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ORIGINAL RESEARCH |
From the Department of Obstetrics and Gynecology, Division of Maternal Fetal Medicine, The Ohio State University College of Medicine, Columbus, Ohio.
Address reprint requests to: David S. McKenna, MD, Wright State University, US Air Force Medical Corp., Department of Obstetrics and Gynecology, 74th Medical Group/SGOG, 4881 Sugar Maple Drive, Wright-Patterson AFB, OH 45433; E-mail: david.mckenna{at}wpafb.af.mil.
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ABSTRACT |
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METHODS: Cervicovaginal swabs were obtained before digital examination from women who presented to labor and delivery for evaluation of preeclampsia and compared with fetal fibronectin levels from a group of control subjects with a similar gestational age. Fetal fibronectin was assayed by a specific enzyme-linked immunoassay. A concentration greater than 50 ng/mL was considered a positive result.
RESULTS: Forty women with preeclampsia (17 mild and 23 severe) and 31 normotensive women were analyzed. The control group had 9.7% positive fetal fibronectins, whereas the preeclampsia group had 15% positive, P = .72, with 80% power to detect a 22% difference. The majority of the quantitative values in both groups were less than 20 ng/mL. There was not a significant difference between the two groups in quantitative cervicovaginal fetal fibronectin, P = .72, nor was there a difference between the women with severe preeclampsia and the controls, P = 1.0, or between the nulliparous women with preeclampsia versus the nulliparous controls, P = .3.
CONCLUSION: Fetal fibronectin is not elevated in cervico-vaginal secretions of women with preeclampsia.
Fibronectins are adhesive glycoproteins with multiple isoforms found in the extracellular matrix and in plasma.1 Cellular fibronectin is present in the vascular endothelial basement membrane, and the soluble form has been proposed as a marker of endothelial cell activation and damage.2 Several investigators have shown the soluble form of cellular fibronectin is elevated in women with preeclampsia compared with controls, even before the appearance of clinical disease.2–4 Oncofetal fibronectin, a specific isoform unique to the pregnant state and malignant cell lines, is found in the extracellular matrix surrounding the invading cytotrophoblasts in uterine decidua.5–7 Fetal fibronectin is important in the normal adherence of the chorion to the decidua and is also detected in maternal plasma during gestation.5,8,9
Kupferminc et al reported that fetal fibronectin is elevated in the maternal plasma and the amniotic fluid of women with severe preeclampsia compared with controls, and speculated this may be due to crumbling of the normal architecture of the extracellular matrix that binds the chorion to the decidua.9 The presence of fetal fibronectin in the cervix or vagina after the 20th week of pregnancy is abnormal in uncomplicated pregnancies and may indicate disruption of the attachment of the membranes to the decidua because of labor or inflammation.5 Several clinical studies have demonstrated an association between spontaneous preterm delivery before 37 weeks and the presence of fetal fibronectin in cervico-vaginal secretions at concentrations greater than 50 ng/mL.5,10,11
There are similarities in the pathology of the chorionic-decidual interface in preterm labor and preeclampsia. Several investigators have described vascular abnormalities and decidual ischemia in placentas of women with spontaneous preterm delivery.12,13 Pregnancies complicated by preeclampsia are known to be associated with decreased uteroplacental blood flow and endothelial injury in the placental bed vessels.14,15 Based on these similarities and the report by Kupferminc et al,9 we postulated that fetal fibronectin in cervicovaginal secretions of women with preeclampsia would be elevated compared with normotensive controls, and the level of fetal fibronectin may be correlated to the severity of the preeclampsia.
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MATERIALS AND METHODS |
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Pregnant women with gestational ages greater than 22 0/7 weeks presenting to the labor and delivery unit with signs or symptoms of preeclampsia were screened for eligibility. Women who met the criteria for preeclampsia-eclampsia or chronic hypertension with superimposed preeclampsia were eligible for enrollment and were categorized as having mild or severe disease.17 Women with gestational hypertension or chronic hypertension without superimposed preeclampsia were not eligible. Normotensive women presenting to labor and delivery during the study period for other complaints, with gestational ages greater than 22 0/7 weeks, were eligible to be enrolled as controls. The policy at the Ohio State University labor and delivery unit is for all women between the gestational ages of 22–34 weeks who have vaginal examinations on labor and delivery to have cervicovaginal fetal fibronectin obtained. If the woman is found to be at risk for preterm delivery, then the fetal fibronectin specimen is sent to the lab for clinical use; otherwise, the specimen is discarded. For the purposes of this study, specimens that were destined for disposal were obtained by the authors and stored for potential use as controls. Enrollment exclusion criteria for the study subjects and controls consisted of confirmed rupture of membranes, digital examination, endovaginal ultrasound, or coitus within the previous 24 hours, known untreated cervical infection, cervical dilatation 3 cm or more, presence of a cervical cerclage, vaginal bleeding, uterine anomalies, placenta previa, or abruptio placenta. In addition, women who had spontaneous preterm delivery before 37 weeks’ gestational age were excluded from the analyses.
Specimens were collected for fetal fibronectin assay before performing digital examination of the cervix. Fetal fibronectin specimens were obtained by performing a sterile speculum exam and swabbing the posterior fornix of the vagina and external cervical os with a single sterile Dacron swab (Adeza Biomedical, Sunnyvale, CA). Care was taken to avoid contaminating the swab with blood. The swab was placed into a sterile antiprotease buffer containing bovine serum albumin and then frozen at -80C until assayed. If subsequent to obtaining the swab for fetal fibronectin a woman was found to have an exclusion criterion, the swab was discarded and she was not included in the analyses.
Assays for fetal fibronectin were performed by enzyme-linked immunosorbent assay using a specific monoclonal antibody for oncofetal fibronectin, FDC-6. The inter- and intra-assay variabilities were less than 10%.5 Results were reported quantitatively as ng/mL of fetal fibronectin, and qualitatively as positive when the fetal fibronectin concentration exceeded 50 ng/mL, or negative if 50 ng/mL or less. Demographic, intrapartum, and delivery data were obtained from patient charts and a computerized obstetric database.
Statistical and data analyses were performed with JMP Statistical Discovery Software 4.02 (SAS Institute Inc., Cary, NC) and Microsoft Excel (Microsoft Corp., Redmond, WA). Mean values for continuous variables were compared for significant differences with the unpaired Student t test, using an 
of 0.05. To achieve 80% power (ß of 0.2) and assuming the cervicovaginal fetal fibronectin values to have a standard deviation of ±10 ng/mL, 16 women were required in each group to detect a 20% difference in quantitative fetal fibronectin. The 20% difference was believed to be the minimum level that would be clinically significant (eg, an increase in the mean fetal fibronectin level of 5 ng/mL in the preeclamptic group over a mean fetal fibronectin level of 25 ng/mL in the control group). Categoric variables were compared for independence with the Fisher exact test. Data that did not fit a normal distribution were described by the median and interquartile (25–75%) range, and were compared by the Wilcoxon rank sum test or nonparametric analysis of variance.
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RESULTS |
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). The mean gestational age at delivery and birth weight were significantly less, and there was a higher percentage of nulliparous patients in the preeclamptic group.
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contains the quantitative fetal fibronectin values for the control and preeclamptic groups. The median and quartile range (25–75%) of cervicovaginal fetal fibronectin from the control women was 1.0 ng/mL (0.0–8.0 ng/mL) versus 1.0 ng/mL (0.0–7.8 ng/mL) for the women with preeclampsia, P = .73, by the Wilcoxon rank sum test. There were three of 31 (9.7%) positive qualitative fetal fibronectin results in the control women and six of 41 (15.0%) positives in the preeclamptic women, P = .72, by Fisher exact test. Four of the positive fetal fibronectins in the preeclamptic group were from women with mild disease and two from women with severe disease. There was not a significant difference in the quantitative fetal fibronectin levels when the severe preeclamptic, 2.0 ng/mL (0–8.0 ng/mL), mild pre-eclamptic, 0.0 ng/mL (0–39.5 ng/mL), and normotensive controls were compared by nonparametric analysis of variance (Kruskal-Wallis test), P = .74, and by nonparametric repeated measures (Friedman test), P = .78. There were four of 17 (23.5%) positive fetal fibronectin results in the mild preeclampsia group, two of 23 (8.7%) positives in the severe group, and six of 41 (15.0%) in the controls, P = 1.0, by Cochran-Mantel-Haenszel 
2. To assess for a subtle difference that was skewed and masked by the few positive results, the quantitative values for only the negative fetal fibronectins were compared. The median value of the negatives in the control group was 0 ng/mL (0–4.8 ng/mL) versus 0 ng/mL (0–4.0 ng/mL) in the preeclampsia group, P = .97, by Wilcoxon rank sum test. Finally, the multiparous patients were excluded, and the nulliparous patients were compared. There were two of 11 (18%) nulliparous women in the control group with positive fetal fibronectins and three of 26 (12%) nulliparous women with positives in the preeclampsia group, P = .62. The median fetal fibronectin in the nulliparous women in the control group (n = 11) was 4 ng/mL (0–48 ng/mL) versus 2 ng/mL (0–7.3 ng/mL) in the group with pre-eclampsia (n = 26), P = .3.
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DISCUSSION |
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A second limitation was the higher percentage of multiparous patients in the control group. If multiparous patients inherently have higher cervicovaginal fetal fibronectin levels than nulliparous patients, then this may have masked increased levels in the preeclamptic group. However, when only the nulliparous patients were analyzed, there was still no difference between the groups, and the quantitative levels remained low in both groups.
Another limitation may be due to the inclusion of women with both severe and mild preeclampsia. Kupferminc et al found elevated plasma and amniotic fluid fetal fibronectin in women with severe preeclampsia.9 Perhaps, it is only the group of women with severe pre-eclampsia who have elevations in their cervicovaginal fetal fibronectin? This was not the case in our study, as the group of patients with severe preeclampsia did not have cervicovaginal fetal fibronectin levels that were significantly different from the control group, and the levels were mostly undetectable or very low.
The results may be due to a type II error. The study was designed to detect a 20% difference in quantitative cervicovaginal fetal fibronectin, but this was based on the values having a normal distribution. The quantitative fetal fibronectin distribution was not normal, and it was highly skewed on the low end, with few values in either group exceeding 50 ng/mL. Another way to examine these results is to consider fetal fibronectin as a categoric variable. Post hoc power analysis of the proportion positive in the preeclampsia (0.15) group versus the control (0.097) demonstrates there was power to detect a 22% difference, but the actual difference was only 5.3%. Greater than 500 subjects would be required in each group to have enough power for the observed difference of 5.3% to be statistically significant.
The vast majority of the quantitative cervicovaginal fetal fibronectin values were extremely low in the women with preeclampsia. It is unlikely that cervicovaginal fetal fibronectin will have any clinical utility in the diagnosis or prediction of preeclampsia, and does not appear to be a marker for severe disease. The findings do not support proceeding with a larger study to further investigate this. Further research will be necessary to elicit the source of elevated fetal fibronectin in maternal serum and amniotic fluid in women with preeclampsia, but it does not appear to originate from disruption of the chorionic-decidual interface.
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Footnotes |
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The authors wish to thank Adeza Biomedical, Sunnyvale, California, for their support (fetal fibronectin kits and assays) of this study.
Received November 27, 2001. Received in revised form February 5, 2002. Accepted March 7, 2002.
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REFERENCES |
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2. Stubbs TM, Lazarchick J, Horger EO. Plasma fibronectin levels in pre-eclampsia: A possible biochemical marker for vascular endothelial damage. Am J Obstet Gynecol 1984; 150:885–7.[Medline]
3. Taylor RN, Crombleholme WR, Friedman SA, Jones LA, Casal DC, Roberts JM. High plasma cellular fibronectin levels correlate with biochemical and clinical features of preeclampsia but cannot be attributed to hypertension alone. Am J Obstet Gynecol 1991;165:895–901.[Medline]
4. O’Brien WF. Predicting preeclampsia. Obstet Gynecol 1990;75:445–52.
5. Lockwood CJ, Senyei AE, Renate Dische M, Casal D, Shah KD, Thung SN, et al. Fetal fibronectin in cervical and vaginal secretions as a predictor of preterm delivery. N Engl J Med 1991;325:669–74.[Abstract]
6. Stewart EA, Floor AE, Jain P, Nowak RA. Increased expression of messenger RNA for collagen type I, collagen type III, and fibronectin in myometrium of pregnancy. Obstet Gynecol 1995;86:417–22.[Abstract]
7. Pulkkinen MO, Lehto M, Jalkanen M, Nanto-Salonen K. Collagen types and fibronectin in the uterine muscle of normal and hypertensive pregnant patients. Am J Obstet Gynecol 1984;149:711–7.[Medline]
8. Feinberg RF, Kilman HJ, Lockwood C. Is oncofetal fibronectin a trophoblast glue for human implantation? Am J Pathol 1991;138:537–43.[Abstract]
9. Kupferminc MJ, Peaceman AM, Wigton TR, Rehnberg KA, Socol ML. Fetal fibronectin levels are elevated in maternal plasma and amniotic fluid of patients with severe preeclampsia. Am J Obstet Gynecol 1995;172:649–53.[Medline]
10. Iams JD, Casal D, McGregor JA, Murphy Goodwin T, Seshadri Kreaden U, Lowensohn R, et al. Fetal fibronectin improves the accuracy of diagnosis of preterm labor. Am J Obstet Gynecol 1995;173:141–5.[Medline]
11. Peaceman AM, Andrews WW, Thorp JM, Cliver SP, Lukes A, Iams JD, et al. Fetal fibronectin as a predictor of preterm birth in patients with symptoms: A multicenter trial. Am J Obstet Gynecol 1997;177:13–8.[Medline]
12. Salafia CM, Vogel CA, Vintzileos AM, Bantham KF, Pezzullo J, Silberman L. Placental pathologic findings in preterm birth. Am J Obstet Gynecol 1991;165:934–8.[Medline]
13. Arias F, Rodriquez L, Rayne SC, Kraus FT. Maternal placental vasculopathy and infection: Two distinct subgroups among patients with preterm labor and preterm ruptured membranes. Am J Obstet Gynecol 1993;168:585.[Medline]
14. Frusca T, Morassi L, Percorell S, Grigolato P, Gastaldi A. Histological features of uteroplacental vessels in normal and hypertensive patients in relation to birthweight. Br J Obstet Gynaecol 1989;96:835–9.[Medline]
15. Shanklin DR, Sibai BM. Ultrastructural aspects of pre-eclampsia. I. Placental bed and uterine boundary vessels. Am J Obstet Gynecol 1989;161:735.[Medline]
16. National High Blood Pressure Education Program Working Group. Report on high blood pressure in pregnancy. Am J Obstet Gynecol 2000;183:S1–S22.
17. American College of Obstetricians and Gynecologists. Hypertension on pregnancy. ACOG technical bulletin no. 219. Washington, DC: American College of Obstetricians and Gynecologists, 1996.
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) and mild preeclampsia (
) and normotensive controls (
). The scale for the y axis is log10 and fetal fibronectin values less than 1 ng/mL (n = 15 for controls, n = 18 for severe preeclampsia, and n = 10 for mild preeclampsia) are not shown.