Association Between Estimated Geocoded Residential Maternal Exposure to Lithium in Drinking Water and Risk for Autism Spectrum Disorder in Offspring in Denmark

Title	Association Between Estimated Geocoded Residential Maternal Exposure to Lithium in Drinking Water and Risk for Autism Spectrum Disorder in Offspring in Denmark
Authors	Zeyan Liew, Qi Meng, Qi Yan, Jörg Schullehner, Birgitte Hansen, Søren Munch Kristiansen, Denitza D. Voutchkova, Jørn Olsen, Annette Kjær Ersbøll, Matthias Ketzel, Ole Raaschou-Nielsen, Beate R. Ritz
Magazine	JAMA Pediatrics
Date	04/03/2023
DOI	10.1001/jamapediatrics.2023.0346
Introduction	Lithium, a naturally occurring trace element with mood-stabilising properties, has shown associations between its therapeutic maternal use and adverse birth outcomes. Animal studies indicate lithium's role in modulating Wnt/β-catenin signalling, crucial for neurodevelopment. The impact of lithium exposure through drinking water on early brain health remains unclear. This study aimed to assess whether maternal exposure to lithium in drinking water during pregnancy correlates with autism spectrum disorder (ASD) in offspring. A nationwide population-based case-control study in Denmark included 8,842 children diagnosed with ASD, born between 2000 and 2013, and 43,864 control participants matched by birth year and sex from the Danish Medical Birth Registry. Data analysis occurred from March 2021 through November 2022. Maternal residential addresses during pregnancy were geocoded and linked to estimated lithium levels (ranging from 0.6 to 30.7 μg/L) in drinking water. These levels were determined using kriging interpolation based on 151 waterworks measurements across Denmark. ASD diagnoses were confirmed using International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes from the Danish Psychiatric Central Register. The research team calculated odds ratios (ORs) and 95% confidence intervals (CIs) for ASD, considering estimated geocoded maternal lithium exposure in drinking water as both a continuous (per IQR) and categorical (quartile) variable. Adjustments were made for sociodemographic factors and ambient air pollutant levels. Stratified analyses were also conducted by birth year, child’s sex, and urbanicity. The study involved 8,842 participants with ASD (79.3% male) and 43,864 control participants (79.2% male). A consistent increase in estimated geocoded maternal lithium exposure from drinking water, quantified per IQR, correlated with higher odds for ASD in offspring (OR, 1.23; 95% CI, 1.17-1.29). Elevated odds for ASD in offspring were observed starting from the second quartile (7.36 to 12.67 μg/L) of estimated maternal lithium exposure, with the highest quartile (over 16.78 μg/L) showing an OR of 1.46 (95% CI, 1.35-1.59) compared to the reference group (below 7.39 μg/L). These associations remained consistent after adjusting for air pollution, and no significant differences were evident in stratified analyses. The study established an association between estimated maternal prenatal exposure to lithium from natural drinking water sources in Denmark and an elevated ASD risk in offspring. This work indicates that naturally occurring lithium in drinking water could represent a novel environmental risk factor for ASD development, warranting further investigation.
Quote	Zeyan Liew, Qi Meng and Qi Yan et al. Association Between Estimated Geocoded Residential Maternal Exposure to Lithium in Drinking Water and Risk for Autism Spectrum Disorder in Offspring in Denmark. JAMA Paediatrics. 2023. DOI: 10.1001/jamapediatrics.2023.0346
Element	Lithium (Li)
Industry	Research & Laboratory