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We searched Medline for the year 2000, using as key words fetal
alcohol syndrome (FAS), fetal alcohol spectrum disorder(s) (FASD),
and attention-deficit hyperactivity disorder (ADHD) in children.
We undertook a comprehensive review of the history of FAS, FASD,
and ADHD, with initial reference to the original descriptions of
these conditions, including early animal research in the case of
FAS.
FAS, partial fetal alcohol syndrome (PFAS), and alcohol-related
neurodevelopmental disorder (ARND) are part of FASD (1–3).
They are chronic neurodevelopmental and neuropsychiatric conditions
that have a significant and sustained impact on mental health service
providers and public health service providers. Recent estimates
have suggested that FASD has a prevalence of 1 in 100 individuals
(4).Through the lifespan, patients with FASD commonly present clinical
symptoms consistent with a diagnosis of ADHD, especially the inattention
subtype (as defined according to DSM-IV 314.00, 314.01) (5). The
ADHD is especially prevalent in childhood (6–9).
FASD and ADHD History
The teratogenic effects of alcohol on the developing fetus have
been recognized since 1968 (10). In 1973, Jones and Smith named
this effect “fetal alcohol syndrome” (11). Further studies
have confirmed this observation throughout the world (1,8,12–15).
ADHD was initially identified in Heinrich Hoffman’s 19th century
descriptions of “Fidgety Phil” (16). The DSM-IV describes
3 classifications of ADHD: ADHD, predominantly hyperactivity-impulsivity
subtype; ADHD, predominantly inattention subtype; and ADHD, combined
subtype (5,17–19).
FASD and ADHD Link
The proposed link between FASD and ADHD is based on the premise
that the teratogenic effects of prenatal alcohol exposure disturb
the neurochemical and structural environment of the developing fetal
brain. Affected infants can have difficulty with mood and state
regulation and self-soothing, as well as hypersensitivity to sensory
stimuli, irritability, and hyperactivity. Infants exposed to prenatal
alcohol can thus present a primary regulatory disorder from birth,
with a difficult-to-settle or slow-to-warm temperament, followed
by early-onset ADHD (20,21). Some of these clinical symptoms were
initially shown in the Seattle Longitudinal Prospective Study, which
described neonates at days 1 and 2. The study, which began in 1974,
described infant problems in state regulation and habituation, as
well as poor suck and long latency to suck (9,22).
In this review, we will consider 5 different hypotheses regarding
the link between FASD and ADHD. These hypotheses are as follows:
1. The prevalence of ADHD in children is high (3% to 11%), irrespective
of etiology, and there may be no etiologic relation between FASD
and ADHD (16,18,23).
2. Adults with ADHD are more likely to drink. As a result, pregnant
adult women pass ADHD to their infants through genetic transmission
(23–29).
3. In the developing fetus, there is a common etiologic cause of
both FASD with ADHD symptoms and ADHD without FASD. This could be
a dysregulation in the dopamine neurotransmitter system (23,30,31).
4. ADHD resulting from prenatal alcohol exposure is an acquired
form related to alcohol’s effect on the developing dopamine
neurotransmitter system, particularly in the D1 mesolimbic area
(8,13,30–34).
5. ADHD associated with FASD is a particular clinical subtype of
ADHD (6,35–38).
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Evidence to Support Hypotheses 1 and 2: The Lack of an Etiologic
Relation
With regard to the first hypothesis, some studies indicate that
ADHD has become the most common developmental disorder of childhood,
affecting 3% to 11% of children. Often, it continues into adulthood
(16–18,39). It is not a unitary condition, and overlapping
symptoms are often present (for example, conduct disorder, mood
disorder, or anxiety disorder) (40,41). Prevalence of the comorbid
issues has been variously estimated at 50% for conduct or oppositional
disorder, 25% for anxiety, 25% to 30% for depression, and 25% for
learning disorder.
With regard to the hypothesis that ADHD is genetically transmitted,
genetic studies have revealed an association between the dopamine
transporter gene (DAT) and the hyperactivity-impulsivity subtype
of ADHD and, similarly, between the dopamine D4 receptor gene and
the inattention subtype of ADHD (24–28,42).
Evidence to Support Hypotheses 3 and 4: Neurochemistry Changes in
ADHD and FASD
The presence of these changes supports the hypothesis that there
is a common etiologic cause of FASD with ADHD and ADHD without FASD.
It also supports the hypothesis that ADHD resulting from prenatal
alcohol exposure is an acquired form primarily related to alcohol’s
effect on the developing dopamine and noradrenergic neurotransmitter
systems.
The 2 main hypotheses on the neurochemistry of ADHD are as follows:
- The condition is related to a dysregulation in the frontal-nigrostriatal
dopamine system that manifests itself as varying states of arousal
(43).
- The condition is caused by a dysregulation of the noradrenergic
system (norepinephrine) (16,44). Numerous animal and human studies
involving various body fluids (for example, urine, blood, and
cerebrospinal fluid) have implicated catecholamine abnormalities,
but results have been inconsistent (45).
The neurochemistry of FASD has been informed by 25 years of animal
research. Deficits have been found in most systems, including the
dopaminergic, noradrenergic, serotonergic, cholinergic, glutamatergic,
GABAergic, and histaminergic systems (13,30,31,46–50). Deficits
in the dopaminergic and noradrenergic systems likely relate to the
ADHD symptoms seen in animals with prenatal alcohol exposure (13,31).
The years of animal and human research have demonstrated a group
of symptoms (for example, increased activity, exploration, and reactivity,
as well as decreased attention, inhibition deficits, and impaired
habituation), all of which are consistent with ADHD symptomatology
and linked to dopamine and noradrenaline neurotransmitter disturbance
(8,13,30,31, 51,52). Rat research has shown that the D1 receptors
of the mesolimbic dopamine system are more affected by alcohol exposure
than is the nigrostriatal or tegmental dopamine system (30).
Evidence to Support Hypothesis 5: Behavioural Phenotype and Psychostimulant
Response
Some studies support the hypothesis that ADHD associated with FASD
is a particular clinical subtype of ADHD with an earlier onset,
different clinical and neuropsychological presentation, and probable
differential medication response. FAE or ARND has been described
by some authors as a possible subtype of ADHD (6,35–38). The
Seattle Longitudinal Prospective Study showed possible evidence
of an infant regulatory disorder and temperamental disturbance predating
the ADHD diagnosis (1,12,20,21).
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