Basic & Clinical Pharmacology & Toxicology

Doi: 10.1111/bcpt.12306

Nifedipine versus Terbutaline, Tocolytic Effectiveness and

Maternal and Neonatal Adverse Effects: A Randomized,
Controlled Pilot Trial
Tania Regina Padovani1,2, Gordon Guyatt3 and Luciane Cruz Lopes1
Pharmaceutical Sciences Post graduate Course, University of Sorocaba, UNISO, Sorocaba, Brazil, 2Pontificia Universidade Cat
olica S~ao Paulo,
S~ao Paulo, Brazil and 3Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, ON, Canada

(Received 5 April 2014; Accepted 5 August 2014)

Abstract: Although previous evidence suggests advantages of nifedipine over terbutaline as tocolytic agents, in some jurisdictions, terbutaline is approved for use and nifedipine is not. In women in preterm labour, we compared the impact of terbutaline
versus nifedipine on inhibition of uterine contractions, preterm birth, neonatal sepsis, intracranial haemorrhage or necrotizing
enterocolitis, death or admission to a neonatal intensive care unit and maternal adverse reactions. We randomized 32 women to
nifedipine and 34 to terbutaline. We found no difference between groups in tocolysis or preterm birth. No serious maternal
adverse effects or serious neonatal adverse outcome occurred in either group. Less serious maternal adverse effects less common
with terbutaline included flushing (2.94% versus 43.7%) and headache (5.9% versus 31.2%). The administration of terbutaline
increased tremor (76.4% versus 0%), nausea (58.8% versus 9.4%) and dizziness (29.4% versus 6.25%). The total number of side
effects, and the proportion of women experiencing one or more side effects, proved greater with terbutaline. In this study, terbutaline and nifedipine performed similarly in their tocolytic effects. Each drug has specific side effects, although overall, nifedipine
was associated with fewer adverse effects.

Premature birth is common (over 5% and, in some countries,

over 10%) [1,2] and is responsible for approximately 75% of
all neonatal deaths and 50% of childhood neurological morbidities [3,4]. Preterm infants often require intensive care that
is associated with emotional and economic costs to both the
family and society [5].
Approximately 75% of preterm birth is attributable to spontaneous preterm labour [1]. Delay in preterm labour therefore
provides a potential opportunity for decreasing neonatal morbidity and mortality [6].
The optimal medical management of threatened preterm
labour is controversial [7]. Despite theoretical benefits of
keeping the foetus in utero long enough to enable administration of a full course of corticosteroids to assist in foetal lung
maturation, and to organize transfer to an appropriate neonatal
care unit, no agent has been shown to improve neonatal outcome [2,7]. Thus, the choice of therapy has focused on delay
in delivery and minimization of adverse effects.
The drugs registered for tocolysis include the b adrenoceptor agonist ritodrine (United States and Europe), terbutaline
(Brazil) and the oxytocin receptor antagonist atosiban (Europe)
[8]. Calcium channel blockers (nifedipine) and cyclooxygenase
inhibitors (indomethacin) are also used for inhibiting preterm
labour although, in many countries, they are not currently registered for this indication [9].

Author for correspondence: Luciane Cruz Lopes, Pharmaceutical Sciences

Post graduate Course, University of Sorocaba, UNISO, Rodovia Raposo
Tavares, KM 92,5 Sorocaba, SP, Brasil CEP 18023-000, Brazil (e-mail
luslopes@terra.com.br).

Betamimetics (isoxsuprine, ritodrine, terbutaline, fenoterol

and salbutamol) delay labour [1012], but their use has been
limited by a high incidence of maternal adverse effects
[10,13,14]. Many centres use nifedipine, which also has established effectiveness in delaying labour [15] and has advantages of oral administration and relatively low cost. Several
randomized, controlled trials have compared the efficacy of
calcium channel blockers, usually nifedipine and betamimetics.
Although most trials had important methodological limitations,
and conclusions varied regarding effectiveness (most reporting
similar tocolysis [1620] and some suggesting the superiority
of nifedipine [21,22], all reported a better side effect profile
with nifedipine with fewer women requiring cessation of therapy due to adverse events [6,2124].
Despite this evidence, sponsors have not sought regulatory
approval for nifedipine as a tocolytic agent in many countries;
its use is therefore off-label. Furthermore, hesitations about its
use arise from reports of maternal hypotension [25] and
concerns about placental perfusion [26]. Finally, some have
suggested that as calcium channel blockers are not licensed
for tocolysis, under-reporting of adverse events may be occurring [8].
In the face of the current situation in which terbutaline
remains the most common tocolytic used in many low- and
middle-income and some high-income (e.g. Germany) countries and nifedipine is only being used off-label, we considered
that an additional randomized trial comparing the efficacy of
nifedipine with terbutaline on tocolytic and on maternal and
neonatal outcome could help to inform optimal management
of preterm labour.

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TANIA REGINA PADOVANI ET AL.

2
Methods

The protocol for this trial and a CONSORT checklist are available as
supporting information; see Data S1.
Ethics statement. This study was conducted in accordance with the
principles of the Declaration of Helsinki. The protocol and its
amendments received independent ethics committee or institutional
review board approval before site initiation and recruitment of
patients. The protocol was approved by the Ethics Committee at
University of Sorocaba (#2010-20), and the study protocol was
registered in Platforms Brazil.
Participants. Eligible participants were Brazilian women aged 18
40 years, with singleton pregnancies, presenting to the labour ward
with all of the following: at least four painful and regular uterine
contractions in each 20-min. interval, cervical dilatation of 03 cm
(for nulliparous) or 13 cm (for multiparae), cervical effacement of
50%, 2433+6 weeks of gestation and intact membranes who were
diagnosed as threatened preterm labour. Gestational age was
confirmed by either a documented first-trimester ultrasound scan or a
reliable menstrual date confirmed by ultrasonography performed
before 20 weeks of gestation [27].
Exclusion criteria were maternal comorbidity including bronchial
asthma, diabetes mellitus, cardiovascular diseases, severe anaemia,
pregnancy-induced hypertension (>140/90 mmHg) and hypotension
(<80/50 mmHg); complications at delivery (no reassuring foetal
heart rate tracing, severe pre-eclampsia, placental abruption, antepartum haemorrhage, fever above 38C); foetal complications (congenital anomaly, hydramnios and chorioamnionitis and intrauterine
growth retardation < fifth percentile); contra-indication to the use of
betamimetic or calcium blocker agents; previous treatment with
tocolytics in current pregnancy; and refusal to give informed
consent.
Study design. The trial was performed in three centres in Brazil
between August 2010 and March 2012. Consecutive patients meeting
eligibility criteria were randomized in a 1:1 ratio to oral nifedipine or
intravenous terbutaline. At each centre, a pharmacist investigator
created a computer-generated randomization schedule and, after
confirming eligibility for each participant, informed the attending
physician regarding allocation to terbutaline or nifedipine, thus
ensuring concealment of allocation (those enrolling patients were
unaware of the arm to which the patient would be allocated). The
doctors and nurses were not blind to allocation. Data were collected
by a physician in training, and outcome were adjudicated by one of
two physicians blind to group assignment.
Intervention. The participants received terbutaline or nifedipine as
follows:
1 Terbutaline (ampoule 0.5 mg/mL): intravenous infusion of 2.5 lg/
min. followed by an increase of 2.5 lg/min. every 15 min. to a
maximum of 20 lg/min. When the minimum dose capable of stopping contractions was established, this infusion was maintained for
24 hr. After 24 hr of drug administration, the dose was decreased
by 2.5 lg/min. every 15 min. until full discontinuation [28].
2 Nifedipine (tablet 20 mg) given orally. If contractions did not cease
after 30 min., a second dose was given. Once tocolysis was
achieved, nifedipine 20 mg orally was administered every 8 hr for
a period of 48 hr. The total dose administered during 48 hr was
120 mg.
Uterine contractions were monitored continuously by an external
tocodynamometer for 24 hr after initiation of the study drug followed
by two to three times a day for 3060 min.

Tocolytic drugs were discontinued in the face of progression to a

cervical dilatation of 4 cm or more or rupture of membranes, no
decrease in contractions after 12 hr, or if there was a suspicion of chorioamnionitis. Recurrence of preterm labour during the first 48 hr after
effective tocolysis was treated with the same agent as the initial tocolysis. Other tocolytic agents were not permitted concomitantly unless,
after at least 1 hr of observation during treatment, there was an
increase or no change in the frequency of the contractions, or an
increase in cervical dilatation of 1 cm or more.
All patients were monitored throughout the intervention for haemodynamic and metabolic changes. Continuous cardiotocography was used to
monitor foetal heart rate patterns. For both groups, monitoring of heart
rate, blood pressure and contractions were monitored every 15 min. for
the first hour, hourly for the next 24 hr, every 6 hr during the next 48 hr
and thereafter daily when uterine quiescence had been achieved.
Prophylactic antibiotics for group B streptococcus and corticosteroids were administered according to standard clinical indications.
Outcome measures. The effectiveness outcome of interest were failure
of tocolysis (continued uterine contractions 12 hr after drug initial
administration or cervical dilatation to >4 cm); delivery prior to 48 hr
from the initiation of contractions; delivery before 34 and 37 weeks
gestation; the interval between trial entry and delivery; and gestational
age at delivery using the capurro method [29].
The outcome of interest related to adverse events were severe
maternal adverse drug reactions, maternal less serious adverse events
and discontinuation of treatment because of adverse events.
The neonatal outcome of interest were perinatal death or admission to
neonatal intensive care unit, birth weight, Apgar score at 1 and 5 min.,
respiratory distress syndrome, need for oxygen, intubation, intraventricular or intracranial haemorrhage, necrotizing enterocolitis, retinopathy
of prematurity, neonatal jaundice, neonatal sepsis, foetal death, neonatal
death, length of stay in the neonatal intensive care unit blood pressure
(hypertension 90/140 mmHg or hypotension 50/80 mmHg) and foetal tachycardia or bradycardia.
Outcome ascertainment was complete, and no patients were lost to
follow-up.
Statistical analysis. We present patient characteristics using the
arithmetic mean, standard deviation, median, minimum and maximum
values, and frequencies as appropriate. The analyses were intention-totreat. For conducting parametric tests of outcome, we confirmed data
normality and homogeneity of variances, using histograms and the
Levene test, respectively. We used the Students t-test for independent
samples when these assumptions were met, and otherwise used the
MannWhitney U-test. We calculated risk ratios (RR) and associated
95% confidence intervals (95% CI). The criterion for statistical
significance in all analyses was <5%. Data were analysed using the
SPSS statistical feature, version 15.0 for Windows (Statistical Package
for the Social Sciences, SPSS, Chicago, Illinois, USA), and Biostat
V5, Analystsoftware, Sao Paulo, Brazil.

Results
Of 663 women presenting with preterm labour, 597 failed to
meet eligibility criteria (fig. 1). Of the remaining 66, 34 were
randomized to terbutaline and 32 to nifedipine (fig. 1). Baseline demographic and obstetric characteristics were similar in
the two groups (table 1).
Effectiveness outcome.
Table 2 presents comparisons of the effect of terbutaline versus nifedipine on outcome related to tocolysis. Tocolytic drugs

2014 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society)

NIFEDIPINE AND TERBUTALINE IN TOCOLYSIS

Assessed for eligibility

(n = 663)
MET EXCLUSION CRITERIA
(n = 363)
malformations of the genital tract as bicornuate uterus,
fibroids importantly, among others: 3
oligo -hydramnios: 28
foetal malformation: 12
proven foetal diseases such as intrauterine growth restriction,
hydrops, among other detected by ultrasound: 72
did not agreed to participate: 1
any maternal comorbidity such as heart disease,
hypertension, diabetes, among others: 136
obstetric diseases such as preeclampsia, eclampsia,
diabetes in pregnancy among others: 96
placenta previa or any uterine bleeding of unknown cause: 8
foetal distress: 2
clinical suspicion of fever or confirmed diagnosis of
chorioamnionitis: 5

Term or near term (n = 234)

- did not have indicaon to tocolysis: 234

Randomised
(n = 66)

Allocated to terbutaline
(n = 34)

ALLOCATION

Loss to follow-up
(n = 0)

Allocated to nifedipine
(n = 32)
Loss to follow-up
(n = 0)

FOLLOW-UP

Analysed (n = 34)
-34 paents were included in all intent-to-treat analysis

ANALYSIS

Analysed(n = 32)
- 32 paents were included in all intent-to-treat analysis

Fig. 1. Flow diagram of the trial.

Table 1.
Baseline demographic and obstetric characteristics according to treatment allocation.
General characteristics of patients
Age (years) n (%)
Race n (%)
White
Black/Asian
Gestational age (weeks)
Dilation of the cervix (cm)
Cervical length (cm)
Uterine contractions (number per
10 min.)
SBP (mmHg)
DBP (mmHg)
Maternal heart rate (bpm)
Foetal heart rate (bpm)

Terbutaline
(n = 34)

Nifedipine
(n = 32)

24.7  4.7

24.8  4.5

24 (70.8%)
10 (29.2%)
31.6  2.2
3.0  0.6
2.1  0.7
2.8  0.5

23 (72.0%)
9 (27.0%)
30.8  1.9
3.0  0.7
2.2  0.5
2.8  0.6

123.5
73.1
87.3
144.1






10.3
7.6
7.0
10.8

118.8
71.6
86.3
145.5






10.6
6.5
7.7
10.2

SBD, systolic blood pressor; DBP, diastolic blood pressure, bpm: beat
per minute.
Values are mean  S.D.

were discontinued in three patients in the terbutaline group

(two because of progression to a cervical dilatation of >4 cm
and one because of rupture membranes) and in three patients
in the nifedipine group (one because of progression to a cervical dilatation of >4 cm and two because of rupture mem-

branes). Time of tocoloysis in the terbutaline group

(2.45  1.67) was not different from the nifedipine group
(2.78  2.1); mean difference 0.35 (95% CI 1.21 to 0.52,
p = 0.2). Other results were also similar in the two groups,
with generally good outcome for most of the women; we
found no statistically significant differences. The confidence
intervals around most estimates were, however, very wide.
Adverse effect associated with tocolytic therapy.
We observed no serious adverse effects. No women in either
group required cessation of therapy due to adverse events.
Table 3 presents the pattern of less serious adverse effects.
Flushing and headache were both frequent and occurred more
often after the administration of nifedipine. The administration
of terbutaline, however, increased the risk of other side effects,
including tremor, nausea and dizziness. Most women in both
groups experienced at least one adverse effect (94.1% terbutaline versus 71.9% nifedipine); more women in the terbutaline
group experienced two or more side effects (84.8% terbutaline
versus 33.3% nifedipine); and the total number of adverse
effects was higher in the terbutaline group (78 events in terbutaline versus 35 in nifedipine).
Two hypotensive events that occurred with the use of nifedipine were controlled with the administration of volume
(sodium chloride 9%) and placing the patient in the left lateral
decubitus position.

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TANIA REGINA PADOVANI ET AL.

Table 2.
Effectiveness outcome.
Parameters of effectiveness

Terbutaline
(n = 34)

Nifedipine
(n = 32)

Tocolysis within 12 hr
Birth <48-hr treatment
Recurrence within 48 hr
Pregnancy prolongation (days)3
Birth after 34 weeks
Birth after 37 weeks

31
6
5
12
19
4

29
4
8
23
20
6

(91.1)
(17.6)
(17.0)
(227)
(55.8)
(11.7)

(90.6)
(12.5)
(25.0)
(332)
(62.5)
(18.7)

RR
(95% CI)
1.01
1.55
0.59
4.00
0.89
0.63

(0.86 to 1.17)
(0.48 to 4.96)
(0.21 to 1.61)
( 12.5 to 4.5)
(0.60 to 1.34)
(0.19 to 2.02)

p
1.01
0.72
0.52
0.054
1.02
0.72

RR, relative risk; CI 95%, confidence interval 95%.

1
Fishers exact test.
2 2
v -test.
3
Median and interquartile range.
4
MannWhitney U-test.

Table 3.
Maternal adverse effects associated with tocolytic treatment.
Adverse
effects
Transient
hypotension
Tremor
Tachycardia
Flushing
Nausea
Vomiting
Dizziness
Headache
Women
experiencing
1 AE2

Terbutaline
n = 34
(%)
0
26
2
1
20
5
10
2
32

Nifedipine
n = 32
(%)
2 (6.25)

(76.4)
(5.8)
(2.94)
(58.8)
(14.7)
(29.4)
(5.88)
(94.1)

0
1
14
3
1
2
10
23

(3.12)
(43.7)
(9.37)
(3.12)
(6.25)
(31.2)
(71.9)

RR
(CI 95%)

2.00
0.07
6.27
4.71
4.71
0.19
1.39

pValue
0.41

(0.1314.19)
(0.010.48)
(2.1019.10)
(0.5838.13)
(1.1219.85)
(0.040.79)
(1.101.76)

0.001
1.001
0.031
0.011
0.601
0.021
0.02
0.01

preterm labour up to 48 hr, allowing enough time for the

administrations of corticosteroid and pulmonary maturation,
and despite most deliveries occurring after 34 weeks of pregnancy, the number of newborn babies developed respiratory
distress syndrome was still high in both groups (35.2% in terbutaline, 31.2% in nifedipine).

Discussion

Strengths and weaknesses of this study.

Strengths of this study include the careful confirmation of preterm labour [7,27]; the low risk of bias (concealed randomization, blinding of outcome assessment, no loss to follow-up,
analyse as randomized); and the rigorous and comprehensive
collection of data relevant to the efficacy of tocolysis, adverse
effects on the mothers and neonatal outcome.
The trials primary limitation is its small sample size and
the resulting wide confidence intervals. Another limitation is
that we did not follow infants beyond discharge from hospital.
A third limitation is the relatively small number of women
presenting with premature labour who proved eligible for this
study. Unfortunately, the incidence of potential contra-indications to tocolytic therapy, in particular foetal and maternal
abnormalities and complications, are frequent in women presenting in premature labour. For example, in another study of
tocolytic therapy, of 566 potentially eligible women, only 64
proved eligible and were included [30].

We found no significant differences between terbutaline and

nifedipine and concerning effective tocolysis, the recurrence of
preterm labour in the first 48 hr and the time of delivery
(table 2). We observed no serious adverse effects in either
treatment arm. The proportion of patients who experienced
one or more less serious adverse effects during tocolytic therapy was greater in women who received terbutaline than in
those who received nifedipine (table 3). Women who received
terbutaline significantly more frequently developed tremors,
nausea and dizziness (table 3). Headache and flushing, however, occurred significantly more frequently with nifedipine
(table 3), and the only two important hypotensive events
occurred in the nifedipine group.
Neonatal adverse outcome were similar in the two groups
(table 4). Despite both agents proving effective in prolonging

Relation to previous work.

The most compelling summary of results of previous trials
thus far comes from a network meta-analysis examining all
the randomized trials of all agents used for tocolysis [6]. This
meta-analysis found that, in comparison with terbutaline, calcium channel blockers have a higher probability of achieving
delay in delivery beyond 48 hr. Our failure to replicate this
finding may well be a result of our small sample size; the confidence interval includes the benefit of nifedipine seen in the
meta-analysis. Two previous meta-analyses have suggested
nifedipine is superior to terbutaline in terms of prevention of
neonatal adverse events, although they failed to show a difference in these events between nifedipine and placebo [22,24]
while the network meta-analysis [6] failed to find differences

RR, relative risk; CI 95%, confidence interval of 95%.

AE adverse effects.
1
Fishers exact test.
2
Median (interquartile range).

Table 4 presents the impact of the two agents on foetal outcome. Outcome were similar between groups. No foetus experienced either bradycardia or tachycardia.

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NIFEDIPINE AND TERBUTALINE IN TOCOLYSIS

Table 4.
Neonatal outcome after tocolytic therapy with terbutaline or nifedipine.
Neonatal outcome
1

Birth weight (kg)

Apgar (1 min.)1
Apgar (5 min.)1
Capurro (weeks)1
Need for oxygen
Intubation
Admission to ICU
Days of hospitalization in the ICU1
Respiratory distress syndrome
Neonatal sepsis
Intracranial haemorrhage
Necrotizing enterocolitis
Neonatal jaundice
Death

Terbutaline
n = 34 (%)

Nifedipine
n = 32 (%)

RR or Mean difference
(CI 95%)

2.5  0.4
6.9  1.0
8.2  0.9
34.4  1.9
16 (44.1)
4 (11.7)
13 (38.2)
11.6  15.7
12 (35.2)
2 (5.8)
0
0
9 (26.4)
0

2.4  0.5
6.7  1.2
7.5  1.4
34.0  2.6
24 (75.0)
11 (34.3)
10 (31.2)
7.7  11.7
10 (31.2)
1 (3.1)
0
0
14 (43.7)
0

0.10
0.20
0.70
0.42
0.76
0.41
1.16
3.90
1.10
1.83

0.69

p-Value

( 0.11 to 0.29)
( 0.44 to 0.86)
( 0.04 to 1.25)
( 0.69 to 1.5)
(0.46 to 1.26)
(0.14 to 1.19)
(0.57 to 2.37)
( 2.8 to 10.7)
(0.53 to 2.27)
(0.17 to 19.30)

0.172
0.252
0.063
0.222
0.074
0.074
0.604
0.775
0.624
0.616

(0.33 to 1.42)

0.344

RR, relative risk; CI 95%, confidence interval 95%.

Mean  S.D.
2
Students t-test.
3
U-MannWhitney test.
4 2
v -Pearson test.
5
Fishers exact test.
1

in respiratory distress between agents. If there is indeed a difference between neonatal adverse events between the two
agents, the small sample size in our study could once again be
an explanation for our failure to detect the difference.
Our findings regarding adverse effects with terbutaline (in
particular tremors and nausea) are similar to those reported in
previous meta-analyses by Tsatsaris et al. [24] and King et al.
[15] However, these authors also report a higher frequency of
tachycardia, palpitations and chest pain, which our patients did
not experience. Previous trials also reported treatment discontinuation because of side effects with terbutaline from 6% to 38%,
whereas terbutaline adverse effects in our trial did not require
discontinuation in any patient [31]. In our trial, the dose of terbutaline was adjusted to a safe range according to guidance from
Klasco [28,32]; our doses were lower than in previous trials of
this agent [33,34]. This may explain both our failure to observe
either cardiovascular adverse events or the necessity to discontinue terbutaline because of adverse effects.
We observed no serious adverse effects with terbutaline. This
result is consistent with data suggesting that adverse effects are
rare: acute pulmonary oedema, estimated from 1:350 to 1:400,
which may result in the mothers death. Over 25 deaths related
to the administration of terbutaline in order to inhibit preterm
labour have been reported [24]. Due to the risks involved, the FDA
has warned about the use of this drug as a tocolytic agent [35].
We observed more frequent headaches with nifedipine than
terbutaline, presumably secondary to nifedipines vasodilatory
effects [3638], a result consistent with previous studies
[10,39,40]. Overall, however, previous evidence summaries
[2,21,22,31,41] have reported that nifedipine generates fewer
total adverse events than terbutaline, a finding that our study
confirmed. On the other hand, anti-hypertensive drugs as in
the case of nifedipine may produce maternal hypotension
[42,43], which causes concern about placental perfusion,

excessive hypotension, myocardial infarction and heart failure.

Two women receiving nifedipine in our study became hypotensive. In many countries, these considerations led to the
withdrawal from the market of nifedipines quick release presentation [26]. Considering possible under-reporting of adverse
effects, authors recommend precaution, particularly in women
with cardiovascular morbidity [2,44,45].

Implications for future research.

Given nifedipines toxicity advantages, such a study might
appropriately use a non-inferiority design to ensure that an
important outcome, such as failure to achieve tocolysis within
12 hr, was not appreciably higher with nifedipine than terbutaline. Given the rate of failure of tocolysis in the terbutaline
group of approximately 9%, and assuming conventional values
of type 1 and type 2 error, one would require 2547, 1140 and
647 participants per group to definitively demonstrate that
nifedipine did not increase the frequency of failure of tocolysis
in 12 hr by, respectively, 2%, 3% or 4%.

Conclusion
The results of this study support previous evidence suggesting
that nifedipine is as effective as terbutaline in its impact on
tocolysis and neonatal outcome with fewer maternal and foetal
adverse effects. The oral administration of nifedipine, as well
as its low cost (it does not involve skilled technicians for the
administration and does not require parenteral application),
further recommends the treatment.
Acknowledgements
Elton Luis Faggioni Trani and Victor Simezo for adjudications outcomes. No funding was received for this project.

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TANIA REGINA PADOVANI ET AL.

6
Disclosure
The authors declare no conflict of interest.
Author contributions

All authors participated in the preparation of the manuscript

and agreed to the submitted version of the paper. Tania Padovani and Luciane Lopes involved in the study concept and
design. Tania Padovani participated in acquisition of data.
Gordon Guyatt and Luciane Lopes analysed and interpreted
the data. Gordon and Luciane Lopes drafted the manuscript.
Tania Padovani, Luciane Lopes and Gordon Guyatt critically
revised the manuscript for important intellectual content.
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Supporting Information
Additional Supporting Information may be found in the
online version of this article:
Data S1. CONSORT 2010 checklist of information to
include when reporting a randomised trial.*

2014 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society)