Journal of Biosciences and Medicines, 2021, 9, 1-15

https://www.scirp.org/journal/jbm
ISSN Online: 2327-509X
ISSN Print: 2327-5081

Perinatal Factors of Developmental Attention

Deficit Hyperactivity Disorder in Children
Evangelia Antoniou1,2, Nikolaos Rigas1, Alexandros Papatrechas2, Eirini Orovou1,
Garyfallia Lemoni3, Georgios Iatrakis1
1
Department of Midwifery, University of West Attica, Athens, Greece
2
Non-Profits/Non-Governmental Organizations (NGO) “Fainareti”, Athens, Greece
3
Department of Special Education, University of Thessaly, Volos, Greece

How to cite this paper: Antoniou, E., Abstract

Rigas, N., Papatrechas, A., Orovou, E., Le-
moni, G. and Iatrakis, G. (2021) Perinatal
Background: Attention deficit hyperactivity disorder is a common pediatric
Factors of Developmental Attention Deficit neurobehavioral disorder often treated in the primary care setting. It shows a
Hyperactivity Disorder in Children. Journal high and chronic level of inattention, impulsivity/hyperactivity and/or both,
of Biosciences and Medicines, 9, 1-15. and can affect more than 2 million school-age children. The researchers are
https://doi.org/10.4236/jbm.2021.91001
not sure about the exact causes of the disorder, but it seems that apart from
Received: December 3, 2020 genetic factors, perinatal factors seem to dynamically contribute to the de-
Accepted: January 9, 2021 velopment of the disorder. Purpose: The aim of this review was to investigate
Published: January 12, 2021 the perinatal and obstetric factors related to the development of the attention
deficit hyperactivity disorder in childhood. Method: An online review of Eng-
Copyright © 2021 by author(s) and
lish language studies published from 2002 to 2020, using the Embase, Psy-
Scientific Research Publishing Inc.
This work is licensed under the Creative chINFO, PubMed and Google Scholar databases. From 1100 studies only 17
Commons Attribution International were included in the review since they met the inclusion criteria. Conclu-
License (CC BY 4.0). sions: The results of the review showed that apart from heredity and genetic
http://creativecommons.org/licenses/by/4.0/
factors, various conditions in pregnancy or the mother’s way of life in preg-
Open Access
nancy, adverse conditions in labor and infancy can contribute on their own
or in combination to the development of the attention deficit hyperactivity
disorder in childhood. Obstetric vigilance to detect risk factors in pregnancy
in combination with the prevention of obstetric complications is the key in
preventing attention deficit hyperactivity disorder.

Keywords
Attention Deficit Hyperactivity Disorder, Perinatal Factors, Postnatal Factors

1. Definition, Symptoms and Diagnosis of Attention Deficit

Hyperactivity Disorder
Attention deficit hyperactivity disorder (ADHD) is “one of the best-researched

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E. Antoniou et al.

disorders in medicine, and the overall data on its validity are far more compel-
ling than for most mental disorders and even for many medical conditions” [1].
Despite the on-going research, there is a lack of knowledge about the causes of
ADHD. ADHD is a chronic disorder, manifested in childhood and affecting
about 5% of the children and adolescents globally, irrespective of their country
of living [2] (Figure 1) and lasting until early adulthood in about 65% - 75% of
the cases [3].
In terms of gender, boys are more often affected by the disorder compared to
girls, 34:1, and although the family’s socioeconomic class does not seem to be a
burdening factor, it seems that children with ADHD mainly come from dishar-
monious families with parental psychiatric pathology or alcoholism [4]. ADHD
symptoms are responsible for severe social dysfunction, such as low educational
level because of school-leaving and family life problems, up to low self-esteem
and decreased emotional growth [5]. People with ADHD also run a significant
risk of simultaneous or future mental comorbidity, such as behavior disorder,
stress and mood disorders, antisocial conduct and substance abuse [3].
ADHD is diagnosed using reliable clinical criteria. In 2013 the Diagnostic and
Statistical Manual of Mental Disorders (DSM)-5th edition (DSM-5) was revised
to increase the reliability of diagnosis. The key characteristic of the disorder is a
combination of inattention, hyperactivity and impulsivity and is essential for the
diagnosis [6]. The ADHD definition has developed since 1900 from “hyperki-
netic disease” to minimal brain dysfunction (DSM-I) in the 1970s. The disorder
was renamed as “hyperactive reaction” of childhood (DSM-II); then as “deficit
disorder with or without hyperactivity” (DSM-III), as “deficit disorder” and cur-
rently as ADHD (DSM-V). Maintaining the 18 key ADHD symptoms in DSM-V
reflects the significance of the definition of (ADHD) DSHD-IV and has endured
over time [7].
Many studies have shown that ADHD-related symptoms remain up to adult-
hood in half of the sample cases [8]. Hyperactivity/impulsivity symptoms in
children may be reduced over time, but inattention symptoms seem to remain to
a high degree in adulthood [3] [9] [10]. A key phenomenon also of ADHD is
comorbidity. ADHD usually co-exists with specific and global developmental

Figure 1. Global prevalence of ADHD in

children and adolescents.

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 E. Antoniou et al.

and learning problems, including autistic spectrum disorders (ASDs), speech

and language difficulties, motor coordination and reading difficulties and a range
of mental disorders, such as conduct and mood problems [11] [12] [13] [14] and
IQ [15].

2. Causes of ADHD
ADHD, as other common medical and mental disorders, is affected by multiple
genes, non-hereditary factors and their interaction [16]. The genetic factors can
indirectly interact with environmental factors and modify the sensitivity to en-
vironmental risks (gene-environment interaction) [16]. Hereditary contribution
also plays a big role in ADHD. Various studies have found steadily higher
ADHD percentages (up to eight times) in parents and siblings of affected people
compared to relatives of non-affected controls [17].
Various researchers have found that there is dopamine deficit in ADHD
children and that its antagonist, methylphenidate, can therapeutically help. Brain
stimulation and attention is controlled by two neurotransmitters, dopamine and
noradrenalin, and it has been found that there is a correlation between the dis-
order and dopamine transfer (DΑΤ 1) polymorphisms with dopamine receptors
(DRD4, DRD5) and the serotonin transporter (5HTT) [18]. The interaction of
dopamine and glutamic acid, released in the corpus striatum, has been blamed
for the cognitive function of these people, while the serotonin/SNAP-25 protein
disorder seems to result in the hyperactivity symptom in ADHD patients [19].

3. Gender Differences in ADHD

Boys and girls have both been shown to be affected by the attention deficit
hyperactivity disorder (ADHD), although the literature supports a higher degree
of prevalence in boys [20] [21]. Girls with ADHD are not usually hyperactive but
tend to show an attention deficit as part of the disorder. The usual ADHD stan-
dard is expressed by a hyperactive boy. Girls with ADHD, though, who have not
been diagnosed and treated, run the risk of low self-esteem and problems, such
as depression and stress. They are more prone to become pregnant and start
smoking before they become adults [22]. On the other hand, delinquent beha-
viors are more frequent in males who are more often imprisoned. The available
data show, however, that treatments are more possible to be equally effective in
boys and girls [20].

4. Perinatal Factors of ADHD

A total of 1.100 articles were identified, out of which 17 research studies were in-
cluded in the study (Figure 2). The Embase, PsychINFO, PubMed and Google
Scholar databases were used for this review. We conducted a review of different
articles on perinatal causes of ADHD between the time period of 2002 to 2020
and the articles were all in English. Therefore, systematic reviews and meta-analyses
were excluded from the study. The keywords used were: “ADHD and Perinatal

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E. Antoniou et al.

Figure 2. Flow chart.

factors”, “ADHD and alcohol during pregnancy”, “ADHD and Drugs during
pregnancy”, “ADHD and smoking during pregnancy”, “ADHD and maternal
stress during pregnancy”, “ADHD and preterm birth”, “ADHD and low Apgar
score”, “ADHD and cesarean section”, “ADHD and low birth weight”.

4.1. Maternal Smoking, Drug and Alcohol Use and Stress in

Pregnancy
There is strong evidence supporting hereditary contribution to ADHD, although
non-hereditary factors, including environmental causes (mother smoking, alco-
hol, drug abuse and stress in pregnancy, low weight at birth, low Apgar score,
abnormal presentation, cesarean section), are implicated in its etiology. The re-
sults of this study show that apart from the gene phenotype and the hereditary
psychopathological background [23], the contribution of environmental va-
riables to ADHD must not be ignored (Table 1).

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 E. Antoniou et al.

Table 1. Studies included in the review.

Author/Year Design N Population Country Outcome (ADHD)

Association of prenatal and perinatal

factors, such as metabolic disorder in
1) Roigé-Castellví, Cross-sectional Children from General the pregnancy, difficulties in childbirth
6720 Spain
J. (2020) [23] study population and specific family phenotype
(expression of the genetic risk)
with childhood ADHD

2) Markussen Singletons born from 60% increased risk of hyperactivity

Follow-up
Linnet, K. (2006) 1355 mothers who smoking Denmark in children born from mothers
study
[25] during pregnancy who smoke

Children born from

3) Gustavson, K. Smoking during pregnancy is an
Cohort study N > 100,000 mothers who smoking Norway
(2017) [29] unmeasured confounding
during pregnancy

Parents of 7 to 12 year-old A higher frequency of substance abuse,

4) Parvaresh, N. Case-control children who referred to smoking, and anxiety disorders was
200 Iran
(2016) [31] study child and adolescent observed among parents of children
psychiatric clinics suffering from ADHD

Children born from Prenatal exposure to stress was

5) Rodriguez, A. mothers who smoking independently associated with later
Cohort study 414 Sweden
(2005) [33] and who had stress symptoms of ADHD. Results are
during pregnancy less clear for smoking

Children born from Stressful life events are associated

6) Ronald, A.
Cohort study 2900 mothers who had stress UK with autistic traits as well as ADHD
(2011) [34]
during pregnancy behaviors independently

Binge drinking at any time during

Children born from pregnancy or low-moderate alcohol
7) Pagnin, D.
Cohort study 449 mothers who used alcohol Brazil consumption in all trimesters of
(2019) [40]
during pregnancy pregnancy was associated with fivefold
increased odds of child ADHD

ADHD may be an additional

deleterious outcome associated with
Children born from
prenatal exposure to alcohol
8) Mick, E. (2002) Case-control mothers who used alcohol,
522 USA independently of the association
[43] study drugs and smoking during
between prenatal exposure to nicotine
pregnancy
and smoke products and other familial
risk factors for the disorder

Low paternal education, prenatal

9) Sagiv, S. (2013) Children who exposed to smoking, prenatal illicit drug use,
Cohort study 604 USA
[44] perinatal risk factors maternal depression, were associated
with greater risk for ADHD

Children born from Possibly causal association with

10) Eilertsen, E. mothers who measured maternal alcohol use during pregnancy,
Cohort study 114,247 Norway
(2017) [46] from using alcohol during but no such effect was observed for
pregnancy clinical ADHD diagnosis

The Intensity of depression and trait

11) Soltanifar, A. Mothers of children who
Cohort study 50 Iran anxiety in mothers of ADHD children
(2009) [48] have ADHD
are more than the control group

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E. Antoniou et al.

The research of Langley K. et al., determines the double increase of ADHD

risk for people whose mothers smoke in pregnancy, although the mechanisms
for the operation of such risks are unknown [24]. Similar conclusions were
drawn in the Markussen K. et al., cohort that studied the relationship of intra-
uterine exposure to smoke and behaviour disorders in school-age children [25]
[26]. A number of biological reasonable mechanisms from correlative findings in
studies in people have been experimentally tested in animals. Animal studies
based on multiple methods and use of multiple species demonstrate that the
prenatal exposure to nicotine results in hyperactivity of their descendants [27]
[28]. Other studies have not found a causal link between the mother smoking
and ADHD; this is a confusing factor, as women under stress are extremely
possible to smoke and, as a result of smoking, they give birth to a low-weight
baby. Furthermore, a percentage of women may have been smoking at a differ-
ent level in their pregnancy [29] [30] or may have at the same time abused sub-
stances [31]. Furthermore, young women of low social and educational level may
be smokers, which may decrease the value of generalizing the findings [32].
In general lines, the results for smoking are less clear, but the results correlat-
ing perinatal stress with ADHD are more specific [33]. Many studies have shown
that high stress levels in pregnancy are a risk factor both for autism and ADHD
[34]. Stress is also a risk factor for the development of other mental childhood
disorders, such as cognitive and language problems, even schizophrenia [35].
Family problems [36], stressful life events [37] and natural disasters [38] in
pregnancy have been proven to be related to an increased risk of mental disord-
ers in childhood.
On the other hand, alcohol is a known teratogenic substance, strengthening
the migration of nerve cells, and is suspected to be involved in behavioral dis-
orders in childhood. Furthermore, it intervenes in the production of neuroen-
docrine hormones, which can disturb brain development [39]. More specifically,
the mothers of ADHD children are more possible to have consumed alcohol in
their pregnancy trimesters [40] [41]. Prenatal exposure to heavy alcohol con-
sumption by the mother can cause the fetal alcohol syndrome, including hyper-
activity symptoms, and is a risk factor for the development of psychopathology
in childhood [26] [42] [43]. The study of Biederman, M., et al. mentions that
prenatal alcohol exposure can be a significant risk factor, if there is excessive
consumption in pregnancy [43], while the study of Sagiv, K. et al., did not show
strong correlation between alcohol consumption in pregnancy and ADHD in
childhood [44]. Of course, in some studies, the correlation between alcohol con-
sumption in pregnancy and ADHD symptoms in childhood seems to get con-
fused by family factors and heredity [45] [46]. Generally, however, the harmful
consequences of the alcohol in a developing fetus are related to many cases of
neurodevelopmental disorders and, consequently, alcohol consumption in preg-
nancy must be recognized as a global public health problem [40].
An equally important factor for ADHD seems to be drug abuse by the mother

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 E. Antoniou et al.

in pregnancy. The study of Farokhzadi et al., showed that the drug abuse fre-
quency by parents of ADHD children compared to parents of normal children was
21.0% higher, with poorer levels of skills and significant psychopathology [47].
It is worth noting that stress, depression, and substance abuse (alcohol, smok-
ing, drugs) affect the relationship of parents-ADHD children and harmfully im-
pact their upbringing standards. For example, stressed parents are more con-
cerned about accidents and, therefore, show higher degree of vigilance and less
persistence in their children’s education. In these cases, the repercussions in the
upbringing of ADHD children are negative. Furthermore, depressed parents are
more possible to be obsessive about the inabilities and mistakes made by child-
ren with ADHD. Stability and monitoring of behaviour are the principles of pa-
rental care and in cases of parental addiction, depression or other mental dis-
orders, the parents are not able to comply with these principles and, thus, either
generate or deteriorate behaviour problems [48].

4.2. Cesarean Section, Low Birth Weight, Preterm Birth and

Apgar Score
Delivery complications have also been implicated for ADHD (Table 2). There
are studies correlating the low Apgar score at birth with the development of
ADHD in these children [49]. The Apgar score is widely used to assess the phys-
ical status of a baby immediately after birth and can be considered a perinatal
complication indicator; it is based on a 5-point check (skin color, heart rate, ref-
lexes, muscle tone and breathing effort) [50]. Apgar scores are usually checked at
minute 1, minutes 5 and 10 and when ranging from 7 to 10 are considered nor-
mal [49]. Low Apgar scores at minutes 1 and 5, have been related to an increased
risk for neurological and psychiatric disorders, such as autism spectrum disorder
[51] and ADHD [52] [53]. Furthermore, the results of the study of Grizenko N.,
et al., showed that low Apgar scores in minute 1 are related to an increased se-
verity of ADHD symptoms [50].
Breech presentation and perinatal conditions that can cause neonatal hypoxia
were found to be a risk factor for ADHD. According to Zhu, T., et al., this was
explained by the possible decreased movement of the fetus due to neurological
anomalies or by the delivery procedure that may be extremely difficult resulting
in neonatal hypoxia [54]. Neonatal hypoxia that may be due to normal child-
birth complications but also due to complications in the first two months of the
baby’s life (hospitalization, oxygen administration) [55] seem to contribute more
to ADHD in childhood. Therefore, the prevention of hypoxia in pregnancy and
delivery are of major importance to prevent ADHD in childhood. The findings
also show that particularly stressful conditions at the beginning of a person’s life
can be a cause of ADHD and these children must be followed up and be re-
checked in childhood.
The delivery method and, specifically, scheduled CS is interesting for the de-
velopment of ADHD in childhood and experts still try to explain this relationship

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E. Antoniou et al.

Table 2. Studies included in the review.

Author/Year Design N Population Country Outcome (ADHD)

Low 1-minute Apgar scores are

1) Grizenko, N. 2 groups of children with
Cohort study 452 Canada associated with a significant increase in
(2016) [49] and without ADHD
ADHD symptom severity

ADHD was significantly associated with

2) Gustafsson, P. Retrospective preterm birth < 32 weeks and Apgar
237 Children with ADHD Sweden
(2011) [52] study scores at 5 minutes below 7 were
significantly associated with ADHD

Children who had diagnosed Cesarean sections and perinatal

3) Sucksdorff, M. Population-based
10,409 with ADHD and a control Finland adversities leading to lower Apgar
(2018) [53] study
group scores increased the risk of ADHD

The children with ADHD had

4) Ben Amor Retrospective significantly higher rates of neonatal
70 Children with ADHD France
(2005) [55] study complications compared with their
unaffected siblings

Children. The sample was

5) Hatch, B. Longitudinal lower birth weight was associated
197 a part from a larger USA
(2014) [61] study with ADHD symptoms
longitudinal study

Children. Sample from

6) van Mil Higher birth weight was related to less
Cohort study 6015 a population based birth Holland
(2015) [62] attention problems
cohort

Prevalence of ADHD increases as

7) Perapoch, J. Children who born gestational age decreases, 12.7% for those
Cohort study 3744 Spain
(2019) [66] premature born ≤28 gw, compared to 3.2% for those
born after the 37 gw

[56]. Many reasons seem to exist leading to a scheduled operation, such as the
mother’s desire, disproportion, pathology of pregnancy or the mother’s mental
disorders [53] [57]. Scheduled cesarean delivery affect early childhood as it
changes the microbial colonization of the neonatal [58], and is related to many
illnesses, including autism [59]. Scheduled cesarean section also decreases the
possibility for successful breastfeeding [60]. The impact of anesthetic factors on
the brain of the newborn baby is unknown to date to a big degree [53].
A correlation of low birth weight and ADHD has been found and some stu-
dies show that children with low birth weight run a higher risk of developing a
series of neuropsychological deficits, many of which overlap with the ones found
in ADHD children [61]. More specifically, low birth weight (≤2500 g) has been
related to working memory, and cognitive flexibility tasks, which involve aspects
of executive functioning as well as, visuo-spatial reasoning, and motor control
[62]. Some studies, of course, correlated low birth weight with low IQ but not
with ADHD [63] while according to van Mil, N. et al., in 2015, the bigger the
birth weight, the fewer the ADHD symptoms. However, in children from obese
mothers (BMI > 30 kg/m2), high birth weight can increase the risk of attention
problems [64]. Furthermore, apart from low birth weight, prematurity has also

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 E. Antoniou et al.

been implicated for ADHD in school age [65]. Indeed, a recent study of Pera-
poch, J., et al., observed an increase in ADHD prevalence when the pregnancy age
decreases and ranges from 3.2% for the neonates born after week 37 of gestation
up to 12.7% for neonates born ≤28 weeks of gestation [66].

5. Discussion/Conclusions
According to the above results we come to the conclusion that the cesarean sec-
tion seems to play a role in the manifestation of ADHD. Also, cesarean section is
recommended when there are complications during delivery. Therefore, it is
possible that the fetus may have already been affected by cerebral hypoxia or
other causes and later in life and syndromes such as autism or ADHD may be-
come clinically evident. Furthermore, maternal conditions such as smoking,
drugs and alcohol use may affect fetal brain development intrauterine, as well as
birth weight and week of delivery and often lead to cesarean section. During va-
ginal delivery, part of the mother’s microbiome is transferred to the fetus and
stimulates its immune system. This procedure is disrupted at the cesarean sec-
tion with unknown consequences. Neonatal complications (included several
events occurring during the first 2 months of life) may be a risk factor with a
putative causal link to the development of ADHD. Although neonatal complica-
tions do not point to a single event that may lead to behavioral or cognitive
problems, they support that children with ADHD have a higher rate of stressful
events in early life. Therefore, except the specific family phenotype, the combi-
nation of these factors is interpreted by above results.
In conclusion, this study presents the correlation between prenatal factors,
such as maternal stress, difficult family conditions, smoking, alcohol consump-
tion and drug abuse, with ADHD. Furthermore, various factors that may occur
during or after labor, relating to CS, fetal hypoxia, low Apgar score, low birth
weight and prematurity, were correlated. Although the mother’s habits in preg-
nancy could, on their own or in combination result in ADHD in childhood, the
factors related to conditions during labor seem to have a strong correlation with
ADHD. Therefore, although the early detection of the specific disorder by men-
tal health experts plays a critical role in the progression of the disease, the timely
detection of perinatal conditions and the prevention of complications during
labor contribute to the prevention of the disorder. Furthermore, the decrease in
the number of unnecessary cesarean sections and the provision of information
for women about its complications, the frequent follow-up of children with low
birth weight, prematurity and neonatal hypoxia shall contribute to the timely
detection of the syndrome. Additionally, the thorough monitoring of women in
pregnancy and the timely detection of risk factors that may contribute to the
development of neuropsychiatric disorders in a child is of major importance for
the special monitoring of the pregnant woman. ADHD concerns a person before
birth, while prevention, diagnosis and treatment are related to a wide range of
sciences.

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E. Antoniou et al.

Conflicts of Interest
The authors declare no conflicts of interest regarding the publication of this pa-
per.

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