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Received: 15 February 2019    Revised: 13 August 2019    Accepted: 11 October 2019    First published online: 8 November 2019

DOI: 10.1002/ijgo.12998

CLINICAL ARTICLE
Obstetrics

Use of an antiemetic to shorten the length of labor in

nulliparous women, exploring a potential role of an old drug:
A randomized controlled trial

Mohamed Ellaithy1,2,* | Suriaya Rasheed1 | Adel Shafik1 | Sara Abees3

1
Obstetrics and Gynecology Department,
King Faisal Military Hospital, Khamis
Mushait, Saudi Arabia
2
Obstetrics and Gynecology Department,
Faculty of Medicine, Ain Shams University,
Cairo, Egypt
3
Pharmacy Department, King Faisal Military
Maternity Hospital, Khamis Mushait, Saudi
Arabia
*Correspondence
Mohamed Ellaithy, Ain Shams University
Maternity Hospital, Abbasiya Square, Cairo,
Egypt.
Email: drmellisy@hotmail.com
Abstract
Objective: To assess whether metoclopramide is effective in shortening the duration of
the first stage of labor in primiparous women.
Methods: The present randomized, double-­blind, placebo-­controlled trial was conducted
at King Faisal Hospital, Saudi Arabia (between July 30, 2013, and September 1, 2016), and
sequentially recruited young nulliparous women admitted in spontaneous active labor
with or without ruptured membranes. Eligible participants were randomly assigned to
receive a slow intravenous injection of either metoclopramide or placebo and consistently
managed according to the local institutional intrapartum protocol and received identical
monitoring and supportive care. The primary outcome was the cervical dilatation rate.
Results: Fifty-­nine women were included in the metoclopramide group and 52 in the
placebo group. The first stage of labor was significantly shorter in the metoclopramide
group (203 minutes vs 230 minutes in the placebo group, P=0.019), with a faster cervi-
cal dilatation rate (2.4 ± 0.4 cm/h vs 1.9 ± 0.5 cm/h in the placebo group, P<0.001) and
shorter interval from treatment administration until full cervical dilatation. There was a
significantly higher probability of faster delivery among women who were treated with
metoclopramide (log-rank test, χ2=5.997, P=0.014).
Conclusion: Metoclopramide safely reduced the duration of the first stage of labor and
was not associated with major maternal or neonatal adverse outcomes.
ClinicalTrials.gov: NCT01937234

KEYWORDS
Antispasmodics; Cervical dilatation; Dystocia; First stage of labor; Labor progress;
Metoclopramide; Nulliparous women

1 | INTRODUCTION The cervical smooth muscles act independently of those in the

For the last few decades, healthcare providers have worked with the
aim of shortening the duration of painful labor.1
The cervix uteri consists mostly of connective tissue (85%–90%)
2
covered by a thin layer of smooth muscle (10%–15%). However, as
the uterus contracts more during labor, the cervix also contracts but
with less intensity, allowing for softening and dilatation to permit pas-
sage of the fetus through the birth canal.3
uterine corpus.4 This independent uterine activity is important for
understanding the role of the cervix in normal and abnormal preg-
nancy and labor. The intensity of smooth muscle fiber activity in the
cervix uteri is of extreme importance in determining the course of the
latent and active phases of labor.5
Metoclopramide is frequently employed in delivery rooms, some-
times being used to reduce the duration of labor in several hospi-
tals in Saudi Arabia and elsewhere in the world. The mechanism by

72  |  wileyonlinelibrary.com/journal/ijgo
© 2019 International Federation of Int J Gynecol Obstet 2020; 148: 72–78
Gynecology and Obstetrics
Ellaithy ET AL.
which it acts in this context is not fully understood and evidence of its
safety and efficacy is largely anecdotal with no well-­designed interna-
tionally published studies. Metoclopramide is principally a dopamine
D2 receptor antagonist but also acts as an agonist serotonin 5-­HT4
receptors and as a weak antagonist 5-­HT3 receptors.6 Endogenous
dopamine is present in uterine muscle fibers and dopaminergic recep-
tor agonists can increase uterine contractility and pressure, indicating
that endogenous dopaminergic activity may play an important role
in the control of pregnancy and delivery.7 Thus, metoclopramide
may have some effect on the smooth muscles of the cervix, inhibit-
ing spasms that impair effective cervical dilatation and thus aiding in
cervical relaxation. The present study assessed the effectiveness of
metoclopramide in reducing the duration of the first stage of labor in
primiparous women.
2 |  METHODOLOGY
A randomized, double-­blind, placebo-­controlled trial (RCT) was con-
ducted in the labor and delivery unit of King Faisal Military Hospital,
Saudi Arabia (between July 30, 2013, and September 1, 2016). Young
nulliparous women admitted in spontaneous active labor with or with-
out ruptured membranes were recruited sequentially. The study was
approved by the local institutional ethics and research committee and
prospectively registered at ClinicalTrials.gov (NCT0193723). Written
informed consents were obtained from all participants.
Study inclusion criteria included nulliparity, spontaneous onset of
active labor, singleton term gestation (≥37 weeks of gestation), and a
live fetus with cephalic presentation. Gestational age was calculated
according to Naegele's rule and confirmed by reviewing the early preg-
nancy ultrasound scan.
Once established labor and cervical dilatation were confirmed by
vaginal examination, eligible participants were randomly assigned to
receive a slow intravenous injection of either metoclopramide or pla-
cebo (same volume of physiological saline, 0.9% sodium chloride) via a
2-­mL prefilled syringe. Randomization was achieved using a computer-­
generated randomization sequence, stratified by unit. Allocation was
in a 1:1 ratio. Records of group allocation were maintained by a res-
ident physician who was responsible for randomization and drawing
up the injectate, but who had no direct involvement in intrapartum
decision making. The metoclopramide and saline solution were identi-
cal in appearance. Women assigned to the intervention group received
intravenously 10 mg (in 2 mL) metoclopramide hydrochloride, whereas
women assigned to the placebo group received intravenously 2 mL of
normal saline. An injection was given at the start of the active phase
of labor and repeated every 2 hours for a maximum of three doses.
All participants were consistently managed according to the local
intrapartum protocol and received identical monitoring and support-
ive care. Before enrolment, all participants were thoroughly assessed
to confirm eligibility and to exclude malpresentations, malpositions,
multifetal pregnancy, cephalopelvic disproportion, history of cervical
surgery or injury, hypersensitivity to metoclopramide, and/or any con-
traindication for vaginal delivery.
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      73
Vaginal examination was performed every 1–2 hours, and earlier
if clinically indicated (e.g. increased frequency of labor pains, sense
of pelvic heaviness, and during the acceleration phase of first stage
of labor, for early diagnosis of the onset of second stage of labor).
Amniotomy was considered for women with intact membranes if there
was poor progress of labor. Oxytocin, if required, was begun 2 hours
after rupture of fetal membranes via a low-­dose titration approach.
The intrapartum fetal heart rate pattern and uterine contractions were
interpreted in accordance with the American College of Obstetricians
and Gynecologists (ACOG) guidelines.8
The primary study outcome was the rate of cervical dilatation; sec-
ondary outcomes included the duration of the active first stage of labor
(from first injection until full cervical dilatation), mode of delivery, intra-
partum blood loss, postpartum hemorrhage (i.e. blood loss >500  mL,
after vaginal delivery), cervical laceration, duration of the second and
third stages of labor, meconium-­stained liquor, fetal distress (i.e. abnor-
mal fetal heart rate pattern), major maternal drug adverse effects (i.e.
dystonia, extrapyramidal manifestations, hallucination, visual distur-
bance, skin rash, hypersensitivity reaction, and cardiac dysrhythmia),
and pain score, measured via a visual analog scale (VAS), recorded
before and after the injected solution at 30, 60, and 120  minutes.
Neonatal outcomes included Apgar score at 1 and 5 minutes, neonatal
intensive care unit admission rate, and neonatal birth weight.
The study sample size was calculated based on the cervical dila-
tation rate; however, the study may be underpowered for the other
outcomes. A minimum sample size of 41 women in each group was
required to achieve 80% power and a level of significance of 0.05 to
detect an increase in cervical dilatation by 50% from 1.65  cm/h to
2.48 cm/h, with a standard deviation of 1.32 cm/h. As we anticipated
a cesarean delivery rate of about 10%, the sample size was increased
from 41 to 45 per group to correct for post-­randomization exclusions.
Calculation of sample size was performed by MedCalc software, ver-
sion 15.0 (MedCalc Software, Ostend, Belgium).
Statistical analysis was done via SPSS version 20 (IBM, Armonk, NY,
USA). Qualitative variables were compared between the two groups
by the χ2 test; quantitative variables were compared by an indepen-
dent sample t test for parametric data and by the Mann-­Whitney test
for non-­parametric data. A P value of less than 0.05 (with Bonferroni
correction) was considered statistically significant. A Kaplan-­Meier
survival analysis was used to detect the probabilities of faster delivery
with the use of metoclopramide and placebo. The two curves were
compared using a log-rank test.
3 | RESULTS
Among the 301 young nulliparous women who were screened for par-
ticipation in the study, 165 were excluded and 136 were eligible (12
declined to participate). Seven (10.6%) and six (10.3%) women deliv-
ered by cesarean during the first stage of labor in the metoclopra-
mide and in the placebo group, respectively. Thus, the final statistical
analysis included 59 participants in the metoclopramide group and 52
participants in the placebo group (Fig. 1).
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74       Ellaithy ET AL.

Enrollment Assessed for eligibility (n=301)

Nulliparous women admitted in
labor during the study period

Excluded (n=165)
 Contraindication to vaginal delivery (n=32)
 Induced labor (n=46)
 Cervical dilatation <5cm (n=22)
 Gestational age <37 wk (n=27)
 Twins (n=5)
 Others (n=33)

Eligible women (n=136)

Excluded (n=12)
 Declined to participate

Allocation
Received Metoclopramide (n= 66) Received Placebo (n= 58)

Analysis
Analyzed (n= 59) Analyzed (n= 52)
 Excluded from analysis (Cesarean delivery  Excluded from analysis (Cesarean delivery
before full cervical dilatation) (n= 7) before full cervical dilatation) (n= 6)

F I G U R E   1   Participants’ flowchart.

There were no differences between the randomized groups regard-
ing baseline data. The mean age of participants was 23.6 ± 4.5 years.
The mean height and weight were 154.3 ± 7.0 cm and 71.2 ± 14.8 kg
respectively, the mean gestational age was 38.7  ±  2.6  weeks, and
the two groups had comparable initial cervical findings and Bishop
scores (Table 1).
The median duration of the first stage of labor was signifi-
cantly shorter in the metoclopramide group (203 vs 230  minutes in
the placebo group, P=0.019), with a faster cervical dilatation rate
(2.4 ± 0.4 cm/h vs 1.9 ± 0.5 cm/h in the placebo group, P<0.001) and
a shorter interval from initial treatment administration to full cervical
dilatation. However, there were no significant differences between
metoclopramide and placebo with regards to the duration of the sec-
ond (P=0.075) stage of labor or in the cesarean delivery rate during
the second stage of labor (P=0.782). Similarly, the overall cesarean
delivery rate was not significantly different (14/66 [21.2%] and 14/58
[24.1%] for metoclopramide and placebo respectively, P=0.83).
There was no statistically significant difference in the peripartum
blood loss between the studied groups, and no cases of postpartum
hemorrhage. The median Apgar scores at 1 and 5  minutes were 8
(interquartile range [IQR], 8–9) and 9 (IQR, 9–9) respectively, with no
neonatal mortalities. There were no significant differences between
the 1-­and 5-­minute Apgar scores. Metoclopramide was well tolerated
by all participants and no major maternal or neonatal adverse effects
were noted in either group. No difference was found in birth weight.
Fetal distress rate, Apgar scores at 1 and 5 minutes, meconium-­stained
liquor rate, and rate of admission to the neonatal intensive care unit
did not differ significantly between the two groups (Table 2).
Ellaithy ET AL. |
      75

T A B L E   1   The studied baseline parameters.

Studied groups

Group 1 Group 2
Studied parameters Metoclopramide (n=59) Placebo (n=52) P value

Maternal age (y) 23.8 ± 4.2 23.5 ± 5.0 0.697

Weight (kg) 71.8 ± 15.9 70.7 ± 13.8 0.722
Height (cm) 153.6 ± 8.0 155.0 ± 5.6 0.280
2
BMI (kg/m ) 29.9 ± 8.9 28.9 ± 4.8 0.486
Gestational age (wk) 38.4 ± 3.4 39.1 ± 1.3 0.183
Baseline cervical dilatation (cm) 5 (5–6) 5 (5–6) 0.690
Baseline Bishop score 8 (7–11) 8 (7–13) 0.083
Initial labor pain score (VAS) 4 (2–6) 4 (2–6) 0.077
Oxytocin augmentation, no. (%) 11 (18.6%) 16 (30.8) 0.184

Abbreviations: BMI, body mass index (calculated as weight in kilograms divided by the square of height in meters); no., number; VAS, visual analog scale.
Data are presented as median (interquartile range), number (%) or mean ± standard deviation as appropriate.

Figure  2 shows the Kaplan-­Meier survival analysis; a significant 4 | DISCUSSION

difference was observed in the probability of faster delivery among
women who were treated with metoclopramide compared with those The present study showed that intrapartum administration of meto-
who were treated with placebo (log-rank test, χ2=5.997, P=0.014). clopramide reduced the duration of the first stage of labor and

T A B L E   2   The studied clinical outcomes.

Studied groups

Group 1 Group 2
Studied parameters Metoclopramide (n=59) Placebo (n=52) P value

Labor pain score (VAS) after 30 min 6 (4–6) 6 (4–6) 0.093

Labor pain score (VAS) after 60 min 6 (6–6) 6 (6–6) 0.842
Labor pain score (VAS) after 120 min 6 (6–6) 6 (6–6) 0.559
Cervical dilatation rate (cm/h) 2.4 ± 0.7 1.9 ± 0.5 0.000a
First stage duration (minutes) 203 (150–265) 230 (200–300) 0.019a
Second stage duration (minutes) 27 (15–43) 20 (16–30) 0.075
Third stage duration (minutes) 5 (5–7) 5 (5–6) 0.027b
Normal vaginal delivery rate, no. (%) 51 (86.4%) 41 (78.8%) 0.423
Instrumental delivery rate, no. (%) 1 (1.7%) 3 (5.8%)
Second stage cesarean delivery rate, no. (%) 7 (11.9%) 8 (15.4%)
Blood loss (mL) 152 (150–200) 150 (132–200) 0.058
Cervical lacerations, no. (%) 2 (3.4%) 6 (11.5%) 0.144
Fetal distress, no. (%) 14 (23.7%) 16 (30.8%) 0.521
Apgar score at 1 min 8 (8–9) 8 (8–8) 0.287
Apgar score at 5 min 9 (9–9) 9 (9–9) 0.391
Meconium-­stained liquor, no. (%) 20 (33.9%) 17 (32.7%) 1.000
NICU admission, no. (%) 4 (6.8%) 8 (15.4%) 0.221
Neonatal birth weight (gram) 2955.5 ± 424.2 2892.6 ± 465.2 0.458

Abbreviations: NICU, neonatal intensive care unit; no., number; VAS, visual analog scale.
Data are presented as median (interquartile range), number (%) or mean ± standard deviation as appropriate.
a
Indicates statistical significance.
b
Statistically significant but clinically insignificant.
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76       Ellaithy ET AL.
F I G U R E   2   Kaplan-­Meier survival analysis.
increased the probability of faster delivery by enhancing cervical dila-
tation, without significant maternal or neonatal morbidity.
The precise mechanism by which metoclopramide could speed up
cervical dilatation is unclear. The onset of action of metoclopramide
occurs 1–3  minutes after intravenous administration and its phar-
macologic effect persists for 1–2  hours.9 Metoclopramide binds to
dopamine D2 receptors with nanomolar affinity (Ki 28.8  nM), acting
as a receptor antagonist, and it is also a mixed 5-­HT3 receptor antago-
nist/5-­HT4 receptor agonist. Cervical smooth muscle cells, which com-
prise 10%–15% of cervical tissue, may have a role in parturition but
this has not been thoroughly investigated. However, metoclopramide
could potentially decrease spasms of the smooth muscle of the cer-
vix that remains richly innervated at birth and thus have a regulatory
effect on cervical contractility an interaction that might be important
in aiding maximal tissue compliance, promoting cervical dilatation
during labor, and helping to reduce dystocia. Dopamine and other
­catecholamines have been identified in rabbit, rat, guinea-­pig, sheep,
10
and human uteri.
Only two previous in-­vitro studies have reported a relaxant effect
of metoclopramide on myometrial stripes excised from the lower
uterine segment during cesarean delivery.11,12 Lechner et al. studied
the change in activity of a pregnant uterus after applying metoclopr-
amide in clinically relevant doses. They observed a highly significant
reduction in myometrial activity and demonstrated that metoclopra-
mide exerts a relaxant effect on the uterus, in contrast to its tonifying
effect on stomach and ureter.11 Tang et al. investigated metoclopra-
mide's relaxant properties on pregnant uterus and studied the possible
reversing effects of oxytocin and cabergoline, a D2 receptor agonist.
Metoclopramide inhibited myometrial muscle contractions by pro-
longing contractile intervals and suppressing the contractile force in a
concentration-­dependent manner. Oxytocin had no significant impact
on the suppressive effect of metoclopramide on contractile force, but
cabergoline completely reversed the relaxant effects of metoclopr-
amide, leading the authors to suggest that the relaxant mechanism
of metoclopramide is probably mediated via blockade of dopamine
D2 receptors.12
The potential side effects of using intrapartum metoclopramide
should be acknowledged. Generally, metoclopramide is a safe medi-
cation; the major side effects are rare. In the present study, no major
adverse events were reported, a finding supported by a previous
study that ruled out any evidence of major fetal or maternal adverse
effects.13 A large cohort study also found no evidence that metoclopr-
amide increases the risk of congenital malformations, low birth weight,
preterm birth, or perinatal mortality.14 Furthermore, a study by Howard
and Sharp on the effect of metoclopramide on gastric emptying during
labor found that metoclopramide had no detectable adverse effects on
the women, the fetuses, or the progress of labor.15 With the highest
breast milk concentration of metoclopramide, the relative infant dose
(RID) is 4.6%. As breastfeeding is generally acceptable if the RID is less
than 10%,16 there is no need to abstain from breastfeeding immedi-
ately after delivery.
A Cochrane review reported that intrapartum antispasmodics sig-
nificantly accelerate the first stage of labor by increasing the ­cervical
dilatation rate without compromising the durations of the second
and third stages of labor or the rate of normal vertex deliveries.17
The current study demonstrated that metoclopramide significantly
reduced the duration of the first stage of labor and increased the
cervical dilatation rate. However, there was no statistical difference
in the duration of the second stage of labor in metoclopramide-­and
placebo-­treated women, implying that metoclopramide primar-
ily acts on the cervix rather than promoting uterine activity. This
obviates any concern regarding an excessively rapid second stage,
which can result in both maternal and neonatal complications. Of
equal importance, the average blood loss at delivery was identical in
both groups, suggesting that metoclopramide has no adverse effect
on the contractile ability of the uterus in the postpartum period.
Metoclopramide needs to reach a plasma level of 100–300 mcg/mL
to produce sufficient uterine relaxation to interfere with the prog-
ress of labor.11,12 Intravenous injection of 10  mg metoclopramide
produces plasma levels of 11–152  ng/mL,18 which are unlikely to
have a negative impact on the intrapartum and postpartum uterine
activities. The difference in average Apgar scores for the neonates
in the two groups was not statistically significant, suggesting that
there were no clinically significant effects of metoclopramide on any
of the major organ systems of the neonates.
There are several potential benefits of using metoclopramide
during the first stage of labor. First is the acceleration of cervical dila-
tation and reduced first stage duration, resulting in reduced duration
of pain, and reduced incidence of chorioamnionitis, neonatal sepsis,
and puerperal sepsis. In addition, the need for repeat doses of opioid
analgesia, which is associated with neonatal respiratory depression, may
be reduced. Second is the potential analgesic effect19; metoclopramide
significantly reduced the total patient-­controlled analgesia require-
ments during induced labor.20 Metoclopramide enhances the analgesic
Ellaithy ET AL.
effect of meperidine, an effect that has been explained by an action of
metoclopramide on smooth muscle. In addition, Kandler and Lisander
suggest a direct analgesic effect of metoclopramide.21 Third is the anti-
emetic effect.22 [Last,] metoclopramide-­induced hyperprolactinemia
could potentially enhance the onset of breastfeeding, although this is
questionable.23 Because unnecessary frequent vaginal examinations
are not convenient to the patient and increase the risks of ascending
infection, 1–2 hours intervals for repeat vaginal examination were cho-
sen in accordance with the standard hospital intrapartum management
protocol. This might raise concerns about the accuracy of estimating the
exact duration of the first stage of labor and render the clinical signifi-
cance of the result marginal. This inevitable limiting point was adjusted
for as follows: All studied women were enrolled at the active phase of
labor, with almost the same baseline cervical dilatation. No patient in
the latent phase of labor was enrolled in the study. In addition, when-
ever indicated, vaginal examination was repeated more frequently and
thus diagnosis of onset of the second stage of labor was unlikely to be
much delayed. Finally, the present study was a double-­blind RCT and
thus all women were treated using a standard intrapartum protocol with
no selection bias. Metoclopramide significantly reduced the duration of
the first stage of labor by approximately half hour, but it is questionable
whether this has any clinical relevance.
Only one study, conducted in Egypt, reported the beneficial role
of drotaverine, hyoscine-­N-­butylbromide, and metoclopramide on
shortening the duration of the first stage of labor.24 To the best of our
knowledge, the present study is the largest prospectively registered,
adequately powered double-­blind RCT to investigate the potential
role of metoclopramide in shortening the first stage of labor other
merits include the use of a standard labor management protocol and
a good participation rate (111/301 [36.9%]). Last but not least, the
present study was limited to primigravid women with the exclusion of
multigravidas, who are expected to have shorter labor. In 2014, the
World Health Organization (WHO) published a weak recommendation
based on very low-­quality evidence against giving antispasmodics to
reduce the duration of labor as they did not consider a 1-­hour reduc-
tion clinically significant especially with limited safety data. However,
on the other hand, the WHO guideline development group considered
studying the use of antispasmodics to treat labor delay a research pri-
ority.25 Larger RCTs are needed to evaluate the effect of metoclopr-
amide on prolonged labor and to evaluate this effect in a context of
expectant management of labor.
In conclusion, the present study shows that metoclopramide sig-
nificantly reduced the duration of the first stage of labor and was not
associated with any apparent major maternal or fetal adverse out-
comes. Further long-­term evaluation is required to assess the potential
benefits that this reduction may confer.
AUT HOR CONTRI BUTI O N S
ME: Idea conception, study design, manuscript writing, data collec-
tion. SR: Idea conception, protocol development, follow up of cases.
AS: Idea conception, data analysis, study design, manuscript editing.
SA: Idea conception, project development, data management. All the
|
      77
authors: Revised the manuscript for the important intellectual ­content;
approved the final version of the manuscript; and are in agreement
with all aspects of the work.
AC KNOW L ED G M ENTS
The study was funded by the authors.
CO NFL I C TS O F I NT ER ES T
The authors have no conflicts of interest.
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