ADHD is the most prevalent and frequently studied psychiatric disorder in preterm/LBW populations. All but one (51) of the earliest studies using DSM-based questionnaires reported a significant excess of ADHD with prevalence rates ranging 16 to 19% and ORs of 2 to 3 in VLBW/ELBW children (41,42,52). More recent studies report prevalence estimates of 9 to 11% in VPT/VLBW (26,53) and 17 to 20% in EPT/ELBW children (26,27), indicating a GA-related gradient (26). The pooled relative risk (RR) for ADHD in VPT/VLBW survivors in six studies was 2.64 (95% CI, 1.85–3.78) (18) and a recent epidemiological study has reported an RR of 2.7 (95% CI, 1.8–4.1) in children born <34 wk (6).

Of the five diagnostic studies, four reported varying prevalence estimates ranging from 7 to 23% in LBW/VLBW children born in the 1980s (Table 2) (16,19,45,46). Increased risk has also been described in cohorts born in the 1990s: 11.5% prevalence in EPT children (Fig. 1) (47) and 17% in those with ELBW (43). Although these two studies used measures with different diagnostic accuracy, the ORs of 4.3 and 4.2, respectively, are remarkably similar. Thus, existing reports indicate a 2- to 3-fold increased risk for ADHD in VPT/VLBW children and a 4-fold increased risk in those born EPT/ELBW (Table 2).

Table 2: Studies reporting the prevalence of ADHD using DSM-based diagnostic criteria in preterm and LBW children Full size table

The correlates and comorbidities of ADHD in preterm children are indicative of a different clinical presentation than for children born at term. First, the male predominance in ADHD in the general population (44) is typically not observed in preterm cohorts (16,19,47). Second, the association with comorbid conduct disorders in the general population is lacking in preterm children; there is no significant increase in conduct disorders in preterm/LBW populations (16,41–43,45–47), and VPT/VLBW children with ADHD are less likely to have comorbid conduct disorders than term children with ADHD (19,42,47), Third, there appears to be a weaker association of ADHD with sociodemographic and family risk in preterm cohorts than in the general population (44), in that, there is a closer association between ADHD and medical variables than social factors (16,41,42,46,50,54).

Finally, VLBW/VPT birth appears to be associated with a greater risk for symptoms of inattention than hyperactivity/impulsivity. Using rating scales that differentiate these two dimensions, preterm children were found to have significantly higher mean scores than controls for inattention but not hyperactivity (16). In more recent studies of VPT, EPT, and ELBW children, there are markedly larger effect sizes for inattention compared with hyperactivity as rated by both parents and teachers (43,55). Parallel findings are reported in diagnostic studies using DSM-IV-based definitions (Table 2). In an early study, Botting et al. found higher rates of ADHD/inattentive (ADHD/I) compared with ADHD/hyperactive (ADHD/H) subtype disorders in VLBW children. In two more recent studies, the excess risk for ADHD in EPT/ELBW children was accounted for by a specific risk for ADHD/I and ADHD/H were not significantly increased in comparison with term children (43,47). We also observed that there was no significant increase in hyperkinetic disorders classified using International Classification of Diseases (ICD)-10 (56) criteria, in which features of hyperactivity are required for diagnosis (47). It thus seems preferable to use DSM-IV-TR (40) classifications in preterm children.

These converging strands of evidence are indicative of a different causative pathway for ADHD in preterm populations. This has led authors to suggest that VPT/VLBW children are susceptible to a “purer,” more biologically determined form of attention deficit associated with a neurological etiology (36,41). VPT/VLBW birth is associated with cognitive impairment and impaired brain growth, evidenced by structural abnormalities on MRI (11,57,58). A number of studies have provided evidence indicative of a mediating role of neurodevelopmental factors in the relationship between preterm birth and ADHD, with significant group differences being accounted for by the high prevalence of cognitive impairment in EPT/ELBW children (41,42,47). Significant independent associations between ADHD symptoms and indices of brain structure and maturation in preterm populations including head circumference, intraventricular hemorrhage, parenchymal lesions, and/or ventricular enlargement on neonatal cranial ultrasound and structural MRI at school-age are reported (45,50,59–61). Indredavik et al. (62) found that ADHD symptoms were associated with reduction in white matter volumes and thinning of the corpus callosum in VLBW adolescents after adjustment for sex and socioeconomic factors. The correlation between symptoms and white matter volume was due to a specific association with inattention scores. Skranes et al. (63) also found that inattention but not hyperactivity scores were associated with fractional anisotropy measurements of white matter in VLBW adolescents. They also found that ADHD was associated with lower fractional anisotropy values in six different anatomical areas and speculate that this may be indicative of disturbed white matter connectivity in extensive areas throughout the brain.

ADHD/I and other ADHD may be considered as separate disorders that are characterized by dissociable cognitive, behavioral, and neurobiological profiles with different patterns of comorbidities and responses to medication (64–66). In contrast to classical ADHD, children with ADHD/I can be considered as having a childhood-onset dysexecutive syndrome that is characterized by social difficulties related to shyness and withdrawal, internalizing problems, an absence of aggression/delinquent behavior, academic difficulties, and primary deficits in working memory and processing speed (67). This profile bears a striking resemblance to that associated with VPT birth (68–70). Hyperactivity in preterm survivors may be accounted for by poor general cognitive ability, but inattention may be a specific feature of development after preterm birth that is associated with specific executive deficits. This is supported by Nadeau et al. (71) who observed that general cognitive ability mediated the relationship between EPT birth and hyperactivity, whereas the relationship between EPT birth and inattention was mediated specifically by working memory.

In summary, in VPT/VLBW children, there is evidence of increased risk for the inattentive subtype of ADHD, itself associated with impairment in normal brain growth and maturation. Further research is needed to elucidate the etiology and clarify the profile of impairment associated with such deficits to improve identification, management, and treatment of ADHD in preterm populations.