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OBSTETRICS

OBSTETRICS

Contingent Use of Fetal Fibronectin Testing and


Cervical Length Measurement in Women With
Preterm Labour
Franois Audibert, MD, MSc, Suzanne Fortin, MD, Edgard Delvin, PhD, Anissa Djemli, PhD,
Suzanne Brunet, RT, Johanne Dub, MD, FRCOG, William D. Fraser, MD, MSc
Dpartement dObsttrique Gyncologie, Centre Hospitalier Universitaire Sainte-Justine, Universit de Montral, Montral (Quebec)

Abstract
Objective: To evaluate the contingent use of fetal fibronectin (fFN)
testing and cervical length (CL) measurement to predict preterm
delivery, and to validate the use of phosphorylated IGFBP-1 as a
predictor of preterm delivery.
Methods: We recruited 71 women with a clinical diagnosis of
preterm labour between 24 and 34 weeks, and tested for the
presence of fFN and IGFBP-1 in the cervicovaginal secretions of
all women immediately before CL measurement.
Results: Among the 66 women with complete outcome, four were
excluded from the final analysis as two had assessment for fFN
but no CL measurement, and another two had CL measured but
no screening for fFN. Among 62 women with complete results, the
mean gestational age at recruitment was 29.4 2.5 weeks. Six
women (9.6%) delivered within two weeks of assessment, and 14
(22.5%) delivered before 34 weeks. A positive fFN test resulted in
a sensitivity of 83%, a specificity of 84%, a positive predictive
value of 36%, and a negative predictive value of 98% for delivery
within two weeks; for CL < 25 mm, these figures were 50%, 52%,
10%, and 91%, respectively, and for a positive IGFBP-1, they were
17%, 93%, 20%, and 91%, respectively. A policy of contingent use
of fFN (in which the test was assumed to be positive if CL 15 mm,
and fFN was only measured if the CL was between 16 and 30 mm)
gave sensitivity, specificity, positive and negative predictive values
of 80%, 61%, 17%, and 97%, respectively for delivery within two
weeks. Using this contingent use protocol, only one third of
women needed fFN screening after CL measurement.
Conclusion: In this study, IGFBP-1 screening did not predict preterm
delivery and fFN screening provided the best predictive capacity.
A policy of contingent use of testing for fFN after CL measurement,
or contingent use of CL measurement after fFN screening
(depending on available resources) is a promising approach to
limit use of resources.

Rsum
Objectif : valuer lutilisation contingente du dpistage de la
fibronectine ftale (FNf) et de la mesure de la longueur cervicale
(LC) pour prdire laccouchement prterme, ainsi que valider
lutilisation de lIGFBP-1 phosphoryle titre de facteur prdictif
de laccouchement prterme.
Mthodes : Nous avons recrut 71 femmes ayant obtenu un
diagnostic clinique de travail prterme entre 24 et 34 semaines,
et nous avons cherch dterminer la prsence de FNf et
dIGFBP-1 dans les scrtions cervicovaginales de toutes les
femmes, immdiatement avant la mesure de la LC.
Rsultats : Parmi les 66 femmes ayant connu une issue complte,
quatre ont t exclues de lanalyse finale puisque deux dentre
elles avaient subi un dpistage de la FNf sans quune mesure de
la LC ne soit effectue, tandis que la LC des deux autres avait t
mesure sans quun dpistage de la FNf ne soit men. Chez les
62 femmes prsentant des rsultats complets, lge gestationnel
moyen au moment de ladmission ltude tait de 29,4
2,5 semaines. Six femmes (9,6 %) ont accouch dans les deux
semaines suivant lvaluation et 14 (22,5 %) ont accouch avant
e
la 34 semaine de gestation. Un rsultat positif au test FNf donnait
lieu une sensibilit de 83 %, une spcificit de 84 %, un
coefficient de prvision dun test positif de 36 % et un coefficient
de prvision dun test ngatif de 98 % pour ce qui est dun
accouchement dans les deux semaines; en ce qui concerne une
LC <25 mm, ces valeurs taient de 50 %, de 52 %, de 10 % et de
91 %, respectivement, tandis que dans le cas dun rsultat positif
au test IGFBP-1, elles taient de 17 %, de 93 %, de 20 % et de
91 %, respectivement. Une politique dutilisation contingente du
dpistage de la FNf (selon laquelle le test tait prsum positif
lorsque la LC 15 mm et la FNf ntait mesure que lorsque la LC
se situait entre 16 et 30 mm) a donn lieu une sensibilit, une
spcificit, un coefficient de prvision dun test positif et un
coefficient de prvision dun test ngatif de 80 %, de 61 %, de
17 % et de 97 %, respectivement, pour ce qui est dun
accouchement dans les deux semaines. En utilisant ce protocole
dutilisation contingente, seul le tiers des femmes ncessitait un
dpistage de la FNf la suite de la mesure de la LC.

Received on June 11, 2009

Conclusion : Dans le cadre de cette tude, le dpistage de


lIGFBP-1 na pas permis de prdire laccouchement prterme; le
dpistage de la FNf a prsent la meilleure capacit de prvision.
Ladoption dune politique dutilisation contingente du dpistage de
la FNf la suite de la mesure de la LC ou dutilisation contingente
de la mesure de la LC la suite du dpistage de la FNf (selon les
ressources disponibles) constitue une approche prometteuse pour
ce qui est de limiter lutilisation des ressources.

Accepted on August 27, 2009

J Obstet Gynaecol Can 2010;32(4):307312

Key Words: Preterm labour, cervical length, fetal fibronectin,


IGFBP-1
Competing Interests: None declared.

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INTRODUCTION

reterm birth remains a major cause of perinatal morbidity and mortality,1 and its rate has not declined over the
last two decades despite the improvement in perinatal management.2 Assessing the probability of preterm delivery is
still a clinical challenge and is important because standard
clinical interventions (tocolysis, corticosteroid administration, and transfer to a tertiary care facility) are potentially
risky and expensive. Previous studies have shown that a
diagnosis of preterm labour based on digital examination
was less reliable than a diagnosis based on objective tests,
such as detection of fetal fibronectin in cervicovaginal
secretions and ultrasound measurement of cervical length.3

Fetal fibronectin, an extracellular matrix glycoprotein localized at the maternalfetal interface of the amniotic membranes between the chorion and the decidua, is found at
very low levels in cervicovaginal secretions under normal
conditions. Levels 50 ng/mL at or after 22 weeks gestation have been associated with an increased risk of spontaneous preterm birth.36 A recent meta-analysis has shown
that birth before 37 weeks was significantly decreased in
patients whose management was based on knowledge of
fFN results compared with controls whose fFN results
were not known.7
Transvaginal CL measurement is the other validated test to
predict preterm birth in women with threatened preterm
labour as well as in asymptomatic high-risk and low-risk
women.3,814 A CL measurement of 25 mm or less is generally considered an excellent indicator of an increased risk of
preterm delivery, particularly among women with preterm
labour.
Several studies have reported that fFN screening and CL
measurement provided similar results in predicting the risk
of preterm delivery.1520 However, whether combined fFN
and CL measurement improves the prediction of preterm
delivery and how the tests should be combined remain
unclear.3 Availability of one of the two tests may be an issue
in some facilities because the ultrasound expertise for CL
measurement may not be always available in small centres.
On the other hand, the additional cost of fFN testing may
be difficult to justify in centres where CL measurement is
readily available. Therefore, the use of CL or fFN as the
first-line test might be a more rational option, limiting the

ABBREVIATIONS
CL

cervical length

fFN

fetal fibronectin

IGFBP-1 insulin-like growth factor binding protein-1

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use of a second test to selected cases in a contingent


approach.
More recently, a rapid test for the determination of the insulin-like growth factor binding protein phosphorylated
isoform in endocervical secretions has been proposed.2124
Although IGFBP-1 is synthesized in the decidua and the
liver, decidual cells predominantly secrete the
phosphorylated form, which in normal conditions is not
present in amniotic fluid and cervical secretions.
The objective of the present study was to determine the performance of a contingent use of fFN testing and ultrasound
CL measurement for the prediction of preterm delivery in
patients with preterm labour. A secondary objective was to
validate the use of cervical IGFBP-1 measurement for the
prediction of preterm delivery.
MATERIALS AND METHODS

Women admitted to our tertiary care unit with a clinical


diagnosis of preterm labour and intact membranes between
24 and 34 weeks were approached to participate in the study
and were included after providing informed consent.
Preterm labour was defined by the presence of regular uterine contractions, lasting at least 30 seconds and occurring at
least four times per 30 minutes, and significant cervical
changes on digital examination. Women were excluded if
they had confirmed or suspected rupture of membranes,
cervical dilatation > 3 cm, cervical cerclage, vaginal bleeding, placenta previa, placental abruption, severe intrauterine
growth restriction, preeclampsia, or medically indicated
preterm delivery before 34 weeks.
The study investigations were carried out either on admission or within 24 hours of admission if a digital examination
had been performed in the 24 hours before the patients
inclusion in the study. Each subject was first examined with
a vaginal speculum. A Dacron swab was rotated in the posterior fornix of the vagina and sent to the laboratory. The
presence or absence of fFN was measured by a qualitative
test (Full Term, Hologic, Marlborough, MA), and results
were expressed as positive or negative. A second swab
(Actim Partus, Somagen, Edmonton AB) was taken in the
cervix and held for 15 seconds, then dipped into a sterile
medium and held for another 10 seconds. Following this, a
dipstick was used to determine if the test was positive (two
blue lines), suggesting a concentration of IGFBP-1 in the
cervical secretions higher than 10 mg/L, or negative (single
blue line after 5 minutes). Immediately after the sampling, a
transvaginal sonographic measurement of the cervical
length was performed by a trained sonographer, or by a resident under direct supervision of a faculty member, using a
standard protocol (empty bladder, minimal pressure,
measurement of the maximum length between the internal

Contingent Use of Fetal Fibronectin Testing and Cervical Length Measurement in Women With Preterm Labour

Figure 1. Contingent use of fetal fibronectin testing

Figure 2. Contingent use of cervical length measurement

and external os, before and after Valsalva manoeuvre).25,26


The clinical team were not blinded to the results of fFN
testing and CL measurement, and these results were available in the medical record. The results of IGFBP-1 testing
were not disclosed to the clinician in charge and were not
reported in the medical record. The standard local management protocol for preterm labour was applied to the study
patients: administration of corticosteroids, administration
of tocolytics for a maximum of 48 hours, and bed rest were
prescribed by the attending physician, depending on clinical
evaluation and on the results of investigations, including
fFN and CL measurement. The reproducibility of CL measurement or fFN assessment was not tested in this study.

RESULTS

The outcome of the pregnancy was recorded in a database


with other information pertinent to the project. The outcomes of interest were delivery within two weeks of admission to the study and delivery before 34 weeks.
Predictive values and likelihood ratios with their 95% confidence interval were first calculated for each test considered
separately, then for different combinations of both markers
used in a contingent manner. The contingent use of fFN
test was considered positive if cervical length was 15 mm
or between 16 and 30 mm with positive fFN, as described
by Schmitz et al.20 The test was considered negative if cervical
length was > 30 mm or between 16 and 30 mm with negative
fFN (Figure 1). The contingent use of CL test was considered positive if fFN was positive, or if fFN was negative
with a CL 15 mm. The test was considered negative if fFN
was negative and CL > 15 mm (Figure 2). Predictive values
were compared using the McNemar chi-square test. All
analyses were performed with Stata 10.0 software
(StataCorp LP, College Station, TX).
The Ethics Committee of Centre Hospitalier Universitaire
Sainte-Justine approved this prospective study.

Seventy-one women were recruited for the study between


January 2006 and January 2007. The outcome of pregnancy
could not be determined for five women who had been discharged and delivered in another centre. Among the 66
remaining women, two had a fFN assessment but no CL
measurement, and another two had CL measured but no
evaluation of fFN. These cases were excluded from further
analysis. Sixty-two women were included in the final analysis, including seven twin pregnancies, and 37 (60%) women
were initially transferred from another centre because of
preterm labour. Six women (9.6%) delivered within two
weeks, and 14 women (22.5%) delivered before 34 weeks.
General characteristics and pregnancy outcome in study
subjects are summarized in Table 1.
The values of the different tests in predicting delivery within
two weeks and before 34 weeks are shown in Table 2. The
best single test for the prediction of delivery within two
weeks was fFN (sensitivity 83% and specificity 84%),
whereas CL measurement had a slightly better sensitivity
than fFN (71 vs. 50%, respectively) for predicting delivery
before 34 weeks. The specificity of fFN was significantly
better than CL measurement (P < 0.001) and similar to the
specificity of contingent testing. With a policy of contingent
use of fFN (fFN tested only for CL more than 15 mm but
less than 30 mm), the fFN testing could have been avoided
in 40 of 62 women (65%). With a policy of contingent measurement of CL (CL measured only if negative fFN), the CL
measurement could have been avoided in 14 of 62 women
(23%). Overall, we found no significant difference between
the sensitivity of fFN testing, CL measurement, and their
combinations.
The predictive values of the IGFBP-1 test were very poor,
with a sensitivity of 17% and 14% for the prediction of
preterm delivery within two weeks and before 34 weeks,
respectively.
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Table 1. General characteristics, pregnancy outcome,


and test results
Characteristics

N = 62

Maternal age in years, mean SD

27.6 6.2

Nulliparous, n (%)

29 (46.8)

Maternal transfer, n (%)

37 (59.7)

Gestational age at inclusion in weeks, mean SD

29.4 2.5

Gestational age at delivery in weeks, mean SD

36.5 3.2

Received tocolytics, n (%)

44 (71.0)

Delivery within 2 weeks, n (%)


Delivery before 34 weeks, n (%)
Delivery before 37 weeks, n (%)

6 (9.7)
14 (22.6)
23 (37.1)

Admission to delivery interval in days, mean SD

49.9 22.8

Median cervical length in mm (range)

26.5 (051)

Cervical length < 15 mm

16 (28.8)

Cervical length < 25 mm

30 (48.4)

Cervical length 30 mm

24 (38.7)

Positive fFN, n (%)


Positive IGFBP-1, n (%)

14 (22.6)
5 (8.1 )

DISCUSSION

The results of this study confirm that both cervicovaginal


fFN testing and endovaginal CL measurement provide
good prediction of delivery within two weeks or before
34 weeks in women with threatened preterm labour. In
addition, we have tested two different strategies combining
both tests, with the aim of improving the predictive value while
decreasing the need for additional resources. For the prediction of delivery within two weeks, the best performance
was provided by fFN testing alone, whereas contingent use
of CL measurement was the best predictor of delivery
before 34 weeks. However, the sensitivities did not differ
significantly between the various combinations; this means
that, depending on local resources, a choice can be made
among these options. In facilities where vaginal ultrasound
equipment and expertise are readily available (especially in
tertiary care centres), CL measurement is a good test for the
initial triage. When CL results are in an intermediate range,
fFN testing clearly provides useful additional information
to decide whether the woman with resolved preterm labour
can be discharged. In facilities where vaginal ultrasound is
not routinely offered, fFN testing offers an excellent option
to decide if a woman with preterm labour requires treatment and referral to a tertiary facility. Whatever the strategy
used, it is important to perform the fFN swab sampling
before any other vaginal examination (CL measurement or
digital examination) as routinely recommended for fFN
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testing. The swab is simply discarded if the test is deemed


unnecessary on the basis of CL measurement
There is no consensus about the benefits of combining fFN
testing and CL measurement in women with preterm
labour. Rozenberg et al.,16 using a one-step combination
(both tests performed for every patient), found the combination of tests to have limited value, whereas several other
studies reported increased predictive values when both tests
were combined in various ways.15,1820 The selective use of
fFN after CL measurement, similar to the contingent use we
tested, was proposed by Hincz et al.18 and by Schmitz et al.20
Both studies found an improved specificity when fFN testing was limited to cases of intermediate measurement of CL
(2131 mm for Hincz, and 1630 mm for Schmitz). Gomez
et al.19 found a significant improvement in the prediction of
preterm delivery when fFN was tested after a CL < 30 mm.
We were unable to find any report of the contingent use of
CL measurement after fFN testing.
Our study has some limitations. First, the clinicians providing care for the women, except for IGFBP-1, were not
blinded to the results of the tests, and the results of the tests
might have changed the management of the pregnancy.
However, the primary goal of this study was not to validate
fFN and CL as markers of the risk of preterm delivery,
which has been done previously, but rather to test their contingent use. Another limitation of the study is its relatively
small sample size. We cannot exclude a lack of statistical
power to detect subtle differences in the predictive values
between the various combinations of tests. However, we
believe that this study provides important information to
obstetric care providers who have to choose a rational
algorithm for management in cases of threatened preterm
labour, adapted to the local resources. The reproducibility
of measurements was not tested in this study. However,
numerous reports have confirmed that both cervical length
measurement and fFN testing had a good to excellent
reproducibility.3 We chose not to perform a cost-effectiveness
analysis,27 because the cost of cervical length measurement
is highly dependent on the availability of vaginal ultrasound
and expertise. Depending on the type of facility and
available staff, the choice of the first-line test, fFN testing, or
CL measurement, provides similar predictive values among
women with threatened preterm labour.
A secondary objective of this study was to validate the use
of phosphorylated IGFBP-1 as a marker of an increased
risk of preterm delivery. In contrast to previous
reports,2124,2830 our study found that IGFBP-1 was a very
poor predictor of preterm delivery. Only five women out of
62 tested had a positive result, and the sensitivity for the
detection of preterm delivery was extremely low, below
20%. The reasons for this poor performance are unclear.

Contingent Use of Fetal Fibronectin Testing and Cervical Length Measurement in Women With Preterm Labour

Table 2. Predictive values for preterm birth of cervical length, fFN, IGFBP-1, and contingent use of fFN and cervical
length
Delivery

Sensitivity
% (95% CI)

Specificity
% (95% CI)

LR+
(95% CI)

LR
(95% CI)

PPV
% (95% CI)

NPV
% (95% CI)

83 (36100)

84 (7292)

5.2 (2.610.4)

0.2 (0.01.2)

36 (1365)

98 (89100)

Within 2 weeks
(prev 9.7%)
fFN +
IGFBP-1

17 (064)

93 (8398)

2.3 (0.317.6)

0.9 (0.61.3)

20 (0.572)

91 (8197)

CL < 25 mm

50 (1288)

52 (3865)

1.0 (0.42.4)

1.0 (0.42.2)

10 (226)

91 (7598)

Contingent fFN

50 (1288)

64 (5077)

1.4 (0.63.3)

0.8 (0.31.8)

13 (334)

92 (7998)

Contingent CL

83 (36100)

62 (4875)

2.2 (1.43.6)

0.3 (0.01.6)

19 (639)

97 (85100)

fFN +

50 (2377)

85 (7294)

3.4 (1.48.1)

0.6 (0.31.0)

50 (2377)

85 (7294)

IGFBP-1

14 (243)

94 (8399)

2.3 (0.412.4)

0.9 (0.71.1)

40 (585)

79 (6689)

CL < 25 mm

71 (4292)

58 (4372)

1.7 (1.12.7)

0.5 (0.21.2)

33 (1753)

87 (7196)

Contingent fFN

64 (3587)

71 (5683)

2.2 (1.23.4)

0.5 (0.21.0)

39 (2061)

87 (7396)

Contingent CL

71 (4292)

67 (5280)

2.1 (1.33.6)

0.4 (0.21.0)

38 (2059)

89 (7497)

75 (6486)

< 34 weeks
(prev 22.6%)

< 37 weeks
(prev 37.1%)
fFN +

48 (3560)

92 (8699)

6.2 (1.920.0)

0.5 (0.40.8)

79 (6889)

IGFBP-1

13 (521)

95 (89100)

2.5 (0.514)

0.9 (0.81.1)

60 (4872)

65 (5377)

CL < 25 mm

74 (5290)

67 (5081)

2.2 (1.33.7)

0.4 (0.20.8)

57 (3774)

81 (6493)

Contingent fFN

56 (3477)

74 (5887)

2.2 (1.24.2)

0.6 (0.41.0)

56 (3477)

74 (5887)

Contingent CL

65 (4384)

72 (5585)

2.3 (1.34.1)

0.5 (0.30.9)

58 (3777)

78 (6190)

fFN+: positive fetal fibronectin test; CL: cervical length; contingent fFN: CL measured in all cases, and fFN only for CL between 16 and 30 mm; contingent CL: fFN
tested in all cases, and CL only for negative fFN; LR+: likelihood ratio for a positive result; LR:likelihood ratio for a negative result; PPV: positive predictive value;
NPV: negative predictive value; prev: prevalence;
P > 0.05 for all comparisons between sensitivities; P< 0.001 vs. CL.

We followed the manufacturers instructions carefully. The


sample size of the current study is similar to those of previous reports. As with all new techniques, there is a potential
publication bias, since positive results are more likely to be
published than studies with negative results.31 We therefore
believe that the use of IGFBP-1 as a marker of preterm
delivery with intact membranes requires further prospective
and adequately powered studies, and cannot yet match the
reliability of fFN.
CONCLUSION

We have confirmed that fFN testing in patients selected by


use of cervical sonography is more specific for predicting
preterm birth than cervical length measurement alone, and
is as effective as fFN testing in all women. Using this contingency testing can reduce the number of fFN tests performed by 65%. On the other hand, cervical ultrasound
after fFN triage is an acceptable option, depending on the
resources available. The effect of the contingent use of

these tests on preterm birth rates, the duration of hospitalization, and overall costs now must be evaluated in
prospective studies.
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