Importance

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.

Objective

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.

Design

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.

Exposure

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.

Main outcomes and measures

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.

Results

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.

Conclusion and relevance

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.

中文翻译：

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妊娠期 C 反应蛋白水平升高对儿童晚期大脑形态的长期影响

重要性

动物研究表明，母体免疫激活 (MIA) 可能对胎儿大脑发育产生不利影响。临床研究提供了 MIA 后人类新生儿大脑结构异常的证据，但没有研究调查 MIA（用生物标志物测量）在暴露十年后对人类大脑形态的长期影响。

客观的

我们的目的是评估 MIA 对 10 岁儿童大脑形态的长期影响，包括出生时胎龄的可能中介作用。

设计

我们利用了 R 代的数据，这是一项大规模的前瞻性妊娠队列研究。在 2002 年至 2006 年期间纳入孕妇，并在 2013 年至 2015 年期间邀请她们的孩子参加 MRI 研究。要被纳入，母子二人组必须有妊娠期间母体 C 反应蛋白水平的数据和良好的质量10 岁时对孩子的大脑进行 MRI 扫描。在扫描的 3,992 名儿童中，共有 2,053 名 10 岁儿童被纳入本研究。

暴露

在妊娠的前 18 周测量母体 C 反应蛋白。对于分析，我们使用连续方法和基于临床临界值的分类方法来确定是否存在剂量反应关系。

主要成果和措施

高分辨率 MRI 脑形态测量被用作主要结果。使用超声确定的出生胎龄被包括作为使用因果中介分析的中介。对相关的混杂因素和多重比较进行了更正。生物性作为调节剂进行调查。

结果

我们发现持续性 MIA 与小脑体积减小之间存在直接关联。在女孩中，我们通过出生时的中介胎龄证明了持续性 MIA 与总脑容量之间存在负间接关联。在多次测试校正后，我们没有观察到与分类 MIA 的关联。

结论和相关性

我们的结果表明 MIA 后对大脑形态的性别特异性长期影响。分类分析表明，这种关联可能是由急性感染或其他严重炎症来源驱动的，鉴于 COVID-19 大流行目前正在影响全球数百万孕妇，这具有临床相关性。