The Journal of Maternal-Fetal & Neonatal Medicine

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A comparative study on the efficacy of nifedipine

and indomethacin for prevention of preterm birth
as monotherapy and combination therapy: a
randomized clinical trial

Maryam Kashanian, Shaghayegh Shirvani, Narges Sheikhansari & Forough

Javanmanesh

To cite this article: Maryam Kashanian, Shaghayegh Shirvani, Narges Sheikhansari & Forough
Javanmanesh (2019): A comparative study on the efficacy of nifedipine and indomethacin for
prevention of preterm birth as monotherapy and combination therapy: a randomized clinical trial,
The Journal of Maternal-Fetal & Neonatal Medicine, DOI: 10.1080/14767058.2019.1570117

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Published online: 29 Jan 2019.

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THE JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE
https://doi.org/10.1080/14767058.2019.1570117

ORIGINAL ARTICLE

A comparative study on the efficacy of nifedipine and indomethacin for

prevention of preterm birth as monotherapy and combination therapy: a
randomized clinical trial
Maryam Kashaniana, Shaghayegh Shirvania, Narges Sheikhansarib and Forough Javanmanesha
a
Department of Obstetrics and Gynecology, Iran University of Medical Sciences, Tehran, Iran; bFaculty of Medicine, University of
Exeter, Exeter, United Kingdom

ABSTRACT ARTICLE HISTORY

Introduction: Preterm delivery is an important issue in obstetrics, which is the most common Received 8 October 2018
cause of neonatal mortality and morbidity. Therefore, finding a way to prevent it is always under Revised 4 January 2019
serious concern. Accepted 11 January 2019
Objective: The study aimed to compare the efficacy of two tocolytic agents, nifedipine and
KEYWORDS
indomethacin, for inhibiting preterm uterine contractions as monotherapy and combin- Indomethacin; nifedipine;
ation therapy. pregnancy; preterm
Materials and methods: A double-blind randomized clinical trial was performed on pregnant delivery; preterm labor
women with gestational age of 26–34 weeks of pregnancy who referred to hospital for preterm
labor. They were randomly assigned to three groups. Indomethacin plus placebo, nifedipine
plus placebo, and a combination of indomethacin and nifedipine were administered to the three
groups. Inhibiting contractions for 2 hours and prevention of delivery for 48 hours and 7 days
were evaluated. Also, duration of pregnancy, the number of preterm births, and the interval
between entering the study and delivery were compared between three groups.
Results: One hundred fifty women were eligible for the study. Two women in the nifedipine
group and one woman in the combined group were excluded from the study because of hypo-
tension. The women of the three groups did not have significant difference according to age,
BMI, gravidity, parity, Bishop score, gestational age, and the number of contractions at entering
the study. Thirty-six women (72%) in the indomethacin group, 36 women (72%) in the nifedi-
pine group, and 41 women (89.4%) in the combination group had stopped contractions within
the first 2 hours of intervention (p ¼ .002). Inhibiting contractions for 48 hours (p ¼ .003), inhibit-
ing contractions for 7 days (p ¼ .021), gestational age at birth (p ¼ .001), number of pregnancies
more than 37 weeks (p ¼ .007), and neonatal weight (p ¼ .020) were significantly more in the
combination group.
Conclusion: Combination therapy with nifedipine and indomethacin was more effective than
monotherapy with either of these two medications for inhibiting preterm labor, delaying deliv-
ery, and prolongation of the duration of pregnancy.

Introduction for at least 48 h in order to administer corticosteroids

Preterm delivery is defined when a neonate is born
before the completion of 37 weeks of pregnancy [1,2].
It is an important issue in obstetrics; is the most com-
mon cause of neonatal mortality and morbidity and
accounts for two-thirds of infant deaths. The incidence
of severe morbidity in newborns decreases for each
week of increase in gestational age, therefore, inhibit-
ing preterm labor may reduce infants’ morbidity and
mortality [1,3].
Considering the advances in the care of premature
infants, the most important goal of the pharmaco-
logical treatment of preterm labor is to delay delivery
for enhancing neonatal respiratory maturation [1,4,5].
Corticosteroid therapy is effective in reducing the inci-
dence of respiratory distress syndrome and neonatal
mortality and morbidity and requires delaying delivery
for a duration of at least 24 h after initiation of cortico-
steroid therapy [6]. So far, numerous studies have
been performed on the medications used as tocolytics
for inhibiting preterm contractions in order to find the
best option for tocolysis. These agents include calcium
channel blocking agents, oxytocin antagonists, prosta-
glandin inhibitors, beta-adrenergic receptor agonists,
magnesium sulfate, and nitric oxide containing

CONTACT Maryam Kashanian maryamkashanian@yahoo.com Department of Obstetrics and Gynecology, Iran University of Medical Sciences, No 9,
Mostaghimi Alley, Khajeh Nasir Toosi Avenue, Tehran, Iran
ß 2019 Informa UK Limited, trading as Taylor & Francis Group
2 M. KASHANIAN ET AL.
drugs [7–11]. However, there are some controversies
on their efficacies and adverse effects. Combination
therapy for inhibiting preterm labor may be an option
for the prevention of preterm delivery and deserves to
be studied further in order to have its advantages and
disadvantages discussed [10]. In the present study, a
calcium channel blocker (nifedipine) and one prosta-
glandin inhibitor (indomethacin) were compared as a
single and combined therapy. Indomethacin is a non-
steroidal anti-inflammatory drug (NSAID) that can be
prescribed either orally or rectally and is a prostaglan-
din inhibitor [3,12]. Since prostaglandins are the major
contributors for the beginning of labor contractions,
this drug has been used as a tocolytic. Nifedipine is a
calcium channel blocking agent that inhibits uterine
contractions by preventing the entry of calcium
through the cell membrane channels and is one of
the best options for this purpose [13]. Both medica-
tions may have some maternal adverse effects includ-
ing hypotension, tachycardia, headache, asthenia,
syncope, diarrhea, muscle cramps, and heartburn
[14–16]. However, the severe maternal complications
are rare and indometacin and nifedipine have been
reported as the drugs not associated with serious
maternal adverse drug reactions except for hypoten-
sion and tachycardia caused by nifedipine [17]. Using
indomethacin has been proposed to increase the risk
of intraventricular hemorrhage, necrotizing enterocoli-
tis, and periventricular leukomalacia in neonates,
although a meta-analysis reported no increased risk
for serious neonatal complications [8,18]. Its prolonged
use has been reported to be associated rarely with
ductus arteriosus constriction and oligohydramnios
[8,19]. To the best of our knowledge, no research has
been performed on the treatment of preterm labor
with a combination of nifedipine and indomethacin
[10]. In the present study, these two medications were
used as monotherapy and combination therapy for
inhibiting preterm uterine contractions.
Materials and methods
This study was performed as a randomized clinical trial
on pregnant women who have been referred to
Akbarabadi Teaching Hospital in Tehran, Iran between
May 2016 to March 2018 with signs and symptoms of
preterm labor.
The inclusion criteria included gestational age
between 26 and 34 weeks (according to reliable LMP
and ultrasound confirmation of the first trimester of
pregnancy), singleton, and uterine contractions with a
frequency of at least four forceful uterine contractions
per 20 min or a minimum cervical dilatation of 1 cm
and minimum cervical effacement of 50%. The women
with rupture of membranes, intrauterine fetal death,
cervical dilatation of more than 5 cm, multiple preg-
nancies, polyhydramnios, preeclampsia and eclampsia,
vaginal bleeding more than bloody show, any mater-
nal and fetal condition that contradicted postponing
preterm delivery, severe fetal anomalies contradicting
fetal life, fetal distress, those who were receiving other
tocolytics and those who had received tocolytic within
previous 24 h were excluded.
The study was approved by the Ethics Committee
of Iran University of Medical Sciences, Tehran, Iran and
was then registered in Iranian Registry of Clinical Trials
(IRCT) and received a clinical trial code number;
IRCT20091023002624N26. An informed consent was
obtained from all participants after considering the
inclusion and exclusion criteria.
The eligible women were then randomly assigned
into three groups (the first group received rectal indo-
methacin with oral placebos; the second group
received oral nifedipine plus rectal placebo, and the
third group received rectal indomethacin plus oral
nifedipine). Randomization was performed using ran-
dom numbers allocation software. To avoid informa-
tion bias, the study was conducted as a double-blind,
in which participants and investigators did not know
how the patients were allocated to the three groups.
In the indomethacin group, 100 mg rectal indo-
methacin was administered along with oral placebo. In
the case of inhibiting contractions after 2 h, 25 mg of
oral indomethacin was administered every 4 h plus
placebo. The maximum daily dosage of indomethacin
was 200 mg/day and the maximum duration of admin-
istration was 48 h. Oral placebo was repeated after
90 min of the first dosage and was then prescribed
every 4 h (similar to the nifedipine group).
In the nifedipine group; 20 mg oral nifedipine was
administered along with a rectal placebo and was
repeated again after 90 min. In case of inhibiting con-
tractions for 2 h, 20 mg of oral nifedipine was contin-
ued every 4 h for 48 h, with a maximum dose of
180 mg per day. Placebo was given similarly to the
indomethacin group.
In the combination group; a combination of rectal
indomethacin and oral nifedipine was administered
per protocol as mentioned above.
Before entering the study, 500 ml of normal saline
was administered for all women and blood pressure
was measured. After beginning the interventions,
blood pressure was monitored every 15 min for 1 h

and then every 4 h. If the blood pressure was lower
than 90/50 mmHg, nifedipine was discontinued and
the patient was administered a further 500 ml normal
saline and was then excluded from the study.
Uterine contractions were monitored for the first
2 h after administration of the tocolytics. If the con-
tractions were the same as those before the drug
administration, it was considered as a failure of treat-
ment and another tocolytic was started.
The primary outcome was inhibiting uterine con-
tractions for 48 h and the number of preterm deliv-
eries before 37 weeks of gestation. The efficacy of the
treatment for inhibiting the contractions in the first
2 h after the intervention was also evaluated. In add-
ition, other variables including delivery within 7 days
after interventions, gestational age at the time of
birth, duration of prolongation of pregnancy, birth
weight, Apgar score minutes 1 and 5, and neonatal
NICU admission were compared between the three
groups. Drug adverse effects (mostly included hypo-
tension and gastrointestinal symptoms) were recorded
every 6 h.
A sample size of 150 women (50 people per group)
was considered enough using type one error of 0.05
and the study power of 80%. Statistical analysis was
performed using SPSS 18 (IBM Corp, New York, NY).
Chi-square test and analysis of variance (ANOVA test)
were used to compare Data. p Values of lower than
.05 was considered significant.
Results
One hundred seventy-two women were assessed for
eligibility and 152 were eligible for the study. The eli-
gible women were then randomly assigned into three
groups. Two women in the nifedipine group and one
woman in the combined group were excluded from
the study because of hypotension (Figure 1).
Comparison of maternal baseline data showed no
significant difference between the three groups
(Table 1). The women in all three groups did not have
significant difference regarding their age, BMI, gravid-
ity, parity, Bishop score, number of contractions, and
gestational age upon entering the study (Table 1).
Thirty-six women (72%) in the indomethacin group,
36 women (72%) in the nifedipine group, and 41
women (89.4%) in the combination group had
stopped contractions within the first 2 h of interven-
tion (p values =.002). Inhibiting contractions for 48 h
(p ¼ .003), inhibiting contractions for 7 days (p ¼ .021),
gestational age at birth (p ¼ .001), number of pregnan-
cies lasting more than 37 weeks (p ¼ .007) and
THE JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE 3
neonatal weight (p ¼ .020) were significantly higher in
the combination group (Table 2). Two women in the
nifedipine group and one woman in the combined
group had bothersome hypotension and were
excluded from the study. There were no severe gastro-
intestinal adverse effects in three groups except for
two women who had epigastric pain in the indometa-
cin group.
Discussion
The present study was performed as a randomized
placebo-controlled clinical trial and the results showed
that the combination therapy with nifedipine and
indomethacin was more effective than monotherapy
with either of these drugs, for inhibiting uterine con-
tractions and delaying delivery for 2 h, 48 h, and 7 days
in patients at risk of preterm delivery. In addition, the
mean gestational age at the end of pregnancy was
higher in the combination therapy group. The adverse
effects were minimal.
A systematic review by Vogel et al. [10] on nine
trials showed inconclusive results on combination
therapy. However, all studies in this systematic review
were about beta mimetics or magnesium sulfate in
combination with indomethacin, vaginal progesterone,
hexoprenaline sulfate, metoprolol, and pentoxifylline
and one study was on fenoterol plus oral naproxen.
No study was found on popular and more widely used
tocolytic agents, such as calcium channel blockers
(nifedipine) and indomethacin. To the best of our
knowledge, the present study is the first study on
combination therapy with these two common toco-
lytic agents. A study on myometrial samples which
was obtained during a cesarean section from preterm
and term deliveries showed additive tocolytic activity
on myometrial muscle contractility in combination
therapy with atosiban plus nifedipine [20]. A similar
study [21] was performed using combination therapy
with different popular tocolytics including nifedipine,
ritodrine, nitroglycerin, and atosiban, on myometrial
strips obtained during cesarean sections. Combination
therapy with nifedipine plus ritodrine produced more
inhibition of contractility than any of the mentioned
drugs alone. The combination of nifedipine plus nitro-
glycerin or nifedipine plus atosiban also showed more
efficacy than nitroglycerin or atosiban alone. The
authors concluded that some combinations of toco-
lytics, but not all of them, produced a significantly
greater inhibitory effect on contractility than each
drug alone. These additive effects depend on the
mechanism of action of the two tocolytics used for
4 M. KASHANIAN ET AL.

Assessed for eligibility (n= 172)

Excluded (n= 20)

Not meeting inclusion criteria
(n=16)
Enrollment Refused to participate
(n=4)
Other reasons (n= 0)

Allocaon

Allocated to intervention Allocated to intervention

(Indomethacin group Allocated to intervention combination group
(n= 50) Nifedipine group (n= 50)
Received allocated intervention (n= 52) Received allocated intervention
(n= 50) Received allocated (n= 50)
Did not receive allocated intervention intervention Did not receive allocated intervention
(n= 0) (n= 50) (n= 0)
Did not receive allocated
intervention
(n= 2)

Excluded for Excluded for Excluded for

Hypotension: 0 Hypotension: 2 Hypotension: 1
Non response to treatment: 14 Non response to treatment: Non response to treatment: 8
12

Analyzed (n=36)
Analyzed (n=36) Excluded from analysis (n=0) Analyzed (n=41)

Excluded from analysis (n=0) Excluded from analysis (n=0)

Figure 1. The consort E-flowchart.

Table 1. Baseline characteristics of the women of three groups.

Indomethacin Nifedipine Nifedipine and Indomethacin
Variables N ¼ 36 N ¼ 36 N ¼ 41 p value
Age (year) m ± sd 26.19 ± 6.29 27.11 ± 5.99 28.27 ± 6.55 .881
BMI m ± sd 26.76 ± 5.65 25.98 ± 4.68 25.88 ± 4.60 .654
Gravidity m ± sd 1.83 ± 0.94 2.44 ± 1.46 2.19 ± 1.36 .121
Parity m ± sd 0.52 ± 0.55 0.97 ± 1.10 0.78 ± 0.85 .055
Gestational age at recruitment (weeks) m ± sd 30.26 ± 2.39 30.96 ± 1.81 30.46 ± 2.42 .254
Bishop Score m ± sd 5.69 ± 1.23 5.55 ± 1.10 5.73 ± 1.30 .592
Dilatation (cm) m ± sd 1.40 ± 0.49 1.31 ± 0.45 1.29 ± 0.71 .726
Effacement (%) m ± sd 55.20 ± 8.01 51.00 ± 9.84 53.90 ± 8.03 .459
No of Contractions at recruitment m ± sd 3.17 ± 1.54 3.08 ± 0.99 3.14 ± 1.23 .485

tocolysis. The other studies on combination therapy
on myometrial samples showed similar results [22,23].
These studies were in vitro and were performed on
myometrial samples but not in clinical practice. One
study used tocolytics in combination, not simultan-
eously, but following each other, in case there was no
response to the first tocolytic agent [24]. There are
very few studies on combination therapy with simul-
taneous administration of two tocolytic drugs. It is
suggested that further studies with a combination of
different tocolytics and especially more popular agents
are performed, with the inclusion of larger sample
 THE JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE 5

Table 2. Outcomes in three groups.

Indomethacin Nifedipine Nifedipine and Indomethacin
Variables N ¼ 36 N ¼ 36 N ¼ 41 p value
Inhibiting contractions for 2 hours n (%) 36 (72.0%) 36 (72.0%) 41 (82.0%) .002
n ¼ 50
Inhibiting contractions for 48 hours n (%) 30 (83.3%) 31 (86.1%) 39 (95.1%) .003
Inhibiting contractions for 7 days n (%) 26 (72.2%) 28 (77.7%) 37 (90.2%) .021
Gestational age at birth (weeks) m ± sd 33.20 ± 3.69 33.87 ± 3.05 35.82 ± 4.03 .001
No of pregnancies more than 37 weeks n (%) 9 (25.0%) 9 (25.0%) 24 (58.5%) .007
Neonatal weight (gr) m ± sd 2349.64 ± 716.68 2578.33 ± 564.88 2890.00 ± 910.18 .020
Apgar score minute 1 m ± sd 7.00 ± 1.70 7.22 ± 1.74 7.93 ± 1.69 .615
Apgar score minute 5 m ± sd 8.56 ± 1.40 8.89 ± 1.41 9.29 ± 1.16 .169
NICU admission n (%) 15 (41.7%) 17 (47.2%) 15 (36.6%) .640
NICU Time m ± sd 0.40 ± 0.49 0.39 ± 0.49 0.98 ± 3.87 .271
Significant.

sizes and placebo-controlled studies. Performing such
studies will enable the researchers to find the best
drug combinations, adverse effects, and advantages
for neonates and mothers alike.
Since no study had compared the combination
therapy with indomethacin and nifedipine versus
monotherapy with either of these two drugs, the pre-
sent research could not be compared with other stud-
ies. The present study showed that the combination
of indomethacin and nifedipine was more effective for
inhibiting uterine contractions and delaying delivery
with minimal adverse effects compared to monother-
apy with either of these two drugs. However, more
studies should be performed in order to reach a
definitive conclusion.
Conclusion
The results of this study indicated that combination
therapy with both nifedipine and indomethacin was
more effective than monotherapy with either of these
two drugs for inhibiting preterm labor and delaying
delivery in patients at risk of preterm delivery with
a gestational age of 26–34 weeks and single-
ton pregnancy.
Disclosure statement
All authors have no conflict of interest.
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