1. Prenatal Stressors as Risk Factors for ADHD

Author: Ulrich Brennecke
Review (June 2024): Waldemar Zdero, M.A. in Psychology

Even before birth, the unborn child can be harmed by toxic influences or diseases.
Many toxins and diseases that increase a child’s risk of ADHD do so by affecting the dopaminergic system. Toxins can also increase the risk of ADHD even before conception through epigenetic mechanisms.
Mental and physical stress (toxins, illnesses) generally have a similar effect on the stress systems (HPA axis, autonomic nervous system, and others).
The percentage values listed for a potential increase in ADHD risk indicate the magnitude of the impact of the respective risk factor. For entries without a percentage value, we have no known figures.

The use of nicotine, alcohol, or harder drugs during pregnancy increases the risk of ADHD in children. Nicotine increases the risk even if the parents smoked only before conception.
Another source of risk is toxins to which the mother is exposed during pregnancy. These include pesticides such as organophosphates and pyrethroids, as well as chemicals such as lead, cadmium, thallium, bisphenols, polychlorinated biphenyls, and polycyclic aromatic hydrocarbons.

Air pollution, particularly fine 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 maternal health factors, such as illness, obesity, stress, infections, and hormonal disorders, are also associated with an increased risk of ADHD in the child. Thyroid hormone levels, in particular, should be closely monitored. Higher levels of omega-3 fatty acids in newborns may reduce the risk and severity of ADHD and autism spectrum disorders. Vitamin D3 deficiency during pregnancy and after birth is associated with dopaminergic abnormalities in the brain.
High cortisol exposure in the fetus or newborn—whether due to cortisol administration or the mother’s 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-adrenergic receptor agonists, pregabalin, antibiotics, and valproate are of particular relevance during pregnancy.
Finally, factors related to the pregnancy—such as whether the child is the firstborn or whether the interval between this pregnancy and the previous one was particularly short or long—influence the child’s risk of ADHD.

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

There appear to be gender differences with regard to 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
  • The increased risk of ADHD diminished with age
  • The increased risk of depressive symptoms rose over time
• with accelerated age-related cortical thinning in 36 of 68 cortical regions
• with higher total CBCL scores and accelerated cortical thinning in 5 cortical regions among siblings

It remains unclear to what extent the factors mentioned are causal (responsible for) ADHD. Many of these factors could also be consequences of genetic causes passed from the mother to the child, which affect the mother just as much as they do the child. For example: Is a mother’s smoking during pregnancy the cause of ADHD in her child, or is it a consequence of the mother’s genes, which she simultaneously passes on to the child? Methods that can help clarify this include prenatal cross-fostering studies (egg and embryo donation from unrelated donors), studies on prenatal cross-fostering (surrogacy involving an unrelated surrogate mother), children of identical twins, multiple pregnancies by the same mother under different environmental conditions (e.g., with and without smoking), or comparisons between mothers and fathers.³ In this context, animal studies should be considered, as they allow for comparisons that are ethically prohibited in humans.

The percentage values indicate the potential increase in ADHD risk associated with each cause.

Although the following list is extensive, there are likely many other factors associated with an increased risk of ADHD.
Each of these factors represents only a part of a complex mosaic of risk factors and does not automatically lead to ADHD.
We have begun to identify the possible mechanisms through which environmental factors can cause ADHD.

1.1. Preconception Exposure to Toxins as a Risk Factor for ADHD—Epigenetic Inheritance¶

1.1.1. Nicotine use by a parent before conception (+259%)¶

Children whose fathers smoked before their mothers became pregnant were 2.59 times more likely to have ADHD than children whose fathers had never smoked.
Children whose parents were exposed to smoking or secondhand smoke before pregnancy had a 1.96-fold increased risk of ADHD.
Children whose parents were exposed to tobacco smoke both before and during pregnancy had a 2.01-fold increased risk of ADHD.¹⁶

Signal transduction pathway: Epigenetics

1.1.2. Parental drug use prior to conception (+44%)¶

Maternal drug use (heroin, amphetamine, ketamine, or other substances) prior to conception was associated with an increased risk for the offspring (registry study, N = 1,969,006)²⁶

• by 43% to 45% for ADHD
• by 5% for ASA
• by 18% to 21% for intellectual disabilities

Dopaminergic drugs taken before conception increase ADHD symptoms in offspring up to the second generation. This suggests an epigenetic mechanism.

• Long-term methamphetamine use causes epigenetic changes in mice²⁷
• MPH administered in injectable form over a 3-week period starting at 6 weeks of age in male ICR mice (not ADHD model animals) causes ADHD symptoms in their offspring
  • in the first generation²⁸
  • second generation²⁹

1.1.3. Penicillin use up to 2 years before conception¶

A mother’s use of penicillin increased the child’s risk of ADHD even if the penicillin was taken 2 years before pregnancy. Repeated use of penicillin further increased the risk of ADHD.³⁰

Possible mechanism of action: gut microbiome
Antibiotics affect the gut microbiome. The gut microbiome is passed from the mother to the newborn during vaginal birth and breastfeeding (especially during the first three months). See there.

1.1.4. Silver nanoparticles across 4 generations¶

Offspring of rats that were administered silver nanoparticles orally were bred to exhibit 1.8 times the level of hyperactivity within four generations through the selection of hyperactive individuals.³¹ The offspring appeared to maintain hyperactivity across generations via DNA methylation status in the mesencephalon.
It is unclear to us whether the increased hyperactivity in the fourth generation is a consequence of breeding or a consequence of the silver nanoparticles.

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

Exposure to green spaces prior to conception was associated, for each interquartile increase (IQR = 0.12) in the green space index within the ZIP code area, with a reduced risk of:³²

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

1.2. Toxins and Adverse Effects During Pregnancy (up to +778%)¶

Toxic effects on the unborn have been demonstrated for:

1.2.1. Alcohol During Pregnancy (up to +778%)¶

About 5% of children in the U.S. are believed to have FASD, meaning they have been harmed by their mother’s alcohol consumption during pregnancy.³³
The vast majority of studies conclude that maternal alcohol consumption during pregnancy significantly increases the likelihood of ADHD in children.³⁴³⁵ up to 8.78 times,³⁶ Attention problems are also more common.³⁷ In rats, male offspring are particularly affected.³⁸
A combination of alcohol and stress in the mother during pregnancy increased the likelihood that male rats would develop more feminine sexual behavior.³⁹
Among children with FAS (fetal alcohol syndrome), 47.2% also had ADHD.⁴⁰
In a Taiwanese cohort study of 5-year-old children, the risk of ADHD was 71% higher, although this increase was not statistically significant.⁴¹

There is evidence that a mother’s alcohol consumption during pregnancy or while breastfeeding has significant effects on the child’s dopamine system.^{4243 44 45} The regulation of the neurotransmitters serotonin⁴⁶, glutamate, norepinephrine, acetylcholine, and histamine is also affected.^{47 48}

Some studies found no association between:

• Alcohol consumption during pregnancy and ADHD.⁴⁹⁵⁰⁵¹
• Binge drinking during early pregnancy and the risk of ADHD in children aged 5 to 19.⁵²
  A study found a correlation between ethoxyacetic acid (one of six alcohol metabolites examined) in the mother’s urine and behavioral problems in 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 at lower risk from alcohol exposure during pregnancy than girls.

Neill et al. focus on the differential diagnosis of ADHD and FASD (Fetal Alcohol Spectrum Disorder).⁵⁵

Mechanisms of action, including:

• Changes in the endocannabinoid system as they relate to the VTA⁵⁶
• Hypoxia (lack of oxygen)⁵⁷

1.2.2. Nicotine During Pregnancy (up to +478%)¶

1.2.2.1. Maternal nicotine use during pregnancy (+49% to +478%)¶

Prenatal smoking is associated with an increased risk of ADHD in children^{5859 60} on the

• A 5.36-fold increase (436% higher) in the risk of⁶¹, as well as an increased risk of bipolar disorder by 533%, major depression by 92%, and anxiety disorder by 3%. Not significantly increased: ASA and schizophrenia.
• 4.78 times (a 378% increase)³⁶
• 3.34 times higher among the 10% of mothers who smoke the most⁶²
• 2.7 times (an increase of 170%)⁶³
• 2.5 times (increased by 150%)⁶⁴
• 2.33 times higher (+133%) for smoking during pregnancy and for one year afterward; no statistically significant increase in the risk of ASS (cohort study covering 25 years, N = 16,365).⁶⁵
• 2.21 times higher in cases of heavy nicotine exposure (cotinine level > 50 ng/ml)⁶²
• 2.11 times (cohort study, N = 5,548)⁶⁶
  • 4.18 times higher for girls
  • 1.64 times higher for boys
• 1.75 times higher among heavy female smokers⁶⁷
• 1.60 times higher (a 60% increase) on average among female smokers⁶⁷
• 1.58 times (a 58% increase; meta-analysis, N = 17,304)⁶⁸
• 1.54 times higher among light female smokers⁶⁷
• 1.5 times higher, even with secondhand smoke, but only for boys⁶⁹
• 1.5 times (here: risk of hyperactivity/impulsivity symptoms in the child)⁶⁹
• 1.49 times⁷⁰
• 1.42 times higher in preschoolers, dose-dependent⁷¹
• 1.34-fold (OR) in a meta-analysis of k = 10 studies with N = 7,014; for CD and ODD, an OR of 2.19 was found in each case⁷²
• 1.09-fold (OR) when the mother’s socioeconomic status, maternal age, maternal psychopathology, paternal age, paternal psychopathology, and the child’s birth weight for gestational age were taken into account
• No statistically significant association in a relatively small study (N = 142, n = 26)⁷³

Other studies also found significantly elevated risk levels.^{74757618777879}

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

• 1.72 times⁸⁰
• 3.21 times⁸¹⁸²

Two studies (with overlapping authors)³⁸³ , a study with a small sample size⁸⁴, a larger study⁵¹, and a meta-analysis reached a different conclusion⁸⁵; one study found rather weak evidence.⁸⁶
Studies that distinguished between maternal smoking during pregnancy and genetic influences found no evidence of a causal effect of prenatal smoking on the risk of ADHD.⁸⁷
However, there are several arguments against this:

• Mice exposed to nicotine prenatally serve as an animal model for ADHD^{8889 90 91} In addition, prenatal nicotine exposure in the mouse model leads to reduced birth weight in offspring⁹², which constitutes a risk factor for ADHD in its own right.    
• Studies have examined the link between prenatal smoking and certain genetic polymorphisms:
  • In the absence of genetic risk factors, maternal smoking during pregnancy increases the child’s risk of ADHD by 20 to 30 percent.
  • Risk genes alone (if the mother does not smoke during pregnancy) increase the risk by 20 to 40 percent.
  • However, when risk genes and maternal smoking during pregnancy occur together, the child’s risk of ADHD increases significantly:
    • DAT1-9R (440 bp): 2.6 times
    • DRD4-7R by a factor of 2.9
    • both together, about 9 times as much⁹³⁹⁴
      Another study confirms the role of DRD4-7R in gene-environment interactions.⁹⁵
• The risk of ADHD in children of mothers who smoke was slightly reduced when the mothers quit smoking:⁹⁶
  • Overall risk compared to the offspring of nonsmoking women:
    • ADHD: OR = 2.07 = 207%, learning disability: OR = 1.93 = 193%
  • when quitting smoking during the first trimester
    • ADHD: OR = 1.72 = 172%, learning disability: OR = 1.52 = 152%
  • when quitting smoking during the second or third trimester
    • ADHD: OR = 2.13 = 213%, learning disability: OR = 1.82 = 182%
  • not quitting smoking
    • ADHD: OR = 2.17 = 217%, learning disability: OR = 2.10 = 210%
• In rodents, nicotine consumed even before conception causes ADHD in offspring, and this ADHD is passed down epigenetically across several generations (see above)

The rate of smoking among pregnant women has been declining for a long time. Between 1959 and 1966, 59% of all pregnant women are said to have smoked.⁸⁷ In Germany, the rate of mothers who smoked during pregnancy fell from 19.9% between 1996 and 2006 to 10.9% between 2007 and 2016.⁹⁷⁹⁸ In the U.S., the prevalence of smoking during pregnancy fell from 15.2% in 2000 to 13.8% in 2005⁹⁹ and to 7.2% in 2021 ¹⁰⁰ or to 5.4% based on self-report (which is subject to social desirability bias).¹⁰¹
The prevalence of smoking after childbirth fell from 18.1% in 2000 to 16.4% in 2005⁹⁹ and to 7.2% in 2021 after childbirth; 12.1% reported having smoked before pregnancy, based on self-reports.¹⁰¹
Smoking during pregnancy is also associated with a lower level of education (2008: 4.3% among those with a high school education, 36% among those without a high school education) and a low socioeconomic status (2008: 7.4% among those with an annual income of 40 TUSD or more, 18.7% if annual income is at or below 150% of the poverty line)¹⁰², both of which are, in turn, risk factors for ADHD.
Nevertheless, more than 70 million women in the EU smoked during pregnancy in 2020.¹⁰³

There are no studies examining the extent to which the decline in smoking during pregnancy has influenced the prevalence of ADHD. While there are studies comparing the development of emotional problems over a 20-year period¹⁰⁴, we have not yet found any such study that explicitly addresses ADHD. Since awareness of ADHD has increased significantly today, it will be difficult to compare prevalence rates retrospectively. Furthermore, while smoking during pregnancy is strongly correlated with ADHD, it is not the sole cause of the disorder, so conclusions suggesting that the declining rate of smoking during pregnancy has had no impact on ADHD rates⁴ are, in our view, so difficult to substantiate that they can barely be used as an argument against a causal link between smoking during pregnancy and ADHD.
While the correlation between smoking and depression was still weak in 1952 and 1970, by 1992 the risk of depression among smokers was three times higher than among nonsmokers.¹⁰⁵ Participants who became depressed were more likely to start smoking, were more likely to continue smoking, and were less likely to quit.

Mechanisms of action:

Most experiments on prenatal nicotine exposure show a reduction in dopamine levels in the PFC and striatum.⁹⁰ Under certain circumstances, elevated dopamine levels have also been observed.¹⁰⁶ Neurophysiologically, ADHD is closely associated with reduced dopamine levels in the dlPFC (impaired working memory) and the striatum (impaired motivation and motor hyperactivity).
This should be distinguished from smoking by people with ADHD—which increases dopamine levels (at least in the striatum), as it reduces DAT, which is overly active in ADHD and lowers extracellular dopamine levels in the striatum. Acute smoking thus increases dopamine levels in the striatum.
Prenatal Nicotine

• reduces birth weight⁹², which is a risk factor for ADHD in its own right.
• increases the risk of apnea and hypoxia¹⁰⁷
• delays brain development¹⁰⁸.
• increases the risk of birth complications¹⁰⁹¹¹⁰ , which is a risk factor for ADHD in itself.

Maternal smoking during pregnancy alters glutamate NMDA receptors in the laterodorsal tegmentum of offspring.¹¹¹ Another study also found changes in glutamatergic signaling in the hippocampus due to increased glutamate receptor expression,¹⁰³, which was associated with learning difficulties, attention problems, and increased impulsivity.
ProBDNF proteolysis is disrupted by an imbalance between proBDNF and BDNF and by the downregulation of furin, the enzyme responsible for processing proBDNF. Glucocorticoid receptor activity is altered by a reduced relative nuclear localization of GR. Basal plasma corticosterone levels are decreased. The HPA axis is disrupted. This affects not only the offspring themselves but also their children, meaning it is passed down through generations.¹¹²

A study of mice whose mothers were exposed to nicotine during pregnancy found evidence that nicotine exposure during pregnancy causes various consequences that persisted into the grandchild generation, suggesting epigenetic inheritance:¹¹³

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

Maternal smoking increases fetal testosterone levels.¹¹⁴ Elevated prenatal testosterone levels are a risk factor for ADHD. For more information, see Gender Differences in ADHD.

Compared to other environmental factors, maternal smoking was associated only with ADHD, but not with autism alone. A history of psychiatric disorders in the parents showed similar associations with all subgroups. Living in an urban area was most strongly associated with autism and ADHD and least strongly associated with ADHD alone.¹¹⁵

It is possible that the effects of a mother’s nicotine use during pregnancy could be offset by breastfeeding.¹¹⁶

1.2.2.1. Secondhand Smoke During Pregnancy¶

Even secondhand smoke—that is, a mother’s passive exposure to tobacco smoke during pregnancy—increases the risk that her unborn child will develop ADHD symptoms later in life.⁶⁹

• 4.6 times (+360%).¹¹⁷
• to 1.20 times (+20%)⁷⁰

Similar findings were reported regarding the link between secondhand smoke and developmental coordination disorder (DCD).¹¹⁸
Secondhand smoke exposure during pregnancy, combined with maternal stress during the child’s fifth year of life, increased the risk of attention problems at age 7.¹¹⁹
A study found no evidence of a correlation.⁸⁴

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

Prenatal exposure to polycyclic aromatic hydrocarbons appears to exacerbate the damage caused by early childhood stress and contribute to later attention and memory problems.¹²⁰
High prenatal PAH exposure was correlated with

• Attention symptoms¹²¹ according to DSM-IV (OR = 5.06, +406%)¹²². dose-dependent¹²³
• Total ADHD score according to DSM-IV (OR = 3.37, +237%)¹²²¹²⁴
• Anxiety and Depression¹²¹¹²⁵

A meta-analysis found that four studies by one author suggested a 1.57-fold increase in the risk of ADHD associated with PAHs (OR 2.57), while the combined results of all studies suggested a twofold increase in risk (OR 1.99), although this was not statistically significant.¹²⁶

PAHs enter the body through microplastics and nanoplastics, among other sources.¹²⁷

1.2.4. Lead Exposure During Pregnancy (up to +243%)¶

Lead exposure during pregnancy^{128129 130} affects the mesocorticolimbic circuit and increases the risk of ADHD in children.¹³¹
Female rats were exposed to acute stress and lead during pregnancy. The effects on their offspring differed depending on whether the exposure was to lead alone or to lead combined with stress. Male rat pups showed elevated corticosterone levels and reduced dopamine levels in the PFC only when exposed to lead alone, while female rat pups showed these changes only when exposed to a combination of lead and stress. Even short-term lead exposure of the mothers caused this effect.¹³² In female rat pups, maternal lead exposure and stress during pregnancy contributed to learning difficulties as cumulative factors. Neurophysiologically, these effects were mediated by the glucocorticoid system acting on the mesocorticolimbic system.¹³³
A doubling of lead levels in umbilical cord blood increased hyperactivity by a factor of 3.43 (+243%) at ages 7 to 8 only among boys, while girls showed no significant association.¹³⁴

Other studies have also found evidence that lead exposure, like stress during pregnancy, impairs the mesocorticolimbic dopamine/glutamate system in female offspring (to a lesser extent in males) and that these effects potentiate each other.¹³⁵ Under similar conditions, male rat pups showed a tendency toward serotonergic disorders of the mesocorticolimbic system and altered delay discounting.¹³⁶
Even lead levels in drinking water that are below the limits are said to be problematic.¹²⁹
In general, lead water pipes pose little danger in areas with hard water, since the calcium deposits form a reliable protective layer inside the pipes. However, in such cases, a water softener must not be installed for the drinking water. Nevertheless, it is generally recommended to replace lead-containing water pipes during renovations.

In ADHD, metabolism may be altered with regard to cobalt, copper, lead, zinc, and vanadium. Reduced cycle stability (determinism), duration (mean diagonal length), and complexity (entropy) of the exposure profiles were observed.¹³⁷

Lead is a divalent cation that mimics Ca2+ and activates PKC signaling.¹³⁸

Arnsten¹³⁹ describes lead as a toxin that causes symptoms that can be mistaken for ADHD.

Mechanisms of action:

Lead appears to have a number of harmful neurophysiological effects, which, among other things, also affect the dopaminergic system:

• Impairment of the mesocorticolimbic dopaminergic system¹⁴⁰
• Impairment of dopamine receptors¹⁴⁰
• Impairments in attention regulation in the PFC¹⁴¹
• Apoptosis¹⁴²
• Excitotoxicity¹⁴²
• Reduced cellular energy metabolism¹⁴²
• Impaired heme biosynthesis and anemia¹⁴²
• Oxidative stress¹⁴²
• Lipid peroxidation¹⁴²
• Altered activity of the second messenger system¹⁴²
• Altered neurotransmitter release¹⁴²
• Altered neurotransmitter receptor density¹⁴²
• Impaired neuropsychological functioning¹⁴²
• Impaired development and function of oligodendrocytes¹⁴²
• Abnormal myelination¹⁴²
• Abnormal expression of neurotrophic factors¹⁴²
• Abnormal dendritic branching patterns¹⁴²
• Disorder of the blood-brain barrier¹⁴²
• Disorder in transport of thyroid hormones to the brain¹⁴²
• Altered regulation of gene transcription¹⁴²
• Reduction in gray matter volume in the PFC, particularly in the ACC¹⁴³

Lead also appears to be capable of triggering the following behaviors:

• Impulsivity¹⁴¹
• sociopathic behavior¹⁴⁴¹⁴⁵
• irresponsible behavior¹⁴⁴¹⁴⁵
• criminal behavior¹⁴⁴¹⁴⁵
• Lower IQ¹⁴²
• Impaired academic performance¹⁴²

In the United States, lead poisoning is strongly correlated with crime rates and out-of-wedlock pregnancies.¹⁴⁴¹⁴⁵

Children with elevated blood lead levels are said to be particularly vulnerable to other toxins during early childhood.¹⁴⁶ In particular, warnings have been issued about lead in wall paint. 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. Exposure to Organochlorine Compounds During Pregnancy (up to +171%)¶

Exposure to hexachlorobenzene during pregnancy increased the risk of ADHD among 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 skills problems (RR = 4.04; +304%) and ADHD (RR = 2.71; +171%). Cognitive and psychomotor performance remained unaffected.¹⁴⁷
A large study of 7 European birth cohorts found no correlation between HCB or DDE (a breakdown product of DDT) during pregnancy or the first 2 years of life and ADHD.¹⁴⁸ Another study found that a doubling of p,p’-DDE in umbilical cord blood was associated with a 4.71-fold increase in scores on the Strengths and Difficulties Questionnaire at ages 7 to 8 among girls only, while boys showed no significant association.¹³⁴
Children of mothers with high serum HCB levels in the first trimester (≥90th percentile) (but not those whose mothers were exposed to HCB during pregnancy) showed the following at age 4:¹⁴⁹
– impaired perceptual performance

• impaired general cognitive abilities
• impaired executive functions
• impaired working memory

Organochlorine compounds (dichlorodiphenyltrichloroethane (DDT), dieldrin, heptachlor, endosulfan) have been shown to affect neural development following prenatal exposure (in rodents), for example:¹⁵⁰

• DAT increased
• Increased dopamine reuptake
• Loss of dopaminergic cells
• Changes in key dopaminergic proteins at the presynapse in response to organochlorine pesticides in the striatum or substantia nigra
• Norepinephrine increases
• Increased serotonin
• Reduced GABA receptors
• Reduced NMDA receptors
• Altered mGluR5 receptors
• altered GABAergic, glutamatergic, and dopaminergic responses to endosulfan in the PFC
• Altered dopaminergic responses to heptachlor exposure identified

with disabilities affecting, among other things:

• Attention processes
• cognitive ability
• Memory
• Social Development
• cognitive and psychomotor development
• Fine motor skills
• Reflexes
• visual processing

Organochlorine compounds were, however, primarily associated with ASS.

Organochlorine compounds are believed to have been largely replaced by organophosphates commercially by the end of the 2010s, but they are very persistent and therefore still present in the environment.⁴

1.2.5.2. Exposure to Organophosphates During Pregnancy¶

The organophosphates chlorpyrifos and diazinon had significant effects on brain development in newborns, including the dopaminergic system.¹⁵¹ Prenatal exposure to the widely used pesticide chlorpyrifos impaired IQ and working memory in 7-year-old children¹⁵²¹⁵³ as well as executive functions.¹⁵⁴

Organophosphates inhibit acetylcholinesterase (the enzyme that breaks down acetylcholine).¹⁵⁰ In addition to the well-known downregulation of cholinergic receptors, the organophosphate diisopropyl fluorophosphate (DFP) has been reported to increase dopamine and GABA receptors. A single dose of 1 mg/kg DFP resulted in elevated dopamine levels, while a single toxic dose of 2 mg/kg DFP led to increased dopamine breakdown. After 6 hours, the levels had returned to normal. Chronic administration of 1 mg/kg DFP resulted in reduced dopamine levels after 1 and 2 weeks, which returned to normal with continued administration. A single dose of DFP increased dopamine turnover in the striatum of rats, while chronic administration decreased it. The authors hypothesized that the changes in dopamine and GABA levels might be consequences of the downregulation of cholinergic receptors.¹⁵⁵

Chlorpyrifos disrupts the serotonin system. Exposure during pregnancy can cause tremors in children and impair their cognitive and neurobehavioral development.³⁹

A study based on prenatal urinary dialkyl phosphate metabolites (diethyl phosphate and dimethyl phosphate), as well as an analysis of the maternal PON1 gene variants Q192R and L55M, found no association between the mother’s exposure to organophosphates during pregnancy and the child’s subsequent ADHD.¹⁵⁶

A Norwegian cohort study found an increased risk of ADHD in children when the following were detected in the mother’s blood during pregnancy:¹⁵⁷

• 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 as the level of exposure increases.

Higher levels of vitamin D in the mother appear to reduce the negative effect of the organophosphate chlorpyrifos on the risk of ADHD in their children.¹⁵⁸¹⁵⁹

Chlorpyrifos inhibits FAAH, an enzyme that breaks down endocannabinoids. As a result, chlorpyrifos causes changes in exploratory and social behavior in young rats during puberty.¹⁶⁰

Another Norwegian registry study found no evidence of an increased risk of ADHD in children when the mother was exposed to organophosphates during the 17th week of pregnancy.¹⁶¹

1.2.5.3. Exposure to pyrethroids 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 during the 28th pregnancy week increased the child’s risk of ADHD by 3% and the risk that any ADHD diagnosis would fall among the 10% of the most severe ADHD cases by 13%.¹⁶²

The pyrethroid deltamethrin appears to impair the dopaminergic system in mice following early exposure:¹⁶³

• DAT reduced
• Reduced D1 receptor
• Apoptosis

The pyrethroid deltamethrin impairs long-term potentiation (LTP) at CA3-CA1 synapses in the hippocampus, a functional correlate of learning and memory.¹⁶⁴

Furthermore, (in cases of prenatal, but not postnatal, exposure)¹⁶⁵ permanent behavioral changes were observed with regard to:¹⁶³

• Physical activity
• acoustic startle reflex
• Learning
• Memory

3-PBA and chlorpyrifos mutually enhance each other’s effects with regard to ADHD.¹⁶²

Each detection of trans-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane-1-carboxylic acid (trans-DCCA), a metabolite of permethrin, cypermethrin, and cyfluthrin (trans isomers of pyrethroids), in urine increased the risk of ADHD in offspring by 76%.¹⁶²

Prenatal and postnatal exposure to low doses of the pyrethroid pesticide deltamethrin (within officially approved limits) led to molecular disorders in the brains of adult mice in signaling pathways that regulate the circadian rhythm and neuronal growth (MAP kinase), as well as to behavioral changes relevant to neurodevelopmental disorders.¹⁶⁶

The pyrethroid fenvalerate is known for its developmental toxicity.
Offspring of female mice that received fenvalerate orally during pregnancy exhibited epigenetic changes in the regulation of dopamine synthesis:¹⁶⁷

• reduced dopamine levels in the striatum
• reduced levels of tyrosine hydroxylase in the midbrain of both fetal and weaned puppies
• reduced levels of 5-hydroxymethylcytosine (5hmC) in CpG-rich regions and specific sites within the TH gene in the fetal midbrain
• reduced activity of the Ten-Eleven translocation enzymes (TET) in the fetal midbrain
  • A dose of ascorbic acid, a cofactor for TET enzymes
    • attenuated the fenvalerate-induced decrease in 5hmC levels in CpG-rich regions of the TH gene in the fetal midbrain
    • reversed the Fenvalerat-induced downregulation of TH expression in the midbrain and of striatal DA levels in weaned offspring
    • eliminated the ADHD-like behavior in the weaned offspring

A study conducted in 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% (20.55% for boys, 10.27% for girls) and was, strangely enough, described as “moderate” in the study.¹⁶⁸

• Elevated 4F3PBA concentrations at age 2 were associated with a 6% increased risk of ADHD in preschool-aged children
• Elevated ΣPYRs at age 1 were associated with a 2% increased risk of ADHD in preschool-aged children
• Elevated 3PBA levels in 1-year-old boys were associated with a 7% increased risk of ADHD in preschool age
• Elevated 4F3PBA levels in 2-year-old boys were associated with a 5% increased risk of ADHD in preschool age
• Elevated DBCA levels in girls aged 1 were associated with a 30% increased risk of ADHD in preschool-aged children
• Elevated 4F3PBA levels in 2-year-old girls were associated with a 10% increased risk of ADHD in preschool age
• Elevated ΣPYRs scores in girls aged 1 were associated with a 2% increased risk of ADHD in preschool age

1.2.5.4. Exposure to Glyphosate During Pregnancy¶

Glyphosate (e.g., Roundup) is a broad-spectrum herbicide belonging to the phosphonic acid group.
In rats, oral exposure of the mother to glyphosate (0.5 and 50 mg/kg body weight/day) during pregnancy and lactation resulted (in particular) in the following effects in the (female) offspring:¹⁶⁹

• Symptoms of depression
• Symptoms of anxiety
• 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 gut microbiota in female offspring
  • reduced prevalence of Akkermansia
  • increased abundance of Alistipes and Blautia
    (Bacteria involved in tryptophan metabolism and associated with depression- and anxiety-like disorders)

This suggests a link between glyphosate and depression and anxiety disorders. However, this does not yet establish a connection to ADHD.

Glyphosate is also suspected of being a possible cause of ASS.¹⁷⁰

1.2.5.5. Neonicotinoids¶

Neonicotinoids are the most widely used type of insecticide. There is evidence that neonicotinoids may harm the fetus during pregnancy.¹⁷¹ Neonicotinoids lead to reduced size in certain brain regions, such as the striatum and the corpus callosum. The corpus callosum is often smaller in individuals with ADHD,

1.2.6. Phthalates During Pregnancy (up to +142%)¶

According to most studies, phthalate esters increase the risk of ADHD in the unborn child,^{172173 174} although the mechanisms underlying these associations remain unclear.¹⁷⁵¹⁷⁶ The potential impact on thyroid function¹⁷⁷ and inflammatory pathways¹⁷⁸ is discussed. Higher levels of phthalate metabolites in the urine of pregnant women correlated with increased distractibility in preschool-aged children¹⁷⁹ as well as with impaired executive functions¹⁸⁰.
Prenatal exposure to dimethoxyethyl phthalate (DMEP) 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 cortical development and disrupted dendritic spine architecture and synaptic activity in the parietal cortex. In addition, prenatal DMEP exposure in mice induced hyperactivity and reduced anxiety-related behavior.¹⁸¹
Prenatal phthalate exposure, in combination with a genetic predisposition to phthalate-induced inflammation, increased the risk of ADHD in offspring at age 11.5 years by a factor of 2.42 and the risk of ASD by a factor of 2.15.¹⁷⁸

High levels of phthalates in umbilical cord blood were associated with a risk of:¹⁸²

• ASS: 2.09 times
  • ASS in boys: 2.47 times

The risk of ASD was increased by:¹⁸²

• High LMWP values: 3.43 times the risk
• High DEHP levels: 3.24-fold increased risk
• High total phthalate levels: 4.87 times the risk

The risk of ADHD was increased by:¹⁸²

• High MBP exposure in late pregnancy: 1.61-fold increased risk

High phthalate exposure impaired the metabolism of linoleic acid and arachidonic acid.¹⁸²

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, particularly conduct disorder, with a very high Effect size comparable to that of prenatal alcohol or cannabis exposure. Internalizing problems remained unchanged. Furthermore, when mothers consumed more than 3 cups of coffee per day, the children’s BMI and consumption of soft drinks were elevated. Prenatal caffeine exposure correlated with structural changes in the brain, including greater thickness of the posterior and inferior frontal cortex and altered depth of the parieto-occipital sulcus.¹⁸³ Higher caffeine consumption during pregnancy was associated with increased internalizing and externalizing symptoms in the parents.
A review found no correlation between caffeine consumption during pregnancy and ADHD in 4 out of 5 studies.¹⁸⁴

Caffeine consumption of 10 cups of coffee a day or more was associated with a 130% increased risk of ADHD in children.¹⁸⁵

A study found a slight increase in risk associated with caffeinated soft drinks during pregnancy, but not with coffee or tea.¹⁸⁶

Caffeine consumption during pregnancy—at less than 10 cups a day—did not increase the risk of ADHD.^{18718818919019151192}

Children of mothers who drank tea consistently throughout their entire pregnancy had higher scores for cognition, fine motor skills, and gross motor skills than children whose mothers drank tea only during the first trimester of pregnancy. Tea consumption during the second and third trimesters was more strongly associated with these outcomes than tea consumption during the first trimester. Coffee consumption showed no significant association with the children’s cognitive development.¹⁹³

Caffeine consumption during pregnancy is associated with a higher BMI in children.^194195191

1.2.8. Maternal drug use during pregnancy (up to +80%)¶

Children who were exposed to their mothers’ multiple drug use before birth and who subsequently grew up in foster care were found to have a threefold increased risk of ADHD between the ages of 17 and 22.¹⁹⁶

7.7% of mothers used cannabis during pregnancy (meta-analysis, k = 17, N = 534,445).¹⁹⁷
Several studies have linked cannabis use during pregnancy to an increased risk of ADHD in children.^198199200
A meta-analysis found a relatively small increase in risk of ADHD—13%—associated with maternal cannabis use during pregnancy, and a 4% increase associated with ASA; a 29% increased risk of psychosis, a 34% increased risk of anxiety, and a 28% reduced risk of depression (k = 17, N = 534,445)¹⁹⁷
A study of N = 141,570 children of N = 117,130 mothers found a reduced risk among their children for ADHD (16% lower) and disruptive behavior disorder (DBD, 17% lower).²⁰¹ One study does not address the risk of ADHD in offspring associated with cannabis use during pregnancy, but notes that cannabis use during pregnancy correlates with localized differences in the gray and white matter of the frontal and parietal cortex, the associated white matter tracts, and the connectivity of the striatum at rest.²⁰²

Translated with DeepL.com (free version)

Maternal drug use (heroin, amphetamine, ketamine, or other substances) during pregnancy was associated with an increased risk for the offspring (registry study, N = 1,969,006)²⁶

• by 77% to 80% for ADHD
• 35% to 41% for intellectual disability
• by 7% to 12% for ASS

1.2.9. Copper (+51%)¶

Elevated copper levels in the placenta increased the risk of ADHD by 51%.²⁰³

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

Exposure to cadmium during pregnancy increased the risk of ADHD in 6-year-old girls, but not in boys. A twofold increase in the mother’s cadmium exposure during pregnancy increased the risk of ADHD in girls by 22.3%.²⁰⁴
Elevated cadmium levels in the placenta increased the risk of ADHD by 36%.²⁰³
A twofold increase in cadmium levels in umbilical cord blood was associated with a 1.53-fold increase (+53%) in emotional problems at ages 7 to 8 only among boys, while girls showed no significant association.¹³⁴

Possible mechanism of action: blood-brain barrier.²⁰⁵

1.2.11. Manganese (up to +34%)¶

There is limited evidence suggesting a link to ADHD, although elevated manganese levels have been found only in the hair—and not in the blood—of people with ADHD.²⁰⁶
A doubling of the manganese content in teeth from both the prenatal and postnatal periods increased the risk of attention problems and ADHD symptoms during school age by 5%. Manganese exposure during childhood had no effect.²⁰⁷
An animal model involving developmental manganese exposure showed that manganese can cause persistent attention and sensorimotor deficits similar to those seen in ADHD-I. Oral methylphenidate was able to completely reverse the deficits caused by early manganese exposure.²⁰⁸
Elevated manganese levels in the placenta increased the risk of ADHD by 34%.²⁰³

1.2.12. Air Pollution During Pregnancy (up to +26%)¶

A study found that air pollution causes changes in the immune systems of children.²⁰⁹
A study of approximately 43,000 families in Shenzhen found positive correlations between ADHD, beginning at age 3, and exposure during pregnancy to²¹⁰

• Steam cooking
• Tobacco smoke
• Fumes from home renovations
• Mosquito coils (burned-out mosquito pyramids; especially when used in combination with incense smoke)
• Incense smoke (especially when combined with mosquito-repellent smoke)

Another study found no increased risk of ADHD associated with air pollution.²¹¹

A meta-analysis found that more studies (not related to pregnancy) supported a link between air pollution and ADHD than refuted it.²¹²

1.2.12.1. Particulate matter (+26%)¶

To avoid repetition, 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 examining prenatal exposure to fine particulate matter using satellite data found that a 10 μg/m³ increase in PM2.5 concentration during the first trimester increased the risk of ADHDrisk by 26% and that this risk continued to rise at PM2.5 concentrations above 16 μg/m³.²¹³
In one study, exposure to fine particulate matter during pregnancy was associated with a reduced volume of the corpus callosum and a tendency toward increased hyperactivity.²¹⁴ Another study found a link between fine particulate matter and ADHD at low exposure levels, while higher exposure levels caused more severe brain damage.¹²⁴

In rats, inhaled printer particles led to a fivefold increase in dopamine levels, which was likely due to increased synthesis rather than reduced breakdown.²¹⁵

In laboratory experiments, diesel exhaust particles caused functional impairments in dopamine neurons. Prenatal exposure via inhalation resulted in the following effects in mice:²¹⁶

• in the striatum
  • reduced dopamine turnover
  • reduced levels of dopamine metabolites
• in the amygdala
  • elevated dopamine levels
  • elevated levels of dopamine metabolites
• in the nucleus accumbens
  • elevated dopamine levels

Traffic-related ultrafine particulate matter in the air inhaled after birth caused the following effects in female mice:²¹⁶

• increased dopamine turnover in the hippocampus

Both prenatal and postnatal exposure to reduced levels of particulate matter and gaseous pollutants in rodents reduced the expression of oxytocin receptors in the hippocampus²¹⁷ and hypothalamus, resulting in reduced maternal caregiving behavior.²¹⁸ Oxytocin and vasopressin signaling appears to be disrupted by endocrine-active chemicals²¹⁹, many of which are present in outdoor air.²¹⁶

Studies have found an association between PM2.5 and symptoms of hyperactivity and inattention (OR = 1.12)²²⁰, hyperactivity²²¹, ADHD symptoms²²², and between PM2.5 exposure during the first trimester and a tendency toward attention problems and hyperactivity.²²³

Other studies found no association between PM2.5 and ADHD^224225226

A meta-analysis reports a correlation between PM10 and ASA.²²⁷ One study broke down the increased risk of ASA by PM1 (+86%), PM2.5 (+76%), and PM10 (+68%).²²⁸

The following are considered potential pathways linking prenatal exposure to fine particulate matter to ADHD:²²⁹

• In the placenta
  • Increased inflammation
  • Oxidative stress
  • Disorder in blood flow and placental development
  • Effects on nutrient and oxygen supply
  • Epigenetic dysfunction
• In the fetal brain
  • Increased neuroinflammation
  • Elevated cytokines

1.2.12.2. Nitrogen oxides (+26%)¶

Several studies have found a correlation between exposure to nitrogen oxides during pregnancy and ADHD.¹²⁰

• NOx was correlated with hyperactivity, with a stronger association between ADHD and NO than between ADHD and NO2. (NO: aOR = 1.26)²²⁶
• NO₂ exposure during pregnancy was strongly correlated with ADHD symptoms, such as
  • Impulsivity
    • Interrupting others²²²
    • Inability to wait for one’s turn while playing²²²
  • Attention problems
    • Not paying attention when crossing the street²²²
    • Attention problems at ages 4–5²³⁰
  • Hyperactivity²²¹
  • Oppositional behavior (not a core symptom of ADHD)
    • Lies²²²
    • Disorder of the Peace²²²

Other studies found no significant or clear correlations between NOx and ADHD.^224231232
A study found a correlation with ASA in children, but not with ADHD.²³³

Nitrogen oxide emissions in Germany fell by just under two-thirds between 1990 and 2020.²³⁴

1.2.12.3. Ozone¶

Ozone had the following effects on rats:²¹⁶

• 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

To date, no correlation with ADHD has been found in humans.²²¹¹²⁰

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

Polychlorinated biphenyls (PCBs) may increase the risk of ADHD.²³⁵²³⁶ PCBs inhibit dopamine synthesis, as well as the storage of dopamine in vesicles and its release, thereby causing dopamine levels to be too low. Polychlorinated biphenyls caused hyperactivity and impulsivity (in rats even at subtoxic doses).²³⁷ Polychlorinated biphenyls can directly affect dopaminergic processes, disrupting the dopamine system and causing Parkinson’s-like symptoms.²³⁸ Other studies have also found that PFAS reduce dopamine levels.²³⁹²⁴⁰ as well as effects on acetylcholine, serotonin, and glutamate neurotransmitter balance.²⁴¹
PFOS can cross the placenta and the blood-brain barrier.²⁴²
Children of mothers with high serum PCB levels during the first trimester (≥90th percentile) (but not those whose mothers were exposed to PCBs during pregnancy) showed the following at age 4:¹⁴⁹

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

A meta-analysis of k = 30 meta-studies examined the association between prenatal exposure to PFOA and PFOS and ADHD in children aged 4–11 years.²⁴³
A statistically significant increase in the risk of ADHD was found among girls, but not among boys.
It is also possible that newer PFAS alternatives increase the risk of ADHD.²⁴⁴
A large-scale study of 7 European birth cohorts found no correlation between PCB-153 exposure during pregnancy or the first 2 years of life and ADHD.¹⁴⁸

PFOS also increases the risk of obesity. This risk is compounded by 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 the distance traveled. PFOS may therefore promote hyperactivity, while a combination of PFOS and HFD altered social behaviors such as rearing and withdrawal. PFOS exposure affects calcium signaling, MAPK signaling pathways, transmembrane ion transport, and developmental processes. The combination of HFD with PFOS amplifies the effect of PFOS in the brain and affects signaling pathways associated with ER stress, axon guidance and elongation, and neuronal migration. PFOS and HFD increase the effects on inflammatory pathways, the regulation of cell migration and proliferation, and MAPK signaling pathways.²⁴²

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

A long-term study found no correlation between perfluoroalkyl exposure during pregnancy and ADHD. Weak correlations—both positive and negative—were found with working memory functions in childhood.²⁴⁵ A meta-analysis also found no significant correlation between maternal PFAS exposure and the prevalence rate of early childhood ADHD. Nevertheless, the odds ratios were elevated in some cases:²⁴⁶

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

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

Another study found a correlation between perfluorooctanoic acid (PFOA) and ADHD, but not between perfluorooctanesulfonate (PFOS) and ADHD or ASD.²⁴⁷ Another study found an increased risk of ADHD among school-aged children exposed to low to moderate levels of PFAS at age 2.²⁴⁸

1.2.15. Thallium During Pregnancy¶

High thallium exposure during the second trimester of pregnancy increased the risk of ADHD in 3-year-old boys, but not in girls.²⁴⁹

1.2.16. Bisphenols During Pregnancy¶

Bisphenol A (BPA) increases the risk of ADHD (meta-analysis, k = 32, N = 15,669).^250236251
Bisphenol A is one of the most widely produced synthetic compounds in the world. BPA is found in epoxy resins and polycarbonate plastics, which are commonly used for food storage and baby bottles.²⁵²
BPA can cross the placenta^{253254 255} and is found in human breast milk.²⁵⁶ BPA disrupts the gut-brain axis and the blood-brain barrier.^{257252258259260}

BPA can:

• impair memory (meta-analysis, k = 22)²⁶¹
• impair cognitive abilities (meta-analysis, n = 22)²⁶¹
• bind to estrogen receptors²⁵²²⁶¹
• cause various structural and molecular changes in the brain²⁵²
• promote oxidative stress²⁵²
• alter the expression levels of several important genes and proteins²⁵²
• Affect neurotransmitters²⁵²
  • Alter neurotransmitter levels (meta-analysis, k = 22)²⁶¹
• Cause excitotoxicity²⁵²
• Promote neuroinflammation²⁵²
• impair the function of the blood-brain barrier²⁵²
• cause nerve damage²⁵²
• Promote apoptosis²⁵²
• disrupt intracellular Ca2+ homeostasis²⁵²
• increase reactive oxygen species (ROS)²⁵²
• influence the release of intracellular lactate dehydrogenase²⁵²
• reduce the length of the axon²⁵²
• cause DNA damage in microglia²⁵²
• Trigger astrogliosis²⁵²
• cause a significant reduction in myelination²⁵²
• acts as a broad-spectrum endocrine disruptor²⁶²
• is metabolized via glucuronidation²⁶²
  • This process involves the attachment of glucose to the target molecule and is catalyzed by uridine-5’-diphospho-glucuronosyltransferases (UGTs)
  • The mechanism linking BPA glucuronidation efficiency to disease could be direct or indirect
    • Direct mechanism of action: free BPA is the actual cause; impaired BPA detoxification leads to elevated BPA levels in sensitive tissues, where it can act as an endocrine disruptor
    • Indirect mechanism of action: BPA is not the causative agent; rather, it serves as a marker for the reduced glucuronidation efficiency of other compounds that are metabolized by a similar combination of UGTs and efflux transporters as BPA
• inhibit the ERK-CREB-BDNF signaling pathway (meta-analysis, k = 22)²⁶¹
• alter the expression of synaptic proteins (meta-analysis, k = 22)²⁶¹
• affect the morphology of pyramidal neurons in the hippocampus (meta-analysis, k = 22)²⁶¹
• Dysregulate thyroid hormones (meta-analysis, n = 22)²⁶¹

Exposure to BPA increases the risk of neurological disorders, including

• neurovascular disorders (e.g., stroke)²⁵²
• neurodegenerative diseases (e.g., Alzheimer’s and Parkinson’s)²⁵²²⁶²
• Neurodevelopmental disorders
  • ADHD²⁶²; (meta-analysis, k = 32, N = 15,669).²⁵⁰
    • Another meta-analysis found no clear evidence of an effect from prenatal or postnatal exposure in children and adolescents (k = 46; N = 21,896)²⁶³
  • ASS²⁵²²⁶²
• Depression²⁵²
• emotional problems²⁵²
• Anxiety²⁵²
• cognitive disorders²⁵²
• Polycystic ovary syndrome (PCOS)²⁶²

Bisphenol A (BPA) is a glucocorticoid receptor agonist and has been linked to changes in the HPA axis response. In female rats, prenatal BPA exposure correlated with elevated basal corticosterone levels as well as reduced glucocorticoid receptor expression in the hypothalamus. In response to stress, these female rats exhibited anxious coping behavior and a blunted 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 administered to the rat mothers during pregnancy and lactation—40 micrograms/kg/day—was very low.²⁶⁴
5 milligrams per cubic meter in the air we breathe can cause eye irritation.²⁶⁵ A review confirmed evidence that bisphenol A during pregnancy may increase the risk of ADHD in children, particularly boys.¹⁷⁶

BPA and BPS caused a sharp increase in dopamine (3- to 5-fold) and a sharp decrease in serotonin (by 80%) in mouse placentas. GABA levels remained unchanged.²⁶⁶ BPA is an endocrine disruptor and mimics estrogenic activity. As a result, BPA affects various dopaminergic processes to increase mesolimbic dopamine activity, leading to hyperactivity, attention deficits, and increased susceptibility to substance abuse.²³⁸

1.2.17. Dioxin Exposure During Pregnancy¶

Children who were exposed to dioxin during pregnancy have an increased risk of ADHD.²⁶⁷

1.2.18. Prenatal Sulfur Dioxide Exposure¶

Prenatal exposure to sulfur dioxide (SO2) was associated with DNA methylation and increased ADHD symptoms.²⁶⁸²⁶⁹
According to a review at¹²⁰, two other studies found no significant association.²²⁶²²¹

1.2.19. Polybrominated diphenyl ethers¶

Polybrominated diphenyl ethers (PBDEs) are brominated organic chemicals. They were used as flame retardants in many plastics and textiles.
Its concentration in breast milk rose exponentially between 1972 and 1998.
German industry voluntarily stopped using it in 1986. Sweden banned its production and use in 1999.
Throughout the EU, since 2003, PentaBDE and OctaBDE may be placed on the market or used only at concentrations of up to 0.1 percent by weight.

Prenatal exposure to PBDEs appears to increase ADHD symptoms in girls.²⁷⁰

1.2.20. Low urinary fluoride levels in the mother¶

A study found an inverse association between fluoride levels in the mother’s urine and cognitive problems in her children at age 11. The higher the fluoride concentration, the fewer cognitive problems were observed.²⁷¹ This did not align with the results of other studies, which found an increased risk of ADHD associated with elevated urinary fluoride levels in the children themselves.²⁷²²⁷³

1.3. Illnesses of the Mother / Parents (up to +370%)¶

Psychiatric disorders in the family increased the child’s risk of ADHD by a factor of 9.37.¹¹⁷

Children with ADHD were more likely to have mothers who experienced health problems during pregnancy:⁸¹

• Maternal illnesses during pregnancy:
  Among children with ADHD, 34.4% had a mother who was ill during pregnancy, compared with 14.4% of children without ADHD.
  • Children with ADHD: 34.7%
    The mother’s illnesses during pregnancy occurred in the following trimester:
    • 1st and 2nd trimesters only: 56.4%
    • 3rd trimester only: 12.7%
    • Entire pregnancy: 30.9%
  • Children not affected: 14.4%
    The mother’s illnesses during pregnancy occurred in the following trimester:
    • 1st and 2nd trimesters only: 0%
    • 3rd trimester only: 33.3%
    • Entire pregnancy: 66.7%
• Other pregnancy-related issues:
  • Children with ADHD: 14.5%
  • Children not affected: 3.8%

A 25-year cohort study (N = 16,365) found no statistically significant increase in the risk of ADHD associated with maternal illnesses unrelated to pregnancy; however, it did find a 1.52-fold increase in the risk of ASD (+52%).⁶⁵ Furthermore, maternal infections during pregnancy were not a risk factor for ADHD, but were a risk factor for ASD in the offspring: 1.33-fold (+33%) (25-year cohort study, N = 16,365)⁶⁵

1.3.1. Intrahepatic cholestasis (ICP) during pregnancy (+7% to +370%)¶

Intrahepatic cholestasis of pregnancy (ICP) is the most common pregnancy-related liver disease. It is associated with an increased risk of iatrogenic preterm birth and adverse consequences for the infant.²⁷⁴
An ICD increased the risk of ADHD/ASD:

• before the 28th week of pregnancy
  • 2.62 times the risk of ADHD (+162%)
  • 1.69 times the risk of ASS (+69%)

Weeks 28 through 36 of pregnancy

• 1.36 times the risk of ADHD (+36% (+37%))

• 1.37 times the risk of ASS

• after the 36th week of pregnancy

  • 1.07 times the risk of ADHD (+7%)
  • 1.13 times the risk of ASS (+13%)

Of 30 people with ADHD who have citrine-induced cholestasis, 14 were diagnosed with ADHD (47%).²⁷⁵ Assuming an ADHD prevalence of 10% among children, this translates to a 370% increased risk of ADHD.

1.3.2. Parental asthma during and outside of pregnancy (+26% to +330%)¶

1.3.2.1. Maternal Asthma During Pregnancy¶

Asthma in the mother during pregnancy increases the risk of ADHD and ASD in her child.²⁷⁶

• 330%. Among the children of mothers in the COPSAC2000 birth cohort (all of whom have asthma), 20% have ADHD.²⁷⁷
• 49% of children born to N = 106,163 mothers who had asthma during pregnancy showed a risk of:²⁷⁸
• 47% risk of ADHD by age 18 if the mother had asthma during pregnancy²⁷⁹
• 43% (meta-analysis, k = 12, N = 7.38 million)²⁸⁰
  • Boys: +36%
  • Girls: +45%
  • ASS: +36%
• A 41% increased risk of ADHD in children whose mothers have asthma (cohort study, N = 961,202 children)²⁸¹
  • an additional 21% increase in risk due to an asthma flare-up in the mother during pregnancy²⁸¹
  • an additional 25% increase due to an asthma flare-up after pregnancy²⁸¹

Another study also found an increased risk of ADHD among the children of mothers with asthma, particularly among girls.²⁸²

Children of N = 106,163 mothers who had asthma during pregnancy had a risk of:²⁷⁸

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

1.3.2.2. Father’s Asthma¶

• 26% for ADHD up to the 18th birthday if the father had asthma during pregnancy²⁷⁹
• 13% increased risk if the father has asthma²⁸¹

1.3.3. Elevated or decreased thyroxine levels¶

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

Abnormal thyroid hormone levels during pregnancy can have profound effects on a child’s brain development and cognition²⁸³²⁸⁴ and impair

• Neurodevelopmental processes²⁸⁵
  • Cell differentiation
  • Neurite growth
  • Synaptogenesis
  • Myelination
• Neurotransmitter systems²⁸⁶
  • monoaminergic system
  • cholinergic system
  • which can lead to attention deficits and hyperactivity

Even temporary subclinical thyroid abnormalities during pregnancy can have serious consequences.²⁸⁷ Treating severe maternal hypothyroidism before the third trimester appears to prevent cognitive impairments²⁸⁸ and preterm births.²⁸⁹

Studies in mice with a mutated human thyroid receptor TRb-1 gene (TRbeta transgenic mice)²⁹⁰ found that these

• Normal levels of the thyroid hormones triiodothyronine (T3) and thyroxine (T4) (euthyroid), except for a brief 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 whose mothers had a thyroid disorder during pregnancy.²⁹¹

One study found a 7% increased risk of ADHD in children when the mother had untreated mild thyroxine deficiency during early pregnancy.²⁹² In another study, reduced or untreated normal thyroxine levels in the mother had no effect on ADHD in the children. In contrast, thyroxine treatment in the mother—particularly when thyroxine levels are elevated due to an overdose—appears to increase the risk of ADHD in children.²⁹³ Another study also found evidence suggesting that thyroxine may be a possible cause of ADHD,²⁹⁴ while yet another study found no effect of the mother’s thyroxine levels during pregnancy.²⁹⁵
A Norwegian cohort study found a 2.27-fold increased risk of ADHD (+127%) when the mother’s thyroid hormone T3 levels at 17 weeks of gestation were in the top 1/5 compared to the bottom 1/5. For free T4, both elevated and reduced levels were associated with an increased risk: the top 1/5 as well as the bottom 1/5 showed a 1.6-fold increased risk of ADHD in the offspring.²⁹⁶

A study of male mice found significantly reduced dopamine and serotonin turnover in the striatum, nucleus accumbens, hypothalamus, and hippocampus as a consequence of prenatal thyroxine deficiency.²⁹⁷ Dopamine deficiency in the striatum and nucleus accumbens is responsible for hyperactive symptoms in ADHD.

A study found that maternal hyperthyroidism or hypothyroidism diagnosed and treated before the child’s birth had no effect on the child’s risk of ADHD or ASD.
However, maternal hyperthyroidism—which was first diagnosed and treated after the child’s birth—increased the child’s risk of ADHD by 23%, while hypothyroidism diagnosed in this manner increased the risk of ASD by 34%.²⁹⁸

1.3.3.2. Decreased and increased TSH levels in newborns (ranging from +14% in boys to +310% in girls)¶

Children with congenital hypothyroidism (congenital hypothyroidism, connatal hypothyroidism) had an ADHD incidence of 3.97% (versus 1.87%, +112%) and a rate of ASD of 0.71% (versus 0.13% = +346%).²⁹⁹
A cohort study from Norway found that newborns with TSH levels that were either too low or too high had an increased risk of ADHD later in life, but only among girls. TSH levels in the lowest 20% increased the risk of ADHD in girls by a factor of 3.1, but only by 14% in boys.³⁰⁰

In rodents, primary hypothyroidism reduced the levels of the glucose transporter GLUT1 in the brain, had no effect on GLUT3, and compensatorily increased hexokinase enzyme activity. However, these changes were pronounced only during the immediate neonatal period and disappeared after weaning.³⁰¹

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

1.3.4.1. Severe obesity in the mother before or during pregnancy (+14% to +280%)¶

Severe obesity in the mother during pregnancy increased the risk of the child developing ADHD later in life

• by a factor of 2.8.³⁰²
• by 62%³⁰³
• by 57% for ADHD and 42% for ASD³⁰⁴
• by 46% for ADHD and CD, by 67% for eating disorders, by 55% for specific developmental disorders, by 44% for mood disorders, and by 33% for anxiety disorders (aHR = 1.33) and by 23% for other behavioral and emotional disorders³⁰⁵
  • Being overweight (rather than obese) was associated with a 26% increased risk of intellectual disability, a 15% increased risk of mood disorders, a 12% increased risk of ADHD or conduct disorder, and a 9% increased risk of other behavioral and emotional disorders³⁰⁵

The risk of ADHD among children increased³⁰⁶

• by 23% to 28% due to being overweight
• by 47% to 89% due to obesity
• by 88% to 95% due to severe maternal obesity

In a Finnish registry study (n = 392,098 mothers, 649,956 children), children of mothers who were overweight or underweight during pregnancy had an increased risk of mental disorders:³⁰⁷

• Severe obesity in the mother (BMI of 35.0 or higher)
  • ADHD and CD: 1.88 (+88%)
  • ASS: 1.74 (+74%)
  • Social functioning problems and tics: 1.31 (+31%)
  • Affective disorders: 1.67 (+67%)
  • Anxiety: 1.51 (+51%)
  • Feeding problems as an infant or child: 1.10 (+10%, not statistically significant)
  • Sleep disorders: 0.99 (down 1%, not statistically significant)
  • Intellectual disability: 2.04 (+104%)
  • Specific developmental disorders: 1.83 (+83%)
• Maternal overweight (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%)
  • Anxiety: 1.29 (+29%)
  • Feeding problems as an infant or child: 1.06 (+6%, not statistically significant)
  • Sleep disturbances: 1 (+0%, not statistically significant)
  • Intellectual disability: 1.61 (+61%)
  • Specific developmental disorders: 1.48 (+48%)
• The mother is slightly overweight (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%)
  • Anxiety: 1.11 (+11%)
  • Feeding problems as an infant or child: 0.96 (down 4%, not statistically significant)
  • Sleep disorders: 1.08 (+8%, not statistically significant)
  • Intellectual disability: 1.25 (+25%)
  • Specific developmental disorders: 1.20 (+20%)
• Underweight mother (BMI of 18.5 or 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)
  • Anxiety: 1.10 (+10%)
  • Feeding problems as an infant or child: 1.07 (+7%, not statistically significant)
  • Sleep disturbances: 0.98 (down 2%, not statistically significant)
  • Intellectual disability: 1.33 (+33%)
  • Specific developmental disorders: 1.18 (+18%)

A study from Benin reports increased motor activity and impaired cognitive function in children whose mothers were underweight.³⁰⁸

Even a high BMI in the mother before pregnancy increased the risk of ADHD in her future children.³⁰⁹ 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%.³¹⁰
Other fluctuations in the mother’s weight before and at the end of pregnancy do not appear to affect the risk of ADHD.⁷⁴ In rats, however, there is evidence of an effect on the offspring’s dopamine levels.³¹¹
A Norwegian registry study found only limited evidence that a mother’s pre-pregnancy BMI influences her child’s risk of ADHD.³¹²

If obesity was accompanied by high blood pressure, this led to an increased risk of:³⁰⁵

• + 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 to the reference group (Figure 1 and Table S2). Nevertheless, the effect sizes of the combined exposure were no greater than those of individual exposure to chronic hypertension or overweight.

1.3.4.2. Eating Disorders During Pregnancy (+53% to +112%)¶

In a Finnish registry study (n = 392,098 mothers, 649,956 children), children of mothers who had eating disorders during pregnancy had an increased risk of mental disorders:³⁰⁷

• Anorexia in 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%)
  • Anxiety: 1.63 (+63%)
  • Feeding problems as an infant or child: 1.24 (+24%, not statistically significant)
  • Sleep disorders: 2.12 (+112%)
  • Intellectual disability: 1.08 (+8%, not statistically significant)
  • Specific developmental disorders: 1.37 (+37%)
• The mother’s bulimia
  • ADHD and CD: 1.94 (+94%)
  • ASS: 1.75 (+75%)
  • Social functioning problems and tics: 2.48 (+148%)
  • Affective disorders: 1.92 (+92%)
  • Anxiety: 1.88 (+88%)
  • Feeding problems as an infant or child: 1.88 (+88%)
  • Sleep disorders: 2.35 (+135%)
  • Intellectual disability: 0.89 (down 11%, not statistically significant)
  • Specific developmental disorders: 1.09 (+9%, not statistically significant)
• Eating disorder in 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%)
  • Anxiety: 2.19 (+119%)
  • Feeding problems as an infant or child: 2.69 (+169%)
  • Sleep disorders: 3.34 (+234%)
  • Intellectual disability: 1.18 (+16%, not statistically significant)
  • Specific developmental disorders: 1.54 (+54%)
• any eating disorder in 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%)
  • Anxiety: 1.79 (+79%)
  • Feeding problems as an infant or child: 1.59 (+59%)
  • Sleep disorders: 2.36 (+138%)
  • Intellectual disability: 1.16 (+16%, not statistically significant)
  • Specific developmental disorders: 1.28 (+28%, not statistically significant)

1.3.5. Preeclampsia (gestosis) during pregnancy (+23% to +277%)¶

The percentage figure in the headline was calculated by excluding the lowest and highest values.

Preeclampsia impairs the fetus’s oxygen supply and is often accompanied by high blood pressure in the mother. Both conditions, even on their own, are risk factors for ADHD in the child.

Preeclampsia (gestosis) during pregnancy increases the risk of ADHD in children³¹³³¹⁴

• by 408%.¹¹⁷
• by 277% (RR 2.77)³¹⁵
• by 30 to 188 percent.³¹⁶
• by 43% (cohort study)³¹⁷
• by 29% (meta-analysis, k = 15)³¹⁸
• by 19%³¹⁹

Among individuals of normal weight, the risk associated with preeclampsia was increased:

• 48% for intellectual disability³⁰⁵

• 43% for specific developmental disorders³⁰⁵

• for ASS

  • by 43%³⁰⁵
  • by 27% (meta-analysis, k = 15)³¹⁸ - +23% for ADHD or CD³⁰⁵

• 35% for epilepsy (meta-analysis, k = 15)³¹⁸

• 34% for other behavioral and emotional disorders³⁰⁵

In cases of overweight, the risk associated with preeclampsia was higher compared to both the reference group and those who had either preeclampsia alone or overweight alone:³⁰⁵

• 123% for affective disorders

• 85% for anxiety disorders

• 82% for specific developmental disorders

• 115% for other behavioral and emotional disorders

In cases of obesity, the risk associated with preeclampsia was increased:³⁰⁵

• 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 intellectual disability by 58% (HR: 1.58). The cause was usually preeclampsia.³²⁰³¹⁴

Preeclampsia combined with a urinary tract infection increased the risk by 53%.³¹⁹

Preeclampsia in some mothers of preterm infants increased the infants’ risk of impairments in gross and fine motor skills, adaptability, language, and social-emotional responses, as well as the rate of abnormal test results.
While no abnormalities were observed in the aforementioned areas at 3 to 6 months of age, by 12 months of age there was a significant decline in gross and fine motor skills, accompanied by a significantly reduced risk of abnormal speech scores.³²¹

Several reviews confirm an increased risk of ADHD associated with preeclampsia during pregnancy.³²²³²³

1.3.6. Maternal psychological stress during pregnancy (+72% to +210%; with 5HTTLPR +800%)¶

Maternal stress during pregnancy increased the risk of ADHD in children

• by 400% (OR = 5.02).³²⁶
• by 210% among boys whose mothers had lost a child or a spouse during pregnancy ³²⁷
• by 147% among boys whose mothers had suffered the death of a child or spouse in the 0–6 months prior to pregnancy³²⁷
• by 100%³²⁸
• a 95% increase in ADHD symptoms at age 16, but no increase in hyperactivity symptoms at age 8 (a 13% decrease)³²⁹
• by 75.1% among children whose mothers experienced significant stress during the first trimester of pregnancy, compared with children of mothers who experienced low levels of stress²⁹¹
• by 72% among boys whose mothers had suffered the unexpected death of a child or a spouse³²⁷
• by 72%³³⁰
• by 60%; no statistically significant increase in the risk of ASA (25-year cohort study, N = 16,365)⁶⁵
• by 56.9% among children whose mothers experienced significant stress during the first trimester of pregnancy, compared with children of mothers who experienced moderate stress²⁹¹
• by 31% due to maternal stress in the third trimester (and by 58% for ASA)³³¹
• Stress during the second and third trimesters did not significantly increase the risk of ADHD in the child²⁹¹
• Administration of corticosterone during pregnancy caused learning and memory problems in the offspring of rats³³²

Prolonged and severe stress (which is anxiety-laden and perceived as threatening = leading to higher cortisolergic levels) significantly increases the risk of colic³³³ (see also 2.2.2.3.2), anxiety disorders, and ADHD.^{334335336337338}
In this context, chronic stress (in this case, financial problems) is more harmful than short-term stress (in this case, the loss of a loved one).³³⁹
High levels of anxiety-laden or perceived as threatening stress also significantly increase the risk of borderline personality disorder in children.

Children with ADHD were more likely to have mothers who experienced stress or emotional problems during pregnancy:⁸¹

• Children with ADHD: 53.8%
  If stress or emotional problems occurred, they occurred during the following trimester:
  • 1st and 2nd trimesters only: 36.0%
  • 3rd trimester only: 6.7%
  • Entire pregnancy: 57.3%
• Children not affected: 27.6%
  If stress or emotional problems occurred, they took place during the following trimester:
  • 1st and 2nd trimesters only: 28.6%
  • 3rd trimester only: 24.9%
  • Entire pregnancy: 28.6%

Hair cortisol levels in mothers and their children indicated that psychological stress experienced by the mothers was transmitted to their children.³⁴⁰
A study found no increased incidence of psychiatric disorders at age 9 among children of women who were exposed to one month of repeated rocket attacks on the civilian population during the 2006 Lebanon War.³⁴¹ It is possible that one month of repeated stress is not a sufficiently intense stressor.

The cortisol released by the mother during anxiety-inducing or threatening stress is absorbed by the unborn child and leads to permanent damage to the HPA axis, which regulates stress responses via cortisol.³⁴²³⁴³

Severe anxiety in the mother during pregnancy, specifically between the 12th and 22nd week after the last menstrual period, significantly increases the risk of ADHD, whereas severe anxiety between the 32nd and 40th week does not increase the risk.³⁴⁴ Elevated cortisol levels in the mother during the third trimester of pregnancy increased the child’s risk of ADHD symptoms only in boys at age 3; however, this risk was no longer significant by age 5. ADHD symptoms were not elevated at either age 3 or age 5.³⁴⁵
So it seems to depend heavily on when the stressful experience occurs.

Severe anxiety in the mother during pregnancy increased the risk of ADHD in the unborn child, depending on the child’s COMT gene variant (gene-environment interaction).³⁴⁶
In mothers with ADGRL3 (Latrophilin 3, LPHN3) gene variants (SNPs)

• rs6551665
• rs1947274
• rs6858066 or
• rs2345039

Even low levels of stress during pregnancy were found to significantly increase the child’s risk of ADHD.³⁴⁷

A combination of the 5-HTTLPR L/L genotype and stress during pregnancy resulted in an eightfold increased risk of ADHD/C or ADHD-HI.³⁴⁸

Children with ADHD whose mothers were exposed to moderate and severe stress during pregnancy tend to develop more severe ADHD symptoms.³⁴⁹

Early prenatal stress increases the levels of immune response genes, including the proinflammatory cytokines IL-6 and IL-1β, particularly in male placentas. Male children exhibit stress-induced motor hyperactivity, a hallmark of dopaminergic dysregulation, which was improved by treatment of the mother with nonsteroidal anti-inflammatory drugs. In addition, the expression of dopamine D1 and D2 receptors was altered in male offspring due to early prenatal stress.³⁵⁰ This confirms the effect of early stress on the dopaminergic system.

High cortisol exposure in 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 elevated glutamate levels. This epigenetic mechanism may increase children’s risk of ADHD.³⁵¹ Exposure to glucocorticoids during hippocampal development in utero influences the onset of the stress response through epigenetic changes involving mRNA and methylation.³⁵² Another study reports that the increased risk to the fetus for developmental disorders such as ADHD, mediated by the mother’s psychological stress, may be mediated through mRNA expression of glucocorticoid pathway genes in the placenta.³⁵³
Another study also describes epigenetic changes in the unborn child resulting from the mother’s psychological stress during pregnancy.³⁵⁴
A study found no significant increase in the risk of mental disorders by age 10 due to increased glucocorticoid exposure in the fetus.³⁵⁵
A natural disaster that affected the mother during pregnancy increased the risk of ADHD.³⁵⁶

Elevated cortisol levels caused by maternal stress during pregnancy can cross the placenta³⁵⁷ and alter the fetal epigenome, particularly in genes that regulate the HPA axis and the stress response.³⁵⁸ Maternal depression or anxiety in the third trimester correlated with increased DNA methylation of the NR3C1 promoter in the umbilical cord blood of newborns.³⁵⁹ The NR3C1 gene encodes the glucocorticoid receptor, which is supposed to downregulate the HPA axis (and thereby also cortisol levels) in response to high cortisol levels at the end of a stress response. The specific CpG methylation in NR3C1 triggered by the mother’s stress correlated with reduced 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 infants correlated with greater methylation of the NR3C1 gene.³⁵⁹
Maternal stress during pregnancy can epigenetically program the infant’s HPA axis to be more sensitive to stress, which may increase the risk of anxiety or depression later in life, and that prenatal stress correlates with methylation changes in the offspring’s genes associated with stress regulation, such as NR3C1, FKBP5, and SLC6A4 (serotonin transporter).³⁶⁰

Maternal stress during pregnancy or complications during childbirth—such as maternal infections during pregnancy or oxygen deprivation at birth—also increase the risk of other disorders, such as schizophrenia.³⁶⁶

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

A cohort study of 114,000 children showed that a fever during the first trimester of pregnancy increases the risk of ADHD by 31%, and multiple fevers by 164%. However, fever increased only inattention, not hyperactivity/impulsivity—this was also true for the second trimester. The results were independent of whether or not the mother took paracetamol (acetaminophen).³⁶⁷

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 increased risk of ADHD in the child.³⁶⁸

1.3.9. Chemical/medication intolerance (+110% to 130%; ASA +201% to 470%)¶

Children of mothers with chemical or medication intolerance (positive result on the Quick Environmental Exposure and Sensitivity Inventory (QEESI), a validated screening tool for chemical intolerance) had a 2.3-fold increased risk of ADHD and a 3.01-fold increased risk of ASD.³⁶⁹³⁷⁰

1.3.10. Parental depression before, during, or after pregnancy (up to +100%)¶

Particularly among boys, the severity of the mother’s depression during pregnancy, as well as higher scores on measures of cyclothymic, irritable, and anxious temperament in the mother, appear to be relevant risk factors for the development of ADHD.³⁷¹

A cohort study found that

• Depression in parents increased the risk for their children, depending on when the depression occurred (figures given as HR):³⁷²
  • ADHD (prenatal: 1.95 = 95% increase; at any time: 1.98 = 98% increase; postnatal: 2.0 = 100% increase)
  • ASD (prenatal 1.76, any time 1.52)
  • Tic disorders (prenatal 1.52, at any time 1.40)
  • Developmental delay (prenatal 1.40, any time 1.32, postnatal 1.24)
  • Language development disorder (prenatal 1.29, at any time 1.17)
  • Developmental Coordination Disorder (HR: 1.73; at any time: 1.76; postnatal: 1.78)
  • Intellectual disability (at any time: 1.26)

The risk of ADHD was increased (meta-analysis, k = 21, 796,157 mother-child pairs)³⁷³

• by 67% due to the mother’s antenatal depression (pre-birth)
• by 53% due to the mother’s postpartum depression (after childbirth)

A large-scale study found no causal link between depression, anxiety disorders, or infections in the mother during pregnancy and the child’s risk of neurodevelopmental disorders (ASD, ADHD, intellectual disability, cerebral palsy, or epilepsy).³⁷⁴

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

If a mother has Crohn’s disease or ulcerative colitis during pregnancy, the child’s risk of ADHD increases by 95% by the time the child turns 18.²⁷⁹
A father’s diagnosis of Crohn’s disease or ulcerative colitis did not increase the child’s risk of SADHS until the child’s 18th birthday.²⁷⁹

1.3.12. Polycystic Ovary Syndrome (PCOS) During Pregnancy (+31% to +95% in boys)¶

Children of women with polycystic ovary syndrome (PCOS) appear to have an increased risk of ADHD.³⁷⁵³⁷⁶

A possible link could stem from the fact that one treatment method involves the use of dopamine agonists.³⁷⁷³⁷⁸ Another possible link could be that PCOS is associated with hyperandrogenism. Elevated prenatal testosterone levels are a risk factor for ADHD. For more on this, see Gender Differences in ADHD.

A study found a 95% increased risk of ADHD among 3-year-old boys whose mothers had PCOS, while this risk was not elevated among 3-year-old girls.³⁷⁹ This also suggests a link to sex hormones, although elevated testosterone levels during pregnancy also cause increased ADHD symptoms in female offspring. For more on this, see Gender Differences in ADHD. It is also known that ADHD manifests later in girls than in boys.
A Chinese study found a 31% increased risk of ADHD (only) among boys aged 3 to 6.³⁸⁰ Since ADHD can often not be diagnosed until age 6 or older, we suspect the rate is higher among school-aged children.

Women with PCOS themselves had an increased risk of ADHD, although no association was found between testosterone and ADHD symptoms.³⁸¹

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

Children of mothers whose CRP levels were in the lowest third of the study group had a risk of ASD and ADHD that was nearly double that of children of mothers in the middle third of the CRP distribution.³⁸²

1.3.14. Cerclage for Cervical Insufficiency (up to +70%)¶

A cerclage is a procedure in which a thread is placed around a weak or prematurely dilating cervix (cervical insufficiency). It is usually performed during the second trimester of pregnancy.

Children born to mothers who underwent a cerclage during pregnancy had an increased risk of death:³⁸³

• increased by 1,485% for cerclage performed on or after the 25th week of pregnancy
• increased by 107% with cerclage performed between the 16th and 24th weeks of pregnancy
• increased by 49% in cases of cerclage performed before the 24th week of pregnancy

Furthermore, a cerclage performed on or after the 25th week of pregnancy increased the children’s risk of:³⁸³

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

1.3.15. Rheumatic Diseases / Musculoskeletal Disorders (+64%)¶

Rheumatic diseases or musculoskeletal disorders in the mother during pregnancy increased the child’s risk of ADHD by 64% through his or her 18th birthday.³⁸⁴

1.3.16. Unhealthy diet during pregnancy (+13% to +60%)¶

An unhealthy or “Western” diet during pregnancy increased the likelihood of children developing ADHD by more than 60%.³⁸⁵
A 13% higher risk of ADHD was found among boys who consumed a highly processed, high-fat diet.³⁸⁶

Since stress increases the preference for “convenience foods,” we believe that this correlation could also potentially reflect, indirectly, increased stress levels in the mother during pregnancy, as stress shifts food preferences toward easily digestible foods and convenience foods.

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

Children born to mothers with systemic lupus erythematosus (SLE) were found to have a 60% increased risk of ADHD.³⁸⁷
ADHD, for its part, is associated with a 2.17-fold increased risk of lupus.³⁸⁸

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

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

• ADHD by 51%³⁸⁹
• ADHD by 21% (adjusted) to 31%³⁹⁰
• ASS by 55%.³⁸⁹

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

A cohort study of more than 5 million people found that children had an increased risk of ADHD if one of their parents had diabetes.³⁹¹

Maternal diabetes before or during pregnancy increases the child’s risk of ADHD³⁹² —this applies to gestational diabetes mellitus as well as to pre-existing type 1 diabetes mellitus or type 2 diabetes mellitus,³⁹³ —and also to ASD.³⁹⁴³⁹⁵

• 150%: Type 1 diabetes in the mother during pregnancy increased the child’s risk of ADHD by 95% through his or her 18th birthday.³⁸⁴
• 140%: A study found a 2.4-fold increased risk of ADHD among children of mothers with diabetes mellitus and a 3.7-fold increased risk of ADHD among male offspring of mothers with diabetes mellitus. No differences were found between gestational diabetes and other types of diabetes.³⁹⁶
• 86 High levels of diabetes mellitus throughout pregnancy increased the risk of ADHD at ages 6 to 9 to 2.8%, compared with 1.5% for low levels throughout pregnancy³⁹⁷
• 40%: Maternal diabetes mellitus prior to pregnancy increased the risk of ADHD in children by 40% (meta-analysis, k = 13, N = 5,000,000)³⁹⁸
• 39%: Type 1 diabetes mellitus in the mother before pregnancy increased the risk of ADHD in children by 39% (meta-analysis, k = 13, N = 5,000,000)³⁹⁸
• 20%: Diabetes mellitus or type 1 diabetes mellitus in the father increased the children’s risk of ADHD by 20% (meta-analysis, k = 13, N = 5,000,000)³⁹⁸

Children of severely obese mothers with type 2 diabetes who were not treated with insulin were twice as likely to have psychiatric disorders as children of normal-weight mothers. Children of severely obese mothers with pregestational diabetes who were treated with insulin were 2.7 times more likely to have psychiatric disorders than the children of normal-weight mothers.³⁹⁹
A study found no increased risk of ADHD severe enough to require inpatient treatment.⁴⁰⁰

1.3.20. Migraines in parents (+37%)¶

A cohort study of N = 250,517 participants found an increased risk for children of mothers—but not of fathers—with migraine:⁴⁰¹

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

1.3.21. Immune disorders (+36%)¶

Immune disorders in the mother (excluding allergies) during pregnancy increased the child’s risk of ADHD by 36% through his or her 18th birthday.³⁸⁴

1.3.22. Anemia in the mother during pregnancy (+31%)¶

A cohort study of 532,232 children over 23 years showed that maternal anemia during the first 30 weeks of pregnancy increases the risk of ADHD by 31%, whereas anemia in later weeks of pregnancy increased the risk barely (by 1.4%). ⁴⁰²

In a small Lebanese case-control study (n = 119), maternal anemia during pregnancy increased the risk of ADHD by a factor of 3.7 (OR = 3.654).³²⁶

1.3.23. Infections in 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 children due to maternal infections during pregnancy.⁴⁰³ A registry-based cohort study (n = 2,885,662, of which N = 1,864,660 were full siblings) found a slight increase of 14% (ASD + 19%; intellectual disability +21%), which was no longer significant after adjusting for twin status.⁴⁰⁴
Mycoplasma antibodies at birth were associated with a 30% increased risk of ADHD later in life.⁴⁰⁵

1.3.23.2. Viral Infections¶

A viral infection in the mother during pregnancy increases the risk of ADHD in her child⁴⁰⁶ and can affect the development of the unborn child’s dopaminergic system, for example:⁴⁰⁷

• Measles
• Chickenpox
• Rubella
  • Even a subclinical rubella infection in the mother during pregnancy increases the child’s risk at ages 8 to 9 of:⁴⁰⁸
    • ASS
    • ADHD
    • Developmental Disorders
• Enterovirus 71
• Herpesvirus 6
• Influenza A
• Cytomegalovirus (+30%)⁴⁰⁵

A link seems less certain in the case of

• Streptococcal infection
• Middle ear infection (otitis media)

Birth complications such as maternal infections during pregnancy, maternal stress during pregnancy, or oxygen deprivation during birth also increase the risk of other disorders⁴⁰⁹, such as schizophrenia³⁶⁶, ASD⁴¹⁰, or depression.⁴⁰⁹

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.³¹⁹ Chlamydia/non-gonococcal urethritis, trichomoniasis, urinary tract infections, and candidiasis increased the risk of ADHD, whereas gonorrhea did not.

A urinary tract infection and preeclampsia increased the risk by 53%.³¹⁹

Another study also found an increased risk of ADHD as a consequence of urinary tract infections in the mother during pregnancy.⁴¹¹

1.3.24. Fetal Inflammatory Syndrome (FIRS) (+27%)¶

Children born to mothers with fetal inflammatory syndrome (FIRS, an inflammation of the placenta during pregnancy) had an increased risk of:⁴¹²

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

1.3.25. High blood pressure during pregnancy (+27%)¶

High blood pressure during pregnancy significantly increases the risk of ADHD in offspring.³²³. The cause of the high blood pressure was usually preeclampsia.³²⁰

High blood pressure during pregnancy increased the risk of

• ADHD
  • + 27% (meta-analysis, k = 121, N = 29,649,667)⁴¹³; statistical significance after adjusting for gestational age and birth weight could not be calculated due to a lack of suitable studies
  • +24% (HR: 1.24)³²⁰
• ASS
  • + 65% (meta-analysis, k = 121, N = 29,649,667)⁴¹³; no longer significant after adjusting for gestational age and birth weight
  • +29% (HR: 1.29)³²⁰
• intellectual disability
  • +77% (meta-analysis, k = 121, N = 29,649,667)⁴¹³
  • +58% (HR: 1.58)³²⁰
• Developmental delay
  • +77% (meta-analysis, k = 121, N = 29,649,667)⁴¹³; no longer significant after adjusting for gestational age and birth weight
• Depression +130%.⁴¹⁴

If obesity was present in addition to chronic high blood pressure, this resulted in an increased risk of:³⁰⁵

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

If pregnancy-induced hypertension was accompanied by being overweight (rather than obesity), this resulted (compared to hypertension or being overweight alone) in an increased risk of:³⁰⁵

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

When obesity was present in addition to gestational hypertension, this resulted (compared to those not affected) in an increased risk of:³⁰⁵ (The effect sizes of the combined exposure were no greater than those of the individual exposures 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 risks for ADHD. It will therefore be necessary to determine whether high blood pressure during pregnancy causally increases the risk of ADHD or whether elevated blood pressure during pregnancy is a manifestation of the underlying genetic predisposition that contributes to 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% by the time the child turned 18.³⁸⁴

1.3.27. Uncontrollable nausea (hyperemesis gravidarum) (+16%)¶

Persistent nausea and vomiting in the mother during pregnancy were associated with a 16% (based on two cohort studies) to 287% increased risk of ADHD in the offspring.⁴¹⁵

1.3.28. Mineral and Vitamin Deficiencies During Pregnancy¶

For more information, visit ⇒ Vitamins, Minerals, and Dietary Supplements for ADHD As well as ⇒ Nutrition and Diet for ADHD in the chapter at ⇒ Treatment and Therapy.

1.3.28.1. Vitamin D3 Deficiency During Pregnancy¶

Vitamin D3 deficiency during pregnancy and after childbirth causes permanent developmental abnormalities in the brain, particularly in the dopaminergic system.^416417418419

In a meta-analysis, studies with larger sample sizes and stricter definitions of vitamin D deficiency showed positive associations with ADHD⁴²⁰⁴²¹ and schizophrenia.⁴²¹ Vitamin D3 deficiency during pregnancy reduces dopamine turnover in the offspring’s brain⁴²², leading to a decrease in COMT.⁴²³

Vitamin D3 Deficiency During Pregnancy Increases Risk: 8 Studies

A cohort study of n = 3,937 children showed that the mother’s vitamin D levels, multivitamin supplementation, and better dietary quality were associated with lower rates of ADHDor ASD symptoms in children; that vitamin D and dietary quality were associated with greater volume of certain brain regions in childhood; and that greater volume of these brain regions was associated with fewer ADHD and ASD symptoms.⁴²⁴A study in Finland found a significant correlation between reduced maternal vitamin D3 levels during pregnancy and ADHD in children. The increased risk reached over 50%.⁴²⁵
The prevalence of ADHD-like symptoms in children decreased by 11% for every 10 ng/ml increase in the mother’s 25(OH)D level.⁴²⁶ A relatively low maternal 25(OH)D level at 24 weeks of gestation increased the risk of ADHD and ASD, as well as the severity of ASD. High vitamin D3 supplementation (2,800 iE/day) during pregnancy did not increase the risk of ADHD or ASD.⁴²⁷
The severity of ADHD symptoms in the children correlated with the degree of maternal 25(OH)D deficiency.⁴²⁸⁴²⁹
Lower maternal vitamin D3 levels between the 35th and 37th weeks of pregnancy were significantly correlated with increased signs of ADHD in the children at 6 months and 2 years of age.³³⁸
It remains unclear whether a D3 deficiency during other weeks of pregnancy has different effects, since later mental disorders are associated in particular with those brain regions that are undergoing a developmental surge during the respective week of pregnancy. For more on this, see ⇒ The Effects of Stress at Different Stages of Brain Development In the chapter ⇒ Stress-Induced Damage – Effects of Early / Prolonged Stress.
Rodents whose mothers had a vitamin D deficiency exhibited typical ADHD symptoms:⁴³⁰

• Hyperactivity
• Impulsivity
• Reduced social behavior
• Change in the frequency of ultrasonic vocalizations
• More frequent soiling
• Reduced grooming of the puppies
• Reduced levels of the growth factors NGF and GDNF
• Thinner cortical layers and larger lateral ventricles
• Smaller hippocampus and smaller lateral ventricles

Vitamin D3 Deficiency During Pregnancy Does Not Increase the Risk of ADHD: 3 Studies

Lower serum vitamin D3 levels in the mother during the 30th week of pregnancy were significantly associated with depression in the offspring up to age 22, but not with ADHD.⁴³¹
A large-scale, long-term study in Spain on vitamin D3 deficiency during pregnancy found no correlation between low maternal blood levels of D3 during pregnancy and ADHD in children aged 5 to 18 years.⁴³² Similarly, a Norwegian cohort study found no association between maternal vitamin D levels during pregnancy and the children’s later risk of ADHD, but did find an association between ASA and (consequently) reduced vitamin D levels and ADHD due to (as a consequence) lower omega-3 levels.⁴³³

1.3.28.2. Omega-3 Fatty Acid Levels¶

  1.3.28.2.1. In newborns¶

A meta-analysis found evidence that higher levels of omega-3 fatty acids in newborns may reduce the risk and severity of ADHD and autism spectrum disorders. It is possible that an adequate intake of omega-3 fatty acids during the third trimester of pregnancy could help prevent this.⁴³⁴

  1.3.28.2.2. During Pregnancy¶

Another study found a 13% increased risk of ADHD in children at age 7 associated with an elevated omega-6-to-omega-3 ratio (high omega-6 and low omega-3 levels).⁴³⁵

1.3.29. Sleep Deprivation During Pregnancy¶

Girls whose mothers slept less than 8 hours during the last trimester of pregnancy were more likely to exhibit hyperactivity, inattention, and higher overall ADHD scores.⁴³⁶
Sleep problems during pregnancy were associated with an increased risk of neurodevelopmental disorders and sleep problems in early childhood.⁴³⁷, in particular

• Reduced and poorer sleep during the second trimester of pregnancy was associated with ADHD
• More severe sleep problems during the first trimester were associated with ADHD
• Sleep problems during the third trimester were associated with sleep problems in the child

1.3.30. Testosterone During Pregnancy¶

Prenatal exposure to testosterone was significantly correlated with inattention and hyperactivity/impulsivity in offspring.⁴³⁸ Elevated maternal testosterone levels during pregnancy were significantly correlated with increased signs of ADHD in children at 6 months and 2 years of age.³³⁸

1.3.31. Inflammation in the Mother During Pregnancy¶

Perinatal inflammation is associated with higher ADHD symptom scores in children aged 8–9 years and increases the genetic predisposition to ADHD (the polygenic risk score).⁴³⁹⁴⁴⁰

1.3.32. Bipolar Disorder in a Parent¶

A parent’s bipolar disorder increased the children’s risk of ADHD.⁴⁴³

1.4. Medications Taken by the Mother During Pregnancy as a Risk Factor for ADHD (up to +250%)¶

Children with ADHD were more likely to have mothers who took medication during pregnancy:⁸¹

Medication Use by the Mother During Pregnancy:

• ADHD: 43.5%
  If stress or emotional problems occurred, they took place during the following trimester:
  • 1st and 2nd trimesters only: 36.2%
  • 3rd trimester only: 14.5%
  • Entire pregnancy: 49.3%
• Those not affected: 31.4%
  If stress or emotional problems occurred, they took place during the following trimester:
  • 1st and 2nd trimesters only: 31.1%
  • 3rd trimester only: 46.9%
  • Entire pregnancy: 21.9%

The following list is provided for illustrative purposes only and is by no means exhaustive.

1.4.1. Paracetamol (Acetaminophen) During Pregnancy (+37% to +250%)¶

50% of all women take acetaminophen during pregnancy.⁴⁴⁴
A meta-analysis of 20 studies found consistent evidence that prenatal use of acetaminophen by the mother is associated with a significantly increased risk of ADHD and ASD in the offspring. (Meta-analysis, n = 20)⁴⁴⁵
Taking acetaminophen (known as paracetamol in North America and Iran) during pregnancy increased the risk of ADHD by up to 37%. According to two very comprehensive studies involving a combined total of over 110,000 participants, even short-term use is harmful.⁴⁴⁶⁴⁴⁷ Further studies confirm this.^{448449 450} Gilman et al. offer a critical perspective on this.⁴⁵¹ While previous studies were based on mothers’ self-reports of use, a study based on blood levels found a 2.3- to 3.5-fold increased risk of ADHD and a 1.6- to 4.1–fold increased risk of ASD in children when taken during the second or third trimester of pregnancy.⁴⁵²

The risk of ADHD associated with paracetamol (acetaminophen) increases when taken⁴⁵³

• by 19% during the second trimester of pregnancy
• by 28% in the first and second trimesters
• by 20% during the first through third trimesters

A cohort study of 116,000 children showed that a fever during the first trimester of pregnancy increases the risk of ADHD by 31%, and multiple fevers by 164%. However, fever increased only inattention, not hyperactivity/impulsivity—this was also true for the second trimester. The results were independent of whether or not the mother took paracetamol (acetaminophen).³⁶⁷
A meta-analysis confirms an increased risk of ADHD and ASD in children when paracetamol is taken during pregnancy.⁴⁵⁴

A small study that assessed acetaminophen use based on blood test results rather than self-reported data found a 3.15-fold increased risk of ADHD in children whose mothers took acetaminophen during the second trimester of pregnancy.⁴⁵⁵

A meta-analysis of 22 studies involving N = 367,775 participants found an increased risk of ADHD associated with paracetamol use during pregnancy, which remained unchanged after adjusting for other factors (such as parental diagnoses).⁴⁵⁶

A study calls into question the critical findings to date by focusing on ADHD diagnoses in parents that had not been taken into account previously.⁴⁵⁷ Damkier also expresses skepticism.⁴⁵⁸⁴⁵⁹ Another study found no evidence of an increased risk of ADHD or ASD associated with acetaminophen use during pregnancy.⁴⁶⁰ A review also found no association.⁴⁶¹
A cohort study of N = 217,602 children found a 22% increased risk of ADHD, on the one hand, and evidence that the result may have been inflated due to an overestimation caused by unreported over-the-counter use of acetaminophen, on the other.⁴⁶²

A long-term study analyzed paracetamol, methionine, serine, glycine, and glutamate in umbilical cord plasma and found that elevated acetaminophen levels were associated with an increased risk of ADHD that paralleled the rise in 8-hydroxy-deoxyguanosine levels in umbilical cord blood. An increase in methionine, glycine, serine, and 8-hydroxy-deoxyguanosine levels in umbilical cord blood correlated with a significantly higher likelihood of ADHD in childhood. Methionine and glycine each accounted for 22% of the association between elevated acetaminophen levels and subsequent ADHD.⁴⁶³
The adverse effects of acetaminophen on fetal development during pregnancy appear to be mediated through changes in the endocannabinoid pathway.⁴⁶⁴
Paracetamol is also suspected of being a possible cause of ASS.¹⁷⁰
In any case, the evidence suggesting that acetaminophen increases the risk of ADHD during pregnancy is so strong that pregnant women should be warned against taking it.⁴⁶⁵

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

Possible mechanism of action:

• Cannabinoid pathway / CB1R.⁴⁶⁶
• Mitochondria / Neuroinflammation via the toxic metabolite NAPQ1⁴⁶⁷

1.4.2. SSRIs, Antidepressants During Pregnancy (0% to +63%)¶

According to two meta-analyses of 18 studies, SSRI use during pregnancy is associated with a significantly increased risk of ADHD (OR = 1.26 = approx. +26%) and ASD (OR = 1.42 = approx. +42%) in children. It is unclear whether this results from the SSRIs themselves or from the inheritance of the mother’s mental health issues—for which she was treated with SSRIs—since even when the mother took SSRIs or SNRIs before pregnancy, but not during pregnancy, the children’s risk of ADHD (OR = 1.63 = approx. +63%) and ASD (OR = 1.39 = approx. +39%) was also elevated.⁴⁶⁸⁴⁶⁹ As a precaution, SSRIs should be used with extreme caution during pregnancy.
A meta-analysis found that 7 out of 8 studies on SSRIs during pregnancy showed no increased risk of ADHD in children.⁴⁷⁰ Another study reached the same conclusion.⁴⁷¹ According to one study, antidepressants taken during pregnancy increased the likelihood of ADHD in the child later in life by a factor of 1.81.⁴⁷²
One review found that antidepressants during pregnancy nearly double the risk of ADHD and ASD in newborns in unadjusted studies. In adjusted studies, however—in which, for example, the mother’s ADHD is controlled for as a separate factor—there was barely any statistically significant association. Analyses of discordant sibling pairs suggest that a child’s ADHD is more closely related to whether or not their sibling has a neurodevelopmental disorder (NDD) than to whether or not the child was exposed to an antidepressant in utero.⁴⁷³

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

Valproic acid increases the risk of ADHD in offspring by 39% (meta-analysis, k = 22)⁴⁷⁴ In addition, it increased the risk of congenital malformations by 147 to 830%, the risk of autism by 70% to 338%, for impaired motor development by 600%, and for intellectual disability and low IQ by 140% to 338%.
Offspring of mice that received valproic acid during pregnancy exhibited significantly increased hyperactivity and changes in the dentate gyrus.⁴⁷⁵⁴⁷⁶ There is also evidence of changes in the histaminergic system and social behavior.⁴⁷⁷
Valproic acid during pregnancy increases the risk of ADHD, ASD, impaired cognitive abilities, and speech disorders in children.⁴⁷⁸ In addition, depending on the dose—particularly at doses exceeding 600 mg/day—it causes congenital malformations in 10% of children, such as neural tube defects, heart anomalies, urogenital malformations (e.g., hypospadias, skeletal malformations, and orofacial clefts). High-dose folic acid before and during pregnancy may reduce this risk. Valproic acid concentrations in breast milk appear to be low, so breastfeeding does not pose a risk.

1.4.4. Corticosteroids during pregnancy (+30%)¶

Glucocorticoid administration during pregnancy increased the risk of ADHD in offspring by 30%.⁴⁷⁹ 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 intellectual disability by 30%.
The administration of corticosteroids during pregnancy leads to long-term changes in the brain of the unborn child and increases the risk of ADHD.⁴⁸⁰ These children experience lifelong changes in the dopaminergic system and the HPA axis, which appear to be caused by changes in the expression and ratio of MR and GR receptors.⁴⁸¹ In our view, the ADHD symptoms described in these children could possibly be the consequences of an alteration in the HPA axis.
⇒ The Corticosteroid Receptor Hypothesis of Depression

High cortisol exposure in the fetus or newborn can lead to methylation of the GAD1 / GAD67 gene, which encodes the key enzyme glutamate decarboxylase 1 (GAD1), responsible for converting glutamate to GABA, and leads to elevated glutamate levels. This epigenetic mechanism may increase children’s risk of ADHD.³⁵¹

Exposure to betamethasone during pregnancy only marginally increased the risk of ADHD in the offspring.⁴⁸²⁴⁸³

Dexamethasone administered during pregnancy in mice increased spontaneous activity in female offspring, while it decreased it in males. Dexamethasone administered during pregnancy downregulated dopamine signaling and upregulated glutamate and GABA signaling in females.⁴⁸⁴

1.4.5. β-2-Adrenoreceptor agonists during pregnancy (+30%)¶

Taking β-2-adrenoreceptor agonists (beta-2 sympathomimetics) during pregnancy increases the child’s risk of ADHD by up to 30%.⁴⁸⁵

1.4.6. Pregabalin during pregnancy (+29%)¶

Prenatal exposure to pregabalin increased the risk of ADHD by 29%; however, this effect was attenuated when active comparators were taken into account.⁴⁸⁶

1.4.7. Antibiotics During Pregnancy (up to +19%)¶

Several meta-analyses found an increased risk of ADHD associated with the mother’s use of antibiotics during pregnancy:

• 19% (meta-analysis, k = 30, N = 7,047,853)⁴⁸⁷

• 15% (meta-analysis, k = 9, N = 6,180,434)⁴⁸⁸

• 14% (meta-analysis)⁴⁸⁹

• 14% (meta-analysis)⁴⁹⁰

• 11% during the second trimester (meta-analysis, k = 9, N = 6,180,434)⁴⁸⁸

• 7% in late pregnancy (meta-analysis, k = 9, N = 6,180,434)⁴⁸⁸

Repeated use of antibiotics further increased the risk:

• an additional 21% for women who took antibiotics more than three times during pregnancy (meta-analysis, k = 9, N = 6,180,434)⁴⁸⁸
• an additional 13% for women who took antibiotics twice during pregnancy (meta-analysis, k = 9, N = 6,180,434)⁴⁸⁸

A mother’s use of penicillin during pregnancy increased the child’s risk of ADHD. The risk of ADHD was increased by penicillin even when taken 2 years before pregnancy. Repeated use of penicillin further increased the risk of ADHD.³⁰

Possible mechanism of action: Alteration of the microbiome.⁴⁹¹

The risk of ASS increased by +9% (meta-analysis, k = 30, N = 7,047,853).⁴⁸⁷

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 whose mothers had taken antiepileptic drugs during pregnancy. The risk was primarily attributable to valproate.⁴⁹² Compared to mothers with epilepsy who did not take antiepileptic drugs during pregnancy, which increases the risk of ASD by only 38%.
Valproate use during pregnancy is believed to increase the risk of ADHD in the unborn child.⁴⁹³
Valproates are the salts of valproic acid.

A cohort study of children up to age 6 (which is still too early to diagnose all people with ADHD) found an increased risk of neurodevelopmental disorders associated with the use of antiepileptic drugs during pregnancy:

• Sodium valproate in combination 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 medications during pregnancy: 1.8%

ADHD was the most common diagnosis. 2% of children whose mothers were taking medication received an ADHD diagnosis by the age of 6, and 1.5% were diagnosed with dyspraxia. None of the children in the control group had an ADHD diagnosis.⁴⁹⁴

1.4.8.2. Topiramate During Pregnancy¶

There is ongoing debate regarding the use of the antiepileptic drug topiramate during pregnancy in relation to a possible increased risk of ADHD in the child.⁴⁹⁵⁴⁹⁶

1.4.8.3. Levetiracetam During Pregnancy¶

In mice, levetiracetam caused hyperactivity and repetitive behavior in the offspring during fertilization and pregnancy.⁴⁹⁷

1.4.9. Estrogens, progestins¶

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

Children of women who have undergone this treatment are at increased risk for:⁴⁹⁸

• ADHD
• ASS
• Psychoses
• Schizophrenia
• bipolar disorders
• severe depression
• Anxiety
• Eating Disorders

The descendants of the people with ADHD are also affected (3rd generation: particularly ADHD, ASD, and bipolar disorder). In the 4th generation, which is still very young, the first signs are becoming apparent, such as dyspraxia, which is often a precursor to ADHD
Estrogens and progestins appear to mediate their harmful effects epigenetically through 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 exhibit symptoms of inattention and hyperactivity. One study found a prevalence of SDHS of 15% compared to 4% in the control group (+275%).⁴⁹⁹

1.6. Other Pregnancy Circumstances (up to +100%)¶

1.6.1. Firstborn status (+31% to +100%)¶

See the section on Firstborn status in the article “ : Physical Risk Factors for ADHD”

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

Particularly short or particularly long intervals between the pregnancy and the birth of the preceding sibling increased the risk of ADHD by 30% (less than 6 months) and 12% (60 to 119 months) to 25% (120 months or more), respectively.⁵⁰⁰

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

Exposure to green spaces prior to conception was associated, for each interquartile increase in the green space index within the ZIP code area, with a reduced risk of:⁵⁰¹

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

1.6.4. Protein Deficiency During Pregnancy and the Postpartum Period¶

Rats whose mothers were fed a low-protein diet 15 days before conception and then throughout the lactation period were significantly more susceptible to early-life stressors (intraperitoneal injection of deltamethrin, lipopolysaccharide, or both).⁵⁰²

1.6.5. Western Dietary Patterns During the First and Second Trimesters of Pregnancy¶

A Western diet (high in fat, refined grains, and processed foods; low in fruits and vegetables; also known as the Standard American Diet, or SAD) during the first and second trimesters of pregnancy is associated with an increased risk of ADHD and ASD in the child.⁵⁰³

1.6.6. High Salt Intake During Pregnancy¶

A high intake of salt through the diet during pregnancy could increase the unborn child’s sensitivity to stress.⁵⁰⁴

1.7. Pregnancy Factors Not Associated with an Increased Risk of ADHD¶

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

• Iodine-to-creatinine ratio in the mother’s urine during pregnancy
  • A large study of three cohorts found no effect on the risk of ADHD or ASD⁵⁰⁵
• The mother’s migration
  • A meta-analysis found no evidence of an increased risk of ADHD associated with the mother’s migration, but the situation was different for ASD.⁵⁰⁶
• Mother’s iron levels
  • A study found that the mother’s iron levels during pregnancy had no effect on the child’s risk of ADHD at age 7⁵⁰⁷
• Artificial insemination⁵⁰⁸⁵⁰⁹ using donor sperm⁵¹⁰ or intracytoplasmic sperm injection (ICSI)⁵¹¹
• Non-ionizing magnetic field radiation during pregnancy
  • A study that had initially found a higher rate of ADHD among children born to mothers who were exposed to the highest levels of non-ionizing magnetic field radiation (““electrosmog”)⁵¹² has been retracted⁵¹³. The updated version finds no correlation between particularly high levels of non-ionizing magnetic field radiation and ADHD.
• A cohort study found no increased risk of ADHD associated with the use of nonsteroidal anti-inflammatory drugs (NSAIDs) during pregnancy.⁵¹⁴
• Benzodiazepines during pregnancy appear to increase the risk of internalizing problems in children (anxiety, emotional reactivity, somatic complaints), but not of externalizing problems (hyperactivity, aggression).⁵¹⁵ A cohort study comparing siblings whose mothers took benzodiazepines during pregnancy with those whose mothers did not found no significant increase in the risk of ADHD or ASD associated with benzodiazepines; the authors suggest instead that a link may exist with the mother’s genetic predisposition.⁵¹⁶ A meta-analysis also concluded that, to date, no significant increase in the risk of ADHD in offspring has been found to be associated with benzodiazepine use during pregnancy, although one study suggested a slight increase with benzodiazepine monotherapy in the third trimester.⁵¹⁷ One study found a slight 15% increase in the risk of ADHD associated with benzodiazepine use during pregnancy.⁵¹⁸
• Prenatal exposure to oxytocin does not appear to affect the risk of ADHD and ASD⁵¹⁹
• Organic Foods During Pregnancy⁵²⁰
• Triptans during pregnancy⁵²¹
• Opioid pain relievers during pregnancy⁵²²

This list of medications taken by the mother during pregnancy that may increase the risk of ADHD is merely illustrative and by no means exhaustive.

1.8. Pregnancy Factors Associated with a Reduced Risk of ADHD¶

1.8.1. Mother’s sports during pregnancy > 20 minutes/day (up to a 56% reduction)¶

Among N = 4,184 children aged 3 to 6, a reduced risk of ADHD was found when mothers, during pregnancy, did the following every day:⁵²³

• Participated in sports for 20 to 40 minutes: 56% decrease
• participated in sports for more than 40 minutes: down 51%

compared to children whose mothers participated in sports for less than 20 minutes a day.
Since ADHD is generally not diagnosed until age 7 or older, the overall impact is likely to be even greater.

1.8.2. The mother’s dietary fiber intake during pregnancy (up to a 20% decrease)¶

A high-fiber diet during pregnancy reduced the risk of ADHD in children by up to 20%.⁵²⁴
This was independent of genetic predisposition to ADHD, an unhealthy diet, and sociodemographic factors.

Dietary fiber increases short-chain fatty acids in the gut, which generally reduces the risk of mental health problems. For more on this, see the section “Microbiome and Short-Chain Fatty Acids (SCFAs) in ADHD” in the article The Gut-Brain Axis as a Cause of ADHD

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

A mother’s adherence to the Mediterranean diet during pregnancy reduced the risk of behavioral problems at age 4:⁵²⁵

• 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 symptoms (OR = 0.38)