HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by NUUTILA, M. Articles by RUTANEN, E.-M. Search for Related Content PubMed PubMed Citation Articles by NUUTILA, M. Articles by RUTANEN, E.-M.

Phosphorylated Isoforms of Insulin-Like Growth Factor Binding Protein-1 in the Cervix as a Predictor of Cervical Ripeness

From the Department of Obstetrics and Gynecology, Helsinki University Central Hospital, Helsinki, Finland; and Medix Biochemica, Kauniainen, Finland.

Address reprint requests to: Mika Nuutila, MD Department of Obstetrics and Gynecology Helsinki University Central Hospital Haartmaninkatu 2, PO Box 140 FIN-00029 HUCH Finland E-mail: mika.nuutila{at}huch.fi

	Abstract

Top Abstract Materials and Methods Results Discussion References

 
Objective: To study the isoforms of insulin-like growth factor binding protein-1 (IGFBP-1) in cervical secretion and to evaluate whether their assessment could serve in prediction of cervical ripeness at term.

Methods: We measured the concentrations of IGFBP-1 in cervical swab samples of 64 women scheduled for labor induction by amniotomy or cervical ripening with prostaglandin E₂ gel. Two immunoenzymometric assays were used: a previously described assay 1, which detects the nonphosphorylated and lesser phosphorylated isoforms, and a novel assay 2, which detects the lesser and highly phosphorylated isoforms of IGFBP-1. A set of 39 amniotic fluid (AF) samples also was analyzed to compare the phosphorylation status of IGFBP-1 in cervical secretion with that in AF.

Results: In all cervical samples, IGFBP-1 concentration was higher by assay 2 than by assay 1, whereas in all AF samples, the results were the opposite. Initially, the median IGFBP-1 concentration in the ripe cervices (Bishop scores 6 or greater; n = 29) was approximately four times as high as that in the unripe cervices (Bishop scores 5 or less; n = 35). The cervical IGFBP-1 concentrations increased eight-fold in 6 hours after the first application of PGE₂.

Conclusion: Phosphorylated isoforms of IGFBP-1, different from those in AF, are present in the cervical secretion of women with intact fetal membranes and reflect cervical ripeness. A bedside test for those IGFBP-1 isoforms might help in predicting amenability for labor induction.

The causative and regulating factors in cervical ripening are largely unknown,¹ although the impact of the release of prostaglandin (PG) E₂ from the amnion and choriodecidual tissue is established.² This has led to the use of exogenous PGE₂ for cervical ripening.^3,4

In the United States, induction of labor is performed in as many as 25% of pregnancies.⁵ Prediction of the success of induction has been based traditionally on Bishop scores.⁶ Higher scores (9 or greater) predict high success; transitional (6 to 8) and low (5 or less) scores predict intermediate and lower success. However, the specificity of this prediction is poor.⁷ There is, therefore, a need for a biochemical test to predict cervical ripeness and the success of labor induction more accurately.

The cytokines, such as interleukins -1, -6, and -8, tumor necrosis factor alpha, and fetal fibronectin, are involved in cervical ripening and initiation of labor.^2,7–10 Produced in the choriodecidual interface, fetal fibronectin leaks into the cervix and the vagina, becomes detectable usually 1–2 weeks before the onset of labor,^11,12 and may predict cervical ripening and the success of labor induction.^7,10 The presence of fetal fibronectin in the cervical secretion may thus indicate a risk for preterm birth in a high-risk population.^11,12

Insulin-like growth factor binding protein-1 (IGFBP-1; previously also called placental protein-12) is a 25-kD protein synthesized and secreted by the fetal and adult liver and maternal decidua.^13,14 In the maternal circulation, concentration of IGFBP-1 increases during pregnancy, and it is a major protein in the amniotic fluid (AF) from the second trimester of pregnancy until term.¹⁵ The phosphorylation status of IGFBP-1 varies in different body fluids and tissues.^16–18 In AF, the nonphosphorylated isoform of IGFBP-1 predominates, but all phosphorylated isoforms except the highly phosphorylated isoform of IGFBP-1 exist.^17,18 In contrast, human decidual cells secrete predominantly the phosphorylated isoforms of IGFBP-1, including the highly phosphorylated one.^17,18 The detection of AF isoforms of IGFBP-1 in cervical and vaginal samples is diagnostic for the rupture of fetal membranes.^19,20

We have now used the previously described IGFBP-1 assay that detects the AF isoforms of IGFBP-1 and a new assay that detects the phosphorylated IGFBP-1 isoforms, including the highly phosphorylated one, to clarify the phosphorylation status, and hence the origin of IGFBP-1 in the cervical secretion of women with intact fetal membranes, and to evaluate whether IGFBP-1 in the cervical secretion reflects cervical ripeness at term.

	Materials and Methods

Top Abstract Materials and Methods Results Discussion References

 
Sixty-four consecutive women with a single live fetus in cephalic presentation scheduled for induction of labor between 36 and 42 weeks’ gestation from January through April 1998 were recruited for the study, which was approved by the institutional review board. The indications for labor induction are shown in Table 1. The gestational age was based on fetal sonographic measurements (biparietal diameter and femur length) at 17 to 18 weeks’ gestation. Each woman gave written informed consent. All women were examined by the same doctor (MN), immediately before amniotomy or the first application of PGE₂ gel. The ripeness of the cervix was evaluated by means of Bishop scores⁶; 29 patients had Bishop scores 6 or greater, indicating cervical ripeness, and 35 had Bishop scores 5 or less, indicating unripe cervix. All had intact membranes by clinical examination and a negative test result in a commercial rapid strip test for ruptured fetal membranes (PROM test, Medix Biochemica, Kauniainen, Finland)¹⁹ based on the detection (greater than 50 µg/L) of AF-derived IGFBP-1 in cervical secretion. None of the subjects had evidence of active labor, either subjectively or by cardiotochography recording.

Immediately before the cervical assessment, two Dacron swab samples were taken simultaneously by speculum examination from the external os of the cervix of all 64 women. The specimens were extracted in 0.5 mL of assay buffer as described previously.¹⁹ One specimen was used immediately for the PROM test (Medix Biochemica),¹⁹ and the result was read in 2–5 minutes. The other specimen was frozen and stored at -20C until the IGFBP-1 concentrations were measured. In the women with unripe cervices, sampling was repeated before digital examination of the cervix at 6,12, and 18 hours, ie, before each reapplication of PGE₂ gel or before amniotomy (Bishop scores 6 or greater).

In addition, AF samples, collected previously from 39 parturients, different from the study subjects, between 36 and 42 weeks’ gestation either at amniocentesis performed for fetal lung maturity or at amniotomy for labor induction and stored at -20C, were analyzed for a comparison of the relationship of IGFBP-1 phosphoisoforms in AF and cervical secretion.

Two immunoenzymometric assays that detect different phosphoforms of IGFBP-1 were used. Assay 1, employing monoclonal antibody 6305²¹ (IGFBP-1 IEMA test, Medix Biochemica) has been described previously.¹⁹ This antibody detects the nonphosphorylated and less-phosphorylated isoforms of IGFBP-1, ie, those present in AF.^17,18 Assay 2 uses monoclonal antibody 6303²¹ (Medix Biochemica) and, unlike monoclonal antibody 6305, recognizes the highly phosphorylated isoform of IGFBP-1 that is the primary isoform in decidua but is not present in AF.^17,18 Both antibodies bind the less-phosphorylated IGFBP-1 isoforms.^17,18

In assay 2, microtiter wells (Nunc, Maxisorb, Roskilde, Denmark) were coated with 150 µL of antibody in 50 mM phosphate buffer (10 µg/mL), pH 6.0. After overnight incubation, the wells were washed with Tween-20 (0.05%) (Bio-Rad Laboratories, Hercules, CA), blocked with 0.5% bovine albumin in 50 mM phosphate buffer, dried, and used for the assay. In the assay, 50 µL of assay buffer (50 mM Na₂HPO₄, 50 mM NaCl, 50 mM NaSCN, 10 mM ethylenediaminetetraacetic acid tetrasodium salt [Merck, Darmstadt, Germany], 0.05% 3-[(cholamidopropyl) dimethylammonio]-1-propane sulphonate, 0.3% bovine albumin, 0.03% Tween-20 [Bio-Rad Laboratories], 2 µL/mL normal mouse serum and 0.1% Proclin 300 [Supelco, Bellefonte, PA], pH 8.5), and 50 µL of standard or extracted cervical sample were added into each well. After 30 minutes of incubation and washing with 0.05% Tween-20 (Bio-Rad Laboratories), 100 µL of another antibody labeled with horseradish peroxidase (6301-HRP) diluted 1:50 in the assay buffer was added to each well and incubated for 15 minutes. After washing, 100 µL of substrate (2,2'-azino-di-[3-ethylbenzthiazo-line sulphonate (6)]) (ABTS Peroxidase Substrate, Kirkegaard-Perry Laboratories, Gaithersburg, MD) was added. After 15 minutes, the reaction was stopped by 50 µL of 4% oxalic acid. The absorbances were measured at 415 nm, and the results were read from the standard curve. The detection limit of the assay is 0.3 µg/L, and the intra- and interassay variations were 4.6% and 6.4%, respectively. The linearity of the diluted decidual cytosols and AF samples in the assay buffer was 94–132% and recovery 100–128%, and prostaglandin (PG) does not interfere with this assay (data not shown).

All samples were measured in duplicate, and for each set of samples, the two assays were performed in parallel. The end points for the study were comparison of the IGFBP-1 isoforms present in AF and cervical secretion of women with intact fetal membranes; comparison of the cervical IGFBP-1 concentrations in the unripe and ripe cervix; and comparison of the changes in the cervical IGFBP-1 levels after consecutive PGE₂ applications.

If amniotomy could not be performed (Bishop scores less than 6) after 18 hours and three applications of PGE₂ gel, the induction was judged a failure.

The skewness of the IGFBP-1 values was corrected by logarithmic or exponential transformations before applying parametric tests. The two-tailed t test and the Mann-Whitney test were used for comparison of the cervical IGFBP-1 concentrations between women with unripe and ripe cervix. A multiple logistic regression for the prediction of cervical ripeness was performed including calculations of adjusted odds ratios (ORs) and their 95% confidence intervals. An analysis of variance on repeated measures was applied on the IGFBP-1 levels before and during the PGE₂ treatment. The ² test was used for four-fold tables with Yates’ correction when appropriate. The receiver operating characteristic curves were established by plotting sensitivity (true-positive rate) against 100-specificity (false-positive rate).²² A P value < .05 was considered significant. All calculations were done with NCSS 97 statistical package (NCSS, Kaysville, UT).

	Results

Top Abstract Materials and Methods Results Discussion References

 
The clinical characteristics of the women in the two study groups were otherwise comparable, but the amniotomy group with ripe cervix had fewer nulliparous women (Table 1). The amniotomy-to-vaginal delivery time in women with a ripe cervix was significantly shorter (5.6 ± 2.9 hours; mean ± standard deviation [SD]) than that in women with an initially unripe cervix (8.1 ± 4.3 hours) (P < .01). Cesarean delivery was performed in two cases for failed cervical ripening (Figures 1 and 2), in three cases for failure to progress, and in two cases for fetal asphyxia. The neonatal outcome in all these women was uneventful (Table 1).

View larger version (26K): [in this window] [in a new window]   Figure 1. Cervical IGFBP-1 concentrations by assay 1 at 6-hour intervals before each application of prostaglandin E2 gel. The end of each line denotes ripe cervix allowing amniotomy; the squares denote treatment failure followed by a cesarean delivery. IGFBP-1 = insulin-like growth factor binding protein-1.

View larger version (26K): [in this window] [in a new window]   Figure 2. Cervical IGFBP-1 concentrations by assay 2 at 6-hour intervals before each application of prostaglandin E2 gel. The end of each line denotes ripe cervix allowing amniotomy; the squares denote treatment failure followed by a cesarean delivery. IGFBP-1 = insulin-like growth factor binding protein-1.

An analysis of variance on repeated measures was applied on the log IGFBP-1 concentrations measured at 0, 6, 12, and 18 hours during the ripening process (Figures 1 and 2). The median IGFBP-1 level 6 hours after administration of PGE₂ was significantly higher (assay 1: 20.3 µg/L; assay 2: 51.0 µg/L) (P = .001) than the basal levels, and amniotomy could be performed in 30 women (Figures 1 and 2). Five women received a second dose of PGE₂, and amniotomy could be performed 6 hours later in two women (Figures 1 and 2). The remaining three women received a third application of PGE₂ gel, and 18 hours after the start of the cervical ripening, amniotomy could still be performed in one woman (Figures 1 and 2). The changes of the IGFBP-1 levels were not statistically significant from 0 to 6, 12, or 18 hours in the five women who received two or three applications of PGE₂. The IGFBP-1 concentration at the first examination or immediately before amniotomy failed to predict the amniotomy-to-vaginal delivery time (data not shown).

An IGFBP-1 concentration of 6 µg/L with assay 1 and 26 µg/L with assay 2 predicted cervical ripeness (Bishop scores 6 or greater) with a sensitivity of 52% and 53%, respectively. The false-positive rate for both tests was 20% (Figures 3A and 3B).

View larger version (17K): [in this window] [in a new window]   Figure 3. Receiver operating characteristic curves: sensitivity and 100-specificity for various values of cervical IGFBP-1 concentrations (µg/L) measured by assay 1 (A) and assay 2 (B) in predicting cervical maturity (Bishop scores 5 or greater). IGFBP-1 = insulin-like growth factor binding protein-1.

	Discussion

Top Abstract Materials and Methods Results Discussion References

Insulin-like growth factor binding protein-1 is the major secretory protein of human decidua,^13,14 and its concentration in AF is 100 to 1000 times higher than that in serum.¹⁵ Thus, this protein is an ideal marker for AF, and its detection in cervical/vaginal fluid was found to be valuable for the diagnosis of ruptured fetal membranes.^19,20,23 Recent studies have shown that the phosphorylation status of IGFBP-1 in AF is different from that in decidua and maternal blood.^17,18 Nonphosphorylated and less-phosphorylated IGFBP-1 isoforms predominate in AF, and the highly phosphorylated IGFBP-1 isoform is lacking, whereas in term decidua and maternal blood, the latter predominates with other phosphoisoforms.

In accordance with the differences between assay 1 and assay 2, the IGFBP-1 concentration in each AF sample was higher when measured by assay 1 than by assay 2. The results were opposite in all cervical samples, demonstrating that different IGFBP-1 phosphoisoforms predominate in AF and in cervical secretion of women with intact membranes and indicating that the highly phosphorylated isoform was included in the cervical secretion of the study subjects. This suggests that IGFBP-1 in the cervical secretion of women with intact membranes originates from decidua and leaks from the choriodecidual interface during cervical ripening. A similar mechanism has been thought to account for leakage of fetal fibronectin into the vagina and for increased cervicovaginal fetal fibronectin concentrations along with cervical ripening.^{9,11,12,24,25} Mechanical stress caused by uterine contractions or proteolysis and local inflammatory response are thought to be responsible for the chorionic-decidual detachment.²⁶

In a previous study, using monoclonal antibody 6305 as the detecting antibody, we speculated that microrupture of fetal membranes or leakage from decidual cells at the choriodecidual interface in the lower uterine segment may account for the presence of IGFBP-1 in the cervical secretion of pregnant women in whom no membrane rupture could be demonstrated by clinical means.¹⁹ Retrospectively, and considering the data from our present study, we can now hypothesize that IGFBP-1 in the cervix of those patients reflected cervical ripening, because 78% of them delivered prematurely.¹⁹

Without the combined use of assay 1 and 2, ie, without identifying the highly phosphorylated isoform, we would have been unable, as in the previous studies,^19,23 to determine the origin of IGFBP-1 in the cervical secretion of our patients. Although both assays predicted cervical ripeness with approximately the same accuracy, the IGFBP-1 concentrations were four times greater by assay 2 than by assay 1. The advantage achieved by the combined use of these two assays is that it allows differentiation between AF IGFBP-1 and cervical IGFBP-1. A negative PROM test (Medix Bio-chemica) result and IGFBP-1 concentration greater than 50 µg/L by assay 2 refers to detachment in the choriodecidual interface. In the opposite case, if the PROM test (Medix Biochemica) result is positive but a membrane rupture remains clinically equivocal, a further evaluation of the cervical sample by the two quantitative assays presented here can confirm or exclude the presence of AF.

Maternal blood may interfere with both fetal fibronectin assays²⁷ and IGFBP-1 assays¹⁹; therefore, the value of these tests is limited in patients with apparent cervical bleeding. The advantage of IGFBP-1 over fetal fibronectin in clinical practice is that in contrast to fetal fibronectin,²⁸ it is almost undetectable in seminal plasma,^19,23 and hence, recent sexual intercourse does not interfere with its measurement.

Although increasing with cervical ripeness, the cervical IGFBP-1 concentrations before amniotomy did not predict the amniotomy-to-delivery time. This is not surprising, because the progress of labor is influenced also by uterine activity as well as by various fetal and maternal factors. Presumably, the IGFBP-1 production rate also exhibits interindividual variation that is reflected in the wide range of cervical IGFBP-1 levels. Furthermore, differences in the sampling technique and extraction from the swab into the sample buffer may account for some variation in the absolute IGFBP-1 concentrations.

The cervical IGFBP-1 concentrations increased during cervical ripening with PGE₂. Because the difference in IGFBP-1 concentrations between ripe and unripe cervices was found already at the initial examination before cervical assessment, it is unlikely that PG gel itself or digital examination would have caused the increase observed during the ripening.

There was no absolute level of IGFBP-1 in the cervical samples that could differentiate sharply between the ripe and unripe cervix. However, our data suggest that repeated measurements of cervical IGFBP-1 concentration might help assess the functional maturity of the cervix and predict the success of cervical ripening and labor induction. In the two cases with failed labor induction, the cervical IGFBP-1 level remained low in serial measurements.

This study demonstrates that the highly phosphorylated isoform of IGFBP-1, different from those in the AF, is detectable in cervical secretion, where its concentration rises with cervical ripening. Although a test for this IGFBP-1 isoform in the cervical secretion of patients with intact membranes may provide an additional tool for evaluation of the functional ripeness of cervix at term, a more important potential clinical use could be to predict delivery in patients who present with premature uterine contractions and cervical dilatation. The combined use of two quantitative assays, as presented in this study, is time-consuming, but a rapid bedside test providing the information given by these assays would be valuable for clinical use.

	Footnotes

 
This work was supported by grants from the University Central Hospital of Helsinki.

Financial Disclosure

T. Kärkkäinen, LicPh is an employee of Medix Biochemica, and she and E.-M. Rutanen, MD, PhD, are the inventors and have applied for a patent for the method and test device.

PII S0029-7844(99)00321-X

Received October 7, 1998. Received in revised form February 8, 1999. Accepted February 10, 1999.

	References

Top Abstract Materials and Methods Results Discussion References

 
1. Huszar GB, Walsh MP. Relations between myometrial and cervical functions in pregnancy and labor. Semin Perinatol 1991;15:97–117.[Medline]

2. Romero R, Durum S, Dinarello CA, Oyarzun E, Hobbins JC, Mitchell MD. Interleukin-1 stimulates prostaglandin biosynthesis by human amnion. Prostaglandins 1989;37:13–22.[Medline]

3. Keirse MJNC. Prostaglandins in preinduction cervical ripening. Meta-analysis of worldwide clinical experience. J Reprod Med 1993;38:89–100.[Medline]

4. Nuutila M, Kajanoja P. Local administration of prostaglandin E₂ for cervical ripening and labor induction: The appropriate route and dose. Acta Obstet Gynecol Scand 1996;75:135–8.[Medline]

5. Ewigman BG, LeFevre ML, Hesser J. A randomized trial of routine prenatal ultrasound. Obstet Gynecol 1990;76:189–94.[Abstract/Free Full Text]

6. Bishop EH. Pelvic scoring for elective induction. Obstet Gynecol 1964;24:266–8.[Free Full Text]

7. Garite TJ, Casal D, Garcia-Alonso A, Kreaden U, Jimenez G, Ayala JA, et al. Fetal fibronectin: A new tool for prediction of successful induction of labor. Am J Obstet Gynecol 1996;175:1516–21.[Medline]

8. Osmers RGW, Bläser J, Kuhn W, Tschesche H. Interleukin-8 synthesis and onset of labor. Obstet Gynecol 1995;86:223–9.[Abstract]

9. Inglis SR, Jeremias J, Kuno K, Lescale K, Peeper Q, Chervenak FA, et al. Detection of tumor necrosis factor-alpha, interleukin-6, and fetal fibronectin in the lower genital tract during pregnancy: Relation to outcome. Am J Obstet Gynecol 1994;171:5–10.[Medline]

10. Ekman G, Granström L, Malmström A, Sennström M, Svensson J. Cervical fetal fibronectin correlates to cervical ripening. Acta Obstet Gynecol Scand 1995;74:698–701.[Medline]

11. Lockwood CJ, Senyei AE, Dische MR, Casal D, Shah KD, Thung SW, et al. Fetal fibronectin in cervical and vaginal secretions defines a patient population at high risk for preterm delivery. N Engl J Med 1991;325:669–74.[Abstract]

12. Iams JD, Casal D, McGregor JA, Goodwin TM, Kreaden US, Lowensohn R, et al. Fetal fibronectin improves the accuracy of diagnosis of preterm labor. Am J Obstet Gynecol 1995;173:141–5.[Medline]

13. Julkunen M, Koistinen R, Aalto-Setälä K, Seppälä M, Jänne OA, Kontula K. Primary structure of human insulin-like growth factor binding protein/placental protein 12 and tissue specific expression of its mRNA. FEBS Lett 1988;236:295–302.[Medline]

14. Rutanen EM, Koistinen R, Wahlström T, Bohn H, Ranta T, Seppälä M. Synthesis of placental protein 12 by human decidua. Endocrinology 1985;116:1304–9.[Abstract]

15. 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]

16. Koistinen R, Angervo M, Leinonen P, Hakala T, Seppälä M. Phosphorylation of insulin-like growth factor-binding protein-1 increases in human amniotic fluid and decidua from early to late pregnancy. Clin Chim Acta 1993;215:189–99.[Medline]

17. Westwood M, Gibson JM, Davies AJ, Young RJ, White A. The phosphorylation pattern of insulin-like growth factor-binding protein-1 in normal plasma is different from that in amniotic fluid and changes during pregnancy. J Clin Endocrinol Metab 1994;79:1735–41.[Abstract]

18. Martina NA, Kim E, Chitkara U, Wathen NC, Chard T, Giudice LC. Gestational age-dependent expression of insulin-like growth factor-binding protein-1 (IGFBP-1) phosphoforms in human extraembryonic cavities, maternal serum, and decidua suggests decidua as the primary source of IGFBP-1 in these fluids during early pregnancy. J Clin Endocrinol Metab 1997;82:1894–8.[Abstract/Free Full Text]

19. Rutanen EM, Kärkkäinen T, 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]

20. Lockwood CJ, Wein R, Chien D, Ghidini A, Alvarez M, Berkowitz RL. Fetal membrane rupture is associated with presence of insulin-like growth factor-binding protein-1 in vaginal secretions. Am J Obstet Gynecol 1994;171:146–50.[Medline]

21. Rutanen EM, Kärkkäinen T, Lundqvist C, Pekonen F, Ritvos O, Tanner P, et al. Monoclonal antibodies to the 27-34K insulin-like growth factor binding protein. Biochem Biophys Res Commun 1988;152:208–15.[Medline]

22. Zweig MH, Campbell G. Receiver-operating characteristic (ROC) plots: A functional evaluation tool in clinical medicine. Clin Chem 1993;39:561–77.[Abstract/Free Full Text]

23. Rutanen EM, Pekonen F, Kärkkäinen T. Measurement of insulin-like growth factor binding protein-1 in cervical/vaginal secretions: Comparison with ROM-check membrane immunoassay in the diagnosis of ruptured fetal membranes. Clin Chim Acta 1993;214: 73–81.[Medline]

24. Ahner R, Kub-Csizi P, Heinzl H, Bikas D, Rabi M, Wagenbichler P, et al. The fast-reacting fetal fibronectin test: A screening method for better prediction of the time of delivery. Am J Obstet Gynecol 1997;177:1478–82.[Medline]

25. Sennström MB, Granström LM, Lockwood CJ, Omazic B, Johansson O, Malmström A, et al. Cervical fetal fibronectin correlates to prostaglandin E2-induced cervical ripening and can be identified in cervical tissue. Am J Obstet Gynecol 1998;178:540–5.[Medline]

26. Monzon-Bordonaba F, Wang CL, Feinberg RF. Fibronectinase activity in cultured human trophoblasts is mediated by urokinasetype plasminogen activator. Am J Obstet Gynecol 1997;176:58–65.[Medline]

27. Feinberg RF, Wang CL. Monoclonal antibody FDC-6 exhibits binding to human plasma fibronectin: A caveat for cervicovaginal oncofetal fibronectin testing? Am J Obstet Gynecol 1994;171: 1302–8.[Medline]

28. Shimoya K, Hashimoto K, Shimizu T, Saji F, Murata Y. Effect of sexual intercourse on fetal fibronectin concentration in cervicovaginal secretions. Am J Obstet Gynecol 1998;179:255–6.[Medline]

This article has been cited by other articles:

				H. Honkanen, E.-M. Rutanen, and O. Heikinheimo Differential kinetics of serum and cervical insulin-like growth factor-binding protein-1 during mifepristone-misoprostol-induced medical termination of early pregnancy Mol. Hum. Reprod., January 1, 2004; 10(1): 65 - 70. [Abstract] [Full Text] [PDF]

				E. Kajantie, L. Dunkel, E.-M. Rutanen, M. Seppala, R. Koistinen, A. Sarnesto, and S. Andersson IGF-I, IGF Binding Protein (IGFBP)-3, Phosphoisoforms of IGFBP-1, and Postnatal Growth in Very Low Birth Weight Infants J. Clin. Endocrinol. Metab., May 1, 2002; 87(5): 2171 - 2179. [Abstract] [Full Text] [PDF]

				R. A. Frost, G. J. Nystrom, and C. H. Lang Stimulation of Insulin-Like Growth Factor Binding Protein-1 Synthesis by Interleukin-1{beta}: Requirement of the Mitogen-Activated Protein Kinase Pathway Endocrinology, September 1, 2000; 141(9): 3156 - 3164. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by NUUTILA, M. Articles by RUTANEN, E.-M. Search for Related Content PubMed PubMed Citation Articles by NUUTILA, M. Articles by RUTANEN, E.-M.