Walle Kjersti Maehlum, Gustavson Kristin, Mjaaland Siri, Askeland Ragna Bugge, Magnus Per, Susser Ezra, Lipkin W Ian, Stoltenberg Camilla, Bresnahan Michaeline, Reichborn-Kjennerud Ted, Hornig Mady, Ask Helga
Norwegian Institute of Public Health.
University of Oslo.
Res Sq. 2025 Apr 14:rs.3.rs-5594521. doi: 10.21203/rs.3.rs-5594521/v1.
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.
孕期母亲的免疫介导疾病与后代患注意力缺陷多动障碍（ADHD）的风险增加有关。然而，我们并不清楚这些关联在多大程度上受到共享遗传易感性的影响，而非孕期母亲的炎症/免疫反应。本研究通过将父亲的免疫介导疾病作为阴性对照来探讨这些潜在因素，从而研究孕期母亲的免疫介导疾病与后代ADHD之间的关联。
来自挪威母亲、父亲和儿童队列研究（MoBa）的前瞻性数据与挪威医疗出生登记处（MBRN）和挪威患者登记处（NPR）相链接，以评估孕期暴露于母亲免疫介导疾病与18岁前后代患ADHD风险之间的关联。1999年至2008年在全国范围内招募，共产生了104,270对符合条件的母婴对。其中，21,340名儿童暴露于母亲的过敏性疾病（哮喘、过敏、特应性疾病），7,478名儿童暴露于其他免疫疾病（自身免疫性、炎症性）。父亲自我报告的免疫疾病作为遗传混杂的阴性对照。数据大多通过MoBa收集，额外的母亲疾病病例来自MBRN，儿童的ADHD诊断来自NPR。Cox比例风险模型估计ADHD诊断的风险比。
两个总体类别均与后代ADHD风险增加有关（过敏性疾病风险比1.23，95%置信区间，1.14 - 1.34；其他免疫疾病风险比1.36，95%置信区间，1.21 - 1.53）。具体而言，我们发现母亲的哮喘（风险比1.47，95%置信区间，1.30 - 1.67）、过敏（风险比1.20，95%置信区间，1.10 - 1.31）、风湿性/肌肉骨骼疾病（风险比1.64，95%置信区间，1.28 - 2.10）、克罗恩病/溃疡性结肠炎（调整后风险比1.95，95%置信区间，1.23 - 3.09）以及内分泌疾病（风险比1.42，95%置信区间，1.15 - 1.77），特别是1型糖尿病（调整后风险比2.50，95%置信区间，1.66 - 3.75）与之相关。尽管一些父亲的免疫介导疾病（银屑病、溃疡性结肠炎、克罗恩病）在后代中也显示出类似的ADHD风险增加趋势，但只有父亲的哮喘有显著关联（调整后风险比1.26，95%置信区间，1.10 - 1.45）。
几种母亲的免疫介导疾病与后代ADHD风险增加有关。与父亲的免疫介导疾病相比，大多数母亲的免疫介导疾病在后代中对ADHD风险的估计更高且更一致，这表明未测量的遗传混杂不能完全解释这些关联。这些结果表明，通过母胎界面的事件对胎儿发育有直接影响，这可能会改变胎儿的免疫反应，并可能导致后代患ADHD的风险更高。哮喘可能是这种机制的一个可能例外，因为父亲的哮喘也与后代患ADHD的风险有关。
