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Even before birth, the unborn child can be damaged by toxic influences from the mother.
Maternal stress during pregnancy increases the child’s ADHD risk by 72%.1
Children with ADHD were more likely to have mothers who had health conditions during pregnancy:2
Maternal diseases during pregnancy:
In 34.4% of children with ADHD, the mother had a condition during pregnancy, compared with 14.4% of unaffected children.
Children with ADHD: 34.7
Diseases of the mother in pregnancy were in the following trimester:
1st/2nd trimester only: 56.4 %
3rd trimester only: 12.7 %
Total pregnancy: 30.9
Non-affected children: 14.4 %
Diseases of the mother in pregnancy were in the following trimester:
Children whose fathers smoked before pregnancy had a 3.59-fold risk of ADHD compared with children whose fathers never smoked.
Children of parents exposed to smoking or secondhand smoke before pregnancy had 2.96 times the risk of A(D)HS.
Children whose parents had smoked both before and during pregnancy had a 3.01-fold risk of ADHD.3
Toxic effects to unborn children have been demonstrated for:
1.2.1. Mother’s nicotine consumption during pregnancy (+ 90 to 170%)¶
Prenatal smoking causes a 1.9-fold ADHD risk (increased by 90%)4 to 2.7-fold ADHD risk (increased by 170%)5 for the offspring. Other studies also found significantly increased risk scores.6789
Children with ADHD were more likely to have mothers who had smoked during pregnancy:
Only two studies (with overlapping authors) and one meta-study reached a different conclusion.121314 , one study found rather weak evidence.15
Most experiments with prenatal nicotine exposure show a decrease in dopamine levels in the PFC and striatum. Under certain circumstances, increased dopamine levels were also shown.16ADHD is neurophysiologically closely associated with decreased dopamine levels in the dlPFC (impaired working memory) and striatum (impaired motivation and motor control = hyperactivity).
To be distinguished from this is smoking by sufferers - this increases dopamine levels (at least in the striatum) because it reduces DAT, which is too pronounced in ADHD and reduces dopamine levels in the striatum. Acute smoking thus increases dopamine levels in the striatum.
Prenatal smoking in combination with certain gene polymorphisms increases the probability of ADHD more than when these genetic risks are not present:
If there are no genetic risks, smoking by the mother during pregnancy increases the ADHD risk for the child by 20 to 30%.
The risk genes alone (if the mother does not smoke during pregnancy) increase the risk by 20% to 40%.
However, if risk genes and maternal smoking coincide during pregnancy, the child’s risk of ADHD increases many times over:
DAT1-9R (440 bp): by 2.6 times
DRD4-7R by 2.9 times
Both together by a factor of 9.1718
Another study confirms the involvement of DRD4-7R in gene-environment interactions.19
Smoking by the mother during pregnancy increased the risk of hyperactivity/impulsivity symptoms in the child by 50%.20 Passive smoking already increased this risk by almost 50%, but only for boys.
Maternal smoking during pregnancy alters glutamate NMDA receptors in the laterodorsal tegmentum of the offspring.21 Another study also found changes in glutamatergic signaling in the hippocampus due to increased glutamate receptor expression,22 which was associated with learning problems, attention problems, and increased impulsivity.
ProBDNF proteolysis is impaired by an imbalance between proBDNF and BDNF and downregulation of the proBDNF processing enzyme furin. Glucocorticoid receptor activity is altered by decreased relative nuclear GR localization. Basal plasma corticosterone levels are decreased. The HPA axis is impaired. This affects the offspring themselves, but also their children, so it is inherited.23
In rodents, prenatal nicotine exposure has been found to decrease dopamine levels in the offspring mPFC.24 In ADHD, dopamine levels in the PFC are decreased.
A study of mice whose mothers were exposed to nicotine during pregnancy found evidence that nicotine causes several consequences during pregnancy that persisted in the grandchild generation, suggesting epigenetic heritability:25
Deficits in the expression of corticostriatal DNA methyltransferase 3A (DNMT3A)
Downregulation of methyl CpG-binding protein 2 (MeCP2) in frontal cortices and hippocampus
Downregulation of histone deacetylase 2 (HDAC2) in frontal cortices and hippocampus
Abnormalities in HDAC2 (Ser394) phosphorylation in frontal cortices, striatum, and hippocampus
No change in ten-eleven translocase methylcytosine dioxygenase 2 (TET2) expression
No abnormalities in MeCP2 (Ser421) phosphorylation in frontal cortices, striatum, and hippocampus
Maternal smoking increases fetal testosterone levels.26 Elevated prenatal testosterone levels are a risk factor for ADHD. See more at Sex differences in ADHD.
Even passive smoking, that is, passive exposure of the mother to nicotine smoke during pregnancy, tends to increase the unborn’s risks for ADHD symptoms later in life.20
Similar results were found for the causation of dyspraxia (Developmental Coordination Disorder) by secondhand smoke.27
Over 70 million women in the EU smoke during pregnancy.22
It is possible that the effects of maternal nicotine use during pregnancy could be offset by breastfeeding.28
1.2.1.1. Excursus: nicotine use by a parent before conception: epigenetic inheritance of nicotine damage¶
Nicotine use by one parent before conception: epigenetic inheritance of nicotine damage causes ADHD symptoms in offspring over several generations
Mice whose fathers or mothers were chronically exposed to nicotine before conception, whereas the mothers had no drug exposure, showed hyperactivity, impaired nicotine-induced motor sensitization, and decreased dopamine and norepinephrine levels in the striatum and PFC.299
Nicotine use by father or mother before conception causes epigenetic changes in offspring
Of the dopamine transporter in the striatum and mPFC31
By downregulation of DAT expression due to increased methylation of the DAT gene.32 Increased DRD4 and 5-HT DNA methylation correlates with ADHD.33
Altered expression and dysfunction of nicotinic acetylcholine receptors (nAChRs)31
Hypersensitivity to nicotine-induced nAChR-mediated dopamine release31
Increases nicotine preference, triggers hyperactivity and risk-taking behavior, disrupts rhythmicity of activity, alters nAChR expression and function, impairs DAT function, and causes DNA hypomethylation in the striatum and frontal cortex of both first and second generation adolescent offspring.
The first- and second-generation children showed ADHD-typical impairments:
Generation:
Significantly increased spontaneous locomotor activity (hyperactivity) (males and females)3031
Decreased DAT expression causes increased levels of dopamine in the striatum, which by means of activation of D2 receptors caused dephosphorylation of AKT, leading to increased activation of GSK3α/β and ultimately causing hyperactivity in the offspring of mice.32
It can be assumed that the mechanisms take place accordingly in humans.
1.2.2. Mother’s drug use during pregnancy (+ 200%)¶
Children who were prenatally exposed to multiple drug use by their mothers and who subsequently grew up in residential care were found to have a 3-fold risk of ADHD between the ages of 17 and 22.34
Cannabis use during pregnancy has been associated by several studies with an increased risk of ADHD in children.35
Alcohol consumption by the mother during pregnancy significantly increases the ADHD probability of the children, according to various studies,3637 as well as attention problems.38 A large long-term cohort study and another study found no association.3940
A combination of alcohol and maternal stress during pregnancy increased the likelihood of developing female(r) sexual behavior in male rats.41
A metastudy found that maternal alcohol consumption of less than 70 g/week during pregnancy did not increase ADHD risk.42 Boys were less at risk than girls from alcohol during pregnancy.
A cohort study found no association between alcohol consumption (binge drinking: 1 to 3 binge drinking events; moderate drinking: 1 to 3 or more alcoholic drinks per week) in early pregnancy and ADHD risk in children aged 5 to 19 years.43
One study found a correlation between ethoxyacetic acid (one of 6 degradation products of alcohol studied) in the mother’s urine and inhibition problems in the children.44
There is evidence that alcohol consumption by the mother during pregnancy or while breastfeeding has significant effects on the child’s dopamine system.45464748 Likewise, the regulation of the neurotransmitters serotonin , glutamate, norepinephrine, acetylcholine and histamine is affected495051
Lead disposition during pregnancy535455 affects mesocorticolimbic circulation and increases ADHD risk in the offspring.56
Rat mothers were exposed to acute stress and lead during pregnancy. The effect on the offspring differed between lead exposure alone or lead exposure plus stress exposure. Male rat offspring showed increased corticosterone levels and decreased dopamine levels in the PFC only with lead exposure alone, and female rat offspring only with combined lead and stress exposure. Even short-term exposure of dams to lead caused this effect.57 In female rat pups, maternal lead exposure and stress contributed to learning difficulties as cumulative factors during pregnancy. These were neurophysiologically mediated through the glucocorticoid system to the mesocorticolimbic system.58
Further studies also found evidence that lead exposure, like stress during pregnancy, affects the mesocorticolimbic dopamine/glutamate system of female offspring (less so in males) and mutually increases their effects.59 Male rat offspring showed a tendency to serotonergic disturbances of the mesocorticolimbic system and altered delay discounting under similar conditions.60
Even a lead content in drinking water below the limit values is said to be problematic.54
In principle, lead water pipes are not very dangerous in areas with calcareous water, as lime forms a reliably protective layer in the pipes. However, no decalcification system for the drinking water may then be installed. Nevertheless, it is generally recommended to replace lead-containing water pipes during modernization projects.
It is possible that metabolism is altered in ADHD with respect to cobalt, copper, lead, zinc, and vanadium. Reduced cycle stability (determinism), duration (mean diagonal length), and complexity (entropy) of exposure profiles have been noted.61
Lead is a divalent cation that mimics Ca2+ and activates PKC signaling.62
Arnsten63 describes lead as a toxin that causes symptoms confusable with ADHD.
Lead appears to have quite a few deleterious neurophysiological effects, including effects on the dopaminergic system:
Impairment of the mesocorticolimbic dopaminergic system64
Lead poisoning is strongly correlated with crime rates and out-of-wedlock pregnancies in the United States.6869
Children with elevated blood lead levels are said to be particularly susceptible to other toxins in early childhood.70 In particular, there have been warnings about lead in wall paint. During pregnancy, lead can be transferred from the mother to the child through the placenta.
1.2.6. Cadmium during pregnancy (+ 22 % only in girls)¶
Camdium exposure during pregnancy increased ADHD risk for 6-year-old girls but not for boys. Doubled maternal exposure to cadmium during pregnancy increased the ADHD risk for girls by 22.3%.71
1.2.8.1. Organochlorine compounds contact during pregnancy¶
Organochlorine compounds (dichlorodiphenyltrichloroethanes (DDT), dieldrin, heptachlor, endosulfan) showed an effect on neuronal development in prenatal exposure, which (in rodents), e.g.:73
DAT increased
Dopamine reuptake increased
Loss of dopaminergic cells
Presynaptic changes in major dopaminergic proteins in response to OC pesticides in striatum or substantia nigra
Norepinephrine increased
Serotonin increased
GABA receptors reduced
NMDA receptors reduced
MGluR5 receptors altered
Altered GABAergic, glutamatergic, and dopaminergic response to endosulfan in PFC
Altered dopaminergic responses to heptachlor exposure identified
with impairments from, among others:
Attention processes
Cognitive performance
Memory
Social development
Mental and psychomotor development
Fine motor skills
Reflexes
Visual processing
Organochlorine compounds were nevertheless primarily associated with ASA.
1.2.8.2. Organophosphate contact during pregnancy¶
The organophosphates chlorpyrifos and diazinon showed significant effects on neonatal brain development, including the dopaminergic system.74 Prenatal exposure to the common pesticide chlorpyrifos impaired IQ and working memory in children aged 77576 and executive functions.77
Organophosphates inhibit acetylcholinesterase (= the enzyme that breaks down acetylcholine).73 The organophosphate diisopropyl fluorophosphate (DFP) has been reported to increase dopamine and GABA receptors in addition to the known downregulation of cholinergic receptors. A single administration of 1 mg/kg DFP caused increased dopamine levels, and a single toxic dose of 2 mg/kg DFP caused increased dopamine depletion. Levels returned to normal after 6 hours. Chronic administration of 1 mg/kg DFP caused decreased dopamine levels after 1 and 2 weeks, which returned to normal with continued administration. A single administration of DFP increased dopamine turnover in the striatum of rats, whereas chronic administration decreased it. The authors suggested that the changes in dopamine and GABA may be consequences of downregulation of cholinergic receptors.78
Chlorpyrifos interferes with the serotonin system. Contact during pregnancy may cause tremor in children and impair cognitive and neurobehavioral development.41
Measurement using prenatal urinary dialkyl phosphate metabolites (diethyl phosphate and dimethyl phosphate) and analysis of maternal PON1 gene variants Q192R and L55M found no association between maternal organophosphate contact during pregnancy and subsequent ADHD in the child.79
A Norwegian cohort study found an increased ADHD risk of the offspring when detected in the mother’s blood during pregnancy of:80
Di-n-butyl phosphate (DnBP)
Bis(1,3-dichloro-2-propyl) phosphate (BDCIPP)
Bis(2-butoxyethyl) phosphate (BBOEP)
only in boys. In girls, reduced risk with increasing load.
Another Norwegian registry study found no evidence of increased ADHD risk in the offspring when the mother was exposed to organophosphates at 17 weeks’ gestation.81
1.2.8.3. Pyrethroid contact before or during pregnancy¶
Pyrethroids are widely used as insecticides and pesticides.
Each doubling of the pyrethroid metabolite 3-phenoxybenzoic acid (3-PBA) in the mother’s urine at 28 weeks’ gestation increased the risk of ADHD in the offspring by 3%, as well as the risk that an onset of ADHD was among the 10% most severe ADHD cases by 13%.82
The pyrethroid deltamethrin apparently impairs the dopaminergic system in mice when exposed early:83
DAT reduced
D1 receptor decreased
Apoptosis
Further, permanent behavioral changes resulted (with prenatal but not with postnatal exposure)84 in terms of:83
Movement activity
Acoustic startle reflex
Learning
Memory
3-PBA and chlorpyrifos enhance each other’s effect on ADHD.82
Each urinary measurement of trans-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane-1-carboxylic acid (trans-DCCA), a metabolite of permethrin, cypermethrin, and cyfluthri (trans-isomers of pyrethroids), increased the risk of offspring ADHD by 76%.82
Bisphenol-A (BPA) is a glucocorticoid receptor agonist and has been associated with alterations in HPA axis response. In female rats, prenatal BPA correlated with increased basal corticosterone levels as well as decreased glucocorticoid receptor expression in the hypothalamus. To stress, these female rats showed anxious coping behavior and a muted corticosterone response with a lack of downregulation of glucocorticoid receptor expression in the hypothalamus. In contrast, BPA-exposed male rats showed no altered basal HPA axis function but failed to upregulate CRH-1 receptor expression in the pituitary in response to acute stress.41 The dose given to rat mothers during pregnancy and suckling was very low at 40 micrograms/kg/day.85
5 milligrams / cubic meter in the breath cause eye irritation.86 A review confirmed circumstantial evidence that bishenol-A in pregnancy may increase the ADHD risk of children, especially boys,87
BPA and BPS caused greatly increased dopamine (3- to 5-fold) and greatly decreased serotonin (by 80%) in mouse placentas. GABA remained unchanged.88 BPA is an endocrine disruptor and mimics estrogenic activity. Thus, BPA affects various dopaminergic processes to increase mesolimbic dopamine activity, resulting in hyperactivity, attention deficits, and increased susceptibility to drug abuse.89
Phthalic acid esters are said to increase the risk of ADHD for the unborn according to most studies,90 although the connections are unclear so far.9187 An influence on thyroid balance is discussed.92 Higher phthalate metabolites in the urine of pregnant women correlated with increased distractibility in preschool-aged children.93
1.2.11. Perfluoroalkyl compounds (PFAS) in pregnancy¶
A long-term study found no correlation between perflouralkyl exposure during pregnancy and ADHD. Weak correlations - positive and negative - were found with working memory functions in childhood.94 A metastudy also found no significant correlation between maternal PFAS exposure and prevalence rates of early childhood ADHD. Nevertheless, the odds ratios were partially elevated:95
Perfluorooctanoic acid (PFOA): 1.00
Perfluorooctane sulfonate (PFOS): 1.01
Perfluorohexane sulfonate (PFHxS): 1.08
Perfluorononanoic acid (PFNA): 1.13
Perfluorodecanoic acid (PFDA): 1.23
PFOS concentration in children’s blood and PFNA concentration in mothers’ blood correlated with the prevalence of early childhood ADHD.
Another study found a correlation of perfluorooctanoic acid (PFOA) and AD(H)DS, but not perfluorooctane sulfonate (PFOS) with ADHD or ASD.96
Polychlorinated biphenyls inhibit dopamine synthesis as well as the storage of dopamine in the vesicles and its release, thus causing a too low dopamine level. Polychlorinated biphenyls induced hyperactivity and impulsivity (in rats even at subtoxic doses).97 Polychlorinated biphenyls may act directly on dopaminergic processes to disrupt the dopamine system and produce Parkinson-like symptoms.89 Other studies also found dopamine-reducing effects of PFAs.9899 as well as influences on acetylcholine, serotonin and glutamate neurotransmitter balance.100
Prenatal exposure to polycyclic aromatic hydrocarbons appears to increase damage from early childhood stress exposure and promote later attention and memory problems.101 One meta-study found that 4 studies by one author indicated a 1.57-fold increase in the risk of ADHD from PAHs (OR 2.57), while the total number of all studies indicated a doubled risk (OR 1.99), but this was not significant.102 Another study also showed an association between PAHs and ADHD103
One study found changes related to the immune system of offspring due to air pollution.104
A study of approximately 43,000 families in Shenzen found positive correlations of ADHD beginning at age 3 with exposure during pregnancy to105
Cooking fumes
Tobacco smoke
Steaming from house renovations
Mosquito coils (burnt mosquito pyramids; especially in combination with incense smoke)
Incense smoke (especially in combination with mosquito repellent smoke)
Another study found no increase in risk from air pollution in relation to ADHD.106
A meta-analysis found that more studies (not pregnancy-related) affirmed an association between air pollution and ADHD than denied it.107
A cohort study of 425,736 births on prenatal particulate matter exposure using satellite data found that a 10 μg/m3 increase in PM2.5 concentration during the first trimester increased ADHD risk by 26% and that this increased further at PM2.5 concentrations above 16 μg/m3.108
Air pollution from particulate matter during pregnancy correlated with decreased corpus callosum volume and a tendency toward increased hyperactivity in one study.109 Another study found a correlation between particulate matter and ADHD at low levels of particulate matter exposure, while higher exposure caused more severe brain damage.103
In rats, inhaled printer particles resulted in 5-fold elevations in dopamine levels, although these likely resulted from increased synthesis rather than decreased degradation.110
Diesel exhaust particles caused functional impairment of dopamine neurons in laboratory experiments. Prenatal ingestion with the respiratory air caused in mice:111
In the striatum
Reduced dopamine turnover
Decreased levels of dopamine metabolites
In the amygdala
Increased dopamine level
Elevated dopamine metabolite levels
In the nucleus accumbens
Increased dopamine levels
Traffic ultrafine particulate matter in postnatal breath induced in female mice:111
In the hippocampus
Increased dopamine turnover
Prenatally and postnatally, particulate matter and gaseous pollutants in rodents decreased expression of oxytocin receptors in the hippocampus112 and hypothalamus, with decreased maternal caregiving behavior.113 Oxytocin and vasopressin communication appear to be disrupted by endocrine-disrupting chemicals114, many of which are present in outdoor air.111
Cortisol administration during pregnancy causes long-term changes in the brain of the unborn and increases the risk of ADHD.118 The children suffer a lifelong alteration of the dopaminergic system and the HPA axis, apparently caused by changes in the expression and ratio of MR and GR receptors.119 In our opinion, the ADHD symptoms described in these children could possibly be the result of HPA axis alteration. ⇒ Corticosteroid receptor hypothesis of depression
High cortisol exposure of the fetus or newborn may cause methylation of the GAD1 / GAD67 gene, which encodes the key glutamate-to-GABA-synthesizing glutamate decarboxylase 1 enzyme, leading to increased glutamate levels. This epigenetic mechanism may increase the ADHD risk of children.120
Exposure to betamethasone during pregnancy only marginally increased the ADHD risk of the offspring.121
1.3.2. β-2-Adrenaline receptor agonists in pregnancy (+30%)¶
Taking β-2-adrenaline receptor agonists during pregnancy increases the risk of ADHD for the child by up to 30%.122
1.3.3. Paracetamol (acetaminophen) in pregnancy (+ 37 to 250%)¶
Taking paracetamol (in North America and Iran: acetaminophen) during pregnancy increased the risk of ADHD by up to 37%. Even short-term use is harmful according to two very comprehensive studies with a combined total of over 110,000 participants.123124125126 Critically, Gilman et al. While the previous studies were based on mothers’ intake reports, a study based on blood levels found a 2.3 to 3.5-fold ADHD risk and a 1.6 to 4.1-fold ASA risk in children when taken in the second or third trimester of pregnancy.127128
The ADHD risk from acetaminophen (paracetamol) increases when it is taken129
In the second trimester of pregnancy by 19%
By 28 % in the first and second trimester
In the first to third trimester by 20%
A cohort study of 116,000 children showed that fever in the first trimester of pregnancy increased ADHD risk by 31%, and multiple fevers by 164%. However, fever only increased inattention, not hyperactivity/impulsivity - this was also true for the second trimester. The results were independent of whether the mother was taking acetaminophen (paracetamol) or not.130
A metastudy confirms increased ADHD and ASD risk in offspring when taking acetaminophen during pregnancy131
One study challenges the previous critical findings by focusing on parent ADHD diagnoses not previously considered.132 Also doubting Damkier.133
A long-term study analyzed paracetamol, methionine, serine, glycine, and glutamate in umbilical cord plasma and found an increasing risk of ADHD with elevated paracetamol levels paralleling the increase in 8-hydroxy-deoxyguanosine levels in umbilical cord blood. Increases in cord blood levels of methionine, glycine, serine, and 8-hydroxy-deoxyguanosine correlated with a significantly higher likelihood of ADHD in childhood. Methionine and glycine mediated 22% each of the association between elevated paracetamol levels and later ADHD.134
Ibuprofen, on the other hand, is not thought to trigger an ADHD risk for the unborn child.
SSRIs in pregnancy correlate with significantly increased infant mental disorders, according to a meta-analysis of 18 studies. It is not clear whether this results from the SSRIs or from the mother’s existing mental health problems for which she was treated with SSRIs.135 Purely as a precaution, SSRIs should be used with extreme caution during pregnancy.
One meta-study found no increased risk of ADHD in children in 7 of 8 studies of SSRIs during pregnancy.136 So did another study.137 According to one study, antidepressants during pregnancy increased the likelihood of later ADHD in the child by 1.81 times.138
Valproate in pregnancy is thought to increase the risk of ADHD to the unborn child.141
Valproates are the salts of valproic acid.
When antiepileptic drugs were taken during pregnancy, a cohort study found an increased risk of neurodevelopmental disorders in children up to age 6 (which is too early to diagnose all ADHD sufferers):
Sodium valproate together with other antipsychotics: 15%
Sodium valproate as monotherapy: 12%
Lamotrigine 6.3% (not a statistically significant increase due to the small number of participants in this group)
Carbamazepine 2% (no significant increase)
Children not exposed to any of these drugs during pregnancy: 1.8%
ASD was the most common diagnosis. 2% of children of medicated mothers received an ADHD diagnosis by age 6 years, 1.5% dyspraxia. Among controls, no child had an ADHD diagnosis.142
Several metastudies found a 14% increased ADHD risk from maternal antibiotic use during pregnancy.143144
1.3.8. No increase in risk with NSAIDs, normal caffeine consumption, benzodiazepines¶
A cohort study found no ADHD risk increase with nonsteroidal anti-inflammatory drugs (NSAIDs) in pregnancy.145
Caffeine consumption during pregnancy below 10 cups per day did not increase ADHD risk.146
Benzodiazepines in pregnancy appear to increase the risk for internalizing problems in children (anxiety, emotional reactivity, somatic complaints) but not externalizing problems (hyperactivity, aggressiveness).147 A cohort study comparing siblings with and without maternal benzodiazepine use during pregnancy found no significant increase in risk for ADHD or ASD from benzodiazepines, The authors suggest more of a link to maternal genetic predisposition.148 A meta-study also concluded that no relevant increase in ADHD risk of the offspring has been found for benzodiazepines in pregnancy so far, although one study gave evidence of a slight increase with benzodiazepine monotherapy in the last trimester of pregnancy.149
This list about maternal medications during pregnancy as an ADHD risk is only exemplary and by no means complete.
1.4. Psychological stress of the mother during pregnancy¶
Maternal stress during pregnancy doubled the risk of ADHD in the children.150
Prolonged and severe (fearful, perceived threatening = cortisol tolerant) stress significantly increases the risk for crying children151 (see also 2.2.2.3.2), anxiety disorders and ADHD.152153154155
In this context, prolonged stress (here: financial problems) is more harmful than short-term stress (here: loss of a close person).156
High anxiety/threat perceived stress at the same time significantly increases the risk for borderline in children.
Children with ADHD were more likely to have mothers who experienced stress or emotional problems during pregnancy:2
Children with ADHD: 53.8
If stress/emotional problems occurred, they were in the following trimester:
1st/2nd trimester only: 36.0%
3rd trimester only: 6.7 %
Total pregnancy: 57.3
Non-affected children: 27.6 %
If stress/emotional problems occurred, they were in the following trimester:
1st/2nd trimester only: 28.6 %
3rd trimester only: 24.9 %
Total pregnancy: 28.6
Hair cortisol levels of mothers and their children showed a transmission of psychological stress experiences from mothers to children.157
One study found no increased psychiatric disorders at age 9 in children of women exposed to one month of repeated rocket fire on civilians during the 2006 Lebanon War.158 It is possible that one month of repeated stress is not a sufficiently intense stressor.
The mother’s cortisol, which is released during fearful/threatening stress, is absorbed by the unborn and causes permanent damage to the HPA axis, which uses cortisol to regulate stress responses.159160
Severe maternal anxiety in pregnancy during weeks 12 to 22 after the last menstrual period significantly increases the risk for ADHD, whereas severe anxiety during weeks 32 to 40 does not increase the risk.161
Severe maternal anxiety during pregnancy increased the ADHD risk of the unborn child depending on its COMT (gene-environment interaction) gene variant.162
In mothers with the ADGRL3 (latrophilin 3, LPHN3) gene variants (SNPs)
rs6551665
rs1947274
rs6858066 or
rs2345039
even minor stress during pregnancy caused a significantly increased risk of ADHD for the child.163
Early prenatal stress increases levels of immune response genes, including the proinflammatory cytokines IL-6 and IL-1β, particularly in male placentas. Male infants exhibit stress-induced locomotor hyperactivity, a hallmark of dopaminergic dysregulation that was ameliorated by maternal treatment with nonsteroidal anti-inflammatory drugs. In addition, expression of dopamine D1 and D2 receptors was altered by early prenatal stress in male offspring.164 The actuates the effect of early stress on the dopaminergic system.
High cortisol exposure of the fetus or newborn may cause methylation of the GAD1 / GAD67 gene, which encodes the key enzyme for glutamate-to-GABA synthesis, glutamate decarboxylase 1, and lead to increased glutamate levels. This epigenetic mechanism may increase ADHD risk in children.120 Exposure to glucocorticoids during hippocampal development in pregnancy affects the starting point of the stress response through epigenetic changes via mRNA and methylation.165 Another study reported that the increase in risk to the unborn for developmental disorders such as ADHD mediated by maternal psychological stress may be mediated by mRNA expression of glucocorticoid pathway genes in the placenta.166
Another study also describes epigenetic changes in the unborn due to psychological stress of the mother during pregnancy.167
One study found no significant increase in risk for mental disorders by 10 years of age from increased glucocorticoid exposure in the unborn.168
Maternal exposure to a natural disaster during pregnancy increased ADHD risk.169
In primates, the stress hormone cortisol is converted to its inactive form by the enzyme hydroxysteroid 11-β-dehydrogenase 2 (HSD11B2). This conversion in the placenta also protects the fetus.170171 However, chronic maternal stress (as well as malnutrition or hypoxia) decreases HSD11B2 expression in the placenta.171 Fetuses of chrinically stressed mothers are therefore exposed to high cortisol concentrations, triggering developmental delays and neurodevelopmental disorders such as ADHD.172173171 In rodents, expression of Hsd11b1, which encodes an enzyme regulating the activity of stress-related hormones in the neocortex, is instead reduced.174
1.5. Severe maternal obesity before or during pregnancy (+14 to 280%)¶
Massive maternal obesity during pregnancy increased the risk of later ADHD in the child by 2.8 times in one study.175
Already an excessive BMI of the mother before pregnancy increased the ADHD risk of the later offspring.176 A BMI of 25 to 30 increased the child’s ADHD risk by 14%, a BMI of 30 to 35 by 96% and a BMI of more than 35 by 82%.177
Other variations in maternal weight before and at the end of pregnancy do not appear to affect ADHD risk.6
A Norwegian registry study found little evidence of an effect of parental BMI on the child’s ADHD risk, although here the mother’s pre-pregnancy BMI was the subject of investigation.178 In contrast, another study found that maternal pre-pregnancy obesity increased maternal ADHD risk by 62%.179
1.6. Pre-eclampsia (gestosis) in pregnancy (+ 30 to 188 %)¶
Problems in pregnancy that affect fetal oxygenation increase the risk of ADHD in the child by 30% to 188%.180 One cohort study found a 43% increase in ADHD risk from gestational gestosis.181 Several reviews confirm an increased ADHD risk from preeclampsia in pregnancy.182183
Preeclampsia is related to changes in the adenosine system, including adenosine transporters and adenosine receptors. SHR are born in a preeclampsia-like situation due to maternal hypertension. Caffeine (an adenosine antagonist) in 7-day-old SHR prevented the negative consequences of preeclampsia (hyperactivity, worsened social interaction, worsened contextual fear conditioning), whereas it exacerbated these symptoms in Wistar rats184
Hypoxia (lack of oxygen) increases adenosine. Adenosine antagonists can prevent or correct the negative consequences of hypoxia. For more on this topic, see ⇒ adenosine In the chapter Neurological Aspects.
High levels of the (weak) adenosine antagonist theobromine correlated negatively with preeclampsia185
1.7. Mineral and vitamin deficiency during pregnancy¶
A meta-study found evidence that higher omega-3 fatty acid levels in the newborn may reduce the risk and severity of ADHD as well as autism spectrum disorders. It is possible that an adequate supply of omega-3 fatty acid in the last trimester of pregnancy could counteract this.186
Vitamin D3 deficiency during pregnancy and after birth causes brain maldevelopment,187188189 which, however, is more likely to correlate with schizophrenia. One metastudy found little evidence of an association between prenatal vitamin D deficiency and autism spectrum disorders. Studies with larger sample sizes and more stringent definitions of vitamin D deficiency found positive associations for ADHD and schizophrenia.190
A large long-term study in Spain of vitamin D3 deficiency in pregnancy found no correlation between low maternal blood D3 levels in pregnancy and ADHD in children aged 5 to 18 years.191
A study in Finland, on the other hand, found a clear correlation between reduced maternal D3 levels during pregnancy and ADHD in children. The risk increase reached up to more than 50 %.192
We think it is plausible that the difference could result from the fact that sunlight intensity in Spain is high enough almost all year round to form D3, whereas in Germany, and even more so in more northerly countries, solar radiation intensity is too low during the winter months to mediate D3 formation.
1.8. Unhealthy diet of the mother during pregnancy (+ 60 %)¶
An unhealthy or a “Western” dietary intake by the mother during pregnancy increased the children’s likelihood of ADHD by more than 60%.193
Since stress increases the preference for “convienient foods,” we believe that the correlation could possibly also be an indirect reflection of increased maternal stress during pregnancy, since stress alters food preferences toward rapidly digestible foods and convienient foods.
1.9. Maternal fever during pregnancy (+31 to 164%)¶
A cohort study of 114,000 children showed that fever in the first trimester of pregnancy increased ADHD risk by 31%, and multiple fevers by 164%. However, fever only increased inattention, not hyperactivity/impulsivity - this was also true for the second trimester. The results were independent of whether the mother was taking acetaminophen (paracetamol) or not.130
1.10. Anemia (anemia) of the mother during pregnancy (+ 31 %)¶
A cohort study of 532,232 children over 23 years of age showed that maternal anemia in the first 30 weeks of pregnancy increased ADHD risk by 31%, whereas anemia in later weeks of pregnancy barely increased risk (by 1.4%). 194
1.11. Parents’ asthma in and out of pregnancy (+ 13 to 41%)¶
A cohort study of 961,202 children showed a 41% increased risk of ADHD with maternal asthma and a 13% increased risk with paternal asthma. A maternal asthma episode during pregnancy increased ADHD risk by 21%, and an asthma episode after pregnancy increased ADHD risk by 25%.195 Another study also found an increased ADHD risk in the offspring of mothers with asthma, especially for girls.196
Maternal diabetes before or during pregnancy increases the offspring’s risk for ADHD and ASD.197
A cohort study of more than 5 million people found an increased risk of ADHD in children if a parent had diabetes.198
Diabetes mellitus or type 1 diabetes mellitus of the mother before pregnancy increased the ADHD risk of the children by 40%, type 1 diabetes mellitus of the father by 20%.
Another study found a 2.4-fold ADHD risk of children of mothers with diabetes mellitus and a 3.7-fold ADHD risk of male offspring of mothers with diabetes mellitus. No differences were found between gestational diabetes and diabetes elsewhere.199
Children of non-insulin-treated severely obese mothers with type 2 diabetes were 2 times more likely to show psychiatric disorders than offspring of normal-weight mothers. Children of insulin-treated severely obese mothers with pregestational diabetes were 2.7 times more likely to show psychiatric disorders than offspring of normal-weight mothers.200
Especially in boys, the severity of maternal depression during pregnancy and higher maternal cyclothymic, irritable, and anxious temperament scores seem to be relevant risk factors for the development of ADHD.201
1.14. Increased or decreased thyroxine levels in the mother¶
One study found a 7% increased risk of ADHD in children with untreated mild maternal thyroxine deficiency during early pregnancy.202 In another study, decreased or untreated normal thyroxine levels in the mother showed no effect on ADHD in the children. In contrast, thyroxine treatment of the mother, especially with excessive thyroxine levels due to overdose, appears to increase the ADHD risk of the children.203 Another study also found evidence of thyroxine as a possible cause of ADHD,204 another study found no influence of the mother’s thyroxine levels during pregnancy.205
In male mice, one study found significantly reduced dopamine and serotonin turnover in the striatum, nucleus accumbens, hypothalamus, and hippocampus as a result of prenatal thyroxine deficiency.206Dopamine deficiency in the striatum / nucleus accumbens is responsible for hyperactive symptoms in ADHD.
1.14.1. Decreased and increased neonatal TSH levels (+14% in boys to +310% in girls)¶
A cohort study from Norway found that newborns with TSH levels that were too low or too high had an increased risk of ADHD later in life, but only in girls. TSH levels in the lowest 20% group increased the ADHD risk of girls 3.1-fold, of boys only 14%.207
Another Norwegian cohort study found a 2.27-fold risk of ADHD for maternal thyroid hormone T3 levels at 17 weeks’ gestation within the top 1/5 versus the bottom 1/5. For free T4, increased as well as decreased levels were risk-increasing: the top 1/5 as well as the bottom 1/5 showed a 1.6-fold risk of ADHD in the offspring.208
A large Swedish cohort study found that firstborns are at higher risk for depression and ADHD in childhood and for endocrine disorders after age 50.212
1.17. Particularly short or long intervals from the previous pregnancy (+ 25 to 30 %)¶
Particularly short or particularly long intervals of pregnancy with the preceding sibling increased the risk of ADHD by 30% (less than 6 months) and 12% (60-119 months) to 25% (120 months and more), respectively.213
1.18. Maternal exposure to non-ionizing magnetic field radiation during pregnancy (+100%)¶
Children whose mothers were most exposed to non-ionizing magnetic field radiation (“electrosmog”) during pregnancy (at a 24-hour measurement),214
Showed a doubled risk for ADHD (aHR 2.01)
Persistence of ADHD beyond age 11 was more than three times more likely to correlate with high maternal exposure than remission of ADHD by age 11 (aHR 3.38).
ADHD with comorbid immune-related comorbidities (asthma or neurodermatitis/atopic dermatitis) was 4.57 times more likely to be correlated with high exposure.
A coincidence of ADHD persisting beyond age 11 and immune-related comorbidities was 8.27 times more likely to be associated with exposure.
1.19. Polycystic ovary syndrome (PCOS) in pregnancy (+ 31 to + 95% in boys)¶
Children of women with polycystic ovary syndrome (PCOS) appear to be at increased risk for ADHD.215
Possibly a connection could arise from the fact that one method of treatment is the use of dopamine agonists.216217 Another connection could be that PCOS is associated with hyperandrogenemia. Elevated prenatal testosterone levels are a risk factor for ADHD. For more on this, see Sex differences in ADHD.
One study found a 95% increased risk of ADHD in 3-year-old boys born to mothers with PCOS, while this was not increased in 3-year-old girls.218 This also suggests a link to sex hormones, although increased testosterone levels during pregnancy also causes increased ADHD symptoms in female offspring. See more at Sex differences in ADHD. It is also known that ADHD shows up later in girls than in boys.
A Chinese study found (only) a 31% increased risk of ADHD in boys aged 3 to 6.219 Since ADHD can often only be diagnosed at age 6 and older, we suspect a higher rate at school age.
Women with PCOS were themselves at increased risk of ADHD, although no association was found between testosterone and ADHD symptoms220
High blood pressure during pregnancy significantly increases the ADHD risk of the offspring.183
Hypertension is associated with genetically inherited ADHD risks. It will therefore be necessary to differentiate whether hypertension during pregnancy causally increases ADHD risk or whether elevated blood pressure during pregnancy is an expression of the underlying genetic burden that mediates ADHD.
1.21. Decreased C-reactive protein (CRP) (+ 92 %)¶
Children of mothers whose CRP levels were in the lowest third of the subject group had nearly double the risk of ASD and ADHD compared with children of mothers from the middle third in CRP.221
Children of mothers who had systemic lupus erythematosus (SLE) were found to have a 60% increased risk of ADHD.222
1.23. Less than 8 hours of sleep in the 3rd trimester of pregnancy¶
Girls of mothers with less than 8 hours of sleep in the last trimester of pregnancy were more likely to show hyperactivity, inattention, and ADHD total scores.223
[Thistle, Ramos, Roell, Choi, Manley, Hall, Villanger, Cequier, Sakhi, Thomsen, Zeiner, Reichborn-Kjennerud, Øvergaard, Herring, Aase, Engel (2022): Prenatal organophosphorus pesticide exposure and executive function in preschool-aged children in the Norwegian Mother, Father and Child Cohort Study (MoBa). Environ Res. 2022 May 22:113555. doi: 10.1016/j.envres.2022.113555. PMID: 35613628.)](https://pubmed.ncbi.nlm.nih.gov/35613628/ ↥
