title: Soluble Flt1 and placental growth factor are novel determinants of newborn thyroid (dys)function: the generation R study.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: The 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.
authors.forename: Tim I M
authors.initials: TI
authors.lastname: Korevaar
authors.forename: Eric A P
authors.initials: EA
authors.lastname: Steegers
authors.forename: Sarah
authors.initials: S
authors.lastname: Schalekamp-Timmermans
authors.forename: S
authors.initials: S
authors.lastname: Ligthart
authors.forename: Yolanda B
authors.initials: YB
authors.lastname: de Rijke
authors.forename: W Edward
authors.initials: WE
authors.lastname: Visser
authors.forename: Willy
authors.initials: W
authors.lastname: Visser
authors.forename: Sabine M P F
authors.initials: SM
authors.lastname: de Muinck Keizer-Schrama
authors.forename: Albert
authors.initials: A
authors.lastname: Hofman
authors.forename: Herbert
authors.initials: H
authors.lastname: Hooijkaas
authors.forename: Jacoba J
authors.initials: JJ
authors.lastname: Bongers-Schokking
authors.forename: Henk
authors.initials: H
authors.lastname: Russcher
authors.forename: Henning
authors.initials: H
authors.lastname: Tiemeier
authors.forename: Vincent W V
authors.initials: VW
authors.lastname: Jaddoe
authors.forename: Theo J
authors.initials: TJ
authors.lastname: Visser
authors.forename: Marco
authors.initials: M
authors.lastname: Medici
authors.forename: Robin P
authors.initials: RP
authors.lastname: Peeters
mesh_terms: D025461:Feedback, Physiological / Q000502:physiology; D005260:Female; D005312:Fetal Blood; D005865:Gestational Age; D006801:Humans; D006980:Hyperthyroidism / Q000097:blood* / Q000196:embryology / Q000503:physiopathology; D007037:Hypothyroidism / Q000097:blood* / Q000196:embryology / Q000503:physiopathology; D007231:Infant, Newborn; D008297:Male; D000072483:Placenta Growth Factor; D011247:Pregnancy; D011257:Pregnancy Proteins / Q000097:blood*; D018570:Risk Assessment; D012995:Solubility; D013961:Thyroid Gland / Q000002:abnormalities / Q000502:physiology*; D013972:Thyrotropin / Q000097:blood; D013974:Thyroxine / Q000097:blood; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000097:blood*
chemical_list: C000608036:PGF protein, human; D011257:Pregnancy Proteins; D000072483:Placenta Growth Factor; D013972:Thyrotropin; C501162:FLT1 protein, human; D040281:Vascular Endothelial Growth Factor Receptor-1; D013974:Thyroxine