Mid-Trimester Endovaginal Sonography in Women at High Risk for Spontaneous
Preterm Birth

JAMA. 2001;286:1340-1348

Author Information <http://jama.ama-assn.org/issues/v286n11/rfull/#aainfo>
John Owen, MD; Nicole Yost, MD; Vincenzo Berghella, MD; Elizabeth Thom, PhD;
Melissa Swain, RN; Gary A. Dildy III, MD; Menachem Miodovnik, MD; Oded
Langer, MD; Baha Sibai, MD; Donald McNellis, MD; for the National Institute
of Child Health and Human Development, Maternal-Fetal Medicine Units Network
Context  Although shortened cervical length has been consistently associated
with spontaneous preterm birth, it is not known when in gestation this risk
factor becomes apparent.
Objective  To determine whether sonographic cervical findings between 16
weeks' and 18 weeks 6 days' gestation predict spontaneous preterm birth and
whether serial evaluations up to 23 weeks 6 days' gestation improve
prediction in high-risk women.
Design, Setting, and Participants  Blinded observational study performed
between March 1997 and November 1999 at 9 university-affiliated medical
centers in the United States in 183 women with singleton gestations who
previously had experienced a spontaneous birth before 32 weeks' gestation.
Observation  Certified sonologists performed 590 endovaginal sonographic
examinations at 2-week intervals. Cervical length was measured from the
external os to the functional internal os along a closed endocervical canal.
Funneling and dynamic cervical shortening were also recorded.
Main Outcome Measure  Spontaneous preterm birth before 35 weeks' gestation,
analyzed by selected cutoff values of cervical length.
Results  Forty-eight women (26%) experienced spontaneous preterm birth
before 35 weeks' gestation. A cervical length of less than 25 mm at the
initial sonographic examination was associated with a relative risk (RR) for
spontaneous preterm birth of 3.3 (95% confidence interval [CI], 2.1-5.0;
sensitivity = 19%; specificity = 98%; positive predictive value = 75%).
After controlling for cervical length, neither funneling (P = .24) nor
dynamic shortening (P = .054) were significant independent predictors of
spontaneous preterm birth. However, using the shortest ever observed
cervical length on serial evaluations, after any dynamic shortening, the RR
of a cervical length of less than 25 mm for spontaneous preterm birth
increased to 4.5 (95% CI, 2.7-7.6; sensitivity = 69%; specificity = 80%;
positive predictive value = 55%). Compared with a single cervical
measurement at 16 weeks' to 18 weeks 6 days' gestation, serial measurements
at up to 23 weeks 6 days significantly improved the prediction of
spontaneous preterm birth in a receiver operating characteristic curve
analysis (P = .03).
Conclusions  Cervical length assessed by endovaginal sonography between 16
weeks' and 18 weeks 6 days' gestation, augmented by serial evaluations,
predicts spontaneous preterm birth before 35 weeks' gestation in high-risk
women.
JAMA. 2001;286:1340-1348
JOC10349
Preterm birth is the most important cause of infant morbidity and mortality
and complicates 11% of all pregnancies in the United States. 1
<http://jama.ama-assn.org/issues/v286n11/rfull/#r1>  Most (80%) of these
births result from either spontaneous labor or membrane rupture. 2
<http://jama.ama-assn.org/issues/v286n11/rfull/#r2>  Since the development
of neonatal intensive care units, most neonatal deaths associated with
prematurity occur in infants born at less than 32 weeks' gestation, but
significant morbidities including sepsis, respiratory distress, and
necrotizing enterocolitis do not abate until 35 weeks' gestation, after
which neonatal outcomes are generally good. 3
<http://jama.ama-assn.org/issues/v286n11/rfull/#r3> , 4
<http://jama.ama-assn.org/issues/v286n11/rfull/#r4>  To date, a prior
preterm birth is one of the strongest and most consistent predictors of
prematurity, and the risk of recurrence is inversely proportional to the
gestational age of the prior delivery. 5
<http://jama.ama-assn.org/issues/v286n11/rfull/#r5> , 6
<http://jama.ama-assn.org/issues/v286n11/rfull/#r6>
Endovaginal ultrasound is a reliable technology for imaging the cervix and
lower uterine segment during pregnancy. 7
<http://jama.ama-assn.org/issues/v286n11/rfull/#r7> , 8
<http://jama.ama-assn.org/issues/v286n11/rfull/#r8>  While there is ample
evidence that a shortened cervical length is associated with preterm birth,
9-18 <http://jama.ama-assn.org/issues/v286n11/rfull/#r9>  it is not known
when this risk factor becomes apparent in pregnancy or whether the adverse
cervical ultrasound findings develop over time. Moreover, most of the
current data linking cervical length to subsequent preterm birth have been
collected beyond 20 weeks' gestation. 9-11
<http://jama.ama-assn.org/issues/v286n11/rfull/#r9> , 14
<http://jama.ama-assn.org/issues/v286n11/rfull/#r14> , 15
<http://jama.ama-assn.org/issues/v286n11/rfull/#r15>  Importantly, most of
the available data have been collected either in unselected, low-risk
populations 11 <http://jama.ama-assn.org/issues/v286n11/rfull/#r11> , 13
<http://jama.ama-assn.org/issues/v286n11/rfull/#r13> , 14
<http://jama.ama-assn.org/issues/v286n11/rfull/#r14> , 18
<http://jama.ama-assn.org/issues/v286n11/rfull/#r18>  or without physician
masking, which means interventions were applied on the basis of the
sonographic findings without a control group for comparison, 14
<http://jama.ama-assn.org/issues/v286n11/rfull/#r14> , 15
<http://jama.ama-assn.org/issues/v286n11/rfull/#r15> , 17
<http://jama.ama-assn.org/issues/v286n11/rfull/#r17> , 18
<http://jama.ama-assn.org/issues/v286n11/rfull/#r18>  thus rendering the
predictive value of the cervical sonographic findings uncertain. The
importance of longitudinal observations and the natural history of cervical
characteristics in the mid-trimester have also not been well defined. 12
<http://jama.ama-assn.org/issues/v286n11/rfull/#r12> , 17-19
<http://jama.ama-assn.org/issues/v286n11/rfull/#r17>
Our objective was to determine whether cervical characteristics visualized
with endovaginal sonography as early as 16 weeks' through 18 weeks 6 days'
gestation or longitudinally up to 23 weeks 6 days' gestation would predict
spontaneous preterm birth in women with a previous spontaneous preterm birth
before 32 weeks' gestation. From the standpoint of efficacy and other
biological considerations, certain interventions (cerclage) might be more
effective if applied early in gestation (ie, before 24 weeks). We
hypothesized that endovaginal sonography could identify women whose cervical
anatomy would make them candidates for future mid-trimester clinical
intervention trials of preterm birth prevention.



METHODS



This study was performed at 9 university-affiliated centers, all members of
the National Institute of Child Health and Development, Maternal-Fetal
Medicine Units Network, between March 1997 and November 1999. Women with
singleton pregnancies who had experienced at least 1 prior spontaneous
preterm birth before 32 weeks' gestation were eligible; funding was not
available to study a concurrent, low-risk control population. If obstetric
records were not available, a history consistent with spontaneous preterm
birth (preterm labor or membrane rupture) and a birth weight of less than
1500 g were deemed satisfactory criteria. Women with chronic medical or
obstetric problems that might result in an indicated preterm birth (eg,
hypertension, red blood cell isoimmunization), a history of substance abuse,
or uterine anomalies were ineligible. Women who received a cerclage because
of a clinical history of cervical incompetence were also excluded. The
institutional review board at each center approved the study and potential
participants who gave written, informed consent could be enrolled as long as
their first endovaginal sonogram would be performed between 16 weeks' and 18
weeks 6 days' gestation.
Gestational age was determined by comparing a certain last menstrual period
(if available) with a sonographic evaluation at or before 18 weeks'
gestation. Concordance between the biometric parameters and the menstrual
date of 7 days or less confirmed the last menstrual period; otherwise, the
biometric data were used. After the initial endovaginal sonographic
evaluation, biweekly visits were scheduled to end no later than 23 weeks 6
days' gestation with a maximum of 4 sonograms per patient.
Techniques

All sonograms were performed by physicians, ultrasound technologists, or
research nurses who received uniform training and certification before
patient enrollment. Each sonologist reviewed a training videotape of 8
complete mid-trimester endovaginal sonograms that demonstrated all the
required measurements and subjective assessments. The videotape was
accompanied with a detailed written description of each examination. Each
sonologist independently performed 10 endovaginal examinations on unselected
patients in the mid-trimester. The primary investigator critiqued the
videotapes and accompanying data sheets to identify deficiencies. When
necessary, the sonologist was asked to submit additional taped examinations
and data sheets demonstrating correction of any previously identified
deficiencies. From the videotaped examinations, the primary investigator
also approved the ultrasound unit(s) at each center.
Each sonographic examination was performed according to a defined protocol:
patients were asked to empty their bladder and then placed in a dorsal
lithotomy position. The endovaginal probe covered by a sterile, lubricated
condom was inserted and advanced along the vaginal canal until an adequate
sagittal image of the cervix could be visualized. The probe was withdrawn
slowly until the image blurred and then the insertion pressure was increased
only enough to restore an adequate image. 11
<http://jama.ama-assn.org/issues/v286n11/rfull/#r11> , 20
<http://jama.ama-assn.org/issues/v286n11/rfull/#r20>  An adequate image for
the measurement of cervical length was defined as the visualization of the
internal os, external os, and endocervical canal. 20
<http://jama.ama-assn.org/issues/v286n11/rfull/#r20>
Cervical length was measured with electronic calipers as the linear distance
between the external os and the functional internal os along a closed
endocervical canal ( Figure 1
<http://jama.ama-assn.org/issues/v286n11/fig_tab/joc10349_f1.html> ).
However, if the endocervical canal appeared to be curved, cervical length
was also assessed as the sum of the lengths of 2 contiguous linear segments,
placed along the endocervical canal, connecting the external os and
functional internal os. If the maximum deflection of canal curvature
(defined as the distance between a line connecting the internal os and
external os and the maximum excursion of the 2 linear components) was at
least 5 mm, the recorded cervical length measurement was the sum of the 2
linear segments ( Figure 2
<http://jama.ama-assn.org/issues/v286n11/fig_tab/joc10349_f2.html> A);
otherwise, the single linear distance measurement was recorded ( Figure 2
<http://jama.ama-assn.org/issues/v286n11/fig_tab/joc10349_f2.html> B).
Cervical length measurements were performed 3 times. The sonologist assessed
the overall quality of the 3 images and recorded the cervical length
associated with the image that in his/her opinion was associated with the
subjectively best image. However, if the cervical length differed on images
of similar overall quality, the shortest observed cervical length was
recorded. 11 <http://jama.ama-assn.org/issues/v286n11/rfull/#r11>  If a
normal-appearing internal os could not be recognized, the image was further
assessed for either funneling or a poorly developed lower uterine segment.
Funneling required prolapse of the membranes through a dilated endocervical
canal to the level of the functional internal os. Funnel depth was measured
from the functional internal os to its "shoulder," visible more cephalad
toward the lower uterine segment ( Figure 1
<http://jama.ama-assn.org/issues/v286n11/fig_tab/joc10349_f1.html>  and
Figure 2 <http://jama.ama-assn.org/issues/v286n11/fig_tab/joc10349_f2.html>
B). To be characterized as a funnel, the measured depth had to be at least 5
mm.
A poorly developed lower uterine segment precluded a cervical length
measurement because the internal os could not be visualized as a discrete
structure. This subjective diagnosis was characterized by the presence of an
unusually long cervix (generally >50 mm), an s-shaped endocervical canal, an
increased distance between the bladder reflection and the amniotic cavity, 2
different echogenic areas in the cervix, and an apparent internal os located
appreciably cephalad to the inferior edge of the bladder reflection. For
analyses of cervical length as a continuous variable, cases of poorly
developed lower segments were arbitrarily assigned a cervical length of 62
mm, which was 1 mm greater than the longest measured cervical length (61
mm).
After baseline assessments were performed, fundal pressure was applied for
15 seconds along the axis of the canal by the sonologist 21
<http://jama.ama-assn.org/issues/v286n11/rfull/#r21>  who maintained the
standard sagittal view of the cervix to detect any fundal pressure–induced
dynamic changes in the cervix. If the cervix appeared to shorten, a funnel
developed (or increased in size), or if a poorly developed lower uterine
segment resolved as a result of the fundal pressure, repeat measurements
were obtained. Sonograms lasted a minimum of 5 minutes to detect
spontaneously occurring dynamic changes, which also prompted repeat
measurements. Examinations were videotaped for quality assurance.
According to the study protocol, the results of each scan were not made
available to the patient's managing physicians, except in cases of complete
placenta previa (placental tissue visualized extending >1 cm on both sides
of the internal os) or fetal death. The reason for any notification was
recorded. As part of continuing quality assurance, a sample of the
videotaped examinations was selected from each participating center
proportional to its enrollment. The videotapes and data sheets were reviewed
by the primary investigator in conjunction with another subcommittee member
blinded to the pregnancy outcome. If any measurements or subjective
assessments were deemed incorrect, the responsible sonologist and study
coordinator were notified and asked to reexamine the videotape and make
appropriate corrections. Initially, examinations were chosen at random.
However, with increasing experience we also developed criteria for selected
reviews that included all cases of funneling, cervical lengths less than 20
mm or greater than 50 mm, poorly developed lower uterine segments,
spontaneous or fundal pressure–induced dynamic changes, and cases in which
the physician was notified.
Data Analysis

The primary outcome criterion for this study was a spontaneous preterm birth
before 35 weeks' gestation, defined as a birth that resulted directly from
either preterm labor or spontaneous membrane rupture before the onset of
labor. Deliveries effected for maternal or fetal reasons were coded as
indicated. As part of the study design, we performed a sample size
calculation based on the following assumptions. Since appropriate
mid-trimester sonographic pilot data were unavailable, sample size was based
on data from the Preterm Prediction Study, 11
<http://jama.ama-assn.org/issues/v286n11/rfull/#r11>  which collected
endovaginal sonographic data at both 24 weeks' and 28 weeks' gestation. We
assumed the following: spontaneous preterm birth rate before 35 weeks for
high-risk women with a cervical length of 25 mm or greater would be 10%; a
cervical length less than 25 mm would occur in 20% of women; and the
incidence of spontaneous preterm birth before 35 weeks would be 30%.
Considering also a desired effect size of a relative risk (RR) of 3.0 for
spontaneous preterm birth before 35 weeks (based on the presence or absence
of a cervical length of <25 mm, 2-tailed alpha= .05, beta= .20), 170
patients would have to be studied.
Data were analyzed using SAS version 7.0 (SAS Institute Inc, Cary, NC).
Categorical variables were compared using chi2 or the Fisher exact test, and
continuous data were compared with the Wilcoxon rank sum test. Logistic
regression was used to model the relationship between cervical length and
spontaneous preterm birth controlling for funneling, recognition of dynamic
shortening, and the slope of cervical length over time on serial evaluations
(as derived from linear regression models). Receiver operating
characteristic curves were used to compare the performance of varying
cervical length cutoffs for the prediction of spontaneous preterm birth
before 35 weeks. Statistical significance was represented at P<.05.
Since serial examinations were performed, we also compared spontaneous
preterm birth either with cervical length at the initial examination or the
shortest cervical length observed at any examination. Similarly, we analyzed
cervical length before and after any dynamic shortening occurred. Thus, for
any given patient, up to 4 different cervical lengths could be analyzed: (1)
the length at the initial evaluation before dynamic shortening; (2) the
initial length after dynamic shortening and considering the serial
evaluations; (3) the shortest observed length before dynamic changes; and
(4) the shortest observed length after dynamic shortening.



RESULTS



From all the participating centers, 236 women were initially thought to be
eligible for this study based on their stated obstetric history. A total of
24 patients were found to be ineligible on review of their records. An
additional 19 patients declined to participate, plus 6 more patients
verbally agreed to participate but did not keep their first sonogram
appointment and therefore were not enrolled. We did not collect outcome data
on these 25 women who were eligible but not enrolled. From the original
enrollment of 187, 4 patients were excluded because they were lost to
follow-up.
A total of 590 endovaginal sonographic examinations were performed on our
study population of 183 women between March 1997 and July 1999. The median
duration of the sonographic examinations was 5.3 minutes (range, 4-18
minutes) and the median number of scans per patient was 3 (range, 1-4). Nine
of the 183 women underwent a single sonographic evaluation. Of these 9, 3
delivered within 2 weeks of their first scan, before their next scheduled
study visit. Of the 590 sonographic evaluations, 576 (98%) were videotaped
according to protocol, and 466 (79%) of the taped examinations were later
reviewed. After study inception, 4 women received a cerclage by their
managing physicians. The 183 women in the study had a mean maternal age of
26 years (SD, 5 years); 119 (65%) were African American, 26 (14%) were
white, and 38 (21%) were Hispanic. The earliest prior delivery occurred at a
mean of 24 weeks' (SD, 4.8 weeks') gestation; 135 had a single prior preterm
birth, 37 had 2 prior preterm births, and 10 had more than 2 prior preterm
births. On review, we determined that 1 patient had not experienced a prior
spontaneous preterm birth before 32 weeks but, rather, had experienced an
indicated preterm birth.
The mean gestational age at delivery was 35.2 weeks (SD, 6.3 weeks). A total
of 48 (26%) women experienced a spontaneous preterm birth before 35 weeks;
35 (19%) before 32 weeks; 29 (16%) before 28 weeks; and 20 (11%) before 24
weeks. An additional 5 women underwent an indicated preterm delivery at 31
weeks' to 34 weeks' gestation for obstetric complications. Of the 48
spontaneous births before 35 weeks, 34 (71%) were associated with preterm
labor and 14 (29%) were associated with preterm membrane rupture.
Initial Sonographic Evaluation

A total of 29 women (16%) had a poorly developed lower uterine segment
throughout their entire initial evaluation. Since these women had been
arbitrarily assigned a cervical length of 62 mm, the median baseline
cervical length at the first scan was 37 mm (range, 0-62 mm); the 10th
percentile was 26 mm and the 5th percentile was 23 mm. The relationship
between cervical length at the initial evaluation and spontaneous preterm
birth before 35 weeks was modeled with logistic regression. Women with
shorter cervical lengths had correspondingly higher rates of spontaneous
preterm birth before 35 weeks (P<.001). From the regression model, we
determined that the odds of spontaneous preterm birth before 35 weeks
decreased by 24% for each 5-mm increase in baseline cervical length. We then
examined various cervical length cutoffs for their predictive accuracy
 Table 1
<http://jama.ama-assn.org/issues/v286n11/fig_tab/joc10349_t1.html> ).
Since we had arbitrarily assigned a numeric cervical length value to women
with a poorly developed lower uterine segment, we evaluated separately the
predictive value of this finding. Of the 29 women with a poorly developed
lower uterine segment throughout their initial evaluation, only 3 (10%)
experienced a spontaneous preterm birth before 35 weeks compared with a 29%
rate if the lower uterine segment was not poorly developed (P = .03).
In 9 cases, the sonologist notified the managing physicians after the
sonogram had been performed. A total of 5 of these 9 cases were suspected
placenta previa and were reported according to study protocol. However, in
the other 4 cases, the protocol was not followed. Three were due to specific
cervical findings (cervical bending, funneling, and internal os dilation)
and in 1 case, the physician requested that the cervical length measurement
be unmasked. Considering the potential for bias associated with physician
notification and the 1 patient who had not previously experienced a prior
spontaneous preterm delivery, we determined the effect of omitting these 10
women from the analysis of the initial sonographic evaluation. The RR for
cervical length less than 25 mm and spontaneous preterm birth before 35
weeks increased slightly from 3.3 to 3.6.
Funneling

Funneling was noted in 16 patients (9%) at their initial evaluation. These
women were significantly more likely to have a spontaneous preterm birth
before 35 weeks (56% vs 23%; P = .004). However, women with an observed
funnel also had a significantly shorter cervical length (median, 26 mm vs 38
mm if no funnel was observed; P<.001). Because cervical length was such a
strong predictor of spontaneous preterm birth before 35 weeks, we also
evaluated the finding of a funnel as a potential independent predictor. The
presence of a funnel was not a significant independent predictor,
controlling for cervical length in a logistic regression model (P = .24). We
also included either the presence of funneling or a cervical length cutoff
of less than 25 mm in a contingency table with spontaneous preterm birth
before 35 weeks and observed a lower RR of 2.7 (95% confidence interval
[CI], 1.7-4.3) and a lower positive predictive value of 59% than when we
used an isolated cervical length cutoff of less than 25 mm ( Table 1
<http://jama.ama-assn.org/issues/v286n11/fig_tab/joc10349_t1.html> ).
Dynamic Changes

During their first sonographic evaluation, 16 (9%) of 183 women had observed
dynamic changes. A total of 9 followed fundal pressure and 7 were
spontaneous. The cervical lengths of these 16 women shortened from a mean of
49 mm (median, 62 mm) to a mean of 30 mm (median, 25 mm); 2 of these women
also developed a funnel. In 6 cases, the initially observed, poorly
developed lower uterine segment resolved. Similar to our analysis of
funneling, we included dynamic changes in a logistic regression model with
cervical length and observed a trend toward dynamic changes as a significant
independent predictor of spontaneous preterm birth before 35 weeks (P =
.054). We also considered dynamic changes in a contingency table with a
cervical length cutoff of less than 25 mm and spontaneous preterm birth
before 35 weeks. As with funneling, the inclusion of dynamic changes at the
initial evaluation did not improve the predictive accuracy of a cervical
length cutoff of less than 25 mm (RR, 2.4; 95% CI, 1.5-3.8; positive
predictive value, 52%).
Serial Evaluations

Serial evaluations demonstrated that cervical length shortened from a median
of 37 mm at the first scan to a median of 32 mm at the fourth scan. For each
of the 174 women with at least 2 sonographic evaluations, we computed the
rate of change of cervical length by fitting a linear regression line to
their observed cervical length measurements. The median rate of shortening
in this group was 1.1 mm per week. Removing the 41 women who had a poorly
developed lower uterine segment and therefore an assigned cervical length of
62 mm at any time during their initial and serial evaluations, we observed a
median cervical length shortening of 0.9 mm per week. The 44 women who
experienced a spontaneous preterm birth before 35 weeks shortened their
cervixes at a median rate of 2.5 mm per week compared with a rate of 1.0 mm
per week in the 130 women who did not (P = .03).
To determine the effect of serial observations on the predictive accuracy of
endovaginal sonography, we first included the shortest observed cervical
length for each patient in a logistic regression model with spontaneous
preterm birth before 35 weeks as the dependent variable. In this analysis,
the shortest ever observed cervical length before dynamic changes was a
significantly better predictor than the baseline cervical length at the
first scan. We further analyzed the information from serial evaluations by
including the slope of the derived regression line of cervical length over
time before dynamic changes in a logistic regression model, alone, and also
with the cervical length at the first evaluation. The slope of length over
time was not a significant predictor of spontaneous preterm birth before 35
weeks (P = .07). However, after controlling for initial baseline length, the
slope became a statistically significant predictor in the regression model
(P = .002).
Since previous reports examined the relationship between static cervical
length measured beyond 20 weeks' gestation and spontaneous preterm birth, we
performed a secondary analysis of all sonographic evaluations performed at
or beyond 21 weeks' gestation prior to any dynamic changes. If a patient had
undergone 2 studies during this gestational period, the former was
preferentially selected. In this subgroup of 142 women, the RR of a cervical
length less than 25 mm and spontaneous preterm birth before 35 weeks was 3.5
(95% CI, 1.9-6.5). The associated sensitivity and specificity were 46% and
87%, respectively.
Finally, we examined the clinical utility of the shortest observed cervical
length not considering dynamic changes on serial scans, using a cutoff of
less than 25 mm for the prediction of spontaneous preterm birth before 35
weeks ( Table 2
<http://jama.ama-assn.org/issues/v286n11/fig_tab/joc10349_t2.html> ). Since
cervical lengths tended to shorten over time, more than 4 times as many
women (n = 53 vs n = 12) were found to have a cervical length of less than
25 mm during the study.
Dynamic Changes and Serial Evaluations

We considered the additional effect of spontaneous or fundal
pressure–induced dynamic changes that were observed on serial examinations.
We included the shortest observed cervical length after any dynamic changes
occurred in a logistic regression model with spontaneous preterm birth
before 35 weeks as the dependent variable and found that it was a
significantly better predictor than the shortest observed cervical length at
any scan prior to dynamic changes. From the regression model, we determined
that the odds of spontaneous preterm birth before 35 weeks decreased by 43%
for each 5-mm increase in the shortest observed cervical length after
dynamic changes.
Considering these dynamic changes, the median rate of shortening remained
1.1 mm per week and 0.9 mm per week after removing the 41 women who had a
poorly developed lower uterine segment. We also analyzed cervical length
over time after dynamic changes using logistic regression. In this case, the
slope was a significant predictor of spontaneous preterm birth before 35
weeks by itself (P<.001) and also after controlling for initial baseline
cervical length (P<.001). These analyses confirmed that the inclusion of
dynamic changes (ie, shortening) observed on serial evaluations
significantly improved the predictive accuracy of endovaginal sonography for
a spontaneous preterm birth.
We then examined the summary predictive values of postdynamic
change–cervical length measurements at a cutoff of less than 25 mm (n = 60)
for the prediction of spontaneous preterm birth before 35 weeks. Table 2
<http://jama.ama-assn.org/issues/v286n11/fig_tab/joc10349_t2.html>  contains
the summary predictive values for a cervical length cutoff of less than 25
mm at the baseline scan, the shortest observed cervical length on serial
scans before any dynamic changes, and the shortest observed cervical length
considering dynamic changes from the serial endovaginal sonographic
evaluations.
Figure 3 <http://jama.ama-assn.org/issues/v286n11/fig_tab/joc10349_f3.html>
depicts the receiver operating characteristic curves of the baseline
cervical length at 16 to 18 weeks' gestation prior to dynamic changes and
the shortest observed cervical length observed on serial evaluations after
dynamic changes. The latter measurement represented a statistically
significant improvement over the former with regard to the use of cervical
length as a screening test for the prediction of spontaneous preterm birth
before 35 weeks (P = .03).



COMMENT



We performed a prospective, blinded observational study to determine if
endovaginal sonography of the cervix at 16 weeks' to 23 weeks 6 days'
gestation would predict spontaneous preterm birth with sufficient accuracy
to justify mid-trimester intervention trials in high-risk women. As a single
measurement, cervical length of less than 25 mm at 16 to 18 weeks' gestation
was a significant predictor of spontaneous preterm birth before 35 weeks,
and the inclusion of dynamic shortening and serial observations of cervical
length improved the predictive values. We conclude that the natural history
of cervical anatomy during midpregnancy can contribute significant
information as to the risk of subsequent spontaneous preterm birth.
We had previously recognized that in approximately 10% of mid-trimester
endovaginal sonograms, the cervical anatomy appeared atypical and, in
particular, a normal-appearing internal os could not be readily identified.
This led to our characterization of a poorly developed lower uterine
segment, which in some cases resolved into a measurable cervix. If
resolution occurred during the sonogram, this represented a dynamic change.
We recognized that, in a few of these transient cases, the cervical length
measurement after dynamic change was actually shortened (<25 mm). In other
cases, the poorly developed lower uterine segment persisted throughout the
entire examination, but resolved before the patient's next visit. In no
cases did this finding persist during all scheduled evaluations. We observed
that the incidence of poorly developed lower uterine segments decreased from
16% at the first scan to less than 2% by the fourth evaluation. The finding
of a poorly developed lower uterine segment throughout the entire scan
appeared to be protective and justified our decision to consider it as a
"long" cervix in the analyses. Although primarily a subjective diagnosis, we
have summarized diagnostic criteria and believe that it represents a
reproducible observation with biological significance.
Our findings challenge previous reports that funneling at the internal
cervical os is a useful predictor of preterm birth. 11
<http://jama.ama-assn.org/issues/v286n11/rfull/#r11> , 22
<http://jama.ama-assn.org/issues/v286n11/rfull/#r22> , 23
<http://jama.ama-assn.org/issues/v286n11/rfull/#r23>  We were impressed by
the wide range of biological variability associated with funneling, which
might limit the reproducibility of this finding. For example, some women did
not have a distinctly recognizable shoulder above the functional internal
os, depicted in schematic diagrams of funneling, and thus caliper placement
was operator dependent. Measurement of funnel width as the distance between
shoulders would also have been problematic since some women had only 1
recognizable shoulder. In other cases, asymmetric shoulders occurred, so it
was the sonologist's choice as to which one was used for funnel depth
measurement. Based on these observations, we included funneling as a
categorical variable in the analyses.
Although women with a funnel had significantly shorter cervical lengths than
women with no observed funnel, our analyses confirmed that most, if not all,
of the preterm birth risk was related to cervical length. We postulate that
some cervixes shorten through the process of funneling, but that the
remaining functional length is more important than the precise method of
shortening. However, because our sonographic examination windows were
necessarily limited (nominally, 20 minutes of real-time observations over 6
weeks), it is plausible that some women with a shortened cervical length had
previously experienced funneling that was never observed.
Dynamic change, after controlling for cervical length, was only a marginally
significant predictor of preterm birth; however, dynamic cervical length
shortening during serial evaluations significantly improved the prediction
of preterm birth. Fundal pressure as a provocative maneuver has been
evaluated in women at risk for cervical incompetence. 21
<http://jama.ama-assn.org/issues/v286n11/rfull/#r21>  We purposely excluded
women from our study who had undergone cerclage for a clinical history of
cervical incompetence and also recorded unprovoked, spontaneous dynamic
shortening. 23 <http://jama.ama-assn.org/issues/v286n11/rfull/#r23>  Thus,
patient selection likely explains why fundal pressure–induced dynamic
changes were not commonly observed. Spontaneous dynamic changes were also
uncommon and, as independent findings, did not further improve the
predictive value of shortened cervical length for spontaneous preterm birth.
We conclude that cervical length is the single most important sonographic
finding for preterm birth prediction in high-risk women. Although the
precise mechanisms by which the cervix shortens and contributes to
spontaneous preterm birth may ultimately be shown to have a differential
impact on specific interventions, our results support the concept that for
the prediction of spontaneous preterm birth, the means by which the cervix
shortens may not be as important as the fact that it does shorten.
Gestational age at examination, obstetric history, concurrent risk factors
for preterm birth (eg, multiple gestation), subsequent uncontrolled
interventions, the gestational age used to define the preterm outcome, and
other aspects of study design likely explain the observed variance among
published reports on the significance of cervical length measurement for
preterm birth prediction. 9-14
<http://jama.ama-assn.org/issues/v286n11/rfull/#r9> , 16-18
<http://jama.ama-assn.org/issues/v286n11/rfull/#r16> , 23
<http://jama.ama-assn.org/issues/v286n11/rfull/#r23>  For these reasons, we
defined prematurity as delivery before 35 weeks, which is more clinically
relevant than the traditional 37 week end point; included only women with a
prior early spontaneous preterm birth; and masked the sonographic results.
We chose this study population primarily because it is one of the largest
and most readily identified groups at risk. Although women with multiple
gestations also comprise a sizable and homogeneous risk group, the
mechanisms by which spontaneous preterm birth occurs in multiple gestations
may be different than the pathways that lead to recurrent spontaneous
preterm birth in singleton gestations.
To be clinically useful, the measurement of cervical length should be
reproducible and associated with reasonable thresholds for intervention.
From our quality assurance reviews, we were satisfied that our training and
certification resulted in standardized measurements of cervical length among
participating sonologists. Since reports of cervical length assessment with
endovaginal sonography have become increasingly common in recent years, it
is likely that many centers have developed their own training and
certification protocols. Nevertheless, from our sonologist certification
process, we recognized a learning curve associated with this technique and
caution against the use of cervical length assessment by sonologists who
have not had appropriate supervised experience.
With regard to intervention thresholds, we recognize that the relationship
between cervical length and spontaneous preterm birth functions along a
continuum as depicted in a receiver operating characteristic curve ( Figure
3 <http://jama.ama-assn.org/issues/v286n11/fig_tab/joc10349_f3.html> ).
Therefore, no single cervical length cutoff can completely discriminate
between eventual term and preterm births. Depending on the risks,
effectiveness, and costs of a particular intervention, different thresholds
may be appropriate. We believe that a cervical length cutoff of less than 25
mm represents an optimum threshold for inclusion in future mid-trimester
intervention trials of cerclage. However, our findings do not support the
concept of a "normal" vs "abnormal" cervical length, which is
oversimplified. Our findings support the concept that cervical "competence"
likely represents a continuum, 11
<http://jama.ama-assn.org/issues/v286n11/rfull/#r11> , 24-27
<http://jama.ama-assn.org/issues/v286n11/rfull/#r24>  and that the
mechanisms that underlie the syndrome of spontaneous preterm birth are
multifactorial and incompletely understood. 28
<http://jama.ama-assn.org/issues/v286n11/rfull/#r28>  Further investigations
combining endovaginal sonography and other markers of spontaneous preterm
birth may increase our understanding of these mechanisms and permit a more
individualized and biologically focused approach to preterm birth
prevention. Until properly designed trials of cerclage or other
interventions prove a benefit from the finding of a "short" cervix in the
mid-trimester, 29-32 <http://jama.ama-assn.org/issues/v286n11/rfull/#r29>
we recommend that cervical length measurement in women with a prior
spontaneous preterm birth remain investigational.



Author/Article Information


Author Affiliations: Department of Obstetrics and Gynecology, University of
Alabama at Birmingham (Dr Owen); Department of Obstetrics and Gynecology,
University of Texas Southwestern Medical Center, Dallas (Dr Yost);
Department of Obstetrics and Gynecology, Thomas Jefferson University,
Philadelphia, Pa (Dr Berghella); George Washington University Biostatistics
Center, Bethesda, Md (Dr Thom); Department of Obstetrics and Gynecology,
Wake Forest University, Winston-Salem, NC (Ms Swain); Department of
Obstetrics and Gynecology, University of Utah, Salt Lake City (Dr Dildy);
Department of Obstetrics and Gynecology, University of Cincinnati, Ohio (Dr
Miodovnik); Department of Obstetrics and Gynecology, University of Texas,
San Antonio (Dr Langer); Department of Obstetrics and Gynecology, University
of Tennessee, Memphis (Dr Sibai); and the National Institute of Child Health
and Human Development, Bethesda, Md (Dr McNellis). Dr Dildy is now with the
Louisiana State University, Baton Rouge; Drs Miodovnik and Langer are now
with Columbia University, New York City, NY; Dr Sibai is now with the
University of Cincinnati, Ohio; and Dr McNellis is retired.

Corresponding Author and Reprints: John Owen, MD, Department of Obstetrics
and Gynecology, University of Alabama at Birmingham, 619 19th St S, OHB 458,
Birmingham, AL 35249-7333 (e-mail: [log in to unmask]
<mailto:[log in to unmask]> ).
Author Contributions: Study concept and design: Owen, Thom, Swain,
Miodovnik, Langer, Sibai, McNellis.
Acquisition of data: Owen, Yost, Berghella, Thom, Dildy, Sibai, McNellis.
Analysis and interpretation of data: Owen, Berghella, Thom, Dildy.
Drafting of the manuscript: Owen, Thom.
Critical revision of the manuscript for important intellectual content:
Owen, Yost, Berghella, Thom, Swain, Dildy, Miodovnik, Langer, Sibai,
McNellis.
Statistical expertise: Owen, Thom.
Obtained funding: Sibai, McNellis.
Administrative, technical, or material support: Owen, Yost, Berghella,
Swain, Dildy, Miodovnik, Langer, McNellis.
Study supervision: Owen, Berghella, McNellis.
Funding/Support: This study was supported by grants HD27869, HD21414,
HD27860, HD27905, HD36801, HD34116, HD34201, HD34208, and HD34136 from the
National Institute of Child Health and Human Development.
Previous Presentations: An abstract of this work was presented at the 2000
Annual Meeting of the Society for Gynecologic Investigation, Chicago, Ill,
March 24, 2000.
Other members of the Maternal-Fetal Medicine Units Network and their
contributions: University of Alabama at Birmingham: Cherry Neely, RT, RDMS
(study design, sonologist certification, and sonography), Allison Northen,
RN (data collection), John C. Hauth, MD (study design), and Debbie Thom, RT,
RDMS (sonography); University of Chicago, Ill: Atef H. Moawad, MD (study
design); University of Cincinnati, Ohio: Nancy Elder, MSN, RN (data
collection), Tammy Haskins (sonography), and Deni Schultz (sonography);
George Washington University Biostatistics Center, Washington, DC: Cora
MacPherson, PhD (study design, data analysis, and data quality assurance)
and Sharon Leindecker, MS (data quality assurance); Magee Women's Hospital,
Pittsburgh, Pa: Steve N. Caritis, MD (study design); University of Miami,
Fla: Mary Jo O'Sullivan, MD (study design); National Institute of Child
Health and Human Development, Bethesda, Md: Charlotte Catz, MD (funding),
Sumner J. Yaffe, MD (funding), and Cathy Spong, MD (manuscript editing);
Ohio State University, Columbus: Jay D. Iams, MD (study design and
manuscript editing); University of Tennessee, Memphis: Risa Ramsey, BSN, RN
(data collection), Mary Peterson (sonography), Joyce Fricke (sonography),
and Jeff Livingston (sonography); University of Texas at San Antonio: Susan
Barker, RN (data collection), Connie Leija (sonography); University of
Texas, Southwestern Medical Center, Dallas: Kenneth J. Leveno, MD (study
design and manuscript editing), Julia McCampbell, BSN, RN (data collection),
and Rebecca Benezue (sonography); Thomas Jefferson University, Philadelphia,
Pa: Michelle DiVito RN, MSN (data collection), Ronald J. Wapner, MD (study
design), and George Bega (sonography); University of Utah, Salt Lake City:
Micheal W. Varner, MD (study design), Elaine Taggart, RN (data collection),
and Ruth Zollinger (sonography); Wake Forest University, Winston-Salem, NC:
Paul Meis, MD (study design) and Allison Henshaw (sonography); and Wayne
State University, Detroit, Mich: Mitchell Dombrowski, MD (study design).




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Edward E. Rylander, M.D.
Diplomat American Board of Family Practice.
Diplomat American Board of Palliative Medicine.