Cervicovaginal fibronectin improves the prediction of preterm delivery based on sonographic cervical...

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Cervicovaginal fibronectin improves the prediction of preterm delivery based on sonographic cervical length in patients with preterm uterine contractions and intact membranes Ricardo Gomez, MD, a Roberto Romero, MD, b Luis Medina, MD, a Jyh Kae Nien, MD, b Tinnakorn Chaiworapongsa, MD, c Mario Carstens, MD, a Rogelio Gonza ´lez, MD, a Jimmy Espinoza, MD, b Jay D. Iams, MD, d Sam Edwin, PhD, b Iva ´n Rojas, MD a Center for Perinatal Diagnosis and Research (CEDIP), So ´tero del Rı´o Hospital, P. Universidad Cato ´lica de Chile, Puente Alto, Chile, a Perinatology Research Branch, National Institute of Child Health and Human Development, NIH, DHHS, Bethesda, Md, and Detroit, Mich, b Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, Mich, c and Department of Obstetrics and Gynecology, The Ohio State University, Columbus, Ohio d Received for publication June 14, 2004; revised September 16, 2004; accepted September 23, 2004 KEY WORDS Uterine cervix Ultrasound Fetal fibronectin Preterm delivery Prediction Objective: The purpose of this study was to examine the diagnostic performance of ultrasonographic measurement of the cervical length and vaginal fetal fibronectin determination in the prediction of preterm delivery in patients with preterm uterine contractions and intact membranes. Study design: Ultrasound examination of the cervical length and fetal fibronectin determination in vaginal secretions were performed in 215 patients admitted with preterm uterine contractions (22-35 weeks) and cervical dilatation of %3 cm. Outcome variables were the occurrence of preterm delivery within 48 hours, 7 days, and 14 days of admission, delivery %32 and %35 weeks, as well as the admission-to-delivery interval. Statistical analysis included chi-square test, receiver- operator characteristic (ROC) curve analysis, logistic regression, and survival analysis. Results: The overall prevalence of preterm delivery %35 weeks was 20% (43/215). The prevalence of spontaneous preterm delivery within 48 hours, 7 days, and 14 days of admission, and delivery %32 and %35 weeks were 7.9% (17/215), 13.0% (28/215), 15.8% (34/215), 8.9% (9/101), and 15.8% (34/215), respectively. ROC curve analysis and contingency tables showed a significant relationship between the occurrence of preterm delivery and both cervical length and fetal fibro- nectin results (P ! .01 for each). Both tests performed comparably in the prediction of spontaneous preterm delivery. However, when fetal fibronectin results were added to those of cervical length (!30 mm), a significant improvement in the prediction of preterm delivery was achieved. Presented at the 23rd Annual Meeting of the Society for Maternal-Fetal Medicine, February 3-8, 2003, San Francisco, Calif. Reprints not available from the authors. 0002-9378/$ - see front matter Ó 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.ajog.2004.09.034 American Journal of Obstetrics and Gynecology (2005) 192, 350–9 www.ajog.org

Transcript of Cervicovaginal fibronectin improves the prediction of preterm delivery based on sonographic cervical...

American Journal of Obstetrics and Gynecology (2005) 192, 350–9

www.ajog.org

Cervicovaginal fibronectin improves the prediction ofpreterm delivery based on sonographic cervical lengthin patients with preterm uterine contractions and intactmembranes

Ricardo Gomez, MD,a Roberto Romero, MD,b Luis Medina, MD,a Jyh Kae Nien, MD,b

Tinnakorn Chaiworapongsa, MD,c Mario Carstens, MD,a Rogelio Gonzalez, MD,a

Jimmy Espinoza, MD,b Jay D. Iams, MD,d Sam Edwin, PhD,b Ivan Rojas, MDa

Center for Perinatal Diagnosis and Research (CEDIP), Sotero del Rıo Hospital, P. Universidad Catolica de Chile,Puente Alto, Chile,a Perinatology Research Branch, National Institute of Child Health and Human Development, NIH,DHHS, Bethesda, Md, and Detroit, Mich,b Department of Obstetrics and Gynecology, Wayne State University Schoolof Medicine, Detroit, Mich,c and Department of Obstetrics and Gynecology, The Ohio State University, Columbus,Ohio d

Received for publication June 14, 2004; revised September 16, 2004; accepted September 23, 2004

KEY WORDSUterine cervix

UltrasoundFetal fibronectinPreterm delivery

Prediction

Objective: The purpose of this study was to examine the diagnostic performance ofultrasonographic measurement of the cervical length and vaginal fetal fibronectin determinationin the prediction of preterm delivery in patients with preterm uterine contractions and intact

membranes.Study design: Ultrasound examination of the cervical length and fetal fibronectin determinationin vaginal secretions were performed in 215 patients admitted with preterm uterine contractions

(22-35 weeks) and cervical dilatation of %3 cm. Outcome variables were the occurrence ofpreterm delivery within 48 hours, 7 days, and 14 days of admission, delivery%32 and%35 weeks,as well as the admission-to-delivery interval. Statistical analysis included chi-square test, receiver-operator characteristic (ROC) curve analysis, logistic regression, and survival analysis.

Results: The overall prevalence of preterm delivery%35 weeks was 20% (43/215). The prevalenceof spontaneous preterm delivery within 48 hours, 7 days, and 14 days of admission, and delivery%32 and %35 weeks were 7.9% (17/215), 13.0% (28/215), 15.8% (34/215), 8.9% (9/101), and

15.8% (34/215), respectively. ROC curve analysis and contingency tables showed a significantrelationship between the occurrence of preterm delivery and both cervical length and fetal fibro-nectin results (P! .01 for each). Both tests performed comparably in the prediction of spontaneous

preterm delivery. However, when fetal fibronectin results were added to those of cervical length(!30 mm), a significant improvement in the prediction of preterm delivery was achieved.

Presented at the 23rd Annual Meeting of the Society for Maternal-Fetal Medicine, February 3-8, 2003, San Francisco, Calif.

Reprints not available from the authors.

0002-9378/$ - see front matter � 2005 Elsevier Inc. All rights reserved.

doi:10.1016/j.ajog.2004.09.034

Gomez et al 351

Conclusion: Fetal fibronectin adds prognostic information to that provided by sonographicmeasurement of the cervical length in patients with preterm uterine contractions and intactmembranes.� 2005 Elsevier Inc. All rights reserved.

The diagnosis of preterm labor remains a clinicalchallenge. Meta-analysis of clinical trials in whichpatients presenting with preterm labor were randomizedto either placebo or beta-adrenergic agents indicates that37% of those allocated to placebo delivered after 37weeks.1 This implies that placebo has a high rate ofefficacy in the treatment of preterm labor or, alterna-tively, that the diagnosis of preterm labor is difficult.Assessing the probability of preterm delivery is impor-tant because the standard clinical interventions, namelytocolysis, steroids administration, and transfer to a ter-tiary care facility, are potentially risky and expensive.2,3

Three methods are currently available to assess thelikelihood of preterm delivery in patients with pre-mature uterine contractions: (1) digital examination ofthe cervix; (2) cervical sonography; and (3) fetalfibronectin.4-12 Previous studies have shown that sono-graphic cervical length is more effective than digitalexamination of the cervix.4,5,13 The objective of thisstudy was to determine if the combined use of fetalfibronectin and cervical sonography can improve theprediction of spontaneous preterm delivery in patientspresenting with preterm uterine contractions and intactmembranes.

Patients and methods

Study design

This is a prospective cohort study of patients admittedbetween July 1998 and October 2002 to the Sotero delRio Hospital, Chile, with the diagnosis of increasedpreterm uterine contractility and intact membranes.Criteria for entry into the study were: (1) singletongestation; (2) uterine contractility of 3 in 30 minutes,which brought the patient into the hospital; (3) gesta-tional age between 22 and 35 weeks; (4) cervicaldilatation %3 cm by digital examination; (5) intactmembranes as determined by sterile speculum examina-tion; and (6) signed informed consent, approved by theInstitutional Review Boards of both the Sotero del RioHospital and the National Institute of Child Health andHuman Development (Table I).

Definitions and study procedures

Patients were diagnosed to have increased uterinecontractility in the presence of regular uterine contrac-tions of at least 3 in 30 minutes. Digital examination ofthe cervix was performed, and the dilatation and

effacement recorded. Tocolysis was administered topatients with persistent uterine contractility for at least2 hours after intravenous hydration. The beta-adrenergicagent fenoterol and, occasionally, magnesium sulfatewere used for tocolysis. Magnesium sulfate was used asa second-line agent after fenoterol. Steroids (betame-thasone) were administered between 24 and 34 weeks.Endovaginal ultrasonography was performed shortlyafter admission, around the time of amniocentesis witha 5- to 7.5-MHz transvaginal probe. Patients were askedto empty their bladder before the procedure. Measure-ments were obtained by orienting the transducer so thatthe endocervical canal and the internal cervical os werevisualized in the same sagittal plane, in the absence ofuterine contractions. Three images were obtained, andthe one showing the shortest cervical length was used togenerate cervical biometric parameters. For fetal fibro-nectin determinations, fluid was collected from theposterior fornix of the vagina before ultrasonographicand digital examinations were performed and stored at

Table I Demographic characteristics of the study population

Maternal age (mean G SD, years) 24.7 G 8.2ParityNulliparous (%, n) 45% (97/215)Multiparous (%, n) 55% (118/215)

Prior preterm delivery (%, n) 13% (28/215)Gestational age at admission(mean G SD, weeks)

31.7 G 2.8

Gestational age at delivery(mean G SD, weeks)

37.5 G 2.8

Admission to deliveryinterval (mean G SD, days)

41.2 G 28.1

Table II Frequency of outcome variables, cervical length andfetal fibronectin results

Overall prevalenceof preterm delivery %35 weeks

20% (43/215)

Spontaneous delivery within 48 hours 7.9% (17/215)Spontaneous delivery within 7 days 13.0% (28/215)Spontaneous delivery within 14 days 15.8% (34/215)Spontaneous pretermdelivery % 32 weeks

8.9% (9/101)

Spontaneous pretermdelivery % 35 weeks

15.8% (34/215)

Cervical length (median, range, mm) 29 (1-58)Cervical length ! 15 mm 14% (30/215)Cervical length R 30 mm 50% (107/215)Vaginal fibronectin (C) 24% (52/215)

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Figure 1 ROC curve analysis for cervical length results (mm) and vaginal fetal fibronectin determination (ng/mL) in the

identification of delivery within (A) 48 hours, (B) 7 days, (C) 14 days, (D) delivery %32 weeks, and (E) %35 weeks.

Gomez et al 353

Table III Risk of spontaneous preterm delivery within 48 hours, 7 days and 14 days according to cervical length results and vaginalfibronectin determination

LR LR LR

Delivery within 48 h + / – Delivery within 7 d + / – Delivery within 14 d + / –

Cervical length !15 mm 36.7% (11/30) 6.7 56.7% (17/30) 8.7 56.7% (17/30) 6.9Cervical length R15 mm 3.2% (6/185) 0.4 5.9% (11/185) 0.4 9.2% (17/185) 0.5Cervical length !30 mm 13.9% (15/108) 1.9 23.1% (25/108) 2.0 26.9% (29/108) 1.9Cervical length R30 mm 1.9% (2/107) 0.2 2.8% (3/107) 0.2 4.7% (5/107) 0.3Vaginal fetal fibronectin (+) 19.2% (10/52) 2.8 34.6% (18/52) 3.5 42.3% (22/52) 3.9Vaginal fetal fibronectin (–) 4.3% (7/163) 0.5 6.1% (10/163) 0.4 7.4% (12/163) 0.4Prevalence of the outcome 7.9% (17/215) 13.0% (28/215) 15.8% (34/215)

LR, Likelihood ratio.

Table IV Risk of spontaneous preterm delivery % 32 and % 35 weeks according to cervical length results and vaginal fibronectindetermination

LR LR

Delivery % 32 wk + / – Delivery % 35 wk + / –

Cervical length !15 mm 58.3% (7/12) 14.3 63.3% (19/30) 9.2Cervical length R15 mm 2.2% (2/89) 0.2 8.1% (15/185) 0.5Cervical length !30 mm 18.4% (9/49) 2.2 27.8% (30/108) 2.0Cervical length R30 mm 0% (0/52) 0.1 3.7% (4/107) 0.2Vaginal fetal fibronectin (+) 30.4% (7/23) 4.5 40.4% (21/52) 3.6Vaginal fetal fibronectin (–) 2.6% (2/78) 0.3 8% (13/163) 0.5Prevalence of the outcome 8.9% (9/101) 15.8% (34/215)

LR, Likelihood ratio.

�70(C until assayed with a commercially availableimmunoassay (Adeza Corp., Sunnyvale, Calif). Thedetails of the assays have been previously described.14

The sensitivity of the assay was 16 ng/mL. A concen-tration of 50 ng/mL in the vaginal fluid was indicative ofa positive test. However, the absolute concentration offetal fibronectin was obtained with the immunoassay.The intra- and interassay coefficients of variation were3.7% and 3.6%, respectively.

Analysis

Outcome variables were the occurrence of spontaneouspreterm delivery within 48 hours, 7 days and 14 days ofadmission, delivery %32 weeks and %35 weeks, as wellas the admission-to-delivery interval. Proportions werecompared with chi-square or Fisher exact tests. Di-agnostic indices (sensitivity and specificity) as well aspositive and negative predictive values for endocervicallength and vaginal fibronectin were calculated. Logisticregression analysis was used to investigate the relation-ship between the occurrence of spontaneous pretermdelivery and various explanatory variables, including theresults of both the ultrasonographic examination of theuterine cervix and fetal fibronectin test in the vaginalposterior fornix. A Kaplan-Meier survival analysis wasperformed to assess the admission-to-delivery interval

according to the results of the sonographic cervicallength as well as those of the vaginal fetal fibronectin.Patients who delivered preterm for maternal or fetalindications were included in the analysis with a censoredtime equal to the examination-to-intervention interval.

Results

Clinical characteristics of the study population

Two hundred fifteen patients met the entry criteria for thestudy. Table I describes the clinical characteristics of thepatients enrolled. The mean gestational age at admissionwas 31.7 weeks (G2.8), whereas the mean gestational ageat delivery was 37.5 weeks (G2.8). The overall prevalenceof preterm delivery %35 weeks was 20% (43/215). Therate of spontaneous delivery within 48 hours, 7 days, and14 days of admission, delivery %32 weeks and%35 weekswas 7.9% (17/215), 13.0% (28/215), 15.8% (34/215), 8.9%(9/101), and 15.8% (34/215), respectively.

The median cervical length was 29 mm (range 1-58mm). The frequency of a cervical length !15 mm, !20mm, !25 mm, and !30 mm was 14% (30/215), 22%(48/215), 34% (73/215), and 50% (108/215), respec-tively. Thus, 50% (107/215) of the study population hada cervical length R30 mm. The prevalence of a positive

354 Gomez et al

Table V Relationship between various explanatory variables and spontaneous preterm delivery within 48 hours, 7 days and 14 days, aswell as delivery before 32 and 35 weeks, analyzed by logistic regression

Odds ratio for spontaneous delivery

Explanatory variable within 48 hours within 7 days within 14 days % 32 weeks % 35 weeks

Cervical length ! 15 mm 9.7* 13.2* 8.5* 57.7* 12.7*Positive vaginal fetal fibronectin NS 4.3* 6.6* NS 4.1*Gestational age at admission (weeks) NS 1.4* 1.5* NS NSCervical dilatation (cm) NS NS NS NS NSEffacement (%) NS NS NS 1.04* NS

* P ! .05; NS, Not significant.

Table VI Frequency of spontaneous preterm delivery according to cervical length (cutoff 30 mm) and vaginal fibronectin results

Cervical length! 30 mm

Fetalfibronectin C

Deliverywithin 48 hours

Deliverywithin 7 days

Deliverywithin 14 days

Delivery% 32 weeks

Delivery% 35 weeks

No No 2.2% (2/93) 2.2% (2/93) 3.2% (3/93) 0% (0/47) 1.1% (1/93)No Yes 0% (0/14) 7.1% (1/14) 14.3% (2/14) 0% (0/5) 21.4% (3/14)Yes No 7.1% (5/70) 11.4% (8/70) 12.9% (9/70) 6.5% (2/31) 17.1% (12/70)Yes Yes 26.3% (10/38) 44.7% (17/38) 52.6% (20/38) 38.9% (7/18) 47.4% (18/38)Prevalence of the outcome 7.9% (17/215) 13.0% (28/215) 15.8% (34/215) 8.9% (9/101) 15.8% (34/215)

Table VII Frequency of spontaneous preterm delivery according to cervical length (cutoff 15 mm) and vaginal fibronectin results

Cervical length! 15 mm

Fetalfibronectin C

Deliverywithin 48 hours

Deliverywithin 7 days

Deliverywithin 14 days

Delivery% 32 weeks

Delivery% 35 weeks

No No 2.0% (3/149) 3.4% (5/149) 4.7% (7/149) 1.4% (1/74) 4.7% (7/149)No Yes 8.3% (3/36) 16.7% (6/36) 27.8% (10/36) 6.7% (1/15) 22.2% (8/36)Yes No 28.6% (4/14) 35.7% (5/14) 35.7% (5/14) 25% (1/4) 42.9% (6/14)Yes Yes 48.3% (7/16) 75% (12/16) 75% (12/16) 75% (6/8) 81.3% (13/16)Prevalence of the outcome 7.9% (17/215) 13.0% (28/215) 15.8% (34/215) 8.9% (9/101) 15.8% (34/215)

fetal fibronectin in vaginal fluid was 24% (52/215). Therate of a positive fetal fibronectin was 13% (14/107)among patients with a cervical lengthR30 mm and 35%(38/108) for patients with a cervical length !30 mm(P ! .01). Moreover, the rate of a positive fetal fibro-nectin was 19% (36/185) among patients with a cervicallength R15 mm and 53% (16/30) for those witha cervical length !15 mm (P ! .01). Using this cutoff,the agreement between cervical length and vaginal fetalfibronectin results was 76% (kappa = 0.26, P ! .01).

Relationship between cervical length, vaginalfetal fibronectin, and the occurrence ofpreterm delivery

The rate of spontaneous preterm delivery within 48hours, 7 days, and 14 days of admission, delivery %32weeks and %35 weeks are displayed in Table II.Contingency tables and receiver-operator characteristic(ROC) curve analysis showed a significant relationshipbetween cervical length results or fetal fibronectinconcentration in the vaginal fluid and the occurrence

of preterm delivery or impending preterm delivery(within 48 hours and within 7 days). See area underthe curve and P values for each outcome in Figure 1,A-D, as well as Tables III and IV.

Patients with a cervical length !15 mm had a higherrate of delivery within 48 hours, 7 days, and 14 days ofadmission, delivery %32 weeks and %35 weeks thanthose with a cervical lengthR15 mm (Tables III and IV).Patientswith a cervical lengthR30mmhad a significantlylower frequency of preterm delivery within 48 hours,7 days, and 14 days of admission, delivery %32 weeksand%35weeks than those with a cervical length!30mm(Tables III and IV). Patients with a positive vaginalfibronectin had a significantly higher frequency of pre-term delivery within 48 hours, 7 days, and 14 days ofadmission, delivery %32 weeks and %35 weeks thanthose with a negative test (Tables III and IV).

The likelihood ratios for a positive and negative testfor cervical length (!15 mm or R15 mm and !30 mmor R30 mm, respectively) and vaginal fetal fibronectinwere calculated for the different endpoints of the study.The likelihood ratio for a positive test was higher for

Gomez et al 355

Figure 2 Risk of spontaneous preterm delivery within (A) 48 hours, (B) 7 days, (C) 14 days, (D) delivery %32 weeks, and (E) %35weeks, according to cervical length results and vaginal fetal fibronectin (fFN) determination.

a cervical length !15 mm than in the case of a cervicallength of !30 mm and a positive fetal fibronectin test(for delivery %35 weeks: 9.2, 2.0, and 3.6, respectively,see Tables III and IV for other outcomes).

Logistic regression analysis showed that sonographiccervical length determinations were significantly associ-

ated with the occurrence of delivery within 48 hours, 7days and 14 days of admission, and delivery %32 weeksand %35 weeks. Similarly, vaginal fetal fibronectinresults were significantly associated with preterm de-livery %35 weeks, within 7 and 14 days (Table V).Moreover, contingency tables and regression derived

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Figure 3 Frequency of spontaneous preterm delivery according to cervical length (CL) results (categorized as!15 mm, 15-29 mm,

and R30 mm) and vaginal fetal fibronectin (fFN) determination.

probability plots showed that vaginal fetal fibronectindetermination resulted in a modification of the posttestprobability of all outcome endpoints when used incombination with cervical length results of !30 mm(Tables VI and VII, Figures 2-4).

Analysis of the duration of pregnancy accordingto cervical length and fetal fibronectin results

Survival analysis of the admission-to-delivery intervalwas examined. Patients with an indicated pretermdelivery were included in the analysis with a censoredtime equal to the admission-to-intervention interval.Indications for delivery included clinical chorioamnio-nitis, rupture of membranes, placental abruption, fetaldistress, fetal demise, and others (n = 9). A Kaplan-Meier survival analysis with log rank test was performedto assess the examination-to-delivery interval of thefollowing groups: (1) cervical length R15 mm andnegative fetal fibronectin; (2) cervical length R15 mmand positive fetal fibronectin; (3) cervical length !15mm and negative fetal fibronectin; and (4) cervicallength !15 mm and positive fetal fibronectin. Themedian survival and 95% confident interval were asfollows: (1) 46 days (95% confidence interval [CI] 42-50days); (2) 32 days (95% CI 22-43 days); (3) 15 days(95% CI 0-48 days); and (4) 2 days (95% CI 0-4 days),respectively (P ! .0001, Figure 4).

Discussion

Principal findings

The findings of this study indicate that: (1) cervical lengthis a strong predictor of preterm delivery; (2) a short cervix(defined as a cervical length of less than 15 mm) identifiespatients at risk for impending preterm delivery (thosewho delivered within 48 hours or 7 days of admission); (3)a long cervix (defined as a cervical length of 30 mm or

Figure 4 Survival curve of the admission-to-delivery interval(days) according to cervical length and vaginal fetal fibronectin(fFN) results (Kaplan Meier with log rank test, P ! .0001).

Gomez et al 357

Table VIII Summary of studies about the role of cervical length by transvaginal ultrasound in women with symptoms of preterm laborand singleton pregnacies

Authors n

Gestationalage(weeks)

Cut-off(mm)

Definition ofPTD(weeks)

Prevalenceof PTD (%)

Sensitivity(%)

Specificity(%)

PPV(%)

NPV(%)

Murakawa et al (1993)15 32 18-37 !20 !37 34 27 100 100 72Iams et al (1994)4 60 24-35 !30 !36 40 100 44 55 100Gomez et al (1994)5 59 20-35 %18 !36 37 73 78 67 83Rizzo et al (1996)7 108 24-36 %20 !37 43 68 79 71 76Rozenberg et al (1997)10 76 24-34 %26 !37 26 75 73 50 89Cetin et al (1997)32 65 26-35 !30 !37 74 100 46 58 100Goffinet et al (1997)33 108 24-34 %27 !37 22 79 67 40 92Hincz et al (2002)12 82 24-34 %31 %28 17 100 47 28 100Tsoi et al (2003)9 216 24-36 %15 Within 7 days 8 94 86 37 99

PTD, Preterm delivery; PPV, positive predictive value; NPV, negative predictive value.

more) identifies patients at low risk for preterm deliveryand impending preterm delivery; (4) a positive vaginalfibronectin test was associated with spontaneous pretermdelivery. However, the likelihood ratio of a positive testwas substantially lower in a positive fetal fibronectin thanthat of a short cervix (eg, 3.6 vs 9.2 for delivery %35weeks, see Table III); and (5) the combined use ofsonographic cervical length and a vaginal fetal fibronec-tin test improved the prediction of preterm delivery overthat provided by each test alone. This effect was observedwhen the cervical length was less than 30 mm.

Cervical length and the prediction ofspontaneous preterm delivery

Previous studies focusing on patients with preterm laborand intact membranes have indicated that sonographiccervical length is a powerful predictor of the likelihoodof spontaneous preterm delivery. Table VIII summarizesthe studies reported to date. Iams et al4 proposed thata long cervix (defined as 30 mm or more) will identifypatients at low risk for preterm delivery (negativepredictive value for delivery !36 weeks of 100%;prevalence 40%), whereas Gomez et al5 noted thata short cervix, defined as a cervical length of 18 mmor less, was associated with a high rate of pretermdelivery (positive predictive value of 67% for pretermdelivery !36 weeks; prevalence: 37%). Other studieshave used different cutoff values, starting with the workof Murakawa et al,15 who first reported the use ofcervical ultrasound in patients with threatened pretermlabor. The results of the current study largely confirmthese observations with a larger sample size. Theselection of 30 mm and 15 mm was based on ROCcurve analysis. The likelihood ratios for a negative test(using cervical length R30 mm) were 0.2, 0.1, 0.2, and0.2 for delivery %35 weeks, %32 weeks, within 7 days,and within 48 hours, respectively. Conversely, the

likelihood ratios for a positive test (using cervical length!15 mm) were 9.2, 14.3, 8.7, and 6.7, respectively, forthe same outcomes (see Tables III and IV). Theseobservations, coupled with the results of previousstudies indicating that cervical length is superior todigital examination (effacement and dilatation) to pre-dict preterm delivery,4,5,13 have led us to conclude thatcervical sonography could be used in patients admittedwith preterm uterine contractions to assess the likeli-hood of preterm delivery. Sonographic cervical length ismore objective and reproducible than digital examina-tion of the cervix, providing an image that allows serialobservations. Previous studies indicate that cervicalsonography is acceptable to patients,16 and we see noadvantage in continuing to rely on digital examinationsin units where ultrasound is available and individualsare trained to perform this simple test.

Vaginal fetal fibronectin and spontaneouspreterm delivery

Multiple studies have provided evidence that a positivefetal fibronectin is a predictor of preterm deliveryin patients presenting with preterm uterine contrac-tions.6,11,17-28 Lockwood et al29 were the first to produceevidence in support of this. Recent reviews concludedthat a negative fetal fibronectin test identifies patients atlow risk for preterm delivery, although a positive testhas a limited positive predictive value.30,31 Our resultsare consistent with these findings as the negative pre-dictive value was 92% for delivery %35 weeks, and thepositive predictive value was 40% for this outcome. Thelikelihood ratios for the identification of impendingpreterm delivery are displayed in Table IV. Clearly,the performance of a positive vaginal fetal fibronectintest is limited, which contrasts with that of sonographiccervical length. Further studies are required to deter-mine if the use of different cutoffs for vaginal fetal

358 Gomez et al

fibronectin concentration may improve the clinical valueof the test.

The combined use of fetal fibronectin andcervical length

The most important observation of this study is that thecombined use of sonographic cervical length and fetalfibronectin improves the diagnostic performance of eachtest. Our observations are in contrast to those reportedby Rozenberg et al,10 but are in broad agreement withthose of Rizzo et al7 and Hincz et al.12

A limitation of the present study is that patients withpersistent contractions received tocolysis, a potentialconfounder for the outcomes ‘‘delivery within 48 hours’’and ‘‘delivery within 7 days.’’ However, we did notobserve a significant effect of tocolysis in our logisticmodel to predict preterm delivery when adjusting for theeffect of other explanatory variables. Moreover, theperformance of both cervical length and fetal fibronectinin the prediction of ‘‘delivery within 14 days,’’ a variablenot affected by the potential confounder effect oftocolysis, was comparable to others endpoints.

It is of interest that a positive or negative fetalfibronectin test improved the performance of sono-graphic cervical length only when the sonographiccervical length was less than 30 mm. The practicalconsequence of this fact is that patients can be screenedwith cervical sonography, and testing with fetal fibro-nectin may be restricted to those with a sonographiccervical length below 30 mm. Because approximately50% of patients presenting with preterm contractionshave a cervical length of 30 mm or more, this approachwill reduce the number of fetal fibronectin tests per-formed. On the other hand, below 30 mm, the posttestprobability of cervical length in the prediction ofspontaneous preterm delivery or impending delivery(48 hours and 7 days) is affected by the result of thevaginal fetal fibronectin test. This information can be ofclinical value when deciding the threshold which justifiesthe administration of steroids as well as patient transferto a tertiary care facility. Further studies are required totest these recommendations in clinical practice.

References

1. King JF, Grant A, Keirse MJ, Chalmers I. Beta-mimetics in

preterm labour: an overview of the randomized controlled trials.

Br J Obstet Gynaecol 1988;95:211-22.

2. Ingemarsson I, Lamont RF. An update on the controversies of

tocolytic therapy for the prevention of preterm birth. Acta Obstet

Gynecol Scand 2003;82:1-9.

3. Pryde PG, Besinger RE, Gianopoulos JG, Mittendorf R. Adverse

and beneficial effects of tocolytic therapy. Semin Perinatol

2001;25:316-40.

4. Iams JD, Paraskos J, LandonMB,Teteris JN, JohnsonFF.Cervical

sonography in preterm labor. Obstet Gynecol 1994;84:40-6.

5. Gomez R, Galasso M, Romero R, Mazor M, Sorokin Y,

Goncalves L, et al. Ultrasonographic examination of the uterine

cervix is better than cervical digital examination as a predictor of

the likelihood of premature delivery in patients with preterm labor

and intact membranes. Am J Obstet Gynecol 1994;171:956-64.

6. 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.

7. Rizzo G, Capponi A, Arduini D, Lorido C, Romanini C. The

value of fetal fibronectin in cervical and vaginal secretions and of

ultrasonographic examination of the uterine cervix in predicting

premature delivery for patients with preterm labor and intact

membranes. Am J Obstet Gynecol 1996;175:1146-51.

8. Timor-Tritsch IE, Boozarjomehri F, Masakowski Y, Monteagudo

A, Chao CR. Can a ‘‘snapshot’’ sagittal view of the cervix by

transvaginal ultrasonography predict active preterm labor? Am J

Obstet Gynecol 1996;174:990-5.

9. Tsoi E, Akmal S, Rane S, Otigbah C, Nicolaides KH. Ultrasound

assessment of cervical length in threatened preterm labor. Ultra-

sound Obstet Gynecol 2003;21:552-5.

10. Rozenberg P, Goffinet F, Malagrida L, Giudicelli Y, Perdu M,

Houssin I, et al. Evaluating the risk of preterm delivery: a compar-

ison of fetal fibronectin and transvaginal ultrasonographic mea-

surement of cervical length. Am J Obstet Gynecol 1997;176:196-9.

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.

12. Hincz P, Wilczynski J, Kozarzewski M, Szaflik K. Two-step test:

the combined use of fetal fibronectin and sonographic examination

of the uterine cervix for prediction of preterm delivery in

symptomatic patients. Acta Obstet Gynecol Scand 2002;81:58-63.

13. Berghella V, Tolosa JE, Kuhlman K, Weiner S, Bolognese RJ,

Wapner RJ. Cervical ultrasonography compared with manual

examination as a predictor of preterm delivery. Am J Obstet

Gynecol 1997;177:723-30.

14. Goldenberg RL, Mercer BM, Meis PJ, Copper RL, Das A,

McNellis D. The preterm prediction study: fetal fibronectin testing

and spontaneous preterm birth. NICHD Maternal Fetal Medicine

Units Network. Obstet Gynecol 1996;87:643-8.

15. Murakawa H, Utumi T, Hasegawa I, Tanaka K, Fuzimori R.

Evaluation of threatened preterm delivery by transvaginal ultra-

sonographic measurement of cervical length. Obstet Gynecol

1993;82:829-32.

16. Heath VC, Southall TR, Souka AP, Novakov A, Nicolaides KH.

Cervical length at 23 weeks of gestation: relation to demographic

characteristics and previous obstetric history. Ultrasound Obstet

Gynecol 1998;12:304-11.

17. Lukes AS, Thorp JM Jr, Eucker B, Pahel-Short L. Predictors of

positivity for fetal fibronectin in patients with symptoms of

preterm labor. Am J Obstet Gynecol 1997;176:639-41.

18. Giles W, Bisits A, Knox M, Madsen G, Smith R. The effect of fetal

fibronectin testing on admissions to a tertiary maternal-fetal

medicine unit and cost savings. Am J Obstet Gynecol

2000;182:439-42.

19. Benattar C, Taieb J, Fernandez H, Lindendaum A, Frydman R,

Ville Y. Rapid fetal fibronectin swab-test in preterm labor patients

treated by betamimetics. Eur J Obstet Gynecol Reprod Biol

1997;72:131-5.

20. Lopez RL, Francis JA, Garite TJ, Dubyak JM. Fetal fibronectin

detection as a predictor of preterm birth in actual clinical practice.

Am J Obstet Gynecol 2000;182:1103-6.

21. Malak TM, Sizmur F, Bell SC, Taylor DJ. Fetal fibronectin in

cervicovaginal secretions as a predictor of preterm birth. Br J

Obstet Gynaecol 1996;103:648-53.

22. Coleman MA, Keelan JA, McCowan LM, Townend KM, Mitchell

MD. Predicting preterm delivery: comparison of cervicovaginal

Gomez et al 359

interleukin (IL)-1beta, IL-6 and IL-8 with fetal fibronectin and

cervical dilatation. Eur J Obstet Gynecol Reprod Biol 2001;95:154-

8.

23. McKenna DS, Chung K, Iams JD. Effect of digital cervical

examination on the expression of fetal fibronectin. J Reprod

Med 1999;44:796-800.

24. Senden IP, Owen P. Comparison of cervical assessment, fetal

fibronectin and fetal breathing in the diagnosis of preterm labour.

Clin Exp Obstet Gynecol 1996;23:5-9.

25. LaShay N, Gilson G, Joffe G, Qualls C, Curet L. Will cervicova-

ginal interleukin-6 combined with fetal fibronectin testing improve

the prediction of preterm delivery? J Matern Fetal Med

2000;9:336-41.

26. Bartnicki J, Casal D, Kreaden US, Saling E, Vetter K. Fetal

fibronectin in vaginal specimens predicts preterm delivery and very-

low-birth-weight infants. Am J Obstet Gynecol 1996;174:971-4.

27. Leeson SC, Maresh MJ, Martindale EA, Mahmood T, Muotune

A, Hawkes N, et al. Detection of fetal fibronectin as a predictor of

preterm delivery in high risk asymptomatic pregnancies. Br J

Obstet Gynaecol 1996;103:48-53.

28. Coleman MA, McCowan LM, Pattison NS, Mitchell M. Fetal

fibronectin detection in preterm labor: evaluation of a prototype

bedside dipstick technique and cervical assessment. Am J Obstet

Gynecol 1998;179:1553-8.

29. Lockwood CJ, Senyei AE, Dische MR, 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.

30. Leitich H, Kaider A. Fetal fibronectin–how useful is it in the

prediction of preterm birth? BJOG 2003;110(Suppl 20):66-70.

31. Honest H, Bachmann LM, Gupta JK, Kleijnen J, Khan KS.

Accuracy of cervicovaginal fetal fibronectin test in predicting risk

of spontaneous preterm birth: systematic review. BMJ

2002;325:301.

32. Cetin M, Cetin A. The role of transvaginal sonography in

predicting recurrent preterm labour in patients with intact mem-

branes. Eur J Obstet Gynecol Reprod Biol 1997;74:7-11.

33. Goffinet F, Rozenberg P, Kayem G, Perdu M, Philippe HJ, Nisand

I. [The value of intravaginal ultrasonography of the cervix uteri for

evaluation of the risk of premature labor]. J Gynecol Obstet Biol

Reprod (Paris) 1997;26:623-9.