SERUM INSULIN-LIKE GROWTH FACTOR-BINDING PROTEIN-3 (IGFBP-3) LEVELS AND IGFBP-3 PROTEASE ACTIVITY IN NORMAL, ABNORMAL, AND MULTIPLE HUMAN-PREGNANCY

Proteolytic activity directed against insulin-like growth factor (IGF) -binding protein-3 (IGFBP-3) is found in human pregnancy serum. We hav e investigated changes in this protease activity in pregnancies in whi ch the fetus is small for gestational age and in multiple pregnancies. Maternal serum was obtained from 18 singleton pregnancies at 27 weeks gestational age (GA), and matched fetal serum was collected by cordoc entesis. Fetuses were appropriate for GA (AGA; n = 6), small for gesta tional age (SGA) with evidence of uteroplacental insufficiency (UPI; s tarved SGA; n = 6), or SGA without UPI (nonstarved SGA; n = 6). In a s econd study, serum was obtained from women with singleton (n = 10), tw in (n = 10), and higher multiple pregnancies (n = 10) at 9 weeks GA. A ll women with more than three fetuses underwent embryo reduction to 2 fetuses before 15 weeks gestation, when a second serum sample was obta ined. Circulating IGF-I and IGF-II were measured by RIA, and IGFBP-3 w as measured by both RIA and immunoradiometric assay. IGFBP-3 protease activity was assessed by Western Ligand blotting after incubation with a normal nonpregnancy sera pool, immunoblotting, and specific proteas e assay. In the growth study, circulating maternal IGF-I and IGFBP-3 l evels were not different in the three groups, but fetal IGF-I and IGFB P-3 levels were significantly lower in the UPI fetuses (IGF-I, 6.9 +/- 0.5 mu g/L; IGFBP-3, 547 +/- 70 mu g/L) than in either the nonstarved SGA fetuses (IGF-I, 27.8 +/- 6.3; IGFBP-3, 769 +/- 41 mu g/L; P < 0.0 1) or the AGA fetuses (IGF-I, 39.4 +/- 3.4; IGFBP-3, 872 +/- 91 mu g/L ; P < 0.01). Maternal serum IGFBP-3 protease activity, measured by pro tease using [I-125]IGFBP-3 as substrate, was increased in pregnancies complicated by UPI compared with GA-matched pregnancies in which the f etus was AGA or nonstarved SGA. No significant fetal serum protease ac tivity was demonstrated. In the multiple pregnancies, IGFBP-3 rose sig nificantly from 9-15 weeks GA in singleton (P = 0.005), twin (P = 0.00 4), and multiple (P = 0.007) pregnancies, and levels were higher in mo thers of multiple pregnancies than in those of twin (P < 0.05) or sing leton (P < 0.01) pregnancies at both 9 and 15 weeks GA. IGF-I levels w ere not different in the three groups and did not significantly increa se between 9-15 weeks GA. Maternal IGFBP-3 protease activity was great er in multiple pregnancy than in GA-matched singleton or twin pregnanc ies, and this increase was not reversed by embryo reduction. Different ial proteolytic activity in mothers with multiple fetuses or fetuses a ffected by UPI may reflect modification of IGF biological activity in situations in which fetal growth is threatened.