Review Paper

Clinical Implications of a Link Between Fetal Alcohol Spectrum Disorder and Attention-Deficit Hyperactivity Disorder Kieran D O’Malley, MB, DABPN(P)1, Jo Nanson, PhD2 Objective: To provide an overview of the animal and human research literature on the link between fetal alcohol spectrum disorder ( FASD) and attention-deficit hyperactivity disorder (ADHD). Method: We conducted a comprehensive literature review that addressed the history of, and current research on, fetal alcohol syndrome (FAS) and FASD, as well as that on ADHD in children. Results: In animal and human research, there is emerging clinical, neuropsychological, and neurochemical evidence of a link between FASD and ADHD. Conclusions: The evidence of the link between these 2 conditions has implications for clinical management. The clinical quality of ADHD in children with FASD often differs from that of children without FASD. For children with FASD, ADHD is more likely to be the earlier-onset, inattention subtype, with comorbid developmental, psychiatric, and medical conditions. Children with FASD are commonly not mentally retarded but present complex learning disabilities, especially a mixed receptive-expressive language disorder with deficits in social cognition and communication (reminiscent of sensory aphasia and apraxia), working memory problems, and frequently, a mathematics disorder. Comorbid psychiatric conditions include anxiety, mood, conduct, or explosive disorders. As well, cardiac, renal, or skeletal problems are more likely to be present. Because these children have a disturbance in brain neurochemistry, or even brain structure (that is, in the corpus callosum), their response to standard psychostimulant medication can be quite unpredictable. (Can J Psychiatry 2002;47;349–354) Clinical Implications • One implication of a link between fetal alcohol spectrum disorder (FASD) and attention-deficit hyperactivity disorder (ADHD) is that the ADHD is an earlier-onset, inattention subtype, with comorbid developmental, psychiatric, and medical conditions. • There may also be a differential response to standard psychostimulants. • Appropriate interventions can decrease the occurrence of well-described secondary disabilities that impede lifelong functioning. Limitations • More research is needed on the infant presentation of FASD that predates early-onset ADHD. This should be coupled with study of the FASD attachment profile.

Key Words: fetal alcohol spectrum disorder, FASD, attention-deficit hyperactivity disorder, ADHD

W

e 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 W Can J Psychiatry, Vol 47, No 4, May 2002

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 alcoholrelated neurodevelopmental disorder (ARND) are part of FASD (1–3). They are chronic neurodevelopmental and neuropsychiatric conditions that have a significant and sustained

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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. This could be a dysregulation in the dopamine neurotransmitter system (23,30,31).

FASD and ADHD History

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.

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 in at ten tion sub type; and ADHD, com bined sub type (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-tosettle 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 350

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).

With regard to the hypothesis that ADHD is genetically transmitted, genetic studies have revealed an association between the dopamine transporter gene (DAT) and the hyperactivityimpulsivity 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 frontalnigrostriatal dopamine system that manifests itself as varying states of arousal (43). • The condition is caused by a dysregulation of the nora-

drenergic 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 W Can J Psychiatry, Vol 47, No 4, May 2002

Clinical Implications of a Link Between Fetal Alcohol Spectrum Disorder and Attention-Deficit Hyperactivity Disorder

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). Many clinical descriptions illustrate the natural history of prenatal-alcohol central nervous system (CNS) dysfunction and highlight the prevalence of inattentional-hyperactive and impulsive symptomatology (22,53–55). Clinical features of ADHD with memory and execu tive func tion defi cits per sist through the life span. (2,7,9,54). Animal studies on rats and mice prenatally exposed to alcohol have shown that physical hyperactivity tends to diminish with increasing age and to be worse in males than in females, which appears to parallel the situation in humans with prenatal alcohol exposure (51,56–58). Coles has analyzed the Continuous Performance Task (CPT), as well as a 4-factor model of attention developed by Mirsky, and has reported a qualitative difference in patients with FAS and ADHD (59). Her results suggest that patients with ADHD have more significant problems in the “focus” and “sustain” factors, whereas patients with FAS have more problems with the “encode” and “shift” factors (60). Numerous studies have demonstrated the complex learning disability that accompanies ADHD symptoms, including problems in working memory, executive function, and language (2,5,8,9,13,15,22,35, 53–55,61). Animal researchers have demonstrated that animals prenatally exposed to alcohol tend to show an exaggerated response to psychostimulants (32,33,56) a medication response influenced by age, sex, and drug dosage (30). Pychostimulants have been used to treat patients with developmental disability, mental retardation, and ADHD. Controlled efficacy studies W Can J Psychiatry, Vol 47, No 4, May 2002

have docu mented their bene fit (13,62–68). How ever, O’Malley and Hagerman recently reviewed the action of the stimulants and their use in FAS, PFAS, ARND, and mental retardation (31). Clinical response to stimulants varied: in Denver, patients with ARND had an 80% response rate, whereas patients with FAS had a 48% response rate (13,31,69). In the University of Washington Secondary Disabilities Study, 32% of 415 patients with FAS or Fetal Alcohol Effects (FAE) or ARND were given methylphenidate for ADHD and had a response rate of 47% (7,31). A retrospective case series study undertaken by O’Malley and colleagues found a higher response rate to dextroamphetamine (79%) than to methylphenidate (22%) in 30 children and adolescents with FAS, PFAS, or FAE (ARND) who were followed by 3 psychiatrists in Canada and the US (70). Only 2 controlled studies have been published regarding psychostimulant intervention for ADHD symptomatology in patients with FASD (71,72). Synder and colleagues studied 11 children who were known positive responders to stimulants. They analysed 3 different types of psychostimulant (methylphenidate, dextroamphetamine, and pemoline). The study used short and long acting preparations with different drug dosages on a mg-per-kg basis. Their results showed no significant effect on sustained attention but, as expected, significant effects on parent rating scales (72). A study by Oesterheld analyzed 4 Native American patients. This study used a randomized double-blind crossover design and lasted only 5 days. It employed 2 placebos and a fixed dosage of shortacting methylphenidate (71). As measured daily, using the Conners’ Parent Rating Scales and the Conners’ Teacher Rating Scales, methylphenidate significantly improved scores on the Hyperactivity Index of both measures. However, scores were not improved on the Daydreaming-Attention Index of the Conners’ Teacher Rating Scale. Generally, patients (including those with FASD) who have neurochemical or structural changes in the CNS are often overly sensitive to the effects and side effects of medication (13,31,73–75). Response to psychostimulants may improve with age. Thus, a negative response may occur in a child under the age of 5 years, but a subsequent positive response may be seen when the child is 6 or 7 years of age (20,31,69). There may also be ethnic differences in clinical response to stimulants, and some clinicians have suggested that methylphenidate should not be used to treat the ADHD symptoms of Native American children with FASD, because it possibly lacks effectiveness and may retard growth (36,71). Studies have also indicated that attention should be given to possible medical complications, called alcohol-related birth defects (ARBD), that may occur in individuals with FASD. These include cardiac, renal, eye, or skeletal problems (3,13–15,31). (See Table 1.) 351

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Table 1 Alcohol-related birth defects (ARBD): Congenital anomalies, including malformations and dysplasias Cardiac

Atrial septal defects Ventricular septal defects Aberrant great vessels Tetralogy of Fallot

Skeletal

Hypoplastic nails Shortened fifth digits Radioulnar synstosis Flexion contractures Camptodactyly Clinodactyly Pectus excavatum and carinatum Klippel-Fell syndrome Hemivertebrae Scoliosis

Renal

Aplastic, dysplastic, hypoplastic kidneys Horseshoe kidneys Ureteral duplications Hydronephrosis

Ocular

Strabismus Refractive problems secondary to small globes

Auditory

Conductive hearing loss Neurosensory hearing loss

Other

Virtually every malformation has been described in some patient with fetal alcohol syndrome. The etiologic specificity of most of these anomalies to alcohol teratogenesis remains uncertain

Institute of Medicine. Fetal alcohol syndrome: diagnosis, epidemiology, prevention, and treatment. Washington (DC): National Academy press; 1996 (84).

Discussion It is important to remember that there may be no link between FASD and ADHD, as is suggested by studies supporting hypotheses 1 and 2. ADHD is a common condition, and adults with ADHD are more likely to drink and thereby pass the disorder on to their infants through genetic transmission. Nevertheless, the early onset, CNS dysfunction, complex learning disability, atypical medication response, and complicated psychiatric and medical comorbidity have many implications for management that distinguish children with FASD and ADHD from children with ADHD alone. The implications of this possible link between FASD and ADHD have some practical consequences for clinical management. Patients often present with early-onset ADHD resulting from prenatal brain damage, and their reactions to medication are unpredictable. Thus, medication may sometimes increase a patient’s impulsivity or aggressiveness, and 352

an increase in the dosage may actually worsen the clinical situation, rather than alleviating it (31,34,75). Stimulant medication for children with FASD and ADHD should be considered as part of a multimodal treatment array. Ideally, management will include various treatment modalities, such as sensory integration, language therapy, special schooling, nonverbal play therapy, medication therapy, parent education, and supportive family therapy (32–34,70,75,76). Multimodal treatment to manage childhood ADHD has been recommended by the MTA Cooperative Group and the American Academy of Pediatrics (77,78). One study has indicated that it is unwise to use stimulants to help children cope with an unsafe environment, because ADHD high arousal-vigilance may have a protective role for the child in this environment. Therefore, removal of the ADHD symptoms may potentially decrease the child’s wariness and so increase the risk of abuse (75). The clinical presentation of ADHD in children with FASD is commonly seen with such comorbid developmental, psychiatric, and medical conditions. The complex learning disability in children with FASD can include an unrecognized mixed receptive-expressive language disorder that affects their social cognition and social communication (5,61). Children with FASD and ADHD are commonly quite talkative, and their lack of cognitive understanding, with inappropriate answers, can frequently be misdiagnosed as an oppositional defiant disorder. Commonly, the child will also show problems in working memory. A mathematics disorder is frequently seen, which may underpin an executive-function deficit in deductive reasoning. Thus, children with FASD often do not link cause and ef fect or re spond to stan dard behaviouralmanagement techniques. Judgement and self-awareness are also suspect, not just in childhood but throughout the lifespan (2,5,7,8,75). Morphological changes in the corpus callosum have been tied to the FASD complex learning disability (3). The psychiatric comorbid disorders include; anxiety disorder (with panic attacks), mood disorder or affective instability, conduct disorder, psychotic disorder, and intermittent explosive disorder. Finally, comorbid medical conditions such as cardiac, renal, eye, or skeletal problems are often present and warrant specific interventions (1,2,5,7,8,10,11,13–15,75). Sometimes as well, there may be a complex partial or absence seizure disorder (13,31). Dextroamphetamine may be the more effective first-line stimulant when treating ADHD associated with FASD (31,70). This hypothesis is consistent with the animal work of Hannigan and Randall (30), which demonstrated the impact of prenatal alcohol exposure on the D1 receptors of the mesolimbic dopamine system—the area where dextroamphretamine has been shown to act (15,79). A negative response to methylphenidate has been reported in animals and humans with W Can J Psychiatry, Vol 47, No 4, May 2002

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ADHD and a history of prenatal alcohol exposure, which suggests that the frontal-nigrostriatal dopamine pathway may not be the mechanism involved in patients with FASD and comorbid ADHD (16,31–33,70,80–82). FASD is a chronic neurodevelopmental and neuropsychiatric disorder, and proper treatment of FASD with ADHD symptomatology offers an opportunity to decrease its documented destructive secondary disabilities (2,5,7,75,83).

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Manuscript received May 2001, revised, and accepted February 2002. 1 Formerly, Psychiatric Consultant, Edmonton FAS clinic, Glenrose Hospital, Edmonton, Alberta; now, Acting Assistant Professor, Department of Psychiatry and Behavioral Sciences, Fetal Alcohol and Drug Unit and Henry M Jackson School of International Studies, University of Washington, Seattle, Washington. 2 Associate Professor, Department of Psychology, University of Saskatoon, Saskatoon, Saskatchewan. Address for correspondence: Dr KD O’Malley, University of Washington, Department of Psychiatry and Behavioral Sciences, Fetal Alcohol and Drug Unit, Suite 309, 180 Nickerson Street, Seattle, WA 98109 e mail: kieranom @u.washington.edu

Résumé : Implications cliniques d’un lien entre les effets de l’alcool sur le foetus et le trouble d’hyperactivité avec déficit de l’attention Objectif : Offrir un aperçu de la documentation sur la recherche animale et humaine portant sur le lien entre les effets de l’alcool sur le foetus (EAF) et le trouble d’hyperactivité avec déficit de l’attention (THADA). Méthode : Nous avons mené une revue exhaustive de la documentation abordant les archives et la recherche actuelle sur le syndrome d’alcoolisme foetal (SAF) et les EAF ainsi que sur le THADA chez les enfants. Résultats : Dans la recherche animale et humaine, des preuves cliniques, neuropsychologiques et neurochimiques d’un lien entre les EAF et le THADA ressortent. . Conclusions : La preuve d’un lien entre ces deux affections a des implications sur la prise en charge clinique. La qualité clinique du THADA chez les enfants présentant des EAF diffère souvent de celle des enfants qui n’ont pas d’EAF. Chez les enfants qui ont des EAF, le THADA est plus susceptible d’être du sous-type d’inattention et d’apparition précoce, avec des affections développementales, psychiatriques et médicales comorbides. Les enfants ayant des EAF ne sont habituellement pas déficients intellectuels, mais ils présentent des difficultés d’apprentissage complexes, surtout un trouble mixte du langage réceptif-expressif avec déficits de la cognition sociale et de la communication (qui évoque l’aphasie sensorielle et l’apraxie), des problèmes de mémoire de travail et souvent, un trouble mathématique. Les affections psychiatriques comorbides comprennent l’anxiété, l’humeur, la conduite ou des troubles explosifs. De même, la présence de problèmes cardiaques, rénaux et osseux est plus probable. Parce que ces enfants ont une perturbation de la neurochimie et même de la structure du cerveau (c’est-à-dire, le corps calleux), leur réaction aux psychostimulants réguliers est assez imprévisible. 354

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