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 levels of omega-3 fatty acids 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.

A cohort study found that 78% of all children were exposed to at least one prenatal risk factor. The number of prenatal risk factors correlated in a dose-dependent manner²

• with an increased risk of clinically significant psychopathology according to the CBCL
  • Risk increase for ADHD decreases with age
  • Increased risk of depressive symptoms over time
• with accelerated age-related cortical thinning in 36 of 68 cortical regions
• with higher overall CBCL problems and accelerated cortical thinning in 5 cortical regions in siblings

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 which 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), studies on prenatal cross-fostering (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.³ 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.

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.
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 parents before conception (+ 44 %)
  • 1.1.3. Penicillin intake up to 2 years before conception
  • 1.1.4. Silver nanoparticles over 4 generations
  • 1.1.5. Few green spaces in the area before conception (+ 6 %)
• 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. Intrahepatic cholestasis (ICP) in pregnancy (+7% to +370%)
  • 1.3.2. Parental asthma during and outside pregnancy (+ 26% to + 330%)
    • 1.3.2.1. Asthma in the mother during pregnancy
    • 1.3.2.2. Asthma of the father
  • 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. Crohn’s disease / ulcerative colitis (+ 95 %)
  • 1.3.12. Polycystic ovary syndrome (PCOS) in pregnancy (+ 31 to + 95 % in boys)
  • 1.3.13. Reduced C-reactive protein (CRP) (+ 92 %)
  • 1.3.14. Cerclage for cervical weakness (up to + 70 %)
  • 1.3.15. Rheumatic diseases / Disorders of the musculoskeletal system (+ 64 %)
  • 1.3.16. Unhealthy diet of the mother during pregnancy (+ 60 %)
  • 1.3.17. Systemic lupus erythematosus (SLE) (+ 60 %)
  • 1.3.18. Threatened miscarriage (up to + 51 %)
  • 1.3.19. Diabetes of one parent; diabetes during pregnancy (+ 20 % to + 150 %)
  • 1.3.20. Migraine in parents (+ 37 %)
  • 1.3.21. Immune disorders (+ 36 %)
  • 1.3.22. Anemia of the mother during pregnancy (+ 31 %)
  • 1.3.23. Infections of the mother during pregnancy
    • 1.3.23.1. Infections in general (+ 30 %)
    • 1.3.23.2. Viral infections
    • 1.3.23.3. Urinary tract infections (+ 29 %)
  • 1.3.24. Fetal inflammatory response syndrome (FIRS) (+ 27 %)
  • 1.3.25. High blood pressure during pregnancy (+ 24 %)
  • 1.3.26. Allergies during pregnancy (+ 20 % to 23 %)
  • 1.3.27. Insatiable nausea (hyperemesis gravidarum) (+ 16 %)
  • 1.3.28. Mineral and vitamin deficiency during pregnancy
    • 1.3.28.1. D3 deficiency during pregnancy
    • 1.3.28.2. Omega-3 fatty acid levels
      • 1.3.28.2.1 In the newborn
      • 1.3.28.2.2. During pregnancy
  • 1.3.29. Lack of sleep during pregnancy
  • 1.3.30. Testosterone during pregnancy
  • 1.3.31. Inflammation of the mother during pregnancy
  • 1.3.32. 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
    • 1.4.8.1. Valproate during pregnancy (+ 12 %)
    • 1.4.8.2. Topiramate during pregnancy
    • 1.4.8.3. Levetiracetam during pregnancy
  • 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. Few green spaces in the surrounding area during pregnancy (+ 3 %)
  • 1.6.4. Protein deficiency during pregnancy and after birth
  • 1.6.5. Western diet in the first and second trimester of pregnancy
  • 1.6.6. 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.¹⁶

Pathway: Epigenetics

1.1.2. Drug use by parents 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)²⁶

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

Dopaminergic drugs before conception increase ADHD symptoms in offspring up to the 2nd generation. The latter suggests epigenetic mediation.

• long-term methamfetamine intake causes epigenetic changes in mice²⁷
• MPH in drug form (injected) over 3 weeks from the 6th week of life in male ICR mice (no ADHD model animals) causes ADHD symptoms in the offspring
  • in the 1st generation²⁸
  • in the 2nd generation²⁹

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.³⁰

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.³¹ 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 should be a consequence of breeding or a consequence of the silver nanoparticles.

1.1.5. Few green spaces in the area before conception (+ 6 %)¶

Exposure to green space prior to conception correlated per interquartile range (IQR = 0.12) increase in the green space index in the zip code area with a reduced risk of³²

• ADHD: minus 6 %
• ASS: minus 7 %
• Learning difficulties: minus 11 %
• mental disability: minus 16 %
• Behavioral disorders: minus 11 %

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.³³
The vast majority of studies have found that alcohol consumption by the mother during pregnancy significantly increases the likelihood of ADHD in her children.³⁴³⁵ up to 8.78-fold,³⁶ Attention problems are also increased.³⁷ In rats, the male offspring are particularly affected.³⁸
A combination of alcohol and stress in the mother during pregnancy increased the likelihood of male rats developing female sexual behavior.³⁹
47.2% of children with FAS (fetal alcohol syndrome) also had ADHD⁴⁰
In a Taiwanese cohort study of 5-year-old children, the risk of ADHD was increased by 71%, but not statistically significant.⁴¹

There is evidence that alcohol consumption by the mother during pregnancy or while breastfeeding has a significant impact on the child’s dopamine system.^42434445 The regulation of the neurotransmitters serotonin , glutamate, noradrenaline, acetylcholine and histamine is also affected^{4647 48}

Individual studies found no connection between:

• Alcohol consumption during pregnancy and ADHD.⁴⁹⁵⁰⁵¹
• Binge drinking in early pregnancy and ADHD risk in children aged 5 to 19 years.⁵²
  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.⁵³
  A meta-analysis found that maternal alcohol consumption of less than 70 g/week during pregnancy did not increase the risk of ADHD.⁵⁴ 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).⁵⁵

Paths of action, among others:

• Alteration of the endocannabinoid system in relation to VTA⁵⁶
• Hypoxia (lack of oxygen)⁵⁷

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^{5859 60} on the

• 5.36-fold (increased by 436%)⁶¹ 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 %)³⁶
• 3.34-fold for the 10% heaviest smoking mothers⁶²
• 2.7-fold (increased by 170 %)⁶³
• 2.5-fold (increased by 150 %)⁶⁴
• 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)⁶⁵
• 2.21-fold with high nicotine exposure (cotinine value > 50 ng/ml)⁶²
• 2.11-fold (cohort study, n = 5,548)⁶⁶
  • 4.18-fold for girls
  • 1.64 times for boys
• 1.75-fold for heavy smokers⁶⁷
• 1.60-fold (increased by 60 %) in the overall average of female smokers⁶⁷
• 1.58-fold (increased by 58%; meta-analysis, n = 17,304⁶⁸
• 1.54-fold for light smokers⁶⁷
• 1.50-fold, even with passive smoking, but only for boys⁶⁹
• 1.50 times (here: risk of hyperactivity/impulsivity symptoms of the child)⁶⁹
• 1.49-fold⁷⁰
• 1.42-fold in preschool children, dose-dependent⁷¹
• 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 ODD⁷²
• 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.^{73747518767778}

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

• 1.72-fold⁷⁹
• 3.21-fold⁸⁰⁸¹

Two studies (with overlapping authors)³⁸² , one study with a small number of subjects⁸³, one larger study⁵¹ and one meta-analysis came to a different conclusion⁸⁴, one study found rather weak evidence.⁸⁵
Studies that distinguished maternal smoking during pregnancy from genetic influence found no evidence of a causal effect of prenatal smoking on ADHD risk⁸⁶
However, there are several arguments against this:

• the prenatal nicotine-exposed mouse is an animal model for ADHD^{8788 89} In addition, prenatal nicotine in the mouse model leads to reduced birth weight of the offspring⁹⁰, 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 smoking by the mother during pregnancy come together, 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 9⁹¹⁹²
      Another study confirms the involvement of DRD4-7R in gene-environment interactions.⁹³
• The ADHD risk of children of smoking mothers decreased somewhat when they stopped smoking:⁹⁴
  • 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 above)

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 1966.⁸⁶ In Germany, the rate of mothers smoking during pregnancy fell from 19.9 % in 1996 to 2006 to 10.9 % in 2007 to 2016.⁹⁵⁹⁶ In the USA, the prevalence of smoking during pregnancy fell from 15.2 % in 2000 to 13.8 % in 2005⁹⁷ and to 7.2 % in 2021 ⁹⁸ and to 5.4 % by self-report (subject to social desirability bias)⁹⁹
The prevalence of smoking after childbirth fell from 18.1 % in 2000 to 16.4 % in 2005⁹⁷ and in 2021 to 7.2 % after childbirth and 12.1 % reported smoking before pregnancy according to self-report⁹⁹
Smoking during pregnancy also correlates 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 of $40k or more, 18.7% if annual income at 150% of the poverty line or lower)¹⁰⁰, both of which are ADHD risk factors in their own right.
Nevertheless, over 70 million women in the EU smoked during pregnancy in 2020.¹⁰¹

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 apart¹⁰², 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 rates⁴ 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.¹⁰³ 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.⁸⁹ Under certain circumstances, increased dopamine levels were also shown.¹⁰⁴ 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 weight⁹⁰, which is a separate ADHD risk factor.
• increases the risk of apnea and hypoxia¹⁰⁵
• delays brain development¹⁰⁶.
• increases the risk of birth complications¹⁰⁷¹⁰⁸ , 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.¹⁰⁹ Another study also found changes in glutamatergic signaling in the hippocampus due to increased glutamate receptor expression,¹⁰¹ 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.¹¹⁰

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:¹¹¹

• 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.¹¹² 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.¹¹³

It is possible that the effects of nicotine consumption by the mother during pregnancy could be compensated for by breastfeeding.¹¹⁴

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 symptoms⁶⁹

• 4.6-fold (+ 360 %)¹¹⁵
• to 1.20 times (+ 20 %)⁷⁰

Similar results were found for the causation of dyspraxia (developmental coordination disorder) by passive smoking.¹¹⁶
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.¹¹⁷
One study found no evidence of a correlation.⁸³

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 problems¹¹⁸
High prenatal PAH exposure correlated with

• Attention symptoms¹¹⁹ according to DSM-IV (OR = 5.06, + 406 %)¹²⁰. dose-dependent¹²¹
• ADHD total score according to DSM-IV (OR = 3.37, + 237 %)¹²⁰¹²²
• Anxiety and depression¹¹⁹¹²³

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 significant¹²⁴

PAH/PAH enter the body through microplastics and nanoplastics, among other things.¹²⁵

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

Lead exposure during pregnancy^{126127 128} affects the mesocorticolimbic circulation and increases the risk of ADHD in the offspring.¹²⁹
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.¹³⁰ 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.¹³¹
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 correlation¹³²

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.¹³³ Under similar conditions, male rat pups showed a tendency to serotonergic disorders of the mesocorticolimbic system and altered delay discounting.¹³⁴
Even a lead content in drinking water below the limit values is said to be problematic.¹²⁷
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.¹³⁵

Lead is a divalent cation that mimics Ca2+ and activates PKC signaling.¹³⁶

Arnsten¹³⁷ 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 system¹³⁸
• Impairment of dopamine receptors¹³⁸
• Impairment of attention regulation in the PFC¹³⁹
• Apoptosis¹⁴⁰
• Excitotoxicity¹⁴⁰
• Reduced cellular energy metabolism¹⁴⁰
• Impaired heme biosynthesis and anemia¹⁴⁰
• Oxidative stress¹⁴⁰
• Lipid peroxidation¹⁴⁰
• Changed activity of the second messenger system¹⁴⁰
• Altered neurotransmitter release¹⁴⁰
• Altered neurotransmitter receptor density¹⁴⁰
• Impaired neuropsychological functioning¹⁴⁰
• Impaired development and function of oligodendrocytes¹⁴⁰
• Abnormal myelin formation¹⁴⁰
• Abnormal neurotrophic factor expression¹⁴⁰
• Abnormal dendritic branching patterns¹⁴⁰
• Disorder of the blood-brain barrier¹⁴⁰
• Disorder of thyroid hormone transport into the brain¹⁴⁰
• Altered regulation of gene transcription¹⁴⁰
• Reduction of gray matter in the PFC, especially in the ACC¹⁴¹

Lead also appears to trigger the following behaviors:

• Impulsiveness¹³⁹
• Sociopathic behavior¹⁴²¹⁴³
• Irresponsible behavior¹⁴²¹⁴³
• Criminal behavior¹⁴²¹⁴³
• Lower IQ¹⁴⁰
• Impaired academic performance¹⁴⁰

Lead poisoning is strongly correlated with crime rates and out-of-wedlock pregnancies in the USA.¹⁴²¹⁴³

Children with elevated blood lead levels are said to be particularly susceptible to other toxins in early childhood.¹⁴⁴ 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.¹⁴⁵
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.¹⁴⁶ 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 association¹³²
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:¹⁴⁷

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

Organochlorine compounds (dichlorodiphenyltrichloroethane (DDT), dieldrin, heptachlor, endosulfan) showed an effect on neuronal development in prenatal exposure, e.g. in rodents:¹⁴⁸

• 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.⁴

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.¹⁴⁹ Prenatal exposure to the common pesticide chlorpyrifos impaired IQ and working memory in children aged 7¹⁵⁰¹⁵¹ and executive functions.¹⁵²

Organophosphates inhibit acetylcholinesterase (= the enzyme that breaks down acetylcholine).¹⁴⁸ 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.¹⁵³

Chlorpyrifos disrupts the serotonin system. Contact during pregnancy can trigger tremor in children and impair cognitive and neurobehavioral development.³⁹

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.¹⁵⁴

A Norwegian cohort study found an increased risk of ADHD in the offspring when detected in the mother’s blood during pregnancy of:¹⁵⁵

• 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.¹⁵⁶¹⁵⁷

Chlorpyrifos inhibits the endocannabinoid degradation inhibitor FAAH. Chlorpyrifos thus leads to altered exploratory and social behavior in young rats during puberty.¹⁵⁸

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.¹⁵⁹

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%.¹⁶⁰

The pyrethroid deltamethrin apparently impairs the dopaminergic system in mice after early exposure:¹⁶¹

• 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.¹⁶²

Furthermore, there were (with prenatal, but not with postnatal exposure)¹⁶³ permanent changes in behavior with regard to:¹⁶¹

• Movement activity
• Acoustic startle reflex
• Learning
• Memory

3-PBA and chlorpyrifos reinforce each other’s effect on ADHD.¹⁶⁰

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%.¹⁶⁰

Prenatal and nursing exposure to the pyrethroid pesticide deltamethrin at low doses (within the officially approved levels) resulted in molecular disorder in signaling pathways regulating circadian rhythm and neuronal growth (MAP kinase) in the brains of adult mice, as well as behavioral changes relevant to neurodevelopmental disorders.¹⁶⁴

The pyrethroid fenvalerate is known for its developmental toxicity.
Offspring of mouse mothers that received oral fenvalerate during pregnancy showed epigenetic changes in the regulation of dopamine synthesis:¹⁶⁵

• reduced dopamine content in the striatum
• reduced tyrosine hydroxylase in the midbrain of both fetal and weaned pups
• reduced 5-hydroxymethylcytosine (5hmC) content in CpG-rich regions and specific sites within the TH gene in the fetal midbrain
• reduced activity of ten-eleven translocation enzymes (TET) in the fetal midbrain
  • Administration of ascorbic acid, a cofactor for TET enzymes
    • attenuated the fenvalerate-induced reduction in 5hmC content in CpG-rich regions of the TH gene in the fetal midbrain
    • reversed the fenvalerate-induced downregulation of midbrain TH expression and striatal DA levels in weanling offspring
    • eliminated the ADHD-like behavior of the weaned offspring

A study from rural China found PYR metabolites in the urine of more than 97% of children aged 1-3 years. The prevalence of ADHD symptoms was a very high 15.14% (boys 20.55%, girls 10.27%) and was curiously described as “moderate” in the study¹⁶⁶

• Elevated 4F3PBA levels at 2 years of age correlated with a 6% increased risk of ADHD at preschool age
• Increased ΣPYRs at 1 year of age correlated with a 2% increased risk of ADHD at preschool age
• Elevated 3PBA levels in boys at age 1 correlated with a 7% increased risk of ADHD at preschool age
• Elevated 4F3PBA levels in boys aged 2 years correlated with a 5% increased risk of ADHD at preschool age
• Elevated DBCA levels in girls aged 1 correlated with a 30% increased risk of ADHD at preschool age
• Elevated 4F3PBA levels in girls aged 2 correlated with a 10% increased risk of ADHD at preschool age
• Elevated ΣPYRs levels in girls aged 1 correlated with a 2% increased risk of ADHD at preschool age

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:¹⁶⁷

• 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.¹⁶⁸

1.2.5.5. Neonicotinides¶

Neonicotinides are the most widely used type of insecticide. There are indications that neonicotinides can affect the offspring during pregnancy.¹⁶⁹ 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,^{170171 172} although the links are still unclear.¹⁷³¹⁷⁴ An influence on the thyroid balance¹⁷⁵ and the inflammatory pathway¹⁷⁶ are discussed. Higher phthalate metabolites in the urine of pregnant women correlated with increased distractibility in preschool children¹⁷⁷ and with impaired executive functions¹⁷⁸.
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.¹⁷⁹
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.¹⁷⁶

High phthalate levels in umbilical cord blood correlated with a risk of:¹⁸⁰

• ASS: 2.09-fold
  • ASA in boys: 2.47-fold

The ASA risk was increased by:¹⁸⁰

• high LMWP values: 3.43 times the risk
• high DEHP values: 3.24 times the risk
• high total phthalate values: 4.87 times the risk

The risk of ADHD was increased by:¹⁸⁰

• high MBP exposure in late pregnancy: 1.61-fold risk

High exposure to phthalates impaired the metabolism of linoleic acid and arachidonic acid.¹⁸⁰

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.¹⁸¹ 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.¹⁸²

Caffeine consumption of 10 cups of coffee a day or more correlated with a 130% increased risk of ADHD in children.¹⁸³

One study found a small increase in risk from caffeinated soft drinks during pregnancy, but not from coffee or tea¹⁸⁴

Caffeine consumption during pregnancy below 10 cups a day did not increase the risk of ADHD.^{18518618718818951190}

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.¹⁹¹

Caffeine consumption during pregnancy correlates with an increased BMI of the children.^192193189

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 22.¹⁹⁴

7.7% of mothers used cannabis during pregnancy (meta-analysis, k = 17, n = 534,445).¹⁹⁵
Cannabis use during pregnancy is associated by several studies with an increased risk of ADHD in children.^196197198
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)¹⁹⁵
A study of n = 141,570 children of n = 117,130 mothers with found a reduced offspring risk of ADHD (minus 16%) and disruptive behavior disorder (DBD, minus 17%).¹⁹⁹ One study does not comment on offspring ADHD risk with cannabis use during pregnancy, but notes that cannabis use during pregnancy correlates with localized differences in gray and white matter of the frontal and parietal cortex, associated white matter pathways, and resting state striatal connectivity.²⁰⁰

Translated with DeepL.com (free version)

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)²⁶

• 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%.²⁰¹

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

Cadmium exposure during pregnancy increased the risk of ADHD for 6-year-old girls, but not for boys. Doubling the mother’s exposure to cadmium during pregnancy increased the risk of ADHD for girls by 22.3%.²⁰²
Cadmium accumulation in the placenta increased the risk of ADHD by 36%.²⁰¹
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 correlation¹³²

Possible route of action: blood-brain barrier.²⁰³

1.2.11. Manganese (up to + 34 %)¶

There is weak evidence of relevance in ADHD, although elevated manganese levels have only been found in the hair, but not in the blood, of people with ADHD.²⁰⁴
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.²⁰⁵
An animal model of 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.²⁰⁶
Manganese accumulation in the placenta increased the risk of ADHD by 34%.²⁰¹

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

One study found changes in the immune system of offspring due to air pollution.²⁰⁷
A study of around 43,000 families in Shenzen found positive correlations between ADHD from the age of 3 and exposure to²⁰⁸

• 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.²⁰⁹

A meta-analysis found that more studies (without reference to pregnancy) affirmed a link between air pollution and ADHD than denied it.²¹⁰

1.2.12.1. Particulate matter (+ 26 %)¶

To avoid duplication, the introduction to the topic of air pollution and particulate matter can be found 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/m³.²¹¹
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.²¹² 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.¹²²

In rats, inhaled printer particles led to a 5-fold increase in dopamine levels, probably due to increased synthesis rather than decreased degradation.²¹³

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:²¹⁴

• 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:²¹⁴

• Increased dopamine turnover in the hippocampus

Pre- and postnatally, particulate matter and gaseous pollutants reduced the expression of oxytocin receptors in the hippocampus²¹⁵ and hypothalamus in rodents, with reduced maternal care behavior.²¹⁶ Oxytocin and vasopressin communication appears to be disrupted by endocrine disrupting chemicals²¹⁷, many of which are present in outdoor air.²¹⁴

Studies found an association between PM2.5 and hyperactivity/attention symptoms (OR = 1.12)²¹⁸, hyperactivity²¹⁹, ADHD symptoms²²⁰ and between PM2.5 in the first trimester and a tendency towards attention problems and hyperactivity.²²¹

Other studies found no link between PM2.5 and ADHD^222223224

A meta-analysis reports a correlation between PM10 and ASD.²²⁵ One study differentiated the risk increase for ASD according to PM1 (+ 86 %), PM2.5 (+ 76 %) and PM10 (+ 68 %).²²⁶

Developmental pathways of prenatal particulate matter exposure for ADHD are considered:²²⁷

• In the placenta
  • Increased inflammation
  • Oxidative stress
  • Disorder of blood flow and development of the placenta
  • Effects on the supply of nutrients and oxygen
  • Epigenetic dysfunction
• In the brain of the fetus
  • Increased neuroinflammation
  • Cytokines increased

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

Several studies found a correlation between nitrogen oxide exposure during pregnancy and ADHD.¹¹⁸

• NOx correlated with hyperactivity, with a stronger association between ADHD and NO than between ADHD and NO2. (NO: aOR = 1.26)²²⁴
• NO2 exposure during pregnancy correlated strongly with ADHD symptoms, such as
  • Impulsiveness
    • Interrupting others²²⁰
    • Inability to wait your turn when playing²²⁰
  • Attention problems
    • Carelessness when crossing the road²²⁰
    • Attention impaired at the age of 4-5 years²²⁸
  • Hyperactivity²¹⁹
  • Oppositional behavior (not an original ADHD symptom)
    • Lies²²⁰
    • Public Disorder²²⁰

Other studies found no significant or clear correlations between NOx and ADHD ^{222 229230}
One study found a correlation with ASD in children, but not with ADHD.²³¹

Emissions of nitrogen oxides in Germany fell by almost 2/3 between 1990 and 2020.²³²

1.2.12.3. Ozone¶

Ozone caused in rats:²¹⁴

• 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.²¹⁹¹¹⁸

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

Polychlorinated biphenyls (PCBs) can increase the risk of ADHD.²³³²³⁴ 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).²³⁵ Polychlorinated biphenyls can act directly on dopaminergic processes to disrupt the dopamine system and produce Parkinson’s-like symptoms.²³⁶ Further studies also found dopamine-reducing effects of PFAS.²³⁷²³⁸ as well as influences on the acetylcholine, serotonin and glutamate neurotransmitter balance.²³⁹
PFOS can cross the placenta and the blood-brain barrier.²⁴⁰
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:¹⁴⁷

• 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 years²⁴¹
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.²⁴²
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.¹⁴⁶

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.²⁴⁰

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.²⁴³ 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:²⁴⁴

• 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.²⁴⁵ Another study found an increased risk of ADHD in school children with low to moderate exposure to PFAS at 2 years of age.²⁴⁶

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.²⁴⁷

1.2.16. Bisphenols during pregnancy¶

Bisphenol A (BPA) increases the risk of ADHD (meta-analysis, k = 32, n = 15,669).^248234249
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.²⁵⁰
BPA can cross the placenta^{251252 253} and is found in human breast milk.²⁵⁴ BPA affects the gut-brain axis and the blood-brain barrier.^{255250256257258}

BPA can:

• impair memory (meta-analysis, k = 22)²⁵⁹
• impair cognitive abilities (meta-analysis, k = 22)²⁵⁹
• bind to estrogen receptors²⁵⁰²⁵⁹
• various structural and molecular changes in the brain cause²⁵⁰
• promote oxidative stress²⁵⁰
• change the expression level of several important genes and proteins²⁵⁰
• Neurotransmitters impair²⁵⁰
  • Change neurotransmitter levels (meta-analysis, k = 22)²⁵⁹
• Cause excitotoxicity²⁵⁰
• Promote neuroinflammation²⁵⁰
• damage the function of the blood-brain barrier²⁵⁰
• trigger neuronal damage²⁵⁰
• Promote apoptosis²⁵⁰
• disrupt intracellular Ca2+ homeostasis²⁵⁰
• reactive oxygen species (ROS) increase²⁵⁰
• influence intracellular lactate dehydrogenase release²⁵⁰
• reduce the axon length²⁵⁰
• cause microglial DNA damage²⁵⁰
• Trigger astrogliosis²⁵⁰
• cause significantly reduced myelination²⁵⁰
• acts as a broad-spectrum endocrine disruptor²⁶⁰
• is metabolized via glucuronidation²⁶⁰
  • 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)²⁵⁹
• alter the expression of synaptic proteins (meta-analysis, k = 22)²⁵⁹
• affect the morphology of pyramidal neurons in the hippocampus (meta-analysis, k = 22)²⁵⁹
• Dysregulate thyroid hormones (meta-analysis, k = 22)²⁵⁹

Exposure to BPA increases the risk of neurological disorders, including

• neurovascular disorders (e.g. stroke)²⁵⁰
• neurodegenerative diseases (e.g. Alzheimer’s and Parkinson’s)²⁵⁰²⁶⁰
• Neurodevelopmental diseases
  • ADHD²⁶⁰; (meta-analysis, k = 32, n = 15,669).²⁴⁸
    • another meta-analysis found no clear result from pre- or postnatal exposure in children and adolescents (k = 46; n = 21,896)²⁶¹
  • ASS²⁵⁰²⁶⁰
• Depression²⁵⁰
• emotional problems²⁵⁰
• States of anxiety²⁵⁰
• cognitive disorders²⁵⁰
• Polycystic ovary syndrome (PCOS)²⁶⁰

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.³⁹ The dose given to the rat mothers during pregnancy and lactation was very low at 40 micrograms/kg/day.²⁶²
5 milligrams/cubic meter in the air we breathe causes eye irritation.²⁶³ A review confirmed evidence that bisphenol A during pregnancy can increase the risk of ADHD in children, especially boys.¹⁷⁴

BPA and BPS caused greatly increased dopamine (3 to 5-fold) and greatly decreased serotonin (by 80 %) in mouse placentas. GABA remained unchanged.²⁶⁴ 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.²³⁶

1.2.17. Dioxin exposure during pregnancy¶

Children who were exposed to dioxin during pregnancy have an increased risk of ADHD.²⁶⁵

1.2.18. Prenatal exposure to sulphur dioxide¶

Prenatal exposure to sulfur dioxide (SO2) correlated with DNA methylation and increased ADHD symptoms ²⁶⁶²⁶⁷
According to a review¹¹⁸, two other studies found no significant correlation.²²⁴²¹⁹

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.²⁶⁸

1.2.20. Low urine fluoride content of the mother¶

One study found an inverse relationship 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.²⁶⁹ 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.²⁷⁰²⁷¹

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.¹¹⁵

Children with ADHD were more likely to have mothers who had health impairments during pregnancy:⁸⁰

• 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 for ADHD due to maternal illness independent of pregnancy, but a 1.52-fold (+ 52%) increase in risk for ASD.⁶⁵ 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)⁶⁵

1.3.1. Intrahepatic 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.²⁷²
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 who were affected by citrin-induced cholestasis, 14 were found to have ADHD (47%).²⁷³ 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 (+ 26% to + 330%)¶

1.3.2.1. Asthma in the mother during pregnancy¶

Maternal asthma during pregnancy increases the risk of ADHD and ASD in the offspring²⁷⁴

• 330 %. Of the children born to mothers in the COPSAC2000 birth cohort (all of whom have asthma), 20% have ADHD.²⁷⁵
• 49% of children of n = 106,163 mothers who had asthma during pregnancy showed a risk of:²⁷⁶
• 47% for ADHD up to the 18th birthday if the mother had asthma during pregnancy²⁷⁷
• 43% (meta-analysis, k = 12, n = 7.38 million)²⁷⁸
  • Boys: + 36 %
  • Girls: + 45 %
  • ASS: + 36 %
• 41% increased risk of ADHD with maternal asthma (cohort study, n = 961,202 children)²⁷⁹
  • additional 21% risk increase due to the mother’s asthma flare-up during pregnancy²⁷⁹
  • additional 25 % increase due to asthma flare-up after pregnancy²⁷⁹

Another study also found an increased risk of ADHD in the offspring of mothers with asthma, especially for girls.²⁸⁰

Children of n = 106,163 mothers who had asthma during pregnancy showed a risk of:²⁷⁶

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

1.3.2.2. Asthma of the father¶

• 26% for ADHD up to the 18th birthday if the father had asthma during pregnancy²⁷⁷
• 13 % increased risk with asthma in the father²⁷⁹

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 cognition²⁸¹²⁸² and impair

• Neurodevelopmental processes²⁸³
  • Cell differentiation
  • Neurite growth
  • Synaptogenesis
  • Myelination
• Neurotransmitter systems²⁸⁴
  • monoaminergic system
  • cholinergic system
  • which can lead to attention deficits and hyperactivity

Even transient subclinical thyroid abnormalities in pregnancy can have serious consequences.²⁸⁵ Correction of severe maternal hypothyroidism before the 3rd semester of pregnancy appears to prevent cognitive impairment²⁸⁶ and premature births.²⁸⁷

Studies on mice with a mutated human thyroid receptor TRb-1 gene (TRbeta transgenic mice)²⁸⁸ 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

A study of n = 5,602 mother-child pairs found a 54.1% higher risk of ADHD in children aged 3 to 7 years whose mothers had thyroid dysfunction during pregnancy²⁸⁹

One study found a 7% increased risk of ADHD in children with untreated mild thyroxine deficiency in the mother during early pregnancy.²⁹⁰ 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.²⁹¹ Another study also found evidence of thyroxine as a possible cause of ADHD,²⁹² another study found no influence of the mother’s thyroxine levels during pregnancy.²⁹³
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.²⁹⁴

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.²⁹⁵ 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%.²⁹⁶

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 %).²⁹⁷
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%.²⁹⁸

Primary hypothyroidism in rodents reduced the glucose 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 weaning²⁹⁹

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 2.8.³⁰⁰
• by 62 %³⁰¹
• by 57 % for ADHD and 42 % for ASD³⁰²
• 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 disorders³⁰³
  • 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%³⁰³

The children’s risk of ADHD increased³⁰⁴

• 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):³⁰⁵

• 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.³⁰⁶ 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%.³⁰⁷
Other fluctuations in the mother’s weight before and at the end of pregnancy do not appear to influence the risk of ADHD.⁷³ In rats, however, there is evidence of an influence on the dopamine balance of the offspring.³⁰⁸
A Norwegian registry study found only slight evidence of an influence of the mother’s pre-pregnancy BMI on the child’s risk of ADHD³⁰⁹

If high blood pressure was added to obesity, this led to an increased risk of:³⁰³

• + 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):³⁰⁵

• 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 accompanied by 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 child³¹⁰³¹¹

• by 408 %¹¹⁵
• by 277 % (RR 2.77)³¹²
• by 30 to 188 %³¹³
• by 43 % (cohort study)³¹⁴
• by 29 % (meta-analysis, k = 15)³¹⁵
• by 19 %³¹⁶

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

• • 48 % for mental disability³⁰³
• • 43 % for special developmental disorders³⁰³
• for ASS
  • by 43 %³⁰³
  • by 27 % (meta-analysis, k = 15)³¹⁵ - + 23 % for ADHD or CD³⁰³
• • 35 % for epilepsy (meta-analysis, k = 15)³¹⁵
• • 34 % for other behavioral and emotional disorders³⁰³

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:³⁰³

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

Obesity was associated with an increased risk of pre-eclampsia:³⁰³

• • 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.³¹⁷³¹¹

Pre-eclampsia together with a urinary tract infection increased the risk by 53%.³¹⁶

Gestational gestosis in slightly preterm infants increased the risk of the offspring having impairments in gross and fine motor skills, adaptability, language and social-emotional response, as well as in the rate of abnormal scores.
While no deviations in the above-mentioned areas could be detected at the age of 3 to 6 months, at the age of 12 months there was a significant deterioration in gross motor skills and fine motor skills combined with a significantly reduced risk of abnormal speech scores.³¹⁸

Several reviews confirm an increased risk of ADHD due to pre-eclampsia in pregnancy.³¹⁹³²⁰

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).³²³
• by 210 % for boys born to mothers who had a child or spouse during pregnancy ³²⁴
• by 147% in boys born to mothers who had suffered the death of a child or spouse in the 0-6 months prior to pregnancy³²⁴
• by 100 %³²⁵
• aDHD symptoms increased by 95% at 16 years, but no increased hyperactivity symptoms at 8 years (minus 13%)³²⁶
• by 75.1 % in the case of significant maternal stress during the first trimester of pregnancy compared to children born to mothers with low stress²⁸⁹
• by 72% for boys born to mothers who have suffered the unexpected death of a child or spouse³²⁴
• by 72 %³²⁷
• by 60 %; no statistically significant increase in ASA risk (25-year cohort study, n = 16,365)⁶⁵
• by 56.9 % in the case of significant maternal stress during the first trimester of pregnancy compared to children born to mothers with moderate stress²⁸⁹
• by 31% due to maternal stress in the third trimester (and by 58% for ASA)³²⁸
• Stress during the second and third trimester did not significantly increase the offspring’s risk of ADHD²⁸⁹

Persistent and severe (anxiety-induced, perceived threatening = cortisolergic) stress significantly increases the risk of screaming children³²⁹ (see also 2.2.2.3.2), anxiety disorders and ADHD.^{330331332333334}
Persistent stress (here: financial problems) is more harmful than short-term stress (here: loss of a loved one).³³⁵
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:⁸⁰

• 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 transfer of psychological stress experiences from mothers to their children.³³⁶
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.³³⁷ 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.³³⁸³³⁹

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.³⁴⁰ 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 5.³⁴¹
So it seems to depend very much on the time of the stress experience.

Severe maternal anxiety during pregnancy increased the unborn child’s risk of ADHD depending on its COMT gene variant (gene-environment interaction).³⁴²
In mothers with the ADGRL3 (latrophilin 3, LPHN3) gene variants (SNPs)

• rs6551665
• rs1947274
• rs6858066 or
• rs2345039

even minor stress during pregnancy resulted in a significantly increased risk of ADHD for the child.³⁴³

A combination of the 5-HTTLPR L/L genotype and stress during pregnancy caused an eight times higher risk of ADHD-C or ADHD-HI.³⁴⁴

Children with ADHD whose mothers were exposed to moderate and severe stress during pregnancy tend to develop more severe ADHD symptoms.³⁴⁵

Early prenatal stress increases levels of immune response genes, including the proinflammatory cytokines IL-6 and IL-1β, particularly in male placentas. Male infants showed stress-induced locomotor hyperactivity, a hallmark of dopaminergic dysregulation, which was ameliorated by maternal treatment with nonsteroidal anti-inflammatory drugs. In addition, the expression of dopamine D1 and D2 receptors was altered by early prenatal stress in male offspring.³⁴⁶ 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.³⁴⁷ Exposure to glucocorticoids during hippocampal development in pregnancy influences the starting point of the stress response through epigenetic changes via mRNA and methylation.³⁴⁸ 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.³⁴⁹
Another study also describes epigenetic changes in the unborn child due to the mother’s psychological stress during pregnancy.³⁵⁰
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.³⁵¹
Exposure of the mother to a natural disaster during pregnancy increased the risk of ADHD.³⁵²

Elevated cortisol due to maternal stress during pregnancy can pass through the placenta³⁵³ and alter the epigenome of the fetus, particularly in genes that control the HPA axis and the stress response.³⁵⁴ Maternal depression or anxiety in the third trimester correlated with increased DNA methylation of the NR3C1 promoter in the umbilical cord blood of newborns.³⁵⁵ The NR3C1 gene encodes the glucocorticoid receptor, which is designed to shut down the HPA axis (and thus also the cortisol level) in response to high cortisol levels at the end of a stress reaction. Specific CpG methylation in NR3C1 induced by maternal stress correlated with attenuated gene expression, which was functionally associated with increased cortisol reactivity in these infants at three months of age. An increased cortisol response to stress in the 3-month-old babies correlated with greater methylation of the NR3C1 gene.³⁵⁵
Maternal stress during pregnancy may epigenetically prime the infant’s HPA axis for higher stress sensitivity, which may increase the risk of anxiety or depression later in life, and that prenatal stress correlates with methylation changes in offspring genes related to stress regulation, such as NR3C1, FKBP5, SLC6A4 (serotonin transporter)³⁵⁶

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.³⁶²

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.³⁶³

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.³⁶⁴

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 instrument for chemical intolerance) had 2.3 times the risk of ADHD and 3.01 times the risk of ASD.³⁶⁵³⁶⁶

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.³⁶⁷

A cohort study found

• Parental depression increased the risk of offspring depending on the time of onset of depression for (data in HR):³⁶⁸
  • 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 time 1.52)
  • 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)³⁶⁹

• 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.³⁷⁰

1.3.11. Crohn’s disease / ulcerative colitis (+ 95 %)¶

Crohn’s disease / ulcerative colitis in the mother during pregnancy increased the child’s risk of ADHD by 95% up to its 18th birthday.²⁷⁷
Crohn’s disease or ulcerative colitis in the father did not increase the child’s risk of SADHD up to his 18th birthday.²⁷⁷

1.3.12. 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.³⁷¹³⁷²

It is possible that a connection could result from the fact that one treatment method is the use of dopamine agonists.³⁷³³⁷⁴ 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.³⁷⁵ 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).³⁷⁶ 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 symptoms.³⁷⁷

1.3.13. 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.³⁷⁸

1.3.14. Cerclage for cervical weakness (up to + 70 %)¶

A cerclage is a wrapping of a weak or prematurely opening cervix (cervical insufficiency, cervical weakness). It usually takes place in the second trimester of pregnancy.

Children of mothers who received a cerclage during pregnancy had an increased risk of death:³⁷⁹

• increased by 1,485 % for cerclage from the 25th week of pregnancy
• increased by 107% with cerclage in the 16th to 24th week of pregnancy
• increased by 49 % with cerclage before the 24th week of pregnancy

Furthermore, a cerclage from the 25th week of pregnancy increased the risk of the children for:³⁷⁹

• ADHD: 70 %
• ASS: 131 %
• cognitive developmental delay: 81 %
• Cerebral palsy: 1,832 %

1.3.15. Rheumatic diseases / Disorders of the musculoskeletal system (+ 64 %)¶

Rheumatic diseases / disorders of the mother’s musculoskeletal system during pregnancy increased the child’s risk of ADHD by 64% up to its 18th birthday.³⁸⁰

1.3.16. 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%.³⁸¹
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.

1.3.17. 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.³⁸²
ADHD, for its part, is associated with a 2.17-fold risk of lupus.³⁸³

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

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

• ADHD by 51 %³⁸⁴
• ADHD by 21 % (adjusted) to 31 %³⁸⁵
• ASS by 55 %.³⁸⁴

1.3.19. Diabetes of one parent; diabetes during pregnancy (+ 20 % to + 150 %)¶

A cohort study of over 5 million people found an increased risk of ADHD in children if a parent had diabetes.³⁸⁶

Diabetes in the mother before or during pregnancy increases the offspring’s risk of ADHD³⁸⁷, in the case of gestational diabetes mellitus as well as pre-existing type 1 diabetes mellitus or type 2 diabetes mellitus,³⁸⁸ and also for ASD.³⁸⁹³⁹⁰

• 150 %: Type 1 diabetes in the mother during pregnancy increased the child’s risk of ADHD by 95% by his or her 18th birthday.³⁸⁰
• 140 %: One 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.³⁹¹
• 86 High levels of diabetes mellitus throughout pregnancy increased the risk of ADHD at 6 to 9 years of age to 2.8%, compared with 1.5% for low levels throughout pregnancy³⁹²
• 40 %: Maternal diabetes mellitus before pregnancy increased children’s ADHD risk by 40% (meta-analysis, k = 13, n = 5,000,000)³⁹³
• 39 %: Maternal type 1 diabetes mellitus before pregnancy increased children’s ADHD risk by 39% (meta-analysis, k = 13, n = 5,000,000)³⁹³
• 20 %: Diabetes mellitus or type 1 diabetes mellitus in the father increased the children’s ADHD risk by 20% (meta-analysis, k = 13, n = 5,000,000)³⁹³

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.³⁹⁴
One study did not find an increased risk of ADHD severe enough to require inpatient treatment³⁹⁵

1.3.20. Migraine in parents (+ 37 %)¶

A cohort study of n = 250,517 participants found an increased risk of migraine for children of mothers, but not fathers, with migraine:³⁹⁶

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

1.3.21. Immune disorders (+ 36 %)¶

Immune disorders in the mother (without allergies) during pregnancy increased the child’s risk of ADHD by 36% up to its 18th birthday.³⁸⁰

1.3.22. 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%). ³⁹⁷

In a small Lebanese correlational study (n = 119), maternal anemia during pregnancy increased the risk of ADHD 3.7-fold (OR = 3.654).³²³

1.3.23. Infections of the mother during pregnancy¶

1.3.23.1. 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.³⁹⁸ 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 for³⁹⁹
Mycoplasma antibodies at birth were associated with a 30% increased risk of ADHD later in life.⁴⁰⁰

1.3.23.2. Viral infections¶

A viral infection of the mother during pregnancy increases the risk of ADHD for the offspring⁴⁰¹ and can influence the development of the unborn child’s dopaminergic system, e.g.:⁴⁰²

• 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 for⁴⁰³
    • ASS
    • ADHD
    • Developmental disorders
• Enterovirus 71
• Herpes virus 6
• Influenza A
• Cytomegalovirus (+ 30 %)⁴⁰⁰

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 disorders⁴⁰⁴, such as schizophrenia³⁶², ASD⁴⁰⁵ or depression.⁴⁰⁴

1.3.23.3. Urinary tract infections (+ 29 %)¶

A urinary tract infection in the mother during pregnancy was associated with a 29% increased risk of ADHD.³¹⁶ 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%.³¹⁶

Another study also found an increased risk of ADHD as a result of urinary tract infections in the mother during pregnancy⁴⁰⁶

1.3.24. 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:⁴⁰⁷

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

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

High blood pressure during pregnancy significantly increases the risk of ADHD in the offspring.³²⁰. 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.³¹⁷ High blood pressure during pregnancy increased the risk of depression by 130%.⁴⁰⁸

If obesity was added to chronic high blood pressure, this led to an increased risk of:³⁰³

• • 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):³⁰³

• • 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):³⁰³ (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.

1.3.26. Allergies during pregnancy (+ 20 % to 23 %)¶

Allergies in the mother during pregnancy increased the child’s risk of ADHD by 20% to 23% up to the child’s 18th birthday.³⁸⁰

1.3.27. 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%⁴⁰⁹

1.3.28. 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.

1.3.28.1. D3 deficiency during pregnancy¶

Vitamin D3 deficiency during pregnancy and after birth causes permanent maldevelopment of the brain, particularly the dopaminergic system ^{410 411 412413}

In a meta-analysis, studies with larger sample sizes and stricter definitions of vitamin D deficiency showed positive associations for ADHD⁴¹⁴⁴¹⁵ and schizophrenia.⁴¹⁵ D3 deficiency during pregnancy reduces dopamine turnover in the offspring’s brain⁴¹⁶ with a reduction in COMT.⁴¹⁷

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 %.⁴¹⁸
The incidence of ADHD-like symptoms in children decreased by 11% for every 10 ng/ml increase in maternal 25(OH)D levels.⁴¹⁹ 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 ADHD risk or ASD risk⁴²⁰
The severity of the offspring’s ADHD symptoms correlated with the level of maternal 25(OH)D deficiency ⁴²¹⁴²²
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.³³⁴
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:⁴²³

• 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 ADHD⁴²⁴
A comprehensive long-term study in Spain on vitamin D3 deficiency during pregnancy found no correlation between low maternal blood D3 levels during pregnancy and ADHD in children aged 5 to 18 years.⁴²⁵ 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.⁴²⁶

1.3.28.2. Omega-3 fatty acid levels¶

1.3.28.2.1 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 this⁴²⁷

1.3.28.2.2. During pregnancy¶

Another study found a 13% increased risk of ADHD in offspring at age 7 due to an increased omega-6 to omega-3 ratio (high omega-6 and low omega-3).⁴²⁸

1.3.29. 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.⁴²⁹
Sleep problems during pregnancy correlated with an increased risk of neurodevelopmental disorders and sleep problems in early childhood.⁴³⁰, 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

1.3.30. Testosterone during pregnancy¶

Prenatal testosterone exposure correlated significantly with inattention and hyperactivity/impulsivity in the offspring.⁴³¹ Elevated maternal testosterone levels during pregnancy correlated significantly with increased ADHD signs in the children at 6 months and 2 years of age.³³⁴

1.3.31. 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).⁴³²⁴³³

1.3.32. Bipolar Disorder in parent¶

Having a parent with bipolar disorder increased the children’s risk of ADHD.⁴³⁶

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:⁸⁰

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.⁴³⁷
A meta-analysis of 20 studies found consistent evidence of a significantly increased risk of ADHD and ASD in offspring with prenatal use of acetaminophen by the mother. (meta-analysis, k = 20)⁴³⁸
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.⁴³⁹⁴⁴⁰ Further studies confirm this.^441442443 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.⁴⁴⁴⁴⁴⁵

The risk of ADHD from paracetamol (acetaminophen) increases when taken⁴⁴⁶

• 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.³⁶³
A meta-analysis confirms the increased risk of ADHD and ASD in offspring when taking paracetamol during pregnancy⁴⁴⁷

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)⁴⁴⁸

One study questions the previous critical results by focusing on parents’ ADHD diagnoses that have not been taken into account to date.⁴⁴⁹ Damkier is also doubtful.⁴⁵⁰⁴⁵¹ Another study found no evidence of an increased risk of ADHD or ASD from paracetamol during pregnancy.⁴⁵² A review also found no association⁴⁵³
A cohort study of n = 217,602 children found a 22% increased risk of ADHD on the one hand and indications that the result was overestimated due to the unrecorded over-the-counter use of paracetamol on the other⁴⁵⁴

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.⁴⁵⁵
The damage to the development of the offspring caused by paracetamol during pregnancy appears to be mediated by changes in the endocannabinoid pathway⁴⁵⁶
Paracetamol is also suspected as a possible cause of ASA.¹⁶⁸
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.⁴⁵⁷

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

Possible pathway: Cannabinoid pathway / CB1R.⁴⁵⁸

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 mental health problems of the mother for which she was treated with SSRIs, as the children’s risk of ADHD (OR = 1.63 = approx. + 63 %) and ASD (OR = 1.39 = approx. + 39 %) was also increased if the mother took SSRIs or SNRIs before pregnancy but not during pregnancy.⁴⁵⁹⁴⁶⁰ As a purely precautionary measure, SSRIs 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.⁴⁶¹ The same applies to another study.⁴⁶² According to one study, antidepressants during pregnancy increased the likelihood of later ADHD in the child by 1.81 times.⁴⁶³
A review found that antidepressants during pregnancy almost doubled the risk of ADHD and ASD in the newborn in unadjusted studies. In adjusted studies, in which, for example, ADHD of the mother is taken out as a separate factor, barely any statistically significant correlation was found. Analyses of discordant sibling pairs suggest that a child’s ADHD is more likely to be related to whether or not their sibling has NDD than to whether or not the child was exposed to an antidepressant in utero.⁴⁶⁴

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

Valproic acid increased the risk of ADHD in offspring by 39% (meta-analysis, k = 22)⁴⁶⁵ 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.⁴⁶⁶⁴⁶⁷ There are also indications of changes in the histaminergic system and social behavior.⁴⁶⁸
Valproic acid during pregnancy increases the risk of ADHD, ASD, reduced cognitive abilities and speech disorders in the offspring.⁴⁶⁹ In addition, it causes congenital malformations such as neural tube defects, heart anomalies, urogenital malformations (e.g. hypospadias, skeletal malformations and orofacial clefts) in 10 % of children, depending on the dose, especially at more than 600 mg/day. High doses of folic acid before and during pregnancy could reduce the risk. The concentration of valproin in breast milk appears to be low, which is why breastfeeding does not pose a risk.

1.4.4. Corticoids during pregnancy (+ 30 %)¶

Glucocorticoid administration during pregnancy increased the risk of ADHD in the offspring by 30%.⁴⁷⁰ 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.⁴⁷¹ 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.⁴⁷² 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.³⁴⁷

Exposure to betamethasone during pregnancy only marginally increased the risk of ADHD in the offspring.⁴⁷³⁴⁷⁴

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.⁴⁷⁵

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%.⁴⁷⁶

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.⁴⁷⁷

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 ⁴⁷⁸⁴⁷⁹
Exposure to antibiotics in the womb increased the child’s risk of: (meta-analysis, k = 30, n = 7,047,853)⁴⁸⁰

• 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.³⁰

Pathway of action: alteration of the microbiome.⁴⁸¹

1.4.8. Antiepileptic drugs¶

1.4.8.1. Valproate during pregnancy (+ 12 %)¶

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.⁴⁸² Compared to mothers with epilepsy who did not take antiepileptic drugs during pregnancy, which only increased the risk of ASD by 38%.
Valproate during pregnancy is said to increase the risk of ADHD for the unborn child.⁴⁸³
Valproates are the salts of valproic acid.

When taking antiepileptic drugs 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.⁴⁸⁴

1.4.8.2. Topiramate during pregnancy¶

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 offspring ⁴⁸⁵⁴⁸⁶

1.4.8.3. Levetiracetam during pregnancy¶

In mice, levetiracetam led to hyperactivity and repetitive behavior in the offspring during fertilization and pregnancy.⁴⁸⁷

1.4.9. Estrogens, progestins¶

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

Children of women treated in this way have an increased risk of:⁴⁸⁸

• 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 SDHS prevalence of 15% compared to the control group of 4% (+ 275%).⁴⁸⁹

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 to 119 months) to 25% (120 months and more).⁴⁹⁰

1.6.3. Few green spaces in the surrounding area during pregnancy (+ 3 %)¶

Exposure to green space prior to conception correlated per interquartile increase in the green space index in the zip code area with a reduced risk of⁴⁹¹

• ADHD: minus 2 %
• ASS: minus 10 %
• Learning difficulties: minus 7 %
• mental disability: minus 9%
• Behavioral disorders: minus 8 %

1.6.4. 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.⁴⁹²

1.6.5. 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.⁴⁹³

1.6.6. High salt consumption during pregnancy¶

A high salt intake from food during pregnancy could increase the unborn child’s sensitivity to stress.⁴⁹⁴

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 risk⁴⁹⁵
• 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.⁴⁹⁶
• 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 7⁴⁹⁷
• Artificial insemination⁴⁹⁸⁴⁹⁹ through sperm donation⁵⁰⁰ or intracytoplasmic sperm injection (ICSI)⁵⁰¹
• non-ionizing magnetic field radiation during pregnancy
  • A study that had initially found an increased rate of ADHD in offspring of mothers who were most exposed to non-ionizing magnetic field radiation (“electro-smog”) during pregnancy (in a 24-hour measurement)⁵⁰² has been withdrawn⁵⁰³. 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.⁵⁰⁴
• Benzodiazepines during pregnancy appear to increase the risk of internalizing problems in children (anxiety, emotional reactivity, somatic complaints), but not externalizing problems (hyperactivity, aggressiveness).⁵⁰⁵ 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.⁵⁰⁶ 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.⁵⁰⁷ One study found a slight increase of 15% in the risk of ADHD when taking benzodiazepines during pregnancy.⁵⁰⁸
• prenatal oxytocin exposure does not appear to affect ADHD and ASD risk⁵⁰⁹
• Bionutrients during pregnancy⁵¹⁰
• Triptans during pregnancy⁵¹¹

This list of maternal medication during pregnancy as a risk for ADHD 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:⁵¹²

• 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/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 risk of ADHD in the offspring by up to 20 %.⁵¹³
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:⁵¹⁴

• 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)