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The Journal of Maternal-Fetal & Neonatal Medicine

ISSN: 1476-7058 (Print) 1476-4954 (Online) Journal homepage: https://www.tandfonline.com/loi/ijmf20

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

To link to this article: https://doi.org/10.1080/14767058.2019.1570117

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


for enhancing neonatal respiratory maturation [1,4,5].
Preterm delivery is defined when a neonate is born
before the completion of 37 weeks of pregnancy [1,2]. Corticosteroid therapy is effective in reducing the inci-
It is an important issue in obstetrics; is the most com- dence of respiratory distress syndrome and neonatal
mon cause of neonatal mortality and morbidity and mortality and morbidity and requires delaying delivery
accounts for two-thirds of infant deaths. The incidence for a duration of at least 24 h after initiation of cortico-
of severe morbidity in newborns decreases for each steroid therapy [6]. So far, numerous studies have
week of increase in gestational age, therefore, inhibit- been performed on the medications used as tocolytics
ing preterm labor may reduce infants’ morbidity and for inhibiting preterm contractions in order to find the
mortality [1,3]. best option for tocolysis. These agents include calcium
Considering the advances in the care of premature channel blocking agents, oxytocin antagonists, prosta-
infants, the most important goal of the pharmaco- glandin inhibitors, beta-adrenergic receptor agonists,
logical treatment of preterm labor is to delay delivery 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 frequency of at least four forceful uterine contractions
on their efficacies and adverse effects. Combination per 20 min or a minimum cervical dilatation of 1 cm
therapy for inhibiting preterm labor may be an option and minimum cervical effacement of 50%. The women
for the prevention of preterm delivery and deserves to with rupture of membranes, intrauterine fetal death,
be studied further in order to have its advantages and cervical dilatation of more than 5 cm, multiple preg-
disadvantages discussed [10]. In the present study, a nancies, polyhydramnios, preeclampsia and eclampsia,
calcium channel blocker (nifedipine) and one prosta- vaginal bleeding more than bloody show, any mater-
glandin inhibitor (indomethacin) were compared as a nal and fetal condition that contradicted postponing
single and combined therapy. Indomethacin is a non- preterm delivery, severe fetal anomalies contradicting
steroidal anti-inflammatory drug (NSAID) that can be fetal life, fetal distress, those who were receiving other
prescribed either orally or rectally and is a prostaglan- tocolytics and those who had received tocolytic within
din inhibitor [3,12]. Since prostaglandins are the major previous 24 h were excluded.
contributors for the beginning of labor contractions, The study was approved by the Ethics Committee
of Iran University of Medical Sciences, Tehran, Iran and
this drug has been used as a tocolytic. Nifedipine is a
was then registered in Iranian Registry of Clinical Trials
calcium channel blocking agent that inhibits uterine
(IRCT) and received a clinical trial code number;
contractions by preventing the entry of calcium
IRCT20091023002624N26. An informed consent was
through the cell membrane channels and is one of
obtained from all participants after considering the
the best options for this purpose [13]. Both medica-
inclusion and exclusion criteria.
tions may have some maternal adverse effects includ-
The eligible women were then randomly assigned
ing hypotension, tachycardia, headache, asthenia,
into three groups (the first group received rectal indo-
syncope, diarrhea, muscle cramps, and heartburn
methacin with oral placebos; the second group
[14–16]. However, the severe maternal complications received oral nifedipine plus rectal placebo, and the
are rare and indometacin and nifedipine have been third group received rectal indomethacin plus oral
reported as the drugs not associated with serious nifedipine). Randomization was performed using ran-
maternal adverse drug reactions except for hypoten- dom numbers allocation software. To avoid informa-
sion and tachycardia caused by nifedipine [17]. Using tion bias, the study was conducted as a double-blind,
indomethacin has been proposed to increase the risk in which participants and investigators did not know
of intraventricular hemorrhage, necrotizing enterocoli- how the patients were allocated to the three groups.
tis, and periventricular leukomalacia in neonates, In the indomethacin group, 100 mg rectal indo-
although a meta-analysis reported no increased risk methacin was administered along with oral placebo. In
for serious neonatal complications [8,18]. Its prolonged the case of inhibiting contractions after 2 h, 25 mg of
use has been reported to be associated rarely with oral indomethacin was administered every 4 h plus
ductus arteriosus constriction and oligohydramnios placebo. The maximum daily dosage of indomethacin
[8,19]. To the best of our knowledge, no research has was 200 mg/day and the maximum duration of admin-
been performed on the treatment of preterm labor istration was 48 h. Oral placebo was repeated after
with a combination of nifedipine and indomethacin 90 min of the first dosage and was then prescribed
[10]. In the present study, these two medications were every 4 h (similar to the nifedipine group).
used as monotherapy and combination therapy for In the nifedipine group; 20 mg oral nifedipine was
inhibiting preterm uterine contractions. 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-
Materials and methods ued every 4 h for 48 h, with a maximum dose of
This study was performed as a randomized clinical trial 180 mg per day. Placebo was given similarly to the
on pregnant women who have been referred to indomethacin group.
Akbarabadi Teaching Hospital in Tehran, Iran between In the combination group; a combination of rectal
May 2016 to March 2018 with signs and symptoms of indomethacin and oral nifedipine was administered
preterm labor. per protocol as mentioned above.
The inclusion criteria included gestational age Before entering the study, 500 ml of normal saline
between 26 and 34 weeks (according to reliable LMP was administered for all women and blood pressure
and ultrasound confirmation of the first trimester of was measured. After beginning the interventions,
pregnancy), singleton, and uterine contractions with a blood pressure was monitored every 15 min for 1 h
THE JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE 3

and then every 4 h. If the blood pressure was lower neonatal weight (p ¼ .020) were significantly higher in
than 90/50 mmHg, nifedipine was discontinued and the combination group (Table 2). Two women in the
the patient was administered a further 500 ml normal nifedipine group and one woman in the combined
saline and was then excluded from the study. group had bothersome hypotension and were
Uterine contractions were monitored for the first excluded from the study. There were no severe gastro-
2 h after administration of the tocolytics. If the con- intestinal adverse effects in three groups except for
tractions were the same as those before the drug two women who had epigastric pain in the indometa-
administration, it was considered as a failure of treat- cin group.
ment and another tocolytic was started.
The primary outcome was inhibiting uterine con-
Discussion
tractions for 48 h and the number of preterm deliv-
eries before 37 weeks of gestation. The efficacy of the The present study was performed as a randomized
treatment for inhibiting the contractions in the first placebo-controlled clinical trial and the results showed
2 h after the intervention was also evaluated. In add- that the combination therapy with nifedipine and
ition, other variables including delivery within 7 days indomethacin was more effective than monotherapy
after interventions, gestational age at the time of with either of these drugs, for inhibiting uterine con-
birth, duration of prolongation of pregnancy, birth tractions and delaying delivery for 2 h, 48 h, and 7 days
weight, Apgar score minutes 1 and 5, and neonatal in patients at risk of preterm delivery. In addition, the
NICU admission were compared between the three mean gestational age at the end of pregnancy was
groups. Drug adverse effects (mostly included hypo- higher in the combination therapy group. The adverse
tension and gastrointestinal symptoms) were recorded effects were minimal.
every 6 h. A systematic review by Vogel et al. [10] on nine
A sample size of 150 women (50 people per group) trials showed inconclusive results on combination
was considered enough using type one error of 0.05 therapy. However, all studies in this systematic review
and the study power of 80%. Statistical analysis was were about beta mimetics or magnesium sulfate in
performed using SPSS 18 (IBM Corp, New York, NY). combination with indomethacin, vaginal progesterone,
Chi-square test and analysis of variance (ANOVA test) hexoprenaline sulfate, metoprolol, and pentoxifylline
were used to compare Data. p Values of lower than and one study was on fenoterol plus oral naproxen.
.05 was considered significant. 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
Results
knowledge, the present study is the first study on
One hundred seventy-two women were assessed for combination therapy with these two common toco-
eligibility and 152 were eligible for the study. The eli- lytic agents. A study on myometrial samples which
gible women were then randomly assigned into three was obtained during a cesarean section from preterm
groups. Two women in the nifedipine group and one and term deliveries showed additive tocolytic activity
woman in the combined group were excluded from on myometrial muscle contractility in combination
the study because of hypotension (Figure 1). therapy with atosiban plus nifedipine [20]. A similar
Comparison of maternal baseline data showed no study [21] was performed using combination therapy
significant difference between the three groups with different popular tocolytics including nifedipine,
(Table 1). The women in all three groups did not have ritodrine, nitroglycerin, and atosiban, on myometrial
significant difference regarding their age, BMI, gravid- strips obtained during cesarean sections. Combination
ity, parity, Bishop score, number of contractions, and therapy with nifedipine plus ritodrine produced more
gestational age upon entering the study (Table 1). inhibition of contractility than any of the mentioned
Thirty-six women (72%) in the indomethacin group, drugs alone. The combination of nifedipine plus nitro-
36 women (72%) in the nifedipine group, and 41 glycerin or nifedipine plus atosiban also showed more
women (89.4%) in the combination group had efficacy than nitroglycerin or atosiban alone. The
stopped contractions within the first 2 h of interven- authors concluded that some combinations of toco-
tion (p values =.002). Inhibiting contractions for 48 h lytics, but not all of them, produced a significantly
(p ¼ .003), inhibiting contractions for 7 days (p ¼ .021), greater inhibitory effect on contractility than each
gestational age at birth (p ¼ .001), number of pregnan- drug alone. These additive effects depend on the
cies lasting more than 37 weeks (p ¼ .007) and 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 response to the first tocolytic agent [24]. There are
on myometrial samples showed similar results [22,23]. very few studies on combination therapy with simul-
These studies were in vitro and were performed on taneous administration of two tocolytic drugs. It is
myometrial samples but not in clinical practice. One suggested that further studies with a combination of
study used tocolytics in combination, not simultan- different tocolytics and especially more popular agents
eously, but following each other, in case there was no 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.

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of indomethacin and nifedipine was more effective for preterm labor. Obstet Gynecol. 2007;110:61–67.
[7] Papatsonis DN, Flenady V, Liley HG. Maintenance
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Disclosure statement Compare the efficacy of indomethacin and magne-
sium sulphate in prevention of preterm labor. Int J
All authors have no conflict of interest. Curr Res Acad Rev. 2014;2(8).
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