Maternal Immune-Mediated Conditions and ADHD Risk in Offspring

Maternal immune-mediated conditions during pregnancy have been linked with increased risk of attention-deficit/hyperactivity disorder (ADHD) in offspring. However, we do not know the extent to which these associations are influenced by shared genetic predispositions, as opposed to maternal inflammatory/immune responses during pregnancy. This study contributes by using paternal immune-mediated conditions as a negative control to explore these underlying factors, as we investigate associations between maternal immune-mediated conditions during pregnancy and offspring ADHD.

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 resulted in 104,270 eligible mother-child pairs. Among these, 21,340 children were exposed to maternal allergic conditions (asthma, allergies, atopic conditions) and 7,478 to other immune conditions (autoimmune, inflammatory). Paternal self-reported immune conditions served as negative controls for genetic confounding. Data was mostly collected through MoBa, with additional maternal condition cases sourced from MBRN, and children's ADHD diagnoses obtained from NPR. Cox proportional hazard models estimated Hazard ratios for ADHD diagnoses.

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). Specifically, we found associations for 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 of increased ADHD risk in offspring, only paternal asthma was significantly associated (adjusted HR 1.26 95% CI, 1.10-1.45).

Several maternal immune-mediated conditions were associated with increased ADHD risk in offspring. Observations of higher, more consistent estimates of ADHD risk in offspring for most maternal immune-mediated conditions versus 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 potentially lead to greater risk of ADHD in the offspring. Asthma may be a possible exception to this mechanism, as paternal asthma was also linked with risk of offspring ADHD.