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.  

 

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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