Circulating phthalates during critical illness in children are associated with long-term attention deficit: a study of a development and a validation cohort
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Environmental phthalate exposure has been associated with attention deficit disorders in children. We hypothesized that in children treated in the pediatric intensive care unit (PICU), circulating phthalates leaching from indwelling medical devices contribute to their long-term attention deficit.
Circulating plasma concentrations of di(2-ethylhexyl)phthalate (DEHP) metabolites were quantified in 100 healthy children and 449 children who had been treated in PICU and were neurocognitively tested 4 years later. In a development patient cohort (N = 228), a multivariable bootstrap study identified stable thresholds of exposure to circulating DEHP metabolites above which there was an independent association with worse neurocognitive outcome. Subsequently, in a second patient cohort (N = 221), the observed independent associations were validated.
Plasma concentrations of DEHP metabolites, which were virtually undetectable [0.029 (0.027–0.031) µmol/l] in healthy children, were 4.41 (3.76–5.06) µmol/l in critically ill children upon PICU admission (P < 0.001). Plasma DEHP metabolite concentrations decreased rapidly but remained 18 times higher until PICU discharge (P < 0.001). After adjusting for baseline risk factors and duration of PICU stay, and further for PICU complications and treatments, exceeding the potentially harmful threshold for exposure to circulating DEHP metabolites was independently associated with the attention deficit (all P ≤ 0.008) and impaired motor coordination (all P ≤ 0.02). The association with the attention deficit was confirmed in the validation cohort (all P ≤ 0.01). This phthalate exposure effect explained half of the attention deficit in post-PICU patients.
Iatrogenic exposure to DEHP metabolites during intensive care was independently and robustly associated with the important attention deficit observed in children 4 years after critical illness. Clinicaltrials.gov identifier: NCT00214916.
KeywordsPICU Critical illness Sepsis Phthalate Attention Neurocognitive development Plasticizers
This work was supported by the Research Foundation-Flanders (FWO), Belgium (FWO fellowship to SV); by the Methusalem program of the Flemish government (through the University of Leuven to GVdB, METH/08/07 and to GVdB and IV, METH14/06); by an ERC Advanced Grant (AdvG-2012-321670) from the Ideas Program of the European Union 7th framework program to GVdB; and by the Institute for Science and Technology, Flanders, Belgium (through the University of Leuven to GVdB, IWT/070695/TBM).
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Conflicts of interest
The authors declare that they have no conflict of interest.
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