Many children in Bangladesh experience poor nutritional status and environmental lead exposure, both of which are associated with lower scores on neurodevelopmental assessments. Recent studies have suggested that part of lead’s adverse effects on neurodevelopment are caused in part by lead’s effect on growth. New statistical methods are now available to evaluate potential causal pathways in observational studies. This study used a novel statistical method to test the hypothesis that stunting, a measure of linear growth related to poor nutrition, is a mediator and/or an effect modifier of the lead exposure’s adverse effect on cognitive development. Participants were 734 children from a longitudinal birth cohort established in rural Bangladesh to study the health effects of prenatal and early childhood environmental metal exposures. Lead exposure was estimated using umbilical cord blood samples obtained at birth and blood obtained via venipuncture at age 20–40 months. Stunting was determined using the World Health Organization’s standards. Neurodevelopment was assessed at age 20–40 months years using the Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III). We evaluated the effect of lead on stunting and whether the effect of lead on cognitive scores is modified by stunting status in multivariable regression analyses. We then conducted a novel 4-way mediation analysis that allows for exposure-mediator interaction to assess how much of the effect of lead on cognitive scores is explained by the pathway through stunting (mediation) and how much is explained by the interaction between lead and stunt (effect modification). Stunting was not a mediator of the effect of lead in our analyses. Results suggested effect modification by stunting. In an area of Bangladesh with lower lead exposures (median umbilical cord blood lead concentration, 1.7 μg/dL), stunting modified the relationship between prenatal blood lead concentrations and cognitive score at age 2–3 years. A 1-unit increase in natural log cord blood lead concentration in the presence of stunting was associated with a 2.1-unit decrease in cognitive scores (β = − 2.10, SE = 0.71, P = 0.003). This interaction was not found in a second study site where lead exposures were higher (median umbilical cord blood lead concentration, 6.1 μg/dL, β = − 0.45, SE = 0.49, P = 0.360). We used a novel method of mediation analysis to test whether stunting mediated the adverse effect of prenatal lead exposure on cognitive outcomes in Bangladesh. While we did not find that stunting acted as mediator of lead’s effect on cognitive development, we found significant effect modification by stunting. Our results suggest that children with stunting are more vulnerable to the adverse effects of low-level lead exposure.

中文翻译：

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发育迟缓和铅：使用因果中介分析更好地了解环境铅暴露如何影响儿童的认知结果

孟加拉国的许多儿童营养状况不佳和环境铅暴露，这两者都与神经发育评估得分较低有关。最近的研究表明，铅对神经发育的部分不利影响部分是由铅对生长的影响引起的。现在可以使用新的统计方法来评估观察性研究中的潜在因果途径。本研究使用一种新的统计方法来检验以下假设：发育迟缓（一种与营养不良相关的线性生长量度）是铅暴露对认知发展的不利影响的中介和/或效应调节剂。参与者是来自孟加拉国农村建立的纵向出生队列的 734 名儿童，以研究产前和儿童早期环境金属暴露对健康的影响。使用出生时获得的脐带血样本和 20-40 个月大时通过静脉穿刺获得的血液估计铅暴露。发育迟缓是使用世界卫生组织的标准确定的。使用贝利婴幼儿发育量表第三版 (BSID-III) 在 20-40 个月大时评估神经发育。我们在多变量回归分析中评估了铅对发育迟缓的影响，以及铅对认知评分的影响是否会因发育迟缓状态而改变。然后，我们进行了一项新的 4 向中介分析，该分析允许暴露-中介相互作用，以评估铅对认知评分的影响有多少是由通过发育迟缓（中介）的途径解释的，有多少是由铅和铅之间的相互作用解释的。特技（效果修改）。在我们的分析中，发育迟缓不是铅影响的中介。结果表明通过发育迟缓来改变效果。在铅暴露较低的孟加拉国地区（脐带血铅浓度中位数为 1.7 μg/dL），发育迟缓改变了 2-3 岁时产前血铅浓度与认知评分之间的关​​系。在发育迟缓的情况下，自然对数脐带血铅浓度增加 1 个单位与认知评分降低 2.1 个单位相关（β = - 2.10，SE = 0.71，P = 0.003）。在铅暴露较高的第二个研究地点（脐带血铅浓度中位数，6.1 μg/dL，β = - 0.45，SE = 0.49，P = 0.360）未发现这种相互作用。我们使用一种新的中介分析方法来测试发育迟缓是否介导了产前铅暴露对孟加拉国认知结果的不利影响。虽然我们没有发现发育迟缓是铅对认知发展影响的中介，但我们发现发育迟缓可以显着改变影响。我们的研究结果表明，发育迟缓的儿童更容易受到低水平铅暴露的不利影响。