Maternal and fetal health in relation to lithium in drinking water

Lithium is an alkali metal commonly used for treating mood disorders. A more common source of lithium exposure worldwide is drinking water, including bottled water, although few measurements have been performed. Based on clinical and experimental studies, lithium at therapeutic doses may impair fetal growth and development. Also, lithium may impair the thyroid and calcium homeostases in lithium-treated patients, but data on people exposed to lithium through drinking water are very limited.

The overall aim of this PhD thesis was to elucidate the potential impact of the exposure to lithium via drinking water during pregnancy on maternal and fetal health. Specifically, we aimed at elucidating the transfer of lithium through the placenta and mammary gland and the potential impact of lithium exposure during pregnancy on fetal size and maternal thyroid and calcium homeostases.

By analyzing lithium in banked samples from a small mother-child cohort (n=11) recruited in 1996 in San Antonio de los Cobres, an area with elevated lithium in the drinking water in northern Argentina, we evidenced a marked transfer of lithium through the placenta. The lithium concentration in cord blood was at least as high as in maternal blood and both were highly correlated (rs=0.82). In line with this, the lithium concentration in the newborns’ first urine in life was highly elevated. The urinary lithium concentration of the infants decreased during exclusive breastfeeding, consistent with the observed lower transfer of lithium through the mammary gland into breast milk.

To clarify the potential impact of lithium exposure on fetal and birth size and underlying mechanisms, we recruited a larger mother-child cohort from October 2012 to December 2013 (n=194, participation rate 88%) covering most of the Andean part of the Province of Salta in northern Argentina. The lithium concentrations in the drinking water were about 700 μg/L in the main village of San Antonio de los Cobres and from 5.0 to 242 μg/L in the surrounding nine villages. The selected biomarker of lithium exposure was blood lithium (overall median 25 μg/L) which showed a wide range of distribution (1.9-145). Lithium concentration in blood correlated very well with that in plasma (rs=0.99) and urine (rs=0.84), and, to a lesser extent, with that in water (rs=0.40).

In multivariable-adjusted linear regression models, we observed that maternal blood lithium concentrations were inversely associated with fetal size. A 25 μg/L increment in the blood lithium concentrations was associated with a statistically significant decrease of 0.5 cm in birth length. Newborns to mothers in the highest tertile of lithium exposure (median blood lithium 47 μg/L) were on average 0.8 cm shorter than those in the lowest tertile of exposure (median blood lithium 11 μg/L).

Based on multivariable-adjusted quantile regression across pregnancy, blood lithium concentrations were positively associated with thyrotropin (TSH) and inversely associated with free (fT3) and total triiodothyronine (T3) and with transthyretine (TTR).

Using multivariable-adjusted linear mixed-effects models across pregnancy, we observed blood lithium to be inversely associated with plasma vitamin D3 concentrations and with urinary calcium and magnesium, and positively associated with serum magnesium. A 25 μg/L increment in the blood lithium concentrations was associated with an odds ratio of 3.5 for having vitamin D3 concentrations <50 nmol/L, and an odds ratio of 4.6 for having vitamin D3 concentrations <30 nmol/L, an association independent of season of sampling.

Taken together, the results of this thesis provide evidence of a marked transfer of lithium through the placenta and a consequent lithium exposure to the fetus. This elevated fetal exposure seemed to impair the fetal size. Findings of a potential lithium-related impaired homeostasis of the thyroid and calcium systems in the mother during pregnancy might be underlying mechanisms of action of lithium. Further studies are indeed warranted.

List of scientific papers

I. Harari F, Ronco AM, Concha G, Llanos M, Grandér M, Castro F, Palm B, Nermell B, Vahter M. Early-life exposure to lithium and boron from drinking water. Reproductive Toxicology. 2012 Dec;34(4):552-60.
https://doi.org/10.1016/j.reprotox.2012.08.009

II. Harari F, Langeén M, Casimiro E, Bottai M, Palm B, Nordqvist H, Vahter M. Environmental exposure to lithium during pregnancy and fetal size: a longitudinal study in the Argentinean Andes. Environment International. 2015 Apr;77:48-54.
https://doi.org/10.1016/j.envint.2015.01.011

III. Harari F, Bottai M, Casimiro E, Palm B, Vahter M. Exposure to lithium and cesium through drinking water and thyroid function during pregnancy: a prospective cohort study. Thyroid. 2015.
https://doi.org/10.1089/thy.2015.0280

IV. Harari F, Åkesson A, Casimiro E, Lu Y, Vahter M. Exposure to lithium through drinking water and calcium homeostasis during pregnancy: a longitudinal study. [Submitted]