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Soluble Flt1 and placental growth factor are novel determinants of newborn thyroid (dys)function: the generation R
Tim I M Korevaar1, Eric A P Steegers, Sarah Schalekamp-Timmermans
1The Generation R Study Group (T.I.M.K., S.S.-T., V.W.V.J., M.M.) and Departments of Internal Medicine (T.I.M.K., Y.B.d.R., W.E.V., T.J.V., M.M., R.P.P.), Rotterdam Thyroid Center (T.I.M.K., W.E.V., T.J.V., M.M., R.P.P.), Epidemiology (S.L., A.H., H.T., V.W.V.J.), and Immunology (H.H.), Erasmus Medical Center, 3015 GE Rotterdam, The Netherlands; and Departments of Obstetrics and Gynecology (E.A.P.S., S.S.-T., W.V.), Clinical Chemistry (Y.B.d.R., H.R.), Endocrinology (S.M.P.F.d.M.K.-S., J.J.B.-S.), Pediatrics (V.W.V.J.), and Child and Adolescent Psychiatry (H.T.), Erasmus Medical Center, Sophia Children's Hospital, 3015 GJ Rotterdam, The Netherlands.
Insights
Fetal angiogenic factors soluble FMS-like tyrosine kinase-1 (sFlt1) and placental growth factor (PlGF) impact newborn thyroid function. Both abnormal and normal levels of these factors influence thyroid dysfunction risk, potentially affecting neurodevelopment.
Area of Science:
- Endocrinology
- Developmental Biology
- Perinatology
Background:
- Thyroid hormones are vital for fetal growth and neurodevelopment.
- Angiogenesis, crucial for fetal development, involves factors like placental growth factor (PlGF) and its antagonist, soluble FMS-like tyrosine kinase-1 (sFlt1).
- The thyroid gland's vascularity suggests a potential link between angiogenic factors and in utero thyrogenesis.
Purpose of the Study:
- To investigate the association between fetal angiogenic factors (sFlt1 and PlGF) and newborn thyroid function.
- To explore how these factors influence thyrogenesis during fetal development.
- To determine the impact of both abnormal and normal ranges of sFlt1 and PlGF on thyroid dysfunction.
Main Methods:
- Cord serum from 3525 newborns was analyzed for sFlt1, PlGF, TSH, and free T4 (FT4).
- Prospective cohort study design with adjustments for maternal and child covariates.
- Statistical analyses were performed to determine associations and risks.
Main Results:
- sFlt1 positively correlated with TSH and inversely with FT4.
- PlGF showed a positive association with FT4.
- Elevated sFlt1 and decreased PlGF increased the risk of hypothyroxinemia.
- Even normal-range sFlt1 levels demonstrated a dose-dependent effect on thyroid dysfunction, increasing risks for hypothyroxinemia and hyperthyrotropinemia.
Conclusions:
- Fetal sFlt1 and PlGF levels are significantly associated with newborn thyroid function.
- These angiogenic factors likely influence thyroid development in utero.
- Both abnormal and normal ranges of sFlt1 and PlGF impact newborn thyroid function, potentially linking to adverse neurodevelopmental outcomes.
Context:
Adequate thyroid hormone availability during fetal and early life is crucial for normal child growth and development. Fetal growth heavily depends on angiogenesis. Placental growth factor (PlGF) is a proangiogenic factor sharing high homology with vascular endothelial growth factor, whereas soluble FMS-like tyrosine kinase-1 (sFlt1) is a potent antagonist of vascular endothelial growth factor and PlGF signaling. Because the thyroid is a highly vascularized organ, we hypothesized that fetal angiogenic factors influence in utero thyrogenesis and impair newborn thyroid function. Therefore, we investigated the association between sFlt1 and PlGF on newborn thyroid function.
Design, Setting, And Participants:
sFlt1, PlGF, TSH, and free T4 (FT4) were determined in cord serum of 3525 newborns from a large prospective cohort study. Analyses were adjusted for relevant maternal and child covariates.
Results:
sFlt1 levels were positively associated with TSH (β 0.07 ± 0.02 mU/L; P < .001) and inversely with FT4 (β -0.58 ± 0.11; P < .001). PlGF showed a positive association with FT4 (β 0.19 ± 0.02; P < .001). Elevated levels of sFlt1 were associated with a 2.8-fold increased risk of hypothyroxinemia (P = .04). Decreased levels of PlGF were associated with a 6.7-fold increased risk of hypothyroxinemia (P < .001). Within the normal range, a dose-dependent effect of sFlt1 on thyroid dysfunction was observed: high-normal sFlt1 levels were associated with a 17.7-fold increased risk of hypothyroxinemia (P < .001) and a 2.7-fold increased risk of hyperthyrotropinemia (P = .01).
Conclusion:
Fetal angiogenic factors sFlt1 and PlGF are associated with newborn thyroid function. Possible effects are most likely mediated through effects on in utero thyrogenesis. Abnormal as well as normal-range fetal sFlt1 and PlGF levels influence the risk of impaired newborn thyroid function, which has been associated with adverse neurodevelopmental effects. These data provide important novel insights into the physiology of thyrogenesis and into the etiology of newborn thyroid (dys)function.
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