2. Birth circumstances as ADHD cause

Extensive evidence shows that harmful influences during birth are a significant risk factor for the development of neurodevelopmental disorders that occur long after the causative event.¹ This includes ADHD. One long-term study found that of 318 children with birth problems, those who had developed ADHD as children were only 21% ADHD at age 40, but had poorer educational attainment, more ADHD symptoms, and executive problems. Those who had attention problems as children but not full-blown ADHD had 6.6% ADHD at age 40; those who did not show attention problems as children had 6% ADHD. Controls without birth problems had ADHD 1.6% of the time at 40 years.²

• 2.1. Premature birth
• 2.2. Low or high birth weight
• 2.3. Oxygen deficiency at birth
• 2.4. APGAR values below 7 after 1 minute
• 2.5. Cesarean section
• 2.6. Newborns with intensive care needs
• 2.7. Neonatal jaundice
• 2.8. Serotonin metabolites in umbilical cord blood
• 2.9. Antibiotics after birth
• 2.10. Characteristics without increased ADHD risk

2.1. Premature birth¶

Preterm delivery significantly increases the risk of ADHD, and the earlier the preterm delivery, the greater the risk:

Pregnancy week / risk increase for ADHD³

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

A Scottish cohort study found⁴

24. until 27th / 5-fold (plus 400 %)
25. up to 32 / 2-fold (plus 100 %)
26. up to 36th / 1.59x (plus 59 %)
27. / 1.31-fold (plus 31 %)
28. / 1.14 times (plus 14 %)
29. / 0.98 times (minus 2 %)
30. / 0.89-fold (minus 11 %)
31. / 0.87-fold (minus 13 %)
32. / 0.89-fold (minus 11 %)
33. / unchanged
    44 and higher / unchanged

Meta-analyses of 16 studies⁵ and 12 studies⁶ as well as further studies^{78 9} confirm this, one study tends to confirm this,¹⁰ another single study does not,¹¹. A cohort study comes to an increase in ADHD risk by a factor of three for births in the 28th week of pregnancy or earlier.¹² The increased ADHD risk results from the duration of pregnancy itself, i.e. not from the typical preterm birth risks such as oxygen deficiency, cerebral hemorrhage or intrauterine growth retardation.

A study of preterm infants born between 32 and 36 weeks found elevated scores in at least one of the ADHD symptom domains in 65% of 7- to 10-year-olds.¹³

Another study found that ADHD risk was increased more in spontaneous preterm births than in externally medically induced preterm births. In addition, the risk of ADHD caused by preterm birth increased further when chorioamnionitis was added (ADHD risk increased by 175%):¹⁴

It is suspected that prematurity causes the supply of important substances to end too early, which impairs brain development. It is hypothesized that an additional supply of allopregnanolone could be helpful, in addition to the already established administration of corticosteroids (once) and magnesium sulfate.¹⁵¹⁶ However, this is contradicted - at least with regard to ADHD - by the finding that only spontaneous preterm births, but not medically induced preterm births, increase the risk of ADHD.

Extreme preterm infants showed impairments in attentional guidance as preschoolers, but not in alerting efficiency or in executive aspects of attention.¹⁷

In the case of premature birth, the psychological risks to the child seem to result in part more from the premature birth itself, viz¹⁸

• IQ
• Preparation-Watchfulness
• Error processing

and partly to be caused more by social or other family circumstances, viz

• Inhibition
• Verbal working memory

The usual number of weeks of pregnancy is 40.
Transferred children born after the calculated date therefore have no increased risk of ADHD from this.

2.2. Low or high birth weight¶

Low birth weight is likely to increase ADHD risk.¹⁹²⁰²¹ Two other studies did not confirm this result.²²²³

A Scottish cohort study found an impact of birth weight on ADHD risk (determined by centiles for gender)⁴
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% reduced risk of ADHD)

One study found a 77% increased risk of ADHD with a birth weight over 4000 grams.²⁴

2.3. Oxygen deficiency at birth¶

Lack of oxygen at birth increases ADHD risk.²⁵

Oxygen supplementation for the newborn during birth (necessitated by oxygen deprivation) correlated with a nearly tripled risk of ADHD.²³
Hypoxy-ischemic conditions around birth (e.g., asphyxia) cause an inadequate supply of oxygen to the brain. This can lead to cognitive impairment. Their onset is influenced by dopamine transporter gene polymorphisms.²⁶ Oxygen deprivation during birth can cause long-term changes in the dopamine system, and dopamine is important for brain development.²⁷²⁸ Oxygen deprivation at birth correlated with unoccupied (an excess of) D2/D3 dopamine receptors in a very small number of subjects.²⁹
Dysfunction of the dopamine system can trigger brain developmental disorders such as those associated with ADHD.
One study found evidence that attentional problems following oxygen deprivation during birth are moderated by gevnariants of the dopamine transporter in the PFC.³⁰
Key to this, one study describes a reduction in ischemic sequelae by methylphenidate via activation of the AMPK signaling pathway.³¹ Since AMPK affects dopamine balance, this may suggest that dopamine deficiency increases the damage of ischemic conditions.

It is known that hypoxia (lack of oxygen) leads to excess adenosine. Adenosine is closely linked to the dopaminergic system. Adenosine antagonists are able to prevent and correct hypoxia damage. For more information see Adenosine In the chapter Neurological Aspects.

Prenatal hypoxia caused massive changes in the dopaminergic system in mice:³²

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

2.4. APGAR values below 7 after 1 minute¶

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

• Below 5: 7-fold ADHD risk²³ (The authors erroneously calculate 9% in controls instead of 0.9% in the text)
• Between 5 and 7: more than tripled risk of ADHD²³
• Under 7 after 1 minute: significantly increased ADHD risk²²
• From 8 no increased ADHD risk²³

A Scottish cohort study found an impact of the 5-minute APGAR score on ADHD risk⁴
1 to 3: 9-fold ADHD risk
4 to 6: 1.5-fold risk of ADHD
7 to 10: 0.99-fold risk of ADHD

One study found no ADHD risk increase with an APGAR score between 5 and 10 min²²

2.5. Cesarean section¶

A large meta-study of over 20 million births found that cesarean section increased the risk of ADHD by 17%.³³ The risk of autism spectrum disorders was increased by 33%.

In contrast, other sources cite a risk increase of 6%³⁴ or 3% to 9%³⁵ or 5% to 15%.³⁶ One small study found no increased ADHD risk from cesarean section.²³

Several studies showed that only emergency cesarean delivery resulted in a statistically significant increase in risk for ADHD,³⁶ or that children with ADHD were 5% more likely to have an emergency cesarean delivery and 12% less likely to have a planned cesarean delivery⁴
Another study confirmed that only cesarean section at birth (intrapartum) increased ADHD risk.³⁵

2.6. Newborns with intensive care needs¶

Newborns who required intensive medical care showed a 60% increased risk of ADHD between the ages of 4 and 11 years.³⁷

Newborns who had to be treated in an incubator had a 4.5-fold risk of ADHD.²³

2.7. Neonatal jaundice¶

Newborns with jaundice had a 33% increased risk of ADHD. If the jaundice required treatment, the ADHD risk was 2.5 times greater than in unaffected individuals. The ADHD risk was particularly increased if the jaundice was so severe that all of the newborn’s blood had to be replaced.²³
Neonatal jaundice is associated with decreased urinary homovanillic acid in the first few days, suggesting decreased dopamine turnover.³⁸

2.8. Serotonin metabolites in umbilical cord blood¶

Elevated umbilical cord blood levels of serotonin metabolites correlated with increased later ADHD risk:³⁹

• 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 birth¶

One metastudy found a 12% increased ADHD risk from postnatal antibiotic administration.⁴⁰

2.10. Characteristics without increased ADHD risk¶

The following factors do not appear to influence ADHD risk:

• Number of pregnancies of the mother²²
• Mother’s educational level²²
  • However, a lower level of maternal education is reported to correlate with increased screen use by children, which in turn correlates with behavioral problems.⁴¹
• Mother size²²
• Umbilical artery blood values²²
• Breastfeeding²²
• Elevated CRP (C-reactive protein) levels during pregnancy⁴²
• Artificial insemination,⁴³ whereas these mothers had slightly higher education than those in the comparison group.
• Single/multiple birth²³
• Date of delivery²³
• Use of induction drugs²³
• Position of the child during delivery²³
• Changes in the amniotic fluid²³
• Problems with the placenta²³
• Bleeding during delivery²³
• Umbilical cord wrapped around the neck of the child²³
• Epidural analgesia at birth
  • Of 4,498,462 individuals (48.7% female), 1,091,846 (24.3%) were exposed to epidural analgesia during delivery. Of these, 1.2% had ASD and 4.0% had ADHD. At the population level, epidural analgesia at birth showed an increased risk among offspring for ASD (1.20% vs. 1.07%) and ADHD (3.95% vs. 3.32%). However, when comparing full siblings differently exposed to epidural analgesia at birth, the associations were completely attenuated for both conditions (ASD: risk reduced by 2%; ADHD: risk reduced by 1%).⁴⁴