Exposure to heavy metals in utero and autism spectrum disorder at age 3: A meta-analysis of two longitudinal cohorts of siblings of children with autism

Abstract

Background: Autism spectrum disorder (ASD) is a prevalent and heterogeneous neurodevelopmental disorder. Risk is attributed to genetic and prenatal environmental factors, though the environmental agents are incompletely characterized.

Methods: In Early Autism Risk Longitudinal Investigation (EARLI) and Markers of Autism Risk in Babies Learning Early Signs (MARBLES), two pregnancy cohorts of siblings of children with ASD, maternal urinary metals concentrations at two time points during pregnancy were measured using inductively coupled plasma mass spectrometry. At age three, clinicians assessed ASD with DSM-5 criteria. Using multivariable log binomial regression, we examined each metal for association with ASD status, adjusting for gestational age at urine sampling, child sex, maternal age, and maternal education, and meta-analyzed across the two cohorts.

Results: In EARLI (n=170) 17.6% of children were diagnosed with ASD, and an additional 43.5% were classified as having other non-neurotypical development (Non-TD). In MARBLES (n=156), 22.7% were diagnosed with ASD, while an additional 11.5% had Non-TD. In earlier pregnancy metals measures, having cadmium concentration over the level of detection was associated with 1.78 (1.19, 2.67) times higher risk of ASD, and 1.43 (1.06, 1.92) times higher risk of Non-TD. A doubling of early pregnancy cesium concentration was marginally associated with 1.81 (0.95, 3.42) times higher risk of ASD, and 1.58 (0.95, 2.63) times higher risk of Non-TD.

Conclusion: Exposure in utero to elevated levels of cadmium and cesium, as measured in maternal urine collected during pregnancy, was associated with increased risk of developing ASD.

Keywords: Metals exposure; autism spectrum disorder; cadmium; epidemiology; pregnancy cohort.

Figure 1.

Spearman correlations of urinary metals concentrations, measured during early pregnancy, stratified by cohort. The upper right triangle shows the EARLI cohort. The lower left triangle shows the MARBLES cohort. Metals are represented by their chemical symbol along the diagonal. Acronyms: Early Autism Risk Longitudinal Investigation (EARLI), Markers of Autism Risk in Babies-Lear Early Signs (MARBLES)

Figure 2.

Adjusted risk ratios for the associations between maternal urinary metals concentrations measuring during pregnancy and risk of autism spectrum disorder, relative to typically developing. Antimony, cadmium, chromium, and lead compare over limit of detection vs under the limit of detection for that metal. Remaining metals show the risk ratio for a doubling in metal concentration. Analyses were performed stratified by cohort (EARLI and MARBLES) and then meta-analyzed across cohorts. Red denotes a nominal meta-analysis p-value < 0.05, and orange a nominainal meta-analysis p-value < 0.10.

Figure 3.

Adjusted risk ratios for the associations between maternal urinary metals concentrations measuring during pregnancy and risk of non-typically developing, relative to typically developing. Antimony, cadmium, chromium, and lead compare over limit of detection vs under the limit of detection for that metal. Remaining metals show risk ratio for a doubling in metal concentration. Analyses were performed stratified by cohort (EARLI and MARBLES) and then meta-analyzed across cohorts. Red denotes a nominal meta-analysis p-value < 0.05, and orange a nominal meta-analysis p-value < 0.10.