6. Diseases as ADHD risk factors

Author: Ulrich Brennecke
Review (2024): Dipl.-Psych. Waldemar Zdero

Stressful physical or psychological childhood experiences can be a contributory cause of ADHD.
This article discusses diseases as risk factors for 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 and concussions are just as much 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 correlates with the respective factor. The figures do not indicate that the respective factor is a causal cause.

• 6.1. Infections and infectious diseases
  • 6.1.1. Infections in the first year of life (+ 16 % to + 77 %)
  • 6.1.2. Bacterial infections (up to + 593 %)
    • 6.1.2.1. Bacterial meningitis (meningitis) (+ 40 % to + 180 %)
    • 6.1.2.2. Periodontal disease
    • 6.1.2.3. Antibiotics in the first years of life (up to + 33 %)
  • 6.1.3. Viral infections
    • 6.1.3.1. Enteroviruses in general (up to + 182 %)
    • 6.1.3.2. Enterovirus A71 (EV-A71) (+ 200 %)
    • 6.1.3.3. HIV (+ 150 % to + 1000 %)
    • 6.1.3.4. Zoster encephalitis
    • 6.1.3.5. Human endogenous retroviruses (HERV)
  • 6.1.4. Parasitic infections
• 6.2. Craniocerebral trauma (up to + 529 %)
• 6.3. Craniosynostosis (+ 500 %)
• 6.4. Epilepsy (up to + 470 %)
• 6.5. Phenylketonuria (PKU) (+ 375 %)
• 6.6. Sleep-related breathing disorders (SBAS, SDB, SRBD) (up to + 350 %)
  • 6.6.1. Sleep-related breathing disorders in general
    • 6.6.1.1. Prevalence of sleep-related breathing disorders
    • 6.6.1.2. Oxygen supply for SBAS
    • 6.6.1.3. ADHD with SBAS
    • 6.6.1.4. Adenotonsillectomy for SBAS and changes in ADHD symptoms
  • 6.6.2. Snoring (up to + 350 %)
    • 6.6.2.1. Prevalence of snoring
    • 6.6.2.2. Snoring and ADHD symptoms
    • 6.6.2.3. Adenotonsillectomy for snoring and changes in ADHD symptoms
  • 6.6.3. Constricted turbinate (+ 300 %)
  • 6.6.4. Enlarged pharyngeal and palatine tonsils (adenotonsillar hypertrophy) (up to + 275 %)
    • 6.6.4.1. Prevalence of adenotonsillar hypertrophy
    • 6.6.4.2. Adenotonsillar hypertrophy and ADHD symptoms
    • 6.6.4.3. Adenotonsillectomy for adenotonsillar hypertrophy
  • 6.6.5. Breathing interruptions during sleep (sleep apnea, OSA, OSAS) (+ 100 %)
    • 6.6.5.1. Prevalence of OSA
    • 6.6.5.2. ADHD symptoms with OSA
    • 6.6.5.3. Adenotonsillectomy for OSA and changes in ADHD symptoms
  • 6.6.6. Upper airway resistance syndrome (UARS)
• 6.7. Gastroesophageal reflux (+ 248 %)
• 6.8. Anorectal malformations (+ 200 %)
• 6.9. Febrile convulsions (+ 168 %)
• 6.10. D-3 insufficiency (+ 157 %)
• 6.11. (Untreated) type 1 diabetes (+ 145 % to + 719 %)
• 6.12. Premenstrual syndrome (PMS) / Premenstrual dysphoric disorder (PMDD) (+ 143 %)
• 6.13. Dystrophinopathy (muscular dystrophy, muscle weakness) (+ 130 %)
• 6.14. Atopic disorders (excess immunoglobulin E)
  • 6.14.1. Respiratory allergies (+ 83 % to 108 %)
  • 6.14.2. Food allergies (+ 72 %)
  • 6.14.3. Atopic eczema (+ 72 %)
  • 6.14.4. Skin allergies (+ 65 %)
  • 6.14.5. Asthma (+ 34 % to + 62 %)
  • 6.14.6. Neurodermatitis / atopic dermatitis (+ 11.6 % to + 28 %)
• 6.15. Hyperthyroidism / hyperthyroidism (+ 70 %)
• 6.16. Nutrition and food intolerances
  • 6.16.1. Diet high in sugar (+ 41 %)
  • 6.16.2. Highly processed foods (up to + 25 %)
  • 6.16.3. Commercially packaged pasta
  • 6.16.4. Unpackaged flour
  • 6.16.5. Food intolerances
• 6.17. Early puberty (pubertas praecox) (+ 40 %)
• 6.18. Surgical procedures under anesthesia (+ 25 to 39 %)
• 6.19. Selective immunoglobulin A deficiency (+ 30 %)
• 6.20. Inflammatory bowel disease (IBD) (+ 20 %)
• 6.21. Antihistamines in the first years of life
• 6.22. Lack of sleep
• 6.23. Acne vulgaris
• 6.24. Gut-brain axis, gut bacteria, gut flora
• 6.25. Polycystic ovary syndrome (PCOS)
• 6.26. Anabolic androgenic steroids (AAS)
• 6.27. Glucose-6-phosphate dehydrogenase deficiency (G6PD)
• 6.28. Lipodystrophy (lack of fatty tissue)
• 6.29. Lipid metabolism, fatty acids
• 6.30. Gender diversity
• 6.31. Mitochondrial disorder
• 6.32. Diaphragmatic hernia
• 6.33. Factors without risk increase for ADHD
• 6.34. Factors with risk reduction for ADHD

6.1. Infections and 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”.¹

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 of²

• 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.

6.1.1. Infections in the first year of life (+ 16 % to + 77 %)¶

A register-based cohort study (n = 2,885,662 of which n = 1,864,660 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.³
Severe infections within the first week of life increased the risk of ADHD medicated up to 8 to 14 years of age by 12 %. Meningitis in the first week of life increased the risk of ADHD defined in this way by 77% and the risk of ASD by 105% ⁴

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

Severe bacterial infectious diseases in childhood or adolescence massively increase the risk of severe mental disorders (HR):⁵

• 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
• Schizophrenia⁶

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.⁵

6.1.2.1. 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:⁷

• 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

Tuberculous meningitis showed symptoms of ADHD among 21 people with ADHD.⁸ With a population prevalence of 8%, this would be a risk increase of 1,150%.
In a more recent study of 78 children with tuberculous meningitis, the same authors found a clinical total problem score in the CBCL (over 70) in only 13.5 % of the children and clinical social problem scores in 20.6 %. In the group, the ADHD score was significantly increased, without any statement being made about the number of people with ADHD.⁹

The prevalence of Streptococcus agalactiae infection (Group B Streptococcus, GBS) in infants was 0.07%.
GBS has brought about:¹⁰

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

GBS meningitis increased the risk of¹⁰

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

6.1.2.2. Periodontal disease¶

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.¹¹

6.1.2.3. 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 %.¹² 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 risk¹³
Another very large study found that the risk of ADHD increased all the more,¹⁴

• the earlier the first antibiotic was administered (less than 2 years, 2 to 5 years, 5 to 8 years) and
• the longer the antibiotic treatment lasted (less than 7 days, 7 to 14 days, more than 14 days):

ADHD prevalence with antibiotic administration at the age of / for the duration of	under 2 years	2-5 years	5-8 years
< 7 days	10.53 %	7.33 %	5.18 %
7-14 days	10.66 %	8.80 %	7.25 %
&gt; 14 days	11.47 %	11.11 %	8.83 %

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.¹⁵ Two other studies found no increased risk of mental disorders when antibiotics were given in the first 1 ¹⁶ to 2¹⁷ years of life.
One study found no increase in risk for ADHD, but for asthma, food allergies and allergic rhinitis (hay fever),¹⁸ 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:¹⁹

• 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.¹⁹

Exposure to antibiotics in the first years of life increased the child’s risk of: (meta-analysis, k = 30, n = 7,047,853)²⁰

• 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.²¹

6.1.3. 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, including²²

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

6.1.3.1. 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.²³ In addition to encephalitis²⁴, (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.²⁵
One study found an increased risk of ADHD due to mild enterovirus infections (16%) and severe enterovirus infections (182%).²⁶

6.1.3.2. 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.²⁷²⁸ Another study found ADHD particularly common when the A71 infection was accompanied by cardiopulmonary failure.²⁹
EV-A71 often causes weakness, limb atrophy, seizures, hand-foot-and-mouth disease, encephalitis and reduced intelligence.

6.1.3.3. HIV (+ 150 % to + 1000 %)¶

A study of children and adolescents with HIV in a stable health condition found ADHD symptoms in 20%³⁰
A study of 100 African children aged 5 years and older with HIV in 2007 found ADHD symptoms in 88 %: 26 % ADHD-I, 38 % ADHD-HI and 24 % ADHD-C. In addition, the prevalence of ODD was 9.5% (teacher assessment) to 12% (parent assessment). 60% of the caregivers were themselves infected with HIV.³¹
Assuming a population prevalence of 8%, this would result in an increase in ADHD prevalence of + 150% to + 1000%.

6.1.3.4. Zoster encephalitis¶

In one isolated case, ADHD was mentioned in association with zoster encephalitis.³²

6.1.3.5. 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

6.1.4. Parasitic infections¶

A study of 100 children with ADHD and 100 healthy children found a correlation of ADHD with:³³

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

6.2. 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.³⁴

Craniocerebral trauma can trigger secondary ADHD.³⁵
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.³⁶

A review of k = 24 meta-analyses found a correlation of ADHD risk with previous traumatic brain injury:³⁴

• 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 injuries in ADHD are the result of the increased likelihood of accidents and injuries in ADHD remains an open question.
In one study, 30% of boys and 15% of girls with traumatic brain injury had previous ADHD.³⁷ This study also suggests that girls should integrate physical activity and the provision of resources for dealing with school stress into their rehabilitation program. For boys, cognitive support and strategies for coping with ADHD may be more effective.

ADHD correlated with an increased incidence of brain injury trauma^{3839 40} and otorhinologic trauma.⁴¹
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%.⁴²
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 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 the 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 ADHD) was not significantly associated with incidence of injury or concussion⁴³

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.⁴⁴
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.⁴⁵

6.3. Craniosynostosis (+ 500 %)¶

Craniosynostosis is a premature ossification of cranial sutures. In one study, the majority of children with craniosynostosis also showed ADHD symptoms. Maternal smoking during pregnancy significantly increased the risk of craniosynostosis.⁴⁶
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.⁴⁷ Older age at surgery was associated with poorer executive functions.
One study found high CAARS-2 ADHD index scores at age 16 and older in 42.6% of those who had had surgery for craniosynostosis as children.⁴⁸
Craniosynostosis is associated with a significantly increased risk of ADHD symptoms.⁴⁹

6.4. Epilepsy (up to + 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.⁵⁰ Another study found 43.3% of children with epilepsy had ADHD or a learning disorder.⁵¹ One study reported 11.2% ADHD and 19.1% ASD in children with epilepsy at age 7.⁵²

Of children with infection-related epilepsy (FIRES), 33.3% showed symptoms of inattention, 53.3% aggression and 20% mood problems.⁵³

In West syndrome (infantile spasms, BNS epilepsy), which occurs in infants, an ADHD prevalence of 15% was cited.⁵⁴

6.5. Phenylketonuria (PKU) (+ 375 %)¶

See under Monogenetic causes of ADHD.

6.6. Sleep-related breathing disorders (SBAS, SDB, SRBD) (up to + 350 %)¶

Other names: Sleep disordered breathing (SDB), sleep related breathing disorder (SRBD).⁵⁵

Sleep-related breathing disorders (SBAS) as a generic term include, among other things

• primary snoring (pure snoring, without other SBAS)
• Upper airway resistance syndrome⁵⁶
• obstructive sleep apnea (OSA)⁵⁷⁵⁸
• central sleep apnea (CSA)
• sleep-related gas exchange disorders (SAGEA)

SBAS is most common between the ages of 2 and 8 years, presumably due to the relative size of the lymphoid tissue compared to the diameter of the airways⁵⁹

6.6.1. Sleep-related breathing disorders in general¶

6.6.1.1. Prevalence of sleep-related breathing disorders¶

The prevalence of sleep-related breathing disorders (SBAS) was found to be

• Children:
  • 12 %⁶⁰
  • 10 % (study of n = 227 children aged 4 to 2 years)⁵⁹
• Children and young people (6 to 17 years)
  • 10 %⁶¹
• Children and adolescents (5 to 16 years) undergoing orthodontic treatment:⁵⁸
  • SBAS: 10.8 % vs. 5 % in healthy controls
  • Snoring: 13.3 %
  • Drowsiness: 17.9 %
• Teenagers
  • 7 %⁶²
    • male: 5.8 %
    • female: 8 %
    • weekly: 6 %⁶²
  • 5.8 % without obesity⁶²
    • 12.8 % with obesity
• Population
  • from 30 to 60 years, AHI from 5⁶³
    • 9 % for women
    • 24 % for men
  • 20 %⁶⁴
  • 23.4 % for women⁶⁵
    • postmenopausal 3 to 4-fold increase vs. premenopausal⁶⁶
  • Average age 59 years, AHI from 15⁶⁵
    • 49.7 % for men
    • The overall population AHI median was 6.9/h for women and 14.9/h for men⁶⁵
  • from 30 to 69 years (meta-analysis, k = 17)⁶⁷
    • Germany
      • 60.1 % AHI from 5
      • 32.9 % AHI from 15
    • France
      • 72.1 % AHI from 5
      • 36.3 % AHI from 15
    • Austria
      • 48.7 % AHI from 5
      • 28.4 % AHI from 15
    • Switzerland
      • 72.4 % AHI from 5
      • 36.6 % AHI from 15
    • Denmark
      • 48.9 % AHI from 5
      • 28.5 % AHI from 15
    • Sweden
      • 17.0 % AHI from 5
      • 12.7 % AHI from 15
    • USA
      • 33.2 % AHI from 5
      • 14.5 % AHI from 15
• inpatient psychiatric patients
  • 23,9 %⁶⁸
• Prevalence of SBAS (apnea-hypopnea index (AHI), respiratory disturbance index (RDI) or oxygen desaturation index (ODI) from 5/h):⁶⁶
  • 24.0 % to 83.8 % for men
  • 9.0 % to 76.6 % for women
• Prevalence of moderate to severe SBAS (AHI, RDI or ODI from 15/h)⁶⁶
  • 7.2 % to 67.2 % for men
  • 4.0 % to 50.9 % for women

SBD correlates with hearing problems.
44.8% of children with habitual snoring had a recurring middle ear infection⁶⁹
Otitis media correlates with SBD and resulting hypoxia.⁷⁰ Children with otitis media with effusion are more likely to have significant OSA symptoms.⁷¹
Middle ear infections are favored by a lack of oxygen.^7273747576

Untreated mild SBAS gave itself away:

• in 70.8% of children and adolescents aged 6 to 17 years⁶¹
• in 65% of children aged 5 to 9 with mild OSA⁷⁷
• in 52.9% of children with an AHI of 2 or more by adolescence⁷⁸
• in 100 % % of children with an AHI of 5 or more up to adolescence; including⁷⁸
  • 50 % partial remission to AHI 2 to 4
  • 50 % a remission to AHI below 2

Spontaneous remission is less common in moderate or severe SBAS (AHI 5 or higher). Obesity, high BMI, persistent tonsil hypertrophy, male gender or African-American ethnicity are unfavorable predictors for spontaneous recovery from OSAS.⁷⁹

6.6.1.2. Oxygen supply for SBAS¶

TOI: mean nocturnal tissue oxygen index

Unlike in adults, TOI during sleep in children with SBAS does not appear to differ from healthy controls⁸⁰
In apneas and hypopneas, the decrease in TOI precedes peripheral, systemic desaturation.
TOI falls more sharply

• for apneas than for hypopneas
• during REM sleep than in other sleep phases
• in younger children than in older children
• in children with a high AHI than with a low AHI

A study of 65 children with SBAS examined 540 obstructive and mixed apneas, 172 central apneas and 393 obstructive hypopneas.⁸¹

• SpO2 decreased on average by 4.1 % (± 3.1 %)
• TOI decreased on average by 3.4 % (± 2.8 %)
• TOI decreased more strongly
  • for apnea (breathing stops) compared to obstructive hypopnea (reduced breathing depth, shallower breathing)
  • for moderate to severe SBAS compared to mild SBAS
  • in children up to 6 years of age compared to older children
    • Explanatory models: lower residual functional capacity, higher oxygen consumption and immaturity of cerebral autoregulation in children⁸⁰
• TOI declines correlated significantly with the type of event, regardless of the type of event
  • SpO2 decreases
  • Duration of the event
  • Age

A study of 60 children with SBAS analyzed 493 central and 399 obstructive events:⁸²

• Central oxygen supply and heart rate changed more during central events (apneas) than during obstructive events
• Changes were greater in NREM sleep than in REM sleep
• TOI changed more among 3- to 6-year-olds than among 7- to 12-year-olds
• Heart rate changed more in 7- to 12-year-old children than in 3- to 6-year-olds

Two studies found different results:

• Cerebral oxygenation did not correlate with the severity of SBAS. Primary snoring showed significantly worse cerebral oxygenation than mild or severe OSA. Sleep disturbance, male gender, arousal index and NREM sleep correlated with reduced cerebral oxygenation. An increase in mean arterial blood pressure, older age, higher blood oxygen saturation and REM sleep correlated with higher cerebral oxygenation.⁸³
• SBAS in 7- to 12-year-old children was associated with significantly (in primary snoring, AHI max 1) or tendentially (in mild and severe OSA) increased cerebral oxygen (TOI). This could possibly be a compensatory reaction to reduced arterial oxygen saturation during apnea (cerebral autoregulation). In 3- to 6-year-old children, cerebral oxygen was unchanged, regardless of the severity of SBAS. Cerebral oxygen did not correlate with cognitive deficits, but did correlate with behavioral problems in 7- to 12-year-old children. In contrast to cerebral oxygen, oxygen extraction rate (O2-ER or FTOE, which measures tissue oxygen consumption) was lower in all SBAS groups than in controls at all sleep stages. The SpO2 value was the same in all groups.⁸⁴

In adults, obstructive breathing events (especially during REM sleep and in relation to the duration of the event) were associated with⁸⁰

• O2Hb decrease
• TOI acceptance
• HHb increase
• tHb increase

In adults, the cerebral oxygen supply changed⁸⁵

• stronger during obstructive apneas than during obstructive hypopneas
• stronger in severe OSA than in mild or moderate OSA

Repeated drops in oxygen during sleep can damage the respiratory control areas of the brainstem, especially during critical developmental stages, which can cause long-term problems such as unstable breathing, cardiovascular stress or neurological problems.⁸⁶

Hyperactivity correlated with reduced blood oxygen saturation.⁸⁷

Hypoxia is a relevant developmental pathway for ADHD.⁸⁸

Another common developmental pathway of ADHD and SBAS is neuronal inflammation.⁸⁹⁹⁰

6.6.1.3. ADHD with SBAS¶

One review reported a correlation of ADHD with SBAS of 50%.⁸⁹
SBAS showed a medium-strong correlation with ADHD symptoms (Hedges’ g = 0.57, 95% confidence interval: 0.36-0.78; p = 0.000001). A high AHI was associated with lower Effect sizes. (Meta-analysis, k = 18, n = 2518)⁹¹ Adenotonsillectomy correlated with a decrease in ADHD symptoms 2-13 months after surgery (Hedges’ g 0.43 (SMD; 95% confidence interval = 0.30-0.55; p < 0.001; n = 529).

The risk of ADHD is increased with SBAS:⁹²

• by 1,106 % for moderate and severe sleep problems⁹³
• by 759 % (31.8 % vs. 3.8 % for children and adolescents aged 5 to 16) underwent orthodontic treatment:⁵⁸
  • nocturnal enuresis: 13.6 % vs. 0 %
  • Overweight: 18.2 % vs. 2.7 %
• by 393 % for mild sleep problems⁹³
• by 150 % to 200 %⁹⁴
• by more than 100 %⁹⁵
• in children with SBAS
  • Hyperactivity^{9697 98 99}
    • increased by 150¹⁰⁰
    • increased by 57¹⁰¹
    • 6.82 times as often cut-off of the BASC-2-PRF scale for hyperactivity exceeded in persistent SBD compared to never SBD (+ 582 %)¹⁰²
  • Inattention^{10296 99}
    • increased by 110¹⁰⁰
    • increased by 89¹⁰¹
    • in NEPSY increases¹⁰³
  • Hyperactivity and inattention improved significantly with adenotonsillectomy.
• Executive functions deteriorated
  • for 5-year-old children¹⁰⁴
  • at NEPSY¹⁰³
• Impaired memory functions
  • for 5-year-old children¹⁰⁴
• general intellectual abilities impaired
  • for 5-year-old children¹⁰⁴
• externalizing symptoms⁹⁶
  • in 7- to 12-year-old children (CBCL and BRIEF)¹⁰⁵
  • 3.29 times as often cutoff of the BASC-2-PRF scale for externalizing problems exceeded in persistent SBD compared to never SBD (+ 229 %)¹⁰²#
• Aggressiveness¹⁰²⁹⁶
  • increased by 110¹⁰⁰
• reduced social competence¹⁰²
• impaired communication skills¹⁰²
• reduced adaptability¹⁰²
• Behavioral symptoms⁹⁹
  • (but no cognitive symptoms) in 3- to 5-year-old children¹⁰⁶
  • in 7- to 12-year-old children (CBCL and BRIEF)¹⁰⁵
• internalizing symptoms⁹⁶
  • in 7- to 12-year-old children (CBCL and BRIEF)¹⁰⁵

Children with Robin sequence (Pierre Robin sequence, PRS) suffer from a congenital combination of malformations:

• lower jaw too small (micrognathia)
• tongue falling backwards (glossoptosis)
• resulting breathing difficulties due to blockage of the upper airways
• often also have a cleft palate, which exacerbates the breathing and feeding problems
• ADHD symptoms as a possible consequence of breathing difficulties¹⁰⁷
• PRS is a common feature of Stickler syndrome, a genetic disorder that causes underdevelopment of the midface

Among children ages 4 to 12 who attended a dental clinic, SBAS correlated with a greater than 7.35-fold risk for ADHD medication, a 40% increased risk for asthma medication, and a 12.5-fold risk for other medications⁵⁹

• SBAS correlated further with:⁵⁹
  • Allergies: 4.9-fold
  • Developmental disorders: 4.94-fold
  • Behavioral disorders: 3.94-fold
  • Difficulty sleeping through the night: 3 to 6 times
  • Mouth breathing: 4.7- to 5-fold
  • Snoring: 3-fold
    • 70% of children with SBAS snore frequently¹¹⁰
  • fewer birth complications suffered during their own birth
  • 83.3% of parents reported that they snore, compared to 52.2% of parents of children without SBAS
• ADHD medication use correlated low to moderate with mouth breathing (Phi = 0.216)
• Mouth breathing correlated moderately to strongly with snoring (Phi = 0.386, p < 0.001).

Polysomnography studies found a correlation of ADHD and sleep-related disorders only in terms of more movements at night.¹¹¹¹¹² Polysomnography is a sleep laboratory examination with measurement of brain waves (EEG), eye movements (EOG), heart activity (ECG), breathing, oxygen saturation, muscle activity (EMG) and body position.

A study reports increased snoring and breathing interruptions in children with Down syndrome.¹¹³ Downs syndrome is associated with an ADHD rate of 50%. More on this at Monogenetic causes of ADHD.

A genomic correlation was found between ADHD and insomnia, daytime napping, daytime sleepiness, snoring, daytime sleepiness, short sleep duration and long sleep duration. Insomnia, daytime sleepiness and snoring shared genes with ADHD that are involved in neurobiological functions and regulatory signaling pathways¹¹⁴

The upper quartile for the SBAS apnea-hypopnea index (AHI greater than 20.6/h) correlated (independently in each case) with⁶⁵

• metabolic syndrome (OR 2.80)
• Diabetes (OR 2.00)
• Depression (OR 1.92)
• High blood pressure (OR 1.60)

Children with ADHD are more likely to show SBAS symptoms.¹¹⁵

6.6.1.4. Adenotonsillectomy for SBAS and changes in ADHD symptoms¶

Children 6 to 12 years of age with SBAS showed a correlation between lowest blood oxygen saturation and performance on the Modified Wisconsin Card Sorting Test. Adenotonsillectomy significantly improved the apnea-hypopnea index (AHI), and improved mean scores on most neurocognitive and behavioral measures, although residual deficits persisted at 6 months. However, almost half of the children continued to suffer from SBAS. A baseline AHI > 5/h and complete improvement in SBAS (postoperative AHI < 1/h) correlated with improvement in more subscales than a baseline AHI < 5/h or incomplete improvement in SBAS. Impairment of neurocognitive performance in SBAS appears to be due to hypoxemia rather than frequency of SBAS events.¹¹⁶
Children with SBAS who had undergone adenotonsillectomy¹¹⁷

• showed before the operation compared to those not affected
  • more common ADHD (DSM-IV)
  • frequent hyperactivity
  • more inattention in cognitive tests
  • more sleepiness in the Multiple Sleep Latency Test sleepier
• showed significant improvements in all values after the operation and no longer differed from those who were not affected
• the improvements could not be predicted by polysomnographic measurements before the operation

Among 64 children with SBAS (3 to 12 years), there was a significant improvement in quality of life 4 years after adenotonsillectomy, but no improvement in behavior after CBCL.¹¹⁸
Among 20 children with OSA (3 to 13 years), there was a significant improvement in ADHD symptoms, behavior and snoring 4.5 years after adenotonsillectomy.¹¹⁹

Among 54 children with sleep-related gas exchange disorders (SAGEA), surgical tonsillectomy and adenoidectomy resulted in a statistically significant improvement in school performance, while this remained unchanged in children without the surgery.¹²⁰

Children with mild (apnea-hypopnea index (AHI) below 6 or apnea index (AI) below 1) SBAS (AHI average 3.1) and children with OSA (AHI from 5 or AI from 1) (AHI average 25.3; 10 to 48) showed no differences in BASC scores before adenotonsillectomy. After surgery, both groups showed a significant improvement in the behavioural symptom index, as well as in the BASC scales for atypicality, depression, hyperactivity and somatization.¹²¹

Observational differences: symptom perception vs. polysomnographic measurement

Several studies have observed that the symptom severity reported by parents or teachers correlates only to a limited extent with the results of polysomnographic measurements.

SBAS in children aged 5 to 17 years showed for the five domains of executive functions (meta-analysis k = 14, n = 1697)¹²²

• with polysomnographic measurement
  • 0.43 Generativity (SMD)
  • the other four areas of executive functions (vigilance, inhibition, working memory, shifting) were not significantly
• for questionnaire survey
  • for all three measured areas of executive functions significantly from SMD 0.64 to 1.06
    • 0.64 Inhibition (SMD in the parent report)
    • 1.06 Working memory (SMD in the parent report)
    • 0.86 Task change (SMD in parent report)
• Severity of SBAS did not affect executive functions

Children aged 7 to 12 years who were divided into control group (N = 34) based on nocturnal polysomnography; primary snoring (PS: N = 55), mild obstructive sleep apnea (mild OSA: N = 22) and moderate to severe OSA (MS OSA: n = 16) showed deficits in working memory in the Behavior Rating Inventory of Executive Function (BRIEF) at all levels of SBAS severity. While a computer test (recognition of playing cards, CogHealth) found no difference between SBAS and controls, mild OSA showed significantly poorer performance than the group with primary snoring. Parents of children with primary snoring, on the other hand, reported stronger working memory deficits than the objective measure.¹²³

Among children aged 5 to 9 years with adenotonsillar hypertrophy and diagnosed sleep apnea, 42% no longer met the diagnostic criteria for sleep apnea after 7 months without surgery. This remission was statistically significantly more frequent with lower AHI, better oxygen saturation, smaller waist circumference, higher positioned soft palate, smaller neck circumference and non-black skin color. However, of the 167 children with baseline PSQ scores ≥ 0.33, only 15% achieved symptomatic remission. This was predicted by low PSQ and PSQ snoring subscale scores, absence of habitual snoring, loud snoring, observed apnea or smoking in the home, higher quality of life, fewer symptoms of ADHD, and female gender. Only lower PSQ and snoring scores were independent predictors.
In summary, a wait-and-see approach to polysomnography is often associated with an elimination of the OSAS diagnosis, but rarely with a significant improvement in symptoms.¹²⁴

Children aged 3 to 5 years with SBD showed SBD at a follow-up examination 3 years later:¹²⁵

• 60% of the children treated showed a cure for SBAS
• 40% of untreated children showed a cure for SBAS
• cured was defined as: OAHI of max. 1/hour and no snoring on polysomnography and no report of habitual snoring by parents
• no cognitive differences between “cured”, “not cured” and “control group”
• Behavioral function significantly worse in children with initial SBAS diagnosis compared to controls, regardless of cure
• OAHI change did not predict cognitive or behavioral outcomes
• Reduction in nocturnal arousals, independent of complete recovery, correlated with improved alertness and less aggression

6.6.2. Snoring (up to + 350 %)¶

Primary snoring (snoring without OSA) differs from obstructive sleep apnea in the number of hypopneas per hour.
Primary snoring is assumed with an AHI of max. 1, OSA with an AHI of more than 1.

6.6.2.1. Prevalence of snoring¶

6.6.2.2. Snoring and ADHD symptoms¶

Habitual snoring predicted hyperactivity in children 4 years later (+ 340 %, OR 4.4), as did loud snoring (+ 350 %, OR 4.5). The 25% heaviest snorers had a 5.3-fold risk of hyperactivity 4 years later (+ 430%). Sleepiness was associated with a 3-fold risk (+ 200 %), sleep-related breathing disorders with a 4-fold risk (+ 300 %) of hyperactivity 4 years later.¹³⁶

The prevalence of ADHD was doubled (+100%) in children who snored occasionally or often.¹³³

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 of more than 3/h) found that of the snoring children¹³⁷

• 36 % showed hyperactivity/impulsivity
• 24 % showed emotional dysregulation
• Surprisingly, it was not the reduced oxygen supply due to sleep apnea that correlated with hyperactivity/impulsivity or emotional dysregulation, but rather the volume of snoring

Snoring in various forms correlated with 30% increased scores in inattention, hyperactivity and overall ADHD according to the Korean ADHD-RS in a large study of children aged 6 to 12 years:¹³⁸

• Snoring more than half the time
• Always snore
• Loud snoring
• Heavy or noisy breathing

In children aged 5 to 7 years without a diagnosis of ADHD and without hyperactivity, frequent snoring correlated with¹³⁹

• Attention problems
• Social problems
• Anxiety symptoms
• Symptoms of depression
• Poorer cognitive scores

Children aged 6 to 10 years with habitual snoring who had undergone polysomnography (PSG) showed increased levels of¹⁴⁰

• Hyperactivity (ADHD Rating Scale)
• Inattention (ADHD Rating Scale)

ADHD symptoms depended on the level of snoring in children aged 6 to 12 years:¹²⁹

• frequently snoring children
  • 31.3 % Attention deficit
  • 18.2 % Hyperactivity/impulsivity
• occasionally snoring children
  • 16.2 % Attention deficit
  • 9.9 % Hyperactivity/impulsivity
• non-snoring children
  • 13.9 % Attention deficit
  • 8.8 % Hyperactivity/impulsivity

Children aged 2 to 14 who had a clinic appointment showed:¹³¹

• Hyperactivity: 22 % with habitual snoring vs. 12 % with non-snoring

The level of snoring, but not the AHI, correlated in children aged 4 to 10 years with¹⁴¹

• Hyperactivity (CPRS-R)
• Inattention (CPRS-R)
• Cognitive performance (NEPSY, DAS)
• Internalizing symptoms (CBCL)
• Externalizing symptoms (CBCL)
• Understanding instructions (NEPSY)
• The correlation between snoring and AHI was weak (rs = 0.24).

Among snoring children aged 5 to 7 years, an AHI of 5 or more in the NEPSY correlated with poorer scores in terms of¹⁴²

• Inattention
• Executive problems

Habitual snoring in children and adolescents correlated with hyperactivity.¹³⁰¹⁴³

A study of n = 405 children aged 4 to 9 years found clinically relevant hyperactivity in 15.5 % compared to 5.3 % in controls (+ 188 %). In addition, a high probability of hyperactivity was found in 11.1 % compared to 4.1 % in the controls (+ 170 %).

One study found 43% higher levels of hyperactivity and 25% higher levels of inattention in children who snored. Both scores improved significantly with adenotonsillectomy.¹⁰¹

Habitual snoring in primary school children correlated with:

• Hyperactivity increased¹⁴⁴, 180% more frequently¹⁴⁵, 140% more frequently ¹⁴⁶
• Inattention increases¹⁴⁴, 340% more frequently¹⁴⁵, 300% more frequently¹⁴⁶
• Oppositional behavior increases¹⁴⁴
• Behavioral problems 180% more frequent ¹⁴⁶
• Emotional problems 450% more frequent¹⁴⁶
• Problems with peers 870% more frequent ¹⁴⁶
• Daytime sleepiness 970 % more frequent¹⁴⁵
• UARS/OSA at 25 %¹⁴⁵
• poorer school performance¹⁴⁵
  • Mathematics + 160 %
  • Natural sciences + 230 %
  • Spelling + 150 %

The changes were 140% more frequent regardless of intermediate hypoxia.¹⁴⁶ The behavioral problems improved when the snoring disappeared.

In adolescents, frequent snoring correlated with a 130% increased risk of ADHD.¹⁴⁷

Using Mendelian randomization, one study found no statistically significant association between sleep apnea or snoring and ADHD. ADHD correlated significantly with shorter sleep duration.¹⁴⁸

Children with ADHD snored more frequently than non-affected children.^149150151

• 77.8% of children aged 6 to 14 years with ADHD who underwent polysomnography snored heavily. Obstructive sleep apnea syndrome (OSAS) was found in 50.0 %.¹⁵²
• 40% of children with ADHD snored louder than 60 dB at times, compared to 28% of controls.¹⁵³
• 33% of children with ADHD (DSM-IV) snored, compared to 9% to 11% of those without¹³⁴
• 26.7 % of children aged 5 to 13 with hyperkinetic syndrome snored according to¹⁵⁴
• 21% of all children with ADHD (average age 8.9 years) snored¹⁵⁵

Adolescents who had been diagnosed as children with ADHD (DSM-IV),¹⁵⁶

• and whose ADHD persisted in adolescence snored 57.9 % of the time. Snoring was therefore 3.5 times more common than in those not affected (+ 250%)
• and whose ADHD did not fully persist in adolescence (subclinical ADHD) snored 43.4 % of the time, which is 2.0 times as often as those not affected (+ 100 %)
• Snoring was thus 80% more common in persistent ADHD than in subclinical ADHD.
• 28.3 % of non-affected controls were sharp

ADHD at the age of 5 correlated with a 32% higher risk of snoring at the age of 14¹⁵⁷
Among adolescents aged 10 to 17 years, 50.7% of persons with ADHD-I and ADHD-C snored, compared to 33.2% of non-affected persons¹⁵⁸ In contrast, a small study found an increased prevalence of snoring only among persons with ADHD-HI¹⁵⁹

Infrequent snoring in children also correlated with increased ADHD symptoms.¹⁶⁰

Methylphenidate improved snoring and bruxism in ADHD-I after 6 months.¹⁶¹

6.6.2.3. Adenotonsillectomy for snoring and changes in ADHD symptoms¶

Adenotonsillectomy improved snoring in children:

• Attention/concentration by 42¹⁶²
• verbal fluency by 92 %¹⁶²
• Learning/memory by 38 %¹⁶²
• executive functions by 52 %¹⁶²
• general intellectual abilities by 33¹⁶²
• Inattention by 21 %¹⁶²
• Hyperactivity by 21 %¹⁶²
• neurocognitive performance not¹⁶³

See also under Differential diagnosis: Primary organic disorders

6.6.3. Constricted turbinate (+ 300 %)¶

Hypertrophy of the inferior turbinate can cause sleep-related breathing disorders (SBAS) and ADHD symptoms.
The inferior turbinates cause up to 50% of the total resistance of the nasal airways.¹⁶⁴ Up to 20% of the population suffer from chronic nasal congestion due to hypertrophy of the turbinates.¹⁶⁵
Chronic hypertrophy of the turbinates, which is often caused by allergic rhinitis (hay fever) or chronic rhinosinusitis, can significantly impair nasal breathing even without adenotonsillar pathology.¹⁶⁶

A retrospective cohort study of n = 326 children aged 3 to 17 years (mean 9 years, 65% boys) who underwent inferior turbinate reduction (ITR) between December 2020 and May 2023 (in isolation or in combination with adenotonsillectomy, septoplasty or functional endoscopic sinus surgery) found ADHD-like symptoms in 32.5% of participants before surgery. In these, parents reported 12 months after surgery:¹⁶⁶

• 89.6 % improved nasal breathing
• 84.0 % Relief of SBAS symptoms
• 48.1 % improvement in ADHD symptoms, which correlated significantly with an improvement in nasal breathing

Assuming an ADHD prevalence of 8% in children and assuming that ADHD symptoms were equivalent to an ADHD diagnosis, 32.5% would have a 300% increased risk of ADHD.

One study found a significant improvement in sleep quality but no improvement in ADHD symptoms with nasal septum surgery (straightening of a curved nasal septum).¹⁶⁷

6.6.4. Enlarged pharyngeal and palatine tonsils (adenotonsillar hypertrophy) (up to + 275 %)¶

**Adenotonsillectomy: Surgical removal of the palatine tonsils (tonsils) and pharyngeal tonsils (adenoids), often due to recurrent infections or enlargement leading to breathing problems such as obstructive sleep apnoea. Common standard treatment for children with moderate to severe sleep apnea syndromes. Can improve breathing problems, behavioral problems and daytime sleepiness.
**Adenotomy: Surgical removal of only the pharyngeal tonsils (adenoids, infantile adenoids)
**Tonsillectomy: Surgical removal of only the palatine tonsils (tonsils, cervical tonsils)

Adenotonsillar hypertrophy is the most common factor for SBAS in children.⁵⁷¹⁶⁸
Chronic adenotonsillar hypertrophy can lead to various types of breathing-related sleep disorders, from loud snoring to severe obstructive sleep apnea. Chronic adenotonsillar hypertrophy can affect sleep architecture, e.g. increased arousal during sleep, increased REM sleep latency, decreased REM sleep, decreased sleep efficiency
or shortened sleep duration.¹⁶⁹¹⁷⁰
Normally, adenoid enlargement occurs particularly in the first years of life and usually - but not necessarily - disappears during late childhood.
The loss of nasal function during breathing can promote chronic inflammation of the upper respiratory tract.

6.6.4.1. Prevalence of adenotonsillar hypertrophy¶

6.6.4.2. Adenotonsillar hypertrophy and ADHD symptoms¶

The prevalence of ADHD in children with adenotonsillar hypertrophy was (compared to an assumed prevalence of 8%)

• 30 % (+ 275 %)¹⁷⁵
• 30 % (+ 275 %)¹⁷⁶
• 27,1 % (+ 238 %)¹⁷⁷
• 26,8 % (+ 235 %)¹⁷⁸

In n = 35 children aged 5 to 12 years with adenotonsillar hypertrophy and ADHD (DSM-IV), adenotonsillectomy** Six months after surgery:¹⁷⁹

• 57.8 % less ADHD-C (22.9 % after surgery compared to 54.3 % before surgery).
• Inattention significantly reduced
• Hyperactivity significantly reduced
• combined ADHD symptoms significantly reduced

Children with ADHD from 6 to 12 years of age had a 2.71-fold risk of adenotonsillar hypertrophy.¹⁷⁴

Impairments in cognitive function and behavior correlated with snoring, sleep efficiency, sleep latency and ethnicity, but not with tonsil size, in children aged 6 to 12 years. Snoring correlated better with the deficits than the number of apnea and hypopnea episodes per hour of sleep.¹⁸⁰

6.6.4.3. Adenotonsillectomy for adenotonsillar hypertrophy¶

Adenotonsillectomy in children with ADHD and adenotonsillar hypertrophy

• resolved ADHD in 50% at 6 months after surgery. ODD remained unchanged.¹⁷⁵
• resolved ADHD in 70% at 6 months after adenotonsillectomy¹⁸¹
• (even more pronounced after 6 months than after 3 months):¹⁸²
  • Oppositional behavior
  • Inattention / cognitive symptoms
  • Hyperactivity
  • Overall ADHD symptoms
• improved in children with ADHD, but also in children without ADHD¹⁸³
  • Oppositional behavior
  • Inattention / cognitive symptoms
  • Hyperactivity
  • Overall ADHD symptoms
  • In a long-term follow-up, the values did not deteriorate after 2.4 to 3.6 years after the surgery, and remained significantly better than the values before the surgery - except for the ADHD total index.¹⁸⁴
• improved ADHD symptoms more than treatment with MPH without surgery, with symptoms dropping almost to the level of non-affected patients after surgery¹⁸⁵
• in children and adolescents with SBAS and ADHD (according to DSM-IV) significantly improved the values of ^{186187178188189}
  • Hyperactivity
  • Inattention
  • ADHD total score

Similarly, 54% of children with enuresis no longer had enuresis after the operation.¹⁸⁷

In 26.3% of children (3 to 7 years) who underwent adenotonsillectomy, sleep apnea (AHI over 2) was still present after one year.¹⁹⁰

6.6.5. Breathing interruptions during sleep (sleep apnea, OSA, OSAS) (+ 100 %)¶

Sleep apnoea (obstructive sleep apnoea syndrome, OSA, OSAS) is measured using the apnoea-hypopnoea index (AHI). This indicates the number of complete pauses in breathing (apneas) and partial pauses in breathing (hypopneas) per hour of sleep. An AHI below 5 is considered normal, 5 to 14 indicates mild sleep apnea, 15 to 30 indicates moderate sleep apnea and more than 30 indicates severe sleep apnea.¹⁹¹

6.6.5.1. Prevalence of OSA¶

OSA correlates with hypoxia, arousal states during sleep and negative fluctuations in intrathoracic pressure. Consequences can be⁷⁹

• Stress on the cardiovascular system.
  • peripheral vasoconstriction
  • intermittent rise in blood pressure (increased blood pressure variability)
  • increased heart rate
  • reduced heart rate variability
  • Treatment of OSA improves cardiovascular system factors⁷⁹
• Activation of the sympathetic nervous system
  • elevated urine catecholamine levels
• increased oxidative stress
• systemic inflammation
• endothelial dysfunction
• reduced nocturnal baroreflex amplification
  • consequences of increased blood pressure fluctuations
• subclinical abnormalities of cardiac structure and function that can only be detected by ECG
• Enuresis
  • improved by OSA treatment
• Growth restriction
  • Size and weight
  • improved by OSA treatment
• Excessive daytime sleepiness
  • improved by OSA treatment
• Limited quality of life
  • improved by OSA treatment
• ADHD (see below)
  • Hyperactivity
  • Inattention
  • cognitive impairments
  • stressed executive functions
  • improved by OSA treatment

The prevalence of insomnia in OSA is between 39% and 55%¹⁹⁴

6.6.5.2. ADHD symptoms with OSA¶

Breathing interruptions during sleep in children can cause symptoms that resemble ADHD.¹⁹⁷
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 children with OSA, the prevalence of ADHD was doubled (+100%).¹³³

Children aged 6 to 10 years with OSA who had undergone polysomnography (PSG) showed increased levels of¹⁹⁸

• Hyperactivity (ADHD Rating Scale)
• Inattention (ADHD Rating Scale)

Among 110 boys aged 6 years, SBAS correlated with hyperactivity but not with inattention.¹⁹⁹

Children from 4 to 12 years of age with polysomnography-diagnosed mild or moderate OSAHS showed compared to healthy controls²⁰⁰

• FIQ, VIQ and performance IQ (PIQ) scores did not correlate with AHI, OAHI and lowest nocturnal SO2 level
• under 6 years
  • significantly lower scores on overall IQ (FIQ), verbal IQ (VIQ), comprehension test and visual analysis
  • the cumulative time of SO2 below 90 % (p = 0.046) and the percentage of cumulative time of SO2 below 90 % in total sleep time (p = 0.034) correlated significantly negatively and significantly with the PIQ
• from 6 years significantly lower VIQ and classification test results in children with OSAHS significantly lower

Children with ADHD have a significantly higher AHI (apnea-hypopnea index). (meta-analysis, k = 16, n = 1,360)²⁰¹ A case study of 3 adults with ADHD and OSA drew attention to the topic at an early stage²⁰²

Children with ADHD without OSA aged 6 to 13 years showed unremarkable sleep on polysomnography.²⁰³

Children with OSA and ADHD showed compared to children with OSA without ADHD:²⁰⁴

• AHI values increased
• Increased blood oxygen saturation
• IL-4 increased
• IL-12 increased
• IL-13 increased
• transforming growth factor (TGF)-β significantly lower
• Increased dopamine levels (presumably peripheral)
• Noradrenaline levels significantly lower (presumably peripheral)
• Increased serum leptin levels
• Adiponectin reduced
• Resistin reduced

6.6.5.3. Adenotonsillectomy for OSA and changes in ADHD symptoms¶

Children with OSA due to grade 3 and 4 adenotonsillar hypertrophy showed cognitive dysfunction (worse NESPY score). Adenotonsillectomy improved these and reduced serum cytokine levels of tumor necrosis factor-α (TNF-α), interleukin (IL)-6 and 1β. Lifestyle interventions worked satisfactorily for mild OSAS and minimal cognitive dysfunction and improved the results of adenotonsillectomy before surgery. Among the subjects, 33.5% were overweight and a further 55.8% had obesity. Tonsil hypertrophy was grade 4 in 27.7 %, grade 3 in 44.2 %, grade 2 in 27.2 % and grade 1 in 0.9 %. Adenoid hypertrophy was zero in 5.4 %, grade 1 in 5.7 %, grade 2 in 41.1 %, grade 3 in 36.2 % and grade 4 in 11.5 %. Neither tonsil hypertrophy nor adenoid hypertrophy correlated statistically significantly with the OSA AHI score. Severe OSA tended to increase adenoid hypertrophy.²⁰⁵ Of the 181 patients with grade 3 or 4 adenotonsillar hypertrophy, 19 underwent adenoidectomy, 76 underwent tonsillectomy and 86 underwent adenotonsillectomy. Tonsillectomy or adenotonsillectomy was significantly more frequently required for severe OSA. Cognitive performance (NEPSY score) was significantly worse in severe OSA than in mild OSA before treatment. During follow-up, cognitive performance improved in 76.7% of subjects with mild OSA, 84.1% of subjects with moderate OSA and 87.8% of subjects with severe OSA.
The reduced serum levels of inflammatory cytokines indicate the involvement of OSA in inflammatory processes.

In children aged 5 to 9 years and OAI (apneas per hour of sleep) of 1 to 20 or AHI (apneas or hypopneas per hour of sleep) of 2 to 30, adenotonsillectomy correlated with slight improvements (SMD Cohen’s d, 0.20 to 0.24) with respect to²⁰⁶

• non-verbal thinking
• Fine motor skills
• selective attention

A study in children with OSA without prolonged blood oxygen desaturation found a trend (SMD 0.15) but not statistically significant improvement in attention and executive function scores on the Developmental Neuropsychological Assessment with early adenotonsillectomy compared to a wait-and-see approach with supportive treatment. However, early adenotonsillectomy correlated with significantly greater improvements compared to wait-and-see observation in terms of⁷⁷

• Behavior
• Quality of life
• polysomnographic findings (79% normalization compared to 46%)
• ADHD symptoms (SMD 0.28 in the parent rating and SMD 0.29 in the teacher rating of the Conners Rating Scale)

Children with OSA showed

• Before an adenotonsillectomy

  • Significantly poorer cognitive performance compared to controls; postoperatively, the values no longer differed.²⁰⁷

• After an adenotonsillectomy

  • A statistically insignificant tendency towards better scores on the Homework Performance Questionnaire (HPQ-P).²⁰⁸
  • Executive functions moderately improved²⁰⁹
  • Attention moderately improved²⁰⁹
  • moderate improvement in motor skills²⁰⁹
  • internalizing behaviors (parent report) moderately improved²⁰⁹
  • externalizing behaviors (parent report) moderately improved²⁰⁹

Among 52 children with OSA (age 7.1; 2.5-14.9 years) (AHI 16.2; 5.0-88.0), mean BASC-t scores for all behavioral scales and composites were above 50 before adenotonsillectomy. After adenotonsillectomy, there was a significant improvement for²¹⁰

• Aggression
• Atypicality
• Depression
• Hyperactivity
• Somatization

Elevated levels of IL-6, IL-8, IL-17, IL-18, MIF, Hs CRP, TNF-α, PAI-1 and leptin correlated with OSA, of which only IL-18 did not also correlate with BMI, while IL-23 also correlated with BMI.²¹¹

Children aged 6 to 12 years with a low AHI (1 to 4) showed no statistically significant impairment of neuropsychological functions (intelligence, verbal and non-verbal reasoning, attention, executive functions, memory, processing speed and visual-motor skills).²¹²

6.6.6. Upper airway resistance syndrome (UARS)¶

While OSA is associated with apneas (pauses in breathing) and hypopneas (decreased depth of breathing) that last more than 10 seconds (2 to 3 breaths) and are often accompanied by a drop in blood oxygen and an increase in CO2, upper airway resistance syndrome (UARS) is associated with shorter pauses in breathing.⁵⁶

Boys are more frequently affected, as testosterone leads to muscle growth. While the craniofacial skeleton forms in early childhood, the testosterone-induced muscle growth of the tongue and throat muscles, among others, does not begin until puberty in a spatial structure that is already defined by the bone structure.
In addition to a genetic predisposition, increased nasal resistance is favored by various environmental factors:⁵⁶

• Allergies
• Infections
• abnormal size of the nasal lymphatic tissue (which in turn is promoted by allergies and infections of the airways or ears)

Newborns show:⁵⁶

• increased breathing effort, longer than four breaths, measured by the expiratory rate
• a sudden increase in respiratory effort with a negative peak end-expiratory effort immediately followed by a cessation of diaphragmatic movement of two or more breaths. These are not central apneas, but a reaction to the sudden increase in respiratory effort
• an abrupt increase in breathing rate over 4 or more breaths without an increase in breathing effort. The increase in respiratory rate serves as compensation for the decrease in
  Tidal volume
• the events occur without a significant drop in oxygen saturation (pulse oximeter) or oxygen tension (transcutaneous P o 2 electrode)

Infants show:⁵⁶

• clearer nocturnal symptoms
• Difficulty sleeping through the night possible, crying on waking at night
• Thumb sucking can encourage repositioning of the tongue, the combination of pressure and sucking can reduce the initial resistance to inhalation, especially
  for mouth breathing
• rarely also speaking in sleep
• Restless sleep
• Sweating during sleep, the extent of which correlates with fluctuations in nasal resistance
• Head may be hyperextended
• Sleeping position more often on the stomach, sometimes every night with the knees under the stomach and the bottom up
• at least temporary mouth breathing
• intermittent snoring
• Enuresis is possible
• long head with narrow jaw favors UARS

Often accompanied by:

• more frequent earaches
• frequent respiratory infections
• Respiratory allergies

Even at this age, behavioral problems can be the result:⁵⁶

• Attention problems
• Hyperactivity
• rebellious behavior
• inexplicable aggressiveness towards peers
• considerable shyness
• Fear

Schoolchildren and teenagers show:⁵⁶

• frequently:
  • Hyperactivity
  • Attention deficit disorders
  • Poor performance at school
  • sometimes mental absence (teacher’s report)
  • Daytime tiredness
  • Normal weight to underweight
• possible:
  • Drowsiness
  • Difficulties with peers
  • Aggressiveness
  • mild autonomic dysfunction
    • cold hands and/or feet
    • Drowsiness or dizziness when bending down or standing up abruptly

.

• Sleep behavior:
  • frequent snoring
  • continuous movements
  • Difficulties getting up in the morning
    • Teenagers often difficult to wake up in the morning
      • late for school / training
      • shifted chronobiorhythm (eveningness)
      • Daytime tiredness
      • Exhaustion at the end of the day
      • Fear during the day
  • night sweats
  • morning headaches
  • Enuresis
  • Sleep conversations
  • Sleepwalking
    • especially with teenagers
    • sometimes with nightmares or sleep disorders
  • Teeth grinding

Treatment options for children:
- Tonsillectomy
- additional adenoidectomy if necessary
- Orthodontics if required:
- slow maxillary distraction
- maxillary and/or mandibular expansion
- Braces
- Removing wisdom teeth with a narrow jaw

6.7. 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).²¹³
ADHD increases the risk of GERD.²¹⁴

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.

6.8. Anorectal malformations (+ 200 %)¶

Anorectal malformations are congenital malformations of the anus and are associated with an increased risk of ADHD, depression and anxiety disorders.²¹⁵

• 3-fold risk of ADHD and ASD²¹⁶
• 2.26 times the frequency of ADHD medication prescriptions²¹⁶

6.9. Febrile convulsions (+ 168 %)¶

According to clinical and animal studies, febrile convulsions have detrimental effects on neurodevelopment, which can lead to ADHD, increased susceptibility to epilepsy, hippocampal sclerosis and cognitive decline in adulthood²¹⁷
Febrile convulsions in children increased the risk of ADHD by

• 168 % (91 % unadjusted) (meta-analysis, k = 12, n = 958,082)²¹⁸
• 66 %²¹⁹
• 28 %²²⁰

6.10. 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).²²¹

Comprehensive information on vitamin D3 can be found at Vitamin D In the article Vitamins for ADHD in the section Vitamins, minerals, dietary supplements for ADHD in the chapter Treatment

6.11. (Untreated) type 1 diabetes (+ 145 % to + 719 %)¶

An increased risk of ADHD was found in people with ADHD:²²²

• 8.19-fold ADHD risk (HR = 8.19)²²³
• 2.45-fold risk of ADHD in non-treated people in a study of people with ADHD with and without insulin pump treatment, where ADHD was considered a risk factor for inconsistent diabetes treatment²²⁴
• 1.68 times higher risk of ADHD (4.2 % vs. 2.5 %)²²⁵
• Among people with ADHD 1, 15.9% had an existing ADHD diagnosis and a further 31.9% met the ADHD criteria of the ASRS.²²⁶ Assuming an ADHD prevalence of 8%, this would be a doubling (+100%). However, the test subjects were those who had responded to the ASRS sent to them, so a bias towards an inflated ADHD rate can be expected here.
• Children with diabetes have a higher prevalence of ADHD, ASD, seizures and depression, and tend to have lower IQ scores and poorer academic performance²²⁷

One study found no evidence of causality of autoimmune diseases such as diabetes 1 for ADHD.²²⁸

In addition to regulating blood sugar levels, insulin also has tasks in the brain:²²⁷

• acts on IR in brain astrocytes, which affects dopaminergic signaling and can thus modulate cognition and mood
• increases the number of NMDAR channels in the cell surface membrane through regulated exocytosis
  • NMDARs control the entry of calcium ions into the cell and trigger long-term potentiation (LTP), which is associated with learning and memory processes
• influences the activity of AMPA receptors in the hippocampus
  • this leads to LTD in the CA1 region, downregulating the receptor, which is important for memory consolidation and flexibility
• influences brain development
  • controls proliferation, differentiation and growth of neurites²²⁹
• responsible for memory consolidation
• increases GABA receptors in the hippocampus
• Insulin deficiency leads to diabetic neurological complications in the elderly and children
• Insulin activated phosphatidylinositol (PI)-3 kinase, which increases the externalization of DAT on the membrane surface. Chronic hypoinsulinemia, such as in diabetes, appears to reduce the available DAT on the cell surface.²³⁰ This increases extracellular dopamine and, to our understanding, should decrease phasic dopamine as less dopamine enters the cell to be stored in vesicles and released in response to signals.

6.12. Premenstrual syndrome (PMS) / Premenstrual dysphoric disorder (PMDD) (+ 143 %)¶

A study of 290 women with severe PMD / PMDD found increased risks for:²³¹

• ADHD: 2.43-fold (+ 143 %)
• AuDSH: 3.27-fold (+ 227 %)

The risk for ASD without ADHD was unchanged.

6.13. Dystrophinopathy (muscular dystrophy, muscle weakness) (+ 130 %)¶

See under Monogenetic causes of ADHD.

6.14. Atopic disorders (excess immunoglobulin E)¶

Atopy is a hereditary predisposition to react hypersensitively (allergically) to environmental substances that are actually harmless.

In low birth weight infants, a history of T2 inflammatory diseases such as asthma and atopic dermatitis increased the risk of:²³²

• 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 ASDHD symptoms.²³³

6.14.1. Respiratory allergies (+ 83 % to 108 %)¶

For the percentages in the headline, the lowest and highest results were omitted due to the sufficient number of studies.

Children with a respiratory allergy showed an ADHD prevalence of 12.16% vs. 7.63% of children without one. After adjustment for covariates, the risk increase was +50%.²³⁴

Allergic rhinitis increased the risk of ADHD

• by a factor of 3.96 (+ 296 %, OR 3.96). (METASTUDY, k = 2, n = 132,561)²³⁵
• by a factor of 2.08 (+ 108 %)²³⁶
• by a factor of 1.83 (+ 83 %; meta-analysis, k = 18, n = 4,289,444)²³⁷
  • 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 %)

ADHD increased the risk of allergic rhinitis

• correlatively by 1.85-fold (+ 85 %, OR 1.84) (meta-analysis, k = 10, n = 397,799)²³⁵
• correlative by 1.38-fold across all studies (+ 38 %; METASTUDY, k = 18, n = 4,289,444)²³⁷
  • Women compared to men by a further + 86 % (meta-analysis, k = 18, n = 4,289,444)²³⁷
  • Children up to 8 years compared to older children by a further + 75 % (meta-analysis, k = 18, n = 4,289,444)²³⁷
  • correlative by 1.90-fold in cohort study (+ 90 %; meta-analysis, k = 18, n = 4,289,444)²³⁷
• causally by 1.27-fold (+ 27 %) in a genetic association study²³⁸

• Allergic rhinitis was found in children with ADHD (6 to 12 years) at¹⁷⁴
  • 26.6 % of those with sleep disorders
  • 13.8 % of those without sleep disorders

A review (k = 21 meta-analyses, n = 348,405,029) found with highly suggestive evidence (class II) that allergic rhinitis (hay fever) increased the risk:²³⁹
- for tic disorders by 161 % (OR 2.61)
- for sleep disorders by 171 % (OR 2.17)

6.14.2. Food allergies (+ 72 %)¶

A food intolerance is a reaction of the digestive system, whereas a food allergy is a reaction of the immune system.
Food allergies belong to the atopic group.²⁴⁰

Children with a food allergy showed an ADHD prevalence of 12.66% vs. 7.99% of children without one. After adjustment for covariates, the risk increase was +72%.²³⁴

Food allergies appear to mediate behavioral abnormalities possibly via the microbiota-gut-brain axis (MGBA) and there via gut microbiota and amino acid metabolites.²⁴¹ People with food allergies show different microbiome profiles compared to non-affected individuals. Microbial interventions can support the restoration of the gut microbiome structure, e.g:²⁴²

• Nutrition
• Probiotics (living microorganisms such as bacteria and yeasts)
• Prebiotics (indigestible dietary fiber)
• Synbiotics (combination of probiotic and prebiotic)
• Fecal transplantation²⁴³²⁴⁴

6.14.3. Atopic eczema (+ 72 %)¶

Eczema increased the risk of ADHD 1.72-fold (+72%).²³⁶

6.14.4. Skin allergies (+ 65 %)¶

Children with a skin allergy showed an ADHD prevalence of 11.46% vs. 7.83% of children without one. After adjustment for covariates, the risk increase was +65%.²³⁴

6.14.5. Asthma (+ 34 % to + 62 %)¶

While respiratory allergies affect the upper airways, allergic asthma affects the lungs.

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).²³⁹
With highly suggestive evidence (class II), asthma increased the risk of

• Depression by 64 % (OR 1.64)
• Anxiety by 95 % (OR 1.95)
• Tic disorders by 90 % (OR 1.90),
• Suicidal thoughts by 52 % (OR 1.52)
• Suicide attempts by 60 % (OR 1.60)

• Asthma was found in children with ADHD (6 to 12 years) at¹⁷⁴
  • 10.7 % of those with sleep disorders
  • 5.3 % of those without sleep disorders

A large study found an association between ADHD and asthma in children of +79% before and +62% after adjustment for all covariates. ADHD causally increased the risk of asthma in children by 27%.²⁴⁵
Children with bronchial asthma are more likely to have ADHD (SMD 0.29. Meta-analysis, k = 7, n = 104,975).²⁴⁶

A genetic association study found no causal risk increase for ADHD due to asthma²³⁸

6.14.6. Neurodermatitis / atopic dermatitis (+ 11.6 % to + 28 %)¶

The highest and lowest values were disregarded when determining the figures in the headline.

Neurodermatitis / atopic eczema / atopic dermatitis in childhood correlates with an increased risk of ADHD.²⁴⁷

A review (k = 21 meta-analyses, n = 348,405,029) found an increase in risk in atopic dermatitis with highly suggestive evidence (class II)²³⁹

• 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)

A study in Saudi Arabia of people with ADHD found an ADHD prevalence of 20.9% in children and 18.9% in adults. Atopic dermatitis did not correlate with the severity of ADHD symptoms.²⁴⁸

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 %) increased the risk of atopic dermatitis. Only the causal relationship between AD and ASD was independent of the bias due to the inverse effect.²⁴⁹
With urticaria, the risk of ADHD increased by 9%²⁵⁰

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)²⁵¹

In contrast, a cohort study found no significant (+2%) increased risk of ADHD in childhood atopic dermatitis.²⁵²
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.²⁵³

6.15. Hyperthyroidism / hyperthyroidism (+ 70 %)¶

One study found a 1.7-fold prevalence of ADHD in children with hyperthyroidism.²⁵⁴
Children with ADHD showed

• significantly higher T4 levels (total thyroxine).²⁵⁵
• significantly reduced FT4 levels (free thyroxine) and TT3 levels (total triiodothyronine) (meta-analysis, k = 12, n = 11,836)²⁵⁶, 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.²⁵⁷

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.²⁵⁸²⁵⁹

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 levels.²⁶⁰

One cause of hyperthyroidism is Grave’s desease. The prevalence of Grave’s disease in the USA in 1972 was stated to be between 0.02 % and 0.4 %, of which 5 % was in children.²⁶¹ Today, in countries with an adequate iodine supply, the prevalence is assumed to be 2% to 3% in women and 0.2% in men. Most cases occur between the ages of 30 and 60. Others report the highest incidence occurs between the ages of 11 and 15.²⁶²
There is evidence for an increased risk of ADHD in Graves’ disease.^263264265 One small study reported a doubled prevalence of ADHD. One practice reports hyperactivity in 85% of the children with ADHD (n = 21), which subsided in 20 after treatment of the hyperthyroidism.²⁶⁶²⁶¹

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

6.16. Nutrition and food intolerances¶

6.16.1. 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)²⁶⁷ 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.²⁶⁸
In an Egyptian study, a child’s daily consumption of sweets correlated with a 6.82-fold risk of ADHD (+ 582%).²⁶⁹ Whether this is a causal cause or a consequence of changed food preferences due to the predisposition to the disorder remains to be seen.

6.16.2. 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).²⁷⁰

6.16.3. Commercially packaged pasta¶

Childhood consumption of commercially packaged pasta 3 or more times per week correlated with a 57-fold risk of ADHD.²⁶⁹
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.

6.16.4. Unpackaged flour¶

The use of unpackaged flour in cooking correlated with a 44-fold risk of ADHD in an Egyptian study.²⁶⁹

6.16.5. Food intolerances¶

A food intolerance is a reaction of the digestive system, whereas a food allergy is a reaction of the immune system.

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.²⁷¹²⁷² The same was found in people with ADHD and non-affective psychosis.²⁷³

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 symptoms²⁷⁴

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.²³⁹

More information at ⇒ Nutrition and diet for ADHD.

6.17. 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%.²⁷⁵

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

Anesthesia in childhood correlates with an increased risk of ADHD²⁷⁶
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.²⁷⁷ 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.²⁷⁸
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 anesthetics²⁷⁹
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.²⁸⁰
Other studies have come to similar conclusions.²⁸¹²⁸²
A meta-analysis found a 25% increase in the later risk of ADHD due to general anesthesia in childhood (RR = 1.26).²⁸³

• 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.²⁸⁴

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 changes²⁸⁵

6.19. 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.²⁸⁶.

6.20. Inflammatory bowel disease (IBD) (+ 20 %)¶

Inflammatory bowel disease (IBD) correlates with an increased risk of ADHD and an increased intake of stimulants.²⁸⁷
People with an onset of IBD in childhood showed an increased risk of²⁸⁸

• 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%).²⁸⁹

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).²⁹⁰

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.²⁹¹

6.21. 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.²⁹²

6.22. 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.²⁹³
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.

6.23. Acne vulgaris¶

One study found moderately elevated levels in adolescents (12 to 17 years) with acne vulgaris for²⁹⁴

• 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.

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

See under Gut-brain axis

6.25. 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.²⁹⁵
Adolescents with PCOs also showed an increased risk of ADHD.²⁹⁶

6.26. 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.²⁹⁷

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

Glucose-6-phosphate dehydrogenase (G6PD) deficiency increased the risk of ADHD by 16%²⁹⁸

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.

6.28. Lipodystrophy (lack of fatty tissue)¶

One study found evidence of a greatly increased prevalence of ADHD in lipodystrophy.²⁹⁹

6.29. 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.

6.30. Gender diversity¶

A multinational study found evidence that the frequency and severity of ADHD symptoms was particularly high in gender-diverse individuals.³⁰⁰

6.31. Mitochondrial disorder¶

Mitochondrial dysfunction or mitochondrial disorders are being discussed as a possible cause of ADHD.^301302303 So far, no concrete findings have emerged.

6.32. Diaphragmatic hernia¶

Among children with a congenital gap in the diaphragm (diaphragmatic hernia), 26.3%³⁰⁴ to 39%³⁰⁵ of survivors were found to have problems with sustained attention. 51.9% had a formal diagnosis of ADHD, specific learning disability or developmental disability.³⁰⁴
If there is a hole in the peritoneum, organs from the abdominal cavity can penetrate into the lung area and impede lung development and breathing.
The mediation pathway for ADHD is therefore hypoxia.

6.33. Factors without risk increase for ADHD¶

• The prevalence of microcytic anemia was found to be 14% lower in children with ADHD (OR: 0.86)³⁰⁶
• Growing up bilingual did not increase the risk of ADHD³⁰⁷
• Autoimmune diseases showed no evidence of causality of autoimmune diseases for ADHD. The study examined²²⁸
  • Lupus erythematosus
    • in contrast, a retrospective matched cohort study (n = 11,144) found that a lupus diagnosis after 15 years or later correlated with a 61% higher probability of psychiatric disorders and psychiatric disorders correlated with a 120% increased risk of lupus after 10 years or later. A lupus diagnosis correlated with an increased prescription of ADHD medications 10 years earlier.³⁰⁸
  • 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.³⁰⁹ 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-19.³¹⁰
• 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.³¹¹
• Obesity
  • adjusted, there was no significant causal influence of obesity on ADHD³¹²
• Platinum- and taxane-based chemotherapy in children³¹³

6.34. Factors with risk reduction for ADHD¶

• Immigrant status of parents causes a reduced risk of ADHD³¹⁴ within the first 2 generations.³¹⁵
• Lyme disease correlated with a 10% reduction in ADHD prevalence³¹⁶