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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
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SEPTEMBER 2006
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Cervical Ripening
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TABLE 1. Methods and Their Accuracy Used in Uterine Monitoring or Screening of Labor34
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
No
No
No
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Maul et al
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
2/5/02 11:11:22.
560 AM
Chart Window
Uterine Pressure
30
20
10
Control
emg5 (uv)
0
2.00e+04
1.00e+04
0.00e+00
-1.00e+04
-2.00e+04
8200
8100
8300
8400
8500
8700
8600
pressure 3 (mmHg)
Uterine EMG
2/5/02 11:53:25.
Chart Window
560 AM
Uterine Pressure
40
30
20
10
0
BPN
emg3 (uv)
2.00e+04
1.00e+04
0.00e+00
-1.00e+04
-2.00e+04
10700
10800
10900
11000
11100
11200
Uterine EMG
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Maul et al
Abdominal Recordings from Rats at
Term During Labor
20
10
0
Control
100
emg4 (mV)
pressure4 (mmHg)
Chart Window
Abdominal Pressure
30
50
0
-50
-100
23700
23750
23800
23850
pressure1 (mmHg)
EMG bursts
emg1 (mV)
BPN
Chart Window
30
Abdominal Pressure
20
10
0
-10
100
50
0
-50
25000
25050
25100
25150
25200
EMG bursts
Cervical Ripening
557
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
558
Maul et al
FIGURE 8.
Measurements of Cervical
Softening
Evaluation of the first common step,
cervical softening, has been hypothesized
to be useful for the early evaluation of
Cervical Ripening
FLUORESCENCE SPECTROSCOPY OF
COLLAGEN
1.0
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
Sensitivity
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
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TABLE 2. Differences in Bishop Scores Between the 2 Prostaglandin Treatment Groups Before
and After Treatments33
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
References
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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