Suleri Anna, White Tonya, de Witte Lot, Gigase Frederieke, Cecil Charlotte A M, Jaddoe Vincent W V, Breen Michael, Hillegers Manon H J, Muetzel Ryan L, Bergink Veerle
Department of Child and Adolescent Psychiatry/Psychology, Erasmus University Medical Center, Rotterdam, the Netherlands; Generation R Study Group, Erasmus University Medical Center, Rotterdam, the Netherlands.
Section on Social and Cognitive Developmental Neuroscience, National Institute of Mental Health, Bethesda, Maryland.
Biol Psychiatry Cogn Neurosci Neuroimaging. 2025 Feb;10(2):222-235. doi: 10.1016/j.bpsc.2024.10.013. Epub 2024 Nov 2.
Maternal immune activation (MIA) has been hypothesized to have an adverse effect on child neurodevelopment, but only a few neuroimaging studies have been performed to date, mostly in neonates. In this population-based cohort study, we investigated the association between MIA and multiple neuroimaging modalities depicting brain development from childhood to adolescence.
We used data of mother-child pairs from the Generation R Study. To define our exposure, we measured interleukin (IL) 1β, IL-6, IL-17a, IL-23, interferon gamma, and C-reactive protein at 2 time points during pregnancy. Because levels of these 5 cytokines were highly correlated, we were able to compute a cytokine index. We used multiple brain imaging modalities as outcomes, including global and regional measures of brain morphology (structural magnetic resonance imaging, volume; n = 3295), white matter microstructure (diffusion magnetic resonance imaging, fractional anisotropy and mean diffusivity; n = 3267), and functional connectivity (functional magnetic resonance imaging, graph theory measures, and network-level connectivity; n = 2914) in the children at ages 10 and 14 years. We performed mixed effects models using child's age as a continuous time variable.
We found no significant effect of time on any neuroimaging outcomes in children over time, and there was no time × MIA interaction. These associations were similar for the cytokine index, C-reactive protein, and individual cytokines. We observed no evidence for differential effects of timing of prenatal MIA or child sex after multiple testing correction.
In this longitudinal population-based study, we found no evidence for an association between MIA and child brain development in the general population. Our findings differ from previous research in neonates that have shown structural and functional brain abnormalities after MIA.
母体免疫激活（MIA）被认为会对儿童神经发育产生不利影响，但迄今为止仅进行了少数神经影像学研究，且大多针对新生儿。在这项基于人群的队列研究中，我们调查了MIA与描述儿童至青少年期大脑发育的多种神经影像学检查方法之间的关联。
我们使用了“R代研究”中母婴对的数据。为定义我们的暴露因素，我们在孕期的2个时间点测量了白细胞介素（IL）-1β、IL-6、IL-17a、IL-23、干扰素γ和C反应蛋白。由于这5种细胞因子的水平高度相关，我们能够计算出一个细胞因子指数。我们将多种脑成像检查方法作为结局指标，包括大脑形态学的整体和区域测量（结构磁共振成像，体积；n = 3295）、白质微观结构（扩散磁共振成像，分数各向异性和平均扩散率；n = 3267）以及10岁和14岁儿童的功能连接性（功能磁共振成像，图论测量和网络水平连接性；n = 2914）。我们使用儿童年龄作为连续时间变量进行混合效应模型分析。
我们发现随着时间推移，时间对儿童的任何神经影像学结局均无显著影响，且不存在时间×MIA交互作用。细胞因子指数、C反应蛋白和单个细胞因子的这些关联相似。在多次检验校正后，我们未观察到产前MIA时间或儿童性别存在差异效应的证据。
在这项基于人群的纵向研究中，我们未发现一般人群中MIA与儿童大脑发育之间存在关联的证据。我们的研究结果与先前针对新生儿的研究不同，后者显示MIA后存在大脑结构和功能异常。
