1. Prenatal stressors as ADHD environmental causes.

Even before birth, the unborn child can be damaged by toxic influences from the mother.
Maternal stress during pregnancy increases the child’s ADHD risk by 72%.¹

Children with ADHD were more likely to have mothers who had health conditions during pregnancy:²

• Maternal diseases during pregnancy:
  In 34.4% of children with ADHD, the mother had a condition during pregnancy, compared with 14.4% of unaffected children.
  • Children with ADHD: 34.7
    Diseases of the mother in pregnancy were in the following trimester:
    • 1st/2nd trimester only: 56.4 %
    • 3rd trimester only: 12.7 %
    • Total pregnancy: 30.9
  • Non-affected children: 14.4 %
    Diseases of the mother in pregnancy were in the following trimester:
    • 1st/2nd trimester only: 0%
    • 3rd trimester only: 33.3 %
    • Total pregnancy: 66.7
• Other pregnancy problems:
  • Children with ADHD: 14.5
  • Non-affected children: 3.8 %

Basically, psychological stress and physical stress (toxins, diseases) have a comparable effect on the stress systems (HPA axis, autonomic nervous system and others).
In addition, toxins can affect the dopaminergic system of the offspring even before conception. See here ⇒ Excursus: father’s nicotine use before conception: epigenetic inheritance of nicotine damage.

While the following collection is extensive, quite a few other circumstances are likely to be associated with an increased risk of ADHD.

• 1.1. Toxins before pregnancy as risks for ADHD
• 1.2. Toxins during pregnancy as risks for ADHD
  • 1.2.1. Mother’s nicotine consumption during pregnancy (+ 90 to 170%)
    • 1.2.1.1. Excursus: nicotine use by a parent before conception: epigenetic inheritance of nicotine damage
  • 1.2.2. Mother’s drug use during pregnancy (+ 200%)
  • 1.2.3. Alcohol during pregnancy
  • 1.2.4. High salt consumption during pregnancy
  • 1.2.5. Lead disposition during pregnancy
  • 1.2.6. Cadmium during pregnancy (+ 22 % only in girls)
  • 1.2.7. Thallium during pregnancy
  • 1.2.8. Pesticides during pregnancy
    • 1.2.8.1. Organochlorine compounds contact during pregnancy
    • 1.2.8.2. Organophosphate contact during pregnancy
    • 1.2.8.3. Pyrethroid contact before or during pregnancy
  • 1.2.9. Bisphenols in pregnancy
  • 1.2.10. Phthalates in pregnancy
  • 1.2.11. Perfluoroalkyl compounds (PFAS) in pregnancy
  • 1.2.12. Polychlorinated biphenyls / polychlorinated biphenyl ethers (up to + 23 %)
  • 1.2.13. Polycyclic aromatic hydrocarbons (PAH, PAH) (+ 99 to 157 %)
  • 1.2.14. Air pollution during pregnancy
    • 1.2.14.1. Fine dust
    • 1.2.14.2. Nitrogen oxides
    • 1.2.14.3. Ozone
  • 1.2.15. Insatiable nausea (hyperemesis gravidarum)
  • 1.2.16. Dioxin exposure during pregnancy
• 1.3. Maternal medications during pregnancy as an ADHD risk
  • 1.3.1. Cortisol in pregnancy
  • 1.3.2. β-2-Adrenaline receptor agonists in pregnancy (+30%)
  • 1.3.3. Paracetamol (acetaminophen) in pregnancy (+ 37 to 250%)
  • 1.3.4. SSRIs, antidepressants in pregnancy
  • 1.3.5. Valproic acid in pregnancy
  • 1.3.6. Valproate in pregnancy (+ 12 %)
  • 1.3.7. Antibiotics in pregnancy (+ 14 %)
  • 1.3.8. No increase in risk with NSAIDs, normal caffeine consumption, benzodiazepines
• 1.4. Psychological stress of the mother during pregnancy
• 1.5. Severe maternal obesity before or during pregnancy (+14 to 280%)
• 1.6. Pre-eclampsia (gestosis) in pregnancy (+ 30 to 188 %)
• 1.7. Mineral and vitamin deficiency during pregnancy
• 1.8. Unhealthy diet of the mother during pregnancy (+ 60 %)
• 1.9. Maternal fever during pregnancy (+31 to 164%)
• 1.10. Anemia (anemia) of the mother during pregnancy (+ 31 %)
• 1.11. Parents’ asthma in and out of pregnancy (+ 13 to 41%)
• 1.12. Diabetes of one parent (+ 40 %)
• 1.13. Depression of the mother during pregnancy
• 1.14. Increased or decreased thyroxine levels in the mother
  • 1.14.1. Decreased and increased neonatal TSH levels (+14% in boys to +310% in girls)
• 1.15. Infections of the mother during pregnancy
  • 1.15.1. Infections in general (+ 30 %)
  • 1.15.2. Viral infections
• 1.16. First born status
• 1.17. Particularly short or long intervals from the previous pregnancy (+ 25 to 30 %)
• 1.18. Maternal exposure to non-ionizing magnetic field radiation during pregnancy (+100%)
• 1.19. Polycystic ovary syndrome (PCOS) in pregnancy (+ 31 to + 95% in boys)
• 1.20. Hypertension during pregnancy
• 1.21. Decreased C-reactive protein (CRP) (+ 92 %)
• 1.22. Systemic lupus erythematosus (SLE) (+ 60 %)
• 1.23. Less than 8 hours of sleep in the 3rd trimester of pregnancy
• 1.24. Testosterone in pregnancy
• 1.25. Pregnancy circumstances without influence on ADHD

1.1. Toxins before pregnancy as risks for ADHD¶

Children whose fathers smoked before pregnancy had a 3.59-fold risk of ADHD compared with children whose fathers never smoked.
Children of parents exposed to smoking or secondhand smoke before pregnancy had 2.96 times the risk of A(D)HS.
Children whose parents had smoked both before and during pregnancy had a 3.01-fold risk of ADHD.³

1.2. Toxins during pregnancy as risks for ADHD¶

Toxic effects to unborn children have been demonstrated for:

1.2.1. Mother’s nicotine consumption during pregnancy (+ 90 to 170%)¶

Prenatal smoking causes a 1.9-fold ADHD risk (increased by 90%)⁴ to 2.7-fold ADHD risk (increased by 170%)⁵ for the offspring. Other studies also found significantly increased risk scores.⁶⁷⁸⁹

Children with ADHD were more likely to have mothers who had smoked during pregnancy:

• 3.21 times²¹⁰
• 1.72 times¹¹

Only two studies (with overlapping authors) and one meta-study reached a different conclusion.^{1213 14} , one study found rather weak evidence.¹⁵

Most experiments with prenatal nicotine exposure show a decrease in dopamine levels in the PFC and striatum. Under certain circumstances, increased dopamine levels were also shown.¹⁶ ADHD is neurophysiologically closely associated with decreased dopamine levels in the dlPFC (impaired working memory) and striatum (impaired motivation and motor control = hyperactivity).
To be distinguished from this is smoking by sufferers - this increases dopamine levels (at least in the striatum) because it reduces DAT, which is too pronounced in ADHD and reduces dopamine levels in the striatum. Acute smoking thus increases dopamine levels in the striatum.

Prenatal smoking in combination with certain gene polymorphisms increases the probability of ADHD more than when these genetic risks are not present:

• If there are no genetic risks, smoking by the mother during pregnancy increases the ADHD risk for the child by 20 to 30%.
• The risk genes alone (if the mother does not smoke during pregnancy) increase the risk by 20% to 40%.
• However, if risk genes and maternal smoking coincide during pregnancy, the child’s risk of ADHD increases many times over:
  • DAT1-9R (440 bp): by 2.6 times
  • DRD4-7R by 2.9 times
  • Both together by a factor of 9.¹⁷¹⁸
    Another study confirms the involvement of DRD4-7R in gene-environment interactions.¹⁹
• Smoking by the mother during pregnancy increased the risk of hyperactivity/impulsivity symptoms in the child by 50%.²⁰ Passive smoking already increased this risk by almost 50%, but only for boys.

Maternal smoking during pregnancy alters glutamate NMDA receptors in the laterodorsal tegmentum of the offspring.²¹ Another study also found changes in glutamatergic signaling in the hippocampus due to increased glutamate receptor expression,²² which was associated with learning problems, attention problems, and increased impulsivity.
ProBDNF proteolysis is impaired by an imbalance between proBDNF and BDNF and downregulation of the proBDNF processing enzyme furin. Glucocorticoid receptor activity is altered by decreased relative nuclear GR localization. Basal plasma corticosterone levels are decreased. The HPA axis is impaired. This affects the offspring themselves, but also their children, so it is inherited.²³

In rodents, prenatal nicotine exposure has been found to decrease dopamine levels in the offspring mPFC.²⁴ In ADHD, dopamine levels in the PFC are decreased.

A study of mice whose mothers were exposed to nicotine during pregnancy found evidence that nicotine causes several consequences during pregnancy that persisted in the grandchild generation, suggesting epigenetic heritability:²⁵

• Deficits in the expression of corticostriatal DNA methyltransferase 3A (DNMT3A)
• Downregulation of methyl CpG-binding protein 2 (MeCP2) in frontal cortices and hippocampus
• Downregulation of histone deacetylase 2 (HDAC2) in frontal cortices and hippocampus
• Abnormalities in HDAC2 (Ser394) phosphorylation in frontal cortices, striatum, and hippocampus
• No change in ten-eleven translocase methylcytosine dioxygenase 2 (TET2) expression
• No abnormalities in MeCP2 (Ser421) phosphorylation in frontal cortices, striatum, and hippocampus

Maternal smoking increases fetal testosterone levels.²⁶ Elevated prenatal testosterone levels are a risk factor for ADHD. See more at Sex differences in ADHD.

Even passive smoking, that is, passive exposure of the mother to nicotine smoke during pregnancy, tends to increase the unborn’s risks for ADHD symptoms later in life.²⁰
Similar results were found for the causation of dyspraxia (Developmental Coordination Disorder) by secondhand smoke.²⁷

Over 70 million women in the EU smoke during pregnancy.²²

It is possible that the effects of maternal nicotine use during pregnancy could be offset by breastfeeding.²⁸

1.2.1.1. Excursus: nicotine use by a parent before conception: epigenetic inheritance of nicotine damage¶

1.2.2. Mother’s drug use during pregnancy (+ 200%)¶

Children who were prenatally exposed to multiple drug use by their mothers and who subsequently grew up in residential care were found to have a 3-fold risk of ADHD between the ages of 17 and 22.³⁴

Cannabis use during pregnancy has been associated by several studies with an increased risk of ADHD in children.³⁵

1.2.3. Alcohol during pregnancy¶

Alcohol consumption by the mother during pregnancy significantly increases the ADHD probability of the children, according to various studies,³⁶³⁷ as well as attention problems.³⁸ A large long-term cohort study and another study found no association.³⁹⁴⁰
A combination of alcohol and maternal stress during pregnancy increased the likelihood of developing female(r) sexual behavior in male rats.⁴¹

A metastudy found that maternal alcohol consumption of less than 70 g/week during pregnancy did not increase ADHD risk.⁴² Boys were less at risk than girls from alcohol during pregnancy.

A cohort study found no association between alcohol consumption (binge drinking: 1 to 3 binge drinking events; moderate drinking: 1 to 3 or more alcoholic drinks per week) in early pregnancy and ADHD risk in children aged 5 to 19 years.⁴³

One study found a correlation between ethoxyacetic acid (one of 6 degradation products of alcohol studied) in the mother’s urine and inhibition problems in the children.⁴⁴

There is evidence that alcohol consumption by the mother during pregnancy or while breastfeeding has significant effects on the child’s dopamine system.^45464748 Likewise, the regulation of the neurotransmitters serotonin , glutamate, norepinephrine, acetylcholine and histamine is affected^{4950 51}

1.2.4. High salt consumption during pregnancy¶

High dietary salt intake during pregnancy could increase the stress sensitivity of the unborn baby.⁵²

1.2.5. Lead disposition during pregnancy¶

Lead disposition during pregnancy^{5354 55} affects mesocorticolimbic circulation and increases ADHD risk in the offspring.⁵⁶
Rat mothers were exposed to acute stress and lead during pregnancy. The effect on the offspring differed between lead exposure alone or lead exposure plus stress exposure. Male rat offspring showed increased corticosterone levels and decreased dopamine levels in the PFC only with lead exposure alone, and female rat offspring only with combined lead and stress exposure. Even short-term exposure of dams to lead caused this effect.⁵⁷ In female rat pups, maternal lead exposure and stress contributed to learning difficulties as cumulative factors during pregnancy. These were neurophysiologically mediated through the glucocorticoid system to the mesocorticolimbic system.⁵⁸

Further studies also found evidence that lead exposure, like stress during pregnancy, affects the mesocorticolimbic dopamine/glutamate system of female offspring (less so in males) and mutually increases their effects.⁵⁹ Male rat offspring showed a tendency to serotonergic disturbances of the mesocorticolimbic system and altered delay discounting under similar conditions.⁶⁰
Even a lead content in drinking water below the limit values is said to be problematic.⁵⁴
In principle, lead water pipes are not very dangerous in areas with calcareous water, as lime forms a reliably protective layer in the pipes. However, no decalcification system for the drinking water may then be installed. Nevertheless, it is generally recommended to replace lead-containing water pipes during modernization projects.

It is possible that metabolism is altered in ADHD with respect to cobalt, copper, lead, zinc, and vanadium. Reduced cycle stability (determinism), duration (mean diagonal length), and complexity (entropy) of exposure profiles have been noted.⁶¹

Lead is a divalent cation that mimics Ca2+ and activates PKC signaling.⁶²

Arnsten⁶³ describes lead as a toxin that causes symptoms confusable with ADHD.

Lead appears to have quite a few deleterious neurophysiological effects, including effects on the dopaminergic system:

• Impairment of the mesocorticolimbic dopaminergic system⁶⁴
• Impairment of dopamine receptors⁶⁴
• Impairments of attentional regulation in the PFC⁶⁵
• Apoptosis⁶⁶
• Excitotoxicity⁶⁶
• Decreased cellular energy metabolism⁶⁶
• Impaired heme biosynthesis and anemia⁶⁶
• Oxidative stress⁶⁶
• Lipid peroxidation⁶⁶
• Changed activity of the Second Messenger system⁶⁶
• Altered neurotransmitter release⁶⁶
• Altered neurotransmitter receptor density⁶⁶
• Impaired neuropsychological functioning⁶⁶
• Impaired development and function of oligodendrocytes⁶⁶
• Abnormal myelin formation⁶⁶
• Abnormal neurotrophic factor expression⁶⁶
• Abnormal dendritic branching patterns⁶⁶
• Disruption of the blood-brain barrier⁶⁶
• Disruption of thyroid hormone transport to the brain⁶⁶
• Altered regulation of gene transcription⁶⁶
• Reduction of gray matter in the PFC, especially in the ACC⁶⁷

Lead appears to further trigger the following behaviors:

• Impulsivity⁶⁵
• Sociopathic behavior⁶⁸⁶⁹
• Irresponsible behavior⁶⁸⁶⁹
• Criminal behavior⁶⁸⁶⁹
• Lower IQ⁶⁶
• Impaired academic performance⁶⁶

Lead poisoning is strongly correlated with crime rates and out-of-wedlock pregnancies in the United States.⁶⁸⁶⁹

Children with elevated blood lead levels are said to be particularly susceptible to other toxins in early childhood.⁷⁰ In particular, there have been warnings about lead in wall paint. During pregnancy, lead can be transferred from the mother to the child through the placenta.

1.2.6. Cadmium during pregnancy (+ 22 % only in girls)¶

Camdium exposure during pregnancy increased ADHD risk for 6-year-old girls but not for boys. Doubled maternal exposure to cadmium during pregnancy increased the ADHD risk for girls by 22.3%.⁷¹

1.2.7. Thallium during pregnancy¶

High thallium exposure in the second trimester of pregnancy increased ADHD risk for 3-year-old boys but not for girls.⁷²

1.2.8. Pesticides during pregnancy¶

1.2.8.1. Organochlorine compounds contact during pregnancy¶

Organochlorine compounds (dichlorodiphenyltrichloroethanes (DDT), dieldrin, heptachlor, endosulfan) showed an effect on neuronal development in prenatal exposure, which (in rodents), e.g.:⁷³

• DAT increased
• Dopamine reuptake increased
• Loss of dopaminergic cells
• Presynaptic changes in major dopaminergic proteins in response to OC pesticides in striatum or substantia nigra
• Norepinephrine increased
• Serotonin increased
• GABA receptors reduced
• NMDA receptors reduced
• MGluR5 receptors altered
• Altered GABAergic, glutamatergic, and dopaminergic response to endosulfan in PFC
• Altered dopaminergic responses to heptachlor exposure identified

with impairments from, among others:

• Attention processes
• Cognitive performance
• Memory
• Social development
• Mental and psychomotor development
• Fine motor skills
• Reflexes
• Visual processing

Organochlorine compounds were nevertheless primarily associated with ASA.

1.2.8.2. Organophosphate contact during pregnancy¶

The organophosphates chlorpyrifos and diazinon showed significant effects on neonatal brain development, including the dopaminergic system.⁷⁴ Prenatal exposure to the common pesticide chlorpyrifos impaired IQ and working memory in children aged 7⁷⁵⁷⁶ and executive functions.⁷⁷

Organophosphates inhibit acetylcholinesterase (= the enzyme that breaks down acetylcholine).⁷³ The organophosphate diisopropyl fluorophosphate (DFP) has been reported to increase dopamine and GABA receptors in addition to the known downregulation of cholinergic receptors. A single administration of 1 mg/kg DFP caused increased dopamine levels, and a single toxic dose of 2 mg/kg DFP caused increased dopamine depletion. Levels returned to normal after 6 hours. Chronic administration of 1 mg/kg DFP caused decreased dopamine levels after 1 and 2 weeks, which returned to normal with continued administration. A single administration of DFP increased dopamine turnover in the striatum of rats, whereas chronic administration decreased it. The authors suggested that the changes in dopamine and GABA may be consequences of downregulation of cholinergic receptors.⁷⁸

Chlorpyrifos interferes with the serotonin system. Contact during pregnancy may cause tremor in children and impair cognitive and neurobehavioral development.⁴¹

Measurement using prenatal urinary dialkyl phosphate metabolites (diethyl phosphate and dimethyl phosphate) and analysis of maternal PON1 gene variants Q192R and L55M found no association between maternal organophosphate contact during pregnancy and subsequent ADHD in the child.⁷⁹

A Norwegian cohort study found an increased ADHD risk of the offspring when detected in the mother’s blood during pregnancy of:⁸⁰

• Di-n-butyl phosphate (DnBP)
• Bis(1,3-dichloro-2-propyl) phosphate (BDCIPP)
• Bis(2-butoxyethyl) phosphate (BBOEP)
  • only in boys. In girls, reduced risk with increasing load.

Another Norwegian registry study found no evidence of increased ADHD risk in the offspring when the mother was exposed to organophosphates at 17 weeks’ gestation.⁸¹

1.2.8.3. Pyrethroid contact before or during pregnancy¶

Pyrethroids are widely used as insecticides and pesticides.

Each doubling of the pyrethroid metabolite 3-phenoxybenzoic acid (3-PBA) in the mother’s urine at 28 weeks’ gestation increased the risk of ADHD in the offspring by 3%, as well as the risk that an onset of ADHD was among the 10% most severe ADHD cases by 13%.⁸²

The pyrethroid deltamethrin apparently impairs the dopaminergic system in mice when exposed early:⁸³

• DAT reduced
• D1 receptor decreased
• Apoptosis

Further, permanent behavioral changes resulted (with prenatal but not with postnatal exposure)⁸⁴ in terms of:⁸³

• Movement activity
• Acoustic startle reflex
• Learning
• Memory

3-PBA and chlorpyrifos enhance each other’s effect on ADHD.⁸²

Each urinary measurement of trans-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane-1-carboxylic acid (trans-DCCA), a metabolite of permethrin, cypermethrin, and cyfluthri (trans-isomers of pyrethroids), increased the risk of offspring ADHD by 76%.⁸²

1.2.9. Bisphenols in pregnancy¶

Bisphenol-A (BPA) is a glucocorticoid receptor agonist and has been associated with alterations in HPA axis response. In female rats, prenatal BPA correlated with increased basal corticosterone levels as well as decreased glucocorticoid receptor expression in the hypothalamus. To stress, these female rats showed anxious coping behavior and a muted corticosterone response with a lack of downregulation of glucocorticoid receptor expression in the hypothalamus. In contrast, BPA-exposed male rats showed no altered basal HPA axis function but failed to upregulate CRH-1 receptor expression in the pituitary in response to acute stress.⁴¹ The dose given to rat mothers during pregnancy and suckling was very low at 40 micrograms/kg/day.⁸⁵
5 milligrams / cubic meter in the breath cause eye irritation.⁸⁶ A review confirmed circumstantial evidence that bishenol-A in pregnancy may increase the ADHD risk of children, especially boys,⁸⁷

BPA and BPS caused greatly increased dopamine (3- to 5-fold) and greatly decreased serotonin (by 80%) in mouse placentas. GABA remained unchanged.⁸⁸ BPA is an endocrine disruptor and mimics estrogenic activity. Thus, BPA affects various dopaminergic processes to increase mesolimbic dopamine activity, resulting in hyperactivity, attention deficits, and increased susceptibility to drug abuse.⁸⁹

1.2.10. Phthalates in pregnancy¶

Phthalic acid esters are said to increase the risk of ADHD for the unborn according to most studies,⁹⁰ although the connections are unclear so far.⁹¹⁸⁷ An influence on thyroid balance is discussed.⁹² Higher phthalate metabolites in the urine of pregnant women correlated with increased distractibility in preschool-aged children.⁹³

1.2.11. Perfluoroalkyl compounds (PFAS) in pregnancy¶

1.2.12. Polychlorinated biphenyls / polychlorinated biphenyl ethers (up to + 23 %)¶

A long-term study found no correlation between perflouralkyl exposure during pregnancy and ADHD. Weak correlations - positive and negative - were found with working memory functions in childhood.⁹⁴ A metastudy also found no significant correlation between maternal PFAS exposure and prevalence rates of early childhood ADHD. Nevertheless, the odds ratios were partially elevated:⁹⁵

• Perfluorooctanoic acid (PFOA): 1.00
• Perfluorooctane sulfonate (PFOS): 1.01
• Perfluorohexane sulfonate (PFHxS): 1.08
• Perfluorononanoic acid (PFNA): 1.13
• Perfluorodecanoic acid (PFDA): 1.23

PFOS concentration in children’s blood and PFNA concentration in mothers’ blood correlated with the prevalence of early childhood ADHD.

Another study found a correlation of perfluorooctanoic acid (PFOA) and AD(H)DS, but not perfluorooctane sulfonate (PFOS) with ADHD or ASD.⁹⁶

Polychlorinated biphenyls inhibit dopamine synthesis as well as the storage of dopamine in the vesicles and its release, thus causing a too low dopamine level. Polychlorinated biphenyls induced hyperactivity and impulsivity (in rats even at subtoxic doses).⁹⁷ Polychlorinated biphenyls may act directly on dopaminergic processes to disrupt the dopamine system and produce Parkinson-like symptoms.⁸⁹ Other studies also found dopamine-reducing effects of PFAs.⁹⁸⁹⁹ as well as influences on acetylcholine, serotonin and glutamate neurotransmitter balance.¹⁰⁰

1.2.13. Polycyclic aromatic hydrocarbons (PAH, PAH) (+ 99 to 157 %)¶

Prenatal exposure to polycyclic aromatic hydrocarbons appears to increase damage from early childhood stress exposure and promote later attention and memory problems.¹⁰¹ One meta-study found that 4 studies by one author indicated a 1.57-fold increase in the risk of ADHD from PAHs (OR 2.57), while the total number of all studies indicated a doubled risk (OR 1.99), but this was not significant.¹⁰² Another study also showed an association between PAHs and ADHD¹⁰³

1.2.14. Air pollution during pregnancy¶

One study found changes related to the immune system of offspring due to air pollution.¹⁰⁴
A study of approximately 43,000 families in Shenzen found positive correlations of ADHD beginning at age 3 with exposure during pregnancy to¹⁰⁵

• Cooking fumes
• Tobacco smoke
• Steaming from house renovations
• Mosquito coils (burnt mosquito pyramids; especially in combination with incense smoke)
• Incense smoke (especially in combination with mosquito repellent smoke)

Another study found no increase in risk from air pollution in relation to ADHD.¹⁰⁶

A meta-analysis found that more studies (not pregnancy-related) affirmed an association between air pollution and ADHD than denied it.¹⁰⁷

1.2.14.1. Fine dust¶

A cohort study of 425,736 births on prenatal particulate matter exposure using satellite data found that a 10 μg/m3 increase in PM2.5 concentration during the first trimester increased ADHD risk by 26% and that this increased further at PM2.5 concentrations above 16 μg/m3.¹⁰⁸
Air pollution from particulate matter during pregnancy correlated with decreased corpus callosum volume and a tendency toward increased hyperactivity in one study.¹⁰⁹ Another study found a correlation between particulate matter and ADHD at low levels of particulate matter exposure, while higher exposure caused more severe brain damage.¹⁰³

In rats, inhaled printer particles resulted in 5-fold elevations in dopamine levels, although these likely resulted from increased synthesis rather than decreased degradation.¹¹⁰

Diesel exhaust particles caused functional impairment of dopamine neurons in laboratory experiments. Prenatal ingestion with the respiratory air caused in mice:¹¹¹

• In the striatum
  • Reduced dopamine turnover
  • Decreased levels of dopamine metabolites
• In the amygdala
  • Increased dopamine level
  • Elevated dopamine metabolite levels
• In the nucleus accumbens
  • Increased dopamine levels

Traffic ultrafine particulate matter in postnatal breath induced in female mice:¹¹¹

• In the hippocampus
  • Increased dopamine turnover

Prenatally and postnatally, particulate matter and gaseous pollutants in rodents decreased expression of oxytocin receptors in the hippocampus¹¹² and hypothalamus, with decreased maternal caregiving behavior.¹¹³ Oxytocin and vasopressin communication appear to be disrupted by endocrine-disrupting chemicals¹¹⁴, many of which are present in outdoor air.¹¹¹

1.2.14.2. Nitrogen oxides¶

A correlation was found for nitrogen oxides in pregnancy with ASD in children, but not with ADHD.¹¹⁵

1.2.14.3. Ozone¶

Ozone caused in rats:¹¹¹

• In the substantia nigra
  • Reduced number of dopamine neurons
• In the hippocampus
  • Decreased expression of the serotonin receptors 5-HT1A, 5-HT1B and 5-HT4
  • Increased expression of the serotonin receptor 5-HT2C
• In the hypothalamus
  • Decreased serotonin levels

1.2.15. Insatiable nausea (hyperemesis gravidarum)¶

Insatiable maternal emesis and vomiting during pregnancy increased offspring ASD(H)S risk by 16% (in 2 cohort studies) to 287%¹¹⁶

1.2.16. Dioxin exposure during pregnancy¶

Children exposed to dioxin during pregnancy have an increased risk of ADHD.¹¹⁷

1.3. Maternal medications during pregnancy as an ADHD risk¶

Children with ADHD were more likely to have mothers who took medication during pregnancy:²

Medication taken by the mother during pregnancy:

• ADHD: 43.5 %
  If stress/emotional problems occurred, they were in the following trimester:
  • 1st/2nd trimester only: 36.2 %
  • 3rd trimester only: 14.5 %
  • Total pregnancy: 49.3
• Non-affected: 31.4
  If stress/emotional problems occurred, they were in the following trimester:
  • 1st/2nd trimester only: 31.1 %
  • 3rd trimester only: 46.9%
  • Total pregnancy: 21.9

The following list is only exemplary and by no means complete.

1.3.1. Cortisol in pregnancy¶

Cortisol administration during pregnancy causes long-term changes in the brain of the unborn and increases the risk of ADHD.¹¹⁸ The children suffer a lifelong alteration of the dopaminergic system and the HPA axis, apparently caused by changes in the expression and ratio of MR and GR receptors.¹¹⁹ In our opinion, the ADHD symptoms described in these children could possibly be the result of HPA axis alteration.
⇒ Corticosteroid receptor hypothesis of depression

High cortisol exposure of the fetus or newborn may cause methylation of the GAD1 / GAD67 gene, which encodes the key glutamate-to-GABA-synthesizing glutamate decarboxylase 1 enzyme, leading to increased glutamate levels. This epigenetic mechanism may increase the ADHD risk of children.¹²⁰

Exposure to betamethasone during pregnancy only marginally increased the ADHD risk of the offspring.¹²¹

1.3.2. β-2-Adrenaline receptor agonists in pregnancy (+30%)¶

Taking β-2-adrenaline receptor agonists during pregnancy increases the risk of ADHD for the child by up to 30%.¹²²

1.3.3. Paracetamol (acetaminophen) in pregnancy (+ 37 to 250%)¶

Taking paracetamol (in North America and Iran: acetaminophen) during pregnancy increased the risk of ADHD by up to 37%. Even short-term use is harmful according to two very comprehensive studies with a combined total of over 110,000 participants.^123124125126 Critically, Gilman et al. While the previous studies were based on mothers’ intake reports, a study based on blood levels found a 2.3 to 3.5-fold ADHD risk and a 1.6 to 4.1-fold ASA risk in children when taken in the second or third trimester of pregnancy.¹²⁷¹²⁸

The ADHD risk from acetaminophen (paracetamol) increases when it is taken¹²⁹

• In the second trimester of pregnancy by 19%
• By 28 % in the first and second trimester
• In the first to third trimester by 20%

A cohort study of 116,000 children showed that fever in the first trimester of pregnancy increased ADHD risk by 31%, and multiple fevers by 164%. However, fever only increased inattention, not hyperactivity/impulsivity - this was also true for the second trimester. The results were independent of whether the mother was taking acetaminophen (paracetamol) or not.¹³⁰
A metastudy confirms increased ADHD and ASD risk in offspring when taking acetaminophen during pregnancy¹³¹

One study challenges the previous critical findings by focusing on parent ADHD diagnoses not previously considered.¹³² Also doubting Damkier.¹³³

A long-term study analyzed paracetamol, methionine, serine, glycine, and glutamate in umbilical cord plasma and found an increasing risk of ADHD with elevated paracetamol levels paralleling the increase in 8-hydroxy-deoxyguanosine levels in umbilical cord blood. Increases in cord blood levels of methionine, glycine, serine, and 8-hydroxy-deoxyguanosine correlated with a significantly higher likelihood of ADHD in childhood. Methionine and glycine mediated 22% each of the association between elevated paracetamol levels and later ADHD.¹³⁴

Ibuprofen, on the other hand, is not thought to trigger an ADHD risk for the unborn child.

1.3.4. SSRIs, antidepressants in pregnancy¶

SSRIs in pregnancy correlate with significantly increased infant mental disorders, according to a meta-analysis of 18 studies. It is not clear whether this results from the SSRIs or from the mother’s existing mental health problems for which she was treated with SSRIs.¹³⁵ Purely as a precaution, SSRIs should be used with extreme caution during pregnancy.
One meta-study found no increased risk of ADHD in children in 7 of 8 studies of SSRIs during pregnancy.¹³⁶ So did another study.¹³⁷ According to one study, antidepressants during pregnancy increased the likelihood of later ADHD in the child by 1.81 times.¹³⁸

1.3.5. Valproic acid in pregnancy¶

Offspring of mice that received valproic acid during pregnancy showed markedly increased hyperactivity and changes in the dentate gyrus.¹³⁹¹⁴⁰

1.3.6. Valproate in pregnancy (+ 12 %)¶

Valproate in pregnancy is thought to increase the risk of ADHD to the unborn child.¹⁴¹
Valproates are the salts of valproic acid.

When antiepileptic drugs were taken during pregnancy, a cohort study found an increased risk of neurodevelopmental disorders in children up to age 6 (which is too early to diagnose all ADHD sufferers):

• Sodium valproate together with other antipsychotics: 15%
• Sodium valproate as monotherapy: 12%
• Lamotrigine 6.3% (not a statistically significant increase due to the small number of participants in this group)
• Carbamazepine 2% (no significant increase)
• Children not exposed to any of these drugs during pregnancy: 1.8%

ASD was the most common diagnosis. 2% of children of medicated mothers received an ADHD diagnosis by age 6 years, 1.5% dyspraxia. Among controls, no child had an ADHD diagnosis.¹⁴²

1.3.7. Antibiotics in pregnancy (+ 14 %)¶

Several metastudies found a 14% increased ADHD risk from maternal antibiotic use during pregnancy.¹⁴³¹⁴⁴

1.3.8. No increase in risk with NSAIDs, normal caffeine consumption, benzodiazepines¶

A cohort study found no ADHD risk increase with nonsteroidal anti-inflammatory drugs (NSAIDs) in pregnancy.¹⁴⁵

Caffeine consumption during pregnancy below 10 cups per day did not increase ADHD risk.¹⁴⁶

Benzodiazepines in pregnancy appear to increase the risk for internalizing problems in children (anxiety, emotional reactivity, somatic complaints) but not externalizing problems (hyperactivity, aggressiveness).¹⁴⁷ A cohort study comparing siblings with and without maternal benzodiazepine use during pregnancy found no significant increase in risk for ADHD or ASD from benzodiazepines, The authors suggest more of a link to maternal genetic predisposition.¹⁴⁸ A meta-study also concluded that no relevant increase in ADHD risk of the offspring has been found for benzodiazepines in pregnancy so far, although one study gave evidence of a slight increase with benzodiazepine monotherapy in the last trimester of pregnancy.¹⁴⁹

This list about maternal medications during pregnancy as an ADHD risk is only exemplary and by no means complete.

1.4. Psychological stress of the mother during pregnancy¶

Maternal stress during pregnancy doubled the risk of ADHD in the children.¹⁵⁰
Prolonged and severe (fearful, perceived threatening = cortisol tolerant) stress significantly increases the risk for crying children¹⁵¹ (see also 2.2.2.3.2), anxiety disorders and ADHD.^152153154155
In this context, prolonged stress (here: financial problems) is more harmful than short-term stress (here: loss of a close person).¹⁵⁶
High anxiety/threat perceived stress at the same time significantly increases the risk for borderline in children.

Children with ADHD were more likely to have mothers who experienced stress or emotional problems during pregnancy:²

• Children with ADHD: 53.8
  If stress/emotional problems occurred, they were in the following trimester:
  • 1st/2nd trimester only: 36.0%
  • 3rd trimester only: 6.7 %
  • Total pregnancy: 57.3
• Non-affected children: 27.6 %
  If stress/emotional problems occurred, they were in the following trimester:
  • 1st/2nd trimester only: 28.6 %
  • 3rd trimester only: 24.9 %
  • Total pregnancy: 28.6

Hair cortisol levels of mothers and their children showed a transmission of psychological stress experiences from mothers to children.¹⁵⁷
One study found no increased psychiatric disorders at age 9 in children of women exposed to one month of repeated rocket fire on civilians during the 2006 Lebanon War.¹⁵⁸ It is possible that one month of repeated stress is not a sufficiently intense stressor.

The mother’s cortisol, which is released during fearful/threatening stress, is absorbed by the unborn and causes permanent damage to the HPA axis, which uses cortisol to regulate stress responses.¹⁵⁹¹⁶⁰

Severe maternal anxiety in pregnancy during weeks 12 to 22 after the last menstrual period significantly increases the risk for ADHD, whereas severe anxiety during weeks 32 to 40 does not increase the risk.¹⁶¹

Severe maternal anxiety during pregnancy increased the ADHD risk of the unborn child depending on its COMT (gene-environment interaction) gene variant.¹⁶²
In mothers with the ADGRL3 (latrophilin 3, LPHN3) gene variants (SNPs)

• rs6551665
• rs1947274
• rs6858066 or
• rs2345039

even minor stress during pregnancy caused a significantly increased risk of ADHD for the child.¹⁶³

Early prenatal stress increases levels of immune response genes, including the proinflammatory cytokines IL-6 and IL-1β, particularly in male placentas. Male infants exhibit stress-induced locomotor hyperactivity, a hallmark of dopaminergic dysregulation that was ameliorated by maternal treatment with nonsteroidal anti-inflammatory drugs. In addition, expression of dopamine D1 and D2 receptors was altered by early prenatal stress in male offspring.¹⁶⁴ The actuates the effect of early stress on the dopaminergic system.

High cortisol exposure of the fetus or newborn may cause methylation of the GAD1 / GAD67 gene, which encodes the key enzyme for glutamate-to-GABA synthesis, glutamate decarboxylase 1, and lead to increased glutamate levels. This epigenetic mechanism may increase ADHD risk in children.¹²⁰ Exposure to glucocorticoids during hippocampal development in pregnancy affects the starting point of the stress response through epigenetic changes via mRNA and methylation.¹⁶⁵ Another study reported that the increase in risk to the unborn for developmental disorders such as ADHD mediated by maternal psychological stress may be mediated by mRNA expression of glucocorticoid pathway genes in the placenta.¹⁶⁶
Another study also describes epigenetic changes in the unborn due to psychological stress of the mother during pregnancy.¹⁶⁷
One study found no significant increase in risk for mental disorders by 10 years of age from increased glucocorticoid exposure in the unborn.¹⁶⁸
Maternal exposure to a natural disaster during pregnancy increased ADHD risk.¹⁶⁹

1.5. Severe maternal obesity before or during pregnancy (+14 to 280%)¶

Massive maternal obesity during pregnancy increased the risk of later ADHD in the child by 2.8 times in one study.¹⁷⁵
Already an excessive BMI of the mother before pregnancy increased the ADHD risk of the later offspring.¹⁷⁶ A BMI of 25 to 30 increased the child’s ADHD risk by 14%, a BMI of 30 to 35 by 96% and a BMI of more than 35 by 82%.¹⁷⁷
Other variations in maternal weight before and at the end of pregnancy do not appear to affect ADHD risk.⁶
A Norwegian registry study found little evidence of an effect of parental BMI on the child’s ADHD risk, although here the mother’s pre-pregnancy BMI was the subject of investigation.¹⁷⁸ In contrast, another study found that maternal pre-pregnancy obesity increased maternal ADHD risk by 62%.¹⁷⁹

1.6. Pre-eclampsia (gestosis) in pregnancy (+ 30 to 188 %)¶

Problems in pregnancy that affect fetal oxygenation increase the risk of ADHD in the child by 30% to 188%.¹⁸⁰ One cohort study found a 43% increase in ADHD risk from gestational gestosis.¹⁸¹ Several reviews confirm an increased ADHD risk from preeclampsia in pregnancy.¹⁸²¹⁸³

1.7. Mineral and vitamin deficiency during pregnancy¶

A meta-study found evidence that higher omega-3 fatty acid levels in the newborn may reduce the risk and severity of ADHD as well as autism spectrum disorders. It is possible that an adequate supply of omega-3 fatty acid in the last trimester of pregnancy could counteract this.¹⁸⁶

Vitamin D3 deficiency during pregnancy and after birth causes brain maldevelopment,^{187188 189} which, however, is more likely to correlate with schizophrenia. One metastudy found little evidence of an association between prenatal vitamin D deficiency and autism spectrum disorders. Studies with larger sample sizes and more stringent definitions of vitamin D deficiency found positive associations for ADHD and schizophrenia.¹⁹⁰
A large long-term study in Spain of vitamin D3 deficiency in pregnancy found no correlation between low maternal blood D3 levels in pregnancy and ADHD in children aged 5 to 18 years.¹⁹¹
A study in Finland, on the other hand, found a clear correlation between reduced maternal D3 levels during pregnancy and ADHD in children. The risk increase reached up to more than 50 %.¹⁹²
We think it is plausible that the difference could result from the fact that sunlight intensity in Spain is high enough almost all year round to form D3, whereas in Germany, and even more so in more northerly countries, solar radiation intensity is too low during the winter months to mediate D3 formation.

More on this at ⇒ Vitamins, minerals, nutritional supplements for ADHD As well as ⇒ Nutrition and diet in ADHD in the chapter ⇒ Treatment and therapy.

1.8. Unhealthy diet of the mother during pregnancy (+ 60 %)¶

An unhealthy or a “Western” dietary intake by the mother during pregnancy increased the children’s likelihood of ADHD by more than 60%.¹⁹³
Since stress increases the preference for “convienient foods,” we believe that the correlation could possibly also be an indirect reflection of increased maternal stress during pregnancy, since stress alters food preferences toward rapidly digestible foods and convienient foods.

1.9. Maternal fever during pregnancy (+31 to 164%)¶

A cohort study of 114,000 children showed that fever in the first trimester of pregnancy increased ADHD risk by 31%, and multiple fevers by 164%. However, fever only increased inattention, not hyperactivity/impulsivity - this was also true for the second trimester. The results were independent of whether the mother was taking acetaminophen (paracetamol) or not.¹³⁰

1.10. Anemia (anemia) of the mother during pregnancy (+ 31 %)¶

A cohort study of 532,232 children over 23 years of age showed that maternal anemia in the first 30 weeks of pregnancy increased ADHD risk by 31%, whereas anemia in later weeks of pregnancy barely increased risk (by 1.4%). ¹⁹⁴

1.11. Parents’ asthma in and out of pregnancy (+ 13 to 41%)¶

A cohort study of 961,202 children showed a 41% increased risk of ADHD with maternal asthma and a 13% increased risk with paternal asthma. A maternal asthma episode during pregnancy increased ADHD risk by 21%, and an asthma episode after pregnancy increased ADHD risk by 25%.¹⁹⁵ Another study also found an increased ADHD risk in the offspring of mothers with asthma, especially for girls.¹⁹⁶

1.12. Diabetes of one parent (+ 40 %)¶

Maternal diabetes before or during pregnancy increases the offspring’s risk for ADHD and ASD.¹⁹⁷
A cohort study of more than 5 million people found an increased risk of ADHD in children if a parent had diabetes.¹⁹⁸
Diabetes mellitus or type 1 diabetes mellitus of the mother before pregnancy increased the ADHD risk of the children by 40%, type 1 diabetes mellitus of the father by 20%.
Another study found a 2.4-fold ADHD risk of children of mothers with diabetes mellitus and a 3.7-fold ADHD risk of male offspring of mothers with diabetes mellitus. No differences were found between gestational diabetes and diabetes elsewhere.¹⁹⁹
Children of non-insulin-treated severely obese mothers with type 2 diabetes were 2 times more likely to show psychiatric disorders than offspring of normal-weight mothers. Children of insulin-treated severely obese mothers with pregestational diabetes were 2.7 times more likely to show psychiatric disorders than offspring of normal-weight mothers.²⁰⁰

1.13. Depression of the mother during pregnancy¶

Especially in boys, the severity of maternal depression during pregnancy and higher maternal cyclothymic, irritable, and anxious temperament scores seem to be relevant risk factors for the development of ADHD.²⁰¹

1.14. Increased or decreased thyroxine levels in the mother¶

One study found a 7% increased risk of ADHD in children with untreated mild maternal thyroxine deficiency during early pregnancy.²⁰² In another study, decreased or untreated normal thyroxine levels in the mother showed no effect on ADHD in the children. In contrast, thyroxine treatment of the mother, especially with excessive thyroxine levels due to overdose, appears to increase the ADHD risk of the children.²⁰³ Another study also found evidence of thyroxine as a possible cause of ADHD,²⁰⁴ another study found no influence of the mother’s thyroxine levels during pregnancy.²⁰⁵

In male mice, one study found significantly reduced dopamine and serotonin turnover in the striatum, nucleus accumbens, hypothalamus, and hippocampus as a result of prenatal thyroxine deficiency.²⁰⁶ Dopamine deficiency in the striatum / nucleus accumbens is responsible for hyperactive symptoms in ADHD.

1.14.1. Decreased and increased neonatal TSH levels (+14% in boys to +310% in girls)¶

A cohort study from Norway found that newborns with TSH levels that were too low or too high had an increased risk of ADHD later in life, but only in girls. TSH levels in the lowest 20% group increased the ADHD risk of girls 3.1-fold, of boys only 14%.²⁰⁷
Another Norwegian cohort study found a 2.27-fold risk of ADHD for maternal thyroid hormone T3 levels at 17 weeks’ gestation within the top 1/5 versus the bottom 1/5. For free T4, increased as well as decreased levels were risk-increasing: the top 1/5 as well as the bottom 1/5 showed a 1.6-fold risk of ADHD in the offspring.²⁰⁸

1.15. Infections of the mother during pregnancy¶

1.15.1. Infections in general (+ 30 %)¶

One meta-study found a 30% increase in the risk of SADHD in the offspring due to infections in the mothers during pregnancy.²⁰⁹

1.15.2. Viral infections¶

Viral infection of the mother during pregnancy may affect the development of the dopaminergic system of the unborn child, e.g.:²¹⁰

• Measles
• Varicella
• Rubella
  • Also subclinical rubella infection of the mother in pregnancy increases risk of the child at age 8 to 9 years for:²¹¹
    • ASS
    • ADHD
    • Developmental Disabilities
• Enterovirus 71
• Herpes virus 6
• Influenza A

A connection seems less certain for

• Streptococcal infection
• Middle ear infection (otitis media)

1.16. First born status¶

A large Swedish cohort study found that firstborns are at higher risk for depression and ADHD in childhood and for endocrine disorders after age 50.²¹²

1.17. Particularly short or long intervals from the previous pregnancy (+ 25 to 30 %)¶

Particularly short or particularly long intervals of pregnancy with the preceding sibling increased the risk of ADHD by 30% (less than 6 months) and 12% (60-119 months) to 25% (120 months and more), respectively.²¹³

1.18. Maternal exposure to non-ionizing magnetic field radiation during pregnancy (+100%)¶

Children whose mothers were most exposed to non-ionizing magnetic field radiation (“electrosmog”) during pregnancy (at a 24-hour measurement),²¹⁴

• Showed a doubled risk for ADHD (aHR 2.01)
• Persistence of ADHD beyond age 11 was more than three times more likely to correlate with high maternal exposure than remission of ADHD by age 11 (aHR 3.38).
• ADHD with comorbid immune-related comorbidities (asthma or neurodermatitis/atopic dermatitis) was 4.57 times more likely to be correlated with high exposure.
• A coincidence of ADHD persisting beyond age 11 and immune-related comorbidities was 8.27 times more likely to be associated with exposure.

1.19. Polycystic ovary syndrome (PCOS) in pregnancy (+ 31 to + 95% in boys)¶

Children of women with polycystic ovary syndrome (PCOS) appear to be at increased risk for ADHD.²¹⁵

Possibly a connection could arise from the fact that one method of treatment is the use of dopamine agonists.²¹⁶²¹⁷ Another connection could be that PCOS is associated with hyperandrogenemia. Elevated prenatal testosterone levels are a risk factor for ADHD. For more on this, see Sex differences in ADHD.

One study found a 95% increased risk of ADHD in 3-year-old boys born to mothers with PCOS, while this was not increased in 3-year-old girls.²¹⁸ This also suggests a link to sex hormones, although increased testosterone levels during pregnancy also causes increased ADHD symptoms in female offspring. See more at Sex differences in ADHD. It is also known that ADHD shows up later in girls than in boys.
A Chinese study found (only) a 31% increased risk of ADHD in boys aged 3 to 6.²¹⁹ Since ADHD can often only be diagnosed at age 6 and older, we suspect a higher rate at school age.

Women with PCOS were themselves at increased risk of ADHD, although no association was found between testosterone and ADHD symptoms²²⁰

1.20. Hypertension during pregnancy¶

High blood pressure during pregnancy significantly increases the ADHD risk of the offspring.¹⁸³
Hypertension is associated with genetically inherited ADHD risks. It will therefore be necessary to differentiate whether hypertension during pregnancy causally increases ADHD risk or whether elevated blood pressure during pregnancy is an expression of the underlying genetic burden that mediates ADHD.

1.21. Decreased C-reactive protein (CRP) (+ 92 %)¶

Children of mothers whose CRP levels were in the lowest third of the subject group had nearly double the risk of ASD and ADHD compared with children of mothers from the middle third in CRP.²²¹

1.22. Systemic lupus erythematosus (SLE) (+ 60 %)¶

Children of mothers who had systemic lupus erythematosus (SLE) were found to have a 60% increased risk of ADHD.²²²

1.23. Less than 8 hours of sleep in the 3rd trimester of pregnancy¶

Girls of mothers with less than 8 hours of sleep in the last trimester of pregnancy were more likely to show hyperactivity, inattention, and ADHD total scores.²²³

1.24. Testosterone in pregnancy¶

Prenatal testosterone exposure correlated significantly with inattention and hyperactivity/impulsivity in the offspring.²²⁴

1.25. Pregnancy circumstances without influence on ADHD¶

No influence on the ADHD risk of the unborn child was found for the following factors:

• Iodine/creatinine ratio in the mother’s urine during pregnancy
  • A large study of 3 cohorts found no effect on ADHD or ASD risk²²⁵
• Mother migration
  • One metastudy found no evidence of increased ADHD risk from maternal migration, but it was different for ASA.²²⁶
• Mother iron level
  • One study found no effect of mother’s iron level during pregnancy on child’s ADHD risk at age 7 years²²⁷
• Artificial insemination by intracytoplasmic sperm injection (ICSI)²²⁸