The maternal insulin-like growth factor (IGF) and IGF-binding protein response to trisomic pregnancy during the first trimester: a possible diagnostic tool for trisomy 18 pregnancies

Abstract

Many lines of evidence point to an important role for the insulin-like growth factors (IGFs) in embryonic and fetal growth in human pregnancy. The bioavailability of IGFs is modulated by IGF-binding proteins (IGFBP-1 to -6), whose permissive or inhibitory actions are regulated in part by posttranslational modification. In second and third trimester pregnancies, maternal IGFBP-1 is elevated in preeclampsia and intrauterine growth retardation. In the first trimester, trisomic pregnancies result in derangement of maternal serum levels of peptides, including hCG beta and pregnancy-associated plasma protein A. Trisomy 18 is characterized by growth failure in the first trimester, whereas trisomy 21 is not; thus, if maternal serum levels of IGFs and IGFBPs reflect fetal growth, changes specific to trisomy 18 may be expected. We report maternal serum levels of IGF-I, IGF-II, and IGFBP-1,-2, and -3; IGFBP-1 phosphorylation; and IGFBP-3 proteolysis in pregnancies (n = 139) complicated by trisomy 18 or trisomy 21 compared with those in normal controls. Maternal IGF-I, IGF-II, and IGFBP-3 showed no significant difference between fetuses with a normal karyotype and those with trisomy 18 or 21. The mean IGFBP-1 level was significantly higher and the mean IGFBP-2 level was lower in fetuses with trisomy 18 compared with normal fetuses [108.8 +/- 6.1 vs. 36.7 +/- 1.9 micrograms/L (P = 0.0001) and 81.2 +/- 5.5 vs. 206.1 +/- 10.2 micrograms/L (P = 0.0001), respectively]. There was no significant difference between the trisomy 21 and normal groups. The reduction in IGFBP-2 was confirmed by Western ligand and immunoblotting, and there was no evidence of variation in lower mol wt products to suggest differential proteolysis. IGFBP-1 phosphoforms and IGFBP-3 proteolysis were not significantly different between groups. The finding of altered maternal serum levels of IGFBP-1 and IGFBP-2 specific to pregnancies complicated by trisomy 18 suggests that these binding proteins may be important mediators of fetal growth in the first trimester, and the clear differences in the ratio of IGFBP-1 to -2 may serve as an additional diagnostic marker for trisomy 18 pregnancies.