Background While levothyroxine is one of the most extensively prescribed drugs during pregnancy, the possible effects of levothyroxine on the metabolome are not well known. Our aim was to determine levothyroxine treatment-associated changes in the metabolite profile of umbilical cord serum after birth, as well as in maternal serum samples collected at different stages of pregnancy, and link these to the health of the newborn.

Methods The study cohort, 118 levothyroxine-treated and 118 healthy control pregnancies, was collected from Kuopio University Hospital, Finland, during the years 2013–2017. Serum metabolite profiles were determined with nuclear magnetic resonance-based metabolomics from 1) umbilical cord blood samples, 2) samples collected during the 1st trimester and 3) during delivery from the pregnant women. There was no difference in demographic characteristics between study groups including gestational age.

Results There was a negative correlation between cord blood thyroid stimulating hormone (CBTSH) concentrations and Apgar scores at the 1-minute and 5-minute time-points in levothyroxine-treated pregnancies. Furthermore, the concentrations of cord serum metabolites linked with anaerobic glycolysis, e.g., lactate, citrate and glycerol, as well as all measured amino acids were negatively associated with Apgar scores. Furthermore, cord serum concentrations of lactate (β = 0.50, p < 0.0001), glycerol (β = 0.41, p < 0.0001) and alanine (β = 0.34, p = 0.0005) were positively correlated with CBTSH concentrations in the levothyroxine-treated pregnancies. No differences in the 1st trimester samples were observed between the groups. In the during delivery samples, there was small but significant decrease in cholesteryl esters, cholesterol and phospholipids in small very low-density lipoprotein in the levothyroxine-treated pregnancies.

Conclusions In the levothyroxine-treated pregnancies, the alterations detected in the cord serum concentrations of metabolites linked to fetal hypoxia and muscle degradation could explain the association between CBTSH and the health of the newborn measured via Apgar scores.

HS, LKN, and JR report no conflict of interest. OK is affiliated with a metabolomics analysis service company Afekta Technologies Ltd (not used here).

This work was supported by the European Union Horizon 2020 research and innovation programme under grant agreement No 825762 and by a grant from the Avohoidon tutkimussäätiö.

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