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

Abstract

ImportanceLithium is a naturally occurring and trace element that has mood-stabilizing effects. Maternal therapeutic use of lithium has been associated with adverse birth outcomes. In animal models, lithium modulates Wnt/β-catenin signaling that is important for neurodevelopment. It is unknown whether exposure to lithium in drinking water affects brain health in early life.ObjectiveTo evaluate whether autism spectrum disorder (ASD) in offspring is associated with maternal exposure to lithium in drinking water during pregnancy.Design, Setting and ParticipantsThis nationwide population-based case-control study in Denmark identified 8842 children diagnosed with ASD born from 2000 through 2013 and 43 864 control participants matched by birth year and sex from the Danish Medical Birth Registry. These data were analyzed from March 2021 through November 2022.ExposuresGeocoded maternal residential addresses during pregnancy were linked to lithium level (range, 0.6 to 30.7 μg/L) in drinking water estimated using kriging interpolation based on 151 waterworks measurements of lithium across all regions in Denmark.Main Outcomes and MeasuresASD diagnoses were ascertained using International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes recorded in the Danish Psychiatric Central Register. The study team estimated odds ratios (ORs) and 95% CIs for ASD according to estimated geocoded maternal exposure to natural source of lithium in drinking water as a continuous (per IQR) or a categorical (quartile) variable, adjusting for sociodemographic factors and ambient air pollutants levels. The study team also conducted stratified analyses by birth years, child’s sex, and urbanicity.ResultsA total of 8842 participants with ASD (male, 7009 [79.3%]) and 43 864 control participants (male, 34 749 [79.2%]) were studied. Every IQR increase in estimated geocoded maternal exposure to natural source of lithium in drinking water was associated with higher odds for ASD in offspring (OR, 1.23; 95% CI, 1.17-1.29). Elevated odds among offspring for ASD were estimated starting from the second quartile (7.36 to 12.67 μg/L) of estimated maternal exposure to drinking water with lithium and the OR for the highest quartile (more than 16.78 μg/L) compared with the reference group (less than 7.39 μg/L) was 1.46 (95% CI, 1.35-1.59). The associations were unchanged when adjusting for air pollution exposures and no differences were apparent in stratified analyses.Conclusions and RelevanceEstimated maternal prenatal exposure to lithium from naturally occurring drinking water sources in Denmark was associated with an increased ASD risk in the offspring. This study suggests that naturally occurring lithium in drinking water may be a novel environmental risk factor for ASD development that requires further scrutiny.

Lithium in Drinking Water—A Novel Environmental Risk Factor for Autism Spectrum Disorder?

“…Indeed, many chemicals have now been linked to ASD, including air pollution, pesticides, metals, and phthalates . In this issue of JAMA Pediatrics , a study by Liew and colleagues adds lithium to this list, suggesting an association between a woman’s exposure to lithium in drinking water during pregnancy and ASD risk in her child. This is an excellent records-linkage, population-based, nested case-control study conducted in Denmark that included 8842 cases of ASD ( International Statistical Classification of Diseases and Related Health Problems, Tenth Revision code) and 43 864 control participants matched to cases by birth year (2000 to 2013) and sex.…”

“…The ascertainment of children’s ASD status was independent of the exposure assessment and pregnant individuals’ contributions of data to the different registries would not be expected to be associated either with their water lithium exposure or their children’s ASD status. The authors state they performed complete-case analyses because of a low rate of missing data. However, 31% of both the cases and controls initially identified were not included in the analyses, presumably due to missing data.…”

“…First, measurements of internal exposure (ie, biomarkers) were not available. Liew et al cite a study that reported significant correlations (0.40 to 0.44) between water lithium concentration and lithium in serum and urine. Such modest correlations leave considerable room for misclassification of internal exposure when estimated solely on the basis of external exposure.…”

“…Third, the only pathway of lithium exposure considered by Liew et al was drinking water, but exposure from food is also important. In the Second French Total Diet Study, only 35% of an adult’s daily lithium intake was attributed to water consumption, although coffee and other hot beverages also contributed another 31%, presumably from the water used in their preparation.…”

“…The implications of the findings of this study for public health policy are complex. Lithium levels in water, at concentrations that Liew et al found to be associated with a potential increased ASD risk, have also been linked to health benefits, specifically reductions in rates of hospitalization for psychiatric disorders and suicide . If all these of associations are valid, the wisdom of Solomon will be required to develop guidelines for lithium in drinking water that are maximally protective of the entire population.…”