1. Prenatal stressors as ADHD risk factors

Author: Ulrich Brennecke
Review (June 2024): 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 Animal studies may provide further clues.

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 extent to which the factors mentioned are causal for ADHD remains an open question. Several could also be a consequence of genetic causes that are passed on from mother to child and that influence the mother as much as the child. Example: Is smoking by a mother during pregnancy a cause of ADHD in the offspring or a result of genes in the mother that she passes on to the child at the same time? Methods that can help to clarify this are prenatal cross-fostering studies (egg donation and embryo donation from unrelated donors), prenatal cross-fostering studies (gestational surrogacy with an unrelated surrogate mother), children of identical twins, several pregnancies of the same mother with different environmental influences (e.g. with and without smoking) or comparisons between mother and father.² In addition, animal studies should be taken into account that allow comparisons that are not possible in humans for ethical reasons.

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

We have begun to identify the possible pathways through which environmental factors can cause ADHD.

• 1.1. Toxins before conception as risks for ADHD - epigenetic inheritance
  • 1.1.1. Nicotine consumption of one parent before conception (+ 259 %)
  • 1.1.2. Drug use by the mother before conception (+ 44 %)
  • 1.1.3. Penicillin intake up to 2 years before conception
  • 1.1.4. Silver nanoparticles over 4 generations
• 1.2. Toxins and harmful effects during pregnancy (up to + 778 %)
  • 1.2.1. Alcohol during pregnancy (up to + 778 %)
  • 1.2.2. Nicotine during pregnancy (up to + 478 %)
    • 1.2.2.1. Nicotine consumption of the mother during pregnancy (+ 49 % to + 478 %)
    • 1.2.2.1. Passive smoking during pregnancy
  • 1.2.3. Polycyclic aromatic hydrocarbons (PAH) (+ 99 to + 406 %)
  • 1.2.4. Lead disposition during pregnancy (up to + 243 %)
  • 1.2.5. Pesticides during pregnancy (up to + 171 %)
    • 1.2.5.1. Contact with organochlorine compounds during pregnancy (up to + 171 %)
    • 1.2.5.2. Organophosphate contact during pregnancy
    • 1.2.5.3. Pyrethroid contact before or during pregnancy (up to + 76 %)
    • 1.2.5.4. Glyphosate contact during pregnancy
    • 1.2.5.5. Neonicotinides
  • 1.2.6. Phthalates during pregnancy (up to + 142 %)
  • 1.2.7. Caffeine consumption during pregnancy (+ 130 %)
  • 1.2.8. Drug use by the mother during pregnancy (up to + 80 %)
  • 1.2.9. Copper (+ 51 %)
  • 1.2.10. Cadmium during pregnancy (+ 22 % to + 36 %)
  • 1.2.11. Manganese (up to + 34 %)
  • 1.2.12. Air pollution during pregnancy (up to + 26 %)
    • 1.2.12.1. Particulate matter (+ 26 %)
    • 1.2.12.2. Nitrogen oxides (nitrogen oxides) (+ 26 %)
    • 1.2.12.3. Ozone
  • 1.2.13. Polychlorinated biphenyls / polychlorinated biphenyl ethers (+ 23 %)
  • 1.2.14. Perfluoroalkyl compounds (PFAS) in pregnancy (up to + 23 %)
  • 1.2.15. Thallium during pregnancy
  • 1.2.16. Bisphenols during 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
• 1.3. Illnesses of the mother/parents (up to + 370 %)
  • 1.3.1. Itrahepatic cholestasis (ICP) in pregnancy (+ 7 % to + 370 %)
  • 1.3.2. Parental asthma during and outside pregnancy (+ 13% to + 330%)
  • 1.3.3. Increased or decreased thyroxine levels
    • 1.3.3.1. Increased or decreased thyroxine levels in the mother (up to + 310 %)
    • 1.3.3.2. Reduced and increased TSH values in newborns (+ 14 % in boys to + 310 % in girls)
  • 1.3.4. Maternal weight and eating disorders before or during pregnancy (+14% to +280%)
    • 1.3.4.1. Severe maternal obesity before or during pregnancy (+ 14 % to + 280 %)
    • 1.3.4.2. Eating disorders during pregnancy (+ 53 % to + 112 %)
  • 1.3.5. Pre-eclampsia (gestosis) in pregnancy (+ 23 % to + 277 %)
  • 1.3.6. Mental stress of the mother during pregnancy (+ 72 % to + 210 %; with 5HTTLPR + 800 %)
  • 1.3.7. Fever of the mother during pregnancy (+ 31 % to + 164 %)
  • 1.3.8. PTSD during pregnancy (+ 132 %)
  • 1.3.9. Chemical / drug intolerance (+ 110 % to 130 %; ASS + 201 % to 470 %)
  • 1.3.10. Depression of parents before / during / after pregnancy (up to + 100 %)
  • 1.3.11. Polycystic ovary syndrome (PCOS) in pregnancy (+ 31 to + 95 % in boys)
  • 1.3.12. Reduced C-reactive protein (CRP) (+ 92 %)
  • 1.3.13. Unhealthy diet of the mother during pregnancy (+ 60 %)
  • 1.3.14. Systemic lupus erythematosus (SLE) (+ 60 %)
  • 1.3.15. Threatened miscarriage (up to + 51 %)
  • 1.3.16. Diabetes of one parent; diabetes during pregnancy (+ 40 %)
  • 1.3.17. Migraine in parents (+ 37 %)
  • 1.3.18. Anemia of the mother during pregnancy (+ 31 %)
  • 1.3.19. Infections of the mother during pregnancy
    • 1.3.19.1. Infections in general (+ 30 %)
    • 1.3.19.2. Viral infections
    • 1.3.19.3. Urinary tract infections (+ 29 %)
  • 1.3.20. Fetal inflammatory response syndrome (FIRS) (+ 27 %)
  • 1.3.21. High blood pressure during pregnancy (+ 24 %)
  • 1.3.22. Insatiable nausea (hyperemesis gravidarum) (+ 16 %)
  • 1.3.23. Mineral and vitamin deficiency during pregnancy
    • 1.3.23.1. D3 deficiency during pregnancy
    • 1.3.23.2. Omega-3 fatty acid levels
      • 1.3.23.2.1 In the newborn
      • 1.3.23.2.2. During pregnancy
  • 1.3.24. Lack of sleep during pregnancy
  • 1.3.25. Testosterone during pregnancy
  • 1.3.26. Inflammation of the mother during pregnancy
  • 1.3.27. Bipolar Disorder in parent
• 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. Valproic acid during pregnancy (+ 39 %)
  • 1.4.4. Corticoids during pregnancy (+ 30 %)
  • 1.4.5. β-2-Adrenaline receptor agonists in pregnancy (+ 30 %)
  • 1.4.6. Pregabalin during pregnancy (+ 29 %)
  • 1.4.7. Antibiotics during pregnancy (+ 14 % to + 19 %)
  • 1.4.8. Antiepileptic drugs: Valproate in pregnancy (+ 12 %)
  • 1.4.9. Estrogens, progestins
• 1.5. Congenital disorders
  • 1.5.1. Congenital atrial septal defect or ventricular septal defect (+ 275 %)
• 1.6. Other pregnancy circumstances (up to + 100 %)
  • 1.6.1. First-born status (+ 31 to + 100 %)
  • 1.6.2. Particularly short or long intervals to the previous pregnancy (+ 25 % to + 30 %)
  • 1.6.3. Protein deficiency during pregnancy and after birth
  • 1.6.4. Western diet in the first and second trimester of pregnancy
  • 1.6.5. High salt consumption during pregnancy
• 1.7. Pregnancy factors without increased risk of ADHD
• 1.8. Pregnancy factors with risk reduction for ADHD
  • 1.8.1. Maternal sports during pregnancy > 20 minutes / day (up to minus 56 %)
  • 1.8.2. Fiber intake of the mother during pregnancy (up to minus 20 %)
  • 1.8.3. Mediterranean diet (up to minus 64 %)

1.1. Toxins before conception 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.¹⁵

Pathway: Epigenetics

1.1.2. Drug use by the mother before conception (+ 44 %)¶

Drug use (heroin, amphetamine, ketamine or other substances) by the mother before conception correlated with an increased risk of offspring (registry study, n = 1,969,006)²⁵

• by 43 % to 45 % for ADHD
• by 5 % for ASS
• by minus 18 % to minus 21 % for mental disability

1.1.3. Penicillin intake up to 2 years before conception¶

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.²⁶

Possible pathway: intestinal microbiome
Antibiotics influence the gut microbiome. The gut microbiome is passed on from the mother to the newborn during vaginal birth and breastfeeding (especially in the first three months). See there.

1.1.4. Silver nanoparticles over 4 generations¶

Offspring of rats that were orally administered silver nanoparticles were bred to be 1.8 times more hyperactive within 4 generations by selecting the hyperactive individuals.²⁷ The offspring appeared to maintain hyperactivity over generations via the DNA methylation status in the mesencephalon.
It is unclear to us whether the increased hyperactivity in the 4th generation is a consequence of breeding or a consequence of the silver nanoparticles.

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 (up to + 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.²⁸
The vast majority of studies have found that alcohol consumption by the mother during pregnancy significantly increases the likelihood of ADHD in her children.²⁹³⁰ up to 8.78-fold,³¹ Attention problems are also increased.³² In rats, the male offspring are particularly affected.³³
A combination of alcohol and stress in the mother during pregnancy increased the likelihood of male rats developing female sexual behavior.³⁴
47.2% of children with FAS (fetal alcohol syndrome) also had ADHD³⁵
In a Taiwanese cohort study of 5-year-old children, the risk of ADHD was increased by 71%, but not statistically significant.³⁶

There is evidence that alcohol consumption by the mother during pregnancy or while breastfeeding has a significant impact on the child’s dopamine system.^37383940 The regulation of the neurotransmitters serotonin , glutamate, noradrenaline, acetylcholine and histamine is also affected^{4142 43}

Individual studies found no connection between:

• Alcohol consumption during pregnancy and ADHD.⁴⁴⁴⁵⁴⁶
• Binge drinking in early pregnancy and ADHD risk in children aged 5 to 19 years.⁴⁷
  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.⁴⁸
  A meta-analysis found that maternal alcohol consumption of less than 70 g/week during pregnancy did not increase the risk of ADHD.⁴⁹ 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).⁵⁰

Pathways of action among others: Modification of the endocannabinoid system in relation to VTA⁵¹

1.2.2. Nicotine during pregnancy (up to + 478 %)¶

1.2.2.1. Nicotine consumption of the mother during pregnancy (+ 49 % to + 478 %)¶

Prenatal smoking correlates with an increased risk of ADHD for the offspring^{5253 54} on the

• 5.36-fold (increased by 436%)⁵⁵ and an increased risk of bipolar Disorder by 533%, major depression by 92%, anxiety disorder by 3%. Not significantly increased: ASD and schizophrenia.
• 4.78-fold (increased by 378 %)³¹
• 3.34-fold for the 10% heaviest smoking mothers⁵⁶
• 2.7-fold (increased by 170 %)⁵⁷
• 2.5-fold (increased by 150 %)⁵⁸
• 2.33-fold (+ 133 %) for smoking during pregnancy and one year after; ASA risk not statistically significantly increased (25-year cohort study, n = 16,365)⁵⁹
• 2.21-fold with high nicotine exposure (cotinine value >50 ng/ml)⁵⁶
• 1.75-fold for heavy smokers⁶⁰
• 1.60-fold (increased by 60 %) in the overall average of female smokers⁶⁰
• 1.58-fold (increased by 58%; meta-analysis, n = 17,304⁶¹
• 1.54-fold for light smokers ⁶⁰
• 1.54-fold (meta-analysis, k = 55, n = 4,016,522)⁶²
• 1.50-fold, even with passive smoking, but only for boys⁶³
• 1.50 times (here: risk of hyperactivity/impulsivity symptoms of the child)⁶³
• 1.49-fold⁶⁴
• 1.34-fold (OR) in a meta-analysis of k = 10 studies with n = 7,014; an OR of 2.19 each was found for CD and ODD⁶⁵
• 1.09-fold (OR) when maternal socioeconomic status, maternal age, maternal psychopathology, paternal age, paternal psychopathology, and infant birth weight were adjusted for gestational age

Other studies also found significantly increased risk values.^{66676817697071}

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

• 1.72-fold⁷²
• 3.21-fold⁷³⁷⁴

Two studies (with overlapping authors)²⁷⁵ , one study with a small number of subjects⁷⁶, one larger study⁴⁶ and one meta-analysis came to a different conclusion⁷⁷, one study found rather weak evidence.⁷⁸
Studies that distinguished maternal smoking during pregnancy from genetic influence found no evidence of a causal effect of prenatal smoking on ADHD risk⁷⁹
However, there are several arguments against this:

• the prenatal nicotine-exposed mouse is an animal model for ADHD^{8081 82} In addition, prenatal nicotine in the mouse model leads to reduced birth weight of the offspring⁸³, which is an ADHD risk factor in its own right.
• Studies have looked at prenatal smoking in relation to certain gene polymorphisms:
  • 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 9⁸⁴⁸⁵
      Another study confirms the involvement of DRD4-7R in gene-environment interactions.⁸⁶
• The ADHD risk of children of smoking mothers decreased somewhat when they stopped smoking:⁸⁷
  • Overall risk compared to the offspring of non-smokers:
    • ADHD: OR = 2.07 = 207 %, learning disability: OR = 1.93 = 193 %
  • when giving up smoking in the first trimester
    • ADHD: OR = 1.72 = 172 %, learning disability: OR = 1.52 = 152 %
  • if you stop smoking in the second or third trimester
    • ADHD: OR = 2.13 = 213 %, learning disability: OR = 1.82 = 182 %
  • do not give up smoking
    • ADHD: OR = 2.17 = 217 %, learning disability: OR = 2.10 = 210 %
• In rodents, nicotine consumed before conception causes ADHD in the offspring, and this ADHD is passed on epigenetically over several generations (see iben)

Rates of maternal smoking during pregnancy have been falling for a long time.59% of all pregnant women are said to have smoked between 1959 and 1966.⁷⁹ In Germany, the rate of mothers smoking during pregnancy fell from 19.9 % in 1996 to 2006 to 10.9 % in 2007 to 2016.⁸⁸⁸⁹ In the USA, the prevalence of smoking during pregnancy fell from 15.2 % in 2000 to 13.8 % in 2005⁹⁰ and to 7.2 % in 2021 ⁹¹ and to 5.4 % by self-report (subject to social desirability bias)⁹²
The prevalence of smoking after childbirth fell from 18.1 % in 2000 to 16.4 % in 2005⁹⁰ and in 2021 to 7.2 % after childbirth and 12.1 % reported smoking before pregnancy according to self-report⁹²
Smoking during pregnancy is also correlated with low education (2008: 4.3% if high school experience, 36% if no high school experience) and low socioeconomic status (2008: 7.4% if annual income $40k or more, 18.7% if annual income 150% of poverty line or less)⁹³, both of which are ADHD risk factors in their own right.
Nevertheless, over 70 million women in the EU smoked during pregnancy in 2020.⁹⁴

There are no studies on the extent to which smoking cessation during pregnancy has influenced ADHD prevalence. Although there are studies comparing the development of emotional problems 20 years apart⁹⁵, we have yet to find such a study explicitly in relation to ADHD. As there is much more awareness of ADHD today, it will be difficult to compare prevalence retrospectively. In addition, smoking during pregnancy, although highly correlated, is not the only trigger for ADHD, so conclusions to the effect that decreasing smoking rates during pregnancy have shown no effect on ADHD rates³ are, in our view, so difficult to substantiate that they are barely usable as an argument against causality of smoking during pregnancy for ADHD.
While the correlation between smoking and depression was still low in 1952 and 1970, in 1992 the risk of depression among smokers was three times higher than among non-smokers.⁹⁶ Subjects who became depressed started smoking more often, continued smoking more often and stopped smoking less often.

Paths of action:

Most experiments with prenatal nicotine exposure show a reduction in dopamine levels in the PFC and striatum.⁸² Under certain circumstances, increased dopamine levels were also shown.⁹⁷ ADHD is neurophysiologically closely associated with reduced dopamine levels in the dlPFC (impaired working memory) and striatum (impaired motivation and motor hyperactivity).
Smoking by people with ADHD should be distinguished from this - this increases dopamine levels (at least in the striatum), as it reduces DAT, which is too pronounced in ADHD and reduces extracellular dopamine levels in the striatum. Acute smoking thus increases dopamine levels in the striatum.
Prenatal nicotine

• reduces birth weight⁸³, which is a separate ADHD risk factor.
• increases the risk of apnea and hypoxia⁹⁸
• delays brain development⁹⁹.
• increases the risk of birth complications¹⁰⁰¹⁰¹ , which is an ADHD risk factor in its own right.

Maternal smoking during pregnancy alters the glutamate NMDA receptors in the laterodorsal tegmentum of the offspring.¹⁰² Another study also found changes in glutamatergic signaling in the hippocampus due to increased glutamate receptor expression,⁹⁴ 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.¹⁰³

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:¹⁰⁴

• 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.¹⁰⁵ 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.¹⁰⁶

It is possible that the effects of nicotine consumption by the mother during pregnancy could be compensated for by breastfeeding.¹⁰⁷

1.2.2.1. Passive smoking during pregnancy¶

Even passive smoking, i.e. passive exposure of the mother to nicotine smoke during pregnancy, increases the unborn child’s risk of later ADHD symptoms⁶³

• 4.6-fold (+ 360 %)¹⁰⁸
• to 1.20 times (+ 20%)⁶⁴

Similar results were found for the causation of dyspraxia (developmental coordination disorder) by passive smoking.¹⁰⁹
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.¹¹⁰
One study found no evidence of a correlation.⁷⁶

1.2.3. Polycyclic aromatic hydrocarbons (PAH) (+ 99 to + 406 %)¶

Prenatal exposure to polycyclic aromatic hydrocarbons appears to increase the damage caused by early childhood stress and promote later attention and memory problems¹¹¹
High prenatal PAH exposure correlated with

• Attention symptoms¹¹² according to DSM-IV (OR = 5.06, + 406 %)¹¹³. dose-dependent¹¹⁴
• ADHD total score according to DSM-IV (OR = 3.37, + 237 %)¹¹³¹¹⁵
• Anxiety and depression¹¹²¹¹⁶

A meta-analysis found that 4 studies by one author indicated a 1.57-fold increase in the risk of ADHD due to PAH (OR 2.57), while the total number of all studies indicated a doubled risk (OR 1.99), which was not significant¹¹⁷

PAH/PAH enter the body through microplastics and nanoplastics, among other things.¹¹⁸

1.2.4. Lead disposition during pregnancy (up to + 243 %)¶

Lead disposition during pregnancy^{119120 121} affects the mesocorticolimbic circulation and increases the offspring’s risk of ADHD.¹²²
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.¹²³ 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.¹²⁴
A doubling of lead in the umbilical cord blood increased hyperactivity 3.43-fold (+243%) at the age of 7 to 8 years only in boys, while girls showed no significant correlation¹²⁵

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.¹²⁶ Under similar conditions, male rat pups showed a tendency to serotonergic disorders of the mesocorticolimbic system and altered delay discounting.¹²⁷
Even a lead content in drinking water below the limit values is said to be problematic.¹²⁰
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.¹²⁸

Lead is a divalent cation that mimics Ca2+ and activates PKC signaling.¹²⁹

Arnsten¹³⁰ describes lead as a toxin that causes symptoms confusable with ADHD.

Paths of action:

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

• Impairment of the mesocorticolimbic dopaminergic system¹³¹
• Impairment of dopamine receptors¹³¹
• Impairment of attention regulation in the PFC¹³²
• Apoptosis¹³³
• Excitotoxicity¹³³
• Reduced cellular energy metabolism¹³³
• Impaired heme biosynthesis and anemia¹³³
• Oxidative stress¹³³
• Lipid peroxidation¹³³
• Changed activity of the second messenger system¹³³
• Altered neurotransmitter release¹³³
• Altered neurotransmitter receptor density¹³³
• Impaired neuropsychological functioning¹³³
• Impaired development and function of oligodendrocytes¹³³
• Abnormal myelin formation¹³³
• Abnormal neurotrophic factor expression¹³³
• Abnormal dendritic branching patterns¹³³
• Disorder of the blood-brain barrier¹³³
• Disorder of thyroid hormone transport into the brain¹³³
• Altered regulation of gene transcription¹³³
• Reduction of gray matter in the PFC, especially in the ACC¹³⁴

Lead also appears to trigger the following behaviors:

• Impulsiveness¹³²
• Sociopathic behavior¹³⁵¹³⁶
• Irresponsible behavior¹³⁵¹³⁶
• Criminal behavior¹³⁵¹³⁶
• Lower IQ¹³³
• Impaired academic performance¹³³

Lead poisoning is strongly correlated with crime rates and out-of-wedlock pregnancies in the USA.¹³⁵¹³⁶

Children with elevated blood lead levels are said to be particularly susceptible to other toxins in early childhood.¹³⁷ 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.

1.2.5. Pesticides during pregnancy (up to + 171 %)¶

1.2.5.1. Contact with organochlorine compounds during pregnancy (up to + 171 %)¶

Exposure to hexachlorobenzene during pregnancy increased the risk of ADHD in Spanish children between 1997 and 1999. Children with HCB concentrations of more than 1.5 ng/ml at birth showed an increased risk of social competence problems (RR = 4.04; + 304 %) and ADHD (RR = 2.71; + 171 %). Cognitive and psychomotor performance remained unimpaired.¹³⁸
A larger study of 7 European birth cohorts found no correlation between HCB or DDE (a breakdown product of DDT) in pregnancy or the first 2 years of life and ADHD.¹³⁹ Another study found a 4.71-fold increase in Strengths and Difficulties Questionnaire scores at 7 to 8 years of age only in girls when p,p’-DDE was doubled in umbilical cord blood, while boys showed no significant association¹²⁵
Children of mothers with high HCB serum blood levels in the first trimester (≥90th percentile) (but not if the mother was exposed to HCB during pregnancy) showed at 4 years:¹⁴⁰

• deteriorated perceptual performance
• deteriorated general cognitive abilities
• impaired executive functions
• impaired working memory

Organochlorine compounds (dichlorodiphenyltrichloroethanes (DDT), dieldrin, heptachlor, endosulfan) showed an effect on neuronal development in prenatal exposure, which (in rodents), e.g:¹⁴¹

• 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.

Organochlorine compounds are said to have been widely replaced commercially by organophosphates by the end of the 2010s, but are very persistent and therefore still present in the environment.³

1.2.5.2. Organophosphate contact during pregnancy¶

The organophosphates chlorpyrifos and diazinon showed significant effects on neonatal brain development, including on the dopaminergic system.¹⁴² Prenatal exposure to the common pesticide chlorpyrifos impaired IQ and working memory in children aged 7¹⁴³¹⁴⁴ and executive functions.¹⁴⁵

Organophosphates inhibit acetylcholinesterase (= the enzyme that breaks down acetylcholine).¹⁴¹ 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.¹⁴⁶

Chlorpyrifos disrupts the serotonin system. Contact during pregnancy can trigger tremor in children and impair cognitive and neurobehavioral development.³⁴

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.¹⁴⁷

A Norwegian cohort study found an increased risk of ADHD in the offspring when detected in the mother’s blood during pregnancy of:¹⁴⁸

• 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.¹⁴⁹¹⁵⁰

Chlorpyrifos inhibits the endocannabinoid degradation inhibitor FAAS. Chlorpyrifos thus leads to altered exploratory and social behavior in young rats during puberty.¹⁵¹

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.¹⁵²

1.2.5.3. Pyrethroid contact before or during pregnancy (up to + 76 %)¶

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%.¹⁵³

The pyrethroid deltamethrin apparently impairs the dopaminergic system in mice after early exposure:¹⁵⁴

• DAT reduced
• D1 receptor reduced
• Apoptosis

The pyrethroid deltamethrin damages long-term potentiation (LTP) at CA3-CA1 synapses in the hippocampus, a functional correlate of learning and memory.¹⁵⁵

Furthermore, there were (with prenatal, but not with postnatal exposure)¹⁵⁶ permanent changes in behavior with regard to:¹⁵⁴

• Movement activity
• Acoustic startle reflex
• Learning
• Memory

3-PBA and chlorpyrifos reinforce each other’s effect on ADHD.¹⁵³

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%.¹⁵³

Prenatal and lactational exposure to the pyrethroid pesticide deltamethrin at low doses (within the officially approved levels) in the adult mouse brain resulted in molecular disorders in signaling pathways regulating circadian rhythm and neuronal growth (MAP kinase) and behavioral changes relevant to neurodevelopmental disorders.¹⁵⁷

1.2.5.4. 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:¹⁵⁸

• 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 frequency 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.

Glyphosate is also suspected as a possible cause of ASD.¹⁵⁹

1.2.5.5. Neonicotinides¶

Neonicotinids are the most widely used type of insecticide. There are indications that neonicotinides can affect the offspring during pregnancy.¹⁶⁰ Neonicotinids lead to reduced brain regions, e.g. the striatum and the corpus callosum. The corpus callosum is often reduced in ADHD,

1.2.6. Phthalates during pregnancy (up to + 142 %)¶

According to most studies, phthalic acid esters increase the risk of ADHD for the unborn child,^{161162 163} although the links are still unclear.¹⁶⁴¹⁶⁵ An influence on the thyroid balance¹⁶⁶ and the inflammatory pathway¹⁶⁷ are discussed. Higher phthalate metabolites in the urine of pregnant women correlated with increased distractibility in preschool children¹⁶⁸ and with impaired executive functions¹⁶⁹.
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.¹⁷⁰
Prenatal phthalate exposure combined with a genetic predisposition to phthalate-induced inflammation increased the offspring’s risk of ADHD by 2.42-fold and ASD by 2.15-fold at 11.5 years of age.¹⁶⁷

1.2.7. Caffeine consumption during pregnancy (+ 130 %)¶

A study of n = 9,978 children found a correlation between prenatal caffeine intake, even at the widely recommended “safe” dose, and externalizing problems, especially conduct disorder, with very high Effect size, comparable to prenatal alcohol or cannabis. Internalizing problems were unchanged. In addition, with more than 3 cups of coffee per day, the BMI and the consumption of soft drinks was increased in the children. Prenatal caffeine exposure correlated with structural changes in the brain, including increased thickness of the posterior and inferior frontal cortex and altered depth of the parieto-occipital sulcus.¹⁷¹ Greater caffeine consumption during pregnancy correlated with increased internalizing and externalizing symptoms in parents.
A review found no correlation between caffeine consumption during pregnancy and ADHD in 4 out of 5 studies.¹⁷²

Caffeine consumption of 10 cups of coffee a day or more correlated with a 130% increased risk of ADHD in children.¹⁷³

One study found a small increase in risk from caffeinated soft drinks during pregnancy, but not from coffee or tea¹⁷⁴

Caffeine consumption during pregnancy below 10 cups a day did not increase the risk of ADHD ^{175 176 177 178 179 46180}

Children of mothers who drank tea continuously throughout pregnancy had higher scores for cognition, fine motor skills and gross motor skills than children whose mothers only drank tea in the first trimester of pregnancy. Tea consumption in the second and third trimester was more strongly associated with the results than tea consumption in the first trimester. Coffee consumption showed no significant correlation with the cognitive development of the children.¹⁸¹

Caffeine consumption during pregnancy correlates with an increased BMI of the children.^182183179

1.2.8. Drug use by the mother during pregnancy (up to + 80 %)¶

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 22.¹⁸⁴

7.7% of mothers used cannabis during pregnancy (meta-analysis, k = 17, n = 534,445).¹⁸⁵
A meta-analysis found a relatively small risk increase of 13% for ADHD, 4% for ASD, 29% for psychosis, 34% for anxiety and a 28% reduced risk for depression due to maternal cannabis use during pregnancy (k = 17, n = 534,445)¹⁸⁵
Cannabis use during pregnancy is associated by several studies with an increased risk of ADHD in children.¹⁸⁶¹⁸⁷
A study of n = 141,570 children of n = 117,130 mothers with found a reduced risk of offspring for ADHD (minus 16%) and disruptive behavior disorder (DBD, minus 17%).¹⁸⁸

Drug use (heroin, amphetamine, ketamine or other substances) by the mother during pregnancy correlated with an increased risk of offspring (registry study, n = 1,969,006)²⁵

• by 77 % to 80 % for ADHD
• by 35 % to 41 % for mental disabilities
• by minus 7 to minus 12 % for ASS

1.2.9. Copper (+ 51 %)¶

Copper accumulation in the placenta increased the risk of ADHD by 51%.¹⁸⁹

1.2.10. Cadmium during pregnancy (+ 22 % to + 36 %)¶

Exposure to cadmium 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%.¹⁹⁰
Cadmium accumulation in the placenta increased the risk of ADHD by 36%.¹⁸⁹
A doubling of cadmium in the umbilical cord blood increased emotional problems 1.53-fold (+ 53%) at the age of 7 to 8 years only in boys, while girls showed no significant correlation¹²⁵

Possible route of action: blood-brain barrier.¹⁹¹

1.2.11. Manganese (up to + 34 %)¶

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.¹⁹²
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.¹⁹³
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.¹⁹⁴
Manganese accumulation in the placenta increased the risk of ADHD by 34%.¹⁸⁹

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

One study found changes in the immune system of offspring due to air pollution.¹⁹⁵
A study of approximately 43,000 families in Shenzen found positive correlations of ADHD from the age of 3 with exposure to¹⁹⁶

• 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.¹⁹⁷

A meta-analysis found that more studies (without reference to pregnancy) affirmed a link between air pollution and ADHD than denied it.¹⁹⁸

1.2.12.1. Particulate matter (+ 26 %)¶

Introduction to air pollution and particulate matter at Air pollution in childhood

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/m³.¹⁹⁹
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.²⁰⁰ 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.¹¹⁵

In rats, inhaled printer particles led to a 5-fold increase in dopamine levels, probably due to increased synthesis rather than decreased degradation.²⁰¹

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:²⁰²

• 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:²⁰²

• Increased dopamine turnover in the hippocampus

Pre- and postnatally, particulate matter and gaseous pollutants reduced the expression of oxytocin receptors in the hippocampus²⁰³ and hypothalamus in rodents, with reduced maternal care behavior.²⁰⁴ Oxytocin and vasopressin communication appears to be disrupted by endocrine disrupting chemicals²⁰⁵, many of which are present in outdoor air.²⁰²

Studies found an association between PM2.5 and hyperactivity/attention symptoms (OR = 1.12)²⁰⁶, hyperactivity²⁰⁷, ADHD symptoms²⁰⁸ and between PM2.5 in the first trimester and a tendency towards attention problems and hyperactivity.²⁰⁹

Other studies found no link between PM2.5 and ADHD^210211212

A meta-analysis reports a correlation between PM10 and ASD.²¹³ One study differentiated the risk increase for ASD according to PM1 (+ 86 %), PM2.5 (+ 76 %) and PM10 (+ 68 %).²¹⁴

Particulate matter resul

1.2.12.2. Nitrogen oxides (nitrogen oxides) (+ 26 %)¶

Several studies found a correlation between nitrogen oxide exposure during pregnancy and ADHD.¹¹¹

• NOx correlated with hyperactivity, with a stronger association between ADHD and NO than between ADHD and NO2. (NO: aOR = 1.26)²¹²
• NO2 exposure during pregnancy correlated strongly with ADHD symptoms, such as
  • Impulsiveness
    • Interrupting others²⁰⁸
    • Inability to wait your turn when playing²⁰⁸
  • Attention problems
    • Carelessness when crossing the road²⁰⁸
    • Attention impaired at the age of 4-5 years²¹⁵
  • Hyperactivity²⁰⁷
  • Oppositional behavior (not an original ADHD symptom)
    • Lies²⁰⁸
    • Public Disorder²⁰⁸

Other studies found no significant or clear correlations between NOx and ADHD ^{210 206211}
One study found a correlation with ASD in children, but not with ADHD.²¹⁶

Emissions of nitrogen oxides in Germany fell by almost 2/3 between 1990 and 2020.²¹⁷

1.2.12.3. Ozone¶

Ozone caused in rats:²⁰²

• 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.²⁰⁷¹¹¹

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

Polychlorinated biphenyls (PCBs) can increase the risk of ADHD.²¹⁸ PCBs 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).²¹⁹ Polychlorinated biphenyls can act directly on dopaminergic processes to disrupt the dopamine system and produce Parkinson’s-like symptoms.²²⁰ Further studies also found dopamine-reducing effects of PFAS.²²¹²²² as well as influences on the acetylcholine, serotonin and glutamate neurotransmitter balance.²²³
PFOS can cross the placenta and the blood-brain barrier.²²⁴
Children of mothers with high PCB serum blood levels in the first trimester (≥90th percentile) (but not if the mother was exposed to PCBs during pregnancy) showed at 4 years:¹⁴⁰

• impaired working memory
• unchanged: Perceptual performance, general cognitive abilities, executive functions

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 years²²⁵
A statistically significant increase in the risk of ADHD was found in girls, but not in boys.
It is also possible that newer PFAS alternatives increase the risk of ADHD.²²⁶
A larger study of 7 European birth cohorts found no correlation between PCB-153 in pregnancy or the first 2 years of life and ADHD.¹³⁹

PFOS also increase the risk of obesity. This risk adds up to that of a high-fat diet (HFD). A combination of HFD and PFOS worsened general behavior, such as time spent in the center and rearing, while PFOS alone affected distance traveled. PFOS may thus promote hyperactivity, while a combination of PFOS and HFD altered social behaviors such as rearing and retreating. PFOS exposure affects calcium signaling, MAPK signaling pathways, ion transmembrane transport and developmental processes. The combination of HFD with PFOS enhances the effect of PFOS in the brain and affects signaling pathways related to ER stress, axon guidance and elongation, and neuronal migration. PFOS and HFD increase the effects on inflammatory pathways, regulation of cell migration and proliferation, and MAPK signaling pathways.²²⁴

1.2.14. Perfluoroalkyl compounds (PFAS) in pregnancy (up to + 23 %)¶

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.²²⁷ 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:²²⁸

• 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.²²⁹ Another study found an increased risk of ADHD in school children with low to moderate exposure to PFAS at 2 years of age.²³⁰

1.2.15. 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.²³¹

1.2.16. Bisphenols during pregnancy¶

Bisphenol A (BPA) increases the risk of ADHD (meta-analysis, k = 32, n = 15,669).²³²
Bisphenol A is one of the most commonly produced synthetic compounds in the world. BPA is found in epoxy resins and polycarbonate plastics, which are often used to store food and baby bottles.²³³
BPA can cross the placenta^{234235 236} and is found in human breast milk.²³⁷ BPA affects the gut-brain axis and the blood-brain barrier.^{238233239240241}

BPA can:

• impair memory (meta-analysis, k = 22)²⁴²
• impair cognitive abilities (meta-analysis, k = 22)²⁴²
• bind to estrogen receptors²³³²⁴²
• various structural and molecular changes in the brain cause²³³
• promote oxidative stress²³³
• change the expression level of several important genes and proteins²³³
• Neurotransmitters impair²³³
  • Change neurotransmitter levels (meta-analysis, k = 22)²⁴²
• Cause excitotoxicity²³³
• Promote neuroinflammation²³³
• damage the function of the blood-brain barrier²³³
• trigger neuronal damage²³³
• Promote apoptosis²³³
• disrupt intracellular Ca2+ homeostasis²³³
• reactive oxygen species (ROS) increase²³³
• influence intracellular lactate dehydrogenase release²³³
• reduce the axon length²³³
• cause microglial DNA damage²³³
• Trigger astrogliosis²³³
• cause significantly reduced myelination²³³
• acts as a broad-spectrum endocrine disruptor²⁴³
• is metabolized via glucuronidation²⁴³
  • this involves the attachment of glucose to the target molecule and is catalyzed by uridine-5’-diphospho-glucuronosyltransferases (UGTs)
  • the pathway between BPA glucuronidation efficiency and disease could be direct or indirect
    • direct pathway: free BPA is the actual culprit; impaired BPA detoxification causes increased BPA levels in sensitive tissues, where it can act as an endocrine disruptor
    • indirect pathway: BPA is not the causative agent, but BPA serves as a marker for the reduced glucuronidation efficiency of other compounds that are degraded by a similar combination of UGTs and efflux transporters as BPA
• inhibit the ERK-CREB-BDNF signaling pathway (meta-analysis, k = 22)²⁴²
• alter the expression of synaptic proteins (meta-analysis, k = 22)²⁴²
• affect the morphology of pyramidal neurons in the hippocampus (meta-analysis, k = 22)²⁴²
• Dysregulate thyroid hormones (meta-analysis, k = 22)²⁴²

Exposure to BPA increases the risk of neurological disorders, including

• neurovascular disorders (e.g. stroke)²³³
• neurodegenerative diseases (e.g. Alzheimer’s and Parkinson’s)²³³²⁴³
• Neurodevelopmental diseases
  • ADHD²⁴³; (meta-analysis, k = 32, n = 15,669).²³²
    • another meta-analysis found no clear result from pre- or postnatal exposure in children and adolescents (k = 46; n = 21,896)²⁴⁴
  • ASS²³³²⁴³
• Depression²³³
• emotional problems²³³
• States of anxiety²³³
• cognitive disorders²³³
• polycystic ovary syndrome (PCOS)²⁴³

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.³⁴ The dose given to the rat mothers during pregnancy and lactation was very low at 40 micrograms/kg/day.²⁴⁵
5 milligrams / cubic meter in the air we breathe causes eye irritation.²⁴⁶ A review confirmed evidence that bisphenol-A during pregnancy can increase the risk of ADHD in children, especially boys.¹⁶⁵

BPA and BPS caused greatly increased dopamine (3 to 5-fold) and greatly decreased serotonin (by 80 %) in mouse placentas. GABA remained unchanged.²⁴⁷ 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.²²⁰

1.2.17. Dioxin exposure during pregnancy¶

Children who were exposed to dioxin during pregnancy have an increased risk of ADHD.²⁴⁸

1.2.18. Prenatal exposure to sulphur dioxide¶

Prenatal exposure to sulfur dioxide (SO2) correlated with DNA methylation and increased ADHD symptoms ²⁴⁹²⁵⁰
According to a review¹¹¹, two other studies found no significant correlation.²¹²²⁰⁷

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.²⁵¹

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.²⁵² 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.²⁵³²⁵⁴

1.3. Illnesses of the mother/parents (up to + 370 %)¶

Psychiatric disorders in the family increased the child’s risk of ADHD 9.37-fold.¹⁰⁸

Children with ADHD were more likely to have mothers who had health impairments during pregnancy:⁷³

• Maternal illnesses during pregnancy:
  In 34.4% of children with ADHD, the mother had a medical 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 %

A 25-year observational cohort study, n = 16,365, found no statistically significant increase in risk of ADHD due to maternal illness independent of pregnancy, but a 1.52-fold (+ 52%) increase in risk of ASD.⁵⁹ Furthermore, infections of the mother during pregnancy were not a risk factor for ADHD, but for ASD of the offspring: 1.33-fold (+ 33 %)(25-year cohort study, n = 16,365)⁵⁹

1.3.1. Itrahepatic cholestasis (ICP) in pregnancy (+ 7 % to + 370 %)¶

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.²⁵⁵
An ICD increased the risk of ADHD / ASD:

• before the 28th week of pregnancy
  • 2.62 times the risk of ADHD (+ 162 %)
  • 1.69-fold ASS risk (+ 69 %)
• 28th to 36th week of pregnancy
  • 1.36 times the risk of ADHD (+ 36% (+ 37%))
  • 1.37-fold ASS risk
• after the 36th week of pregnancy
  • 1.07 times the risk of ADHD (+ 7 %)
  • 1.13-fold ASS risk (+ 13 %)

Of 30 people with ADHD in children with citrin-induced cholestasis, 14 were found to have ADHD (47%).²⁵⁶ Assuming an ADHD prevalence of 10% in children, this results in a 370% increased risk of ADHD.

1.3.2. Parental asthma during and outside pregnancy (+ 13% to + 330%)¶

Asthma in the mother during pregnancy increases the risk of ADHD and ASD in the offspring.²⁵⁷ 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%.²⁵⁸ Another study also found an increased risk of ADHD in the offspring of mothers with asthma, especially for girls.²⁵⁹
Children of mothers in the COPSAC2000 birth cohort (all of whom have asthma) have 3.3 times the risk of ADHD at 20%.²⁶⁰
Children of n = 106,163 mothers who had asthma during pregnancy showed a risk of:²⁶¹

• ADHD + 49 %
• ASS + 33 %
• motor development disorders + 37 %
• Learning disorders + 51 %

1.3.3. Increased or decreased thyroxine levels¶

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

Abnormal thyroid hormone levels during pregnancy can have profound effects on the development of the child’s brain and cognition²⁶²²⁶³ and impair

• Neurodevelopmental processes²⁶⁴
  • Cell differentiation
  • Neurite growth
  • Synaptogenesis
  • Myelination
• Neurotransmitter systems²⁶⁵
  • monoaminergic system
  • cholinergic system
  • which can lead to attention deficits and hyperactivity

Even transient subclinical thyroid abnormalities during pregnancy can have serious consequences.²⁶⁶ Correction of severe maternal hypothyroidism before the 3rd semester of pregnancy appears to prevent cognitive impairments²⁶⁷ and premature births .²⁶⁸

Studies on mice with a mutated human thyroid receptor TRb 1 gene (TRbeta transgenic mice)²⁶⁹ found that these

• normal thyroid hormone levels of triiodothyronine (T3) and thyroxine (T4) (euthyroid) except for a short period during postnatal development
• into adulthood
  • Changes in the dopaminergic system (increased dopamine turnover)
  • ADHD symptoms
    • Hyperactivity
    • Inattention
  • ADHD symptoms are reduced by MPH

One study found a 7% increased risk of ADHD in children with untreated mild thyroxine deficiency in the mother during early pregnancy.²⁷⁰ 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.²⁷¹ Another study also found evidence of thyroxine as a possible cause of ADHD,²⁷² another study found no influence of the mother’s thyroxine levels during pregnancy.²⁷³
A Norwegian cohort study found a 2.27-fold risk of ADHD (+127%) 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.²⁷⁴

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.²⁷⁵ Dopamine deficiency in the striatum / nucleus accumbens is responsible for hyperactive symptoms in ADHD.

One study found no influence of maternal hyperthyroidism or hypothyroidism detected and treated before the birth of the child on the child’s risk of ADHD or ASD.
However, maternal hyperthyroidism, which was first diagnosed and treated after the birth of the child, increased the risk of ADHD in the child by 23%, while hypothyroidism diagnosed in this way increased the risk of ASD by 34%.²⁷⁶

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

Children with congenital hypothyroidism (congenital hypothyroidism, connatal hypothyroidism) showed an incidence of ADHD of 3.97% (versus 1.87%, + 112%) and of ASD of 0.71% (versus 0.13% = + 346%).²⁷⁷
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%.²⁷⁸

Primary hypothyroidism in rodents reduced the gucose transporter GLUT1 in the brain, did not alter GLUT3 and compensatory increased hexokinase enzyme activity. However, these changes were only pronounced in the immediate neonatal period and disappeared after weaning²⁷⁹

1.3.4. Maternal weight and eating disorders before or during pregnancy (+14% to +280%)¶

1.3.4.1. 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 a factor of 2.8.²⁸⁰
• by 62 %²⁸¹
• by 57 % for ADHD and 42 % for ASD²⁸²
• by 46% for ADHD and CD, by 67% for eating disorders, by 55% for specific developmental disorders, by 44% for affective disorders, by 33% for anxiety disorders (aHR = 1.33) and by 23% for other behavioral and emotional disorders²⁸³
  • Being overweight (rather than obese) increased the risk of mental retardation by 26%, affective disorders by 15%, ADHD or CD by 12%, and other behavioral and emotional disorders by 9%²⁸³

The children’s risk of ADHD increased²⁸⁴

• by 23 % to 28 % due to overweight
• by 47 % to 89 % due to obesity
• by 88 % to 95 % due to severe obesity of the mother

Children of mothers who were overweight or underweight during pregnancy had an increased risk of mental disorders in a Finnish register study (n = 392,098 mothers, 649,956 children):²⁸⁵

• Severely overweight mother (BMI 35.0 and higher)
  • ADHD and CD: 1.88 (+ 88 %)
  • ASS: 1.74 (+ 74 %)
  • Social functioning problems and tics: 1.31 (+ 31 %)
  • Affective disorders: 1.67 (+ 67 %)
  • Fear: 1.51 (+ 51 %)
  • Feeding problems as an infant or child: 1.10 (+ 10 %, not statistically significant)
  • Sleep disorders: 0.99 (minus 1 %, not statistically significant)
  • Mental disability: 2.04 (+ 104 %)
  • Specific developmental disorders: 1.83 (+ 83 %)
• Overweight mother (BMI 30 to 34)
  • ADHD and CD: 1.48 (+ 48 %)
  • ASS: 1.51 (+ 51 %)
  • Social functioning problems and tics: 1.24 (+ 24 %)
  • Affective disorders: 1.31 (+ 31 %)
  • Fear: 1.29 (+ 29 %)
  • Feeding problems as an infant or child: 1.06 (+ 6 %, not statistically significant)
  • Sleep disorders: 1 (+ 0 %, not statistically significant)
  • Mental disability: 1.61 (+ 61 %)
  • Specific developmental disorders: 1.48 (+ 48 %)
• slightly overweight mother (BMI 24 to 29)
  • ADHD and CD: 1.19 (+ 19 %)
  • ASS: 1.16 (+ 16 %)
  • Social functioning problems and tics: 1.01 (+ 1 %, not statistically significant)
  • Affective disorders: 1.16 (+ 16 %)
  • Fear: 1.11 (+ 11 %)
  • Feeding problems as an infant or child: 0.96 (minus 4%, not statistically significant)
  • Sleep disorders: 1.08 (+ 8 %, not statistically significant)
  • Mental disability: 1.25 (+ 25 %)
  • Specific developmental disorders: 1.20 (+ 20 %)
• Underweight mother (BMI 18.5 and lower)
  • ADHD and CD: 1.05 (+ 5 %, not statistically significant)
  • ASS: 1.11 (+ 11 %)
  • Social functioning problems and tics: 1.18 (+ 18 %)
  • Affective disorders: 1.01 (+ 2 %, not statistically significant)
  • Fear: 1.10 (+ 10 %)
  • Feeding problems as an infant or child: 1.07 (+ 7 %, not statistically significant)
  • Sleep disorders: 0.98 (minus 2%, not statistically significant)
  • Mental disability: 1.33 (+ 33 %)
  • Specific developmental disorders: 1.18 (+ 18 %)

Even an excessive BMI of the mother before pregnancy increased the risk of ADHD in the later offspring.²⁸⁶ 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%.²⁸⁷
Other fluctuations in the mother’s weight before and at the end of pregnancy do not appear to influence the risk of ADHD.⁶⁶ In rats, however, there are indications of an influence on the dopamine balance of the offspring.²⁸⁸
A Norwegian registry study found only slight evidence of an influence of the mother’s pre-pregnancy BMI on the child’s risk of ADHD²⁸⁹

If high blood pressure was added to obesity, this led to an increased risk of:²⁸³

• + 219 % for affective disorders
• + 140 % for specific developmental disorders
• + 246 % for ASS
• + 174 % for ADHD or CD

Children of mothers with chronic hypertension and overweight had a higher risk of SDD (aHR = 1.58) and ADHD or CD (aHR = 1.43) compared with the reference group (Figure 1 and Table S2). Nevertheless, the effect sizes of the combined exposure were not larger than those of the individual exposure to chronic hypertension or obesity.

1.3.4.2. Eating disorders during pregnancy (+ 53 % to + 112 %)¶

Children of mothers with eating disorders during pregnancy had an increased risk of mental disorders in a Finnish register study (n = 392,098 mothers, 649,956 children):²⁸⁵

• Anorexia of the mother
  • ADHD and CD: 1.53 (+ 53 %)
  • ASS: 1.56 (+ 56 %)
  • Social functioning problems and tics: 2.16 (+ 116 %)
  • Affective disorders: 1.46 (+ 46 %)
  • Fear: 1.63 (+ 63 %)
  • Feeding problems as an infant or child: 1.24 (+ 24 %, not statistically significant)
  • Sleep disorders: 2.12 (+ 112 %)
  • Mental disability: 1.08 (+ 8 %, not statistically significant)
  • Specific developmental disorders: 1.37 (+ 37 %)
• Bulimia of the mother
  • ADHD and CD: 1.94 (+ 94 %)
  • ASS: 1.75 (+ 75 %)
  • Social functioning problems and tics: 2.48 (+ 148 %)
  • Affective disorders: 1.92 (+ 92 %)
  • Fear: 1.88 (+ 88 %)
  • Feeding problems as an infant or child: 1.88 (+ 88 %)
  • Sleep disorders: 2.35 (+ 135 %)
  • Mental disability: 0.89 (minus 11%, not statistically significant)
  • Specific developmental disorders: 1.09 (+ 9 %, not statistically significant)
• eating disorder of the mother not otherwise specified
  • ADHD and CD: 2.12 (+ 112 %)
  • ASS: 2.04 (+ 104 %)
  • Social functioning problems and tics: 2.79 (+ 179 %)
  • Affective disorders: 2.30 (+ 130 %)
  • Fear: 2.19 (+ 119 %)
  • Feeding problems as an infant or child: 2.69 (+169 %)
  • Sleep disorders: 3.34 (+ 234 %)
  • Mental disability: 1.18 (+ 16 %, not statistically significant)
  • Specific developmental disorders: 1.54 (+ 54 %)
• any eating disorder of the mother
  • ADHD and CD: 1.73 (+ 73 %)
  • ASS: 1.68 (+ 68 %)
  • Social functioning problems and tics: 2.18 (+ 118 %)
  • Affective disorders: 1.66 (+ 66 %)
  • Fear: 1.79 (+ 79 %)
  • Feeding problems as an infant or child: 1.59 (+59 %)
  • Sleep disorders: 2.36 (+ 138 %)
  • Mental disability: 1.16 (+ 16 %, not statistically significant)
  • Specific developmental disorders: 1.28 (+ 28%, not statistically significant)

1.3.5. Pre-eclampsia (gestosis) in pregnancy (+ 23 % to + 277 %)¶

The % figure in the heading was calculated by omitting the lowest and highest values.

Pre-eclampsia impairs the oxygen supply to the fetus and is often associated with high blood pressure in the mother. Both are also risk factors for ADHD in the offspring.

Pre-eclampsia (gestosis) during pregnancy increases the risk of ADHD in the child²⁹⁰²⁹¹

• by 408 %¹⁰⁸
• by 277 % (RR 2.77)²⁹²
• by 30 to 188 %²⁹³
• by 43 % (cohort study)²⁹⁴
• by 29 % (meta-analysis, k = 15)²⁹⁵
• by 19 %²⁹⁶

The risk of pre-eclampsia was increased at normal weight:

• • 48 % for mental disability²⁸³
• • 43 % for special developmental disorders²⁸³
• for ASS
  • by 43 %²⁸³
  • by 27 % (meta-analysis, k = 15)²⁹⁵ - + 23 % for ADHD or CD²⁸³
• • 35 % for epilepsy (meta-analysis, k = 15)²⁹⁵
• • 34 % for other behavioral and emotional disorders²⁸³

The risk of pre-eclampsia was increased in those who were overweight compared to both the reference group and those who had either only pre-eclampsia or only obesity:²⁸³

• • 123 % for affective disorders
• • 85 % for anxiety disorders
• • 82 % for special developmental disorders
• • 115 % for other behavioral and emotional disorders

Obesity increased the risk of pre-eclampsia:²⁸³

• • 94 % for ADHD or CD
• • 98 % for other behavioral and emotional disorders

High blood pressure during pregnancy increased the risk of ADHD by 24% (HR: 1.24), of ASD by 29% (HR: 1.29) and of mental retardation by 58% (HR: 1.58). The cause was mostly pre-eclampsia.²⁹⁷²⁹¹

Pre-eclampsia together with a urinary tract infection increased the risk by 53%.²⁹⁶

Gestational gestosis in slightly premature infants increased the risk of the offspring having impairments in gross and fine motor skills, adaptability, language and social-emotional response, as well as abnormal rates.
While at the age of 3 to 6 months no deviations in the areas mentioned were detectable, at the age of 12 months there was a significant deterioration in gross motor skills and fine motor skills with a significantly reduced risk of abnormal speech values.²⁹⁸

Several reviews confirm an increased risk of ADHD due to pre-eclampsia in pregnancy.²⁹⁹³⁰⁰

Maternal pre-eclampsia as a risk factor for ADHD in offspring has been confirmed in different populations and using different methods. For example, both a population-based case-control study in Western Australia [41] and research from the Millennium Cohort Study (MCS) [42] show that preeclampsia is associated with an increased risk of ADHD in offspring. Genitourinary infections in the mother associated with pre-eclampsia increase the likelihood of ADHD, suggesting that maternal comorbid conditions increase this risk [43]. A similar finding is reported in a large cohort study with data from over 7200 children from the Avon Longitudinal Study of Parents and Children, which found that maternal preeclampsia almost tripled the risk of ADHD in children aged 7 and 10 years, confirmed by log-binomial regression and generalized estimating equation models [44]. A meta-analysis summarizes these findings and confirms that intrauterine exposure to preeclampsia consistently increases the risk of ADHD in all studies [34]. Overall, exposure to maternal preeclampsia probably increases the risk of ADHD in the offspring.

1.3.6. Mental stress of the mother during pregnancy (+ 72 % to + 210 %; with 5HTTLPR + 800 %)¶

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

• by 400 % (OR = 5.02).³⁰³
• by 210% for boys born to mothers who had a child or spouse during pregnancy ³⁰⁴
• by 147% in boys born to mothers who had suffered the death of a child or spouse in the 0-6 months prior to pregnancy³⁰⁴
• by 100 %³⁰⁵
• aDHD symptoms increased by 95% at 16 years, but no increased hyperactivity symptoms at 8 years (minus 13%)³⁰⁶
• by 72% for boys born to mothers who had suffered the unexpected death of a child or spouse³⁰⁴
• by 72 %³⁰⁷
• by 60 %; no statistically significant increase in ASA risk (25-year cohort study, n = 16,365)⁵⁹
• by 31% due to maternal stress in the third trimester (and by 58% for ASA)³⁰⁸

Persistent and severe (anxiety-induced, perceived threatening = cortisolergic) stress significantly increases the risk of screaming children³⁰⁹ (see also 2.2.2.3.2), anxiety disorders and ADHD.^{310311312313314}
Persistent stress (here: financial problems) is more harmful than short-term stress (here: loss of a loved one).³¹⁵
High anxiety/threatening perceived stress also significantly increases the risk of borderline PS in children.

Children with ADHD were more likely to have mothers who experienced stress or emotional problems during pregnancy:⁷³

• 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.³¹⁶
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.³¹⁷ 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.³¹⁸³¹⁹

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.³²⁰ 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 5.³²¹
So it seems to depend very much on the time of the stress experience.

Severe anxiety in the mother during pregnancy increased the unborn child’s risk of ADHD depending on its COMT gene variant (gene-environment interaction).³²²
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.³²³

A combination of the 5HTTLPR L/L genotype and stress during pregnancy caused an eight times higher risk of ADHD-C or ADHD-HI.³²⁴

Children with ADHD whose mothers were exposed to moderate and severe stress during pregnancy tend to develop more severe ADHD symptoms.³²⁵

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.³²⁶ 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.³²⁷ Exposure to glucocorticoids during hippocampal development in pregnancy influences the starting point of the stress response through epigenetic changes via mRNA and methylation.³²⁸ 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.³²⁹
Another study also describes epigenetic changes in the unborn child due to the mother’s psychological stress during pregnancy.³³⁰
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.³³¹
Exposure of the mother to a natural disaster during pregnancy increased the risk of ADHD.³³²

Maternal stress during pregnancy or birth complications such as maternal infections during pregnancy or lack of oxygen during birth also increase the risk of other disorders such as schizophrenia.³³⁸

1.3.7. 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.³³⁹

1.3.8. 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.³⁴⁰

1.3.9. 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.³⁴¹³⁴²

1.3.10. Depression of parents before / during / after pregnancy (up to + 100 %)¶

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.³⁴³

A cohort study found

• Parental depression increased the risk of offspring depending on the time of onset of depression for (data in HR):³⁴⁴
  • ADHD (prenatal 1.95 = increased by 95 %, any time: 1.98 = increased by 98 %, postnatal: 2.0 = increased by 100 %)
  • ASD (prenatal 1.76, any time1.52)
  • Tic disorders (prenatal 1.52, any time 1.40)
  • Developmental delay (prenatal 1.40, any time 1.32, postnatal 1.24)
  • Language development disorder (prenatal 1.29, any time 1.17)
  • Developmental coordination disorder (HR: 1.73, any time 1.76, postnatal 1.78)
  • Mental disability (any time 1.26)

ADHD risk was increased (meta-analysis, k = 21, 796,157 mother-child pairs)³⁴⁵

• by 67% due to antenatal depression of the mother (prenatal)
• by 53 % due to postnatal depression of the mother (after birth)

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.³⁴⁶

1.3.11. 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.³⁴⁷³⁴⁸

It is possible that a connection could result from the fact that one treatment method is the use of dopamine agonists.³⁴⁹³⁵⁰ 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.³⁵¹ 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).³⁵² 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 symptoms³⁵³

1.3.12. 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.³⁵⁴

1.3.13. 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%.³⁵⁵
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.

1.3.14. 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.³⁵⁶
ADHD, for its part, is associated with a 2.17-fold risk of lupus.³⁵⁷

1.3.15. Threatened miscarriage (up to + 51 %)¶

If there was a threat of miscarriage during pregnancy, this increased the risk of

• ADHD by 51 %³⁵⁸
• ADUS by 21 % (adjusted) to 31 %³⁵⁹
• ASS by 55 %.³⁵⁸

1.3.16. 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.³⁶⁰

Diabetes in the mother before or during pregnancy increases the offspring’s risk of ADHD³⁶¹, in the case of gestational diabetes mellitus as well as pre-existing type 1 diabetes mellitus or type 2 diabetes mellitus,³⁶² and also for ASD.^363364365
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.³⁶⁶
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.³⁶⁷

1.3.17. 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:³⁶⁸

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

1.3.18. 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%). ³⁶⁹

In a small Lebanese correlational study (n = 119), maternal anemia during pregnancy increased the risk of ADHD 3.7-fold (OR = 3.654).³⁰³

1.3.19. Infections of the mother during pregnancy¶

1.3.19.1. 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.³⁷⁰ A register-based cohort study (n = 2,885,662 of which n = 1,864,660 were full siblings) found a slight increase of 14 % (ASD + 19 %; mental retardation + 21 %), which was lost when twins were controlled for³⁷¹
Mycoplasma antibodies at birth were associated with a 30% increased risk of ADHD later in life.³⁷²

1.3.19.2. Viral infections¶

A viral infection of the mother during pregnancy increases the risk of ADHD for the offspring³⁷³ and can influence the development of the unborn child’s dopaminergic system, e.g.:³⁷⁴

• 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 for³⁷⁵
    • ASS
    • ADHD
    • Developmental disorders
• Enterovirus 71
• Herpes virus 6
• Influenza A
• Cytomegalovirus (+ 30 %)³⁷²

A connection seems less certain for

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

Birth complications such as maternal infections during pregnancy, maternal stress during pregnancy or lack of oxygen during birth also increase the risk of other disorders³⁷⁶, such as schizophrenia³³⁸, ASD³⁷⁷ or depression.³⁷⁶

1.3.19.3. Urinary tract infections (+ 29 %)¶

A urinary tract infection in the mother during pregnancy was associated with a 29% increased risk of ADHD.²⁹⁶ Chlamydia/non-onococcal urethritis, trichomoniasis, urinary tract infections and candidiasis increased the risk of ADHD, while gonorrhea did not.

A urinary tract infection and pre-eclampsia increased the risk by 53%.²⁹⁶

Another study also found an increased risk of ADHD as a result of urinary tract infections in the mother during pregnancy³⁷⁸

1.3.20. 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:³⁷⁹

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

1.3.21. High blood pressure during pregnancy (+ 24 %)¶

High blood pressure during pregnancy significantly increases the risk of ADHD in the offspring.³⁰⁰. Hypertension during pregnancy increased the risk of ADHD by 24% (HR: 1.24), ASD by 29% (HR: 1.29) and mental retardation by 58% (HR: 1.58). The cause was mostly pre-eclampsia.²⁹⁷ High blood pressure during pregnancy increased the risk of depression by 130%.³⁸⁰

If obesity was added to chronic high blood pressure, this led to an increased risk of:²⁸³

• • 246 % for ASS
• • 219 % for affective disorders
• • 140 % for specific developmental disorders
• • 174 % for ADHD or CD

If overweight (instead of obesity) was added to high blood pressure during pregnancy, this resulted in an increased risk of (compared to high blood pressure or obesity alone):²⁸³

• • 143 % for anxiety disorders
• • 145 % for ADHD or CD

If obesity was added to gestational hypertension, this resulted in an increased risk of (compared to unaffected individuals):²⁸³ (Effect sizes of combined exposure were not greater than those of individual exposure to gestational hypertension or obesity):

• • 60 % for anxiety disorders
• • 40 % for ADHD or CD
• • 84 % for affective disorders
• • 76 % for specific developmental disorders

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.

1.3.22. 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%³⁸¹

1.3.23. 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.

1.3.23.1. D3 deficiency during pregnancy¶

Vitamin D3 deficiency during pregnancy and after birth causes permanent maldevelopment of the brain, particularly the dopaminergic system ^{382 383 384385}

In a meta-analysis, studies with larger sample sizes and stricter definitions of vitamin D deficiency showed positive associations for ADHD³⁸⁶³⁸⁷ and schizophrenia.³⁸⁷ D3 deficiency during pregnancy reduces dopamine turnover in the offspring’s brain³⁸⁸ with a reduction in COMT.³⁸⁹

**D3 deficiency during pregnancy increases risk: 7 studies **

A study in Finland 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 %.³⁹⁰
The incidence of ADHD-like symptoms in children decreased by 11% for every 10 ng/ml increase in maternal 25(OH)D levels.³⁹¹ A relatively 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 the risk of ADHD or ASD³⁹²
The severity of the offspring’s ADHD symptoms correlated with the level of maternal 25(OH)D deficiency ³⁹³³⁹⁴
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.³¹⁴
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.
Rodents whose mothers had a vitamin D deficiency showed typical ADHD symptoms:³⁹⁵

• 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

D3 deficiency during pregnancy does not increase the risk of ADHD: 3 studies

Reduced vitamin D3 serum levels in the mother at 30 weeks’ gestation correlated significantly with depression in the offspring up to the age of 22, but not with ADHD³⁹⁶
A comprehensive long-term study in Spain on vitamin D3 deficiency during pregnancy found no correlation between low D3 blood levels in the mother during pregnancy and ADHD in children aged 5 to 18 years.³⁹⁷ Similarly, a Norwegian cohort study found no correlation between maternal vitamin D levels during pregnancy and the offspring’s later risk of ADHD, but did find a correlation between ASD and (Consequences) lower vitamin D levels and ADHD and (Consequences) lower omega-3 levels.³⁹⁸

1.3.23.2. Omega-3 fatty acid levels¶

1.3.23.2.1 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 this³⁹⁹

1.3.23.2.2. 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).⁴⁰⁰

1.3.24. 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.⁴⁰¹
Sleep problems during pregnancy correlated with an increased risk of neurodevelopmental disorders and sleep problems in early childhood.⁴⁰², 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

1.3.25. Testosterone during pregnancy¶

Prenatal testosterone exposure correlated significantly with inattention and hyperactivity/impulsivity in the offspring.⁴⁰³ Elevated maternal testosterone levels during pregnancy correlated significantly with increased ADHD signs in the children at 6 months and 2 years of age.³¹⁴

1.3.26. Inflammation of the mother 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).⁴⁰⁴⁴⁰⁵

1.3.27. Bipolar Disorder in parent¶

Having a parent with bipolar disorder increased the children’s risk of ADHD.⁴⁰⁸

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:⁷³

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.⁴⁰⁹
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.⁴¹⁰⁴¹¹ Further studies confirm this.^412413414 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.⁴¹⁵⁴¹⁶

The risk of ADHD from paracetamol (acetaminophen) increases when taken⁴¹⁷

• 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.³³⁹
A meta-analysis confirms the increased risk of ADHD and ASD in offspring when taking paracetamol during pregnancy⁴¹⁸

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)⁴¹⁹

One study questions the previous critical results by focusing on parents’ ADHD diagnoses that have not been taken into account to date.⁴²⁰ Damkier is also doubtful.⁴²¹⁴²² Another study found no evidence of an increased risk of ADHD or ASD from paracetamol during pregnancy.⁴²³ A review also found no association⁴²⁴

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.⁴²⁵
The damage to the development of the offspring caused by paracetamol during pregnancy appears to be mediated by changes in the endocannabinoid pathway⁴²⁶
Paracetamol is also suspected as a possible cause of ASA.¹⁵⁹
In any case, the evidence that paracetamol increases the risk of ADHD during pregnancy is so strong that pregnant women should be warned against taking it.⁴²⁷

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

Possible pathway: Cannabinoid pathway / CB1R.⁴²⁸

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.⁴²⁹⁴³⁰ 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.⁴³¹ The same applies to another study.⁴³² According to one study, antidepressants during pregnancy increased the likelihood of later ADHD in the child by 1.81 times.⁴³³

1.4.3. Valproic acid during pregnancy (+ 39 %)¶

Valproic acid increased the risk of ADHD in offspring by 39% (meta-analysis, k = 22)⁴³⁴ It also increased the risk of congenital malformations by 147% to 830%, autism by 70% to 338%, impaired motor development by 600% and mental retardation and low IQ by 140% to 338%.
Offspring of mice that received valproic acid during pregnancy showed significantly increased hyperactivity and changes in the dentate gyrus.⁴³⁵⁴³⁶ In addition, there are indications of changes in the histaminergic system and social behavior.⁴³⁷
Valproic acid during pregnancy increases the risk of ADHD, ASD, reduced cognitive abilities and speech disorders in the offspring.⁴³⁸ In addition, it causes congenital malformations such as neural tube defects, cardiac 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.

1.4.4. Corticoids during pregnancy (+ 30 %)¶

Glucocorticoid administration during pregnancy increased the risk of ADHD in the offspring by 30%.⁴³⁹ The risk of ASD was increased by 30 % to 50 %, the risk of depression, anxiety and stress-related disorders by 40 % to 50 % and the risk of mental retardation by 30 %.
Corticoid administration during pregnancy leads to long-term changes in the unborn child’s brain and increases the risk of ADHD.⁴⁴⁰ 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.⁴⁴¹ 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.³²⁷

Exposure to betamethasone during pregnancy only marginally increased the risk of ADHD in the offspring.⁴⁴²⁴⁴³

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.⁴⁴⁴

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

Taking β-2 adrenaline receptor agonists (beta-2 sympathomimetics) during pregnancy increases the risk of ADHD for the child by up to 30%.⁴⁴⁵

1.4.6. 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.⁴⁴⁶

1.4.7. Antibiotics during pregnancy (+ 14 % to + 19 %)¶

Several meta-analyses found a 14% increased risk of ADHD due to the mother taking antibiotics during pregnancy ⁴⁴⁷⁴⁴⁸
Exposure to antibiotics in the womb increased the child’s risk of: (meta-analysis, k = 30, n = 7,047,853)⁴⁴⁹

• ADHD: + 19 %
• ASS: + 9 %

Penicillin use by the mother during pregnancy increased the child’s risk of ADHD. The ADHD risk was increased by penicillin even when taken 2 years before pregnancy. Repeated penicillin intake further increased the risk of ADHD.²⁶

Pathway of action: alteration of the microbiome.⁴⁵⁰

1.4.8. Antiepileptic drugs: Valproate in pregnancy (+ 12 %)¶

Valproate during pregnancy is said to increase the risk of ADHD for the unborn child.⁴⁵¹
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.⁴⁵²

A large-scale cohort study found an increased risk of ASD (+ 110%) and ADHD (+ 43%) in children of mothers who had taken antiepileptic drugs during pregnancy. The risk was mainly due to valproate.⁴⁵³ Compared to mothers with epilepsy who did not take antiepileptic drugs during pregnancy, which only increased the risk of ASD by 38%.

The use of the antiepileptic drug topiramate during pregnancy is being discussed in relation to a possible increase in the risk of ADHD for the offspring⁴⁵⁴

1.4.9. Estrogens, progestins¶

Before they were banned in the 1970s and 1980s, millions of pregnant women worldwide were given synthetic sexuahomones such as oestrogens or progestogens.
Some progestins are still prescribed today.

Children of women treated in this way have an increased risk of:⁴⁵⁵

• ADHD
• ASS
• Psychoses
• Schizophrenia
• bipolar disorders
• severe depression
• States of anxiety
• Eating disorders

The other offspring of the people with ADHD are also affected (3rd generation: especially ADHD, ASD, bipolar disorder). In the 4th generation, which is still very young, the first signs are visible, such as dyspraxia, which is often a harbinger of ADHD
Estrogens and progestins appear to mediate their damage epigenetically via hypermethylation of the ZFP57 and ADAMTS9 genes, which are important for neurological development.

1.5. Congenital disorders¶

1.5.1. Congenital atrial septal defect or ventricular septal defect (+ 275 %)¶

Children with a congenital atrial septal defect or ventricular septal defect are 3 to 4 times more likely to have inattention and hyperactivity symptoms. One study found an SDHD prevalence of 15% compared to the control group of 4% (+ 275%).⁴⁵⁶

1.6. Other pregnancy circumstances (up to + 100 %)¶

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

See under First-born status In the article Physical ADHD risk factors

1.6.2. 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).⁴⁵⁷

1.6.3. 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.⁴⁵⁸

1.6.4. Western diet in the first and second trimester of pregnancy¶

A Western diet (high in fat, refined grains and processed foods, low in fruit and vegetables; also known as the Standard American Diet (SAD)) in the first and second trimester of pregnancy is associated with an increased risk of ADHD and ASD in the offspring.⁴⁵⁹

1.6.5. High salt consumption during pregnancy¶

A high salt intake from food during pregnancy could increase the unborn child’s sensitivity to stress.⁴⁶⁰

1.7. Pregnancy factors without increased risk of 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 risk⁴⁶¹
• 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.⁴⁶²
• 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 7⁴⁶³
• Artificial insemination⁴⁶⁴⁴⁶⁵ through sperm donation⁴⁶⁶ or intracytoplasmic sperm injection (ICSI)⁴⁶⁷
• non-ionizing magnetic field radiation during pregnancy
  • A study that had initially found an increased ADHD rate in offspring of mothers who were most exposed to non-ionizing magnetic field radiation (“electro-smog”) during pregnancy (in a 24-hour measurement)⁴⁶⁸ has been withdrawn⁴⁶⁹. The updated version finds no correlation between particularly high non-ionizing magnetic field radiation and ADHD.
• A cohort study found no ADHD risk increase with non-steroidal anti-inflammatory drugs (NSAIDs) in pregnancy.⁴⁷⁰
• Benzodiazepines during pregnancy appear to increase the risk of internalizing problems in children (anxiety, emotional reactivity, somatic complaints), but not externalizing problems (hyperactivity, aggressiveness).⁴⁷¹ 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.⁴⁷² 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.⁴⁷³ One study found a slight increase of 15% in the risk of ADHD when taking benzodiazepines during pregnancy.⁴⁷⁴
• prenatal oxytocin exposure does not appear to affect ADHD and ASD risk⁴⁷⁵
• Bionutrients during pregnancy⁴⁷⁶
• Triptans during pregnancy⁴⁷⁷

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

1.8. Pregnancy factors with risk reduction for ADHD¶

1.8.1. Maternal sports during pregnancy > 20 minutes / day (up to minus 56 %)¶

Among n = 4,184 children aged 3 to 6 years, a reduced risk of ADHD was found when mothers during pregnancy daily:⁴⁷⁸

• did 20 to 40 minutes of sports: minus 56 %
• did more than 40 minutes of sports: minus 51 %

compared to children of mothers who did less than 20 minutes of sports per day.
Since ADHD is usually not diagnosed until the age of 7 and up, the overall effect is likely to be even greater.

1.8.2. Fiber intake of the mother during pregnancy (up to minus 20 %)¶

A high-fiber diet for the mother during pregnancy reduced the offspring’s risk of ADHD by up to 20 %.⁴⁷⁹
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

1.8.3. Mediterranean diet (up to minus 64 %)¶

The mother’s adherence to the Mediterranean diet during pregnancy reduced the risk of behavioral problems at the age of 4 years:⁴⁸⁰

• Overall problems (OR = 0.42)
• Externalizing symptoms (OR = 0.29)
• Attention problems (OR = 0.32)
• ADHD (OR = 0.36)
• oppositional defiant behavior (OR = 0.06)
• depressive problems (OR = 0.38)