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ORIGINAL RESEARCH |
From the Helsinki City Maternity Hospital and Department of Obstetrics and Gynecology, Helsinki University Central Hospital, Helsinki, Finland.
Address reprint requests to: Timo Laatikainen, MD, PhD Helsinki City Maternity Hospital Sofianlehdonkatu 5A Helsinki, 00610 Finland
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Abstract |
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Methods: Concentrations of IGFBP-1 were measured using immunoenzymometric assay in serum samples collected for alpha-fetoprotein (AFP) and free ß subunit of hCG (free ß-hCG) determinations in a Down syndrome screening program at 16 weeks’ gestation in a population-based cohort of 1049 nulliparous women. After exclusion of subjects with multiple pregnancies, insulin-dependent diabetes, major fetal malformations, and incomplete data, 917 subjects remained eligible.
Results: The mean levels (± standard deviation) of IGFBP-1 were significantly lower in 34 women who later developed preeclampsia (73 ± 43 µg/L, P < .01) and in 80 women with White A diabetes (84.7 ± 53 µg/L, P < .01) compared with controls (103 ± 58 µg/L). In seven women with White A diabetes and subsequent preeclampsia IGFBP-1 levels were especially low (41 ± 34 µg/L). The concentrations of AFP and free ß-hCG in the subgroups with hypertensive disorders were not significantly different from those of normotensive women.
Conclusion: Decreased IGFBP-1 levels at 16 weeks’ gestation in women who develop preeclampsia might indicate impaired decidual function. Hyperinsulinemia, a known risk factor for preeclampsia, might contribute to decreased concentrations of serum IGFBP-1. However, due to low sensitivity, assay of serum IGFBP-1 was not clinically valuable for predicting preeclampsia.
Insulin-like growth factor–binding protein-1 (IGFBP-1), previously called placental protein 12, was originally isolated from the placenta but it is now known to be synthesized by the predecidualized and decidualized endometrium, where its synthesis dramatically increases during early pregnancy.1–3 In nonpregnant women the liver is the major source of IGFBP-1 in the circulation, where concentrations are negatively regulated by insulin.1,4 During the first and second trimesters, IGFBP-1 levels in maternal serum increase substantially,2 suggesting that the decidua significantly contributes to elevated levels of the protein in maternal circulation.2,3 Major proportions of insulin-like growth factors I and II (IGF I and II) in the circulation are bound to IGFBP-3, which is regulated by growth hormone, and to a lesser extent to IGFBP-1.
Increased levels of circulating IGFBP-1 have been reported in the third trimester in women with preeclampsia,6–8 but there is limited information on serum IGFBP-1 levels at early stages of gestation, during implantation and placentation, when signs of preeclampsia are not yet evident.9 We decided to measure the concentrations of IGFBP-1 in the serum of nulliparous women participating in a Down syndrome screening program to determine whether levels of that protein at the 16th week of gestation are different in women who later develop hypertensive disorders compared with those who remain normotensive.
Women with unexplained elevation of AFP and free ß-hCG values10–13 in maternal serum in the second trimester have been reported to have a higher risk of developing preeclampsia. However, other investigators disputed the value of those markers for predicting it.14 Because AFP and ß-hCG levels were measured for Down syndrome screening, we wanted to determine whether they were abnormal in women who later developed hypertensive disorders.
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Materials and Methods |
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Clinical data, including blood pressure (BP) values and measurement of protein and glucose in urine at each trimester, were collected from the medical records at maternity care units where the women were examined 12 times during pregnancy. Data on those admitted to the hospital and data on deliveries were collected from files at the Helsinki City and University Hospitals, which are responsible for maternity care and deliveries in the area. Twenty-eight women were excluded, 12 for twin pregnancies, five for spontaneous abortions, four for diagnosed fetal defects and terminations of pregnancy, and seven for insulin-dependent diabetes mellitus. Data were missing or incomplete in 104, which were also excluded, leaving 917 women eligible.
Preeclampsia was diagnosed if there were increments in systolic and diastolic BP levels of 30 and 15 mmHg, respectively, or greater, 6 or more hours apart, or an absolute BP of 140/90 mmHg or greater, and proteinuria of 300 mg or more per day after the 20th gestational week in normotensive women. Preeclampsia was considered severe if BP was greater than 160/110 mmHg or if there was consistent proteinuria of more than 5000 mg/day. The criteria for gestational hypertension were similar to those for preeclampsia, except for proteinuria. Superimposed preeclampsia was diagnosed if preeclampsia occurred in women who already had chronic hypertension (blood pressure at least 140/90 mmHg). The mean arterial pressure (MAP) was calculated using the following formula: MAP = (2 x diastolic BP + systolic BP)/3.
The presence of glucosuria and proteinuria was tested by dipstick method. The amount of protein was measured in a 24-hour urine sample in some cases. An oral glucose loading test was done if urinary glucose test results were positive twice or if the body mass index was 25 or greater and in women over 40 years of age. After overnight fast, venous blood samples were collected, the women took 75 g of oral glucose, and blood sampling was repeated at 1 and 2 hours. Values of at least 4.8 mmol/L (87 mg/100 mL) at 0 hour, 10 mmol/L (180 mg/100 mL) at 1 hour, and 8.7 mmol/L (157 mg/100 mL) at 2 hours were considered abnormal.
Maternal serum free ß-hCG and AFP concentrations were measured simultaneously by time-resolved fluoro-immunoassay (Delfia, Wallac Ltd., Turku, Finland).15
Concentrations of IGFBP-1 in maternal serum were measured by immunoenzymometric assay (IGFBP-1 IEMA test, Medix Biochemica, Kauniainen, Finland) as described previously.16 The intra-assay and interassay coefficients of variation were 4% and 7%, respectively.
Analysis of variance with Dunnett’s multiple comparison test was used when more than two groups were compared, unpaired Student t test, Mann-Whitney U test, and Fisher exact test were used in comparisons between two groups. P < .05 was considered statistically significant.
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Results |
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). Values of IGFBP-1 were not statistically significantly different between the subgroup of 11 women with severe preeclampsia (58 ± 30 µg/L, 95% confidence internal [CI] 37, 79) and the remaining 23 women with mild or moderate disease (80 ± 46 µg/L, 95% CI 59, 101). No statistically significant differences were found when the subgroups of women with gestational or essential hypertension were compared with normotensive women (Table 2).
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), and levels were lowest in the subgroup with White A diabetes plus preeclampsia. There were no significant differences in serum AFP and free ß-hCG concentrations between normotensive and hypertensive women (Table 4).
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, which shows individual multiples of the median (MoM). The distribution of the IGFBP-1 values was different from those of AFP and free ß-hCG, with IGFBP-1 values being less than 0.5 MoM in nine of 34 cases (26%) but in no cases for AFP or free ß-hCG.
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). The value of at least two MoM was chosen for AFP and free ß-hCG, and at most 0.5 MoM for IGFBP-1 for predicting gestational hypertension and preeclampsia (Table 5).
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Discussion |
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Our findings confirm those of de Groot et al,9 who showed that IGFBP-1 levels in maternal plasma increased significantly from first to second trimesters in women who remained normotensive but did not increase the same way in women who had preeclampsia. That lesser increase in women who later developed preeclampsia might be related to impaired decidual function and defective placentation. Although it is generally believed that IGFBP-1 inhibits the stimulating effect of insulin-like growth factors on trophoblast proliferation,1,4 there is evidence from in vitro experiments that suggests that IGFBP-1 also acts independently or through integrins. For example, it stimulates migration of first-trimester human cytotrophoblasts.17,18 Thus, the exact role of the protein in the placentation process is not known.
The IGFBP-1 gene has multiple regulatory elements in its promoter that act independently or together to regulate its expression.19 Insulin inhibits and glucocorticoids stimulate its production at the transcriptional level. Decreased IGFBP-1 levels have been reported in various states of hyperinsulinemia and insulin resistance in nonpregnant women.4,5 Pregnancy itself is an insulin-resistant state, and hyperinsulinemia has also been noted in nonpregnant women with hypertension.20 Insulin concentrations in response to an intravenous glucose load were higher in women with hypertension in pregnancy than normotensive controls,21 but a recent study22 showed normal insulin response to intravenous glucose tolerance tests in preeclamptic women. Findings that pregnancyinduced hypertension is more common in women with impaired glucose tolerance23 and that hyperinsulinemia can be detected in women several years after their preeclamptic first pregnancy24 suggest that insulin resistance is an underlying factor in women in whom hypertensive disorders develop during pregnancy. We cannot exclude hyper-insulinemia as a factor for explaining at least part of the lower levels of IGFBP-1 in early gestation in women who develop preeclampsia later in gestation. Insulin concentrations were not measured in our study cohort.
In the present study, 80 (8.7%) of 917 women developed White A diabetes during the third trimester, and in seven (8.9%) of them preeclampsia developed compared with 27 (3.2%, P = .027) nondiabetic women. Although our sample was small, our findings support earlier results that pregnant women with White A diabetes have increased risk of developing preeclampsia.23 In those women IGFBP-1 concentrations were very low at 16 weeks’ gestation, before White A diabetes or preeclampsia was apparent, suggesting a combined effect of impaired decidual function and hyper-insulinemia on circulating IGFBP-1. When either of those disorders was detectable clinically, the levels of IGFBP-1 were elevated.4,6,7 Several investigators have shown that during the third trimester, IGFBP-1 levels are higher in maternal plasma in women with preeclampsia or fetal growth restriction.6–8 Data from a recent study by Tazuke et al25 support the hypothesis that hypoxia, caused by decreased placental perfusion, stimulates IGFBP-1 production. Hypoxia is probably not apparent until the third trimester, so its effect is not detectable during the second trimester.
Although IGFBP-1 levels vary in pregnant women who later have preeclampsia, concentrations of IGFBP-3 do not differ between preeclamptic and normal women during the second and third trimesters of pregnancy,26 which can be explained by the different regulatory mechanisms of those two binding proteins.
Although several authors10–13 found differences in AFP and free ß-hCG levels between normotensive women and those in whom preeclampsia develops, the present findings indicate that abnormal AFP and free ß-hCG results cannot reliably predict pregnancy-induced hypertensive disorders. In this respect, IGFBP-1 appears to be a better marker than AFP or free ß-hCG, although not good enough for effective clinical screening.
Previous studies showed that during clinical preeclampsia and diabetes, serum levels of IGFBP-1 were elevated. In diabetes, the change from decreased to increased serum levels of serum IGFBP-1 is believed to indicate the change in portal venous insulin concentrations during the change from a hyperinsulinemic to an insulin-deficient stage,27 the reason for which is unknown.
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Footnotes |
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Received April 30, 1999. Received in revised form July 6, 1999. Accepted July 22, 1999.
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References |
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2. Rutanen EM, Bohn H, Seppälä M. Radioimmunoassay of placental protein 12: Levels in amniotic fluid, cord blood, and serum of healthy adults, pregnant women and patients with trophoblastic disease. Am J Obstet Gynecol 1982;144:460–3.[Medline]
3. Rutanen EM, Menabawey M, Isaka K, Bohn H, Chard T, Grudzinskas JG. Synthesis of placental protein 12 by the decidua from early pregnancy. J Clin Endocrinol Metab 1986;63:675–9.[Abstract]
4. Jones JI, Clemmons D. Insulin-like growth factors and their binding proteins. Endocrinol Rev 1995;16:3–34.[Medline]
5. Suikkari AM, Koivisto VA, Rutanen EM, Yki-Järvinen H, Karonen SL, Seppälä M. Insulin regulates the serum levels of low molecular weight insulin-like growth factor-binding protein. J Clin Endocrinol Metab 1988;66:266–72.[Abstract]
6. Giudice LC, Martina NA, Crystal RA, Tazuke S, Druzin M. Insulin-like growth factor binding protein-1 at the maternal-fetal interface and insulin-like growth factor-I, insulin-like growth factor II, and insulin-like growth factor binding protein-1 in the circulation of women with severe preeclampsia. Am J Obstet Gynecol 1997;176:51–8.
7. Iino K, Sjöberg J, Seppälä M. Elevated circulating levels of a decidual protein, placental protein 12, in preeclampsia. Obstet Gynecol 1986;68:58–60.[Medline]
8. Howell RJS, Economides D, Teisner B, Farkas AG, Chard T. Placental protein 12 and 14 in pre-eclampsia. Acta Obstet Gynecol 1989;68:237–40.
9. de Groot CJM, O’Brien TJ, Taylor RN. Biochemical evidence of impaired trophoblastic invasion of decidual stroma in women destined to have preeclampsia. Am J Obstet Gynecol 1996;175: 24–9.[Medline]
10. Hamilton MPR, Abdalla HI, Whitfield CR. Significance of raised maternal serum alpha-fetoprotein in singleton pregnancies with normally formed fetuses. Obstet Gynecol 1985;65:465–70.[Medline]
11. Gonen R, Perez R, David M, Dar H, Merksamer R, Sharf M. The association between unexplained second-trimester maternal serum hCG elevation and pregnancy complications. Obstet Gynecol 1992; 80:83–6.
12. Muller F, Savey L, Le Fiblec B, Bussières L, Ndaizamba G, Colau JC, et al. Maternal serum human chorionic gonadotropin level at fifteen weeks is a predictor for preeclampsia. Am J Obstet Gynecol 1996;175:37–40.[Medline]
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14. Morssink LP, Heringa MP, Beekhuis JR, DeWolf BTHM, Mantingh A. The association between hypertensive disorders of pregnancy and abnormal second-trimester maternal serum levels of hCG and alpha-fetoprotein. Obstet Gynecol 1997;89:666–70.[Abstract]
15. Pettersson K, Alfthan H, Stenman UH, Turpeinen U, Suonpää M, Söderholm J, et al. Simultaneous assay of alfafetoprotein and free ß subunit of human chorionic gonadotropin by dual-label timeresolved immunofluorometric assay. Clin Chem 1993;39:2084–9.[Abstract]
16. Rutanen EM, Kärkkäinen TH, Lehtovirta J, Uotila JT, Hinkula MK, Hartikainen AL. Evaluation of a rapid strip test for insulin-like growth factor binding protein-1 in the diagnosis of ruptured fetal membranes. Clin Chim Acta 1996;253:91–101.[Medline]
17. Irving JA, Lala PK. Functional role of cell surface integrins on human trophoblast cell migration: Regulation by TGF-alpha, IGF-II, and IGFBP-1. Exp Cell Res 1995;217:419–27.[Medline]
18. Hamilton GS, Lysiak JJ, Han VK, Lala PK. Autocrine-paracrine regulation of human trophoblast invasiveness by insulin-like growth factor (IGF)-II and IGF-binding protein (IGFBP)-1. Exp Cell Res 1998;244:147–56.[Medline]
19. Powell DR, Allander SV, Scheimann AO, Wasserman RM, Durham SK, Suwanichkul A. Multiple proteins bind the insulin response element in the human IGFBP-1 promoter. Prog Growth Factor Res 1995;6:93–101.[Medline]
20. Modan M, Halkin H, Almog S, Lusky A, Eshkol A, Shefi M, et al. Hyperinsulinemia. A link between hypertension, obesity and glucose intolerance. J Clin Invest 1985;75:809–17.
21. Solomon CG, Graves SW, Green MF, Seely EW. Glucose intolerance as a predictor of hypertension in pregnancy. Hypertension 1994;23:717–21.
22. Roberts RN, Henriksen JE, Hadden DR. Insulin sensitivity in pre-eclampsia. Br J Obstet Gynaecol 1998;105:1095–100.[Medline]
23. Suhonen L, Teramo K. Hypertension and preeclampsia in women with gestational glucose intolerance. Acta Obstet Gynecol Scand 1993;72:269–72.[Medline]
24. Laivuori H, Tikkanen MJ, Ylikorkala O. Hyperinsulinemia 17 years after preeclamptic first pregnancy. J Clin Endocrinol Metab 1996; 81:2908–11.[Abstract]
25. Tazuke SI, Mazure NM, Sugawara J, Carland G, Faessen GH, Suen LF, et al. Hypoxia stimulates insulin-like growth factor binding protein 1 (IGFBP-1) gene expression in Hep G2 cells: A possible model for IGFBP-1 expression in fetal hypoxia. Proc Natl Acad Sci USA 1998;95:10188–93.
26. Varma M, DeGroot CJM, Lanyi S, Taylor RN. Evaluation of plasma insulin-like growth factor binding protein-3 as a potential predictor of preeclampsia. Am J Obstet Gynecol 1993;169:995–9.[Medline]
27. Yki-Järvinen H, Mäkimattila S, Utriainen T, Rutanen EM. Portal insulin concentrations rather than insulin sensitivity regulate serum sex hormone-binding globulin and insulin-like growth factor binding protein in vivo. J Clin Endocrinol Metab 1995;80:3227–32.[Abstract]
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