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International Journal of Gynecology and Obstetrics 124 (2014) 112117

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International Journal of Gynecology and Obstetrics


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CLINICAL ARTICLE

Drotaverine to improve progression of labor among nulliparous women


Moustafa I. Ibrahim a, Hazem A. Alzeeniny a, Mohamed I. Ellaithy a,,
Ahmed H. Salama a, Mohammed A. Abdellatif b
Department of Obstetrics and Gynecology, Ain-shams Faculty of Medicine, Cairo, Egypt
Department of Obstetrics and Gynecology, Sohag Teaching Hospital, Sohag, Egypt

a r t i c l e

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a b s t r a c t

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1. Introduction

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Keywords:
Cervical dilatation rate
Drotaverine hydrochloride
Nulliparous

Objective: To reevaluate the role of the antispasmodic drug drotaverine in shortening the length of the active rst
stage of labor among nulliparous women. Methods: In a randomized, double-blind, placebo-controlled trial, 422
young nulliparous women admitted to Ain-shams University Maternity Hospital, Cairo, Egypt, in spontaneous
labor were initially enrolled between May and December 2012. Drotaverine hydrochloride (40 mg) or placebo
was given at the start of the active phase of labor and then repeated every 2 hours (maximum 3 doses). All participants were consistently managed in accordance with the local institutional intrapartum protocol. The primary
outcome was the rate of cervical dilation. Results: After excluding women who delivered by cesarean, data were
analyzed from 320 women. There was a signicant difference in post-treatment labor pain scores, duration of the
active phase of labor, and rate of cervical dilatation between the 2 groups (P b 0.001 for all). There was no difference in maternal adverse effects. KaplanMeier survival analysis showed a greater probability of faster delivery
among patients treated by drotaverine hydrochloride (log rank test; P b 0.001). Conclusion: Drotaverine hydrochloride was used effectively and safely to shorten the duration of the rst stage of labor among nulliparous
women with active spontaneous labor.
ClinicalTrials.gov: NCT01639027.
2013 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.

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Article history:
Received 1 May 2013
Received in revised form 10 August 2013
Accepted 29 October 2013

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Minimizing the duration of labor without compromising fetomaternal wellbeing is a desirable outcome in all labor and delivery
units [1]. Prolonged labor has been associated with higher rates of neonatal admission to the intensive care unit [2], and is likely to increase the
work burden, especially in busy labor wards, with consequent inadequacy of obstetric care [3].
Hirsch [4] rst described the use of antispasmodic drugs to shorten the rst stage of labor in 1937: he reported that labor duration
could be decreased by 24 hours by using an atropine-like drug.
Antispasmodic drugs can aid faster cervical dilatation of the cervix
during labor via neurotropic and/or musculotropic effects [5].
Drotaverine is a musculotropic agentan inhibitor of type IV phosphodiesterase (PDE)that is structurally related to papaverine. It
has mild calcium channel blocking activity but no anticholinergic
effects and acts directly on smooth muscle cells, inhibiting spasm [6].
A recent Cochrane review [7] found low quality evidence that
antispasmodic drugs reduce the duration of rst stage of labor and
increase the cervical dilatation rate; very low quality evidence that
they reduce the total duration of labor; and insufcient evidence to
make any conclusion about the safety of these medications. It was
Corresponding author at: Building 14, Block 14, Alwaha District, Nasr City, Cairo,
Egypt. Tel.: +20 1006873417.
E-mail addresses: drmellisy@hotmail.com, drmellisy@gmail.com (M.I. Ellaithy).

therefore advised that large, well-designed, randomized controlled


trials are needed to evaluate the role of antispasmodic drugs in the
management of labor [7].
The aim of the current study was to reevaluate the safety and efcacy
of using the antispasmodic drotaverine to reduce the duration of the active rst stage of labor among nulliparous women being managed by a
standard intrapartum protocol.
2. Materials and methods
The present randomized, double-blind, placebo-controlled trial was
conducted among young nulliparous women admitted in spontaneous
active labor to the Labor and Delivery Unit of Ain-shams University
Maternity Hospital, Cairo, Egypt (annual number of deliveries 12
00018 000), between May 11 and December 17, 2012. The study was
approved by the local institutional ethics and research committee. Written signed informed consent was obtained from all participants before
any study-specic procedure was performed.
Women were considered eligible to participate in the study if
they had a singleton term pregnancy with a vertex presentation,
occipitoanterior position, and cervical dilatation of 35 cm. The
presence of 1 or more of the following was considered sufcient to exclude women from the study: prepartum hemorrhage, placenta previa,
prior uterine scar, cephalopelvic disproportion, use of labor-inducing
agent, contraindication for vaginal delivery, non-reassuring fetal status,
hypersensitivity to drotaverine hydrochloride, prior cervical surgery,

0020-7292/$ see front matter 2013 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.ijgo.2013.08.013

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M.I. Ibrahim et al. / International Journal of Gynecology and Obstetrics 124 (2014) 112117

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An injection was given at the start of the active phase of labor and repeated every 2 hours for a maximum of 3 doses if full cervical dilatation
did not happen.
All participants were consistently managed according to the local
institutional intrapartum protocol and received identical monitoring
and supportive care. Before being enrolled, all participants were
thoroughly assessed to conrm eligibility and to exclude allergy
to drotaverine hydrochloride and/or any contraindication for
vaginal delivery.
The presence of normal fetal heart rate pattern and assessment of
uterine activity were assured via cardiotocography for 30 minutes
before the intervention was started. Intrapartum fetal monitoring
was performed via intermittent auscultation for low-risk women
and continuous electronic fetal monitoring for high-risk women.
Vaginal examination was performed every 2 hours, unless clinically
indicated, to dene the progress of cervical dilatation. Articial
rupture of fetal membranes was considered for women with intact
membranes if there was poor progress of labor (cervical dilatation,
b1 cm/hour). Oxytocin, if needed, was begun 2 hours after rupture of fetal membranes via a low-dose titration approach with a
starting dose of 2 mU/minute and increments of 2 mU/minute
every 15 minutes until adequate uterine contractions were achieved

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use of antihypertensive therapy, or use of spasmolytic agents within the


past 48 hours.
Gestational age was calculated at the time of enrollment according
to the Naegele rule and conrmed by reviewing early pregnancy ultrasound scans. Active labor was diagnosed by the presence of regular uterine contractions (each lasting for 30 seconds or more) at a rate of at
least 3 every 10 minutes, with or without rupture of membranes.
Eligible participants were randomly assigned to receive a slow intravenous injection via a syringe prelled with 2 mL of either drotaverine
hydrochloride or placebo during management of the rst stage of labor.
Randomization was performed via a computer-generated sequence: the
randomization list was held in a secure box in the labor ward and the
participants were assigned to their groups by using sequentially numbered opaque sealed envelopes that were opened at enrollment. The syringes were masked with black opaque stickers so that the yellowishcolored drotaverine hydrochloride was undistinguishable from the
translucent saline solution.
Women assigned to the intervention group received intravenously
40 mg of drotaverine hydrochloride (2-mL ampules, 40 mg/ampule;
Do-Spa, Alexandria Pharmaceutical and Chemical Industries, Awayed,
Alexandria, Egypt), whereas women assigned to the placebo group
received intravenously 2 mL of normal saline (0.9% sodium chloride).

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Enrollment

Excluded (n=704)
Contraindication to vaginal delivery (n=141)
Induced labor (n=223)
Cervical dilatation >5 cm (n=87)
Gestational age <37 weeks (n=103)
Twins (n=21)
Others (n=129)

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Assessed for eligibility


(n=1126)
Nulliparous women admitted in
labor during the study period

Eligible women (n=422)

Excluded (n=70)
Declined to participate

Allocation
Received drotaverine (n=176)

Received placebo (n=176)

Analysis
Analyzed (n=161)
Excluded from analysis (cesarean delivery
before full cervical dilatation) (n=15)

Analyzed (n=159)
Excluded from analysis (cesarean delivery
before full cervical dilatation) (n=17)

Fig. 1. Flow of participants through the study.

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M.I. Ibrahim et al. / International Journal of Gynecology and Obstetrics 124 (2014) 112117
Table 2
Comparison of study outcomes between the drotaverine and placebo groups.a
Outcome

Study group
Placebo
(n = 159)

101 (62.7)
96 (59.6)
5 (47)
3 (25)
8 (69)
2.7 (2.43.0)
120.7 53.2
42.2 22.3
9.1 1.5
145 (90.1)
4 (2.5)
2 (1.2)
10 (6.2)
349 97
3 (1.9)
4 (2.5)
8 (89)
9 (99)
5 (3.1)
4 (2.5)
2903 354

96 (60.4)
113 (71.1)
9 (79)
9 (810)
10 (910)
1.8 (1.62.0)
200.8 79.8
38.7 20.8
8.9 1.6
144 (90.1)
5 (3.1)
1 (0.6)
9 (5.7)
367 88
2 (1.3)
6 (3.8)
8 (89)
9 (89)
4 (2.5)
4 (2.5)
2876 298

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Oxytocin augmentation
Meperidine hydrochloride
Labor pain (VAS) after 30 min
Labor pain (VAS) after 60 min
Labor pain (VAS) after 120 min
Cervical dilatation rate, cm/h
First-stage duration, min
Second-stage duration, min
Third-stage duration, min
Normal vaginal delivery
Ventouse-assisted delivery
Forceps-assisted delivery
Second-stage cesarean delivery
Blood loss, mL
Cervical lacerations
Fetal distress
Apgar score at 1 mi
Apgar score at 5 min
Meconium-stained liquor
NICU admission
Neonatal birth weight, g

P value

Drotaverine
(n = 161)

0.73
0.035
b0.001
b0.001
b0.001
b0.001
b0.001
0.15
0.25
N0.99
0.75
N0.99
N0.99
0.083
N0.99
0.54
0.6
0.44
N0.99
N0.99
0.46

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Abbreviations: NICU, neonatal intensive care unit; VAS, visual analog scale.
a
Values are given as mean SD, median (interquartile range), or number
(percentage) unless stated otherwise.

There were no signicant differences regarding maternal age, gestational age at time of enrollment, baseline cervical dilatation, initial labor
pain score, or Apgar scores measured at 1 minute and 5 minutes
(Table 1). However, the 2 groups differed in post-treatment labor pain
scores, duration of the active phase of labor, and rate of cervical dilatation (P b 0.001) (Table 2).
There was no signicant difference between the 2 groups in maternal adverse events: tachycardia and palpitation were reported for 7
women (4.3%) and 8 women (5.0%) in the drotaverine and placebo
groups, respectively, whereas headache was reported for 6 women
(3.7%) and 6 women (3.8%), respectively. Hypotension was reported
for 5 women (3.1%) and 6 women (3.8%) in the drotaverine and placebo
groups, respectively, whereas nausea was reported for 6 women (3.7%)
and 6 women (3.8%), respectively. Dry mouth, ushing, unsteadiness,
photophobia, and retention of urine were not reported for women in
either group. Neonatal adverse events, including fetal distress rate,
median Apgar scores at 1 and 5 minutes, meconium-stained liquor
rate, and rate of admission to the neonatal intensive care unit did not
differ signicantly between the 2 groups (Table 2).

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or the maximum dose (32 mU/minute) was reached. The intrapartum


fetal heart rate pattern and uterine contractions were interpreted in
accordance with ACOG guidelines [8,9].
A partogram was used to document the progress of labor and the duration of the rst stage of labor to determine the study endpoints. The
primary outcome was the rate of cervical dilation; secondary outcomes
included the duration of the active rst stage of labor (from rst injection to full cervical dilatation), mode of delivery, Apgar score of less
than 7 at 1 and 5 minutes, maternal drug adverse effect, and pain assessment via visual analog scale recorded before and after the injected
solution at 30, 60, and 120 minutes.
The required study sample size was estimated via G*Power version
3.1.0 (Institut fr Experimentelle Psychologie, Heinrich Heine
Universitt, Dsseldorf, Germany). The study sample size was calculated on the basis of the duration of the rst stage of labor because this calculation yielded the highest sample size; this powered the study
sufciently to assess many outcomes, including the primary outcome
of the study, which was the rate of cervical dilatation.
It was estimated that a sample size of 160 women in each group
would have a power of 80% to detect an effect size (d) of 0.3. The test
used was the 2-sample t-test and signicance was targeted at an
error of 0.05. The sample size was increased by 10% to compensate for
post-randomization exclusions related to performing cesarean delivery
in the rst stage of labor.
Statistical analysis was done via SPSS version 19 (IBM, Armonk, NY,
USA). Quantitative variables were described as mean SD or median
(interquartile range; IQR) as appropriate. Qualitative variables were
described as number and percentage. Qualitative variables were compared between the 2 groups by 2 test; quantitative variables were compared by an independent sample t-test for parametric data and by
MannWhitney test for non-parametric data. A P value of less than
0.05 was considered to be statistically signicant. A KaplanMeier survival analysis was used to detect the probabilities of faster delivery
with the use of drotaverine hydrochloride and placebo. The 2 curves
were compared via a log rank test.

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3. Results

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During the study period, 422 young nulliparous women were eligible for participation in the study. Seventy women refused consent; as
a result, 176 women were allocated to the drotaverine group and 176
to the placebo group. After excluding women who delivered by cesarean, the nal statistical analysis included 320 women (Fig. 1).
The mean maternal age of participants was 23.8 3.6 years,
and the mean gestational age at the time of enrollment was 38.5
1.1 weeks. The mean duration of the active phase was 160.3
66.4 minutes, and the median rate of cervical dilatation was
2.11 cm/hour (IQR, 1.752.67). The median Apgar score at 1 minute
was 8 (IQR, 89), the median Apgar at 5 minutes was 9 (IQR, 99). In
the drotaverine group, the median number of doses administered
was 2 (IQR, 12).
Table 1
Comparison of baseline parameters between the drotaverine and placebo groups.a
Baseline parameter

Maternal age, y
BMI on admission
Gestational age, wk
Cervical dilatation, cm
Bishop score b10
Initial labor pain score (VAS)

Study group

P value

Drotaverine (n = 161)

Placebo (n = 159)

23.8 3.8
30.1 5.1
38.6 1.1
4.3 0.8
73 (47.2)
7 (69)

23.8 3.4
29.9 4.9
38.5 1.1
4.3 0.8
68 (42.8)
7 (69)

0.92
0.72
0.38
0.69
0.65
0.92

Abbreviations: BMI, body mass index (calculated as weight in kilograms divided by the
square of height in meters); VAS, visual analog scale.
a
Values are given as mean SD, median (interquartile range), or number
(percentage) unless stated otherwise.

Fig. 2. KaplanMeier curves showing the probability of faster delivery among women
treated by drotaverine hydrochloride and placebo.

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Nulliparas (n = 150)
low risk
Cx 4 cm
Mixed parity (n = 300)
low risk
Cx 4 cm
Nulliparas
(n = 100)
low risk
Cx 36 cm
Mixed parity (n = 200)
low risk
Cx 3 cm
Mixed parity
(n = 150)
low/high risk
Cx N3 cm
Mixed parity
(n = 150)
low risk
Cx 4 cm
Nulliparas (n = 320)
low risk
Cx 35 cm

Sharma et al., 2001 [13]

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Drotaverine HCl 40 mg/2 h IMI versus


hyoscine butylbromide 20 mg/30 min IVI
(maximum of 3 doses)
Drotaverine HCl 40 mg/h IMI versus
valethamate bromide 8 mg/h IMI
(maximum of 3 doses)
Drotaverine HCl 40 mg/2 h IVI
(maximum of 3 doses)

Duration of rst stage of labor

Duration of rst stage of labor;


cervical dilatation rate

Duration of rst stage of labor;


cervical dilatation rate

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Drotaverine HCl 40 mg IVI

Duration of rst stage of labor

Duration of whole labor;


pain in labor

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Drotaverine HCl 40 mg/2 h IMI versus


valethamate bromide 8 mg/h IMI
(maximum of 3 doses)
Drotaverine HCl 40 mg/2 h IMI versus
valethamate bromide 8 mg/30 min IMI
(maximum of 3 doses)
Drotaverine HCl 40 mg IMI (second
injection if no progress after 4 h)

Intervention

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Duration of rst stage of labor;


delivery within 6 h;
cervical dilatation rate
Duration of rst stage of labor

Main outcome measures

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Abbreviations: Cx, cervical dilatation; IMI, intramuscular injection; IVI, intravenous injection; RCT, randomized controlled trial.

Current study, 2013

Madhu et al., 2010 [12]

Gupta et al., 2008 [11]

Roy et al., 2007 [15]

Singh et al., 2004 [14]

Khosla et al., 2003 [10]

Population

Study

Table 3
Summary of data from previous trials of drotaverine hydrochloride.

Shorter duration of rst stage of labor,


more effective in multigravida and
when given in more dilated cervix
No difference

Placebo

Shorter duration of rst stage of labor;


faster cervical dilatation

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Shorter duration of rst stage of labor;


faster cervical dilatation

Strictly dened labor management protocol;


largest participant number

Unclear labor management protocol;


women were not stratied according to their
parity

Unclear labor management protocol (labor


onset was not dened);
women with prior cesarean were included

Methods not clearly stated

Unclear labor management protocol;


augmentation after 8 h of dysfunctional labor

First stage of labor was not dened

Shorter duration of rst stage of labor

Shorter duration of labor in the


subgroup randomized at 4 cm
dilatation

Unclear labor management protocol;


rst -stage duration was not dened

Comments

Shorter duration of rst stage of labor;


faster cervical dilatation

Results

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Placebo

None

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None

Placebo

None

None

Control

M.I. Ibrahim et al. / International Journal of Gynecology and Obstetrics 124 (2014) 112117
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M.I. Ibrahim et al. / International Journal of Gynecology and Obstetrics 124 (2014) 112117

Fig. 2 shows the KaplanMeier survival analysis; a signicant difference was observed in the probability of faster delivery among patients
who were treated by drotaverine hydrochloride compared with those
who were treated by placebo (log rank test, P b 0.001).

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Although the potential role of drotaverine hydrochloride in enhancing the progress of the rst stage of labor has been investigated in few
trials [1015], most of those trials had an unclear labor management
protocol with conicting results and heterogeneous populations and
interventions (Table 3).
In the current study, drotaverine was associated with improved
progress of the rst stage of labor without increasing the fetomaternal
compromise among nulliparous women. The precise mechanism by
which drotaverine can speed up cervical dilatation is not clear.
Drotaverine hydrochloride is a potent antispasmodic agent, which is
devoid of anticholinergic activity; it acts mainly by inhibiting type IV
PDE, leading to an increase in intracellular cyclic AMP and cyclic GMP,
smooth muscle relaxation, and cervical dilatation [12]. It has no signicant fetal adverse effects because it does not cross the human placenta.
Drotaverine is excreted via a non-renal route and its half-life is
712 hours. Its metabolites are much more potent in inhibiting type
IV PDE isoenzymes than is drotaverine itself. Its maternal adverse effects
are generally mild and occur mainly when the drug is given by rapid intravenous administration [16,17].
Modern labor management protocols contain interventions that can
directly or indirectly affect the duration of labor, such as epidural analgesia, amniotomy, and oxytocin administration [3]. Unlike amniotomy
and oxytocin augmentation, drotaverine hydrochloride does not enhance myometrial contractility; hence, it does not induce uterine hyperstimulation or compromise fetomaternal outcomes.
Although drotaverine is a smooth muscle relaxant that reduces uterine muscle contraction and subsequently improves uterine perfusion in
the non-pregnant uterus [18], hindrance of uterine contractions is not a
problem during labor. Leroy et al. [16] reported that there is a higher
concentration of type IV PDE in the human myometrium in the third trimester and near term. This predominance suggests its potential role in
labor.
The presence of high-risk maternal and/or fetal conditions would
adversely affect conclusions on the potential benecial role of
drotaverine on the progress of labor; as a result, apart from the study
of Gupta et al. [11], which included women who had prior cesarean delivery, the current trial and other previous trials [10,1215] included
only women with low-risk pregnancies.
Because the problem of dystocia and prolonged labor are more commonly encountered among nulliparous women, the current study and 2
previous studies [13,14] included only nulliparous women. Other studies included both nulliparous and multiparous women [1012,15].
Use of cervical ripening agents would alter the cervical status and
potentially alter the responsiveness to antispasmodic drugs; as a result,
the current study and most previous trials [10,1215] included only
women with spontaneous labor. One study did not specify whether its
participants were in spontaneous labor or not [11].
In previous studies, the duration of labor was the primary outcome
measure [1015]. Although the duration of the rst stage of labor was
the primary endpoint of the current study, the rate of dilatation was
used as the primary outcome measure because women were randomized at different dilatation levels to make the comparison between
groups feasible. In keeping with previous studies [1015], only
women who completed the rst stage of labor were considered in calculating the mean duration of the rst stage of labor and the cervical dilatation rate, and women who delivered via cesarean in the rst stage of
labor were excluded. The current study reported signicantly faster cervical dilatation rates among women receiving drotaverine; these

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4. Discussion

ndings are in agreement with previous reports [12,13] but in contrast


to the results of Gupta et al. [11].
Unexpectedly, the current study has documented a benecial effect
of drotaverine hydrochloride in relieving labor pains. Apart from Singh
et al. [14], no previous trials evaluated the effect of drotaverine on
pain relief [1013,15]. Singh et al. [14] reported no effect of drotaverine
on pain relief. In the current study, drotaverine had no overall signicant effect on the normal delivery rate; this nding is in agreement
with previous data [1014].
Neurotropic antispasmodic agents function by antagonizing acetylcholine at muscarinic receptors, whereas musculotropic antispasmodic
drugs act directly on smooth muscle cells with no anticholinergic effects
[5]. Although there was no signicant difference between the 2 groups
in maternal and neonatal adverse events in the present study, maternal
tachycardia, dry mouth, and ushing have been reported to be signicantly higher in previous multi-interventional studies; however, it
should be mentioned that such adverse effects were reported in the patient subgroups receiving neurotropic agents not drotaverine [1013].
Other adverse events, including maternal headache [12,13], unsteadiness [12,13], and bleeding [14], were not found to be signicantly higher
among women receiving drotaverine; in addition, the rates of fetal distress [13] and NICU admission [11] were not signicantly higher among
women receiving drotaverine.
In addition to the current study, 2 other studies used drotaverine as
the only intervention controlled by placebo [14] or no treatment [15].
Other studies used multiple interventions controlled by placebo [12]
or no treatment [10,11,13].
To the best of our knowledge, this is the largest trial to investigate
the potential role of drotaverine in shortening the rst stage of labor;
other merits include the use of a standard labor management protocol
and the study design of a double-blind placebo-controlled trial. The
study is limited by its inability to evaluate maternal satisfaction.
In conclusion, drotaverine hydrochloride can be considered as an effective and safe pharmaceutical agent to shorten the duration of the rst
stage of spontaneous labor among nulliparous women.
Conict of interest
The authors have no conicts of interest.
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