A Comparative
Study of Nifedipine and Terbutaline
as Tocolytic Agents in the Management of Preterm Labour
Naiya Devgan1, Meenakshi Barsaul2, Rashmi Sindhwani2,
Smiti Nanda2 and Manish Devgan3*
1General Hospital, Rohtak,
Haryana, India,
2PGIMS, Rohtak,
Haryana, India,
3SDM College of Pharmacy, Kaithal, Haryana, India.
ABSTRACT:
The aim of this study was to compare the
effectiveness, safety and possible adverse effects of terbutaline
and nifedipine in prolonging pregnancy beyond 48 hrs.
A randomized controlled trial was conducted with 60 pregnant women admitted
with preterm labor, randomized into two groups, which were given terbutaline (30 patients) and nifedipine
(30 patients) respectively. Bivariate and
multivariate analysis, using regression, were used to analyze the data. No
statistically significant difference was found between the two groups in terms
of prolongation of gestation to 48 hrs. Both the drugs significantly prolonged
the pregnancy (P < 0.001), however
there was no statistically significant (P
> 0.05) difference in the tocolytic efficacy
(mean absolute prolongation of gestation) and birth outcomes between the two
groups. The maximum number of patients in both groups (47 % in group A and 70 %
in group B) delivered between 34.1 to 37 weeks. However, side effects were
significantly more common in the terbutaline group (P < 0.02), especially maternal
tachycardia, transient hypotension and chest pain. In the terbutaline
group, 14.8 % neonates required mechanical ventilation while 11.1 % suffered
intra ventricular hemorrhage. Terbutaline and nifedipine appeared to be equally effective in their tocolytic action. However, nifedipine
did have the advantage of the ease of administration. It also had significantly
less side effects.
KEYWORDS: Terbutaline, Nifedipine,
Preterm labor and Tocolysis.
INTRODUCTION:
Prematurity as a consequence of preterm
labor, accounts for 75-80 % of neonatal mortality and morbidity due to sepsis, intraventricular hemorrhage, respiratory distress syndrome,
bronchio-pulmonary hypoplasia,
necrotizing enterocolitis and retinopathy1,2.
In India the reported incidence of preterm delivery in a survey of hospital
deliveries was found to be 12.3 %3. Tocolytics
prolong pregnancies that allow corticosteroids to promote fetal pulmonary
maturation and thus reduce negative consequences of preterm birth4.
Various tocolytic agents in use are beta adrenergic
agonists (BAA), magnesium sulphate, prostaglandin synthetase inhibitors, oxytocin
receptor agonists, aminophylline, nitric oxide
donors, non selective and selective COX-2 inhibitors and calcium channel
blockers. Among the beta adrenergic agonists, ritodrine
is the only drug approved by the US FDA5.
Intravenous infusion of terbutaline
is used as the standard treatment for preterm labor in many hospitals. Its use
in the management of preterm labor is associated with different form of dosage
and routes of administration; this might lead to differences in efficacy and
side effects6,7. Many maternal and fetal side effects are associated
with terbutaline use, which includes maternal
hypotension and tachycardia.
Nifedipine, a calcium channel blocker, has
been used in preterm labor since 19868. It has demonstrated similar
efficacy with fewer maternal side effects and neonatal morbidity than ritodrine9,10.
It is considered potentially safer and better tolerated tocolytic
agent with no known fetal side effects11. Despite the promising
safety of nifedipine, questions remained, as the
safety data were obtained from trials where terbutaline
was administered in a different manner compared to the present dosing protocol.
The aim of this study was to evaluate and
compare the tocolytic efficacy of terbutaline
and nifedipine and to assess maternal and fetal
neonatal outcomes in both cases.
PATIENTS AND METHODS:
The comparison of safety and tocolytic efficacy of oral nifedipine
with terbutaline intravenous infusion was conducted
in the randomized controlled open trial. The blocks of size 4, 6 and 8 were
used to randomize the patients in order to get the balanced number of patients
in both arms at any time of enrollment. The present study protocol was approved
by the institutional review board. The written informed consent was obtained
from all patients. A sample size of 60 (30 patients in each group) was selected.
Inclusion
criteria:
The eligible population was the women
diagnosed with preterm labor at 28-34 completed weeks of gestation, with intact
membranes, who were admitted to the obstetric ward of Pt. B. D. Sharma PGIMS, Rohtak. These were eligible for inclusion if they had 1)
> 3 painful contractions per 10 min; 2) cervical dilatations of 1-4 cm
and/or 3) changing cervical effacement.
Exclusion
criteria:
Patients with heart diseases, renal
diseases, hypertension, chorioamnionitis, placental
abruption, placental previa, preeclampsia, multiple
pregnancy, diabetes and thyrotoxicosis were excluded
from the study.
A detailed history, general physical
examination, abdominal and per speculum examination, routine as well as specific
investigations such as ultrasonography to rule out
fetal anomalies, placental localization, gestational age confirmation and
cervical dilatation, ECG, plasma glucose levels and serum electrolytes were
performed in all cases.
Intervention:
To enhance fetal lung maturation, each
patient received corticosteroid therapy as injection betamethasone
12 mg, two doses 24 hrs apart.
The treatment protocol for each group was
as follows:
Group A (Nifedipine group, n = 30):
Oral nifedipine
was given 30 mg stat, if uterine contractions persisted at 90 min then another
dose of 20 mg was given and thereafter patients were given 20 mg PO every 8 hrs
from the first dose.
Group B (Terbutaline group, n = 30):
Subcutaneous terbutaline
0.25 mg was given 6 hourly for 24 hrs and thereafter switched to oral therapy
of 5 mg every 6 hrs.
After beginning of tocolysis,
blood pressure was recorded every 10 min for 30 min and then 2 hourly for 4
hrs. Uterine contractions were monitored and per speculum examination done in
case of failure of tocolysis. Tocolytic
failure was defined as recurrence or persistence of more than 4 contractions
per 20 min period after 1 hr of maximal attainable dose of therapy. Progression
of cervical changes, rupture of membrane or presence of hypertension or other
severe side effects necessitated the discontinuation of therapy. Tocolysis was successful if delivery was delayed for at
least 48 hrs whereby the patient was discharged and continued with bed rest and
oral therapy with either nifedipine 20 mg 8 hourly or
terbutaline 5 mg PO 6 hourly till 34 weeks of
gestation.
RESULTS:
Table 1 shows the similarity of the two
groups with respect to maternal age, gestational age, parity, history of
preterm labor and status of cervix. The maximum numbers of patients were in age
group of 18-22 years in both groups. Maximum numbers in both groups were nulliparous. Maximum patients presented at 28-30 weeks
gestation in group A (44 %) and
at 30-32 weeks in group B (40 %). The mean cervical dilatation in group A was
0.61 ± 0.89 cm and in group B was 0.98 ± 0.92 cm, however the difference was
not statistically significant (P >
0.05).
One patient in group A and three patients
in group B delivered within 48 hrs of tocolysis and
were considered treatment failures. Pregnancy was prolonged by at least 48 hrs
in 29 patients (97 %) in nifedipine group and 24
patients (89 %) in the terbutaline group. In four
patients in group B the tocolysis had to be
discontinued due to severe side effects, out of which one patient delivered
immediately. Thus 27 patients were included in group B.
Data for prenatal outcome was available for
all patients in both groups. There were two (7%) neonatal deaths in group A
(n=30) and four (15%) in group B (n=27). The mean birth weight in group A was
2.17 ± 0.53 kg and in group B was 2.11 ± 0.5 kg. The difference was not
statistically significant.
Table 1: Characteristics
of Patients.
Variables |
Group A (Nifedipine) |
Group B (Terbutaline) |
Maternal
age (years), mean
± SD |
20.8 ± 6.4 |
20.2 ± 6.8 |
Gestational
age (weeks), mean
± SD |
29.3
± 1.2 |
31.1
± 1.3 |
Number
of Parity, n (%) |
|
|
0 |
19
(63) |
16
(53) |
≥ |
11
(37) |
14
(47) |
Cervical
dilatation (cm), mean
± SD |
0.61
± 0.89 |
0.98
± 0.92 |
History
of preterm labor |
3
(10%) |
2
(6%) |
SD:
Standard deviation
Table 2 shows the neonatal outcome and
complications. Seven patients of each group required neonatal intensive care
unit (NICU) admissions. All the neonates suffered respiratory distress syndrome.
The complications were similar between groups, but 3 babies (born at 25, 29 and
37 weeks of gestation) in group B developed intraventricular
hemorrhage (IVH). In one baby, IVH was caused by the trauma resulting from
delivery procedure. In group B, four neonates had multiple complications that
required mechanical ventilation. The mean stay of neonates in NICU was 14.57 ±
6.6 days in group A and 16.5 ± 7.89 days in group B and the difference was not
statistically significant.
Table 2: Neonatal complications.
|
Group A (Nifedipine)
(n=30) |
Group B (Terbutaline)
(n=30) |
Neonatal
complications |
7 |
7 |
NICU
admissions |
7
(23.3 %) |
7 (25.9 %) |
Respiratory
distress syndrome |
7
(23.3 %) |
7 (25.9 %) |
Mechanical
ventilation |
3 (10
%) |
4 (14.8
%) |
Intraventricular hemorrhage |
0 |
3
(11.1 %) |
Necrotising enterocolitis |
2
(6.6 %) |
2
(7.4 %) |
Neonatal
deaths |
2
(6.6 %) |
4
(14.8 %) |
NICU: Neonatal
intensive care unit
Table 3 depicts the various secondary outcome
measures evaluated in the two groups of the study. The effect of the two tocolytic agents in prolonging pregnancy was compared in
terms of mean prolongation in days from the time of presentation with preterm
labor and mean gestation in weeks, at delivery. The maximum number of patients
in both groups (47 % in group A and 70 % in group B) delivered between 34.1 to
37 weeks. Both the drugs significantly prolonged pregnancy (P < 0.001), however as shown in table
3, there was no statistically significant (P
> 0.05) difference in the tocolytic efficacy (mean
absolute prolongation of gestation) and birth outcomes between the two groups.
Ninety percent in group A and eighty nine percent in group B had vaginal
delivery.
The side effects in group B were
significantly more (table- 4). Four patients in group B could not complete the tocolysis due to severe side effects. Many patients
developed multiple side effects. Most common side effect in group A was
flushing (10 %) while in group B it was tachycardia (37 %). None of the
patients in either group had post partum hemorrhage or prolonged labor.
DISCUSSION:
The main aim of the tocolytic
therapy is to inhibit uterine activity for at least 48 hrs during which fetal
lung maturity can be accelerated by glucocorticoid
treatment. Terbutaline is a synthetic sympathomimetic amine which exerts a preferential effect on
β2 adrenergic receptors12 causing uterine and
bronchial relaxation as well as peripheral vasodilatation. β2 mimetic
induced metabolic changes are of considerable importance in women with
diabetes, renal disease or cardiac abnormalities. They also cross placenta
rapidly. An increase in fetal heart rate, neonatal hypoglycemia, hyperbilirubinemia and hypocalcemia
has been reported13. An increased risk of intraventricular
hemorrhage has been reported as compared to magnesium sulphate.
Gromme et
al supports the use of alternate form of tocolysis
wherever possible and careful consideration in evaluating the indication of betamimetic therapy14.
Nifedipine is a calcium channel
antagonist. It inhibits the influx of calcium ions across smooth muscle cells
resulting in decreased myometrial activity. A number
of studies have reported a reduced amount of maternal side effects with its
use. Lowering of blood pressure and tachycardia has been reported but was less
common as compared to terbutaline or ritodrine15-17.
No deleterious side effects have reported. The onset of action after oral dose
is less than 20 min with peak plasma concentration in 1 hr (15-90 min). No
apparent cumulative affect has been noted. However,
maternal hypotension is a relative contraindication to its use and concomitant
use with magnesium sulphate should be avoided because
of reports of neuromuscular blockade10,18.
The mean maternal age, mean gestational age
at the time of start of tocolysis, the incidence of multiparity, and the rate of previous preterm deliveries in
the patients of our study was comparable to such similar studies by Smith and
Woodland,15 Papatsonis et al16 and Weerakul et al17.
Table 3: Tocolytic efficacy and birth outcome.
Variables |
Group A (Nifedipine)
(n=30) |
Group B (Terbutaline)
(n=30) |
P Value |
Mean absolute
prolongation of gestation (days) |
28.7
± 17.8 |
23.88 ± 14.5 |
P
> 0.05, NS |
Prolongation
of pregnancy > 48 hr n (%) |
29
(97) |
24
(89) |
|
Gestational
age (GA) at birth (weeks), mean ± SD |
35.22 ± 2.55 |
34.81 ± 2.4 |
P
> 0.05, NS |
GA at
the time of admission (weeks), mean ±
SD |
30.8 ± 1.58 |
30.94 ± 1.32 |
P
> 0.05, NS |
Birth
weight (g), mean ± SD |
2.17 ± 0.53 |
2.11 ± 0.50 |
P
> 0.05, NS |
Birth
weight > 2.5 (Kg), n (%) |
8 (27
%) |
5 (19
%) |
|
Apgar scores, 1 min < 7, n (%) |
6.47 ± 1.69 |
5.88 ± 2.02 |
P
> 0.05, NS |
Apgar scores, 5 min < 7, n (%) |
7.96
± 1.52 |
7.81
v 1.64 |
SD: Standard deviation
NS: Not significant
Table 4: Side
effects with tocolysis.
Synptoms |
Group A (Nifedipine)
(n=30) |
Group B (Terbutaline)
(n=30) |
Headache |
2 (7
%) |
2 (7
%) |
Tachycardia |
2 (7
%) |
11
(37 %) |
Transient
maternal hypotension |
- |
4 (13
%) |
Palpitation |
2 (7
%) |
7 (23
%) |
Flushing |
3 (10
%) |
- |
Chest
pain |
- |
2 (7
%) |
There are other factors as well that
influence the result in preterm labor; apart from use of tocolytics.
These include inclusion of cases with premature rupture of membranes, dose and
duration of tocolytics, use of other tocolytics and maintenance tocolysis.
We did not include cases with preterm premature rupture of membranes. Others
have included such cases in their studies16. The doses of nifedipine and terbutaline used
in the present study were relatively high as compared with other studies4,5,9and17.
In most trials nifedipine was given at the dose of 10
mg every 15-20 min, with the maximum of 40 mg dose in the first hour of
treatment, followed by maintenance therapy with the dose ranged from 30-160
mg/day up to 3 days. Longer treatment duration was done by Papatsonis
et al, where nifedipine was given until 34 weeks
among women with gestational age 20-33.5 weeks at enrollment16. The
proportion of women giving birth after 37 weeks was, however, not significantly
higher (29/68, 43.4 %) when compared with the study done by Weerakul
et al17. This implies that
longer treatment might not be necessary if the women have preterm labor very
early in their pregnancies.
There was one patient (3 %) in group A and
three patients (10 %) in group B who delivered in less than 48 hr and was
considered as treatment failures. It is significantly less than the failure
rates of other studies15-17. It could be due to more number of
patients with previous preterm deliveries in their study also to the fact that
we did not include patients with premature rupture of membranes in our study.
97 % of women in the nifedipine group and 89 % in the
terbutaline group remained undelivered at 48 hrs
(which is relevant because it permits the use of corticosteroids to promote
fetal lung maturation). The percentage of patients in both groups that
delivered after 34 weeks and 37 weeks compares with the rates shown by studies
of Smith and Woodland, 15 Papatsonis et al16 and Weerakul et al17.
The perinatal
mortality rate (group A- 7 % and group B- 15 %) was higher when compared with
other studies, like that done by Smith and Woodland- none, 15 Papatsonis et al-
none16 and Garcia and Gonzalez -none10. The difference
could be due to better nursery and intensive care facilities at their centers.
The results also demonstrate that nifedipine seemed
to have better safety profile than terbutaline. The
changes in maternal and fetal vital signs were similar to that reported in
previous studies5,9,17. In the study conducted by Weerakul et al17,
using the dosage regimens were similar to the present study, 93.2 % of
the patients in the terbutaline group and 4.4 % in
the nifedipine group experienced side effects.
Although the percentage of women having side effects in the terbutaline
group was very close to that found in the present study, that figure in the nifedipine group was much lower than that found in present
study (75 %). However, another study using similar dosing protocol reported
only 13.2 % of women experiencing side effects13. The difference
might be resulted from the way the data were collected.
The present study suggests that nifedipine is an alternative tocolytic
agent that possesses good safety profile. The most common side effects observed
in nifedipine group were flushing (10 %). Garcia and
Gonzalez10 reported headache (38.4 %) and flushing (96 %) as the
most common side effects with the use of nifedipine
for tocolysis. In the terbutaline
group, maximum number of patients developed tachycardia (37 %) followed by
palpitation (23 %) and transient maternal hypotension (13 %). Smith and
Woodland15 reported maternal irritability (54 %) as the most common
side effects followed by tachycardia (42 %). The number of patients that
suffered from side effects was significantly higher in group using terbutaline as tocolytic agents (P < 0.02). Three patients in group B
had to be discontinued with the study due to severe side effects. Although
birth outcomes were comparable, the serious adverse birth outcomes like IVH
were found in the terbutaline group only. It is noted
that nifedipine was a comparable tocolytic
agent when compared with terbutaline. Furthermore, nifedipine had significantly less maternal side effects
than terbutaline. Thus, this study demonstrates that nifedipine has a definite role in the treatment of preterm
labor. The safety profile of nifedipine is higher
than terbutaline while its tocolytic
efficacy should be evaluated in more detailed studies.
REFERENCES:
1 Report of the consensus
development-conference on the effect of corticosteroids for fetal maturation on
perinatal outcomes. Washington: National Institute of
Health; NIH publication. 95; 1994: 3784-3786.
2) Darey BC, Clark
AL, Kernek K, Joseph A and Spinnato
MD. Maintenance of oral nifedipine for preterm labor:
a randomized clinical trial. American
Journal of Obstetrics and Gynecology. 181 (4); 1999: 822-827.
3) Neonatal morbidity and mortality: report
of the national neonatal, perinatal database. Indian Pediatrics. 34; 1997: 1039-1042.
4) Tsatsaris V, Papatsonis, Goffinet F, Dekker G
and Carbonne B. Tocolysis
with nifedipine or betaadrenergic
agonist.: a meta analysis. Obstetrics
and Gynecology. 97; 2001: 840-847.
5) Cartis SN, Toig G, Heddinger LA and Ashmead G. A double blind study comparing ritodrine and terbutaline in the treatment
of preterm labor. American Journal of
Obstetrics and Gynecology. 150; 1984: 7-14.
6) Nanda K, Cook LA, Gallo MF and Grimes DA. Terbutaline pump maintenance therapy after threatened
preterm labor for preventing preterm birth. Cochrane Database of Systematic Reviews. 4; 2002: CD003933.
7) Guinn DA, Goepfert
AR, Owen J, Wenstrom KD and Hauth
JC. Terbutaline pump maintenance therapy for
prevention of preterm delivery: a double blind trial. American Journal of Obstetrics and Gynecology. 179; 1998: 874-878.
8) Read MD and Wellby
DE. The use of a calcium antagonist (nifedipine) to
suppress preterm labor. British Journal
of Obstetrics and Gynecology. 93; 1986: 933-937.
9) Ferguson JE, Dyson DC, Schutz
T and Stevenson DK. A comparison of tocolysis with nifedipine or ritodrine: analysis
of efficacy and maternal, fetal and neonatal outcome. American Journal of Obstetrics and Gynecology.163; 1990: 105-111.
10) Garcia Velasco JA and Gonzalez
GA. A prospective
randomized trial of nifedipine versus ritodrine in threatened preterm labor. International Journal of Gynecology and Obstetrics. 61; 1998:
239-244.
11) Rayamajhi R and Pratap K. A comparative study between nifedipine
and isoxsuprine in the suppression of preterm labor. Kathmandu University Medical Journal. 1
(2); 2003: 85-90.
12) Wallace RL, Caldwell DL, Ansbacher
R and Olterson WN. Inhibition of premature labor by terbutaline. American
Journal of Obstetrics and Gynecology. 57 (4); 1978: 387-392.
13) American College of Obstetricians and Gynecologists.
Assessment of risk factors for preterm birth. ACOG Practice Bulletin No. 31. Obstetrics and Gynecology. 98; 2001:
709-716.
14) Gromme LJ,
Goldenberg RL and Oliver SP. Neonatal periventricular-interventricular
hemorrhage after maternal beta-sympathomimetic tocolysis. American
Journal of Obstetrics and Gynecology. 167; 1992: 873-875.
15) Smith CS and Woodland MB. Clinical
comparison of oral nifedipine and subcutaneous terbutaline for initial tocolysis.
American Journal of Perinatology.
10; 1993: 280-284.
16) Papatsonis DNM,Van HP and Ader HJ. Nifedipine and ritodrine in the
management of preterm labor. A randomized multicenter trial. Obstetrics and Gynecology. 90 (2);
1997: 230-234.
17) Weerakul W, Chettachdroen A and Sulhutvoravul
S. Nifedipine versus terbutaline
in management of preterm labor. International
Journal of Obstetrics and Gynecology. 76; 2002: 311-313.
18) Hearne EA and Nagey
D. Therapeutic agents in preterm labor: tocolytic
agents. Clinical Obstetrics and
Gynecology. 43 (4); 2002: 787-801.
Received on 06.05.2013
Modified on 20.06.2013
Accepted on 28.06.2013
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Research J. Pharmacology and
Pharmacodynamics. 5(4): July–August 2013, 232-236