Abstract
BACKGROUND: Maternal immune-mediated conditions during pregnancy have been linked with increased risk of attention-deficit/hyperactivity disorder (ADHD) in offspring. The relative contributions of maternal inflammatory/immune responses versus shared genetic predispositions remain unclear. This study uses paternal immune-mediated conditions as a negative control to explore these factors, as we investigate associations between maternal immune-mediated conditions during pregnancy and offspring ADHD. METHODS: Prospective data from the Norwegian Mother, Father, and Child Cohort Study (MoBa) was linked with the Medical Birth Registry of Norway (MBRN) and the Norwegian Patient Registry (NPR) to assess associations between prenatal exposure to maternal immune-mediated conditions and offspring ADHD risk up to age 18. Nationwide recruitment from 1999 to 2008 yielded 104,270 eligible mother-child pairs, with 21,340 children exposed to maternal allergic conditions (asthma, allergies, atopic conditions) and 7478 to other immune conditions (autoimmune, inflammatory). Paternal self-reported immune conditions served as negative controls. Children's ADHD diagnoses were obtained from NPR, and Cox proportional hazard models estimated hazard ratios for ADHD. RESULTS: Both overall categories were associated with increased offspring ADHD risk (allergic conditions HR 1.23, 95% CI, 1.14-1.34; other immune conditions HR 1.36, 95% CI, 1.21-1.53). Specific associations included maternal asthma (HR 1.47, 95% CI, 1.30-1.67), allergies (HR 1.20, 95% CI, 1.10-1.31), rheumatologic/musculoskeletal conditions (HR 1.64, 95% CI, 1.28-2.10), Crohn's disease/ulcerative colitis (adjusted HR 1.95, 95% CI, 1.23-3.09), and endocrine conditions (HR 1.42, 95% CI, 1.15-1.77), specifically, type 1 diabetes (adjusted HR 2.50, 95% CI, 1.66-3.75). Although some paternal immune-mediated conditions (psoriasis, ulcerative colitis, Crohn's disease) showed similar trends in ADHD risk, only paternal asthma was significantly associated (adjusted HR 1.26, 95% CI, 1.10-1.45). CONCLUSIONS: Several maternal immune-mediated conditions were associated with increased offspring ADHD risk. The higher, more consistent ADHD risk estimates with maternal conditions compared to paternal ones indicate that unmeasured genetic confounding does not fully explain these associations. These results suggest direct effects on fetal development through events at the maternal-fetal interface which may alter fetal immune responses and lead to greater ADHD risk in offspring. Asthma may be an exception to this mechanism, as paternal asthma was also linked with offspring ADHD risk.