Suleri Anna, Blok Elisabet, Durkut Melisa, Rommel Anna-Sophie, Witte Lot de, Jaddoe Vincent, Bergink Veerle, White Tonya
Department of Child and Adolescent Psychiatry/Psychology, Erasmus MC-Sophia Children's Hospital, University Medical Center Rotterdam, The Netherlands; The Generation R Study Group, Erasmus University Medical Centre, Rotterdam, The Netherlands.
Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, USA.
Brain Behav Immun. 2022 Jul;103:63-72. doi: 10.1016/j.bbi.2022.03.018. Epub 2022 Apr 2.
Animal studies show that Maternal Immune Activation (MIA) may have detrimental effects on fetal brain development. Clinical studies provide evidence for structural brain abnormalities in human neonates following MIA, but no study has investigated the long-term effects of MIA (as measured with biomarkers) on human brain morphology ten years after the exposure.
Our aim was to evaluate the long-term impact of MIA on brain morphology in 10-year-old children, including the possible mediating role of gestational age at birth.
We leveraged data from Generation R, a large-scale prospective pregnancy cohort study. Pregnant women were included between 2002 and 2006, and their children were invited to participate in the MRI study between 2013 and 2015. To be included, mother-child dyads had to have data on maternal C-reactive protein levels during gestation and a good quality MRI-scan of the child's brain at age 10 years. Of the 3,992 children scanned, a total of 2,053 10-year-old children were included in this study.
Maternal C-reactive protein was measured in the first 18 weeks of gestation. For the analyses we used both a continuous approach as well as a categorical approach based on clinical cut-offs to determine if there was a dose-response relationship.
High-resolution MRI brain morphology measures were used as the primary outcome. Gestational age at birth, established using ultrasound, was included as a mediator using a causal mediation analysis. Corrections were made for relevant confounders and multiple comparisons. Biological sex was investigated as moderator.
We found a direct association between continuous MIA and lower cerebellar volume. In girls, we demonstrated a negative indirect association between continuous MIA and total brain volume, through the mediator gestational age at birth. We observed no associations with categorical MIA after multiple testing correction.
Our results suggest sex-specific long-term effects in brain morphology after MIA. Categorical analyses suggest that this association might be driven by acute infections or other sources of severe inflammation, which is of clinical relevance given that the COVID-19 pandemic is currently affecting millions of pregnant women worldwide.
动物研究表明，母体免疫激活（MIA）可能对胎儿大脑发育产生有害影响。临床研究为MIA后人类新生儿大脑结构异常提供了证据，但尚无研究调查MIA（以生物标志物衡量）在暴露十年后对人类大脑形态的长期影响。
我们的目的是评估MIA对10岁儿童大脑形态的长期影响，包括出生时胎龄可能的中介作用。
我们利用了“Generation R”研究的数据，这是一项大规模前瞻性妊娠队列研究。2002年至2006年纳入孕妇，2013年至2015年邀请她们的孩子参与MRI研究。要纳入研究，母婴二元组必须有孕期母亲C反应蛋白水平的数据以及孩子10岁时高质量的脑部MRI扫描数据。在3992名接受扫描的儿童中，共有2053名10岁儿童纳入本研究。
在妊娠的前18周测量母体C反应蛋白。为进行分析，我们既采用了连续变量方法，也采用了基于临床临界值的分类变量方法来确定是否存在剂量反应关系。
高分辨率MRI脑部形态测量指标用作主要结局。使用因果中介分析将通过超声确定的出生时胎龄作为中介变量纳入。对相关混杂因素和多重比较进行了校正。将生物性别作为调节变量进行研究。
我们发现连续MIA与小脑体积减小之间存在直接关联。在女孩中，我们证明连续MIA通过中介变量出生时胎龄与全脑体积之间存在负向间接关联。经过多重检验校正后，我们未观察到分类变量MIA与上述指标之间存在关联。
我们的结果表明MIA后大脑形态存在性别特异性的长期影响。分类分析表明，这种关联可能由急性感染或其他严重炎症来源驱动，鉴于目前新冠疫情正在影响全球数百万孕妇，这具有临床相关性。
