 %)
  • 3.2.12. Febrile convulsions (+ 28 % to + 66 %)
  • 3.2.13. Nutrition
    • 3.2.13.1. Diet high in sugar (+ 41 %)
    • 3.2.13.2. Highly processed foods (up to + 25 %)
  • 3.2.14. Early puberty (pubertas praecox) (+ 40 %)
  • 3.2.15. Surgical procedures under anesthesia (+ 25 to 39 %)
  • 3.2.16. Atopic disorders (immunoglobulin E deficiency)
    • 3.2.16.1. Asthma (+ 34 % to + 296 %)
    • 3.2.16.2. Atopic eczema (+ 72 %)
    • 3.2.16.3. Neurodermatitis / atopic dermatitis (up to + 28 %)
  • 3.2.17. Selective immunoglobulin A deficiency (+ 30 %)
  • 3.2.18. Antihistamines in the first years of life
  • 3.2.19. Insecticides / pesticides
    • 3.2.19.1. Chlorpyrifos
    • 3.2.19.2. Pyrethroid pesticides
    • 3.2.19.3. Organophosphates
  • 3.2.20. Lack of sleep
  • 3.2.21. Acne vulgaris
  • 3.2.22. Spray disinfectant
  • 3.2.23. Pets
  • 3.2.24. Printing ink on food paper
  • 3.2.25. Commercially packaged pasta
  • 3.2.26. Unpackaged flour
  • 3.2.27. Loud snoring
• 3.3. Age-independent physical factors
  • 3.3.1. Toxins (up to + 900 %)
    • 3.3.1.1. Phthalates (+ 200 % to + 900 %)
    • 3.3.1.2. Fluoridated drinking water (+ 510 % if 1 mg/L too high)
    • 3.3.1.3. Lead (+96 % to +133 %)
    • 3.3.1.4. Inorganic arsenic (+ 102 %)
    • 3.3.1.5. Benzene, toluene, ethylbenzene, xylene/xylene (BTEX) (+ 54 %)
    • 3.3.1.6. Smoking by parents (+ 30 %)
    • 3.3.1.7. Polychlorinated biphenyls (PCBs) / polychlorinated biphenyl ethers (+ 26 % to + 92 %)
    • 3.3.1.8. Polyvinyl chloride (PVC)
    • 3.3.1.9. Pesticides
      • 3.3.1.9.1. Organochlorine compounds
      • 3.3.1.9.2. Organophosphates
      • 3.3.1.9.3. Pyrethroids (+ 142 %)
      • 3.3.1.9.4. Carbamate (-)
      • 3.3.1.9.5. Neonicotinoids (- ?)
    • 3.3.1.10. Mercury / Amalgam (Mercury)
    • 3.3.1.11. Manganese
    • 3.3.1.12. Bisphenol A
    • 3.3.1.13. Perfluoroalkyl compounds
    • 3.3.1.14. Triclosan
    • 3.3.1.15. Synergy effects of neurotoxins
  • 3.3.2. Craniocerebral trauma (up to + 529 %)
  • 3.3.3. Food intolerances, allergies
  • 3.3.4. Gut-brain axis, gut bacteria, gut flora
  • 3.3.5. Polycystic ovary syndrome (PCOS)
  • 3.3.6. (Untreated) type 1 diabetes (+ 145 %)
  • 3.3.7. Phenylketonuria (PKU)
  • 3.3.8. Anabolic androgenic steroids (AAS)
  • 3.3.9. Infections
    • 3.3.9.1. Susceptibility to infection and infection burden
    • 3.3.9.2. Viral infections
      • 3.3.9.2.1. Enteroviruses in general (up to + 182 %)
      • 3.3.9.2.2. Enterovirus A71 (EV-A71) (+ 200 %)
      • 3.3.9.2.3. HIV
      • 3.3.9.2.4. Zoster encephalitis
      • 3.3.9.2.5. Human endogenous retroviruses (HERV)
    • 3.3.9.3. Bacterial infections
    • 3.3.9.4. Parasitic infections
  • 3.3.10. Glucose-6-phosphate dehydrogenase deficiency (G6PD)
  • 3.3.11. Kawasaki syndrome
  • 3.3.12. Lipodystrophy (lack of fatty tissue)
  • 3.3.13. Dystrophinopathy (muscular dystrophy, muscle weakness)
  • 3.3.14. Hyperthyroidism / hypothyroidism
  • 3.3.15. Interrupted breathing during sleep (sleep apnea)
  • 3.3.16. Gender diversity
  • 3.3.17. Lipid metabolism, fatty acids
  • 3.3.18. Inflammatory bowel disease (IBD)
  • 3.3.19. Mitochondrial disorder
• 3.4. Factors without risk increase for ADHD
• 3.5. Factors with risk reduction for ADHD

3.1. Newborns, infants¶

3.1.1. Screaming children (up to + 1181 %)¶

3.1.1.1. Increased risk of ADHD in crying children¶

Cry babies have a significantly increased risk of ADHD[{Schmid, Wolke (2014): Preschool regulatory problems and attention-deficit/hyperactivity and cognitive deficits at school age in children born at risk: different phenotypes of dysregulation? Early Hum Dev. 2014 Aug;90(8):399-405. doi: 10.1016/j.earlhumdev.2014.05.001. n = 1120}}¹ The risk of developing hyperactivity at the age of 8 to 10 years was 11.8 times higher (plus 1181%). Behavioral problems and a negative emotional orientation were reported twice as often as in unaffected individuals.²

3.1.1.2. Factors that increase the risk of crying children¶

If the parents are heavy smokers, or if the mother smokes during pregnancy, the risk of a crying child increases by 30 to 150% (several studies); the largest study on this (n = 5845) states a 69% increased risk.³
In addition, there are several other possible causes that should be systematically ruled out.⁴

3.1.2. Febrile convulsions in premature babies (+ 540 %)¶

Febrile convulsions increased the risk of ADHD in premature infants 6.4-fold and the risk of ASD 16.9-fold.⁶

3.1.3. Bottle feeding increases (up to +200%), breastfeeding reduces ADHD risk (-23% to -74%)¶

The % figures were calculated without the highest and lowest values.

The WHO recommends exclusively breastfeeding newborns for the first 6 years.⁷
A cohort study in Taiwan found that of Taiwanese mothers⁷

• 82.1 % breastfed after delivery
• the average duration of breastfeeding was 2 months (59 days)
• 26 % breastfed for 3 months
• 9.8 % breastfed for 6 months
• 21.9% have ever exclusively breastfed their child (average duration of breastfeeding here 125 days)
• only 3.8% adhered to the WHO recommendation of exclusive breastfeeding for up to 6 months

Infants who were not breastfed showed an increased risk of ADHD as children, while children who were breastfed as infants showed a decreased risk of ADHD ^{8 9 10 1112}

• 3.71-fold ADHD risk (+ 271 %, OR = 3.71; meta-analysis of k = 11 studies).¹³
• almost 3 times the risk of ADHD (+ almost 200%)¹⁴
• approx. 1.55-fold ADHD risk (+ 55 %, OR = 1.55; METASTUDY)¹⁵

Children with ADHD were 1.51 times more likely to be exclusively breastfed for less than 3 months and 52% less likely to be exclusively breastfed for more than 3 months. Children with ADHD had a significantly (2.44 months) shorter duration of breastfeeding (SMD: Hedges’ g = - 0.36) (meta-analysis of k = 11 studies). ¹³

In breastfed children (without distinction as to whether exclusively or partially and regardless of duration), the risk of ADHD was

• by 83 %¹⁶ and for major depression by 74 %, and for anxiety disorders by 4 %. The effects on ASD, bipolar Disorder and schizophrenia were not significant.
• reduced by 74 % (OR = 0.263, small study)¹⁷
• by 30 % (meta-analysis, k = 12, n = 106,907).¹⁸
• reduced by 28% (raw value) to 18% (adjusted value) by the age of 5⁷ Since ADHD is usually diagnosed later, the impact is likely to be much greater,
• unchanged¹⁹

Children who were exclusively breastfed had a higher risk of ADHD compared to children who were exclusively bottle-fed,

• reduced by 38% with exclusive breastfeeding for at least 6 months, after adjustment for potential confounding factors²⁰
• hyperactivity reduced by 35% at 8 years of age if breastfeeding was exclusive for at least 3 months²¹
• reduced by 18 %²²
• reduced by 7 %²³
• unchanged ADHD symptoms at the age of 16²¹

Exclusive breastfeeding for more than 6 months increased the risk of ADHD by 15%.⁷

Partially breastfed children had a

• aDHD risk reduced by 44% at the age of 4 years, after breastfeeding for more than 12 weeks²⁴
• aDHD symptoms reduced by 32% at age 16 if breastfed for at least 6 months²¹
• hyperactivity reduced by 24% at 8 years, but not statistically significant²⁵
• aSS risk reduced by 11 % ²²
• aDHD risk reduced by 9 %²²
• improved executive functions at the age of 4 years (increase of 4.9 points after breastfeeding for more than 20 weeks)²⁴
• improved social skills at the age of 4 years (43% reduced risk of being in the worst 20% after breastfeeding for more than 12 weeks)²⁴

The risk of ADHD decreases with the duration of breastfeeding^{2627 28} (25-year observational cohort study, n = 16,365).²⁹. One study found no significant values for ADHD.³⁰
The risk decreased by

• 20% if breastfed for more than 1 month compared to less than 1 month (meta-analysis, k = 12, n = 106,907).¹⁸
• 33% if breastfed for more than 3 months compared to less than 3 months (meta-analysis, k = 12, n = 106,907).¹⁸
• 50% if breastfed for more than 6 months compared to less than 6 months (meta-analysis, k = 12, n = 106,907).¹⁸
• 55% if breastfed for more than 12 months compared to less than 12 months (meta-analysis, k = 12, n = 106,907).¹⁸

Each additional month

• the duration of breastfeeding reduced the risk of ADHD by 8%²⁰
• of exclusive breastfeeding (without complementary food) reduced the risk of ADHD by approx. 8 % (but not statistically significant)²⁰

Prolonged breastfeeding improved cognitive performance,³⁰

Complementary food at the age of 6 months

• Complementary food up to 6 months reduced the risk of ADHD by 28%⁷
  • by 6 % with fruit/vegetable juice (not statistically significant)
  • by 14% with fruit/vegetable porridge (not statistically significant)
  • by 19 % with traditional rice porridge (Taiwan) (not statistically significant)
  • by 27% with rice-based diets without traditional rice porridge (Taiwan)
  • increased by 8 % with solid food made from wheat (not statistically significant)
• had no influence²²²⁰

The risk of ASA was reduced by breastfeeding

• by 36 %²²
• significantly due to prolonged breastfeeding³⁰
• not significant¹⁶

Breast milk contains many substances that are essential for the development of babies, such as

• polyunsaturated fatty acids.¹⁰
• Prebiotics³¹
  • Oligosaccharides
  • promote the growth and activity of beneficial microorganisms

The substances contained in breast milk promote³¹
- antimicrobial active ingredients
- bacterial growth
- secreted IgA for a regulatory immune system

Stilen in the first three months of life influences the intestinal microbiotics:³¹

• increases the frequency of
  • Lactobacillus (Bacillota strain)
  • Bifidobacterium
  • Enterococcus
  • Corynebacterium
  • Propiobacterium
  • Streptococcus
  • Sneathia
• reduces the frequency of
  • Bacteroides (strain Bacteroidota)
  • Staphylococcus

Bottle-fed infants show a different gut microbiome:³¹

• increased frequency of
  • Atopobium (strain Actinomycetota)
  • Bacteroides (strain Bacteroidota)
  • Bilophila (strain Thermodesulfobacteriota)
  • Enterobacter (strain Pseudomonadota)
  • Escherichia (strain Pseudomonadota)
  • Citrobacter (strain Pseudomonadota)
  • Clostridium (Bacillota strain)
  • Enterococcus (Bacillota strain)
  • Lactobacillus (Bacillota strain)
  • Granulicatella (strain Bacillota)

More on the influence of the gut-brain axis on ADHD at Gut-brain axis and ADHD

Bisphenol A is known to increase the risk of ADHD. Exposure to PAHs, particularly bisphenol A (BPA), is associated with ADHD symptoms in primary school children and a significant reduction in the volume of the caudate nucleus³²³³ Bisphenol A was much more common in baby bottles in 2007 than in 2011, which could explain why a study found a five-fold increase in the risk of ADHD in children fed by bottle in 2007, but no increase in risk in children fed by bottle in 2011.³⁴

After all, breastfeeding has its own influence on the well-being and positive development of children, independent of food intake.
Maternal care is the infant’s first social experience and has a decisive influence on its survival, proper development and social skills throughout life.
Infants and puppies do not yet have a high inherent value for their respective mothers at birth.³⁵. Breastfeeding in humans and suckling puppies in animals are rewarding and reinforcing stimuli that promote maternal behavior and bonding. Suckling puppies activates the mesocorticolimbic dopamine system in mothers, which reinforces bonding and nurturing behavior. The extracellular dopamine levels in the nucleus accumbens (the reward center of the brain) increase and correlate with the time spent caring for the offspring.

3.1.4. First-born status (+ 31 to + 100 %)¶

The risk of ADHD in first-born children was

• By 200% compared to children with younger and older siblings, according to a large Spanish registry study.³⁶
• Increased by almost 100 % compared to non-firstborns³⁷
• Increased by 70 % if there was only one (1) sibling³⁸
• Increased by 35% according to a Spanish study of n = 1,104 primary school children³⁹
• According to the German KiGGS study (n = 13,488), the risk of ADHD was 31% higher for first-born children compared to last-born children and children without siblings.⁴⁰
• Increased by 22 %³⁸
• A very large Swedish registry study found an increased risk of ADHD and depression for firstborns.⁴¹
• An Indian study found a high proportion of first-born children among people with ADHD⁴²
• A study of Ethiopian students found a significant ADHD risk increase for first-time mothers⁴³ and explained this conclusively by increased perinatal risk factors and birth-related complications, which are a major contributor to ADHD and are so much more common in first-time mothers that they were labeled high-risk by the authors:⁴⁴

• low birth weight 57% more frequently (evidence that this increases the risk of ADHD)
• Emergency caesarean sections 57 % more frequent
• pregnancy-induced high blood pressure 15.38 % more frequently
• intrauterine growth retardation 19.23 % more frequently
• premature labor 9.61 % more often
• fetal distress 19.23 % more frequent
• Oligohydraminos 17.30 % more frequent

It remains to be seen whether there are other risk factors.

No influence of first-born status on the risk of ADHD found

• a study of n = 598 children and adolescents with ADHD from relatively large families (more than 47% had at least 4 siblings)⁴⁵
• an Iranian study on n = 400 children⁴⁶,
• a study of n = 387 Iranian students.⁴⁷
• two smaller studies (n = 100 and n = 32)⁴⁸
• a smaller study (n = 173)⁴⁹

First-born status increased the risk

• By 45 % for aggressive behavior. The risk was even higher if there were older siblings.⁵⁰
• By 28 % for severe externalizing symptoms⁵¹

Children with ASD had a significantly reduced risk of ADHD if they had an older sibling⁵²

One study did not ask about first-born status, but about the presence of siblings (at 18 months, 3 years and 5 years of age). The siblings could be older and or younger. Among the newborns, about 50.4% were their mothers’ first child and 38.4% were their second child. The remaining newborns were other children.⁵³
Siblings reduced the risk of ADHD by 35%.⁷

3.1.5. Type of complementary food (wheat + 8 %, rice - 26 %)¶

Complementary food at the age of 6 months

• Complementary food up to 6 months reduced the risk of ADHD by 28%⁷
  • by 6 % with fruit/vegetable juice (not statistically significant)
  • by 14% with fruit/vegetable porridge (not statistically significant)
  • by 19 % with traditional rice porridge (Taiwan) (not statistically significant)
  • by 26% with rice-based diets without traditional rice porridge (Taiwan)
  • increased by 8 % with solid food made from wheat (not statistically significant)
• had no influence²²²⁰

3.1.6. Feeding problems with infants¶

Feeding problems in infants correlate with ADHD in adolescence and adulthood.¹
Frequently skipped meals correlated with an increased risk of ADHD.¹²

3.1.7. Sleep problems in infants¶

Sleep problems in infants correlate with ADHD in adolescence and adulthood.¹

3.1.8. Subependymal pseudocysts¶

Subependymal pseudocysts in newborns increase the risk of ADHD and autism.⁵⁴

3.1.9. Valproate¶

Studies in mice suggest that valproate administration in newborns could cause permanent damage similar to that caused by ASA and, in some cases, ADHD.⁵⁵

3.1.10. D-3 insufficiency in the first 12 months¶

A vitamin D3 level of less than 25 ng/ml in the first 12 months of life was dose-dependently associated with an increased risk of ADHD in childhood. This also applied to ASD and emotional behavioral disorders⁵⁶
This is consistent with the findings of an increased risk of ADHD if the mother has a D3 deficiency during pregnancy (see there).

3.1.11. Uncontrolled metabolic decompensation¶

Uncontrolled metabolic decompensation, e.g. as a result of MCAD deficiency (Medium-Chain Acyl-Coenzyme A Dehydrogenase Deficiency), increases the risk of missing developmental milestones and developing aphasia and ADHD.⁵⁷

3.2. Children¶

3.2.1. Infectious diseases¶

An infection is the entry of microorganisms (viruses, fungi, bacteria, parasites) into an organism and their colonization and multiplication.
In a broader sense, infectious diseases are also referred to imprecisely as “infections”.⁵⁸

3.2.1.1. Infections in the first year of life (+ 16 %)¶

A register-based cohort study (n = 2,885,662 of which n = 1,864,660 were full siblings) found a slight increase of 16% in the risk of ADHD due to infections in the child in the first year of life (ASD + 12%; tics + 12%, mental retardation + 63%), which was lost when twins were controlled for ADHD and tics.⁵⁹

3.2.1.2. Bacterial infections (up to + 593 %)¶

Severe bacterial infectious diseases in childhood or adolescence massively increase the risk of severe mental disorders (HR):⁶⁰

• ASS: 13,80
• ADHD: 6.93
  • ADHD medication use: 11.81
• Tic Disorder: 6.19
• OCD: 3.93
• Bipolar Disorder: 2.50
• Depressive disorders: 1.93
  • Antidepressant intake: 2.96
  • Mood stabilizer intake: 4.51
  • Atypical antipsychotic use: 4.23
• Schizophrenia⁶¹

Of the bacterial species examined (streptococci, staphylococci, pseudomonas, klebsiella, haemophilus, mycoplasma, tuberculosis, meningococci, escherichia, chlamydia and scrub typhus), streptococci were associated with the most disorders. ADHD was associated with eight bacterial pathogen infections.⁶⁰

The prevalence of Streptococcus agalactiae infection (Group B Streptococcus, GBS) in infants was 0.07%.
GBS has brought about:⁶²

• increased infant mortality (19.41-fold)
• long-term neurological developmental disorders (3.49-fold)

GBS meningitis increased the risk of⁶²

• ADHD
• cerebral palsy
• Epilepsy
• Hearing impairment
• profound and specific developmental disorders

3.2.1.2.1. Bacterial meningitis (meningitis) (+ 40 % to + 180 %)¶

Consequences, children with bacterial meningitis (but not enteroviral meningitis) had an increased risk of ADHD or ADHD medication use:⁶³

• Meningitis in the first 90 days of life:
  • ADHD risk 2.8-fold (aHR 2.8, + 180 %)
  • ADHD medication intake 2.2-fold
  • ASS risk 1.9-fold
  • Behavioral and emotional disorders 2-fold
  • Learning and intellectual development disorders 4.2-fold
• Meningitis between day 90 and 18 years:
  • ADHD risk 1.4-fold (+ 40 %)
  • ADHD medication intake 1.5-fold
  • Learning and intellectual development disorders 1.5-fold

3.2.1.2.2. Antibiotics in the first years of life (up to + 33 %)¶

In a very large study, antibiotic administration in the second year of life increased the risk of ADHD by 20 to 33 % and of sleep problems by 24 to 50 %.⁶⁴ An even larger study from Korea found a 10% dose-dependent increase in the risk of ADHD, with prenatal and early childhood administration together further increasing the risk⁶⁵
A smaller study found more frequent behavioral difficulties and depressive symptoms in 3 1/2 year old children who had received antibiotics in the first year of life.⁶⁶ Two other studies found no increased risk of mental disorders when antibiotics were given in the first 1 ⁶⁷ to 2⁶⁸ years of life.
One study found no increase in risk for ADHD, but for asthma, food allergies and allergic rhinitis,⁶⁹ which are known to be associated with an increased risk of ADHD.

The administration of antibiotics in the first three years of life reduces the diversity, stability and composition of the microbiome:³¹

• reduced frequency of genera
  • Bacteroides
  • Bifidobacterium
  • Lactobacillus
  • Staphylococcus
  • Sediminibacterium
• increased frequency of
  • Members of the Enterobacteriaceae family
  • of the genus Enterococcus

During the maturation of the microbiome, several processes of the central nervous system take place, such as synaptogenesis, myelination and synaptic pruning, which can be influenced by microbiome-associated metabolites.³¹

Exposure to antibiotics in the first years of life increased the child’s risk of: (meta-analysis, k = 30, n = 7,047,853)⁷⁰

• ADHD: + 33 %
  • not significant in studies that used sibling control groups
• Depression: + 29 %
  • not significant in studies that used sibling control groups
• ASS: + 19 %

A cohort study found no significant increase in the risk of ADHD or ASD due to antibiotic administration in the first two years of life.⁷¹

3.2.1.3. Viral infections¶

Powassan flavivirus is transmitted by ticks and in rare cases causes encephalitis in humans. 6 children with Powassan virus encephalitis, diagnosed between the ages of 14 months and 11 years, all suffered permanent neurological sequelae, including⁷²

• Seizures
• Movement disorders
• Behavioral problems
• ADHD
• Learning problems
• States of anxiety
• Sleep disorders

3.2.2. Craniosynostosis (+ 500 %)¶

Craniosynostosis is a premature ossification of cranial sutures. Maternal smoking during pregnancy significantly increases the risk of craniosynostosis. In one study, the majority of children with craniosynostosis also showed symptoms of ADHD.⁷³

Around one in two children who had surgery for metopic synostosis (trigonocephaly or metopic suture craniosynostosis) at 9.5 (± 7.9) months of age showed at least borderline hyperactivity and inattention scores at 10.3 (± 3.5) years of age.⁷⁴ Older age at surgery was associated with poorer executive functions.

3.2.3. Epilepsy (+ 470 %)¶

Epilepsy is a physical neurological disorder,
One study found a 5.7-fold risk of ADHD in children with epilepsy (41.5 % vs. 7.3 %). ADHD was usually diagnosed in these children after the epilepsy had subsided and the epilepsy medication had been discontinued.⁷⁵ Another study found ADHD or a learning disorder in 43.3% of children with epilepsy.⁷⁶

Of children with infection-related epilepsy (FIRES), 33.3% showed symptoms of inattention, 53.3% aggression and 20% mood problems.⁷⁷

3.2.4. Metals¶

3.2.4.1. Copper (up to + 1,546 % (?))¶

ADHD risk increased by 1,546% in the half of Spanish children (8 to 15 years) with higher urinary copper levels.⁷⁸ Copper was also associated with increased inattention symptoms.

Note: If one were to assume an ADHD baseline prevalence of 6.47 % in children, this would result in a prevalence of 100 % in those 50 % children with the higher copper urine values.

3.2.4.2. Lead (+ 160 % to + 310 %)¶

According to several meta-analyses, lead exposure during development increased the risk of ADHD⁷⁹ by

• 433 % in the half of Spanish children (8 to 15 years) with the higher urinary lead exposure.⁸⁰
• 310 % increased) for the 20 % with the highest blood lead level compared to those with the lowest 20 %⁸¹
• 239 to 306 %⁸²
• 160 to 260 %⁸³
• 95 %⁸⁴
• Every doubling of blood lead levels increased the risk of ADHD in children by 35%⁸⁵ This was true even at very low lead levels of less than 10 mug/dl.

Mice that are chronically exposed to inorganic lead from birth show about three times more spontaneous motor activity than control mice. In addition, their behavioral responses to amphetamine, methylphenidate and phenobarbital are altered.⁸⁶
Elevated lead urine levels correlated with increased inattention and hyperactivity symptoms and reduced IQ in children.⁸⁷
Children with ADHD had significantly higher lead hair levels than children without ADHD.⁸⁸

3.2.4.3. Cadmium (+ 269 % ?)¶

The risk of ADHD was 269% higher in the half of Spanish children (8 to 15 years) with higher urinary cadmium levels.⁷⁸ Cadmium was also associated with increased inattention symptoms.
In a study of children with and without ADHD, children with ADHD-I had the highest urinary cadmium levels.⁸⁷ Cadmium correlated negatively with IQ.
0 %: Cadmium exposure during development did not significantly increase the risk of ADHD, according to a meta-analysis⁸⁴

3.2.4.4. Manganese (+ 163 % to + 257 %)¶

According to a meta-analysis, exposure to manganese during development increased the risk of ADHD by

• 163 %⁸⁹
• 79 %⁸⁴
• Early exposure to manganese causes permanent attention problems via the mTOR pathway and an alteration of the catecholaminergic system⁹⁰ as well as sensorimotor problems.⁹¹
  Manganese intoxication shows a correlation with certain CYP2D6 gene variants⁹²

MPH reduced the attention problems and sensorimotor problems caused by early manganese exposure in rats. 0.5 mg/kg/d completely improved the attention problems, but only after prolonged treatment, 3.0 mg/kg/d improved the sensorimotor deficits immediately. Selective antagonization of D1, D2 or α2A receptors did not affect the manganese-induced attention problems or their improvement by MPH. D2R antagonists reduced the sensorimotor deficits of manganese. D1 antagonists reduced the efficacy of MPH on sensorimotor deficits.⁹¹

In persons with ADHD, elevated manganese levels were only found in the hair, but not in the blood⁹³, another study also found elevated manganese blood levels in schoolchildren with ADHD.⁹⁴ Children with ADHD had manganese hair levels twice as high as children without ADHD. High manganese hair levels increased the risk of ADHD 3.57-fold (+257%).⁸⁸

A doubling of the manganese content in teeth from both the prenatal and postnatal period increased the risk of attention problems and ADHD symptoms in the school years by 5%. Manganese from childhood showed no influence.⁹⁵
An animal model with developmental manganese exposure showed that manganese can cause permanent attention and sensorimotor deficits resembling ADHD-I. Oral methylphenidate was able to fully compensate for the deficits caused by early manganese exposure.⁹⁶

In children with ADHD, urinary manganese levels were slightly lower than in children without ADHD.⁸⁷

An Israeli study addressed the fact that manganese levels in infant formula were often higher than in breast milk and recommended stricter limits.⁹⁷

3.2.4.5. Antimony (up to + 204 %)¶

ADHD risk 204% higher in the half of Spanish children (8 to 15 years) with higher urinary antimony exposure.⁷⁸
In a study of children with and without ADHD, children with ADHD-H/I showed the highest antimony urine levels.⁸⁷ Antimony urine levels correlated with the severity of ADHD symptoms according to the teacher rating.

3.2.4.6. Mercury (up to + 168 %)¶

Exposure to methylmercury during development increased the risk of ADHD by 168% (meta-analysis, k = 47)⁹⁸ One review found an increased risk of ADHD and ASD.⁹⁹ Two reviews describe causality.¹⁰⁰⁸³
Two meta-analyses found no significant increase in risk from mercury.⁸⁴⁷⁹
Mercury urine levels were not significantly elevated in children with ADHD.⁸⁷ Mercury blood levels were unchanged in children with ADHD.⁸⁵
The correlation between mercury exposure and ADHD appears to be influenced by DNA methylation.¹⁰¹

3.2.4.7. Arsenic (+ 53 %)¶

According to a meta-analysis, exposure to arsenic during development increased the risk of ADHD by 53%⁸⁴

Wistar rats given arsenic (50% of the lethal dose, 8 mg/kg) developed hyperactivity.¹⁰²

3.2.4.8. Zinc¶

One study found elevated zinc blood levels in school children with ADHD.⁹⁴

3.2.5. Chemicals¶

3.2.5.1. Phthalates (+ 212% for girls to + 254% for boys)¶

According to a meta-analysis, exposure to phthalates during development increased the risk of ADHD by 212% for girls and 254% for boys.⁸⁹
Another study found that phthalate exposure in early childhood only increased ADHD symptoms by 10% in children with ASD, primarily in the direction of externalizing behaviors.¹⁰³

3.2.5.2. Perfluorooctane sulfonate (PFOS) (+ 77 %)¶

Perfluorooctane sulfonate (PFOS) in breast milk correlated with a 77% increased risk of ADHD per higher interquartile range.¹⁰⁴
PFOS caused ADHD symptoms (hyperactivity, cognitive problems) in zebrafish, decreased dopamine levels and the number of dopaminergic neurons, and disrupted the transcriptional profiles of genes related to the dopaminergic system. MPH alleviated the ADHD symptoms induced by PFOS and restored DA levels, the number of dopaminergic neurons and the expression of genes associated with DA metabolism.¹⁰⁵

3.2.5.3. β-Hexachlorocyclohexane (β-HCH) (+ 75 %)¶

Peβ-hexachlorocyclohexane (β-HCH) in breast milk correlated with a 75% increased risk of ADHD per higher interquartile range.¹⁰⁴

3.2.5.4. Chlorinated kerosenes (+ 57 % / quartile)¶

Chlorinated kerosenes (CP) are widespread environmental and industrial pollutants.
A large study (n = 122,965, including 7,139 with ADHD) examined the ADHD risk of PM2.5, PM2.5-bound short-chain CPs (SCCPs), medium-chain CPs (MCCPs) and long-chain CPs (LCCPs). An increase in CP concentrations in the interquartile range (IQR) increased the risk of ADHD by 57% (OR = 1.57). The risk increased linearly in a dose-dependent manner and was particularly driven by SCCPs and MCCPs.¹⁰⁶

3.2.5.5. Polychlorinated biphenyls (PCBs)¶

Exposure to polychlorinated biphenyls (PCBs) in childhood correlated with an increased risk of ADHD.⁸³
Prenatal PCB exposure slightly reduced internalizing symptoms by 17% and slightly reduced ADHD risk by 16%.¹⁰⁷
Rats that were exposed perinatally to A1221 (a PCB mixture) showed¹⁰⁸

• a reduced sucrose preference (females only)
• a reduced reaction latency in the attention shifting task (males and females)
• TH+ cells in the VTA increased (males and females)
• DRD1 increased in the combined midbrain nuclei (males and females)
• Behavior correlated with number of dopaminergic cells in the VTA (in females)
• Behavior correlated with dopamine signaling genes (in males)
• Conditioned orientation and serum estradiol (E2) unchanged

3.2.6. Gastroesophageal reflux (+ 248 %)¶

Gastroesophageal reflux disease (GERD) increased the risk of ADHD at 3 to 5 years of age (HR = 3.48) (registry study, n = 631,695).¹⁰⁹

It is not clear from the abstract whether it is really about GERD in the children themselves. The full text of the study was not yet available to us.

3.2.7. Passive smoking - smokers in the environment in the first years of life (+ 42 % to + 170 %)¶

Passive nicotine exposure increases the risk of ADHD.¹¹⁰ Nicotine exposure in children is associated with a 1.42-fold¹¹¹ to 2.7-fold⁸⁹ increase in ADHD.²⁷ In one study, children with ADHD were twice as likely to have smokers in the family as children who were not affected.¹¹²
In the case of passive smoking, a connection is made to certain MAO-A gene variants that cause a lower level of serotonin degradation.¹¹³

In children, a linear association was found between salivary cotinine (a nicotine breakdown product) and hyperactivity and behavioral problems. This association remained significant after adjusting for family poverty, parental education, a history of ADHD, hostility, depression, caregiver IQ, and obstetric complications, and also after excluding from the calculation children of mothers who had smoked during pregnancy. This indicates that exposure to nicotine in the first years of life alone can increase hyperactivity and behavioral problems.¹¹⁴

One study found no link between smoke exposure after birth and ADHD.⁸¹

Tobacco smoke exposure can result from secondhand smoke, i.e. the involuntary inhalation of smoke from other people who are actively smoking, and also thirdhand smoke, i.e. involuntary exposure to smoke from objects that come into contact with tobacco smoke contaminants, such as skin, hair, furniture, clothing and dust.¹¹⁵ 15.5% of children aged 0 to 17 years exposed to tobacco smoke showed ADHD, which corresponded to a 30% increased risk (OR 1.3).

3.2.8. D-3 insufficiency (+ 157 %)¶

A meta-analysis of 10,334 children and adolescents found a 2.57-fold risk of ADHD with a D3 insufficiency (between 10 and 30 mg/nl in blood plasma).¹¹⁶

3.2.9. Air pollution in childhood¶

Air pollution consists of a complex mixture of¹¹⁷

• Particulate matter (PM2.5 and PM10)

• Nitrogen oxide (NO)

• Nitrogen dioxide (NO2)

• Carbon monoxide (CO)

• Sulphur dioxide (SO2)

• Ozone (O3)

• volatile organic compounds (VOC)

• Nitrous oxide (laughing gas, N2O)¹¹⁸

• Children in the top third of exposure to organic substances showed a 1.51-fold ADHD risk (+51%) compared to the bottom third¹¹⁹

• Children in the top third of soot exposure showed a 1.29-fold ADHD risk (+29%) compared to the bottom third¹¹⁹

• Children in the top third of sulfate exposure showed a 1.20-fold ADHD risk (+20%) compared to the bottom third¹¹⁹

A large Chinese study of 8,692 children aged 6 to 12 found a significant increase in the children’s risk of ADHD due to:¹²⁰

• Home renovations
• Incense burning
• Cooking oil vapors
• Smokers in the household

3.2.9.1. Particulate matter¶

The percentages indicate the second highest value of the collected studies.

The largest sources of particulate matter are the combustion of fuels in motor vehicles, combustion processes in industrial plants, forest fires and bush fires. 28 % of particulate matter results from diesel exhaust gases, which cause PM10 to PM30 in particular.¹¹⁷

A study of single nucleotide polymorphisms associated with air pollutants found¹³²

• NO2, genetically predicted, causally caused an increased risk of
  • Major depression (OR: 1.13, + 13 %)
  • bipolar Disorder (OR: 1.26, + 26 %)
  • Schizophrenia (OR: 1.57, + 57 %)
  • ADHD (OR: 1.61, + 61 %)
  • ASS (OR: 1.39, + 39 %)
• PM2.5, genetically predicted, causally caused an increased risk of
  • severe depression (OR: 1.21, + 21 %)
  • bipolar Disorder (OR: 1.32, + 32 %)
  • ADHD (OR: 1.57, + 57 %)
• NOx, genetically predicted, causally caused an increased risk of
  • ADHD (OR: 1.64, + 64 %)
• PM10, genetically predicted, causally caused an increased risk of
  • ADHD (OR: 1.70, + 70 %)

3.2.9.1.1. Particulate matter PM10 (up to + 288 %)¶

One study found a 97% increase in the risk of ADHD in children with a 10 μg/m3 increase in PM10.¹³³

• ADHD was found in¹³⁴
  • 11.0% of urban children living in cities who were exposed to air pollution, especially particulate matter (PM10)
  • 2.7 % in the control group
  • Risk thus + 307 %
• Children in the highest third of PM10 exposure had a 3.88-fold risk of ADHD (+288%) compared to children in the lowest tercile¹³⁵
  A Korean cohort study found a 44% increase in the risk of ADHD in children and adolescents for every 10 µg/m3 increase in PM10, with a tendency towards dose-dependent symptom severity.¹³⁶ A Taiwanese register study came to comparable results.¹³⁷

3.2.9.1.2. Particulate matter PM2.5 (up to + 82 %)¶

PM2.5 (airborne particles with a diameter of less than 2.5 μm) can easily penetrate biological systems. They are small enough to reach the alveoli and enter the brain via the bloodstream or the olfactory bulb.¹³⁸¹³⁹

• A review of k = 45 meta-analyses found a 1.82-fold ADHD risk (+82%) from PM2.5 exposure.¹⁴⁰
• There is clear evidence of a link between PM2.5 and NO2 levels
  • in early childhood and ASD¹⁴¹
  • in childhood and ADHD¹⁴¹; (meta-analysis; k = 25)¹⁴²
  • PM2.5 causally increased the risk of ADHD 2.0-fold (+100%)¹⁴³
  • likewise for PM10 (meta-analysis; k = 25)¹⁴²
• Children in the highest quintile of PM2.5 exposure had a 1.70-fold risk of ADHD (+70%) compared to children from the lowest quintile¹⁴⁴
• Children in the top third of PM2.5 exposure showed a 1.37-fold ADHD risk (+37%) compared to the bottom third ¹¹⁹

Another cohort study found a 40% to 78% increased risk of ADHD from PM2.5 exposure in the first to third year of life. The risk was associated with PM2.5 >16 μg/m3 and increased sharply with PM2.5 > 50 μg/m3. There was no gender-dependent association.¹⁴⁵
A meta-analysis of 12 studies found a correlation between particulate matter and ADHD in children in 9 of them.¹⁴⁶

A longitudinal study of 2,750 children found an increased risk of ADHD and ASD from particulate matter PM2.5 and PM10, but not from ambient noise, ozone, sulfur dioxide, soot, nitrogen dioxide, or nitrogen oxide¹⁴⁷
In one study, inhaled printer particles led to a 5-fold increase in dopamine levels in rats, although this was probably due to increased synthesis and not reduced degradation.¹⁴⁸
A database genome study (n = 423,796) found that particulate matter (<2.5 pm) correlated with a 95% increased risk of ADHD. The risk for anxiety disorders was increased by 196%, for schizophrenia by 55% and for depression by 33%. Bipolar was negatively correlated, ASD, PTSD, obsessive-compulsive disorder and anorexia nervosa showed no significant correlation.¹⁴⁹

3.2.9.1.3. Ultrafine dust 23nm¶

Ultrafine particulate matter 23nm has a size of about 1/100 of fine particulate matter PM2.5. Ultrafine particulate matter 23nm is a common lower limit of particle size measurement when analyzing vehicle emissions.
Plastic waste becomes microplastic through abrasion and decomposition and later also nanoplastic the size of ultrafine dust.

Chronic exposure to 23 nm polystyrene nanoplastics at a dose of 10 µg/day/kg (which corresponds to the reality in humans) caused¹⁵⁰

• in case of exposure of the dams
  • important developmental milestones of the offspring disrupted
  • ADHD symptoms in offspring in adulthood
    • Hyperactivity
    • increased risk behavior
    • impaired motor learning and executive functions
• Exposure of aging mice
  • lower epilepsy threshold
  • Development of epileptic seizures
  • Behavioral changes were related to altered gene and synaptic protein expression associated with ADHD and epilepsy.
• lifelong exposure to nanoplastics
  • lysosomal dysfunctions
  • increased lipofuscin accumulation, which indicates accelerated aging of the brain

3.2.9.1.4. Pathways of particulate matter on ADHD¶

3.2.9.2. Nitrogen oxides: nitrogen oxide (NO), nitrogen dioxide (NO2) (up to + 110 %)¶

Nitrogen dioxide (NO2) is a harmful, highly reactive gas that serves as a standard indicator for the group of nitrogen oxides (NOx). NO2 is mainly produced outdoors by the combustion of fuels in vehicles and power plants, and indoors by the combustion of fuels such as wood and gas.¹⁶⁰

• Children in the highest third of NO exposure had a 2.1-fold risk of ADHD (+ 110%) compared to children in the lowest tercile¹³⁵
• Children in the highest quintile of NO2 exposure had 1.63 times the risk of ADHD (+ 63%) compared to children from the lowest quintile¹⁴⁴

A large cohort study found a statistically significant association between nitrogen oxides and particulate matter (<2.5 pm) in childhood and the development of ADHD.¹⁴⁴ A smaller cohort study confirmed this for particulate matter, but not for nitrogen dioxide¹⁶¹
In another study, the risk of ADHD increased by 38% for every 10 μg/m3 increase in nitrogen oxide and by 51% for every 5 μg/m3 increase in particulate matter PM2.5. If both factors were considered together, the influence of nitrogen oxide predominated. A meta-analysis of k = 28 studies found similar results for the majority¹⁶²
One study found no association between exposure to PM2.5 and NO2 at age 12 and ADHD at age 18, but with depression at age 18.¹⁶³
One study found a 32% increase in the risk of ADHD in children due to a 10 μg/m3 increase in nitrogen oxide.¹³³
A meta-analysis examined the effects of traffic-related air pollution on the neurological development of children in several countries using PM2.5 (particulate matter <2.5 µm), PM10, elemental carbon (EC), black carbon (BC), NO2 and NOx:¹⁶⁴
Increased traffic-related air pollution correlated with an increase in ADHD, autism and impaired cognitive development.
PM2.5 reduced the expression of BDNF in the placenta.
Elevated PM2.5 concentrations impaired the cognitive development of adults (episodic memory) and increased major depressive disorders.
Elevated NO2 concentrations correlated with dementia, NOx with Parkinson’s disease.

Children in schools with higher levels of chronic traffic-related air pollution (elemental carbon, nitrogen dioxide and ultrafine particulate matter [10-700 nm]) in the schoolyard and classroom showed slower cognitive development. The improvement in working memory was only 7.4 % (compared to 11.5 %). Growth was reduced in all cognitive measures. Moving from the first to the fourth quartile of indoor elemental carbon levels reduced the gain in working memory by 13.0%.¹⁶⁵ Another study found similar results.¹⁶⁶
Exposure to nitrogen dioxide, ozone and sulfur dioxide has been linked to behavioral and developmental disorders, anxiety to particulate matter (PM10), ozone and sulfur dioxide, and overall pollution to ADHD and eating disorders¹⁶⁷

Prenatal exposure to NO2 or PM2.5 did not additionally increase the risk of ADHD compared to exposure to the two pollutants in the first five years of life.¹⁴⁴
Elevated levels of NO2 and particulate matter in schools appear to impair the development of working memory. For each interquartile range increase in exposure, the annual development of working memory decreased¹⁶⁸

• by 20 % for NO2 outdoors
• by 19.9 % for ultrafine particulate matter indoors

Individual differences in susceptibility to air pollution appear to be related to the ε4 allele of the apolipoprotein E gene (APOE), which is the most important genetic risk factor for Alzheimer’s disease. PAH, EC and NO2 correlated significantly only in carriers of the APOEε4 allele¹⁶⁹

• Behavioral problems,
• a smaller decrease in inattention over time
• a smaller caudate volume

A Polish study found a correlation between¹⁷⁰

• long-term NO2 and PM10 exposure with poorer visual attention in children with ADHD
• short-term NO2 exposure with less efficient executive attention and higher impulsivity in TD children and more errors in children with ADHD
• short-term PM10 exposure with fewer omission errors in the CPT in TD children

One study found an increase in ADHD-related hospital admissions in adolescents after short-term exposure to nitrogen oxide (+68%), short-term exposure to sulphur dioxide (+29%) and short-term exposure to PM10 (+17%)¹⁷¹

3.2.9.3. Nitrous oxide (laughing gas)¶

Increasing exposure to N2O from air pollution could contribute significantly to the development of ADHD¹¹⁸
Environmentally relevant concentrations of N2O, even at trace levels, impair cognitive functions such as working memory in adult males¹¹⁷

3.2.9.4. Ozone¶

Children between the ages of 3 and 12 in China who were exposed to higher concentrations of ozone showed an increased risk of ADHD. This was further increased by sports.²⁸

O3 exposure can constrict the airway muscles, trapping air in the alveoli and causing respiratory symptoms such as wheezing and shortness of breath. Ozone primarily attacks the lungs, but can also enter the bloodstream via the respiratory tract or nose and then into the brain, where it has a neurotoxic effect. Ozone can trigger inflammation in the brain (increased pro-inflammatory cytokines and activated microglia) ¹⁷⁷¹¹⁷
High ozone exposure is a risk factor for neurological diseases.¹⁷⁸ Long-term exposure to ozone leads to cognitive impairments such as memory problems or impaired executive functions.¹⁷⁹

3.2.10. Hyperthyroidism / hyperthyroidism (+ 70 %)¶

One study found a 1.7-fold prevalence of ADHD in children with hyperthyroidism.¹⁸⁰
Children with ADHD showed

• significantly higher T4 levels (total thyroxine).¹⁸¹
• significantly reduced FT4 levels (free thyroxine) and TT3 levels (total triiodothyronine) (meta-analysis, k = 12, n = 11,836)¹⁸², children with ASA showed reduced FT4 and unchanged TT3.

Hyperthyroidism can cause ADHD-like symptoms, including anxiety, nervousness, irritability and physical hyperactivity. One study found a correlation between elevated TSH levels and hyperactivity in ADHD.¹⁸³

For the effects of abnormal thyroid hormone levels during pregnancy, see Prenatal stressors as ADHD environmental causes

3.2.11. Concussions and traumatic brain injuries (+ 68 %)¶

Craniocerebral trauma can trigger SDHD (secondary ADHD).¹⁸⁴
Brain injury severity correlates with significantly higher ADHD symptomatology. Brain injury-altered default mode network (DMN) morphometry predicted higher ADHD symptomatology 12 months after injury, while salience network (SN) and central executive network (CEN) morphometry were not significant independent predictors.¹⁸⁵

ADHD correlated with an increased incidence of brain injury trauma^{186187 188} and otorhinologic trauma.¹⁸⁹
One study examined mild (concussion) and severe traumatic brain injuries before the age of 10. The incidence was 1,156 per 100,000 person-years. At the age of 19, the risk of ADHD was increased by 68% and the risk of learning disability by 29%.¹⁹⁰
In more severe cases of traumatic brain injury, the correlation was not statistically significant. In an analysis of cases with possible traumatic brain injury (equivalent to a concussion), the result was significant (risk of ADHD increased by 105%, risk of learning disability increased by 42%). The risk in adulthood was particularly increased in children with the least severe injuries.
In pure correlation studies, however, the extent to which craniocerebral injuries are a consequence of ADHD (increased accident risk) or ADHD is a consequence of craniocerebral injuries (secondary ADHD) is an open question.

Among 1,709 ice hockey players aged 11 to 17, the rate of concussions correlated with higher self-reported and parent-reported scores for attention problems. Only self-reported hyperactivity, not parent-reported hyperactivity, also correlated significantly with concussion. A T-score ≥ 60 combining attention problems and hyperactivity scores (an estimate of probable attention deficit hyperactivity disorder) was not significantly associated with incidence of injury or concussion¹⁹¹

A Finnish nationwide retrospective cohort study (1998 to 2018) of pediatric traumatic brain injury patients (n > 126,000) found a significant association between pediatric traumatic brain injury and post-traumatic ADHD medication use during a 20-year follow-up, with the association being particularly pronounced after 4 years.¹⁹²
Neurodegeneration due to craniocerebral trauma, subsequent neuroinflammation and oxidative stress was assumed to be the pathway of action, which could impair brain development and neurotransmitters and increase the risk of neurodevelopmental disorders.¹⁹³

3.2.12. Febrile convulsions (+ 28 % to + 66 %)¶

According to clinical and animal studies, febrile convulsions have harmful effects on neurodevelopment, which can lead to ADHD, increased susceptibility to epilepsy, hippocampal sclerosis and cognitive decline in adulthood¹⁹⁴
Febrile convulsions in children increased the risk of ADHD by 28%¹⁹⁵ to 66%.¹⁹⁶

3.2.13. Nutrition¶

3.2.13.1. Diet high in sugar (+ 41 %)¶

A diet high in refined sugar and saturated fats during childhood increased the risk of ADHD by 41%, while a healthy diet reduced the risk of ADHD by 35%. (Meta-analysis, k = 14 studies)¹⁹⁷ Compared to a healthy diet, an unhealthy diet therefore increases the risk by 117%.

One study found a correlation between sugar intake at 30 months and the risk of ADHD, sleep disorders and anxiety. No correlation was found at the age of 12 months.¹⁹⁸
In an Egyptian study, a child’s daily consumption of sweets correlated with a 6.82-fold risk of ADHD (+ 582%).⁸⁸ Whether this is a causal cause or a consequence of changed food preferences due to the predisposition to the disorder remains to be seen.

3.2.13.2. Highly processed foods (up to + 25 %)¶

A high percentage of highly processed foods at age 3 to 4 years increased the risk of ADHD at age 12 to 13 years by 25% (RR 1.25).¹⁹⁹

3.2.14. Early puberty (pubertas praecox) (+ 40 %)¶

Among girls with early puberty (onset of sexual maturation before the age of 8 for girls and before the age of 9 for boys), the prevalence of ADHD was found to be 13.5%.²⁰⁰

3.2.15. Surgical procedures under anesthesia (+ 25 to 39 %)¶

Anesthesia in childhood correlates with an increased risk of ADHD²⁰¹
Children who underwent a single surgical procedure under anesthesia up to the age of 5 were 37% more likely to take ADHD medication in later years.²⁰² A Korean cohort study found a 41% increased risk of ADHD as a consequence of general anesthesia in early childhood. In addition, the duration of general anesthesia correlated with an increased risk of ADHD.²⁰³
One study found a 37% increase in the risk of ADHD with a single anesthetic during surgery up to the age of 5 years, and a 75% increase with multiple anesthetics²⁰⁴
A cohort study of n = 15,072 children, half of whom had received anesthetics between the ages of 0-3 years, found a 39% increased risk of ADHD.Frequency of anesthetic exposure, duration of exposure, male sex, and central nervous system surgery were significant risk factors for ADHD in the future.²⁰⁵
Other studies have come to similar conclusions.²⁰⁶²⁰⁷
A meta-analysis found a 25% increase in the later risk of ADHD due to general anesthesia in childhood (RR = 1.26).²⁰⁸

• 38 % (RR = 1.38) due to single general anesthesia of max. 60 minutes in children
• 55 % (RR = 1.55) by single general anesthesia of max. 61 to 120 minutes or more than 120 minutes in children
• 61 % (RR = 1.61) after several general anesthetics

In contrast, a cohort study in Taiwan found no increased risk of ADHD due to anesthetics in the first 3 years of life.²⁰⁹

It remains to be seen to what extent the probability of a surgical procedure under anesthesia is already influenced by the increased likelihood of accidents among people with ADHD. For more information, see ⇒ Consequences of ADHD.

However, there is evidence that general anesthesia using fentanyl and sevoflurane can cause ADHD symptoms in newborn mice, such as ADHD-like behaviors, cognitive impairments, fine motor skill disorders, as well as disrupt neurogenesis and alter gene expression. These could be reduced by prior administration of vitamin K2. K2 administration before general anesthesia led to significantly different gene expression changes²¹⁰

3.2.16. Atopic disorders (immunoglobulin E deficiency)¶

In low birth weight infants, a history of T2 inflammatory diseases such as asthma and atopic dermatitis increased the risk of:²¹¹

• ADHD by 81 %
• Learning disability by 74 %
• ASS by 47 %
• mental disability by 35 %

Atopic disorders correlated not only with an increased risk of ADHD, but also with the severity of ADHD symptoms.²¹²

3.2.16.1. Asthma (+ 34 % to + 296 %)¶

A review (k = 21 meta-analyses, n = 348,405,029) found an increase in the risk of ADHD due to asthma of 34% (OR 1.34) with convincing evidence (evidence class I).²¹³
With highly suggestive evidence (class II) increased

• Asthma the risk
  • for depression by 64 % (OR 1.64)
  • for anxiety by 95 % (OR 1.95)
  • for tic disorders by 90 % (OR 1.90),
  • for suicidal thoughts by 52 % (OR 1.52)
  • for suicide attempts by 60 % (OR 1.60)
• allergic rhinitis the risk of
  • for Tic Disorders by 161 % (OR 2.61)
  • for sleep disorders by 171 % (OR 2.17)

Allergic rhinitis increased the risk of ADHD

• by a factor of 3.96 (+ 296 %, OR 3.96). (METASTUDY, k = 2, n = 132,561)²¹⁴
• by a factor of 2.08 (+ 108 %)²¹⁵
• by a factor of 1.83 (+ 83 %; meta-analysis, k = 18, n = 4,289,444)²¹⁶
  • Women 1.86 times as often as men (+ 86 %)
  • Children up to 8 years 1.75 times the risk of older children (+ 75%)
  • ASA: 1.90-fold risk (+ 90 %)

A genetic association study found no causal risk increase for ADHD due to asthma²¹⁷

ADHD increased the risk of allergic rhinitis

• correlatively by 1.85-fold (+ 85 %, OR 1.84) (meta-analysis, k = 10, n = 397,799)²¹⁴
• correlative by 1.38-fold across all studies (+ 38 %; METASTUDY, k = 18, n = 4,289,444)²¹⁶
  • Women compared to men by a further + 86 % (meta-analysis, k = 18, n = 4,289,444)²¹⁶
  • Children up to 8 years compared to older children by a further + 75 % (meta-analysis, k = 18, n = 4,289,444)²¹⁶
  • correlative by 1.90-fold in cohort study (+ 90 %; meta-analysis, k = 18, n = 4,289,444)²¹⁶
• causally by 1.27-fold (+ 27 %) in a genetic association study²¹⁷

3.2.16.2. Atopic eczema (+ 72 %)¶

Eczema increased the risk of ADHD 1.72-fold (+72%).²¹⁵

3.2.16.3. Neurodermatitis / atopic dermatitis (up to + 28 %)¶

Neurodermatitis / atopic eczema / atopic dermatitis in childhood correlates with an increased risk of ADHD.²¹⁸
In contrast, a cohort study found no significant (+2%) increased risk of ADHD in childhood atopic dermatitis.²¹⁹
A cohort study of n = 69,732,807 people found an increased risk of learning difficulties (OR = 1.77) and memory problems (OR = 1.69) with atopic dermatitis.
The increase in risk was unevenly distributed: In children with neurodevelopmental disorders such as ADHD, the risk of memory or learning difficulties was increased 2 to 3-fold. In contrast, atopic dermatitis did not change the risk of learning or memory difficulties in children without neurodevelopmental disorders.²²⁰

A review (k = 21 meta-analyses, n = 348,405,029) found an increase in risk in atopic dermatitis with highly suggestive evidence (class II)²¹³

• for ADHD by 28 % (OR 1.28)
• for depression by 60 % (OR 1.60)
• for anxiety by 62 % (OR 1.62)
• for suicidal thoughts by 44 % (OR 1.44)

One study found evidence that susceptibility to atopic dermatitis causally increased the risk of ADHD (+ 11.6 %) and ASD (+ 13.1 %). Conversely, susceptibility to ADHD (+ 11.2 %) and anorexia nervosa (+ 10 %) caused an increased risk of atopic dermatitis. Only the causal relationship between AD and ASD was independent of the reverse effect bias.²²¹
Urticaria increased the risk of ADHD by 9%²²²

People with ADHD had a 45% increased risk of atopic dermatitis (OR = 1.45).
People with atopic dermatitis had a 34% to 42% increased risk of ADHD (OR = 1.34; HRs = 1.42), with severe atopic dermatitis the risk of ADHD was increased by 162% (OR = 2.62), with multiple allergic diseases by 189% (OR = 2.89), with atopic dermatitis and concurrent sleep disorders by 143% (ORs = 2.43). (METASTUDY, k = 49)²²³

3.2.17. Selective immunoglobulin A deficiency (+ 30 %)¶

Selective immunoglobulin A deficiency correlated with a 30% (OR 1.30) higher risk of ADHD and an increased incidence of respiratory and intestinal infections.²²⁴.

3.2.18. Antihistamines in the first years of life¶

A large cohort study found that taking antihistamines (especially first-generation antihistamines) in the first years of life significantly increased the risk of later ADHD. Disorder of REM sleep was cited as a possible cause, which secondarily impaired brain maturation.²²⁵

3.2.19. Insecticides / pesticides¶

Elevated pesticide urine levels (here: Pentachlorophenol (PCP), 3,5,6-trichloro-2-pyridinol (TCPy) and carbofuranphenol (CFP)), particularly in early childhood, led to increased ADHD symptoms in later childhood.²²⁶

3.2.19.1. Chlorpyrifos¶

In children between 1 and 6 years of age, chlorpyrifos residues in the blood correlated with the risk of ADHD.²²⁷ Vitamin D reduced the risk.
Chlorpyrifos also significantly increases the risk of ADHD in the case of prenatal contamination of the mother during pregnancy.

3.2.19.2. Pyrethroid pesticides¶

The pyrethroid pesticide deltamethrin at low doses causes changes in ADHD- and NDD-related behaviors and in the striatal dopamine system during development in male mice.

Deltamethrin during development caused a multimodal biophenotype in the brain relevant to ADHD. Mouse mothers received deltamethrin (3 mg/kg or vehicle every 3 days) during gestation and lactation, which is well below the limits set by the EPA. Male offspring showed alterations in several canonical clock genes. Kinome analysis revealed alterations in the activity of several kinases involved in synaptic plasticity, including mitogen-activated protein kinase (MAP) ERK. Multiomics integration revealed a dysregulated protein-protein interaction network with primary clusters for MAP kinase cascades, regulation of apoptosis and synaptic function²²⁸

The annual number of ADHD cases caused by pyrethroids per million inhabitants was estimated at²²⁹

• 2189 for Israel
• 1710 for France
• 969 for Iceland
• 944 for Switzerland
• 209 for Germany

According to a meta-analysis, pyrethroid insecticides did not significantly increase the odds ratio for ADHD (0.99)⁸⁹

3.2.19.3. Organophosphates¶

Exposure to organophosphates in childhood correlated with an increased risk of ADHD.⁸³

One study examined the urine of 186 Taiwanese children with and without ADHD for²³⁰

• organophosphate flame retardants (OPFRs)
  • TDCPP (1,3-dichloro-2-propyl phosphate)
  • TnBP (tri-n-butyl phosphate)
  • TCEP (tris(2-chloroethyl) phosphate)
  • TBEP (tris(2-butoxyethyl) phosphate)
  • TPHP (triphenyl phosphate)
• and their metabolites
  • BDCPP (bis(1,3-dichloro-2-propyl)phosphate)
  • DNBP (di-n-butyl phosphate)
  • BCEP (bis(2-chloroethyl)hydrogen phosphate)
  • DBEP (di-(2-butoxyethyl) phosphate)
  • DPHP (diphenyl phosphate)

In children with and without ADHD, BCEP and its metabolites were primarily found in the urine.
Children with ADHD showed significantly higher urinary levels of BDCPP, BCEP, DBEP, DPHP, TCEP, TBEP, TNBP, TPHP and Σ10OPFR. After controlling for age, gender, body mass index, PM2.5 exposure scenarios and phthalate metabolites, parabens, bisphenol-A and urinary creatinine, the levels of BDCPP, TDCPP and TBEP showed significant and dose-dependent effects on inattention. DNBP correlated positively with neuropsychological deficits (CPT recognizability, omission and commission). DPHP correlated negatively with CPT recognizability and commission.
Hyperactivity and impulsivity did not correlate with OPFRs or their metabolites.

Pathways of action (among others): Endocannabinoid pathway²³¹

3.2.20. Lack of sleep¶

Short sleep correlated with increased risk of anxiety, attention deficit hyperactivity disorder and activity-limiting emotional and psychological states after adjusting for ethnicity, deprivation, age and gender.²³²
Ethnicity and socioeconomic disadvantage in the neighborhood were independently correlated with short sleep and snoring/noisy breathing during sleep.
Long sleep correlated independently with an increased risk of depression.

3.2.21. Acne vulgaris¶

One study found moderately elevated levels in adolescents (12 to 17 years) with acne vulgaris for²³³

• Hyperactivity
• Hyperactivity/impulsivity
• Inattention
• ADHD total score

Both acne vulgaris and ADHD are thought to be partly caused by increased androgen hormone levels in the womb.

3.2.22. Spray disinfectant¶

Spray disinfectants led to lung diseases in South Korea, as extreme use was widespread there.
One study found a link between spray sanitizer use, especially in early childhood or prolonged use, and ADHD.²³⁴

3.2.23. Pets¶

Preschool children aged 3 to 6 years had a 58% to 66% increased risk of ADHD if the children grew up with pets in a large Chinese population-based study based on parental reports.²³⁵

3.2.24. Printing ink on food paper¶

Using newspapers to wrap food 3 or more times a week increased the risk of ADHD by 105 times in an Egyptian study.⁸⁸ It may depend on the approved printing inks.
With these figures, however, we ask ourselves whether contact with newspapers (when reading) should not already lead to a measurable increase in the risk of ADHD.

3.2.25. Commercially packaged pasta¶

A child’s consumption of commercially packaged pasta 3 or more times per week correlated with a 57-fold risk of ADHD.⁸⁸
Whether this is related to ingredients in commercially packaged noodles in Egypt, food preferences due to ADHD, or a consequence of low family socioeconomic status is an open question.

3.2.26. Unpackaged flour¶

The use of unpackaged flour in cooking correlated with a 44-fold risk of ADHD in an Egyptian study.⁸⁸

3.2.27. Loud snoring¶

A study of n = 512 snoring children and adolescents (70% of whom were overweight or obese and 35% with an elevated obstructive AHI >3/h) found that of the snoring children²³⁶

• 36 % showed hyperactivity/impulsivity
• 24 % showed emotional dysregulation

This would indicate a 300% increased risk of ADHD.
Surprisingly, the reduced oxygen supply due to sleep apnea did not correlate significantly with hyperactivity/impulsivity or emotional dysregulation, while the measure correlated with the volume of snoring.

3.3. Age-independent physical factors¶

3.3.1. Toxins (up to + 900 %)¶

3.3.1.1. Phthalates (+ 200 % to + 900 %)¶

Higher phthalate metabolites in children’s urine correlated with increased likelihood of ADHD by 3 to 9 times.²³⁷
A study of n = 67 drug-naïve children with ADHD aged 6 to 16 years found a significant correlation between urinary phthalate metabolites MEHHP (mono-[2-ethyl-5-hydroxyhexyl] phthalate) and MEOHP (mono-[2-ethyl-5-oxohexyl] phthalate) and commission error T-scores on the visual test for extended attention, which is a marker of impulsivity.²³⁸
Boys with ADHD showed significantly elevated levels of mono-n-butyl phthalate and ethyl paraben, whereas girls with ADHD did notNeither boys nor girls showed significant differences in testosterone, free testosterone, FSH, LH, estradiol, progesterone or SHBG compared to controls. Boys with ADHD correlated elevated urinary levels of monobenzyl phthalate and monoethylhexyl phthalate with serum testosterone. In girls with ADHD, urinary levels of monoethyl phthalate correlated positively with serum levels of LH, testosterone and free testosterone.²³⁹

3.3.1.2. Fluoridated drinking water (+ 510 % if 1 mg/L too high)¶

A review of k = 45 meta-analyses found a 3.8-fold risk of cognitive deficits due to fluoride exposure in childhood.¹⁴⁰

In Canada, a study found that a 1 mg/liter increase in fluoride levels in drinking water above acceptable limits increased the risk of ADHD by 6.1 times in 6- to 17-year-olds. In 14-year-olds living in areas where fluoride was added to drinking water, there was a 2.8-fold risk of an ADHD diagnosis compared to 14-year-olds in areas without fluoridated drinking water. Older children responded with a higher risk.²⁴⁰ Fluorine urine levels, on the other hand, did not correlate with ADHD (1,877 subjects).
A study in Mexico found a link between increased prenatal fluoride exposure and inattention and ADHD, but not hyperactivity²⁴¹ and cognitive problems.²⁴² Another study found similar results.²⁴³ A review summarizes the results.²⁴⁴
A longitudinal study over 22 years from Florida found a significant slight increase in the risk of ADHD and ASD as well as mental retardation and developmental delay for fluoridated water.²⁴⁵
A smaller long-term study in Sweden found an increased risk of ADHD due to fluorides.²⁴⁶

In Germany, 90% of drinking water has a fluoride content of 0.3 mg/liter. Drinking water is not fluoridated in Germany.²⁴⁷ However, fluoridated table salt is available.

A study found an inverse correlation between fluoride levels in the mother’s urine during pregnancy and cognitive problems in the offspring at the age of 11. The higher the pregnancy urine fluoride content, the lower the cognitive problems.²⁴⁸ This was not consistent with the results of other studies, which found an increased risk of ADHD with increased urine fluoride levels in the children themselves.

Sodium fluoride in drinking water (20 ppm to 100 ppm) led to a dose-dependent reduction of dopamine, noradrenaline and acetylcholine in the brain of rats, while the levels of adrenaline, histamine, serotonin and glutamate increased.²⁴⁹

3.3.1.3. Lead (+96 % to +133 %)¶

Elevated blood lead levels lead to an increased risk of ADHD.^{250251252253254} With a blood lead level of ≥ 5 μg/dl, the risk of ADHD was found to be 2.33 times higher (OR 2.33).²⁵⁵
A review of k = 45 meta-analyses found a 1.96-fold ADHD risk.¹⁴⁰

Leaded gasoline was found to be responsible for a 0.42 standard deviation increase in ADHD, particularly among those born between 1966 and 1986 (Generation X). The overall susceptibility to mental disorders in the population increased by 0.13 standard deviations and included an estimated increase of 151 million mental disorders due to lead exposure.²⁵⁶

Lead influenced the dopamine balance in many studies.

• Reduced dopamine signaling
  • caused cognitive deficits with delayed spatial alternation, which could be corrected by L-dopa and without L-dopa only ended 8 years after the 2-year lead exposure²⁵⁷
  • in the nucleus accumbens²⁵⁸
• Increased dopamine signaling
  • in mesolimbic pathways (nucleus accumbens)²⁵⁹
  • Lead increases dopaminergic activity and has been linked to attention deficits, Alzheimer’s disease and increased drug sensitivity.²⁶⁰

The DRD2 gene variant rs1800497r is said to promote a link between ADHD and lead.²⁶¹ A connection to certain MAO-A gene variants is also mentioned, which causes lower serotonin degradation.¹¹³ A study in rats suggests interactions between lead exposure and early stress on the dopaminergic system.²⁶² A long-term study found no directly increased risk of ADHD in people with previous lead exposure, but increased externalizing behaviours and increased risk of addiction²⁶³

In one study, lead altered neostriatal serotonin and norepinephrine levels, increased anxiety and decreased open-field activity.²⁶⁴

Lead exposure during pregnancy may increase the risk of ADHD. See there.
Even a lead content in drinking water below the limit values is said to be problematic.²⁶⁵
Increased lead absorption can occur from old water pipes. In principle, lead water pipes are not very dangerous in areas with calcareous water, as lime forms a reliable protective layer in the pipes. However, if a water softening system is installed, this protective lime layer can be lost. If old lead pipes are still present, this can lead to increased lead absorption.
Lead is barely relevant as a toxin in Central Europe. In less developed countries, however, lead can be a serious problem.

In children who have been exposed to lead, succimer chelation can produce lasting cognitive benefits if chelation sufficiently reduces the lead concentration in the brain. At the same time, succimer treatment without lead exposure leads to permanent cognitive dysfunction.⁹⁶

3.3.1.4. Inorganic arsenic (+ 102 %)¶

Those children who were among the 20% with the highest urinary arsenic levels were found to have double the risk of ADHD (OR 2.02).²⁵⁵

3.3.1.5. Benzene, toluene, ethylbenzene, xylene/xylene (BTEX) (+ 54 %)¶

Higher exposure to these substances in the air correlated with a 1.54-fold increase in the risk of ADHD at kindergarten age.²⁶⁶

3.3.1.6. Smoking by parents (+ 30 %)¶

Postnatal smoking by parents correlates with a 1.3-fold risk (increased by 30%)²⁶⁷ of ADHD in offspring.
This could be related to genetic factors, as people with ADHD are significantly more likely to smoke. The co-morbidity of smoking with ADHD is 40%.²⁶⁸ In contrast, around 25 % fewer of the total population smoke, namely 26.9 % of women and 32.6 % of men.²⁶⁹

3.3.1.7. Polychlorinated biphenyls (PCBs) / polychlorinated biphenyl ethers (+ 26 % to + 92 %)¶

Polychlorinated biphenyls and polychlorinated biphenyl ethers are suspected of causing ADHD.
PCBs are banned in many countries, in Germany since 1989. PCBs were used in particular as lubricants and coolants in electrical appliances and as building materials. Due to their chemical stability, many areas around the world are still contaminated with PCBs. Contaminated food, especially seafood from contaminated rivers and lakes, is the most common source of contamination today.²⁷⁰²⁷¹

Even low levels of PCB exposure during development impair neurobiological, cognitive and behavioral functions.²⁷¹
One study found a 26% to 92% increased risk of ADHD.²⁷² Individual studies found contradictory or weak impairments,²⁷³²⁷⁴ however, the vast majority show evidence of relevance in ADHD.²⁶⁷²⁷⁵

Polychlorinated biphenyls affect the dopamine system.²⁷⁶ PCBs inhibit dopamine synthesis as well as the storage of dopamine in the vesicles and its release, thereby causing low dopamine levels²⁷⁷²⁵³ in the basal ganglia and PFC^{278279 277 280 281 282} , as well as reduced DAT in the striatum²⁸³, which overall corresponds quite closely to the picture of ADHD.

Prenatal exposure to PCBs has an adverse effect:

• Hyperactivity (in rats even at subtoxic doses)²⁷⁷²⁵³
• IQ, memory, attention ²⁸⁴
• Memory, attention²⁸⁵
• Impulsivity (via corpus callosum)²⁸⁶²⁸⁷ in rats even at subtoxic doses²⁷⁷²⁵³
• Male and female offspring were trained as adults to perform asymptotically in a differential reinforcement of low rates (DRL) task. The PCB-exposed groups had a lower ratio of reinforced to non-reinforced responses than the control groups.²⁷⁶
• no effect on sustained attention²⁷³

Possible path of action: Gap junctions²⁸⁸

3.3.1.8. Polyvinyl chloride (PVC)¶

One review describes a suspected correlation between PVC exposure and ADHD.²⁸⁹

3.3.1.9. Pesticides¶

With regard to pesticides (especially organochlorine compounds, pyrethroids, organophosphates), there are indications of relevance in ADHD.²⁶⁷²⁵³

For pesticides during pregnancy and ADHD, see there.

3.3.1.9.1. Organochlorine compounds¶

With regard to organochlorine compounds, there are indications of relevance in ADHD.^267253290

A study of Greek schoolchildren with ADHD found no elevated blood serum levels of²⁹¹

• Dichlorodiphenyltrichloroethane (DDT) Metabolites
• Hexachlorocyclohexane (HCH) isomers
• Cyclodienes
• Methoxychlorine

Other organochlorine compounds are:²⁸⁸

• Lindane
• Dieldrin
• Chlordane, endosulfan, heptachlor, aldrin
• Chlordecone
• Mirex

Possible path of action: Gap junctions²⁸⁸

3.3.1.9.2. Organophosphates¶

According to a large number of studies, organophosphate pesticides have a correlation between prenatal and postnatal exposure and ADHD ^{271292 293 294 290 295} or a theoretically possible increase in ADHD risk.²⁹⁶ One source suggests an increased risk of ADHD from organophosphates, particularly when coinciding with a particular MAO-A gene variant that causes lower serotonin degradation.¹¹³
In contrast, two larger studies found no influence ²⁹⁷²⁹⁸
With regard to hyperactivity, 2 studies found an association between organophosphates and hyperactivity, 4 studies found no association.²⁹⁹
One study found no correlation of chlorpyrifos with hyperactivity in rats³⁰⁰ while another found it in females.³⁰¹
A study in rats was able to induce ADHD-like behaviors in Wystar and SHR rats by organophosphates and found strong circumstantial evidence that these are mediated by reductions in fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) via the cannabinoid receptor.³⁰²
Blood values were measured in Egyptian adolescents, some of whom used pesticides, and the parents were asked about ADHD symptoms in the adolescents:³⁰³ There was no correlation with ADHD in relation to the organophosphate chlorpyrifos.

Higher vitamin D levels appear to reduce the negative effect of chlorpyrifos on the risk of ADHD.²⁹⁵

3.3.1.9.3. Pyrethroids (+ 142 %)¶

Various studies indicate a correlation between pyrethroid exposure in childhood and neurodevelopmental disorders such as ADHD with a 2.42-fold risk of ADHD ³⁰⁴ Other studies also found an association with ADHD³⁰⁵²⁹⁰ , ASD or developmental delay.²⁷¹
Blood levels were measured in Egyptian adolescents, some of whom used pesticides, and the parents were asked about ADHD symptoms in the adolescents:³⁰³ A correlation to ADHD was found in relation to the pyrethroid λCH through the measured value Cis-DCCA (all persons with ADHD reported clinical ADHD symptoms).

3.3.1.9.4. Carbamate (-)¶

One review found no associations between carbamates and ADHD.²⁹⁰

3.3.1.9.5. Neonicotinoids (- ?)¶

One review found no associations between neonicotinoids and ADHD, although there were few studies on this topic.²⁹⁰

3.3.1.10. Mercury / Amalgam (Mercury)¶

There is weak evidence (= not proven) of relevance in ADHD.^267253306
A large study with n = 2073 participants was unable to establish a connection between amalgam and ADHD.³⁰⁷
Mercury is also suspected of being a possible contributory cause of Parkinson’s disease.³⁰⁸ This would be a clear indication of a damaging effect on the dopamine system.

3.3.1.11. Manganese¶

There is weak evidence of relevance in ADHD, although elevated manganese levels were only found in the hair, but not in blood levels, of people with ADHD.²⁶⁷⁹³
An animal model with developmental manganese exposure showed that manganese can cause permanent attention and sensorimotor deficits resembling ADHD-I. Oral methylphenidate was able to fully compensate for the deficits caused by early manganese exposure.⁹⁶
A doubling of the manganese content in teeth from the prenatal and postnatal period increased the risk of attention problems and ADHD symptoms in the school years by 5%. Manganese from the childhood period showed no influence⁹⁵
A study reports benefits of choline supplementation during pregnancy in rats to prevent manganese-induced developmental disorders in the offspring³⁰⁹

3.3.1.12. Bisphenol A¶

Bisphenol A is suspected of increasing the risk of ADHD.²⁵³ A connection with certain MAO-A gene variants that cause lower serotonin degradation¹¹³ and an influence on the thyroid balance is being discussed.³¹⁰
A meta-analysis found a clear link between bisphenol exposure and ADD(H)S.³¹¹

A study of n = 67 drug-naïve children with ADHD aged 6 to 16 years found no significant correlation between bisphenol A, bisphenol F or bisphenol S in urine and ADHD symptoms.²³⁸

Possible path of action: Gap junctions²⁸⁸

3.3.1.13. Perfluoroalkyl compounds¶

Elevated levels of perfluoroalkyl compounds have been observed in ADHD.³¹²

3.3.1.14. Triclosan¶

Prolonged exposure to the environmental pollutant triclosan induced ADHD symptoms in rats. Triclosan appears to cause a reduction in dopamine levels in the PFC.³¹³

A 60-day continuous exposure of rats to triclosan caused ADHD-like behavior in the offspring. It activated microglia in the PFC, which led to the release of inflammatory factors. In vitro, triclosan increased the levels of inflammatory cytokines, including IL-1β, IL-6 and TNF-α, in HMC3 cells. In addition, triclosan upregulated PKM2 via hnRNPA1, which affects the STAT3 signaling pathway and thus continuously activates microglia, promoting the release of inflammatory cytokines.³¹⁴

3.3.1.15. Synergy effects of neurotoxins¶

The synergistic effects of neurotoxins must be taken into account:²⁶⁷³¹⁵

• Formaldehyde increases the toxicity of mercury.
• Amalgam increases the toxicity of PCBs and formaldehyde.
• Mercury and PCBs potentiate each other’s effects.

3.3.2. Craniocerebral trauma (up to + 529 %)¶

Traumatic brain injuries (TBI) are estimated internationally at 349 per 100,000 person-years. Every second person suffers a traumatic brain injury in the course of their life. Traumatic brain injuries have the highest incidence and prevalence of all common neurological disorders and have been linked in studies to Consequences such as neurodegenerative diseases, cognitive impairment, stroke, psychiatric disorders and increased mortality.³¹⁶

A review of k = 24 METASTUDY found a correlation of ADHD risk with previous traumatic brain injury:³¹⁶

• mild traumatic brain injury: + 18 %, not statistically significant, n = 4,098 subjects
• moderate traumatic brain injury: + 266 %, not statistically significant, n = 117
• severe traumatic brain injury: + 529 %, statistically significant, n = 5,092

The extent to which traumatic brain injury in ADHD is the result of the increased likelihood of accident and injury in ADHD remains an open question.
In one study, 30% of boys and 15% of girls with traumatic brain injury had previous ADHD.³¹⁷ This study also suggests that girls should integrate physical activity and resources for coping with school stress into their rehabilitation program. For boys, cognitive support and strategies for coping with ADHD may be more effective.

See also Concussions and traumatic brain injury in children as a risk for ADHD

3.3.3. Food intolerances, allergies¶

It is certain that ADHD is not caused by individual, specific foods, phosphates or additives.

However, individual food intolerances or allergies are just as much stressors as illnesses, toxins or psychological stress and can therefore worsen the stress situation of people with ADHD to such an extent that symptoms develop. This is not a finding specific to ADHD. For example, in a group of children with schizophrenia problems, dietary treatment of an existing gluten intolerance was able to eliminate the schizophrenia symptoms in the children affected by this.³¹⁸³¹⁹ The same was found in people with ADHD and non-affective psychosis.³²⁰

Food additives (here: Sun yellow, carmoisine, tartrazine, ponceau 4R; quinoline yellow, allura red, sodium benzoate) can cause histamine release from circulating basophils. This is not allergic, i.e. not dependent on immunoglobulin E. The increased release of histamine can - in carriers of certain gene variants of the genes that encode histamine-degrading enzymes - increase ADHD symptoms³²¹

To identify rare food intolerances (which, unlike allergies, cannot be detected by blood tests), an elimination diet can be helpful. However, such a diet is very difficult to implement and maintain and is barely adhered to, especially in younger children. In particular, any benefits must be weighed against the sometimes serious social consequences.

In other cases, such a diet can help to alleviate the symptoms of existing intolerances.

When assessing the effectiveness of diets (and other “desirable” therapies), parents’ assessments are often far higher than what tests or teacher evaluations can confirm.

A review (k = 21 meta-analyses, n = 348,405,029) with highly suggestive evidence (evidence class II) found an increased risk of ASA by 179% (OR 2.79) for food allergies.²¹³

More information at ⇒ Nutrition and diet for ADHD.

3.3.4. Gut-brain axis, gut bacteria, gut flora¶

See under Gut-brain axis

3.3.5. Polycystic ovary syndrome (PCOS)¶

Women with polycystic ovary syndrome (PCOS) appear to have an increased risk of mental disorders, primarily anxiety disorders and depression, but also ADHD.³²²
Adolescents with PCOs also showed an increased risk of ADHD.³²³

3.3.6. (Untreated) type 1 diabetes (+ 145 %)¶

A study of persons with ADHD with and without insulin pump treatment found a 2.45-fold increased risk of ADHD in untreated people with type 1 diabetes, with ADHD considered a risk factor for inconsistent diabetes treatment.³²⁴
Another study found no evidence of causality of autoimmune diseases such as diabetes 1 for ADHD.³²⁵
Among people with ADHD, 15.9% had an existing ADHD diagnosis and a further 31.9% met the ADHD criteria of the ASRS.³²⁶ The subjects were those who had responded to the ASRS sent to them, so that a bias towards an inflated ADHD score can be expected here,

3.3.7. Phenylketonuria (PKU)¶

Phenylketonuria (Følling disease, phenylpyruvic acid oligophrenia) is a genetically caused metabolic disorder in which the amino acid phenylalanine cannot be broken down into tyrosine due to the lack of the enzyme phenylalanine hydroxylase (PAH). Tyrosine, in turn, is required for the synthesis of dopamine, so dopamine deficiency is a consequence of PKU.³²⁷ PKU has a prevalence of 1 in 8000 people.

One study found an ADHD rate of 38% in phenylketonuria despite adequate treatment.³²⁸
ADHD is also associated with dopamine deficiency.

3.3.8. Anabolic androgenic steroids (AAS)¶

Strength athletes who take anabolic androgenic steroids are significantly more likely to have ADHD than strength athletes who do not take them.³²⁹

3.3.9. Infections¶

3.3.9.1. Susceptibility to infection and infection burden¶

A higher burden of infection may have a cumulative association with psychiatric disorders beyond what has been described for individual infections. Susceptibility to infections is reflected in the infection burden (the number of specific infection types or sites). An increased burden of infection correlates with an increased risk of³³⁰

• ADHD
• ASS
• bipolar disorders
• Depression
• Schizophrenia
• psychiatric diagnoses overall.
  A modest but significant heritability was found for the burden of infection (h2 = 0.0221) and a high degree of genetic correlation between it and the overall psychiatric diagnosis (rg = 0.4298). There was also evidence of genetic causality of the overall infection for the overall psychiatric diagnosis.

3.3.9.2. Viral infections¶

3.3.9.2.1. Enteroviruses in general (up to + 182 %)¶

(Non-polio) enteroviruses cause a good half of all cases of aseptic meningitis and are therefore among the most important known causes.³³¹ In addition to encephaltitis³³², (non-polio) enteroviruses also frequently cause febrile illnesses, hand-foot-and-mouth disease, herpangina, aseptic meningitis and encephalitis, as well as sometimes serious and threatening infections such as myocarditis or neonatal sepsis.

Enteroviruses are being discussed as a possible cause of ADHD.³³³
One study found an increased risk of ADHD due to mild enterovirus infections (16%) and severe enterovirus infections (182%).³³⁴

3.3.9.2.2. Enterovirus A71 (EV-A71) (+ 200 %)¶

A longitudinal study of 43 adolescents who had a central nervous system infection with enterovirus A71 (EV-A71) between the ages of 6 and 18 found that 34.9% had ADHD. This more than tripled the risk of ADHD. There was also an increase in autistic symptoms. Other psychiatric diagnoses were not elevated.³³⁵³³⁶ Another study found ADHD particularly common when the A71 infection was accompanied by cardiopulmonary failure.³³⁷
EV-A71 often causes weakness, limb atrophy, seizures, hand-foot-and-mouth disease, encephalitis and reduced intelligence.

3.3.9.2.3. HIV¶

A study of children and adolescents with HIV in stable health found ADHD symptoms in 20%.³³⁸

3.3.9.2.4. Zoster encephalitis¶

In one isolated case, ADHD was mentioned in association with zoster encephalitis.³³⁹

3.3.9.2.5. Human endogenous retroviruses (HERV)¶

The topic Human endogenous retroviruses (HERV) and ADHD Is presented due to its high heritability in the chapter Development in the article Genetic and epigenetic causes of ADHD - Introduction

3.3.9.3. Bacterial infections¶

Periodontal disease is a bacterial inflammation of the gums caused by the bacterium P. gingivalis, which secretes toxins. Periodontal disease and is described as a risk factor for ADHD.³⁴⁰

3.3.9.4. Parasitic infections¶

A study of 100 children with ADHD and 100 healthy children found a correlation of ADHD with:³⁴¹

• Toxoplasma
• Toxocara
• Cryptosporidium parvum
• Giardia lamblia
• Entamoeba histolytica
  No difference was found with regard to Schistosoma (coccidia parasites).

3.3.10. Glucose-6-phosphate dehydrogenase deficiency (G6PD)¶

Glucose-6-phosphate dehydrogenase (G6PD) deficiency increased the risk of ADHD by 16%³⁴²

G6PD deficiency is an X-linked genetic disorder and affects around 4.9% of all people.
The enzyme glucose-6-phosphate dehydrogenase (G6PD) facilitates the synthesis of nicotinamide adenine dinucleotide phosphate (NADPH) and glutathione (GSH), which are involved in oxidation-reduction equilibrium regulation. G6PD deficiency causes reduced GSH levels and thus increased oxidative stress.

G6PD deficiency is mostly food-related (favism; hemolytic reaction to the consumption of fava beans) and sometimes genetic (more common in the Mediterranean region and the Middle East, partly in Asia and Africa).
G6PD deficiency can trigger (especially in children):

• severe hemolysis
• Hyperbilirubinemia
• Jaundice
• Hearing disorders
• Behavioral disorders
• lead to long-lasting neurological damage
• increased production of reactive oxygen species (ROS)
  • resulting in activation of astrocytes and microglia, increased proinflammatory chemokines and cytokines, neuroinflammation, impaired brain development
• Imbalance in the antioxidant system
  • this leads to impairment of astrocytes, neuronal death and DNA damage
  • oxidative cell death of leukocytes, myocytes and other immunological players.

3.3.11. Kawasaki syndrome¶

A meta-analysis of k = 4 studies with n = 1,454,499 subjects found a 76% increased risk of ADHD in people with ADHD.³⁴³
One study found an increased prevalence of ADHD in people with ADHD³⁴⁴, other studies found only a tendency³⁴⁵ or no association.³⁴⁶

3.3.12. Lipodystrophy (lack of fatty tissue)¶

One study found evidence of a greatly increased prevalence of ADHD in lipodystrophy.³⁴⁷

3.3.13. Dystrophinopathy (muscular dystrophy, muscle weakness)¶

In dystrophinopathy (e.g. Duchenne muscular dystrophy - complete absence of dystrophin in muscle tissue ³⁴⁸ or Becker muscular dystrophy - dystrophin levels too low³⁴⁹ ), there was evidence of a greatly increased prevalence of ADHD of 18.4%³⁵⁰³⁵¹ , of ASD of 6%³⁵⁰ to 12.73%³⁵¹ and of mental retardation of 22%.³⁵⁰
There are also links between ADHD gene candidates and genes associated with dystrophies. See there.

3.3.14. Hyperthyroidism / hypothyroidism¶

In addition to other cognitive deficits, hyperthyroidism can also cause inattention and hyperarousal. Depending on the degree of hypothyroidism, the cognitive effects can range from mild impairment of memory and attention to complete dementia.³⁵²³⁵³

The THRA gene encodes the thyroid receptor alpha, TRα1, TRHB the thyroid receptor isoforms TRβ1 and TRβ2.
The pituitary hormone TSH (thyroid-stimulating hormone) stimulates the thyroid gland to produce thyroxine (T4; prohormone) and then triiodothyronine (T3). The thyroid hormones (T3 and T4) in the blood in turn regulate the pituitary release of TSH within the hypothalamic-pituitary-thyroid axis, which is mediated by the receptor isoform TRβ2.

In the case of a (rarely occurring genetic) resistance to thyroid hormone β, this negative feedback loop, which stabilizes the TH level in the blood, is disrupted. This leads to increased TH and unsuppressed, i.e. normal TSH levels³⁵⁴

3.3.15. Interrupted breathing during sleep (sleep apnea)¶

Breathing interruptions in children’s sleep can trigger cognitive stress, causing symptoms that resemble ADHD.³⁵⁵

It remains to be seen whether breathing interruptions during sleep can cause such stress that they can contribute to ADHD through epigenetic changes, or whether they merely cause symptoms that are similar to those of ADHD. In the latter case, people who did not previously have ADHD and who have developed ADHD (similar) symptoms as a result of breathing interruptions during sleep should see these symptoms disappear completely once the breathing interruptions during sleep have been eliminated. We are not yet aware of any studies on this.

In contrast, a study of n = 512 snoring children and adolescents (70% of whom were overweight or obese and 35% with an increased obstructive AHI >3/h) found that of the snoring children²³⁶

• 36 % showed hyperactivity/impulsivity
• 24 % showed emotional dysregulation

This would indicate a 300% increased risk of ADHD.
Surprisingly, the reduced oxygen supply due to sleep apnea did not correlate significantly with hyperactivity/impulsivity or emotional dysregulation, while the measure correlated with the volume of snoring.

See also under Differential diagnosis: Primary organic disorders

3.3.16. Gender diversity¶

A multinational study found evidence that the frequency and severity of ADHD symptoms was particularly high in gender-diverse individuals.³⁵⁶

3.3.17. Lipid metabolism, fatty acids¶

To avoid redundancies, we have placed this section under Fatty acids, probiotics and more for ADHD In the chapter Treatment: Medication for ADHD in the section Vitamins, minerals, dietary supplements for ADHD.

3.3.18. Inflammatory bowel disease (IBD)¶

Inflammatory bowel disease (IBD) correlates with an increased risk of ADHD and an increased intake of stimulants.³⁵⁷
People with an onset of IBD in childhood showed an increased risk of³⁵⁸

• ADHD: + 20 %
• ASS: + 40 %
• psychiatric disorders overall: + 60 %
• Anxiety disorders: + 90 %
• Affective disorders: + 60 %
• Eating disorders: + 60 %
• Personality disorders: + 40 %
• Suicide attempts: + 40 %

One study found no significant increase in ADHD from IBD overall, but from Crohn’s disease (CD) (+6.5%) and ulcerative colitis (UC) (+5%).³⁵⁹

A study of individuals with onset of IBD in childhood found a 25% reduced risk of MPH use. Ulcerative colitis was associated with a 37% reduced risk of MPH use and a reduced - although not statistically significant - risk of an ADHD diagnosis. The risk of depression was increased by 50% in IBD and by 73% in people with both IBD subtypes (Crohn’s disease and ulcerative colitis.³⁶⁰

Some studies suggest that IBD in the mother during pregnancy can inflame the central nervous system, which increases the risk of ADHD in the offspring.³⁶¹

3.3.19. Mitochondrial disorder¶

Mitochondrial dysfunction or mitochondrial disorders are being discussed as a possible cause of ADHD.³⁶²³⁶³ So far, no concrete findings have emerged.

3.4. Factors without risk increase for ADHD¶

• Dichlorodiphenyldichloroethylene did not influence the risk of ADHD¹⁰⁷
• Hexachlorobenzene (HCB) showed a non-linear relationship with ADHD, with an increasing risk in the low exposure range, which turned into a decreasing risk at concentrations above 8 ng/g lipid.¹⁰⁴ Another study found no effect on ADHD.¹⁰⁷
• Organic pollutants (OP pesticides, PCBs, pyrethroid insecticides and trichlorophenol (TCP)) did not increase the odds ratio for ADHD (0.99)⁸⁹
• Bismuth urine levels were slightly lower in children with ADHD than in children without ADHD.⁸⁷
• Aluminum blood levels were unchanged in children with ADHD.⁸⁵
• The prevalence of microcytic anemia was found to be 14% lower in children with ADHD (OR: 0.86)³⁶⁴
• Growing up bilingual did not increase the risk of ADHD³⁶⁵
• Autoimmune diseases showed no evidence of causality of autoimmune diseases for ADHD. The study examined³²⁵
  • Lupus erythematosus
    • in contrast, a retrospective matched cohort study (n = 11,144) found that a lupus diagnosis 15 years or more later correlated with a 61% higher probability of psychiatric disorders and psychiatric disorders correlated with a 120% increased risk of lupus 10 years or more later. A lupus diagnosis correlated with an increased prescription of ADHD medications 10 years earlier.³⁶⁶
  • Crohn’s disease
  • Ulcerative colitis
  • Type 1 diabetes (opposite study: see above)
  • rheumatoid arthritis
  • Psoriasis
  • Ankylosing spondylitis
  • Multiple sclerosis
• High blood pressure
  • One study found no statistical significance for a genetic link between high blood pressure and ADHD.³⁶⁷ This is at least countered by the main ADHD model animal, the SHR, which develops hypertension with age.
• COVID-19 gene therapy
  • Gene predisposition, which makes people more susceptible to COVID-19, showed no signs of an increased risk of ADHD. Conversely, however, ADHD and Tourette’s are associated with an increased risk of COVID-19 and a more severe course of COVID-19.³⁶⁸
• T1w/T2w ratio
  • The T1w/T2w ratio is a magnetic resonance imaging (MRI)-based indicator of intracortical myelin. There were no differences in the T1w/T2w ratio between ADHD, ASD and controls.³⁶⁹
• Obesity
  • adjusted, there was no significant causal influence of obesity on ADHD³⁷⁰
• Platinum- and taxane-based chemotherapy in children³⁷¹

3.5. Factors with risk reduction for ADHD¶

• Immigrant status of parents causes a reduced risk of ADHD³⁷² within the first 2 generations.³⁷³
• p,p’-dichlorodiphenyltrichloroethane (p,p’-DDT) was associated with a 36% lower likelihood of ADHD¹⁰⁴
• Lyme disease correlated with a 10% reduction in ADHD prevalence³⁷⁴