Interpregnancy Intervals and ADHD with and without Comorbid Autism Spectrum Disorders: A Finnish Birth Cohort Study

Background: Short or long interpregnancy interval (IPI) has been consistently associated with increased risk of autism spectrum disorders (ASD). Attention deficit hyperactivity disorder (ADHD), like ASD, is a neurodevelopmental disorder with a complex etiology including the influence of the prenatal environment. There is substantial co-morbidity between ASD and ADHD. However, whether there is a relationship between IPI and ADHD, and whether this varies by the presence or absence of co-morbid ASD, has been largely unexplored.

Objectives: To determine whether the IPI is associated with the risk of offspring ADHD in subsequent births, and to assess whether this varies by co-morbidity with ASD.

Methods: A case-control study was nested in a national cohort of all births in Finland. All persons born in Finland between 1991-2005 and diagnosed with ADHD (ICD-9 (314x) or ICD-10 (F90.x)) from 1995-2011 were identified using the Finnish Hospital Discharge Register. Each case was matched to 4 controls based on sex, date of birth, and place of birth. A total of 9564 cases and 34,479 matched controls were included in the analyses. IPI was calculated as the time interval between sibling birth dates minus the gestational age of the second sibling. ASD diagnosis was based on ICD-10 codes F84.0, F84.5, or F84.8-F84.9 in the FHDR. Conditional logistic regression was used to estimate the association between IPI and ADHD, adjusting for potential confounders. Models were stratified by the presence or absence of ASD in the case to assess heterogeneity by ASD comorbidity.

Results: Relative to births with an IPI of 24 to 59 months, those with the shortest IPI (<6 months) had an increased risk of ADHD (adjusted odds ratio [aOR (95% CI)] = 1.25 (1.07, 1.45); p=0.005) and the aORs for longer IPI births (60-119 months and ≥120 months) were 1.17 (95% CI = 1.06, 1.30; p=0.002) and 1.37 (95% CI = 1.18, 1.60; p<0.0001), respectively. Twelve percent of subjects with ADHD also had a comorbid diagnosis of ASD. However, tests of heterogeneity indicated that the association between IPI and ADHD did not significantly differ for cases with versus without ASD. The increased odds of ADHD among children who were first born were greater for those with co-morbid ASD (OR=1.76 (1.42, 2.18)) versus those without (OR=1.17 (1.09, 1.27); p-value for interaction=0.0002).

Conclusions: Similar to ASD, the risk of ADHD may be increased among children born following short or long IPIs. Further study is needed to explain the mechanisms of association, which may be different for short than for long intervals.