1. Prenatal stressors as ADHD environmental causes

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

Even before birth, the unborn child can be damaged by toxic influences or diseases.
Many toxins and diseases that increase the risk of ADHD in offspring do so by affecting the dopaminergic system. Toxins can also increase the risk of ADHD even before conception through epigenetic mediation.
Psychological and physical stress (toxins, illnesses) have a fundamentally comparable effect on the stress systems (HPA axis, autonomic nervous system and others).
The % values given for a possible ADHD risk increase are an indication of the magnitude of the influence of the respective exposure. We are not aware of any values for entries without a % figure.

The consumption of nicotine, alcohol or stronger drugs during pregnancy increases the risk of ADHD in the offspring. Nicotine even increases the risk if the parents only smoked before conception.
Another source of risk is toxins that the mother comes into contact with during pregnancy. These include pesticides such as organophosphates or pyrethroids and chemicals such as lead, cadmium, thallium, bisphenols, polychlorinated biphenyls or polycyclic aromatic hydrocarbons.

Air pollution, especially particulate matter and nitrogen oxides, can also increase the risk of ADHD.
A high salt intake by the mother during pregnancy can increase the unborn child’s sensitivity to stress.

Various health factors in the mother, such as illnesses, obesity, stress, infections and hormonal disorders in the mother, are also associated with an increased risk of ADHD in the child. Thyroid hormones in particular should be closely monitored. Higher omega-3 fatty acid levels in the newborn could reduce the risk and severity of ADHD as well as autism spectrum disorders. Vitamin D3 deficiency during pregnancy and after birth is associated with dopaminergic brain abnormalities.
High exposure of the fetus or newborn to cortisol, through cortisol administration or maternal stress during pregnancy, can also increase the risk of ADHD.

It is well known that many medications can pose a risk to the unborn child during pregnancy. With regard to ADHD, paracetamol (acetaminophen), SSRIs (antidepressants), β-2 adrenaline receptor agonists, pregabalin, antibiotics and valproate are particularly relevant during pregnancy.

Finally, pregnancy circumstances such as first-born status or particularly short or long intervals from the previous pregnancy influence the child’s risk of ADHD.

Higher prenatal stress appeared to promote slower brain development during adolescence only in individuals with higher genetic susceptibility to ADHD (with a higher polygenic risk score for ADHD), while prenatal stress promoted faster brain development in individuals with lower genetic susceptibility to ADHD.¹

There appear to be gender differences for some of these risk factors.

Although the following collection is extensive, a number of other circumstances are likely to be associated with an increased risk of ADHD.
The various factors each represent only parts of a multi-layered risk mosaic and do not automatically lead to ADHD.

The % values indicate the possible ADHD risk increase due to the respective cause.

• 1.1. Toxins before pregnancy as risks for ADHD - epigenetic inheritance
  • 1.1.1. Nicotine consumption of one parent before conception (+ 259 %)
  • 1.1.2. Penicillin intake up to 2 years before pregnancy
• 1.2. Toxins and harmful effects during pregnancy (up to + 778 %)
  • 1.2.1. Alcohol during pregnancy (+ 778 %)
  • 1.2.2. Nicotine consumption of the mother during pregnancy (+ 58 % to + 378 %)
  • 1.2.3. Passive smoking during pregnancy
  • 1.2.4. Drug use by the mother during pregnancy (up to + 200 %)
  • 1.2.5. Polycyclic aromatic hydrocarbons (PAHs) (+ 99 to 157 %)
  • 1.2.6. Exposure of the mother to non-ionizing magnetic field radiation during pregnancy (+ 100 %)
  • 1.2.7. Air pollution during pregnancy (up to + 26 %)
    • 1.2.7.1. Particulate matter (+ 26 %)
    • 1.2.7.2. Nitrogen oxides (nitrogen oxides)
    • 1.2.7.3. Ozone
  • 1.2.8. Polychlorinated biphenyls / polychlorinated biphenyl ethers (+ 23 %)
  • 1.2.9. Cadmium during pregnancy (+ 22 % for girls)
  • 1.2.10. Lead disposition during pregnancy
  • 1.2.11. Thallium during pregnancy
  • 1.2.13. High salt consumption during pregnancy
  • 1.2.13. Pesticides during pregnancy
    • 1.2.13.1. Contact with organochlorine compounds during pregnancy
    • 1.2.13.2. Organophosphate contact during pregnancy
    • 1.2.13.3. Pyrethroid contact before or during pregnancy
    • 1.2.13.4. Glyphosate contact during pregnancy
  • 1.2.14. Bisphenols during pregnancy
  • 1.2.15. Phthalates during pregnancy
  • 1.2.16. Perfluoroalkyl compounds (PFAS) in pregnancy
  • 1.2.17. Dioxin exposure during pregnancy
  • 1.2.18. Prenatal exposure to sulphur dioxide
  • 1.2.19. Polybrominated diphenyl ethers
  • 1.2.20. Low urine fluoride content of the mother
  • 1.2.21. Manganese
• 1.3. Illnesses of the mother/parents (up to + 310 %)
  • 1.3.1. Increased or decreased thyroxine levels in the mother (up to + 310 %)
    • 1.3.1.1. Reduced and increased TSH values in newborns (+ 14 % in boys to + 310 % in girls)
  • 1.3.2. Severe maternal obesity before or during pregnancy (+ 14% to 280%)
  • 1.3.3. Chemical / drug intolerance (+ 110 % to 130 %; ASS + 201 % to 470 %)
  • 1.3.4. Pre-eclampsia (gestosis) during pregnancy (+ 30 % to + 188 %)
  • 1.3.5. Itrahepatic cholestasis (ICP) in pregnancy (+ 7 % to + 162 %)
  • 1.3.6. PTSD during pregnancy (+ 132 %)
  • 1.3.7. Mental stress of the mother during pregnancy (+ 72 % to + 100 %; with 5HTTLPR + 800 %)
  • 1.3.8. Polycystic ovary syndrome (PCOS) in pregnancy (+ 31 to + 95 % in boys)
  • 1.3.9. Unhealthy diet of the mother during pregnancy (+ 60 %)
  • 1.3.10. Fever of the mother during pregnancy (+ 31 % to + 164 %)
  • 1.3.11. Reduced C-reactive protein (CRP) (+ 92 %)
  • 1.3.12. Systemic lupus erythematosus (SLE) (+ 60 %)
  • 1.3.13. Parental asthma during and outside pregnancy (+ 13% to + 41%)
  • 1.3.14. Diabetes of one parent; diabetes during pregnancy (+ 40 %)
  • 1.3.15. Migraine in parents (+ 37 %)
  • 1.3.16. Anemia of the mother during pregnancy (+ 31 %)
  • 1.3.17. Infections of the mother during pregnancy
    • 1.3.17.1. Infections in general (+ 30 %)
    • 1.3.17.2. Viral infections
  • 1.3.18. Fetal inflammatory response syndrome (FIRS) (+ 27 %)
  • 1.3.19. Insatiable nausea (hyperemesis gravidarum) (+ 16 %)
  • 1.3.20. Mineral and vitamin deficiency during pregnancy
    • 1.3.20.1. D3 deficiency during pregnancy
    • 1.3.20.2. Omega-3 fatty acid levels
      • 1.3.20.2.1 In the newborn
      • 1.3.20.2.2. During pregnancy
  • 1.3.21. Depression of the mother during pregnancy
  • 1.3.22. High blood pressure during pregnancy
  • 1.3.23. Lack of sleep during pregnancy
  • 1.3.24. Testosterone during pregnancy
  • 1.3.25. Inflammation during pregnancy
• 1.4. Mother’s medication during pregnancy as ADHD risk (up to + 250 %)
  • 1.4.1. Paracetamol (acetaminophen) in pregnancy (+ 37 % to + 250 %)
  • 1.4.2. SSRI, antidepressants during pregnancy (0 % to + 63 %)
  • 1.4.3. β-2-Adrenaline receptor agonists in pregnancy (+ 30 %)
  • 1.4.4. Pregabalin during pregnancy (+ 29 %)
  • 1.4.5. Antibiotics during pregnancy (+ 14 %)
  • 1.4.6. Valproate during pregnancy (+ 12 %)
  • 1.4.7. Corticoids during pregnancy
  • 1.4.8. Valproic acid during pregnancy
  • 1.4.9. Taking penicillin during pregnancy
  • 1.4.10. No increase in risk due to NSAIDs, normal caffeine consumption, benzodiazepines
• 1.5. Other pregnancy circumstances (up to + 30 %)
  • 1.5.1. First-born status
  • 1.5.2. Particularly short or long intervals to the previous pregnancy (+ 25 % to + 30 %)
  • 1.5.3. Protein deficiency during pregnancy and after birth
• 1.6. Pregnancy circumstances without influence on ADHD
• 1.7 Preventive factors
  • 1.7.1. Fiber intake of the mother during pregnancy

1.1. Toxins before pregnancy as risks for ADHD - epigenetic inheritance¶

1.1.1. Nicotine consumption of one parent before conception (+ 259 %)¶

Children whose fathers smoked before pregnancy had a 2.59-fold risk of ADHD, compared to children whose fathers never smoked.
Children of parents who were exposed to smoking or passive smoking before pregnancy had 1.96 times the risk of A(D)HS.
Children whose parents were exposed to tobacco smoke both before and during pregnancy had a 2.01-fold risk of ADHD.²

1.1.2. Penicillin intake up to 2 years before pregnancy¶

Penicillin intake by the mother increased the child’s risk of ADHD even if the intake took place 2 years before the pregnancy. Repeated penicillin intake further increased the risk of ADHD.⁹

1.2. Toxins and harmful effects during pregnancy (up to + 778 %)¶

Toxic effects on unborn babies have been proven for:

1.2.1. Alcohol during pregnancy (+ 778 %)¶

Around 5% of children in the USA are said to suffer from FASD, i.e. are affected by the mother’s alcohol consumption during pregnancy.¹⁰
The vast majority of studies find that alcohol consumption by the mother during pregnancy significantly increases the likelihood of ADHD in children.¹¹¹² up to 8.78 times,¹³ Attention problems are also increased¹⁴
A combination of alcohol and stress in the mother during pregnancy increased the likelihood of male rats developing female sexual behavior.¹⁵
47.2% of children with FAS (fetal alcohol syndrome) also had ADHD¹⁶

There is evidence that alcohol consumption by the mother during pregnancy or while breastfeeding has a significant impact on the child’s dopamine system.^17181920 The regulation of the neurotransmitters serotonin , glutamate, noradrenaline, acetylcholine and histamine is also affected^{2122 23}

Individual studies found no connection between:

• Alcohol consumption during pregnancy and ADHD.²⁴²⁵
• Binge drinking in early pregnancy and ADHD risk in children aged 5 to 19 years.²⁶
  One study found a correlation between ethoxyacetic acid (one of 6 degradation products of alcohol examined) in the mother’s urine and inhibition problems in the children.²⁷
  A meta-analysis found that maternal alcohol consumption of less than 70 g/week during pregnancy did not increase the risk of ADHD.²⁸ Boys were less at risk from alcohol during pregnancy than girls.

Neill et al. deal with the differential diagnosis of ADHD and FASD (Fetal Alcohol Spectrum Disorder).²⁹

1.2.2. Nicotine consumption of the mother during pregnancy (+ 58 % to + 378 %)¶

Prenatal smoking causes an increased risk of ADHD for the offspring on the

• 1.58-fold (increased by 58 %)³⁰
• 2.7-fold (increased by 170 %)³¹
• 4.78-fold (increased by 378 %)¹³

Other studies also found significantly increased risk values.^{3233344353637}

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

• 3.21-fold³⁸³⁹
• 1.72-fold⁴⁰

Only two studies (with overlapping authors) and one meta-analysis came to a different conclusion^{4142 43} , one study found rather weak evidence.⁴⁴

Most experiments with prenatal nicotine exposure show a reduction in dopamine levels in the PFC and striatum. Under certain circumstances, increased dopamine levels were also shown.⁴⁵ ADHD is neurophysiologically closely linked to reduced dopamine levels in the dlPFC (impaired working memory) and striatum (impaired motivation and motor control = hyperactivity).
Smoking by people with ADHD should be distinguished from this - this increases dopamine levels (at least in the striatum), as it reduces the DAT, which is too pronounced in ADHD and reduces dopamine levels in the striatum. Acute smoking thus increases the dopamine level in the striatum.

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

• If there are no genetic risks, smoking by the mother during pregnancy increases the risk of ADHD 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 a factor of 2.6
  • DRD4-7R by a factor of 2.9
  • Both together by a factor of 9⁴⁶⁴⁷
    Another study confirms the involvement of DRD4-7R in gene-environment interactions.⁴⁸
• Smoking by the mother during pregnancy increased the risk of hyperactivity/impulsivity symptoms in the child by 50%.⁴⁹ Even passive smoking increased this risk by almost 50%, but only for boys.

Maternal smoking during pregnancy alters the glutamate NMDA receptors in the laterodorsal tegmentum of the offspring.⁵⁰ Another study also found changes in glutamatergic signaling in the hippocampus due to increased glutamate receptor expression,⁵¹ 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. The basal plasma corticosterone level is reduced. The HPA axis is disturbed. This affects the offspring themselves, but also their children, and is therefore inherited.⁵²

In rodents, it was found that prenatal nicotine exposure reduces dopamine levels in the mPFC of the offspring.⁵³ In ADHD, the dopamine level in the PFC is reduced.

A study of mice whose mothers were exposed to nicotine during pregnancy found evidence that nicotine causes various Consequences during pregnancy that persisted in the grandchildren’s generation, indicating epigenetic heritability:⁵⁴

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

Maternal smoking increases fetal testosterone levels.⁵⁵ Elevated prenatal testosterone levels are a risk factor for ADHD. More on this under Gender differences in ADHD.

Maternal smoking was associated with only ADHD, but not with only autism, compared to other environmental causes. Parental psychiatric history showed similar associations with all subgroups. Living in an urban area was most strongly associated with autism+ADHD and least strongly associated with ADHD only. ⁵⁶

Over 70 million women in the EU smoke during pregnancy.⁵¹

It is possible that the effects of nicotine consumption by the mother during pregnancy could be compensated for by breastfeeding.⁵⁷

1.2.3. Passive smoking during pregnancy¶

Even passive smoking, i.e. passive exposure of the mother to nicotine smoke during pregnancy, tends to increase the unborn child’s risk of ADHD symptoms later on.⁴⁹
Similar results were found for the causation of dyspraxia (developmental coordination disorder) by passive smoking.⁵⁸
Passive smoking during pregnancy in combination with maternal stress in the 5th year of the child’s life increased the risk of attention problems in the 7th year of life.⁵⁹

1.2.4. Drug use by the mother during pregnancy (up to + 200 %)¶

Children who were prenatally exposed to multiple drug use by their mothers and who subsequently grew up in institutions were found to be three times more likely to develop ADHD between the ages of 17 and 22.⁶⁰

Cannabis use during pregnancy is associated by several studies with an increased risk of ADHD in children.⁶¹
A meta-analysis found a relatively small 13% increase in the risk of ADHD due to cannabis use by the mother during pregnancy.⁶²

1.2.5. Polycyclic aromatic hydrocarbons (PAHs) (+ 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.⁶³ A meta-analysis found that 4 studies by one author indicated a 1.57-fold increase in the risk of ADHD due to PAHs (OR 2.57), while the total number of all studies indicated a doubled risk (OR 1.99), which was not significant⁶⁴
High prenatal PAH exposure correlated with

• Attention symptoms⁶⁵ according to DSM-IV (OR = 5.06)⁶⁶. dose-dependent⁶⁷
• ADHD total score according to DSM-IV (OR = 3.37)⁶⁶⁶⁸
• Anxiety and depression⁶⁵⁶⁹

1.2.6. Exposure of the mother to non-ionizing magnetic field radiation during pregnancy (+ 100 %)¶

Children whose mothers were most strongly exposed to non-ionizing magnetic field radiation (“electro-smog”) during pregnancy (in a 24-hour measurement),⁷⁰

• Showed a doubled risk of 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 atopic dermatitis) was 4.57 times more likely to be correlated with high exposure.
• A co-occurrence of ADHD persisting beyond age 11 and immune-related comorbidities was 8.27 times more likely to be associated with exposure.

1.2.7. Air pollution during pregnancy (up to + 26 %)¶

One study found changes in the immune system of offspring due to air pollution.⁷¹
A study of around 43,000 families in Shenzen found positive correlations between ADHD from the age of 3 and exposure to⁷²

• Cooking vapors
• Tobacco smoke
• Vapors 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.⁷³

A meta-analysis found that more studies (without reference to pregnancy) affirmed a link between air pollution and ADHD than denied it.⁷⁴

1.2.7.1. Particulate matter (+ 26 %)¶

A cohort study of 425,736 births on prenatal particulate matter exposure using satellite data found that an increase in PM2.5 concentration of 10 μg/m³ during the first trimester increased the risk of ADHD by 26% and that this increased further at PM2.5 concentrations above 16 μg/m³.⁷⁵
Air pollution from particulate matter during pregnancy correlated in one study with a reduced volume of the corpus callosum and a tendency towards increased hyperactivity.⁷⁶ Another study found a link between particulate matter and ADHD at low levels of particulate matter exposure, while higher levels caused more severe brain damage.⁶⁸

In rats, inhaled printer particles led to a 5-fold increase in dopamine levels, probably due to increased synthesis rather than decreased degradation.⁷⁷

Diesel exhaust particles led to functional impairment of dopamine neurons in laboratory tests. Prenatal ingestion with the air we breathe had the same effect in mice:⁷⁸

• In the striatum
  • Reduced dopamine metabolism
  • Reduced levels of dopamine metabolites
• In the amygdala
  • Increased dopamine levels
  • Increased dopamine metabolite levels
• In the nucleus accumbens
  • Increased dopamine levels

Traffic ultrafine particulate matter in the air breathed after birth had the following effects on female mice:⁷⁸

• In the hippocampus
  • Increased dopamine turnover

Pre- and postnatally, particulate matter and gaseous pollutants reduced the expression of oxytocin receptors in the hippocampus⁷⁹ and hypothalamus in rodents, with reduced maternal care behavior.⁸⁰ Oxytocin and vasopressin communication appears to be disrupted by endocrine disrupting chemicals⁸¹, many of which are present in outdoor air.⁷⁸

Studies found an association between PM2.5 and hyperactivity/attention symptoms (OR = 1.12)⁸², hyperactivity⁸³, ADHD symptoms⁸⁴ and between PM2.5 in the first trimester and a tendency towards attention problems and hyperactivity.⁸⁵

Other studies found no link between PM2.5 and ADHD⁸⁶⁸⁷⁸⁸

1.2.7.2. Nitrogen oxides (nitrogen oxides)¶

Several studies found a correlation between nitrogen oxide exposure during pregnancy and ADHD.⁶³

• NOx correlated with hyperactivity, with a stronger association between ADHD and NO than between ADHD and NO2. (NO: aOR = 1.26)⁸⁸
• NO2 exposure during pregnancy was strongly correlated with ADHD symptoms, such as
  • Impulsiveness
    • Interrupting others⁸⁴
    • Inability to wait your turn when playing⁸⁴
  • Attention problems
    • Carelessness when crossing the road⁸⁴
    • Attention impaired at the age of 4-5 years⁸⁹
  • Hyperactivity⁸³
  • Oppositional behavior (not an original ADHD symptom)
    • Lies⁸⁴
    • Public Disorder⁸⁴

Other studies found no significant or clear correlations between NOx and ADHD ^{86 8287}
One study found a correlation with ASD in children, but not with ADHD.⁹⁰

Emissions of nitrogen oxides in Germany fell by almost 2/3 between 1990 and 2020.⁹¹

1.2.7.3. Ozone¶

Ozone caused in rats:⁷⁸

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

No correlation with ADHD has yet been found in humans.⁸³⁶³

1.2.8. Polychlorinated biphenyls / polychlorinated biphenyl ethers (+ 23 %)¶

Polychlorinated biphenyls inhibit dopamine synthesis as well as the storage of dopamine in the vesicles and its release, thereby causing dopamine levels to be too low. Polychlorinated biphenyls cause hyperactivity and impulsivity (in rats even at sub-toxic doses).⁹² Polychlorinated biphenyls can act directly on dopaminergic processes to disrupt the dopamine system and produce Parkinson’s-like symptoms.⁹³ Further studies also found dopamine-reducing effects of PFAS.⁹⁴⁹⁵ as well as influences on the acetylcholine, serotonin and glutamate neurotransmitter balance.⁹⁶

A review study of k = 30 meta-analyses analyzed the association between prenatal exposure to PFOA and PFOS and ADHD in children aged 4-11 years⁹⁷
A statistically significant increase in the risk of ADHD was found in girls, but not in boys.

1.2.9. Cadmium during pregnancy (+ 22 % for girls)¶

Cadmium exposure during pregnancy increased the risk of ADHD for 6-year-old girls, but not for boys. Doubling the mother’s exposure to cadmium during pregnancy increased the risk of ADHD for girls by 22.3%.⁹⁸

1.2.10. Lead disposition during pregnancy¶

Lead disposition during pregnancy^{99100 101} affects the mesocorticolimbic circulation and increases the offspring’s risk of ADHD.¹⁰²
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 pups only showed increased corticosterone levels and decreased dopamine levels in the PFC when exposed to lead alone, female rat pups only when exposed to lead and stress in combination. Even short-term lead exposure of the dams caused this effect.¹⁰³ In female rat pups, lead exposure and maternal stress contributed as cumulative factors to learning difficulties during pregnancy. These were neurophysiologically mediated by the glucocorticoid system to the mesocorticolimbic system.¹⁰⁴

Further studies also found evidence that lead exposure as well as stress during pregnancy affect the mesocorticolimbic dopamine/glutamate system of female offspring (less so in males) and mutually increase their effects.¹⁰⁵ Under similar conditions, male rat pups showed a tendency to serotonergic disorders of the mesocorticolimbic system and altered delay discounting.¹⁰⁶
Even a lead content in drinking water below the limit values is said to be problematic.¹⁰⁰
In principle, lead water pipes are not very dangerous in areas with calcareous water, as limescale forms a reliable protective layer in the pipes. However, a descaling system for the drinking water must not be installed. Nevertheless, it is generally advisable to replace lead-containing water pipes during modernization work.

It is possible that the metabolism of cobalt, copper, lead, zinc and vanadium is altered in ADHD. Reduced cycle stability (determinism), duration (mean diagonal length) and complexity (entropy) of the exposure profiles were found.¹⁰⁷

Lead is a divalent cation that mimics Ca2+ and activates PKC signaling.¹⁰⁸

Arnsten¹⁰⁹ describes lead as a toxin that causes symptoms confusable with ADHD.

Lead appears to have a number of harmful neurophysiological effects, including on the dopaminergic system:

• Impairment of the mesocorticolimbic dopaminergic system¹¹⁰
• Impairment of dopamine receptors¹¹⁰
• Impairment of attention regulation in the PFC¹¹¹
• Apoptosis¹¹²
• Excitotoxicity¹¹²
• Reduced cellular energy metabolism¹¹²
• Impaired heme biosynthesis and anemia¹¹²
• Oxidative stress¹¹²
• Lipid peroxidation¹¹²
• Changed activity of the second messenger system¹¹²
• Altered neurotransmitter release¹¹²
• Altered neurotransmitter receptor density¹¹²
• Impaired neuropsychological functioning¹¹²
• Impaired development and function of oligodendrocytes¹¹²
• Abnormal myelin formation¹¹²
• Abnormal neurotrophic factor expression¹¹²
• Abnormal dendritic branching patterns¹¹²
• Disorder of the blood-brain barrier¹¹²
• Disorder of thyroid hormone transport into the brain¹¹²
• Altered regulation of gene transcription¹¹²
• Reduction of gray matter in the PFC, especially in the ACC¹¹³

Lead also appears to trigger the following behaviors:

• Impulsiveness¹¹¹
• Sociopathic behavior¹¹⁴¹¹⁵
• Irresponsible behavior¹¹⁴¹¹⁵
• Criminal behavior¹¹⁴¹¹⁵
• Lower IQ¹¹²
• Impaired academic performance¹¹²

Lead poisoning correlates strongly with the crime rate and out-of-wedlock pregnancies in the USA.¹¹⁴¹¹⁵

Children with elevated blood lead levels are said to be particularly susceptible to other toxins in early childhood.¹¹⁶ In particular, warnings have been issued about lead in wall paints. During pregnancy, lead can be transferred from the mother to the child through the placenta.

1.2.11. Thallium during pregnancy¶

High thallium exposure in the second trimester of pregnancy increased the risk of ADHD for 3-year-old boys, but not for girls.¹¹⁷

1.2.13. High salt consumption during pregnancy¶

A high salt intake from food during pregnancy could increase the unborn child’s sensitivity to stress.¹¹⁸

1.2.13. Pesticides during pregnancy¶

1.2.13.1. Contact with organochlorine compounds during pregnancy¶

Organochlorine compounds (dichlorodiphenyltrichloroethanes (DDT), dieldrin, heptachlor, endosulfan) showed an effect on neuronal development in prenatal exposure, which (in rodents), e.g:¹¹⁹

• DAT increased
• Increased dopamine reuptake
• Loss of dopaminergic cells
• Alterations at the presynapse in key dopaminergic proteins in response to OC pesticides in striatum or substantia nigra
• Noradrenaline increased
• Increased serotonin
• GABA receptors reduced
• NMDA receptors reduced
• MGluR5 receptors altered
• Altered GABAergic, glutamatergic and dopaminergic response to endosulfan in the 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.

1.2.13.2. Organophosphate contact during pregnancy¶

The organophosphates chlorpyrifos and diazinon showed significant effects on neonatal brain development, including on the dopaminergic system.¹²⁰ Prenatal exposure to the common pesticide chlorpyrifos impaired IQ and working memory in children aged 7¹²¹¹²² and executive functions.¹²³

Organophosphates inhibit acetylcholinesterase (= the enzyme that breaks down acetylcholine).¹¹⁹ 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 dose of 1 mg/kg DFP caused increased dopamine levels, a single toxic dose of 2 mg/kg DFP caused increased dopamine degradation. The levels returned to normal after 6 hours. Chronic administration of 1 mg/kg DFP resulted in 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, while chronic administration reduced it. The authors hypothesized that the changes in dopamine and GABA could be Consequences of downregulation of cholinergic receptors.¹²⁴

Chlorpyrifos disrupts the serotonin system. Contact during pregnancy can trigger tremor in children and impair cognitive and neurobehavioral development.¹⁵

A measurement based on prenatal urinary dialkyl phosphate metabolites (diethyl phosphate and dimethyl phosphate) and an analysis of the maternal PON1 gene variants Q192R and L55M found no association between organophosphate contact of the mother during pregnancy and later ADHD in the child.¹²⁵

A Norwegian cohort study found an increased risk of ADHD in the offspring when detected in the mother’s blood during pregnancy of:¹²⁶

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

Higher vitamin D levels in the mother appear to reduce the negative effect of the organophosphate chlorpyrifos on the risk of ADHD in the offspring.¹²⁷¹²⁸

Another Norwegian registry study found no evidence of an increased risk of ADHD in the offspring when the mother was exposed to organophosphates during the 17th week of pregnancy.¹²⁹

1.2.13.3. 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% and the risk of any ADHD occurring among the 10% most severe ADHD cases by 13%.¹³⁰

The pyrethroid deltamethrin apparently impairs the dopaminergic system in mice after early exposure:¹³¹

• DAT reduced
• D1 receptor reduced
• Apoptosis

Furthermore, there were (with prenatal, but not with postnatal exposure)¹³² permanent changes in behavior with regard to:¹³¹

• Movement activity
• Acoustic startle reflex
• Learning
• Memory

3-PBA and chlorpyrifos reinforce each other’s effect on ADHD.¹³⁰

Each 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), in urine increased the risk of offspring ADHD by 76%.¹³⁰

1.2.13.4. Glyphosate contact during pregnancy¶

Glyphosate (e.g. Roundup) is a broad-spectrum herbicide from the group of phosphonic acids.
In rats, oral exposure of the mother to glyphosate (0.5 and 50 mg/kg body weight/day) during pregnancy and lactation (especially) affected the (female) offspring:¹³³

• Symptoms of depression
• Anxiety symptoms
• social deficits
• reduced expression and hypermethylation of the tryptophan hydroxylase 2 gene in the hippocampus
  • Tryptophan hydroxylase is involved in serotonin synthesis in the brain
• altered intestinal microbiota of the female offspring
  • reduced abundance of Akkermansia
  • increased abundance of Alistipes and Blautia
    (Bacteria involved in tryptophan metabolism and associated with depression and anxiety-like disorders)

This indicates that glyphosate is involved in depression and anxiety disorders. A link to ADHD has not yet been established.

1.2.14. Bisphenols during pregnancy¶

Bisphenol-A (BPA) is a glucocorticoid receptor agonist and is associated with changes in the HPA axis response. In female rats, prenatal BPA correlated with increased basal corticosterone levels and decreased glucocorticoid receptor expression in the hypothalamus. In response to stress, these female rats showed anxious coping behavior and a dampened 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 were unable to upregulate CRH-1 receptor expression in the pituitary gland in response to acute stress.¹⁵ The dose given to the rat mothers during pregnancy and lactation was very low at 40 micrograms/kg/day.¹³⁴
5 milligrams / cubic meter in the air cause eye irritation.¹³⁵ A review confirmed evidence that bishenol-A during pregnancy can increase the risk of ADHD in children, especially boys,¹³⁶

BPA and BPS caused greatly increased dopamine (3 to 5-fold) and greatly decreased serotonin (by 80 %) in mouse placentas. GABA remained unchanged.¹³⁷ BPA is an endocrine disruptor and mimics estrogenic activity. Thus, BPA affects various dopaminergic processes to increase mesolimbic dopamine activity, leading to hyperactivity, attention deficits and increased susceptibility to drug abuse.⁹³

1.2.15. Phthalates during pregnancy¶

According to most studies, phthalic acid esters are said to increase the risk of ADHD for the unborn child,¹³⁸ although the connections are still unclear.¹³⁹¹³⁶ An influence on the thyroid balance is being discussed.¹⁴⁰ Higher phthalate metabolites in the urine of pregnant women correlate with increased distractibility in preschool children.¹⁴¹
Prenatal di-methoxyethyl phthalate (DMEP) exposure caused abnormal brain morphology and function in mice. DMEP significantly reduced the number of neurons in the parietal cortex by impairing neurogenesis and gliogenesis during cortex development and impaired dendritic spine architecture and synaptic activity in the parietal cortex. In addition, prenatal DMEP induced hyperactivity and reduced anxiety behavior in mice.¹⁴²

1.2.16. Perfluoroalkyl compounds (PFAS) in pregnancy¶

A long-term study found no correlation between exposure to perfluoroalkyl during pregnancy and ADHD. There were weak - positive and negative - correlations with working memory functions in childhood.¹⁴³ A meta-analysis also found no significant correlation between maternal PFAS exposure and the prevalence rate of early childhood ADHD. Nevertheless, the odds ratio was partially increased:¹⁴⁴

• 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

The PFOS concentration in the children’s blood and the PFNA concentration in the 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 of perfluorooctane sulfonate (PFOS) with ADHD or ASD.¹⁴⁵ Another study found an increased risk of ADHD in school children with low to moderate exposure to PFAS at 2 years of age.¹⁴⁶

1.2.17. Dioxin exposure during pregnancy¶

Children who were exposed to dioxin during pregnancy have an increased risk of ADHD.¹⁴⁷

1.2.18. Prenatal exposure to sulphur dioxide¶

Prenatal exposure to sulfur dioxide (SO2) correlated with DNA methylation and increased AD(H)S symptoms ¹⁴⁸¹⁴⁹
According to a review⁶³, two other studies found no significant correlation.⁸⁸⁸³

1.2.19. Polybrominated diphenyl ethers¶

Polybrominated diphenyl ethers (PBDEs) are organic chemicals containing bromine. They were used as flame retardants in many plastics and textiles.
Their concentration in breast milk increased exponentially between 1972 and 1998.
The German industry voluntarily abandoned its use in 1986. Sweden banned its production and use in 1999.
Throughout the EU, pentaBDE and octaBDE may only be placed on the market or used up to a maximum of 0.1 percent by weight since 2003.

Prenatal PBDE exposure appears to increase ADHD symptoms in girls.¹⁵⁰

1.2.20. Low urine fluoride content of the mother¶

One study found an inverse correlation between fluoride levels in the mother’s urine and cognitive problems in the offspring at the age of 11. The higher the fluoride content, the lower the cognitive problems.¹⁵¹ This was not consistent with the results of other studies, which found an increased risk of ADHD with increased urinary fluoride levels in the children themselves.¹⁵²¹⁵³

1.2.21. Manganese¶

There is weak evidence of relevance in ADHD, although elevated manganese levels were only found in the hair, but not in blood levels, of people with ADHD.¹⁵⁴
A doubling of the manganese content in teeth from both the prenatal and postnatal period increased the risk of attention problems and ADHD symptoms in the school years by 5%. Manganese from childhood showed no influence.¹⁵⁵
An animal model with developmental manganese exposure showed that manganese can cause permanent attention and sensorimotor deficits resembling ADHD-I. Oral methylphenidate was able to fully compensate for the deficits caused by early manganese exposure.¹⁵⁶

1.3. Illnesses of the mother/parents (up to + 310 %)¶

Children with ADHD were more likely to have mothers who had health impairments during pregnancy:³⁸

• Maternal illnesses during pregnancy:
  In 34.4% of children with ADHD, the mother had a condition during pregnancy, compared with 14.4% of children who were not affected.
  • Children with ADHD: 34.7 %
    Diseases of the mother during pregnancy were in the following trimester:
    • 1st/2nd trimester only: 56.4 %
    • 3rd trimester only: 12.7 %
    • Entire pregnancy: 30.9 %
  • Non-affected children: 14.4 %
    Diseases of the mother during pregnancy were in the following trimester:
    • 1st/2nd trimester only: 0 %
    • 3rd trimester only: 33.3 %
    • Entire pregnancy: 66.7 %
• Other pregnancy problems:
  • Children with ADHD: 14.5%
  • Non-affected children: 3.8 %

1.3.1. Increased or decreased thyroxine levels in the mother (up to + 310 %)¶

One study found a 7% increased risk of ADHD in children with untreated mild thyroxine deficiency in the mother during early pregnancy.¹⁵⁷ In another study, reduced 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 risk of ADHD in the children.¹⁵⁸ Another study also found evidence of thyroxine as a possible cause of ADHD,¹⁵⁹ another study found no influence of the mother’s thyroxine levels during pregnancy.¹⁶⁰

In male mice, a study found a significantly reduced dopamine and serotonin turnover in the striatum, nucleus accumbens, hypothalamus and hippocampus as a consequence of prenatal thyroxine deficiency.¹⁶¹ Dopamine deficiency in the striatum / nucleus accumbens is responsible for hyperactive symptoms in ADHD.

1.3.1.1. Reduced and increased TSH values in newborns (+ 14 % in boys to + 310 % in girls)¶

A cohort study from Norway found an increased risk of ADHD later in life in newborns with low or high TSH levels, but only in girls. TSH values in the lowest 20% group increased the risk of ADHD in girls 3.1-fold, in boys by only 14%.¹⁶²
Another Norwegian cohort study found a 2.27-fold risk of ADHD for thyroid hormone T3 levels in the mother at 17 weeks’ gestation within the top 1/5 compared to the lowest 1/5. For free T4, both increased and decreased levels were risk-increasing: the top 1/5 as well as the lowest 1/5 showed a 1.6-fold risk of ADHD in the offspring.¹⁶³

1.3.2. 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.¹⁶⁴
Even an excessive BMI of the mother before pregnancy increased the risk of ADHD in the later offspring.¹⁶⁵ A BMI of 25 to 30 increased the child’s risk of ADHD by 14%, a BMI of 30 to 35 by 96% and a BMI of more than 35 by 82%.¹⁶⁶
Other fluctuations in the mother’s weight before and at the end of pregnancy do not appear to affect the risk of ADHD.³²
A Norwegian registry study found only slight evidence of an influence of the parents’ BMI on the child’s ADHD risk, whereby the mother’s pre-pregnancy BMI was the subject of the study.¹⁶⁷ In contrast, another study found that maternal obesity before pregnancy increased the mother’s risk of ADHD by 62%.¹⁶⁸

1.3.3. Chemical / drug intolerance (+ 110 % to 130 %; ASS + 201 % to 470 %)¶

Children of mothers with chemical / drug intolerance (positive result of the Quick Environmental Exposure and Sensitivity Inventory (QEESI), a validated screening tool for chemical intolerance) had 2.3 times the risk of ADHD and 3.01 times the risk of ASD.¹⁶⁹¹⁷⁰

1.3.4. Pre-eclampsia (gestosis) during pregnancy (+ 30 % to + 188 %)¶

Problems during pregnancy that affect the oxygen supply to the fetus increase the risk of ADHD in the child by 30 to 188%.¹⁷¹ One cohort study found a 43% increase in ADHD risk due to gestational gestosis.¹⁷² Several reviews confirm an increased risk of ADHD due to pre-eclampsia during pregnancy.¹⁷³¹⁷⁴

1.3.5. Itrahepatic cholestasis (ICP) in pregnancy (+ 7 % to + 162 %)¶

Intrahepatic cholestasis in pregnancy (ICP) is the most common obstetric liver disease. It is associated with an increased risk of iatrogenic premature birth and adverse Consequences for the child.¹⁷⁷
An ICD increased the risk of ADHD / ASD:

• before the 28th week of pregnancy
  • 2.62 times the risk of ADHD
  • 1.69-fold ASS risk
• 28th to 36th week of pregnancy
  • 1.36 times the risk of ADHD
  • 1.37-fold ASS risk
• after the 36th week of pregnancy
  • 1.07 times the risk of ADHD
  • 1.13-fold ASS risk

1.3.6. PTSD during pregnancy (+ 132 %)¶

According to a Swedish cohort study, post-traumatic stress disorder in the mother during pregnancy is associated with a 2.32-fold risk of ADHD in the offspring.¹⁷⁸

1.3.7. Mental stress of the mother during pregnancy (+ 72 % to + 100 %; with 5HTTLPR + 800 %)¶

Stress of the mother during pregnancy increased the risk of ADHD in the children

• by 100 %¹⁷⁹
• by 72 %.¹⁸⁰
• by 400 % (OR = 5.02).¹⁸¹

Persistent and severe (anxiety-induced, perceived threatening = cortisolergic) stress significantly increases the risk of screaming children¹⁸² (see also 2.2.2.3.2), anxiety disorders and ADHD.^{183184185186187}
Persistent stress (here: financial problems) is more harmful than short-term stress (here: loss of a loved one).¹⁸⁸
High anxiety/threatening perceived stress also significantly increases the risk of borderline in children.

Children with ADHD were more likely to have mothers who experienced stress or emotional problems during pregnancy:³⁸

• 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 %
  • Entire 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 %
  • Entire pregnancy: 28.6 %

Hair cortisol levels of mothers and their children showed a transmission of psychological stress experiences from mothers to their children.¹⁸⁹
A 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.¹⁹⁰ It is possible that one month of repeated stress is not a sufficiently intense stressor.

The cortisol released by the mother during anxiety/threatening stress is absorbed by the unborn child and leads to permanent damage to the HPA axis, which regulates stress reactions by means of cortisol.¹⁹¹¹⁹²

Severe maternal anxiety in pregnancy during the 12th to 22nd week after the last menstrual period significantly increased the risk of ADHD, while severe anxiety in the 32nd to 40th week did not increase the risk.¹⁹³ Elevated maternal cortisol levels in the 3rd trimester of pregnancy increased the offspring’s risk of ASD symptoms only in boys at 3 years of age, but were no longer significant at 5 years of age. ADHD symptoms were not elevated at either age 3 or age 5.¹⁹⁴
So it seems to depend very much on the time of the stress experience.

Severe maternal anxiety during pregnancy increased the unborn child’s risk of ADHD depending on its COMT gene variant (gene-environment interaction).¹⁹⁵
In mothers with the ADGRL3 (latrophilin 3, LPHN3) gene variants (SNPs)

• rs6551665
• rs1947274
• rs6858066 or
• rs2345039

even low levels of stress during pregnancy resulted in a significantly increased risk of ADHD for the child.¹⁹⁶

A combination of the 5HTTLPR L/L genotype and stress during pregnancy caused an eight times higher risk of ADHD-C or ADHD-HI.¹⁹⁷

Early prenatal stress increases levels of immune response genes, including the proinflammatory cytokines IL-6 and IL-1β, particularly in male placentas. Male infants show stress-induced locomotor hyperactivity, a hallmark of dopaminergic dysregulation, which was ameliorated by maternal treatment with nonsterioid anti-inflammatory drugs. In addition, the expression of dopamine D1 and D2 receptors was altered by early prenatal stress in male offspring.¹⁹⁸ This emphasizes the effect of early stress on the dopaminergic system.

High cortisol exposure of the fetus or newborn can 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 the risk of ADHD in children.¹⁹⁹ Exposure to glucocorticoids during hippocampal development in pregnancy influences the starting point of the stress response through epigenetic changes via mRNA and methylation.²⁰⁰ Another study reports that the maternal psychological stress-mediated increase in risk to the unborn child for developmental disorders such as ADHD may be mediated by mRNA expression of glucocorticoid pathway genes in the placenta.²⁰¹
Another study also describes epigenetic changes in the unborn child due to the mother’s psychological stress during pregnancy.²⁰²
One study found no significant risk increase for mental disorders up to the age of 10 years due to increased glucocorticoid exposure in unborn babies.²⁰³
Exposure of the mother to a natural disaster during pregnancy increased the risk of ADHD.²⁰⁴

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

Children of women with polycystic ovary syndrome (PCOS) appear to have an increased risk of ADHD.²¹⁰

It is possible that a connection could result from the fact that one treatment method is the use of dopamine agonists.²¹¹²¹² Another connection could be that PCOS is associated with hyperandrogenemia. Elevated prenatal testosterone levels are a risk factor for ADHD. More on this under Gender 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.²¹³ This also suggests a link with sex hormones, although increased testosterone levels during pregnancy also cause increased ADHD symptoms in female offspring. More on this at Gender differences in ADHD. It is also known that ADHD shows up later in girls than in boys.
A Chinese study found a 31% increased risk of ADHD in boys aged 3 to 6 (only).²¹⁴ As ADHD can often only be diagnosed from the age of 6, we suspect a higher rate at school age.

Women with PCOS had an increased risk of ADHD themselves, although no link was found between testosterone and ADHD symptoms²¹⁵

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

An unhealthy or “westernized” dietary intake by the mother during pregnancy increased the children’s likelihood of ADHD by more than 60%.²¹⁶
Since stress increases the preference for “convenient food”, we believe that the correlation could possibly also be an indirect reflection of an increased stress load on the mother during pregnancy, since stress changes food preferences in the direction of quickly digestible foods and convenient food.

1.3.10. Fever of the mother during pregnancy (+ 31 % to + 164 %)¶

A cohort study of 114,000 children showed that fever in the first trimester of pregnancy increased the risk of ADHD by 31%, and multiple fevers by 164%. However, fever only increased inattention, not hyperactivity/impulsivity - this also applied to the second trimester. The results were independent of whether the mother took paracetamol (acetaminophen) or not.²¹⁷

1.3.11. Reduced C-reactive protein (CRP) (+ 92 %)¶

Children of mothers whose CRP levels were in the lowest third of the subject group had an almost doubled risk of ASD and ADHD compared to children of mothers from the middle third of CRP.²¹⁸

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

Children of mothers who suffered from systemic lupus erythematosus (SLE) were found to have a 60% increased risk of ADHD.²¹⁹

1.3.13. Parental asthma during and outside pregnancy (+ 13% to + 41%)¶

Asthma in the mother during pregnancy increases the risk of ADHD and ASD in the offspring.²²⁰ A cohort study of 961,202 children showed a 41% increased risk of ADHD if the mother had asthma and a 13% increased risk if the father had asthma. An asthma episode in the mother during pregnancy increased the risk of ADHD by 21%, and an asthma episode after pregnancy by 25%.²²¹ Another study also found an increased risk of ADHD in the offspring of mothers with asthma, especially for girls.²²²

1.3.14. Diabetes of one parent; diabetes during pregnancy (+ 40 %)¶

A cohort study of over 5 million people found an increased risk of ADHD in children if a parent had diabetes.²²³

Diabetes in the mother before or during pregnancy increases the risk of ADHD and ASD in the offspring.^224225226
Diabetes mellitus or type 1 diabetes mellitus in the mother before pregnancy increased the children’s risk of ADHD by 40 %, type 1 diabetes mellitus in the father by 20 %.
Another study found a 2.4-fold ADHD risk in children of mothers with diabetes mellitus and a 3.7-fold ADHD risk in male offspring of mothers with diabetes mellitus. No differences were found between gestational diabetes and other diabetes.²²⁷
Children of non-insulin-treated severely obese mothers with type 2 diabetes were 2 times more likely to have 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 have psychiatric disorders than offspring of normal-weight mothers.²²⁸

1.3.15. Migraine in parents (+ 37 %)¶

A cohort study of n = 250,517 participants found an increased risk for children of mothers but not fathers with MIgraine:²²⁹

• ADHD (+ 37 %)
• Bipolar Disorder (+ 35 %)
• Depression (+ 33 %)

1.3.16. 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 the risk of ADHD by 31%, while anemia in later weeks of pregnancy barely increased the risk (by 1.4%). ²³⁰

In a small Lebanese correlational study (n = 119), maternal anemia during pregnancy increased the risk of ADHD 3.7-fold (OR = 3.654).¹⁸¹

1.3.17. Infections of the mother during pregnancy¶

1.3.17.1. Infections in general (+ 30 %)¶

A meta-analysis found a 30% increase in the risk of ADHD in the offspring due to infections in the mother during pregnancy.²³¹

1.3.17.2. Viral infections¶

A viral infection of the mother during pregnancy increases the risk of ADHD for the offspring²³² and can affect the development of the unborn child’s dopaminergic system, e.g.:²³³

• Measles
• Varicella
• Rubella
  • Subclinical rubella infection of the mother during pregnancy also increases the child’s risk at the age of 8 to 9 years for²³⁴
    • ASS
    • ADHD
    • Developmental disorders
• Enterovirus 71
• Herpes virus 6
• Influenza A

A connection seems less certain for

• Streptococcal infection
• Inflammation of the middle ear (otitis media)

1.3.18. Fetal inflammatory response syndrome (FIRS) (+ 27 %)¶

Children born to a mother with fetal inflammatory response syndrome (FIRS, an inflammation of the placenta during pregnancy) had an increased risk of:²³⁵

• neuropsychiatric disorders diagnosed (OR = 1.21)
• ASS (OR = 1.35)
• ADHD (OR = 1.27)
• Conduct disoder (OR = 1.50)
• PTBS (OR = 2.46)

1.3.19. Insatiable nausea (hyperemesis gravidarum) (+ 16 %)¶

Insatiable nausea and vomiting of the mother during pregnancy led to an increased risk of ADHD in the offspring by 16% (in 2 cohort studies) to 287%²³⁶

1.3.20. Mineral and vitamin deficiency during pregnancy¶

Find out more at ⇒ Vitamins, minerals, dietary supplements for ADHD And ⇒ Nutrition and diet for ADHD in the chapter ⇒ Treatment and therapy.

1.3.20.1. D3 deficiency during pregnancy¶

Vitamin D3 deficiency during pregnancy and after birth causes permanent maldevelopment of the brain, particularly the dopaminergic system.^237238239240 In a meta-analysis, studies with larger sample sizes and stricter definitions of vitamin D deficiency showed positive associations for ADHD and schizophrenia.²⁴¹
The incidence of ADHD-like symptoms in children decreased by 11% for every 10 ng/ml increase in maternal 25(OH)D levels.²⁴² Another study also found that a reletively low maternal 25(OH)D level at 24 weeks gestation increased the risk of ADHD and ASD and ASD severity. High D3 supplementation (2,800 iU/day) during pregnancy did not increase ADHD risk or ASD risk.²⁴³ In our opinion, this could indicate that D3 levels, especially before 24 weeks of gestation, influence ASD and ADHD risk.
The severity of the offspring’s ADHD symptoms correlated with the level of maternal 25(OH)D deficiency ²⁴⁴²⁴⁵
D3 deficiency during pregnancy reduces dopamine turnover in the offspring’s brain²⁴⁶ by reducing COMT.²⁴⁷
Decreased serum vitamin D3 levels in the mother at 30 weeks gestation correlated significantly with depression in the offspring up to 22 years of age, but not with ADHD.²⁴⁸ Decreased maternal D3 levels at 35 to 37 weeks of gestation correlated significantly with increased ADHD signs in the children at 6 months and 2 years of age.¹⁸⁷
It remains to be seen whether D3 deficiency has different effects in other weeks of pregnancy, as later mental disorders are particularly related to those regions of the brain that are undergoing a developmental boost in the respective week of pregnancy. More on this at ⇒ Exposure to stress at different stages of brain development In the chapter ⇒ Stress damage - effects of early / prolonged stress.

An extensive long-term study in Spain on vitamin D3 deficiency during pregnancy found no correlation between low maternal blood levels of D3 during pregnancy and ADHD in children aged 5 to 18 years.²⁴⁹
A study in Finland, on the other hand, found a clear correlation between a reduced D3 level in the mother during pregnancy and ADHD in the children. The risk increase reached over 50 %.²⁵⁰
It is possible that the difference could result from the fact that sunlight intensity in Spain is high enough almost all year round to produce D3 (so that the Spanish participants with relatively low levels still had sufficient levels), whereas in Germany, and even more so in more northern countries, sunlight intensity is too low in the winter months to mediate D3 production.

Rodents whose mothers had a vitamin D deficiency showed typical ADHD symptoms:²⁵¹

• Hyperactivity
• Impulsiveness
• Reduced social behavior
• Changed frequency of ultrasound vocalization
• More frequent self-pollution
• Reduced grooming of puppies
• Reduced growth factors NGF and GDNF
• Thinner cortical layers and larger lateral ventricles
• Smaller size of the hippocampus and smaller lateral ventricles

1.3.20.2. Omega-3 fatty acid levels¶

1.3.20.2.1 In the newborn¶

A meta-study found evidence that higher levels of omega-3 fatty acids in newborns can reduce the risk and severity of ADHD and autism spectrum disorders. It is possible that an adequate supply of omega-3 fatty acids in the last trimester of pregnancy could counteract this²⁵²

1.3.20.2.2. During pregnancy¶

Another study found a 13% increased risk of ADHD in offspring at the age of 7 due to an increased omega 6 to omega 3 ratio (high omega 6 and low omega 3 levels).²⁵³

1.3.21. Depression of the mother during pregnancy¶

In boys in particular, the severity of the mother’s depression during pregnancy as well as higher cyclothymic, irritable and anxious temperament levels in the mother appear to be relevant risk factors for the development of ADHD.²⁵⁴
A large-scale study found no causal influence of maternal depression, anxiety disorder or infection during pregnancy on the risk of neurodevelopmental disorders (ASD, ADHD, mental retardation, cerebral palsy or epilepsy) in the child.²⁵⁵

1.3.22. High blood pressure during pregnancy¶

High blood pressure during pregnancy significantly increases the risk of ADHD in the offspring.¹⁷⁴
High blood pressure is associated with genetically inherited ADHD risks. It will therefore be necessary to differentiate whether high blood pressure during pregnancy causally increases the risk of ADHD or whether elevated blood pressure during pregnancy is an expression of the underlying genetic burden that mediates ADHD.

1.3.23. Lack of sleep during pregnancy¶

Girls born to mothers with less than 8 hours of sleep in the last trimester of pregnancy were more likely to show hyperactivity, inattention and ADHD totals.²⁵⁶
Sleep problems during pregnancy correlated with an increased risk of neurodevelopmental disorders and sleep problems in early childhood.²⁵⁷, in particular

• reduced and poorer sleep in the second trimester of pregnancy correlated with ADHD
• major sleep problems in the first trimester correlated with ADHD
• Sleep problems in the third trimester correlated with the child’s sleep problems

1.3.24. Testosterone during pregnancy¶

Prenatal testosterone exposure correlated significantly with inattention and hyperactivity/impulsivity in the offspring.²⁵⁸ Elevated maternal testosterone levels during pregnancy correlated significantly with increased ADHD signs in the children at 6 months and 2 years of age.¹⁸⁷

1.3.25. Inflammation during pregnancy¶

Perinatal inflammation correlates with increased ADHD symptom scores in children aged 8-9 years and increases genetic predisposition to ADHD (the Polygenic Risc Score).²⁵⁹²⁶⁰

1.4. Mother’s medication during pregnancy as ADHD risk (up to + 250 %)¶

Children with ADHD were more likely to have mothers who took medication during pregnancy:³⁸

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 %
  • Entire pregnancy: 49.3 %
• Not 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 %
  • Entire pregnancy: 21.9 %

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

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

50% of all women use paracetamol during pregnancy.²⁶¹
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 total of over 110,000 participants.²⁶²²⁶³ Further studies confirm this.^264265266 Critically, Gilman et al. While the previous studies were based on the mothers’ reports of intake, a study based on blood levels found a 2.3 to 3.5-fold risk of ADHD and a 1.6 to 4.1-fold risk of ASA in the children if taken in the second or third trimester of pregnancy.²⁶⁷²⁶⁸

The risk of ADHD from paracetamol (acetaminophen) increases when taken²⁶⁹

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

A cohort study of 116,000 children showed that fever in the first trimester of pregnancy increased the risk of ADHD by 31%, and multiple fevers by 164%. However, fever only increased inattention, not hyperactivity/impulsivity - this also applied to the second trimester. The results were independent of whether the mother took paracetamol (acetaminophen) or not.²¹⁷
A meta-analysis confirms the increased risk of ADHD and ASD in offspring when taking paracetamol during pregnancy²⁷⁰

One study questions the previous critical results by focusing on parents’ ADHD diagnoses that have not been taken into account to date.²⁷¹ Damkier is also doubtful.²⁷² A meta-analysis of 22 studies with n = 367,775 participants found an increased risk of ADHD due to paracetamol during pregnancy, which remained unchanged by other factors (such as parental diagnoses)²⁷³

A long-term study analyzed paracetamol, methionine, serine, glycine and glutamate in umbilical cord plasma and found that increased paracetamol levels increased the risk of ADHD in parallel with the increase in 8-hydroxy-deoxyguanosine levels in umbilical cord blood. Increased levels of methionine, glycine, serine and 8-hydroxy-deoxyguanosine in cord blood correlated with a significantly higher likelihood of ADHD in childhood. Methionine and glycine each mediated 22% of the association between elevated acetaminophen levels and later ADHD.²⁷⁴
The damage to the development of the offspring caused by paracetamol during pregnancy appears to be mediated by changes in the endocannabinoid pathway²⁷⁵

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

1.4.2. SSRI, antidepressants during pregnancy (0 % to + 63 %)¶

According to two meta-analyses of 18 studies, SSRIs during pregnancy correlate with a significantly increased risk of ADHD (OR = 1.26 = approx. + 26 %) and ASD (OR = 1.42 = approx. + 42 %) in children. It is not clear whether this results from the SSRIs or from an inheritance of psychological problems of the mother for which she was treated with SSRIs, as the risk of ADHD (OR = 1.63 = approx. + 63 %) and ASD (OR = 1.39 = approx. + 39 %) was also increased in the children if the mother took SSRIs or SNRIs before pregnancy but not during pregnancy.²⁷⁶²⁷⁷ a caring SSRI should be used with extreme caution during pregnancy.
A meta-analysis found no increased risk of ADHD in children in 7 of 8 studies of SSRIs during pregnancy.²⁷⁸ The same applies to another study.²⁷⁹ According to one study, antidepressants during pregnancy increased the likelihood of later ADHD in the child by 1.81 times.²⁸⁰

1.4.3. 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%.²⁸¹

1.4.4. Pregabalin during pregnancy (+ 29 %)¶

Prenatal pregabalin exposure increased the risk of ADHD by 29%, but this was attenuated when active comparators were taken into account.²⁸²

1.4.5. Antibiotics during pregnancy (+ 14 %)¶

Several meta-analyses found a 14% increased risk of ADHD due to antibiotic use by the mother during pregnancy.²⁸³²⁸⁴

1.4.6. Valproate during pregnancy (+ 12 %)¶

Valproate during pregnancy is said to increase the risk of ADHD for the unborn child.²⁸⁵
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 the age of 6 (which is still too early to diagnose all people with ADHD):

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

ASD was the most common diagnosis. 2% of children of medicated mothers were diagnosed with ADHD by the age of 6 and 1.5% with dyspraxia. No child in the controls had an ADHD diagnosis.²⁸⁶

1.4.7. Corticoids during pregnancy¶

Cortisol administration during pregnancy leads to long-term changes in the unborn child’s brain and increases the risk of ADHD.²⁸⁷ 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.²⁸⁸ In our opinion, the ADHD symptoms described in these children could possibly be the consequence of HPA axis alteration.
⇒ Corticosteroid receptor hypothesis of depression

High cortisol exposure of the fetus or newborn can cause methylation of the GAD1 / GAD67 gene, which encodes the key enzyme glutamate-to-GABA-synthesizing glutamate decarboxylase 1 and leads to increased glutamate levels. This epigenetic mechanism may increase the risk of ADHD in children.¹⁹⁹

Exposure to betamethasone during pregnancy only marginally increased the risk of ADHD in the offspring.²⁸⁹²⁹⁰

Dexamethasone during pregnancy in mice increased spontaneous activity in female offspring, while reducing it in males. Dexamethasone during pregnancy downregulated dopamine signaling and upregulated glutamate and GABA signaling in females.²⁹¹

1.4.8. Valproic acid during pregnancy¶

Offspring of mice that received valproic acid during pregnancy showed significantly increased hyperactivity and changes in the dentate gyrus.²⁹²²⁹³ In addition, there are indications of changes in the histaminergic system and social behavior.²⁹⁴
Valproic acid during pregnancy increases the risk of ADHD, ASD, reduced cognitive abilities and speech disorders in the offspring.²⁹⁵ In addition, it causes congenital malformations such as neural tube defects, heart anomalies, urogenital malformations (e.g. hypospadias, skeletal malformations and orofacial clefts) in 10 % of children, depending on the dose, especially at more than 600 mg/day. High doses of folic acid before and during pregnancy could reduce the risk. The concentration of valproin in breast milk appears to be low, which is why breastfeeding does not pose a risk.

1.4.9. Taking penicillin during pregnancy¶

Penicillin use by the mother during pregnancy increased the child’s risk of ADHD. The ADHD risk was increased by penicillin itself when taken 2 years before pregnancy. Taking penicillin more than once further increased the risk of ADHD.⁹

1.4.10. No increase in risk due to NSAIDs, normal caffeine consumption, benzodiazepines¶

A cohort study found no ADHD risk increase with non-steroidal anti-inflammatory drugs (NSAIDs) in pregnancy.²⁹⁶

Caffeine consumption during pregnancy below 10 cups a day did not increase the risk of ADHD.²⁹⁷

Benzodiazepines during pregnancy appear to increase the risk of internalizing problems in children (anxiety, emotional reactivity, somatic complaints), but not externalizing problems (hyperactivity, aggressiveness).²⁹⁸ A cohort study comparing siblings with and without benzodiazepine use by the mother during pregnancy found no significant risk increase for ADHD or ASD due to benzodiazepines; the authors rather suspect a connection with a genetic disposition of the mother.²⁹⁹ A meta-analysis also came to the conclusion that no relevant increase in the risk of ADHD in the offspring has been found for benzodiazepines during pregnancy, even though one study indicated a slight increase with benzodiazepine monotherapy in the last trimester of pregnancy.³⁰⁰ One study found a slight increase of 15% in the risk of ADHD when taking benzodiazepines during pregnancy.³⁰¹

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

1.5. Other pregnancy circumstances (up to + 30 %)¶

1.5.1. First-born status¶

A large Swedish cohort study found that first-born children have a higher risk of depression and ADHD in childhood and of endocrine disorders after the age of 50.³⁰²

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

Particularly short or particularly long intervals between pregnancies with the preceding sibling increased the risk of ADHD by 30% (less than 6 months) or 12% (60 - 119 months) to 25% (120 months and more).³⁰³

1.5.3. Protein deficiency during pregnancy and after birth¶

Rats whose mothers were fed a low-protein diet 15 days before conception and then continued to do so during lactation were significantly more susceptible to early childhood stressors (intraperitoneal injection of deltamethrin, lipopolysaccharide, or both) to develop ADHD symptoms such as hyperactivity, attention problems, and decreased anxiety.³⁰⁴

1.6. Pregnancy circumstances without influence on ADHD¶

The following factors were found to have no influence on the unborn child’s risk of ADHD:

• Iodine/creatinine ratio in the mother’s urine during pregnancy
  • A large study of 3 cohorts found no effect on ADHD or ASD risk³⁰⁵
• Migration of the mother
  • A meta-analysis found no evidence of an increased risk of ADHD due to maternal migration, but this was not the case with ASD.³⁰⁶
• Iron level of the mother
  • One study found no effect of the mother’s iron levels during pregnancy on the child’s risk of ADHD at age 7³⁰⁷
• Artificial insemination by intracytoplasmic sperm injection (ICSI)³⁰⁸

1.7 Preventive factors¶

1.7.1. Fiber intake of the mother during pregnancy¶

A high-fiber diet for the mother during pregnancy reduced the offspring’s risk of ADHD by up to 20 %.³⁰⁹
This was independent of genetic predisposition to ADHD, unhealthy diet and socio-demographic factors.

Fiber increases short-chain fatty acids in the intestine, which generally reduces the risk of mental health problems. More on this in the section Microbiome and short-chain fatty acids (SCFA) in ADHD Of the article Gut-brain axis as a cause of ADHD