Ischemic-hypoxic perinatal conditions and attention deficit hyperactivity disorder

Attention deficit hyperactivity disorder (ADHD) is a common psychiatric disorder in the nation affecting 8%-13% of all school-aged children. ADHD diagnoses have reached epidemic proportions in the U.S. with an estimated annual cost of $36 to $52.4 billion, in 2005 dollars. The etiology of ADHD is largely unknown. Emerging evidence suggests that Ischemic-hypoxic conditions (IHC) have profound effects on fetal brain development that are not apparent in infants. Given that rates of ADHD are increasing and IHC increases the risk of fetal brain injury, we hypothesize that IHCs are important and independent risk factor for ADHD. In this nested case-control study, we evaluated the risk of ADHD in a cohort of children aged 5-11 years, born at ≥28 weeks of gestation, and cared for at Kaiser Permanente Southern California (KPSC) between 1995-2010 (n =308,634; 4.3% had ADHD). Electronic clinical, laboratory, and pharmacy records were obtained for these children and their mothers. Cases were children with a clinical diagnosis of ADHD (ICD-9 codes 314.x) and positive for at least 2 ADHD prescriptions during the follow-up period. For each case, five controls were matched to cases on child age at diagnosis. IHC was defined based on ICD-9 codes. Compared to control children, case children were more likely to be male and of white or black race/ethnicity. Mothers of case children were more likely to be older, have ≥12 years education, history of smoking and psychosocial disorders during pregnancy. In contrast to control children, case children were more likely (odds ratio [OR] 1.16, 95% confidence interval [CI] 1.11, 1.21) to experience IHC. Stratified analyses by gestational age revealed that case children than controls were more likely to experience IHC at 28-33 (OR 1.5, 95% CI 1.2, 2.0), 34-36 (OR 1.2, 95% CI 1.1, 1.5), and 37-42 (OR 1.1, 95% CI 1.0, 1.2) weeks of gestation. IHC was associated with increased odds of ADHD across all race/ethnicity groups. These findings suggest that IHC is an independent risk factor for ADHD, especially in preterm birth. This suggests that events in pregnancy contribute to the etiology of this condition over and above the well-known familial/genetic influences.