School of Public Health, University of California, Berkeley, CA, USA.
Division of Infectious Diseases and Geographic Medicine, Stanford University, Stanford, CA, USA.
Psychoneuroendocrinology. 2024 Jun;164:107023. doi: 10.1016/j.psyneuen.2024.107023. Epub 2024 Mar 11.
Hundreds of millions of children in low- and middle-income countries are exposed to chronic stressors, such as poverty, poor sanitation and hygiene, and sub-optimal nutrition. These stressors can have physiological consequences for children and may ultimately have detrimental effects on child development. This study explores associations between biological measures of chronic stress in early life and developmental outcomes in a large cohort of young children living in rural Bangladesh.
We assessed physiologic measures of stress in the first two years of life using measures of the hypothalamic-pituitary-adrenal (HPA) axis (salivary cortisol and glucocorticoid receptor gene methylation), the sympathetic-adrenal-medullary (SAM) system (salivary alpha-amylase, heart rate, and blood pressure), and oxidative status (F2-isoprostanes). We assessed child development in the first two years of life with the MacArthur-Bates Communicative Development Inventories (CDI), the WHO gross motor milestones, and the Extended Ages and Stages Questionnaire (EASQ). We compared development outcomes of children at the 75th and 25th percentiles of stress biomarker distributions while adjusting for potential confounders using generalized additive models, which are statistical models where the outcome is predicted by a potentially non-linear function of predictor variables.
We analyzed data from 684 children (49% female) at both 14 and 28 months of age; we included an additional 765 children at 28 months of age. We detected a significant relationship between HPA axis activity and child development, where increased HPA axis activity was associated with poor development outcomes. Specifically, we found that cortisol reactivity (coefficient -0.15, 95% CI (-0.29, -0.01)) and post-stressor levels (coefficient -0.12, 95% CI (-0.24, -0.01)) were associated with CDI comprehension score, post-stressor cortisol was associated with combined EASQ score (coefficient -0.22, 95% CI (-0.41, -0.04), and overall glucocorticoid receptor methylation was associated with CDI expression score (coefficient -0.09, 95% CI (-0.17, -0.01)). We did not detect a significant relationship between SAM activity or oxidative status and child development.
Our observations reveal associations between the physiological evidence of stress in the HPA axis with developmental status in early childhood. These findings add to the existing evidence exploring the developmental consequences of early life stress.
数以亿计的中低收入国家的儿童长期暴露于压力源，如贫困、卫生条件差和环境卫生差以及营养不足。这些压力源可能对儿童的生理产生影响，并最终对儿童的发育产生不利影响。本研究探讨了在孟加拉国农村地区的一大群幼儿中，生命早期慢性应激的生物学测量指标与发育结果之间的关联。
我们使用下丘脑-垂体-肾上腺（HPA）轴的生理测量指标（唾液皮质醇和糖皮质激素受体基因甲基化）、交感-肾上腺髓质（SAM）系统（唾液 α-淀粉酶、心率和血压）和氧化状态（F2-异前列腺素）评估生命最初两年的应激生物标志物。我们使用麦克阿瑟-贝茨交际发展量表（CDI）、世界卫生组织粗大运动里程碑和扩展年龄和阶段问卷（EASQ）在生命最初两年评估儿童的发育情况。我们使用广义加性模型（一种潜在非线性函数预测结果的统计模型）比较了处于压力生物标志物分布第 75 百分位数和第 25 百分位数的儿童的发育结果，同时调整了潜在混杂因素。
我们分析了在 14 个月和 28 个月时均有数据的 684 名儿童（49%为女性）；我们还包括了 28 个月时的另外 765 名儿童。我们检测到 HPA 轴活动与儿童发育之间存在显著关系，其中 HPA 轴活动增加与发育不良的结果有关。具体而言，我们发现皮质醇反应性（系数-0.15，95%CI（-0.29，-0.01））和应激后水平（系数-0.12，95%CI（-0.24，-0.01））与 CDI 理解评分相关，应激后皮质醇与 EASQ 综合评分相关（系数-0.22，95%CI（-0.41，-0.04）），总糖皮质激素受体甲基化与 CDI 表达评分相关（系数-0.09，95%CI（-0.17，-0.01））。我们没有发现 SAM 活性或氧化状态与儿童发育之间存在显著关系。
我们的观察结果揭示了 HPA 轴中应激的生理证据与儿童早期发育状况之间的关联。这些发现增加了探索生命早期压力对发育影响的现有证据。
