Predictive Value of Cervical Length Measurement and Fibronectin Testing in Threatened Preterm Labor

Article (PDF Available)inObstetrics and Gynecology 123(6) · May 2014with178 Reads
DOI: 10.1097/AOG.0000000000000229 · Source: PubMed
Abstract
To estimate the performance of combining cervical length measurement with fetal fibronectin testing in predicting delivery in women with symptoms of preterm labor. We conducted a prospective nationwide cohort study in all 10 perinatal centers in The Netherlands. Women with symptoms of preterm labor between 24 and 34 weeks of gestation with intact membranes were included. In all women, qualitative fibronectin testing (0.050-microgram/mL cutoff) and cervical length measurement were performed. Logistic regression was used to predict spontaneous preterm delivery within 7 days after testing. A risk less than 5%, corresponding to the risk for women with a cervical length of at least 25 mm, was considered as low risk. Between December 2009 and August 2012, 714 women were enrolled. Fibronectin results and cervical length were available for 665 women, of whom 80 (12%) delivered within 7 days. Women with a cervical length of at least 30 mm or with a cervical length between 15 and 30 mm with a negative fibronectin result were at low risk (less than 5%) of spontaneous delivery within 7 days. Fibronectin testing in case of a cervical length between 15 and 30 mm additionally classified 103 women (15% of the cohort) as low risk and 36 women (5% of the cohort) as high risk. Cervical length measurement, combined with fetal fibronectin testing in case of a cervical length between 15 and 30 mm, improves identification of women with a low risk to deliver spontaneously within 7 days. LEVEL OF EVIDENCE:: II.
Original Research
Predictive Value of Cervical Length
Measurement and Fibronectin Testing in
Threatened Preterm Labor
Gert-Jan van Baaren, MD, Jolande Y. Vis, MD,PhD, Femke F. Wilms, MD, Martijn A. Oudijk, MD,PhD,
Anneke Kwee, MD,PhD, Martina M. Porath, MD,PhD,GuidOei,MD,PhD, Hubertina C. J. Scheepers, MD,PhD,
Marc E. A. Spaanderman, MD,PhD,KittyW.M.Bloemenkamp,MD,PhD, Monique C. Haak, MD,PhD,
Antoinette C. Bolte, MD,PhD,CarolineJ.Bax,MD,PhD,JérômeM.J.Cornette,MD,
Johannes J. Duvekot, MD,PhD,BasW.A.NijBijvanck,MD,JimvanEyck,MD,PhD,
Maureen T. M. Franssen, MD,PhD, Krystyna M. Sollie, MD,PhD, Frank P. H. A. Vandenbussche, MD,PhD,
Mallory Woiski, MD, William A. Grobman, MD,MBA, Joris A. M. van der Post, MD,PhD,
Patrick M. M. Bossuyt, PhD, Brent C. Opmeer, PhD, and Ben W. J. Mol, MD,PhD
OBJECTIVE: To estimate the performance of combining
cervical length measurement with fetal fibronectin test-
ing in predicting delivery in women with symptoms of
preterm labor.
METHODS: We conducted a prospective nationwide
cohort study in all 10 perinatal centers in The Netherlands.
Women with symptoms of preterm labor between 24 and
34 weeks of gestation with intact membranes were
included. In all women, qualitative fibronectin testing
(0.050-microgram/mL cutoff) and cervical length measure-
ment were performed. Logistic regression was used to
predict spontaneous preterm delivery within 7 days after
testing. A risk less than 5%, corresponding to the risk for
women with a cervical length of at least 25 mm, was
considered as low risk.
RESULTS: Between December 2009 and August 2012,
714 women were enrolled. Fibronectin results and
cervical length were available for 665 women, of whom
80 (12%) delivered within 7 days. Women with a cervical
length of at least 30 mm or with a cervical length
between 15 and 30 mm with a negative fibronectin result
were at low risk (less than 5%) of spontaneous delivery
within 7 days. Fibronectin testing in case of a cervical
length between 15 and 30 mm additionally classified 103
women (15% of the cohort) as low risk and 36 women
(5% of the cohort) as high risk.
CONCLUSION: Cervical length measurement, combined
with fetal fibronectin testing in case of a cervical length
between 15 and 30 mm, improves identification of women
with a low risk to deliver spontaneously within 7 days.
(Obstet Gynecol 2014;123:1185–92)
DOI: 10.1097/AOG.0000000000000229
LEVEL OF EVIDENCE: II
Spontaneous preterm delivery remains one of the
most challenging problems in obstetrics. It occurs
in 513% of deliveries and is a major cause of perina-
tal mortality and neonatal morbidity.
1
In the devel-
oped world, women presenting with symptoms of
preterm labor before 32 weeks of gestation are often
From the Departments of Obstetrics and Gynecology, Academic Medical Center and
VU University Medical Center, Amsterdam, University Medical Center Utrecht,
Utrecht, Maastricht University Medical Center, Maastricht, Máxima Medical Cen-
ter, Veldhoven, Erasmus Medical Center, Rotterdam, Isala Clinics, Zwolle, Uni-
versity Medical Center Groningen, Groningen, Leiden University Medical Center,
and Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands,
Northwestern University Medical School, Chicago, Illinois, and The Robinson
Institute, School of Paediatrics and Reproductive Health, University of Adelaide,
Adelaide, Australia; Clinical Epidemiology, Biostatistics and Bioinformatics and
the ClinicalResearch Unit, Academic Medical Center, Amsterdam, and the Depart-
ment of Clinical Chemistry and Haematology, University Medical Center Utrecht,
Utrecht, The Netherlands.
This investigator-initiated study was funded by The Netherlands Organization
for Health Research and Development (ZonMw, grant number 80-82310-98-
09056).
Presented at the 33rd Annual Meeting of the Society of Maternal Fetal Medicine,
February 1116, 2013, San Francisco, California.
Corresponding author: Gert-Jan van Baaren, MD, Department of Obstetrics and
Gynecology, Academic Medical Centre, 1105 DE, Amsterdam, The Netherlands;
e-mail: g.j.vanbaaren@amc.uva.nl.
Financial Disclosure
The authors did not report any potential conflicts of interest.
© 2014 by The American College of Obstetricians and Gynecologists. Published
by Lippincott Williams & Wilkins.
ISSN: 0029-7844/14
VOL. 123, NO. 6, JUNE 2014 OBSTETRICS & GYNECOLOGY 1185
transferred to a perinatal center and receive treatment
with tocolysis and corticosteroids. However, 7595% of
these women will not deliver within 7 days after pre-
sentation, and half of these women will continue preg-
nancy until term.
25
Consequently, many women are
transferred and exposed to interventions without bene-
fit. If we could improve identification of women who
will not deliver in the short termsay within 7 dayswe
would be able to avoid side effects from unnecessary
treatments, reduce health care costs, and lower stress for
pregnant women and their families.
68
Cervical length measurement and fetal fibronectin
testing are often used in the clinical evaluation of
women with symptoms of preterm labor. Either
a cervical length of at least 25 mm or a negative
fibronectin test (less than 0.050 micrograms/mL) signi-
fies that the risk of preterm delivery within 7 days is less
than 5%, giving a sound argument to withhold treat-
ment.
3,5,9
However, a cervical length below 25 mm and
a positive fibronectin test both have a poor positive
predictive value for preterm birth. Treating all symp-
tomatic women with a short cervix or a positive fibro-
nectin test would lead to overtreatment.
3,5
A recently published meta-analysis concluded that
combining fibronectin results with cervical length may
result in more accurate identification of women who
will not deliver preterm, thereby reducing the number
of hospital referrals, admissions, treatments, and costs.
In these studies, preterm delivery before either 35 or 37
weeks of gestation was the most frequently used
outcome measure, yet these outcome measures do not
give an answer to the most acute clinical question,
namely, whether a woman with symptoms of preterm
labor needs immediate treatment and referral to
a perinatal center to optimize circumstances if preterm
delivery occurs. Two studies, which included only
192 women, reported on the outcome of preterm
delivery within 7 days, which is a more relevant clinical
outcome. The predictive value of combining cervical
length and fibronectin results seems to be promising for
the outcome preterm delivery within 7 days and more
accurate compared with long-term outcomes.
10
We analyzed data from a nationwide cohort study
to evaluate whether the combination of fibronectin
testing and cervical length measurement leads to more
accurate identification of women who will not deliver
within 7 days compared with either cervical length
measurement or fibronectin testing in isolation.
METHODS
We collected data in a prospective cohort study between
December 2009 and August 2012 in all 10 Dutch
perinatal centers that serve as tertiary referral centers
for high-risk obstetrics. In The Netherlands, symptom-
atic women with a high risk of preterm delivery before
34 weeks of gestation are referred to one of these 10
perinatal centers and managed according to national
guidelines.
11
The study protocol was approved by the
ethics committee of the Amsterdam Medical Center
(MEC 08/363) and was published thereafter.
12
Womenwithsymptomsconsistentwithpreterm
labor such as contractions (more than 3/30 min), vaginal
bleeding, or abdominal or back pain, who were between
24 and 34 weeks of gestation, and who had intact
membranes were eligible for the study. Women either
presented directly to one of the participating perinatal
centers or were referred by their primary gynecologist in
a general hospital (secondary care) or by a general
practitioner or midwife (primary care). Women who
had received tocolysis within the previous 7 days were
excluded with the exception of women who had
received a single dose of tocolytic treatment for transport
to the referral center. Women with contraindications for
tocolysis such as a lethal congenital abnormality, sus-
pected intrauterine infection, or nonreassuring fetal status
were excluded as were women in whom the cervix was
more than 3 cm dilated. Women who had iatrogenic
delivery within 7 days after study enrollment for
hypertensive disorders, nonreassuring fetal status, or
other reasons for immediate delivery also were excluded.
Eligible women were identified by study personnel and
invited to participate in the study. They participated if
they had given written informed consent. We intended
to include 660 women.
12
At the time the study started, cervical length
measurement, but not fibronectin testing, was stan-
dard care in The Netherlands for risk stratification in
women with symptoms of preterm labor. In The
Netherlands clinically active physicians are trained in
transvaginal ultrasonography and perform cervical
length measurements themselves. To standardize
these measurements, all participating physicians were
given a set of instructions and a pocket card with
illustrated examples of accurate cervical length meas-
urements. Before this study, fibronectin tests were not
performed as part of routine care. Before the study
started, physicians and midwives were trained on
how to collect a fetal fibronectin specimen from
the posterior fornix of the vagina. Preferably,
a specimen had to be collected before vaginal
examination or cervical length measurement. In
four participating centers, the fibronectin test was
done at the hospitals central laboratory and in six
within the obstetric departments. The involved per-
sonnel were trained to perform the fibronectin test. We
used the qualitative rapid fibronectin TLI
IQ
analyzer
1186 van Baaren et al Cervical Length and Fibronectin in Preterm Labor OBSTETRICS & GYNECOLOGY
with a 0.050-microgram/mL positivity cutoff. All centers
guaranteed the results of the fibronectin tests to be avail-
able within 1 hour.
12
No strict protocol was available for treatment
decisions, but recommendations were provided. We
recommended to start tocolysis in women with cervical
length below 10 mm and in women with a cervical
length between 10 and 30 mm with a positive fibronectin
result and to withhold tocolysis in women with a cervical
length above 30 mm. For women with a cervical length
between 10 and 30 mm in combination and a negative
fibronectin test, the clinician on call decided whether to
start tocolysis in these women. Clinicians could prescribe
nifedipine, indomethacin, atosiban, ritodrine, or all of
these. Corticosteroids were given to women at the
discretion of the clinician on call.
12
The primary outcomes were spontaneous pre-
term delivery within 7 days after enrollment and
stratification into a low-risk and a high-risk group
using a 5% risk threshold. This threshold has been
derived from the interpretation of cervical length
because it is currently applied in women with signs
of preterm labor. A cervical length between 20 and 30
mm decreases the risk of delivery within 7 days from
a prior of 11% to a posttest probability of 45%.
3
The
Dutch guideline, for example, uses 25 mm as a cutoff
for cervical length, which corresponds to a risk of 5%
to deliver within 7 days.
11
To assess whether the combination of both tests
could better identify women who will not deliver within
7 days as compared with current practice, four logistic
regression models were developed: a model with only
cervical length as predictor, a model with only fibronec-
tinaspredictor,amodelwithbothfibronectinand
cervical length as predictors, and a combined model in
which the increase of the risk associated with cervical
length could differ for women with a positive fibronectin
test result and for those with a negative result (an
interaction model).
13,14
Cervical length was analyzed as
a continuous variable. Linearity of the association
between cervical length and the risk of preterm delivery
was assessed using cubic spline analyses. Bootstrapping
techniques were used for internal validation of the four
models to avoid overfitting. Two hundred samples, of
a size equaling that of the original data set, were drawn
from the original data set with replacement. A shrinkage
factor calculated from these additional analyses was used
to adjust regression coefficients.
13,15
A test was considered positive when the predicted
risk was equal to or greater than 5%. Positive and
negative predictive values were calculated for the
prediction model. The model with the best overall
performance in term of overall fit, discrimination,
calibration, and reclassification (with further details
provided in Supplement S1) was used to create a risk
graph and decision rule for clinical use.
16
To facilitate
the use of the prediction model in clinical practice,
where cervical length cutoffs are frequently defined in
5-mm steps, we defined the cutoff accordingly. The
performance of this decision rule was compared with
that of other widely applied other decision rules: cervi-
cal length only, with a 25-mm cutoff, and fibronectin
testing only, with a 0.050-microgram/mL cutoff.
3,11,17
Data analyses were performed in R 2.10.0 and
SPSS 20.0.
RESULTS
Between December 2009 and August 2012, 758
potentially eligible women were identified. Five
women did not meet the inclusion criteria, 23 had
one or more exclusion criteria, and 16 did not consent
to the study. In the remaining 714 participating
women, we performed cervical length measurement
and fibronectin testing. Fibronectin results were
invalid in 21 women, whereas fibronectin and cervical
length were not recorded in nine and 13 women
(n543), respectively. We excluded six women who
underwent labor induction or had an elective caesar-
ean delivery within 7 days after study entrance, leav-
ing 708 women in the study group (Fig. 1).
Two hundred forty-three women (37%) presented
directly to one of the perinatal centers, 210 women
(32%) were referred to a perinatal center from second-
ary care centers, and 208 women (31%) were referred
from primary care midwifery practices (Table 1). The
mean gestational age at study entrance was 29 weeks
(interquartile range 2731). There were 103 women
(16%) with a multiple pregnancy, 143 (22%) with a pre-
vious preterm delivery before 37 weeks of gestation,
and 107 (16%) with a previous preterm delivery before
34 weeks of gestation. The median cervical length was
25 mm (interquartile range 1835 mm) and the fibro-
nectin result was negative in 364 women (55%). Eighty
women (12%) delivered within 7 days. The median
time to delivery in these 80 women was 2.2 days
(interquartile range 0.63.6).
The models for spontaneous preterm delivery
within 7 days based on cervical length and fibronectin
are shown in Table 2. A positive fibronectin test was
associated with an increased risk of preterm delivery
within 7 days regardless of whether it was considered
on its own (odds ratio [OR] 10.7, 95% confidence
interval [CI] 5.421.2) or conditionally on cervical
length (OR 4.2, 95% CI 2.09.0). Adding fibronectin
to a model with cervical length increased the positive
predictive value from 0.23 (95% CI 0.190.29) to
VOL. 123, NO. 6, JUNE 2014 van Baaren et al Cervical Length and Fibronectin in Preterm Labor 1187
0.27 (95% CI 0.220.33). It also significantly increased
model fit (x
2
test statistic 23; P,.001) and improved
calibration. Overall discrimination did not improve
(area under the curve 0.89, 95% CI 0.860.93). Add-
ing the interaction term to the model including cervi-
cal length and fibronectin did not lead to a significant
improvement in model fit and caused the positive pre-
dictive value and calibration to deteriorate. After
these analyses, the model including cervical length
and fibronectin (without interaction term) was selected
as the best model. Further performance characteristics
of these models, including a receiver operating charac-
teristic curve and a calibration plot of the best perform-
ing model, can be found in Appendix 1, available
online at http://links.lww.com/AOG/A486.
The risk graph based on the model including
cervical length and fibronectin (without interaction term)
isshowninFigure2.Whenthefibronectinresultis
taken into account, we found that fibronectin-negative
women with a cervical length of 17 mm and fibronectin-
positive women with a cervical length of 27 mm have
a5%orhigherriskofpretermdeliverywithin7days.
To facilitate its use in clinical practice, we redefined this
interval to be from 15 to 30 mm. The corresponding
decision rule translates into women with a cervical
length of 30 mm or higher being classified as at low risk
of preterm delivery and women with a cervical length of
15 mm or lower being classified as at high risk of pre-
term delivery. For women with a cervical length
between 15 and 30 mm, classification is contingent on
the fibronectin result: those with a positive fibronectin
test result are classified as high risk, whereas those with
a negative fibronectin test result as low risk.
Table 3 illustrates the reclassification of participants
according to the contingent decision rule. Compared
with cervical length with a 25-mm cutoff, the contingent
test resulted in 139 women (21%) being reclassified: 103
women (15%) were reclassified as low risk, of whom
three (3%) delivered within 7 days. Conversely, 36
women(5%)werereclassifiedashighrisk,ofwhomfour
(11%) delivered within 7 days. Summing these results
shows that 67 low-risk women (10% of the cohort) and
one woman with spontaneous preterm delivery within 7
days were additionally identified by using the contingent
(on the fibronectin results) decision rule. Compared with
fibronectin testing only, the contingent decision rule re-
classified 84 women (13%): 62 (9%) were reclassified as
low risk, of whom two (3%) delivered within 7 days. In
addition, 22 women (3%) were reclassified as high risk, of
whom six (27%) delivered within 7 days.
The risk of delivering within 1 week in case of
alow-riskoutcome of the decision rule is 6 of 404
(1.5%; 95% CI 0.73%); in case of high riskit is 74
of 261 (28%; 95% CI 2334%). Reclassification rates
were similar regardless of whether participants were
from midwife practices, from general hospitals, or
directly from home (Appendix 2, available online at
http://links.lww.com/AOG/A487).
Fig. 1. Participant flow diagram.
van Baaren. Cervical Length and Fibro-
nectin in Preterm Labor. Obstet Gynecol
2014.
1188 van Baaren et al Cervical Length and Fibronectin in Preterm Labor OBSTETRICS & GYNECOLOGY
DISCUSSION
This study assessed the value of fibronectin testing
when used as an adjunct to cervical length mea-
surement in women with symptoms of preterm
labor between 24 and 34 weeks of gestation. Our
analyses showed that fetal fibronectin testing in
women with a cervical length between 15 and
30 mm was helpful in stratifying women as low risk
(ie, risk of delivery within 7 days less than 5%) or
high risk. We found that the combination of cervical
length and fibronectin results could reduce the
number of referrals and admissions to perinatal
centers in 10% of all women compared with cervical
length as the sole predictor regardless of whether
women initially presented to a primary, secondary,
or tertiary care setting. Such a reduction would also
result in fewer medication side effects, less maternal
stress, and lower health care costs.
18
The strengths of this study include the use of
a well-described, large, nationwide and clinically
diverse cohort of women, in which the occurrence
of preterm delivery within 7 days was high (12.0%).
All Dutch perinatal centers that serve as a referral
center for high-risk obstetrics participated, which is,
besides the strict inclusion criteria, an explanation for
the high delivery rate within 7 days. Because of the
high density of midwifery practices and general
hospitals in The Netherlands, two-thirds of our study
population were from these centers. This composition
gave the opportunity to estimate the potential reduc-
tion of false-positive results by combining cervical
length and fibronectin in each clinical setting. To
enhance the general applicability of the model, we
focused on cervical length and fibronectin, both of
which can be collected by any clinician on call. We
used delivery within 7 days as the primary outcome,
because the probability to deliver within 7 days has
consequences for clinical decision-making; women
who have a low risk of preterm delivery within 7
days can be sent home or stay in secondary care for
monitoring and therefore avoid transport and pre-
scription of unnecessary medications.
An important question is whether this model also
applies to twin pregnancies, because the tests may
behave differently in multiple pregnancies. It would be
preferable to repeat all analyses in multiple pregnancies,
yet the sample included too few women with preterm
delivery to develop a separate prediction model for this
group (in our cohort, 20/103 [19.4%]). As a solution we
created reclassification tables for singleton and multiple
pregnancies (Appendices 3 and 4, available online at
http://links.lww.com/AOG/A488). According to these
results, the contingent rule enhances prediction
for both groups. The question of whether other
factors, such as ethnicity, body mass index (calcu-
lated as weight (kg)/[height (m)]
2
) or age, affect the
accuracy of fibronectin levels also has not been
resolved. To answer these questions we need larger
sample sizes.
A final issue is whether tocolysis reduces the
number of women who had preterm delivery within 7
days, and consequently, whether it affects the reported
decision rule. There is no good evidence that
Table 1. Demographic and Clinical Characteristics
(n5665)
Characteristics Values
Delivery within 7 d after study entrance 80 (12)
Maternal age (y) 29.765.3
BMI* (kg/m
2
) 22.5 (20.4–25.3)
White 454 (68)
Maternal smoking* (n5619) 90 (15)
Education
Primary school 6 (0.9)
Secondary school 29 (4.4)
Lower professional school 17 (2.6)
Medium professional school 164 (25)
Higher professional school 117 (18)
University 68 (10)
Unknown 263 (40)
Nulliparous 343 (52)
Previous preterm delivery, less than 34 wk
of gestation
107 (16)
Previous preterm delivery, less than 37 wk
of gestation
143 (22)
Previous term delivery, more than 37 wk
of gestation
206 (31)
Twin gestation 100 (15)
Triplet gestation 3 (0.5)
Symptoms
Objectified contractions
(cardiotocogram or manual)
529 (80)
Last prenatal visit in
Perinatal center 243 (37)
General hospital 210 (32)
Midwifery practice 208 (31)
Unknown 3 (0.5)
Cervical length (mm) 25 (18–35)
Fetal fibronectin
Positive 301 (45)
Negative 364 (55)
Digital examination* (n5510)
Cervical dilation, 1 cm 152 (30)
Cervical dilation, 2 cm 39 (7.6)
Cervical dilation, 3 cm 18 (3.6)
BMI, body mass index.
Data are n (%), mean6standard deviation, or median (interquartile
range).
* Data are missing.
Lower, medium, and higher professional schools denote pre-
paratory, intermediate, and higher vocational education,
respectively.
VOL. 123, NO. 6, JUNE 2014 van Baaren et al Cervical Length and Fibronectin in Preterm Labor 1189
tocolytics can delay delivery by this amount of time,
because double-blind placebo-controlled trials are
scarce and only include betamimetics and indometh-
acin as tocolytic agents. Aggregated data suggest that
these tocolytics might have an effect on the outcome
delivery within 7 days.
19
However, if tocolysis had an
effect on the outcome measure preterm delivery
within 7 days, it would mainly have affected the
high-risk fibronectin-positive women in our study,
because these women disproportionately received to-
colysis, which would have decreased our estimate of
the potential predictive capacity of fibronectin and
attenuated the contrast in outcomes between low-
and high-risk women. That is, the positive predictive
value that we report is a conservative estimate.
The outcome measure of preterm delivery within 7
days has been used in three prior studies that combined
cervical length and fibronectin results.
4,20,21
The
first prospective cohort study (n551) concluded
that additional fibronectin testing in cases of cervi-
cal length below 25 mm improved accuracy com-
pared with cervical length measurement only.
19
The
second prospective cohort study (n5215) concluded
that additional fibronectin measurement improved
Table 2. Risk of Preterm Delivery Within 7 Days as Predicted With Cervical Length and Fetal Fibronectin
Results (n5665)
Predictors and
Predictive Values
Cervical Length
Model
Fetal Fibronectin
Model
Fetal Fibronectin
and Cervical Length
Model
Fetal Fibronectin
and Cervical Length
Model (Interaction)
Cervical length (mm)* 0.84 (0.81–0.86) 0.86 (0.83–0.89) 0.81 (0.74–0.88)
Positive fibronectin
test*
10.7 (5.4–21.2) 4.2 (2.0–8.9) 1.4 (0.27–6.7)
Interaction term* 1.1 (0.98–1.2)
Positive predictive
value
0.23 (0.19–0.29) 0.23 (0.19–0.29) 0.27 (0.22–0.33) 0.26 (0.21–0.32)
Negative predictive
value
0.97 (0.95–0.99) 0.97 (0.95–0.99) 0.98 (0.96–0.99) 0.98 (0.96–0.99)
* Values expressed as odds ratios (95% confidence interval) estimated with logistic regression modeling, shrunk with a bootstrap technique.
Values expressed as proportions based on a 5% risk threshold (95% confidence interval); —, not included in the model.
Fig. 2. Risk graph for clinical use
based on the model including fetal
fibronectin and cervical length as
predictors. Dashed black line in-
dicates whether the predicted risk to
deliver within 7 days is above or
below the threshold of 5%. Above this
threshold, women are classified as
high risk to deliver within 7 days. The
dashed red and blue lines represent
95% confidence intervals.
van Baaren. Cervical Length and Fibro-
nectin in Preterm Labor. Obstet Gynecol
2014.
1190 van Baaren et al Cervical Length and Fibronectin in Preterm Labor OBSTETRICS & GYNECOLOGY
diagnostic accuracy significantly in cases of cervical
length below 30 mm.
4
The a priori risks of preterm
delivery and the results of both studies correspond
in general with our study, but these studies did
not assess whether there was a cervical length cutoff
below which the fibronectin test is redundant
because the risk of preterm delivery is already
high based on cervical length only. Furthermore,
the potential effect of implementing the additional
fibronectin test was not studied. A third study
(n5141), in which a retrospective cohort was ana-
lyzed, concluded that implementation of a strict
protocol using cervical length and fibronectin could
reduce costs.
20
Unfortunately, comparing their
results with the present findings is difficult, because
the a priori risks of preterm delivery within 7 days
was so different (3.6% compared with 12.0% in
our study).
Future analyses need to focus on further individ-
ualized risk assessment using additional biomarkers
such as vaginal examination, laboratory findings, and
patient characteristics, eg, age, socioeconomic status,
and previous preterm delivery. The quantitative
fibronectin test and other point-of-care tests also
may improve prediction of preterm delivery. We also
need to externally validate prediction models and
evaluate the cost-effectiveness of implementing these
models and corresponding treatment strategies in
clinical practice. To increase external validity and
enhance sample size, this requires individual patient
data meta-analysis.
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Table 3. Risk of Preterm Delivery Within 7 Days: Reclassification With the Fetal Fibronectin Test of Women
With Different Cervical Lengths
Cervical Length (mm)
Fetal Fibronectin Negative Fetal Fibronectin Positive Fetal Fibronectin Positive and Negative
n PTD Within 7 d (%) n PTD Within 7 d (%) n PTD Within 7 d (%)
Less than 15 mm 22 6 (27)* 91 47 (52)* 113 53 (47)
15–20 mm 41 0 (0)
54 9 (17)* 95 9 (9.5)
20–25 mm 62 3 (4.8)
58 8 (4)* 120 11 (9.2)
25–30 mm 46 1 (2.2)
36 4 (11)* 82 5 (6.1)
30 mm or greater 193 0 (0)
62 2 (3.2)
255 2 (0.7)
All cervical lengths 364 10 (2.7) 301 70 (23) 665 80 (12)
Twenty-five millimeters was the cervical length cutoff.
* Risk equal to or greater than 5% to deliver within 7 days.
Risk less than 5% to deliver within 7 days.
VOL. 123, NO. 6, JUNE 2014 van Baaren et al Cervical Length and Fibronectin in Preterm Labor 1191
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1192 van Baaren et al Cervical Length and Fibronectin in Preterm Labor OBSTETRICS & GYNECOLOGY
    • "For our study we used data from one prospective cohort study and three multicentre randomised controlled trials (RCTs) on preterm birth performed in the Dutch consortium for women's health research between 2006 and 2012. The prospective cohort study was the APOSTEL I (NTR 1857), which evaluated the use of fetal fibronectin testing and cervical length in 714 women with threatened preterm labour [12]. The APOSTEL II-trial (NTR 1336) compared maintenance tocolysis with nifedipine to placebo in 406 women with threatened preterm labour [13]. "
    [Show abstract] [Hide abstract] ABSTRACT: To estimate costs of preterm birth in singleton and multiple pregnancies. Cost analysis based on data from a prospective cohort study and three multicentre randomised controlled trials (2006-2012) in a Dutch nationwide consortium for women's health research. Women with preterm birth before 37 completed weeks were included for analysis. Direct costs were estimated from a health care perspective, from delivery until discharge or decease of the neonates. Costs and adverse perinatal outcome per pregnancy were measured. Adverse perinatal outcome comprised both perinatal mortality and a composite of neonatal morbidity defined as chronic lung disease, intraventricular haemorrhage≥grade 2, periventricular leukomalacia≥grade 1, proven sepsis or necrotising enterocolitis. Using a moving average technique covering three weeks per measurement, costs and adverse perinatal outcome per woman delivering for every week between 24 and 37 weeks are reported. Data of 2802 women were available of whom 1503 (53.6%) had a preterm birth; 501 in 1090 singleton (46%) and 1002 in 1712 multiple pregnancies (58.5%). The most frequent perinatal outcomes were perinatal mortality, chronic lung disease and sepsis. For singleton pregnancies the peak of total costs was at 25 weeks (€88,052 per delivery), compared to 27 weeks for multiple pregnancies (€169,571 per delivery). The total costs declined rapidly with increasing duration of pregnancy. Major cost drivers were length of stay on the NICU and airway treatments. The peaks seen in costs paralleled with the prevalence of adverse perinatal outcome. These data can be used to elaborate on the impact of preterm birth in case only data are available on duration of pregnancy. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.
    Full-text · Article · Mar 2015
  • [Show abstract] [Hide abstract] ABSTRACT: Large randomized controlled trials have demonstrated that universal maternal cervical length screening and treatment with daily vaginal progesterone in women with short cervical length reduces the risk of preterm birth, but large numbers of women must be screened to prevent a relatively small number of preterm deliveries. Issues that should be considered while implementing universal cervical length screening include: (1) the standards of quality and reproducibility for transvaginal ultrasound cervical length ascertainment; and (2) the implications of screening on the application of therapeutic strategies to populations not known to benefit (so-called "indication creep"). Optimal strategies to employ cervical ultrasound and progesterone treatment might be revealed by additional studies investigating cervical length cutoffs, frequency of screening, selective screening in higher-risk groups, and the use of transabdominal cervical length screening as a surrogate for transvaginal cervical length screening.
    Article · Jun 2014
  • [Show abstract] [Hide abstract] ABSTRACT: The APOSTEL-II trial was a multicenter randomized placebo-controlled trial, assessing the effectiveness of maintenance tocolysis with nifedipine. The trial showed maintenance tocolysis not to have an effect on perinatal outcome. Objective of the current study is to evaluate the effect of a negative trial on the length of hospital admission of women with threatened preterm labor. We evaluated length of hospital admission of all patients admitted with threatened preterm labor with a gestational age <32 weeks in 8 perinatal centers that participated in the APOSTEL-II trial. We studied only the first admission with threatened preterm labor, readmissions were excluded. We distinguished between the period before, the period during and the period after the trial. In a subgroup analysis, we differentiated for the group of women who delivered and for the group of women who did not deliver during the initial admission. The mean length of hospital admission was 9.3 days before the start of the trial, 8.4 days during the recruitment period and 8.1 days after the trial was completed. The difference in mean length of hospital admission before and during the recruitment period was significantly different (p<001). The length of hospital admission of women with threatened preterm labor is found to be reduced during the recruitment period of the APOSTEL-II trial. This shows that the conduct of a randomized controlled trial itself has the potential to change daily practice. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.
    Full-text · Article · Dec 2014
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