doi:10.1111/jog.13691 J. Obstet. Gynaecol. Res.

2018

Premaquick versus modified Bishop score for preinduction

cervical assessment at term: A double-blind randomized
trial

George U. Eleje1,2, Euzebus C. Ezugwu3, Emmanuel O. Ugwu3,

Ifeanyichukwu U. Ezebialu4, Lydia I. Eleje5, Nnabuike O. Ojiegbe6, Leonard O. Ajah3,
Chukwudi C. Obiora7, Richard O. Egeonu2, Chigozie G. Okafor2,
Perpetua K. Enyinna7, John O. Egede8, Nzubechukwu J. Ugochukwu2,
Amarachukwu C. Asiegbu9 and Joseph I. Ikechebelu1,2
1
Effective Care Research Unit, Department of Obstetrics and Gynecology, 5Measurement and Evaluation Unit, Department of
Educational Foundations, Nnamdi Azikiwe University, 4Department of Obstetrics and Gynecology, Chukwuemeka Odumegwu
Ojukwu University Teaching Hospital, Awka, 2Department of Obstetrics and Gynecology, Nnamdi Azikiwe University Teaching
Hospital, Nnewi, 3Department of Obstetrics and Gynaecology, College of Medicine, University of Nigeria Enugu Campus,
7
Department of Obstetrics and Gynecology, ESUT Teaching Hospital, Enugu, 6Department of Obstetrics and Gynecology, Federal
Medical Center, Umuahia, 8Department of Obstetrics and Gynecology, Federal Teaching Hospital, Abakaliki and 9Department of
Obstetrics and Gynecology, Federal Medical Center, Owerri, Nigeria

Abstract
Aim: To test whether Premaquick biomarkers were superior to modified Bishop score for preinduction cer-
vical assessment at term.
Methods: A multicenter, double-blind randomized clinical trial in 151 nulliparous, cephalic presenting and
singleton pregnancies was conducted. The cervix was considered ‘ripe’ when at least two out of three Pre-
maquick biomarkers are positive or a Bishop score of ≥6. Main outcome measures were proportion of
women who were administered or had additional prostaglandin E1 analogue (PGE1) as a preinduction agent
and incidence of uterine rupture. The trial was registered in PACTR registry with approval number
PACTR201604001592143. Analysis was performed by intention-to-treat principle.
Results: The need for initial PGE1 analogue (77.6% vs 98.7%, risk ratio [RR] =0.47, 95% confidence intervals
[95% CI] =0.38–0.59, P < 0.001) and additional PGE1 analogue for cervical ripening after one insertion
(44.7% vs 68.0%, RR = 0.63, 95% CI = 0.46–0.86, P = 0.004) was significantly lower in Premaquick group.
There was no significant difference in incidence of uterine rupture (0% vs 1.4%, RR = 0.000, P = 0.324); however,
the frequency of transition to labor was statistically higher in Premaquick group (44.7% vs 22.7%, RR = 1.59, 95%
CI = 1.17–2.15, P = 0.004). Interval from start of induction to any type of delivery, need for oxytocin aug-
mentation, vaginal delivery, number of women with cesarean section for failed induction and number of
infants admitted to neonatal intensive care unit were similar between the two groups (P > 0.05).
Conclusion: Preinduction cervical assessment with Premaquick was significantly associated with higher fre-
quency of transition to labor and reduced need for PGE1 analogue when compared to modified Bishop
score. Further similar trials in other settings are necessary to strengthen or refute this observation.
Key words: cervical assessment, induction, labor, modified Bishop score, Premaquick.

Received: November 9 2017.

Accepted: April 27 2018.
Correspondence: Dr George U. Eleje, Effective Care Research Unit, Department of Obstetrics and Gynaecology, Nnamdi Azikiwe
University, Nnewi Campus, P.M.B. 5025, Nnewi, Anambra State, Nigeria. Email: georgel21@yahoo.com

© 2018 Japan Society of Obstetrics and Gynecology 1

G. U. Eleje et al.
Introduction
Induction of labor remains a common obstetric proce-
dure with prostaglandin E1 analogues (PGE1) com-
monly used for preinduction cervical ripening when
the cervix is unfavorable.1 Cervical ripening is a pro-
cess of preparing the cervix to enhance the success of
induction of labor. Induction of labor is the artificial
initiation of uterine contraction in women who were
not already in labor, leading to progressive dilation of
the cervix to vaginal delivery.2 There is increasing
incidence of induction of labor globally with one out
of every four babies in developed country delivered
via induction of labor at term.3
Bishop score (now modified) remains the most fre-
quently used and age-old method for selection of
women who should be treated with prostaglandins
for cervical ripening.4,5 However, the digital assess-
ment of cervical changes based on this technique
alone is subjective and the predictive value for failed
induction is poor in women with a low score. This is
because of the difficulty in assessing changes in the
internal cervical os when the external cervical os is
closed.6,7 Moreover, digital cervical examination is
prone to wide interobserver errors among examiners.8
As a result, evidence demonstrates that misjudgments
are often made on digital cervical assessment.9 The
implication of continued use of Bishop score in clini-
cal practice is that a few women with a low Bishop
score, otherwise considered to benefit from the
administration of prostaglandins, may be treated
inappropriately, with all the attendant risks associated
with prostaglandin use.10 This scenario could be
avoided by utilizing new methods of more appropri-
ate cervical assessment. The new methods involve
testing for the presence of phosphorylated insulin-like
growth factor binding protein-1 (pIGFBP-1), interleu-
kin 6 (IL-6), fetal fibronectin or their combination in
cervicovaginal fluid. They may ultimately comple-
ment the findings of Bishop score parameters.11
Several observational studies and nonsystematic
reviews have reported the usefulness of cervical ultra-
sound and testing for the presence of pIGFBP-1 in
comparison with modified Bishop score or transvagi-
nal ultrasound of the cervical length in assessing the
ripeness of the cervix for labor induction.7,12–16 The
transvaginal ultrasound for the cervical length is thought
to be less subjective compared with the Bishop score in
assessing preinduction cervical ripening, but the major
concern is that it is not clear which cutoff value of sono-
graphically measured cervical length is most likely to
2 © 2018 Japan Society of Obstetrics and Gynecology
indicate benefit from a method of cervical ripening prior
to induction of labor.17
A recent Cochrane systematic review in 2015 indi-
cated that direct comparisons via randomized control
trials between Bishop score and other modalities such
as pIGFBP-1 and vaginal fetal fibronectin for asses-
sing preinduction cervical ripening among parturients
at term gestations was yet to be carried out.17 The
use of IGFBP-1 could permit the feasibility of self-
sampling and self-assessment for preinduction cervi-
cal ripening.
Although previous study on this combination of
biomarkers has revealed that they are useful in pre-
dicting preterm labor.18 However, term and preterm
labor events share common pathways of cervical rip-
ening, even though the instigating prompts may dif-
fer.19 The detection of insulin-like growth factor
binding protein-1 in the cervicovaginal fluid indicates
a disruption of the choriodecidual interface, which
can occur in cases of preterm and term labor events.
We therefore hypothesize that cervicovaginal fluid
biomarkers predictive of labor may be similar in both
the term and preterm labor setting and will be supe-
rior to Bishop score in preinduction cervical assess-
ment. None of the previous studies, to the best of our
knowledge, has compared the combinations of
insulin-like growth factor binding protein-1 (native
and total [total meaning Native and cleaved] and IL-6
(Premaquick) and Bishop score for predicting success-
ful induction of labor at term gestation. This study
aims to compare native and total insulin-like growth
factor binding protein-1 and IL-6 (Premaquick) and
Bishop score in determining the need for administra-
tion of prostaglandin for preinduction cervical ripen-
ing among women with singleton gestations at term.
Methods
Study site
Pregnant women who were admitted to the Nnamdi
Azikiwe University Teaching Hospital (NAUTH),
Nnewi, and other recruiting hospitals (University of
Nigeria Teaching Hospital, Ituku-Ozalla, Enugu;
Madonna University Teaching Hospital, Elele; Chuk-
wuemeka Odumegwu Ojukwu University Teaching
Hospital, Awka; Federal Medical Center, Umuahia;
Federal Teaching Hospital, Abakaliki; ESUT Teaching
Hospital, Parklane, Enugu and Federal Medical Center,
Owerri), for induction of labor were eligible for the
study. The study was carried out over a 13-month

period between August 2016 and September 2017.
Women were recruited by the researchers in the labor
ward when they were admitted for induction of labor.
Study design
This was a randomized double-blind trial. Consecu-
tive women admitted to the Obstetrics units of the
recruiting hospitals for induction of labor at term
(37 completed weeks of gestation to 42 weeks of ges-
tation) participated in the study. Women who gave
informed consent were assigned with the aid of
computer-generated random numbers (block size
four, 1: 1 randomization ratio) to have preinduction
cervical assessment and induction of labor based on
the Premaquick or modified Bishop score. Assign-
ments were concealed by sequentially numbered opa-
que envelopes prepared by a person not involved in
the clinical care of the women.
Study population
These were all consenting pregnant women seen in
the labor and delivery suite for induction of labor at
term during the period of the study and who met the
inclusion criteria, until the calculated minimum sam-
ple size was reached.
Inclusion criteria
Nulliparous pregnant women scheduled for induction
of labor at or beyond 37 weeks of gestation with a
singleton pregnancy in cephalic presentation, absence
of labor (labor defined as the presence of regular and
painful uterine contractions) and intact membranes
were eligible for inclusion.
Exclusion criteria
Exclusion criteria were previous uterine scars, multi-
parity and premature rupture of membranes. The
dates of the confinements were calculated according
to the duration of amenorrhea based on last men-
strual period and checked by an ultrasound examina-
tion performed before 20 weeks of gestation.
Procedure
Following a written informed consent, a cervical swab
sample for assay of Premaquick was taken before dig-
ital cervical examination for Bishop score in all the eli-
gible participants. Thereafter, a trained obstetrics care
provider opened sequentially numbered, sealed, opa-
que envelopes containing the participants’ group
assignment and participants were randomly allocated,
in a 1:1 ratio, to be assessed by either Premaquick
© 2018 Japan Society of Obstetrics and Gynecology
Premaquick vs Bishop score assessment
method or modified Bishop score method. Group allo-
cation was predetermined and placed in sequentially
numbered, sealed, opaque envelopes with a piece of
paper inside bearing the label ‘Premaquick’ or ‘Bishop
score’. Following allocation, all the women underwent
cervical assessment by Premaquick and modified
Bishop score, but clinical management of the women
was based on the group she belonged following the
randomization.
We used a modified Bishop score, which has five
parameters and 0–13 points. Thus, cervical dilatation,
cervical effacement assessed by cervical length, consis-
tency, position and station of the presenting part were
assessed. All Premaquick evaluations were performed
by trained obstetrics care providers. When necessary,
participants were re-examined by the same person.
The cervix was considered unripe if the Bishop
score was <6 or Premaquick was negative. In cases
with an unripe (unfavorable) cervix (when Bishop
score was <6 or Premaquick was negative), 50 μg of
misoprostol (cytotec Pfizer comprimidos misoprostol,
lot b13221) was administered intravaginally every 6 h
for a maximum of four doses. No further oxytocics
were administered when uterine contractions reached
a frequency of 3 in 10 min. If cervical ripening was
not achieved, cesarean section was performed after
the 4th dose of misoprostol. In cases with a ripe cervix
(when Bishop score was >6 or Premaquick was posi-
tive), oxytocin infusion was commenced (using stan-
dard induction protocol of the hospital). Thus,
intravenous oxytocin (10 IU in 1 L of isotonic saline
or 5% dextrose in water) administration was started
using the manual drip pawns at 10 drops per min
and increased every 30 min by 10 drops per min to a
maximum of 60 drops per min and given for a maxi-
mum of 16 h. If the woman had not reached the active
phase by the end of this period, cesarean section was
performed.
Active phase was defined as dilatation of at least
4 cm. Once in labor, women were cared for as per
NAUTH, Nnewi, Nigeria obstetric protocols. For the
purpose of this study, other hospitals adopted the
hospital protocol of NAUTH (as stated earlier). Mem-
branes were ruptured when the cervix was at least
80% effaced: (cervical lenght <0.5cm) and dilated at
least 4 cm, and the fetal head well applied to the cer-
vix. If the progress of labor halts at <1 cm cervical
dilatation per hour in the course of the process of
induction of labor, oxytocin infusion in incremental
doses, as per protocol above, was commenced. How-
ever, the oxytocin augmentation was delayed until
3
G. U. Eleje et al.
the duration from the last dose of misoprostol admin-
istration was at least 4 h to minimize the risk of hyper-
tonus or hyperstimulation syndrome. Continuous
electronic fetal heart rate monitoring with cardiotoco-
graph was used in all cases.
The sample for the Premaquick test was simulta-
neously obtained from the posterior fornix of the
vagina with a Dacron swab (supplied by the manu-
facturers), and was analyzed, and evaluated at the
bedside. The technique was performed by placing the
lower end of the Dacron swab stick in the posterior
fornix of the vagina for 30 s (to allow for swab satura-
tion) during a sterile speculum examination. Following
collection, the swab was inserted into a tube containing
1 mL of extraction buffer containing proprietary con-
centrations. Three drops of the extraction buffer (con-
taining the cervical secretion) were dropped into each
of the sample wells. The results were interpreted after
10 min waiting time with the sample wells placed in
flat horizontal position. Three biomarkers (total IGFBP-
1, native IGFBP-1 and IL-6) were tested. The detection
limit of the two versions of IGFBP-1: total IGFBP-1
and native IGFBP-1B were 40 ng/mL and 20 ng/mL
of recombinant IGFBP-1, respectively.
Following the tests, the outcome measures were
assessed in the women by the investigators or
research assistants who were not aware of the inter-
vention or group assignment. The Premaquick was
defined to be positive when at least two of the three
(2/3 rule) biomarkers were positive. The investigators
were blinded to the results of the Premaquick assay.
The Bishop score for the participant was obtained
through a single digital vaginal examination, with
scoring modified by the use of cervical length instead
of percentage as a score component for cervical efface-
ment. The parameters recorded at pelvic examination
also included the state of fetal membranes. The collec-
tion of specimen for Premaquick assay consistently
preceded each digital cervical examination for the
assessment of the modified Bishop score.
Outcome assessment
The primary endpoints were the number of women
with unripe cervix, that is, the number of women
who were administered PGE1 analogue (misoprostol)
as a preinduction agent, the number of women who
were administered additional prostaglandin (miso-
prostol) as a preinduction agent after one dose and
uterine rupture. The secondary endpoints included
frequency of transition to labor during cervical ripen-
ing, interval from start of induction to any type of
4 © 2018 Japan Society of Obstetrics and Gynecology
delivery, need for oxytocin augmentation, interval
from start of induction to beginning of active phase,
vaginal delivery, number of women with cesarean
section for failed induction, meconium staining of the
amniotic fluid, Apgar score at 1 min and number of
infants admitted to neonatal intensive care unit.
Sample size determination
Sample size calculations were based on the expecta-
tion of a comparable effect as observed by Park et al.5
who compared Bishop score in determining the
requirement for prostaglandin administration for pre-
induction cervical ripening in nulliparae at term.
Using the mean number of doses of prostaglandin per
woman during entire period of serial induction of
0.84  0.56 and 0.47  0.70 in the Bishop score study
and transvaginal ultrasound groups, respectively,
with a mean difference of 0.37 and a standard devia-
tion of 0.56, an α of 0.05, and power of 0.8, Epi info
2016 version 7.0 (Centers for Disease Control and Pre-
vention) and Stata PASS version 10 (NCSS) both yielded
a sample size of 48 women per group (60 assuming a
25% drop out rate).
Statistical analysis
Following entry, checking and cleaning of the data, the
randomization code was broken. Epi info 2016 version
7.0 and Stata PASS version 10 were used for analysis.
Student’s t-test was used for analyzing continuous var-
iables. The statistical significance of differences
between groups for continuous variables was assessed
and differences in proportions were assessed using
Mantel–Haenszel or Fisher’s exact test. The analysis
was based on the intention-to-treat principle. The value
of P < 0.05 was considered statistically significant.
Ethical consideration
Our study does not violate the policies and/or proce-
dures established by journal such as those described
in ‘Specific Inappropriate Acts in Publication Process’.
Also, the protocol for this research project was approved
by NAUTH Ethics committee and other recruiting hospi-
tals (approval number: NAUTH/CS/66/vol 9/143,
approval date: July 25, 2017) and it conforms to the
provisions of the Declaration of Helsinki (as revised
in Tokyo 2004), available at http://www.wma.net/en/
30publications/10policies/b3/index.html. The study
was registered with the pan African Clinical trial
registry at www.pactr.org with approval number
PACTR201604001592143, with a date of registration
of April 18, 2016.

Results
Between August 2016 and September 2017, 173 women
were screened for this study. Ten women did not meet
the inclusion criteria and two women declined to partic-
ipate before randomization. Therefore, 151 women
were randomized and participated in the trial. Seventy-
six women were randomized to Premaquick group and
75 to Bishop score group. Eight protocol violations
occurred (premature rupture of membranes prior to
enrolment [n = 2], participants had intrauterine fetal
death prior to enrolment [n = 2], multiparity [n = 2],
induction was abandoned due to participants bad
obstetric history [n = 1] or on request [n = 1]). None of
these women was excluded and ‘intention-to-treat anal-
ysis’ was performed.
A flow diagram describing the women’s flow
through the study is as shown in Figure 1. There were
no significant differences between the two groups
with respect to their baseline characteristics including
body mass index, maternal age, gestational age at
induction, indication for induction of labor, initial Pre-
maquick test results and initial Bishop scores at enrol-
ment (P < 0.05). Details are as shown in Table 1.
Following repeat evaluation for cervical assessment
after group allocation, 17 (22.4%) women had a ripe
cervix using the Premaquick technique (Premaquick
group), while 1 (1.3%) had a ripe cervix using the
Bishop scoring technique (Bishop score group). The
observed difference was statistically significant: 17/76
(22.4%) vs 1/75 (31.1%); RR 2.13; 95% CI 1.71–2.66;
P < 0.001. Thus, the need for prostaglandin agent for
cervical ripening prior to induction of labor was sig-
nificantly less in the Premaquick group compared to
the Bishop score group (59/76 [77.6%] vs 74/75
[98.7%]; RR: 0.47; 95% CI: 0.38–0.59; P < 0.001). Fur-
thermore, the need for additional dose of prostaglan-
din agent for cervical ripening after insertion of first
dose was significantly less in the Premaquick group
compared to the Bishop score group (34/76 [44.7%]
vs 51/75 [68.0%]; RR: 0.63; 95% CI: 0.46–0.86;
P = 0.004) .
The incidence of transition to labor during cervical
ripening was significantly higher in the Premaquick
group compared to the Bishop score group (34/76
[44.7%] vs 51/75 [68.0%]; RR: 0.63; 95% CI: 0.46–0.86;
P = 0.004). Other outcome measures including inter-
val from start of induction to any type of delivery,
need for oxytocin augmentation, interval from start
of induction to beginning of active phase, vaginal
delivery, number of women with cesarean section for
© 2018 Japan Society of Obstetrics and Gynecology
Premaquick vs Bishop score assessment
failed induction, meconium staining of the amniotic
fluid, Apgar score at 1 min, number of infants admit-
ted into the neonatal intensive care unit, and so forth
did not show any significant difference between
the two groups (P > 0.05). Details are as shown in
Table 2.
We also did a sensitivity analysis by analyzing the
findings using the per-protocol principle, excluding
the eight women that had protocol violations.
Seventy-three women remained in the Premaquick
group and 70 women remained in the Bishop score
group. The results of the per-protocol analyses were
not statistically different from those performed under
the intention-to-treat principle (data not shown).
Discussion
Our findings show that women undergoing preinduc-
tion cervical ripening assessment with Premaquick
had a significantly lower need for prostaglandin or
additional prostaglandin agent for cervical ripening
after one dose of insertion than in women assessed by
Bishop score method, and the rate of transition to
labor was statistically higher in the Premaquick
group. There were no significant differences between
the Premaquick and Bishop score groups in interval
from start of induction to any type of delivery, rates
of uterine rupture, need for oxytocin augmentation,
interval from start of induction to beginning of active
phase, vaginal delivery, and number of women with
cesarean section for failed induction. There were also
lower adverse infant outcomes in Premaquick group
(meconium staining of the amniotic fluid, Apgar score
at 1 min and number of infants admitted to neonatal
intensive care unit), though such differences did not
reach statistically significant.
This study has become the first study in published
literature to demonstrate that the use of Premaquick,
instead of Bishop score, significantly reduces the need
for prostaglandin or additional prostaglandin agent
for cervical ripening after one dose of insertion. A ran-
domized control trial by Park et al.5 aimed at compar-
ing sonographically measured cervical length with
the Bishop score in determining the requirement for
prostaglandin administration for preinduction cervical
ripening in nulliparae at term, revealed that the use of
sonographic cervical length for assessing the cervix
prior to induction of labor can reduce the need for
prostaglandin administration by approximately 50%
without adversely affecting the outcome of induction
5
G. U. Eleje et al.
Enrollment
Allocated to Premaquick (n=76)
♦ Received allocated intervention (n=76)
♦ Did not receive allocated intervention (n=0 )
Lost to follow-up (n=0)
Discontinued intervention (n=0)
Number of patients that completed the trial (n=76)
Analysed (n=76)
♦ Excluded from analysis (n=0)
♦ Protocol strict (n=73)
♦ Protocol violations (n=3)
Figure 1 Flow chart of the women in Premaquick vs Bishop score study. PROM, premature rupture of membranes.
in nulliparae at term. In another randomized con-
trolled trial by Bartha et al.,4 it was concluded that the
use of transvaginal ultrasound instead of Bishop score
for preinduction cervical assessment to choose induc-
tion agent significantly reduces the need for intracer-
vical prostaglandin treatment without adversely
affecting the success of induction. However, the major
problem of transvaginal ultrasound is that both the
equipment and skill are not readily available in low-
resource settings and there is no clear cutoff cervical
6 © 2018 Japan Society of Obstetrics and Gynecology
Assessed for eligibility (n=173)
Excluded (n= 22)
♦ Not meeting inclusion criteria (n=20)
[Breech (n=4), PROM (n=3), Multiparity
(n=13)]
♦ Declined to participate (n=2)
♦ Other reasons (n=0 )
Randomized (n=151)
Allocation
Allocated to Bishop score (n=75)
♦ Received allocated intervention (n=75)
♦ Did not receive allocated intervention (n=0)
Follow-Up
Lost to follow-up (n=0)
Discontinued intervention (n=0)
Number of patients that completed the trial (n=75)
Analysis
Analysed (n=75)
♦ Excluded from analysis (n=0)
♦ Protocol strict (n=70)
♦ Protocol violations (n=5)
length value that is most likely to indicate benefit
from a cervical ripening agent prior to induction of
labor.17 This result is very interesting because need-
less use of prostaglandin agents could trigger uterine
hyperactivity and uterine hyperstimulation, which
can jeopardize the perinatal life, increase operative
intervention and hospital costs.
Although both methods have not been directly
compared in any randomized studies, few prospective
studies have compared the effects of pIGFBP-1 and
 Premaquick vs Bishop score assessment

Table 1 Baseline demographic and clinical characteristics of the participants

Parameter Premaquick (n = 76) Bishop score (n = 75) RR (95% CI) P value
Frequency (%) Frequency (%)
Age (years) (mean  SD) 24.7  3.9 25.8  4.1 ŧ = −1.69 0.093
BMI (mean  SD) 29.2  5.1 29.7  4.3 ŧ = −0.65 0.516
Gestational age at induction (weeks):
1. 37–39 17 (22.4) 16 (21.3)
2. 40–42 59 (77.6) 59 (78.7) 0.95 (0.84–1.09) 0.961
Booking status
1. Booked 72 (94.7) 71 (94.7) 1.01 (0.49–2.05) 0.985
2. Unbooked 4 (5.3) 4 (5.3)
Bishop score at enrolment (mean  SD) 3.2  1.8 3.1  2.3 ŧ = 0.000 1.000
Dilatation
0–1 cm 62 63 0.92 (0.62–1.37) 0.858
2–3 cm 14 12 1.09 (0.73–1.62) 0.858
Effacement
<0.5 cm 62 60 1.05 (0.70–1.60) 0.968
0.5–2.0 cm 13 13 1.06 (0.69–1.63) 0.938
>2.0 cm 1 2 0.65 (0.13–3.28) 0.619
Consistency
Firm 68 64 1.22 (0.70–2.12) 0.602
Medium 6 9 0.77 (0.41–1.48) 0.568
Soft 2 2 0.99 (0.37–2.68) 1.000
Position
Posterior 66 71 0.67 (0.46–0.98) 0.169
Central 9 4 1.43 (0.95–2.13) 0.256
Anterior 1 0 2.00 (1.70–2.34) 1.000
Station
0 1 1 0.99 (0.25–4.01) 1.000
−1 to −3 75 74 1.01 (0.25–4.06) 1.000
+1 to +3 0 0
Bishop score < 6 at enrolment 70 (92.1) 74 (98.7) 0.65 (0.42–1.00) 0.153
Bishop score 5 4 5 0.91 (0.43–1.93) 1.000
Bishop score 4 17 20 0.93 (0.62–1.38) 0.853
Bishop score 3 49 49 1.10 (0.75–1.59) 0.758
Negative result for Premaquick at 59 (77.6) 62 (82.7) 0.86 (0.60–1.24) 0.440
enrolment
Birth weight (mean  SD) 3.2  0.6 3.3 0.4 ŧ = −1.203 0.231
Indication for Induction:
1. Postdatism 51 (67.1) 53 (70.7) 0.85 (0.42–1.70) 0.638
2. PIH 9 (11.8) 6 (8.0) 1.22 (0.78–1.90) 0.432
3. Chronic HTN 2 (2.6) 3 (4.0) 0.79 (0.27–2.34) 0.640
4. Preeclampsia 2 (2.6) 2 (2.7) 0.99 (0.37–2.68) 0.989
5. Others 12 (15.8) 11 (14.7) 1.04 (0.68–1.60) 0.848
*Statistically significant values.; Others = social reason (n = 1), stabilizing induction (n = 1), bad obstetrics history (n = 2), diabetes mellitus
(n = 3), intrauterine fetal death (n = 3), oligohydramnios (n = 1), intra uterine growth restriction (n = 3); ŧ = t-test or Z-test. Values are
expressed as number (percentage) of women. and BMI, body mass index; CI, confidence interval; HTN, hypertension; RR, risk ratio; SD,
standard deviation.

Bishop score. Dogl et al.13 revealed that pIGFBP-1 pre-
dicts both the spontaneous onset of labor and success-
ful induction in post-term pregnancy than Bishop
score. Consistent with Dogl et al., Vallikkannu et al.14
found pIGFBP-1 to be a moderately strong indepen-
dent predictor of successful induction and neither
Bishop score nor transvaginal ultrasound (TVUS) of the
cervical length was independently predictive of vaginal
delivery (P > 0.05). Similarly, Cheung et al.15 and
Kosinska-Kaczynska et al.16 found a positive association
between cervical pIGFBP-1 and vaginal delivery fol-
lowing induction of labor. Their findings are in sharp
similarity to ours, although our study population is
exclusive of nulliparous women and more than 65%
had their labor induction for post-date pregnancy. Thus,
cervical pIGFBP-1 is a better tolerated test and a stron-
ger predictor of a transition to successful labor in nulli-
paras with intact membranes than the Bishop score.

© 2018 Japan Society of Obstetrics and Gynecology 7

G. U. Eleje et al.

Table 2 Primary and secondary outcomes by study group

Parameter Premaquick (n = 76) Bishop score (n = 75) RR (95% CI) P value
Frequency (%) Frequency (%)
Primary outcome
Need for prostaglandin agent for
cervical ripening
59 (77.6) 74 (98.7) 0.47 (0.38–0.59) *<0.001
Need for additional prostaglandin
agent for cervical ripening
after one insertion
34 (44.7) 51 (68.0) 0.63 (0.46–0.86) *0.004
Uterine rupture
0 (0.0) 1 (1.3) 0.000 0.324
Secondary outcomes for the women
1. Transition to labor 34 (44.7) 17 (22.7) 1.59 (1.17–2.15) *0.004
2. Interval from start of 9.2  4.1 h 9.4  5.3 h 0.840
induction to beginning
of active phase of labor
3. Interval from start of 14.2  7.9 h 15.1  9.7 h 0.66 (−3.74–1.94) 0.533
induction to any
type of delivery
4. Vaginal delivery 60 (78.9) 61 (81.3) 0.92 (0.63–1.35) 0.682
5. Number of women with cesarean 7 (9.2) 6 (8.0) 1.09 (0.64–1.85) 0.772
section for failed induction
6. Number of women with 5 (6.6) 4 (5.3) 1.11 (0.61–2.04) 0.747
cesarean section for
failed cervical ripening
7. Number of women with 4 (5.3) 4 (5.3) 0.99 (0.49–2.02) 0.985
cesarean section for fetal
heart rate abnormalities
8. Need for oxytocin augmentation 29 (38.2) 27 (36.0) 1.22 (0.88–1.69) 0.246
Secondary outcomes for the infant
1. Meconium staining of the 24 (31.6) 26 (31.0) 0.90 (0.62–1.32) 0.579
amniotic fluid
2. Apgar score at 1 min 8.3  1.5 8.5  1.2 0.382
3. Number of infants admitted 3 (3.9) 7 (9.3) 0.58 (0.22–1.52) 0.191
to neonatal intensive care unit.
*Statistically significant values. Values are expressed as number (percentage) of patients.

This trial also showed that the rate of transition to
labor was statistically higher in the Premaquick group
than in women assessed by Bishop score method. The
reason for this finding was not clear. However, it
could be as a result of the cutoff value of Bishop score
used in the study which was <6. However, other pre-
vious studies20,21 used ≤4, but a more recent random-
ized clinical trial by Bansiwal et al.22 used <6 as a
cutoff. In some studies, misoprostol has been used
both for cervical ripening and induction, with regular
doses of misoprostol used in place of the oxytocin
infusion characteristic of most induction protocols.
The misoprostol used for ripening may be contribu-
tory to the transition to labor.
The fear that misoprostol could be dangerous to the
fetus because of irreversible hyperstimulation has not
been confirmed in studies included in a recent
Cochrane systematic review.23 This is an interesting
finding with higher tendency to have very high
obstetrics significance. In the index study, women
assessed by the Bishop score method, 76.1% of
women needed to proceed to an oxytocin infusion,
which, in settings like ours without electronic infusion
pumps, can be the most hazardous part of the induc-
tion procedure for the fetus. There could be varied
instabilities in the rates of infusion when manual drip
pawns are used. Furthermore, the intrapartum use of
oxytocin in low-income settings is closely associated
with neonatal morbidity and mortality and uterine
rupture.24 Therefore, the safety of the Bishop score for
preinduction cervical ripening assessment has the
dangers of the oxytocin infusion on the flipside.

8 © 2018 Japan Society of Obstetrics and Gynecology


Contrariwise, misoprostol causes both cervical ripen-
ing and uterine contractions. As a result, more
women progress through to vaginal birth without
requiring an oxytocin infusion, which has potential
safety benefits in the use of Premaquick for preinduc-
tion cervical assessment.
Although neonatal morbidity did not differ signifi-
cantly between the two intervention groups, this
study had insufficient power to detect anything other
than major differences in rare outcomes. Although
babies born to women assessed by the Bishop score
had a higher number of adverse infant outcomes, the
difference was not statistically significant. For
instance, women in the Bishop score group had more
often number of meconium-stained liquor, which was
also a common cause of cesarean section in that
group. The direct smooth muscle effect of misoprostol
on the fetal intestine, may be responsible for the
meconium staining of the liquor since more women
received multiple courses of prostaglandin agents in
the Bishop score group.
In settings without access to electronic fetal moni-
toring, meconium-stained liquor is an important clini-
cal sign of fetal compromise and so might, in itself, be
an indication for cesarean sections in these high-risk
inductions. Although not associated with fetal hyp-
oxia, meconium-stained liquor does carry risks of
meconium aspiration and so can cause clinically sig-
nificant neonatal morbidity.
One mechanisms of action of Premaquick for prein-
duction cervical assessment was that IGFBP-1 and IL-
6 concentration in ripe cervices (determined by Bishop
score) is four times higher than in unripe cervices,
and IGFBP-1 has been shown to predicts both sponta-
neous labor onset and successful induction than
Bishop score and cervical length which perform
equally well.13,25 Ideally, the obstetrics advantage of
Premaquick for preinduction cervical assessment was
that it appears to be a more objective assessment than
Bishop score and it may not require instrument just as
Bishop score and could even be assessed by the
patient herself since the Premaquick kits could be self-
administered. It will also obviate the need for multi-
ple vaginal examinations commonly seen in Bishop
score assessment and thus could be useful in women
with HIV/AIDS in pregnancy and hepatitis B or C
virus in pregnancy.
The strengths of our study are as follows: To the
best of our knowledge, this is the first study to date
on Premaquick vs Bishop score method coupled with
its randomized design. Among the three biomarkers
© 2018 Japan Society of Obstetrics and Gynecology
Premaquick vs Bishop score assessment
of Premaquick, two biomarkers (native IGFBP1 and
total IGFBP1) have never been evaluated for assess-
ment of induction of labor. Previous studies have only
tested phosphorylated IGFBP-1 compared with
Bishop score and or TVUS13–16 or TVUS compared
with Bishop score,4,5 and very recent Cochrane sys-
tematic review by Ezebialu et al. indicated that direct
comparisons between Bishop score and pIGFBP-1 and
IL-6 for assessing preinduction cervical ripening
among parturients at term gestations was yet to be
carried out.17 We have only tested the kits in cervi-
covaginal secretions, which is another strength to our
study as it makes the technique useful in facilities
without need for speculum. Evidence has shown that
parity is a robust predictor of successful induction of
labor; therefore, identical populations of nulliparous
women were used in this study so as to attain a suit-
able comparison of the two preinduction cervical
assessment methods.26 Additionally, this is a multi-
center study thus make the findings more generaliz-
able to the general population. It is our belief that this
study expands current literature by providing perfor-
mance metrics for the novel Premaquick for preinduc-
tion cervical assessment.
Despite these strengths, our study has some limita-
tions. The obstetrics care providers were not masked
as this was necessary so as to know when to com-
mence oxytocin agents. However, we think that it is
unlikely that knowledge of intervention arms by
obstetrics care providers may have influenced out-
comes assessed since double-blinding (study investi-
gators and participants) was still achieved because
each method was performed simultaneously on the
same individual participants throughout the study,
with only the obstetrics care provider on duty
knowing the particular method the women were
randomized to receive and the study investigators
only performing outcome assessments. This there-
fore decreased the risk of bias. Furthermore, it
would have been necessary to show the differences
in parturition outcomes between modified Bishop
score and the conventional Bishop unfortunately
only the modified Bishop score was the routine
method of preinduction cervical assessment in the
study hospitals.
Another possible limitation was our use of 50 μg of
misoprostol for cervical ripening as the preformed
25 μg tablet of misoprostol was rarely available at the
time of the trial. However, a recent PROBAAT-II mul-
ticenter Dutch study by Eikelder et al.27 and Uruguay
study by Conde et al.28 used similar (50 μg) dose.
9
G. U. Eleje et al.
Another very recent INFORM two-center-Indian
study by Mundle et al.29 used similar (50 μg) dose in
primigravid women. However, our study used a 6-h
dosing regimen instead of a 2-h dosing regimen
used in these previous studies,27,29 and these could
have contributed to the relative safety observed in
our trial. A very recent clinical trial in Nigeria by
Adebayo et al revealed that 50 μg of misoprostol is
as safe as 25 μg for cervical ripening and induction
of labor.30 Thus, according to the American College
of Obstetricians and Gynecologists (ACOG), the use
of misoprostol is safe and effective for cervical ripen-
ing and/or induction of labor.31 Additionally, our
study did not evaluate the performance of Prema-
quick compared to transvaginal ultrasound for cer-
vical length assessment, which findings of previous
studies13–15 have shown that both could compare
favorably. Such comparison could be a subject for
future studies.
In conclusion, Premaquick use for preinduction cer-
vical assessment was superior to modified Bishop
score method for preinduction cervical assessment
especially in terms of reduced need for prostaglandin
agent for preinduction cervical ripening and higher
incidence of transition to labor during the ripening
process. Both methods appear to be safe. Further
studies in other settings are required to confirm
whether the use of age-old Bishop score for preinduc-
tion cervical assessment could be supplanted by Pre-
maquick immunoassay.
Acknowledgments
The authors would like to thank Dr Thierry Paper,
Deputy General Manager, Business Development, of
Biosynex, France for his kind support and free supply
of the Premaquick test kits and other materials used
in the study. The authors wished to thank the staffs in
the hospitals that participated in the study and the
women who had participated in this study.
Disclosure
Biosynex SA, which supported the study and sup-
plied Premaquick tests, did not get involved or par-
ticipate in the study design, collection and
manuscript development. None of the authors is an
employee of, and/or holds stock in, Biosynex SA,
France.
10
References
1. Dogl M, Vanky E, Heimstad R. Changes in induction
methods have not influenced cesarean section rates among
women with induced labor. Acta Obstet Gynecol Scand 2016;
95: 112–115.
2. National Collaborating Centre for Women’s and Children’s
Health. Induction of labour. London: National Institute for
Health and Clinical Excellence (NICE), 2008 32 p. (Clinical
guideline; no. 70).
3. Talaulikar VS, Arulkumaran S. Failed induction of labour:
Strategies to improve the success rates. Obstet Gynecol Surv
2011; 66: 717–728.
4. Bartha JL, Romero-Carmona R, Martínez-Del-Fresno P,
Comino-Delgado R. Bishop score and transvaginal ultra-
sound for preinduction cervical assessment: A randomized
clinical trial. Ultrasound Obstet Gynecol 2005 Feb; 25: 155–159.
5. Park KH, Kim SN, Lee SY, Jeong EH, Jung HJ, Oh KJ. Com-
parison between sonographic cervical length and bishop
score in preinduction cervical assessment: A randomized
trial. Ultrasound Obstet Gynecol 2011; 38: 198–204. https://
doi.org/10.1002/uog.9020.
6. Hendrix NW, Chauhan SP, Morrison JC, Magann EF,
Martin JN Jr., Devoe LD. Bishop score: A poor diagnostic
test to predict failed induction versus vaginal delivery. South
Med J 1998; 91: 248–252.
7. Roman H, Verspyck E, Vercoustre L et al. Does ultrasound
examination when the cervix is unfavorable improve the
prediction of failed labor induction? Ultrasound Obstet Gyne-
col 2004; 23: 357–362.
8. Holcomb WL, Smeltzer JS. Cervical effacement: Variation in
belief among clinicians. Obstet Gynecol 1991; 78: 43–45.
9. Lauzon L, Hodnett E. Labour assessment programs to delay
admission to labour wards. Cochrane Database Syst Rev 2001;
CD000936.
10. Ugwu EO, Onah HE, Obi SN et al. Effect of the Foley cathe-
ter and synchronous low dose misoprostol administration
on cervical ripening: A randomized controlled trial. J Obstet
Gynaecol 2013; 33: 572–577.
11. Uygur D, Ozgu-Erdinc AS, Deveer R, Aytan H, Mungan MT.
Fetal fibronectin is more valuable than ultrasonographic
examination of the cervix or Bishop score in predicting suc-
cessful induction of labor. Taiwan J Obstet Gynecol 2016 Feb;
55: 94–97. https://doi.org/10.1016/j.tjog.2014.06.009.
12. Baacke KA, Edwards RK. Preinduction cervical assessment.
Clin Obstet Gynecol 2006; 49: 563–572.
13. Dogl M, Skogvoll E, Heimstad R. Cervical insulin-like growth
factor binding protein-1 (IGFBP-1) to predict spontaneous
onset of labor and induction to delivery interval in post-term
pregnancy. Acta Obstet Gynecol Scand 2011; 90: 57–62.
14. Vallikkannu N, Lam WK, Omar SZ, Tan PC. Insulin-like
growth factor binding protein 1, Bishop score, and sono-
graphic cervical length: Tolerability and prediction of vagi-
nal birth and vaginal birth within 24 hours following labour
induction in nulliparous women. BJOG 2017 Jul; 124:
1274–1283. https://doi.org/10.1111/1471-0528.14175 Epub
2016 Jun 27.
15. Cheung CW, Leung TY, Sahota DS et al. Outcome of induc-
tion of labour using maternal characteristics, ultrasound
assessment and biochemical state of the cervix. J Matern Fetal
Neonatal Med 2010; 23: 1406–1412.
© 2018 Japan Society of Obstetrics and Gynecology

16. Kosinska-Kaczynska K, Bomba-Opon D, Bobrowska K et al.
Phosphorylated IGFBP-1 in predicting successful vaginal
delivery in post-term pregnancy. Arch Gynecol Obstet 2015;
295: 45–52.
17. Ezebialu IU, Eke AC, Eleje GU, Nwachukwu CE. Methods
for assessing pre-induction cervical ripening. Cochrane Data-
base Syst Rev 2015; CD010762. https://doi.org/10.
1002/14651858.CD010762.pub2.
18. Eleje GU, Ezugwu EC, Eke AC et al. Accuracy of a combined
insulin-like growth factor-binding protein-1/interleukin-6
test (Premaquick) in predicting delivery in women with
threatened preterm labor. J Perinat Med 2017 (Feb 25); 45:
915–924. https://doi.org/10.1515/jpm-2016-0339.
19. Heng YJ, Liong S, Permezel M, Rice GE, Di Quinzio MK,
Georgiou HM. Human cervicovaginal fluid biomarkers to
predict term and preterm labor. Front Physiol 2015; 6: 151.
https://doi.org/10.3389/fphys.2015.00151.
20. Pandis GK, Papageorghiou AT, Ramanathan VG,
Thompson MO, Nicolaides KH. Preinduction sonographic
measurement of cervical length in the prediction of success-
ful induction of labor. Ultrasound Obstet Gynecol 2001; 18:
623–628.
21. Gonen R, Degani S, Ron A. Prediction of successful induc-
tion of labor: Comparison of transvaginal ultrasonography
and the Bishop score. Eur J Ultrasound 1998; 7: 183–187.
22. Bansiwal R, Ratna R, Misra N, Kapur V. Bishop score and
transvaginal ultrasound for preinduction cervical assess-
ment: A randomized clinical trial. Int J Reprod Contracept
Obstet Gynecol 2013; 2: 611–615.
23. Alfirevic Z, Aflaifel N, Weeks A. Oral misoprostol for induc-
tion of labour. Cochrane Database Syst Rev 2014; 6: CD001338.
24. Lovold A, Stanton C, Armbruster D. How to avoid iatro-
genic morbidity and mortality while increasing availability
© 2018 Japan Society of Obstetrics and Gynecology
Premaquick vs Bishop score assessment
of oxytocin and misoprostol for PPH prevention? Int J
Gynaecol Obstet 2008; 103: 276–282.
25. Nuutila M, Hiilesmaa V, Karkkainen T, Ylikorkala O,
Rutanen EM. Phosphorylated isoforms of insulin-like
growth factor binding protein-1 in the cervix as a predictor
of cervical ripeness. Obstet Gynecol 1999; 94: 243–249.
26. Rane SM, Pandis GK, Guirgis RR, Nicolaides KH. Pre-
induction sonographic measurement of cervical length in
prolonged pregnancy: The effect of parity in the prediction
of the need for cesarean section. Ultrasound Obstet Gynecol
2003; 22: 40–44.
27. Eikelder ML, Oude Rengerink K, Jozwiak M et al. Induction
of labour at term with oral misoprostol versus a Foley cathe-
ter (PROBAAT-II): A multicentre randomised controlled
non-inferiority trial. Lancet 2016; 387: 1619–1628.
28. Conde A, Ben S, Tarigo J et al. Comparison between vaginal
and sublingual misoprostol 50 μg for cervical ripening prior
to induction of labor: Randomized clinical trial. Arch Gynecol
Obstet 2017; 295: 839–844. https://doi.org/10.1007/s00404-
017-4297-9 Epub 2017 Feb 16.
29. Mundle S, Bracken H, Khedikar V et al. Foley catheterisation
versus oral misoprostol for induction of labour in hyperten-
sive women in India (INFORM): A multicentre, open-label,
randomised controlled trial. Lancet 2017 Aug 12; 390:
669–680. https://doi.org/10.1016/S0140-6736(17)31367-3
Epub 2017 Jun 28.
30. Adebayo FO, Onafowokan O, Adewole N. A comparison of
25 μg with 50 μg misoprostol for cervical ripening and
induction of labor. J Women’s Health Care 2017; 6: 378.
https://doi.org/10.4172/2167-0420.1000378.
31. ACOG Committee on Practice Bulletins. Obstetrics. ACOG
practice bulletin no. 107: Induction of labor. Obstet Gynecol
2009; 386: 114.
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