Triglycerides Mediate the Relationship Between Maternal Free Thyroxine and Birth Weight: A Prospective Cohort Study from China

Background: Fetal overgrowth (large for gestational age, LGA) is associated with an increased risk of maternal and fetal morbidity and adverse health outcomes. Thyroid hormones are key regulators of metabolism during pregnancy and fetal development. Lower maternal free thyroxine (fT4) and higher maternal triglyceride (TG) levels during early pregnancy are associated with higher birth weight. We aimed at examining the mediating role of maternal TG in the association between maternal fT4 and birth weight. Methods: We performed a large prospective cohort study including pregnant Chinese women who were treated at a tertiary obstetric center during the period of January 2016 to December 2018. We included 35,914 participants with complete medical records. We performed causal mediation analysis to decompose the overall effect of fT4 on birth weight and LGA with maternal TG as the mediator. Results: We observed statistically significant associations between maternal fT4, TG levels, and birth weight (all p < 0.0001). Using a four-way decomposition model, we identified a controlled direct effect (coefficient [confidence interval, CI], -0.038 [-0.047 to -0.029], p < 0.0001) that accounted for 63.9% of the total effect, in addition to the other three estimated effects (reference interaction, coefficient [CI] = -0.006 [-0.009 to -0.001], p = 0.008; mediated interaction, coefficient [CI] = 0.0004 [0.000 to 0.001], p = 0.008; and pure indirect effect, coefficient [CI] = -0.009 [-0.013 to -0.005], p < 0.0001) of TG on the association between fT4 and birth weight Z score. Moreover, maternal TG accounted for 21.6% and 20.7% (via mediation) and 13.6% and 41.6% (via maternal fT4 and TG interaction) of the total effect of maternal fT4 on fetal birth weight and LGA, respectively. The proportions of the total associations that could be reduced by "eliminating" the effect of maternal TG were 36.1% for birth weight and 65.1% for LGA, respectively. Conclusions: High maternal TG levels may play substantial mediating roles in the relationship between low fT4 levels in early pregnancy and increased birth weight and a higher risk of LGA. Further, the occurrence of fetal overgrowth may also be influenced by possible synergistic effects between fT4 and TG.