Placental proteases PAPP-A and PAPP-A2, the binding proteins they cleave (IGFBP-4 and -5), and IGF-I and IGF-II: Levels in umbilical cord blood and associations with birth weight and length

Metabolism. 2019 Nov:100:153959. doi: 10.1016/j.metabol.2019.153959. Epub 2019 Aug 8.

Abstract

Background: A newborn's birth weight for gestational age provides important insights into his or her fetal growth and well-being. While the underlying mechanisms regulating fetal growth remain to be fully elucidated, the IGF axis plays an important role. Some components of this axis have been well-characterized in umbilical cord blood, but others have not yet been studied. We measured the proteases PAPP-A and PAPP-A2, the binding proteins they cleave (IGFBP-4 and -5), and the established molecules IGF-I and -II in umbilical cord blood to better characterize the IGF axis in relation to birth weight and length.

Methods: We performed a case-control study of 180 neonates born at a tertiary teaching hospital in Boston. To maximize power, infants were recruited in a 1:3:1 ratio with 37 SGA, 111 AGA, and 37 LGA infants matched by gestational age, sex, and delivery mode. IGF-I, IGF-II, IGFBP-4, IGFBP-5, PAPP-A, and PAPP-A2 were measured in umbilical cord blood by ELISA. Associations between birth weight and birth length Z-scores and the Z-scores of the above molecules were analyzed using linear regression models and analysis of covariance.

Results: Birth weight and length Z-scores were positively associated with Z-scores of IGF-I, IGF-II, total IGFBP-4, and IGFBP-5, with IGF-I having the strongest association. Birth weight and length Z-scores were negatively associated with Z-scores of intact IGFBP-4, PAPP-A, and PAPP-A2 levels.

Conclusions: We confirm previous findings of significant associations between the IGFs in cord blood and newborn size and for the first time show positive associations between cord blood total IGFBP-4 and -5 and birth weight and a negative association between intact IGFBP-4 and birth weight. We also show for the first time a reciprocal relationship between cord blood levels of PAPP-A and PAPP-A2 and newborn size. The implications of these findings need to be further examined in large longitudinal studies and likely have diagnostic and therapeutic potential.

Keywords: Cord blood; Fetal growth; IGF axis; IGF binding proteins; Placental proteases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Case-Control Studies
  • Female
  • Humans
  • Infant, Newborn
  • Insulin-Like Growth Factor Binding Protein 4 / metabolism*
  • Insulin-Like Growth Factor Binding Protein 5 / metabolism*
  • Insulin-Like Growth Factor I / metabolism*
  • Insulin-Like Growth Factor II / metabolism*
  • Isoenzymes / chemistry
  • Isoenzymes / metabolism*
  • Placenta / enzymology*
  • Pregnancy
  • Pregnancy-Associated Plasma Protein-A / chemistry
  • Pregnancy-Associated Plasma Protein-A / metabolism*
  • Protein Binding
  • Proteolysis

Substances

  • Insulin-Like Growth Factor Binding Protein 4
  • Insulin-Like Growth Factor Binding Protein 5
  • Isoenzymes
  • Insulin-Like Growth Factor I
  • Insulin-Like Growth Factor II
  • Pregnancy-Associated Plasma Protein-A