CLINICAL OBSTETRICS AND GYNECOLOGY

Volume 49, Number 3, 551563

r 2006, Lippincott Williams & Wilkins

Cervical Ripening:
Biochemical,
Molecular, and
Clinical
Considerations
HOLGER MAUL, MD, MMSC,* LYNETTE MACKAY, BS,w
and ROBERT E. GARFIELD, PhDw
* Department of Obstetrics and Gynecology, University
of Heidelberg, Heidelberg, Germany; and w University of
Texas Medical Branch, 301 University, Department of
Obstetrics and Gynecology, Division of Reproductive
Sciences, Galveston, Texas
Abstract: The physiologic and pathologic changes of
the uterine cervix during pregnancy leading to
cervical ripening are not well understood though
are related to the chief pathology and a commonly
performed intervention in obstetrics: Preterm birth
and labor induction. Normal cervical ripening is
thought to be controlled by a variety of hormonal
changes occurring during pregnancy leading to
softening and dilation. Abnormal premature ripening, usually resulting in preterm labor, is thought to
be associated with infection and inflammatory
events. Despite many studies of the cervix, we still
rely upon relatively crude methods for clinical
evaluation of the cervix. In the past several years,
we have developed and evaluated a method to
measure cervical collagen noninvasively using an
instrument called Collascope. Studies in animals and
humans conducted in a variety of settings indicate

Correspondence: Robert E. Garfield, PhD, Professor,

Director of the Division of Reproductive Sciences,
Department of Obstetrics and Gynecology, The
University of Texas Medical Branch, Galveston, TX
77555-1062. E-mail: rgarfiel@utmb.edu
CLINICAL OBSTETRICS AND GYNECOLOGY

that cervical function can be successfully monitored

using the Collascope during pregnancy. We suggest
that this technique might be useful to better define
management in cases of spontaneous preterm and
induced term cervical ripening.
Key words: cervical ripening, preterm labor, collascope, light-induced fluorescence, LIF, cervical
incompetence, induction of labor, parturition

In developed countries, obstetrics has

dramatically changed during the past
decades. Although maternal morbidity
and mortality were the key issues in the
first half of the 20th century, the second
half of the 20th century lead to discoveries that further reduction of maternal
morbidity and mortality was difficult
and methodologies to do so were ineffective. Therefore, obstetrics in the
second half of the 20th century became
focused on the fetus, fetal complications,
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NUMBER 3

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Maul et al

and reduction of fetal and neonatal

morbidity and mortality. In fact, for
the first time, the fetus itself is now
considered to play a significant role in
medicine. However, at present, fetal and
neonatal morbidity and mortality seem
to have reached a plateau at 5 to 10 per
1000 live births in Western Europe and
North America.
From our point of view, the next
factors that must be taken into consideration are the processes themselves
leading to maternal and fetal pathology.
That is to say that focus should reside on
not only the outcomes but also the
methods to assess these outcomes to find
further clues for improvement of human
well-being.
Therefore, future parturition research
will focus on differing issues including
safety, patient acceptance, and tolerance
of various interventions. Parturition is a
complex process involving different compartments with changes on the maternal
side (myometrium and cervix) and on the
fetal side (fetus itself, fetal membranes)
leading to delivery of the fetus. The
interrelationship between these compartments is not well understood. Further,
the methods to monitor myometrial and
cervical changes involved in parturition
are crude and only the end points can be
detected reliably. Active labor (ie, significant uterine contractions leading to
changes in the shape of the uterus while
contracting over the incompressible volume containing amniotic fluid, placenta,
and fetus), cervical changes (ie, softening
and dilation of the cervix), and changes
in fetal membranes occur at different
times (see model of these changes,
Fig. 1). Early changes, such as increased
electrical conductance between uterine
smooth muscle cells, or the degradation
of cervical collagen leading to softening
of the cervix are not taken into account,
unless one relies on only subjective and
not well reproducible methods such as
digital palpation of the cervix. Table 1

FIGURE 1. Model of uterine cervical and

fetal membrane changes during parturition.
The uterus, cervix, and fetal membranes go
through changes as they prepare for labor
and ultimately for delivery. These changes
may be driven, at least partially, by independently timed mechanisms.35

summarizes the current methods and

their accuracy used in uterine monitoring
or screening of labor.
Preterm labor is the tautology for a
syndrome occurring in a variety of
different clinical patterns responsible
for approximately 7% to 11% of neonates being born prematurely each
year.1,2 Immaturity and prematurity account for 85% of infant mortality and
50% of infant neurologic morbidity.3
The development of effective means to
prevent or reduce the occurrence of
preterm delivery depends on the understanding of the conditions that initiate
labor. In fact, despite intensive investigation, the rate of preterm births has not
declined in several decades. The key
issue, in judgment of the effectiveness
of preterm labor, is the ability of the
rigid or soft cervix to withstand
the pressure induced by the uterine
contractions. In addition, preterm
cervical ripening may result in cervical
incompetence and may contribute to
the occurrence, enhancement, and maintenance of uterine contractions by
mechanisms only partially understood.
On the other hand, with increasing
frequency, labor is induced using drugs
that enhance cervical ripening and

Cervical Ripening

553

TABLE 1. Methods and Their Accuracy Used in Uterine Monitoring or Screening of Labor34

Monitoring of contractions in combination with

pelvic examination
Monitoring the state of the cervix
Symptomatic self-monitoring
Intrauterine pressure monitoring
External uterine monitor (tocodynamometer)
Ultrasound, remote sensing, temperature
monitoring, blood flow monitors
Endovaginal ultrasonography
Fetal fibronectin screening test
Salivatory estriol test

support uterine contractions to effect

delivery and prevent complications for
mothers and newborns that would otherwise be associated with continuation of
pregnancy. Labor induction has become
a common procedure in obstetrics that is
accompanied by a number of potential
complications such as uterine overstimulation, uterine rupture, and fetal compromise.

Cervical Ripening
At present in clinical routine there is no
reliable, objective, and quantitative
method to monitor early cervical changes
for a variety of clinical scenarios. These
would include detection of the early
phases of cervical ripening leading to
cervical incompetence and eventual preterm birth, and the assessment of the
effect of cervical ripening agents for
labor induction.
Indeed, many biochemical and functional changes occur in cervical connective tissue during pregnancy46 that are
summarized in the term cervical ripening. These changes precede the clinical
symptoms, which are currently evaluated, that is, uterine contractions and
cervical dilatation. Cervical ripening is a
chronic process, which begins within the
first trimester of pregnancy and progressively proceeds until term, and is usually
described as softening, effacement (thin-

Accuracy

Invasive

Moderate

No

Moderate
Low
High
Erratic
Mixed

No
No
Yes
No
No

High negative predictive values

High negative predictive values
High negative predictive values

No
No
No

ning), and dilation of the cervix. (The

latter 2 are acute events, which occur
before delivery). Obviously with this
3-step preparation process, which must
occur in sequence, complex systems must
be in place to control each forward and
irreversible step. Softening must be
considered a vital process because effacement and dilation cannot occur without
remodeling of the cervix during the
softening phase. However, none of our
current methods to assess the cervix
measures this event. Effacement and
dilation are often associated with or
contributed to uterine contractions, but
it is evident that softening occurs
independent of contractions. Further,
effacement and dilation are often
present without uterine contractions.
The cervix, which is dominated by
fibrous connective tissue, is composed of
an extracellular matrix consisting predominantly of collagen (70% Type I and
30% Type III) along with elastin and
proteoglycans, and a cellular portion
consisting of smooth muscle, fibroblasts,
epithelium, and blood vessels.7 Throughout most of gestation the cervix remains
rigid and closed to secure the products of
conception. A dramatic functional shift
occurs during parturition as it dilates
through a cervical destructive process.
The cascade responsible for the process
of cervical ripening, and which finally
enables uterine contractions to efface

554

Maul et al

FIGURE 2. Changes in the rat cervix in

nonpregnant animals, during pregnancy and
postpartum. Cervical ripening as measured
with the cervimeter.8,9 The slope of cervical
extensibility changes is shown.

FIGURE 4. Diagram of the components of

the collascope. Parts include a light source,
fiber optic cable, spectrometer, a CCD
camera, and a computer.34

and dilate the cervix, is still not fully

understood. There is a progressive softening of the cervix beginning early
pregnancy in women, and in rats, during
the second half of gestation, beginning
around day 13. Studies in cervical
resistance and light-induced fluorescence
(LIF) have measured these changes in
rats.8,9 Nonpregnant and timed-pregnant
rats were examined in our laboratory for
cervical softening using a cervimeter. The

uterine cervices were collected at several

time points during pregnancy and were
subjected to incremental stretching. The
length-tension curve was derived and the
slope of the regression line indicated the
degree of cervical extensibility (Fig. 2). In
our laboratory, LIF studies with the
Collascope paralleled these results showing a gradual ripening from mid-gestation in rats (Figs. 3, 4 for illustration of
the Collascope).

FIGURE 3. Gradual changes in rat cervix during cervical ripening as

measured with collascope.8,9 Shown are LIF measurements as ratios of
the collagen peak versus the reference peak values.

Cervical Ripening
Many studies show that hormones
seem to control cervical ripening
although the mechanisms and effects on
each step in ripening are not clear.
Because antiprogestins induce cervical
ripening, this process seems to be controlled at least in part by hormones,
including progesterone and estrogen,10
relaxin11 and androgens.12 Knock-out
mouse models, such as steroid 5a-reductase type 1,13,14 demonstrate failure to
deliver owing to failure of cervical
ripening. The gene is involved in androgen production, and the parturition
defect can be overcome by treatment
with 5a-reduced androgens. The enzyme
plays an essential role in progesterone
catabolism in the cervix inhibiting the
conversion of testosterone to dihydrotes-

555

tosterone resulting in localized failure of

progesterone withdrawal. Other mutant
models, such as null PGF2a, do not
undergo luteolysis at term and high
progesterone levels lead to failed parturition. In animal models, the physiologic
decrease in the concentration of progesterone during the third trimester of
pregnancy initiates a cascade that is
analogous to an inflammatory response
with influx of polymorphonuclear cells15
and release of matrix-metalloproteinases
into the cervical stroma, culminating in
the degradation of collagen7 (in humans,
a functional decrease of progesterone
concentration is mostly probably due to
decreased sensitivity of the hormone
receptor). Autocrine and paracrine mediators like cytokines,16 prostaglandins,17

Uterine Recordings from Rats at Term

During Labor
pressure 5 (mmHg)

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Uterine EMG

FIGURE 5. Recordings of uterine electromyographic (EMG) bursts and

contractions in laboring control and neurectomized rats. The control rat shows
pressure and spikes superimposed on the uterine contractions as it pushes. The
neurectomized rat does not push and, therefore, does not have spikes on top of the
contractions (unpublished).

556

Maul et al
Abdominal Recordings from Rats at
Term During Labor

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FIGURE 6. Recording of abdominal muscle EMG bursts and abdominal pressure

spikes during pushing in laboring control rat (upper traces) and in laboring
neurectomized rat (bottom traces). Note that the neurectomized rat does not push
(unpublished).

platelet activating factor,18 and nitric

oxide19 produced by different isoforms
of its synthases20 have been shown to
take part in physiologic or pathologic
cervical ripening thereby forming
a complex and poorly understood network with short-circuits and parallel
pathways, widely influenced by hormones and their sensitivities.21 Conversely, cytokines (interleukin-1b22), prostaglandins (eg, prostaglandin E223),
platelet activating factor, nitric oxide24
and antiprogestins10 are potent agents
that have been used for induction of
cervical ripening in animals and humans.18,24 Similarly, lipopolysaccharides
are well known to trigger the hypothetical cascade described above. Therefore,

these factors may also be operative

in premature cervical ripening associated
with genital tract infection.24
The nervous system has significant
involvement in the process of reproduction and could also be involved in
cervical ripening. Sensory, sympathetic,
and parasympathetic fibers are numerous in the cervix.25 The sensory component largely comes from the pelvic nerves
L6-S1 dorsal root ganglia and terminates
in the cervix as unmyelinated, small,
capsaisin-sensitive sensory neurons.
These synthesize neurotransmitters such
as vasoactive neuropeptides calcitonin
gene-related peptide, substance P, and
secretoneurin, which are locally released
in the cervix and act through their

Cervical Ripening

557

Model for Cervical Ripening

Infection

LPS

P4

Term

E2

Preterm
TN F-

IL -1
IL-8
(chemotaxis, leukocyte infiltration)
COX2
PGE2

Vascular
permeability

MMPs

iNOS

amplif

ication

GAG
remodeling

Relaxin

NO

Collagen
remodeling

Apoptosis

ECM Degradation

FIGURE 7. Diagram summarizing steps involved in pathologic or

physiologic control of cervical ripening and extracelluar matrix
degradation involving lipopolysaccharides (LPS) or steroid hormones
(P4 and E2), cytokines (IL-10, IL-8, TNF-a), prostaglandin, and nitric
oxide synthesis enzymes (COX-2 or NOS) leading to changes in vascular
permeability, matrix metalloproteinases (MMPs), gycosoaminoglycans
(GAG), collagen remodeling, and apoptosis.

receptors to induce inflammatorylike

cervical changes with vasodilatation,
vascular leakage, and plasma and leukocyte extravasations. Estrogen acts via its
receptors, particularly ER-a, to modulate neuropeptide synthesis. Our studies
(presented at the 2004 scientific meeting
of the Society for Gynecologic Investigation, Abstract No. 755), and others26,27
show that pelvic neurectomy in rats does
not inhibit cervical ripening or initiation
of labor, but blocks normal parturition
by elimination of the pushing response
(contraction of abdominal muscles) associated with forceful contractions of the
uterus during labor. For our telemetric
studies in conscious, unrestrained rats,
electrodes were attached to uterine and
abdominal muscles, and pressure catheters were introduced into the uterine
and abdominal cavities, to record

electromyographic bursts, and pressure

changes from laboring control and neurectomized rats (Figs. 5, 6). The sensory
fibers of the pelvic nerve seem to relay
responses from the stretching cervix to
the abdominal muscles of the rat to
stimulate these contractions to assist in
pushing the pups through the birth
canal.
Very little is known about how cervical ripening can be prevented or inhibited. Recently, it has been found that
oral administration of a platelet activating factor receptor antagonist in rats
significantly increases the duration of
parturition.28 Similarly and in addition
we have found that platelet activating
factor-antagonist WEB-2170 effectively
inhibits preterm cervical ripening
induced by lipopolysaccharides in an
in vivo animal model, whereas it was

558

Maul et al

FIGURE 8.

Cervical changes and methods of evaluation.

not effective in overcoming induction of

this process by an antiprogestin (RU
486).29 A variety of mediators contribute
to cervical ripening as summarized in
Figure 7. This figure illustrates that there
are at least 2 parallel pathways that lead
to extracellular matrix degradation and
ripening of the cervix involving a pathologic pathway with infection and a
physiologic pathway involving changes
in steroids with both pathways converging on the generation of cytokines,
prostaglandins, and nitric oxide resulting
in cervical remodeling.

Measurements of Cervical
Softening
Evaluation of the first common step,
cervical softening, has been hypothesized
to be useful for the early evaluation of

alterations in cervical ripening either

spontaneously occurring or medically
induced. Secondly, it has been suggested
to use such a parameter for the prediction of preterm birth.
During the past 6 years, our group has
developed and improved a procedure to
objectively detect and quantify early
changes in the cervical ripening process
during pregnancy. The method is noninvasive, easy to master, rapid, and
allows for the quantitative estimation of
cervical ripening. The device, called a
Collascope (Fig. 4), was developed in our
lab and uses the light-induced fluorescence of cross-linked collagen to permit
the attending physician to differentiate
between the labor versus the nonlabor
state of the cervix earlier than the
methods used clinically today (Fig. 8).
No other devices or tests currently in use
in the clinic can do this.

Cervical Ripening
FLUORESCENCE SPECTROSCOPY OF
COLLAGEN

1.0

Fluorescence spectroscopy is a widely

used research tool in the biosciences,
primarily due to the amount of information that it can reveal in terms of
molecular and physical states.30 Fluorescence spectra offer important details on
the structure and dynamics of macromolecules and their location at microscopic levels. Fluorescence spectroscopy
has been used to examine collagen
content of a variety of tissues including
cancers.31 We have used this methodology taking advantage of the fluorescent
properties of cross-linked collagen in the
cervix.

0.8

559

0.9

LIF-Ratio

0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
>24 hrs

<24 hrs

Time to Delivery

FIGURE 9. Receiver operating characteristics curve for the prediction of labor within
24 hours. Using a cutoff for LIF of 0.57,
sensitivity was 59%, specificity was 100%,
and positive and negative predictive values
were 100 and 63% respectively (P<0.01).32

CERVICAL LIF

(area under ROC curve: 0.73; P<0.01;

sensitivity = 59%, specificity = 100%,
PPV = 78.9%, and NPV = 80.0%, at
an LIF cutoff of 0.57) (Fig. 9).
In another study,33 we investigated
whether the application of prostaglandins for labor induction in women Z37
weeks of gestation influences the fluorescence of cervical collagen. We used the
Collascope as described, and in addition,
100
90
80
70

Sensitivity

One study involving cervical collagen

was conducted to investigate gestational
changes of cervical LIF, an index for
cross-linked collagen, and to estimate
whether LIF correlates with the time-todelivery interval and is predictive of
delivery within 24 hours.32 In 29 healthy
gravidas without signs of labor, LIF was
measured about weekly during the last
trimester and also in 29 patients with
signs of labor. Cervical LIF was obtained noninvasively using the collascope, which was specifically designed
for this purpose. Spearmans correlation,
1-way analysis of variance followed by
multiple pairwise comparisons, and receiver operating characteristics curve
analysis (ROC analysis, Fig. 9) was
performed. LIF-measurements correlated negatively with gestational age
(r = 0.508; P<0.01) and positively
with the time-to-delivery interval
(r = 0.458; P = 0.01). Patients who delivered within less than 24 (n = 19) hours
of measurement had significantly lower
LIF than those who delivered more than
24 hours later (n = 12) [mean (SD): 0.571
0.413 vs. 0.894 (0.228); P = 0.021] (Fig.
10). ROC analysis showed that LIF was
predictive of delivery within 24 hours

60
50
40
30

AUC = 0.73
p<0.01

20
10
0
0

10

20

30

40

50

60

70

80

90

100

1-Specificity

FIGURE 10. LIF in rule-out labor patients

according to time-to-delivery ranges. Nineteen patients delivered within 24 hours,
whereas 12 patients exhibited greater timeto-delivery intervals *P = 0.021 (t test).32

560

Maul et al

FIGURE 11. LIF of cervical collagen in pregnant

women at term before and 4 hour after prostaglandin
application.33

we compared the LIF parameter with the

Bishop score. Forty-one gravidas at Z37
completed weeks of gestation were
enrolled. Twenty-five of the subjects
received a half tablet of misoprostol
(Cytotec) 50 mg intravaginally and 16
subjects received dinoprostone (Prepidil)
500 mg gel intracervically. The type of
prostaglandin administered was guided
by obstetric indications as determined by
physicians not involved in the research
project. LIF was measured in a standard
fashion and 3 separate readings were
taken from each subject at the same
location on the cervix. Bishop score and
LIF were measured before and 4 hours
after prostaglandin application by the
same investigator. We found the LIF
ratio of cervical collagen in all 41
patients before prostaglandin application
to be significantly decreased from
0.982 0.04 to 0.885 0.037 four hours
after application (P = 0.025) (Fig. 11).
The decrease in LIF of collagen correlated with the initial LIF before
PG-application (r = 0.61, P<0.001)
(Fig. 12): the higher the initial LIF the
greater the decrease in LIF. Sixteen out

FIGURE 12. LIF in cervices before and 4

hours after prostaglandin application with
an initial LIF of Z1 (A) or <1 (B).33

Cervical Ripening

561

TABLE 2. Differences in Bishop Scores Between the 2 Prostaglandin Treatment Groups Before
and After Treatments33

Parity [median (25%/75%)]

Bishop score before treatment (mean SEM)
Bishop score after treatment (mean SEM)

of 19 patients with an initial high

collagen fluorescence (>1) showed a
decrease after prostaglandins in contrast
to only 11/22 patients with an initial low
collagen fluorescence value <1 (Fig. 12).
The Bishop score in all 41 patients
increased from 4 (2-5) to 5 (3-5),
P = <0.001, and there were no correlations between initial LIF and initial
Bishop score, final LIF and final Bishop
score, and change in LIF and change in
Bishop score (Table 2).33
We concluded from these studies that
cervical LIF values decrease significantly
as gestational age increases, that they are
predictive of delivery within 24 hours,
and that LIF allows prediction of the
course of induction.

Dinoprostone

Misoprostol

l (l25)
2.813 0.39
3.813 0.41

0 (01)
4.56 0.332
6 0.451

0.039
0.002
0.002

classification and therefore treatments

during pregnancy. We believe that physicians will soon begin using the cervical
LIF instrument to their advantage and to
the betterment of the patients in
their own practices. Some already are
further exploring the uses of this device
with research protocols. With refinements, these tools could be routinely
used with little or no training. Considering the great need for improved diagnostic capabilities, the widespread
implementation of this technology could
lead to better patient management and
classification, and likely benefits
from reductions in infant mortality and
morbidity.

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Conclusions
From our studies and others, it is clear
that in forecasting labor and delivery, the
capability of the technologies and bioassays that have been generally accepted
into clinical practice are limited, especially in sensitivity and positive predictive values (Table 1).34 Clearly, any
devices that can be shown to be superior
to the clinically accepted tests currently
used should be quite useful for clinicians.
Such is the case for the cervical LIF
device when comparing its capabilities
against those of other predictive technologies and bioassays. And just as
importantly, no current tests can offer a
direct objective measurement of both
the function and state of the cervix that
the LIF provides the clinician. Such
measurements can guide proper patient

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