Nappi, C.

Pellicano, M.

Regine, V.

Ronsini, S.

Tolino, A.

Zullo, F.

TOLINO, ACHILLE

PELLICANO, MASSIMILIANO

NAPPI, CARMINE

Ronsini S

Zullo F

Regine V

Archivio della ricerca - Università degli studi di Napoli Federico II

Fetal fibronectin as a screening test for premature delivery in multiple pregnancies.

International Journal of Gynecology & Obstetrics 52 (1996) 3-7 GYNECOLOGY & OBSTETRICS Article Fetal fibronectin as a screening test for premature delivery in multiple pregnancies A. Tolino* a, S. Ronsinia, F. Zullob, M. Pellicano”, V. Reginea, C. Nappi” aDepartment of Gynecology and Obstetrics, University of Naples ‘Federico II: Naples, Italy bDepartement of Gynecologic and Pediatric Sciences, University of Reggio Calabria, Catanzaro, Italy Received 1 May 1995; revision received 20 July 1995; accepted 27 July 1995 Abstract Objective: To evaluate fetal libronectin as a screening test for premature delivery in asymptomatic women with multi- ple pregnancies. Method: In the mid-second trimester, the concentrations of fetal tibronectin in the cervical and vaginal secretions of 68 patients with multiple gestations were sampled weekly by monoclonal antibody immunoassay in order to predict preterm labor. Results: The results for the prediction of preterm labor differ according to whether we con- sider a single positive result (fetal libronectin > 50 @ml) as predictive of preterm labor or whether we only consider at least two consecutive positive results as predictive of preterm labor. The fetal tibronectin test had a sensitivity for preterm birth before 37 weeks of 90.9% and 86.6%, respectively, with a specificity of 68.5% vs. 78.9% and positive and negative values of 73.1% vs. 76.4% and 88.8% vs. 88.2%, respectively. Similar results were obtained for preterm birth before 34 weeks. Conclusion: In a condition such as multiple pregnancy which is already at risk for premature delivery the possibility of raising the specificity of the test with virtually no decrease in sensitivity guarantees better recognition of patients likely to develop premature labor. This possibility can be achieved simply by considering two positive con- secutive samples as predictive of pretenn labor. Keywords: Fetal fibronectin; Pretenn delivery; Multiple pregnancy 1. Introduction In multiple pregnancies there is an increased in- cidence of polyhydramnios, gestosis, anemia and preterm delivery. The main complication in these cases is preterm delivery, since it represents a life- threatening situation for the twins. * Corresponding author, Fax: +39 81 7462903. It has been calculated that the mean duration of twin pregnancies is 37 weeks. In other words, about half of these pregnancies are delivered before 37 weeks. Moreover the risk linked with prematurity is increased by the low birth weight of the twins in comparison with that of single fetuses of the same gestational age [l]. Premature birth, defined as delivery before 37 complete weeks of gestation, is the leading cause of 0020-7292MXS15.00 0 1996 International Federation of Gynecology and Obstetrics SSDI 0020-7292(95)02529-L 4 A. Tolino et al. /International Journal of Gynecology & Obstetrics 52 (19%) 3-7 perinatal mortality and short- and long-term fetal morbidity. Most of the morbidity and mortality at- tributed to preterm birth occur in births before 34 weeks of gestation [ 11. Various strategies have been used to lower this incidence including risk screening during the peri- natal period, patient education, monitoring of uterine activity, long-term tocolysis, perinatal home nursing care and early prenatal care. How- ever obstetric management could be more effective if women at risk for this condition could be iden- tified by the early use of a biochemical marker. Recently some authors [2-41, in a multicenter cross- sectional study of symptomatic women with suspected preterm labor, demonstrated that detec- tion of fetal libronectin in cervical and vaginal secretions identified pregnant women at high risk for preterm delivery. These authors postulated that because fetal libronectin is a component of the extracellular matrix of the fetal membranes and is normally present in amniotic fluid and placental tissue, its appearance in the cervix and vagina is suggestive of mechanical or inflammation-mediated damage to the mem- branes. The objective of this study was to evaluate fetal fibronectin as a screening test for premature deliv- ery in multiple pregnancies. 2. Materials and methods We evaluated the presence of fetal libronectin in the cervical and vaginal secretions of 68 con- secutive asymptomatic women with multiple gesta- tions (two or more fetuses) presenting at our centers. Six of the 68 pregnancies were triplets (8.8%). Documentation of the intact membranes and undilated cervix was performed at the start of the study. Gestational age was calculated on the basis of the last menstrual period and early vaginal ul- trasonography. Informed consent was obtained from each patient at recruitment. The study started in the mid-second trimester (24 weeks). Cervical and vaginal secretions, both from the posterior vaginal fornix and from the ex- ternal cervical ostium, were sampled weekly using a sterile speculum. The samples were collected using sterile dacron swabs and analyzed im- mediately for the presence of fetal fibronectin. The presence of fetal libronectin was determined qualitatively using a commercial kit based on a monoclonal antibody specifically recognizing fetal fibronectin (Fetal Fibronectin Membrane Im- munoassay; Adeza Biomedical, Sunnyvale, USA) [5,6]. A sample was defined as positive if its absor- bance was greater than that of the positive control (50 rig/ml). We then evaluated reliability by a different method, considering first a positive result obtained on one single occasion, and then a positive result obtained on at least two consecutive occasions. The reliability of this assay in predicting preterm labor was evaluated by means of the classic par- ameters of sensitivity, specificity and predictive values. Categoric clinical data were evaluated by rela- tive risk ratios and the X2-test; P < 0.01 was con- sidered to be statistically significant. 3. Results Sixty-eight pregnant women with multiple preg- nancies were examined. Thirty-three (48.5%) delivered before 37 weeks and 35 (5 1 So/) delivered after 37 weeks of gestation. No patient was delivered before 37 weeks for reasons other than preterm labor or preterm rupture of the mem- branes. There were no statistical differences in ma- ternal age, parity or history of prior preterm birth between the women delivered before or after 37 weeks. The results of our study differ according to whether we considered a positive result obtained from a single sample or one obtained from at least two consecutive samples. If we take the first case (i.e. a single positive sample), the sensitivity of fetal llbronectin was 90.9%, the specificity was 68.5%, the positive pre- dictive value was 73.1% and the negative predictive value was 88.8% for the prediction of delivery before 37 weeks (Table 1). The relative risk of preterm delivery for one positive fetal tibronectin result was 6.57 (95% C.I. 4.80-77.59, X2-test 22.67, P < 0.000001). If we take a positive result from at least two con- A. Tolino et al. /International Journal of Gynecology & Obstetrics 52 (1996) 3-7 5 Table 1 Reliability of fetal fibronectin in predicting delivery before 37 weeks from a single positive sample Multiple pregnancy Fetal Fetal Total tibronectin iibronectin positive negative Delivery <37 weeks 30 3 33 >37 weeks 11 24 35 Total 41 27 68 Sensitivity 90.9%, specificity 68.5%, positive predictive value 73.1%. negative predictive value 88.8%, relative risk 6.57 (95% C.I. 4.80-77.59). &test 22.67, P < O.OOOOO1. secutive samples, the sensitivity of fetal Iibronectin was 86.6%, but the specificity increased to 78.9%, with a positive and a negative predictive value of 76.4% and 88.2%, respectively, for the prediction of delivery before 37 weeks (Table 2). The relative risk of a preterm delivery was 6.52 (95% C.I. 5.71-115.67, X2-test 26.3, P < O.OflOOOl). The reliability of this test in true preterm births, i.e. those delivered before 34 weeks, showed similar results (Tables 3 and 4). When using a single positive sample for diagno- sis, the mean time of diagnosis (f SD.) was 25.7 f 1.8 weeks. When using two consecutive positive samples for diagnosis, the mean time was 27.1 * 2.1 weeks. In either case the mean time of diagnosis was sufficient to begin an intervention program in those patients shown to be at high risk. Our data show a clear difference, although not sig- Table 2 Reliability of fetal fibronectin in predicting delivery before 37 weeks from two consecutive positive samples Multiple pregnancy Fetal Fetal Total fibronectin fibronectin positive negative Delivery <37 weeks 26 4 30 z-37 weeks 8 30 38 Total 34 34 68 Sensitivity 86.6%, specificity 78.9%. positive predictive value 76.4%. negative predictive value 88.2%. relative risk 6.52 (95% C.I. 5.71-115.67). X2-test 26.3, P < O.GQOOO1. Table 3 Reliability of fetal fibronectin in predicting delivery before 34 weeks from a single positive sample Multiple pregnancy Fetal Fetal Total fibronectin fibronectin positive negative Delivery < 34 weeks > 34 weeks Total 14 I 15 18 35 53 32 36 68 Sensitivity 93.3%, specificity 66.0%, positive predictive value 37.8%, negative predictive value 96.7%, relative risk 27.22 (95% C.I. 3.23-151.39). X2-test 14.24, P < 0.0001. n&ant, between the mean interval from obtaining a positive result to delivery (Table 5). 4. Discussion The significant increase in perinatal mortality and morbidity in multiple gestations in com- parison with single gestations depends on the higher incidence of preterm birth. Indeed 50% of twins are preterm and those born before 34 weeks have a still higher risk of complications. In the last 20 years a number of protocols have been proposed for the prevention of preterm labor, such as bed rest, prophylactic cerclage and the prophylactic administration of /3-mimetics and progestatives [7]. Objective signs of impending preterm delivery such as cervical modifications and uterine contrac- Table 4 Reliability of fetal tibronectin in predicting delivery before 34 weeks from two consecutive positive samples Multiple pregnancy Fetal Fetal Total fibronectin tibronectin positive negative Delivery < 34 weeks 10 1 11 > 34 weeks 13 44 57 Total 23 45 68 Sensitivity 90.90/o, soecificitv 77.1%. oositive oredictive value 38.4%. negative predictive v&e 97.6%, relative’ risk 33.84 (95% C.I. 3.75-188.23), x2-test 16.18, P < 0.0005. 6 A. Tolino et al. /International Journal of Gynecology & Obstetrics S2 (19%) 3-7 Table 5 Comparison of the positive sample-delivery interval between the two groups Single posi- Two con- tive sample secutive posi- tive samples No. of patients Sample-delivery interval Idavsb 32 21 54 l 31 43 * 39 P < 0.05 tions have shown a sensitivity and specificity of less than 45%. Vaginal pH has a higher sensitivity but its specificity is very poor [4-81. Less reliable indicators are obstetric anamnesis, demographic factors and obstetric risk factors [4,9]. The first evaluation of the effectiveness of fetal tibronectin content in cervical and vaginal secre- tions in predicting preterm delivery was performed by Lockwood et al. [4]. They studied 117 pregnant women between 24 and 37 weeks’ gestation with uterine contractions or precocious cervical modifications, comparing fetal libronectin levels with gestational age at the time of onset of labor [4]. They were able to demonstrate the clinical ef- fectiveness of fetal libronectin in predicting preterm delivery in symptomatic patients. Morrison et al. [lo] evaluated fetal fibronectin vaginal and cervical levels in 28 pregnant women between 24 and 34 weeks’ gestation with regular uterine contractions (> 10/h), with unruptured membranes and a cervical dilatation I 1 cm. Cer- vical fetal fibronectin levels > 50 rig/ml identified patients with preterm labor who subsequently had a preterm delivery, with a sensitivity of 90%, a specificity of 72%, a positive predictive value of 64% and a negative predictive value of 93%. In the present study a single positive test for the presence of fetal fibronectin in the cervical and vaginal secretions of women with multiple gesta- tions was predictive of preterm delivery before 37 weeks’ gestation with a sensitivity of 90.9% and a specificity of 68.5%. If at least two positive con- secutive samples were considered diagnostic, the sensitivity was 86.6% and the specificity was 78.9%. This means that in a condition that is al- ready at risk for premature delivery such as multi- ple pregnancy the specificity of the test can be raised with virtually no decrease in sensitivity, guaranteeing a better recognition of patients likely to go into premature labor. Our results show that serial determinations of cervical and vaginal fetal libronectin levels are pre- dictive of preterm delivery in an asymptomatic risk group such as women with multiple pregnancies. The presence of fetal fibronectin in cervical and vaginal secretions in the second or third trimester may identify women with multiple gestations who are still asymptomatic but at high risk for preterm labor. Identification of these patients could lead to an early therapeutic approach such as bed rest, ad- ministration of tocolytic agents, patient education, perinatal monitoring with tocodynamometry and home nursing care, all of which may preclude early onset of labor [11,12]. Additional work needs to be carried out to con- firm these results and to determine whether fetal tibronectin is present in cervical and vaginal secre- tions before uterine contractions become appar- ent. In addition, future studies may better evaluate the time interval between a positive test and the beginning of preterm labor. In this way the test could also be useful for calculating induction of labor. From our data we can conclude that in multiple pregnancies a biochemical marker such as fetal tibronectin could be considered a useful tool in clinical practice for the early identification of pa- tients likely to develop preterm labor. References 111 PI 131 I41 151 Tucker JM, Goldenberg RL, Davis RO, Cooper RL, Winkler CL, Hauth JC. Etiologies of preterm birth in an indigent population: is prevention a logical expectation? Obstet Gynecol 1991; 77: 343. Hulin N. Fibronectin fcetal et delivrance imminent. Medisearch 1991; 52: 15. Lockwood CJ, Feinberg AF. Communication presented at the Society of Perinatal Obstetricians, San Francisco, 1991. Lockwood CJ, Senyei AE, Dische MR. Casal D, Kumudini DS, Thung SN et al. Fetal tibronectin in cervi- cal and vaginal secretions as a predictor of preterm deliv- ery. N Engl J Med 1991; 325: 669. Matsuura H. Hakomori SI. The oncofetal domain of A. Tolino et al. /International Journal of Gynecology & Obstetrics 52 (19%) 3-7 libronectin defined by the monoclonal antibody FDC-6: its presence in fibronectin from fetal and tumor tissues and its absence from adult tissues and plasma. Proc Nat1 Acad Sci USA 1985; 82: 6517. [6] Matsuura H, Takio K, Tatani K et al. The oncofetal structure of human libronectin defined by monoclonal antibody FDC-6. Unique structural requirement for the antigen specificity provided by a glycosylhexapeptide. J Biol Chem 1988; 263: 331. [7] Creasy R, Merkatez I. Prevention of preterm birth: clini- cal opinion. Obstet Gynecol 1990; 76: 25. [8] Schreyer P, Caspi E, Bar Natan N, Tal E, Weinraub 2. The predictive value of fetal breathing movement and Bishop score in the diagnosis of ‘true’ preterm labor. Am J Obstet Gynecol 1989; 161: 886. [9] Eganhouse D. A comparative study of variables differen- tiating false labor from early labor. J Perinatol 1991; I I: 249. [IO] Morrison J, Albert J, McLaughlin B, Whitworth N, Roberts W, Martin R. Oncofetal fibronectin in patients with false labor as a predictor of pretenn delivery. Am J Obstet Gynecol 1993; 168: 538. [I I] Nageotte MP, Hollembach KA, Vanderwahl BA, Hutch KM. Oncofetal tibronectin in patients at increased risk for preterm delivery. Presented at the Society of Perinatal Obstetricians Meeting, Orlando (USA), 1992. [I21 Nageotte MP, Casal D, Senyei AE. Fetal tibronectin in patients at increased risk for premature birth. Am J Obstet Gynecol 1994; 170: 19. 

Fetal fibronectin as a screening test for premature delivery in multiple pregnancies

Fetal fibronectin as a screening test for premature delivery in multiple pregnancies

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Archivio della ricerca - Università degli studi di Napoli Federico II

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Archivio della ricerca - Università degli studi di Napoli Federico II