Prenatal exposure to multiple metallic and metalloid trace elements and the risk of bacterial sepsis in extremely low gestational age newborns: A prospective cohort study

Abstract

Background: Prenatal exposures to metallic and metalloid trace elements have been linked to altered immune function in animal studies, but few epidemiologic studies have investigated immunological effects in humans. We evaluated the risk of bacterial sepsis (an extreme immune response to bacterial infection) in relation to prenatal metal/metalloid exposures, individually and jointly, within a US-based cohort of infants born extremely preterm.

Methods: We analyzed data from 269 participants in the US-based ELGAN cohort, which enrolled infants delivered at <28 weeks' gestation (2002-2004). Concentrations of 8 trace elements-including 4 non-essential and 4 essential-were measured using inductively coupled plasma tandem mass spectrometry in umbilical cord tissue, reflecting in utero fetal exposures. The infants were followed from birth to postnatal day 28 with bacterial blood culture results reported weekly to detect sepsis. Discrete-time hazard and quantile g-computation models were fit to estimate associations for individual trace elements and their mixtures with sepsis incidence.

Results: Approximately 30% of the extremely preterm infants developed sepsis during the follow-up period (median follow-up: 2 weeks). After adjustment for potential confounders, no trace element was individually associated with sepsis risk. However, there was some evidence of a non-monotonic relationship for cadmium, with hazard ratios (HRs) for the second, third, and fourth (highest) quartiles being 1.13 (95% CI: 0.51-2.54), 1.94 (95% CI: 0.87-4.32), and 1.88 (95% CI: 0.90-3.93), respectively. The HRs for a quartile increase in concentrations of all 8 elements, all 4 non-essential elements, and all 4 essential elements were 0.92 (95% CI: 0.68-1.25), 1.19 (95% CI: 0.92-1.55), and 0.77 (95% CI: 0.57-1.06). Cadmium had the greatest positive contribution whereas arsenic, copper, and selenium had the greatest negative contributions to the mixture associations.

Conclusions: We found some evidence that greater prenatal exposure to cadmium was associated with an increased the risk of bacterial sepsis in extremely preterm infants. However, this risk was counteracted by a combination of arsenic, copper, and selenium. Future studies are needed to confirm these findings and to evaluate the potential for nutritional interventions to prevent sepsis in high-risk infants.

Keywords: metals; mixtures; pregnancy; preterm (birth); sepsis.

Figure 1

Heatmap displaying Spearman's rank correlation coefficients between all possible pairs of the trace elements, as measured in ELGAN umbilical cord tissue samples (n = 269).

Figure 2

Forest plot showing adjusted* hazard ratios with 95% confidence intervals for neonatal bacterial sepsis in the first 28 days of life by trace element mixture. *Adjusted for geographic region, maternal race/ethnicity, age, educational attainment, Medicaid coverage, pre-pregnancy BMI, and smoking status during pregnancy.

Figure 3

Forest plots showing adjusted* hazard ratios with 95% confidence intervals for neonatal bacterial sepsis in the first 28 days of life by trace element quartiles. p_trend for linear associations with sepsis calculated by modeling the median trace element concentration in each quartile as a continuous variable. *Adjusted for geographic region, maternal race/ethnicity, age, educational attainment, Medicaid coverage, pre-pregnancy BMI, and smoking status during pregnancy.

Figure 4

Bar plot showing the weights assigned to each trace element composing the overall mixture as estimated by the quantile g-computation model for neonatal bacterial sepsis in the first 28 days of life after adjustment for geographic region, maternal race/ethnicity, age, educational attainment, Medicaid coverage, pre-pregnancy BMI, and smoking status during pregnancy. The size of the bar corresponds to the proportional contribution of a given trace element to the association with sepsis in a particular direction (negative or positive). Because the size of the bars should only be compared relative to others in the same direction, the shading reflects the absolute contribution of the individual trace element, regardless of directionality.