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Meta-Analysis
. 2024 Jul 5;23(1):62.
doi: 10.1186/s12940-024-01101-2.

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

John F Dou  1 , Rebecca J Schmidt  2 , Heather E Volk  3 , Manon M Nitta  1 , Jason I Feinberg  3 , Craig J Newschaffer  4 , Lisa A Croen  5 , Irva Hertz-Picciotto  2 , M Daniele Fallin  6 , Kelly M Bakulski  7
Affiliations
Meta-Analysis

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

John F Dou et al. Environ Health. .

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, urinary metals concentrations during two pregnancy time periods (< 28 weeks and ≥ 28 weeks of gestation) were measured using inductively coupled plasma mass spectrometry. At age three, clinicians assessed ASD with DSM-5 criteria. In an exposure-wide association framework, using multivariable log binomial regression, we examined each metal for association with ASD status, adjusting for gestational age at urine sampling, child sex, age at pregnancy, race/ethnicity and education. We meta-analyzed across the two cohorts.

Results: In EARLI (n = 170) 17% of children were diagnosed with ASD, and 44% were classified as having non-neurotypical development (Non-TD). In MARBLES (n = 231), 21% were diagnosed with ASD, and 14% classified as Non-TD. During the first and second trimester period (< 28 weeks), having cadmium concentration over the level of detection was associated with 1.69 (1.08, 2.64) times higher risk of ASD, and 1.29 (0.95, 1.75)times higher risk of Non-TD. A doubling of first and second trimester cesium concentration was marginally associated with 1.89 (0.94, 3.80) times higher risk of ASD, and a doubling of third trimester cesium with 1.69 (0.97, 2.95) times higher risk of ASD.

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

Keywords: Autism spectrum disorder; Cadmium; Epidemiology; ExWAS; Metals exposure; Pregnancy cohort.

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Conflict of interest statement

The authors declare they have no competing interests.

Figures

Fig.1
Fig.1
Spearman correlations of urinary metals concentrations, measured during trimester 1 or 2 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
Fig. 2
Fig. 2
Adjusted risk ratios for the associations between 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/diamond denotes a nominal meta-analysis p-value < 0.05, and orange/square a nominal meta-analysis p-value < 0.10
Fig. 3
Fig. 3
Adjusted risk ratios for the associations between 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/diamond denotes a nominal meta-analysis p-value < 0.05, and orange/square a nominal meta-analysis p-value < 0.10
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