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2. Birth circumstances as the cause of ADHD

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2. Birth circumstances as the cause of ADHD

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Extensive evidence shows that harmful influences during birth are a significant risk factor for the development of neurodevelopmental disorders such as ADHD that occur long after the causative event1

The earlier the premature birth, the greater the risk of ADHD. A low birth weight also appears to increase the risk of ADHD, while a high birth weight reduces the risk.
Furthermore, oxygen deprivation at birth, low APGAR values after 1 minute, emergency caesarean sections, need for intensive medical care, neonatal jaundice, high serotonin metabolite levels in the umbilical cord blood and postnatal administration of antibiotics are associated with an increased risk of ADHD.

A long-term study found that of 318 children with birth problems, those who had developed ADHD as children only had 21% ADHD at age 40, but had poorer educational attainment, more ADHD symptoms and executive problems. Those who had attention problems as a child but no full-blown ADHD had 6.6% ADHD at age 40, while those who had no attention problems as a child had 6% ADHD. Controls without birth problems had 1.6% ADHD at the age of 40.2

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

2.1. Premature birth

Premature delivery significantly increases the risk of ADHD, and the earlier the premature birth, the greater the risk.3 The effect of premature birth on inattention (but not hyperactivity) ADHD appears to be mediated by reduced lung function and therefore oxygen deprivation4

Pregnancy week / increased risk of ADHD5

  • 23. to 28th / 2.1-fold (plus 110 %)
  • 29. to 32 / 1.6-fold (plus 60 %)
  • 33. to 34th / 1.4-fold (plus 40 %)
  • 35. to 36th / 1.3-fold (plus 30 %)
  • 37. to 38th / 1.15-fold (plus 15 %).

A Scottish cohort study found6

24. to 27th / 5-fold (plus 400 %)
28. to 32nd / 2-fold (plus 100 %)
33. to 36th / 1.59-fold (plus 59 %)
37. / 1.31-fold (plus 31 %)
38. / 1.14-fold (plus 14 %
39. / 0.98-fold (minus 2 %)
40. / 0.89-fold (minus 11 %) (usual duration of pregnancy)
41. / 0.87-fold (minus 13 %)
42. / 0.89-fold (minus 11 %)
43. / unchanged
44. and higher / unchanged

A Swedish cohort study found that the duration of the treatment was 37 weeks or longer:7

22. to 27th / 2.79-fold
28. to 31 / 1.61-fold
32. to 36th / 1.18-fold
SGA / 1.62-fold (SGA: small for gestational age, birth weight below the 10th percentile)
Preclampsia was associated with ADHD
Placental abruption was not associated with ADHD

Meta-analyses of 16 studies8 and 12 studies9 as well as further studies1011 12 confirm this, one study tends to confirm this.13
A single study found no correlation.14. A cohort study found a 3-fold increase in the risk of ADHD for births in the 28th week of pregnancy or earlier.15 The increased risk of ADHD results from the duration of pregnancy itself, i.e. not from the typical premature birth risks such as oxygen deficiency, cerebral haemorrhage or intrauterine growth retardation. This is also shown by the comparison with non-preterm twin siblings.16

Girls appear to have an increased risk of ADHD due to premature birth.16

A study of premature babies born between the 32nd and 36th week found that 65% of 7- to 10-year-olds had elevated levels in at least one of the ADHD symptom areas.17

One study found that the risk of ADHD was higher in spontaneous preterm births than in external medically induced preterm births. In addition, the risk of ADHD caused by a premature birth increased further if chorioamnionitis was added (ADHD risk increased by 175%):18 Another study found that spontaneous as well as medically induced preterm births increased the risk of ADHD,19

It is assumed that premature birth causes the supply of important substances to end too early, which impairs brain development. Repeated hypoxic-ischemic events are particularly common in premature infants, which could explain the high incidence of ADHD.20 It is hypothesized that an additional supply of allopregnanolone could be helpful, in addition to the already established administration of corticosteroids (once) and magnesium sulphate.2122 However, the fact that only spontaneous premature births, but not medically induced premature births, increase the risk of ADHD speaks against this - at least with regard to ADHD.
The association between preterm birth and inattention problems seems to be reinforced by lung problems.23 We hypothesize a connection with hypoxia.

The psychological risks to the child in the event of a premature birth appear to result more from the premature birth itself, namely24

  • IQ
  • Preparation vigilance
  • Error processing

and partly caused more by social or other family circumstances, namely

  • Inhibition
  • Verbal working memory

The usual number is 40 weeks of pregnancy.
Transferred children who were born after the due date do not have an increased risk of ADHD.

In the case of extremely premature birth, obesity and diabetes in the mother also increased the risk of ADHD by 55 to 65% in each case25

Extremely preterm infants showed impairments in attentional guidance as preschoolers, but not in alerting efficiency or executive aspects of attention.26 Extreme prematurity appears to be associated with inattention rather than hyperactivity,1627 as well as anxiety and social difficulties.27

If, in addition to the premature birth, the mother also had an autoimmune disease, which alone also appears to increase the risk of ADHD, these risks did not add up.28

2.2. Low or high birth weight

A low birth weight is likely to increase the risk of ADHD.293031 Two other studies did not confirm this result.3233

A Scottish cohort study found an influence of birth weight on the risk of ADHD (determined on a gender-specific basis according to centiles)6
1 to 3: 134.1% (the 3% with the lowest birth weight had a 34% increased risk of ADHD)
4 to 10: 117.8 %
11 to 20: 109.2 %
21 to 80: 95.7 %
81 to 90: 86 %
91 to 97: 92.6 %
98 to 100: 95.5 % (the 3 % with the highest birth weight had a 4.5 % lower risk of ADHD)

Studies have found the risk of ADHD in

  • extremely low birth weight (< 1,000 g) of 13.8 %34
  • very low birth weight (< 1,500 g) increased by 51 %35
  • low birth weight (1,500-2,500 g) increased by 32 %35 to approx. 125 % (OR = 2.25)34
  • normal birth weight (from 2,500 g) unchanged35

One study found a 77% increased risk of ADHD with a birth weight over 4000 grams.36

2.3. Oxygen deficiency at birth

Lack of oxygen at birth increases the risk of ADHD.37

An oxygen supply for the newborn during birth (which became necessary due to a lack of oxygen) correlates with an almost tripled risk of ADHD.33
Hypoxy-ischemic conditions around birth (e.g. asphyxia) cause an inadequate supply of oxygen to the brain. This can lead to cognitive impairment. Their occurrence is influenced by dopamine transporter gene polymorphisms.38 Oxygen deprivation during birth can cause long-term changes in the dopamine system, where dopamine is important for brain development.3940 Oxygen deprivation at birth correlated with unoccupied (an excess of) D2/D3 dopamine receptors in a very small number of subjects.41
Disorders of the dopamine system can trigger brain development disorders such as those associated with ADHD.
One study found evidence that attention problems following oxygen deprivation during birth are moderated by gene variants of the dopamine transporter in the PFC.42
A study conclusively describes a reduction in the consequences of ischemia by methylphenidate through activation of the AMPK signaling pathway.43 As AMPK influences the dopamine balance, this could indicate that a dopamine deficiency increases the damage caused by ischemic conditions.

It is known that hypoxia (lack of oxygen) leads to an excess of adenosine. Adenosine is closely linked to the dopaminergic system. Adenosine antagonists are able to prevent and correct hypoxia damage. More on this under Adenosine In the chapter Neurological aspects.

Prenatal hypoxia caused massive changes in the dopaminergic system in mice:44

  • a reduction in dopaminergic progenitor cells
  • delayed early lateral migration of DA neurons
  • delayed expression of the receptors that control this process
  • reduced expression of tyrosine hydroxylase in the postnatal striatum
  • an increased density of dopamine release sites with high probability within the TH varicosities.

2.4. APGAR values below 7 after 1 minute

The lower the APGAR values, the higher the risk of ADHD:

  • Under 5 after 1 minute: 7-fold ADHD risk33 (the authors incorrectly calculate 9% for controls instead of 0.9% in the text)
  • Between 5 and 7 after 1 minute: more than tripled risk of ADHD33
  • Under 7 after 1 minute: significantly increased risk of ADHD32
  • From 8 after 1 minute no increased risk of ADHD33

A Scottish cohort study found an influence of the 5-minute APGAR score on the risk of ADHD6
1 to 3: 9-fold ADHD risk
4 to 6: 1.5 times the risk of ADHD
7 to 10: 0.99 times the risk of ADHD

A meta-study found a significantly increased risk of ADHD (OR = 1.3 = approx. + 30%) in under 7s after 5 minutes.34

One study found no increase in ADHD risk with an APGAR score after 5 and 10 minutes32

2.5. Caesarean section

A comprehensive meta-study of over 20 million births found that a caesarean section increases the risk of ADHD by 17%.45 The risk of autism spectrum disorder was increased by 33%.

Other sources, however, cite a risk increase of 6%46 or 3 to 9%47 or 5 to 15%.48 One small study found no increased risk of ADHD due to caesarean section.33

Several studies showed that only an emergency caesarean section resulted in a statistically significant increase in the risk of ADHD,48 or that children with ADHD were 5% more likely to have an emergency caesarean birth and 12% less likely to have a planned caesarean birth6
Another study confirmed that only a caesarean section at birth (intrapartum) increased the risk of ADHD.47

A meta-study found that a caesarean section increased the risk of ASD in girls by 66% and in boys by 17%.49 The risk of ADHD was also increased.

2.6. Newborns requiring intensive care

Newborns who required intensive medical care showed a 60% increased risk of ADHD at the age of 4 to 11 years.50

Newborns who had to be treated in an incubator had a 4.5-fold risk of ADHD.33

2.7. Neonatal jaundice

Jaundice is a yellowing of the skin and whites of the eyes caused by excess bilirubin. Bilirubin is a yellow breakdown product in the blood.

Newborns with jaundice show an increased risk of ADHD and ASD. The ADHD risk was increased by 14 to 31%51 and 33% respectively. If the jaundice required treatment, the risk of ADHD was 2.5 times higher than in those not affected. The risk of ADHD was particularly increased if the jaundice was so severe that all of the newborn’s blood had to be replaced.33
Neonatal jaundice is associated with reduced urinary homovanillic acid in the first few days, indicating reduced dopamine turnover.52

(Neonatal) hyperbilirubinemia, a (neonatal) bilirubin excess is associated with ADHD, a severe bilirubin excess with ASD.53
Hyperbilirubinemia in early childhood can cause a similar impairment of the frontostriatal network and similar symptoms to ADHD.5455 A registry study of n = 157,366 children found no correlation.56

Bilirubin dose-dependently inhibited the uptake of tyrosine (a precursor of dopamine) in the striatum in vitro.57 Bilirubin inhibits cAMP-stimulated dopamine synthesis58 and reduces the vesicular storage of dopamine and glutamate59.
Bilirubin (20-80 microM) did not directly affect dopamine release from striatal synaptosomes. It inhibited the initial rate of synaptosomal dopamine uptake and dopamine levels in the synaptosome after 10 minutes. Bilirubin appears to primarily inhibit neurotransmitter reuptake and the response to depolarizing stimuli.60

2.8. Serotonin metabolites in umbilical cord blood

Elevated umbilical cord blood levels of serotonin metabolites correlated with an increased risk of ADHD later in life:61

  • Tryptophan: 25 %
  • 5-HTP: 32 %
  • N-acetyltryptophan: 27 %

The risk of ASD or other mental disorders remained unchanged.

Elevated umbilical cord blood levels of the serotonin metabolite

  • 5-Methoxytryptophol

correlated with a 21% reduced risk of ADHD and a 44% reduced risk of ASD)

2.9. Antibiotics after the birth

A meta-study found a 12% increased risk of ADHD due to postnatal administration of antibiotics.62

2.10. Month of birth influences ADHD risk

Several studies found consistent data on how the month of birth influences the risk of ADHD and other mental disorders.63 This follows a general pattern of neurological disorders having the lowest risk at birth in spring, while cardiovascular disorders have the highest risk at birth in spring. Relevant factors could be vitamin D3 production during pregnancy and in the first months of life or, as most studies suggest, the relative age at school entry (in relation to the other children in the class).64656667
A Taiwanese study found a clear correlation with age at school enrollment.68

Interestingly, the asthma risk depending on the month of birth has an opposite pattern, although ADHD and asthma often occur comorbidly.69

2.11. Congenital heart defects (+ 200 %)

Congenital heart disease is a general term for a number of birth defects that affect the normal functioning of the heart.
A meta-study found a significantly increased risk of ADHD with congenital heart defects (OR = 3.04, approx. + 200 %).34

2.12. Characteristics without an increased risk of ADHD

The following factors do not appear to have any influence on the risk of ADHD:

  • Number of pregnancies of the mother32
  • Mother’s level of education32
    • However, a lower level of education of the mother is said to correlate with an increased screen consumption of the children, which in turn correlates with behavioral problems.70
  • Size of the mother32
  • Blood values of the umbilical artery32
  • Elevated CRP values (C-reactive protein) during pregnancy71
  • Artificial insemination,72 whereby these mothers had a slightly higher level of education than those in the comparison group.
  • Single/multiple birth33
  • Date of delivery33
  • Position of the child during delivery33
  • Changes in the amniotic fluid33
  • Problems with the placenta33
  • Bleeding during childbirth33
  • Umbilical cord wrapped around the baby’s neck33
  • Epidural analgesia during childbirth
    • Of 4,498,462 people (48.7 % female), 1,091,846 (24.3 %) were exposed to epidural analgesia during childbirth. Of these, 1.2% had ASD and 4.0% had ADHD. At the population level, epidural analgesia at birth showed an increased risk in offspring for ASD (1.20% vs. 1.07%) and ADHD (3.95% vs. 3.32%). However, when comparing full siblings exposed to epidural analgesia at birth in different ways, the associations were completely attenuated for both conditions (ASD: risk reduced by 2%; ADHD: risk reduced by 1%).73
  • Induction of labor
    • Use of induction drugs33
    • Through exogenous oxytocin74

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