Placental Angiogenic Factors Are Associated With Maternal Thyroid Function and Modify hCG-Mediated FT4 Stimulation

Context: The thyroid has a high vascular density and this vascularity may be influenced by pregnancy-specific angiogenic factors. Proangiogenic placental growth factor (PlGF) and antiangiogenic soluble FMS-like tyrosine kinase-1 (sFlt1; a vascular endothelial growth factor [VEGF] and PlGF antagonist) are important pregnancy-specific angiogenesis regulators. We previously showed that fetal levels of sFlt1 and PlGF are associated with newborn thyroid function. However, the maternal thyroid may also be affected as PlGF and VEGF are secreted into the maternal circulation and cause a concomitant increase of sFlt1 to overcome adverse effects of angiogenesis overstimulation. Design, Setting, and Participants: Maternal sFlt1, PlGF, TSH, FT4, or human chorionic gonadotropin (hCG) levels were determined during early pregnancy (<18 wk) in 5517 women from the Generation R study. Analyses were adjusted for relevant covariates and interaction between hCG and angiogenic factors was investigated. Results: Increasing levels of sFlt1 were associated with a decrease in FT4 and T4 (both P < .001), and an increased risk of subclinical hypothyroidism (odds ratio [OR] for high levels, 2.37; 95% CI, 1.16-4.83; P = .02) and isolated hypothyroxinemia (linear P = .02; OR, 3.05; 95% CI, 1.42-6.55; P = .004). Increasing levels of PlGF were associated with a decrease in TSH and FT4 levels (both P = .001), and an increased risk of isolated hypothyroxinemia (linear P = .002; OR, 1.77; 95% CI, 1.02-3.06; P = .04). High levels of hCG decreased the difference in FT4 between low and high sFlt1. In women with high PlGF levels, the hCG-mediated increase in FT4 levels was attenuated. Conclusion: sFlt1 and PlGF are novel determinants of maternal thyroid (dys)function during early pregnancy and the response of the maternal thyroid function to hCG stimulation. These data provide novel insights into the pregnancy specific thyroid function physiology and suggest that high levels of pro- and anti-angiogenic factors may be a risk factor for adverse pregnancy outcomes via their effects on maternal thyroid function.