April 3, 2023

expert reaction to association between maternal exposure to lithium in drinking water and risk for autism spectrum disorder in offspring

A study published in JAMA Pediatrics looks at estimated maternal exposure to lithium in drinking water in Denmark, and risk for autism spectrum disorder in offspring.

Dr Rosa Hoekstra, Reader in Global Perspectives on Neurodevelopmental Disabilities, Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King’s College London, said:

“This is an interesting paper. It does a good job in adjusting for possible confounders such as the child’s sex and age, and neighbourhood socioeconomic measures. If I were a journalist reporting on this study I would nevertheless be asking: are there any additional factors that may influence the likelihood of autism being diagnosed (that is, not whether a child is actually autistic or not, but whether they have received a formal clinical diagnosis)? This study is based on the Danish National Patient Register, so relies on administrative data of clinical autism diagnoses. Children who may have autism but do not (yet) have a diagnosis because their autism is not yet identified or they lack access to diagnostic services, are not included in a study like this. So what the study really does is looking for associations between lithium levels in the water around the mother’s address during pregnancy, and the likelihood of her child being diagnosed with autism in the first 3 to 16 years of life. That likelihood may be higher if you live near good autism diagnostic services. We know from international studies that successfully getting a diagnosis can be associated with socioeconomic, demographic and sociocultural factors. The authors try to adjust for some of these, for example neighbourhood socioeconomic measures, and whether the child was born in an urban, town or rural area. However, the nuance in this broad urban/town/rural stratification may have got lost, especially since there is one major urban area in Denmark: the capital region of Copenhagen.

“The authors do not provide exact details of the lithium levels throughout Denmark used in their analyses. Perhaps a map of lithium levels across Denmark was provided in the supplementary materials. I did not have access to these so could not check. They do refer to a paper by Knudsen et al. (2017) that used the same method and that paper presents a map of Denmark with estimated lithium levels (here: https://www.mdpi.com/1660-4601/14/6/627). The map suggests the lithium levels are highest in the Capital and Zealand regions in the east of Denmark, where Copenhagen is located. What I would like to ask the authors of this paper: Could it be that obtaining an autism diagnosis is relatively easier if you live in the Capital or Zealand regions, because you live within easy travel distance from specialist autism centres in Copenhagen? Could this perhaps partly explain the findings reported here?

“As the authors also acknowledge themselves, further studies are needed to better understand if lithium exposure plays a role in the likelihood of developing autism.”

Prof Dorothy Bishop, Professor of Developmental Neuropsychology, University of Oxford, said:

“It is difficult to interpret a study of environmental risk factors for autism without knowing how many risk factors were evaluated by the authors. It would be useful for this purpose to see the original research protocol. The reason why this is important is that the statistical association between lithium and autism could have arisen by chance during an evaluation of the many environmental factors that could plausibly be considered (e.g. air pollution, lead, pesticides, arsenic, phthalates): if these substances were also considered but were not reported because they gave null associations, then the statistics reported here would need adjustment for multiple testing.

“On the other hand, if there is documentation showing that prior to seeing the data the authors planned this analysis that focused solely on associations with lithium (with air pollution as covariate), then the statistical association is more convincing.

“Pre-registration of analyses in observational studies is not widespread in epidemiology, but would be very useful to bolster confidence in the robustness of specific associations such as this one.”

Association Between Estimated Geocoded Residential Maternal Exposure to Lithium in Drinking Water and Risk for Autism Spectrum Disorder in Offspring in Denmark’ by Zeyan Liew et al. was published in JAMA Pediatrics at 16:00 UK time on Monday 3 April.

DOI: 10.1001/jamapediatrics.2023.0346

Declared interests

Dr Rosa Hoekstra: “My research is funded by the National Institute for Health and Care Research (NIHR).”

Prof Dorothy Bishop: “I declare I have no Conflict of Interests.”

For all other experts, no reply to our request for DOIs was received.