Journal of Perinatology (2014), 1–5 © 2014 Nature America, Inc. All rights reserved 0743-8346/14 www.nature.com/jp
ORIGINAL ARTICLE
Comparison between nitroglycerin dermal patch and nifedipine for treatment of preterm labor: a randomized clinical trial M Kashanian1, Z Zamen1 and N Sheikhansari2 OBJECTIVE: Preterm labor and delivery are of the most important complications of pregnancy and have a major role in neonatal mortality and morbidity. Management of preterm labor and prevention from preterm delivery in order to lower these risks have always been under serious concern. The purpose of this study was to compare the effect of nifedipine and nitroglycerin (NG) dermal patch for taking control of preterm labor. STUDY DESIGN: The study was performed as a randomized clinical trial on women who had been admitted in the hospital diagnosed with preterm labor. In one group, the NG dermal patch and in the other group, nifedipine was prescribed. Then the women of the two groups were followed up to delivery and were compared according to arrest of labor for 2 h, 48 h, 7 days, gestational age at the time of delivery and their adverse effects. The primary outcome was to postpone delivery for 48 h in order to have enough time for prescribing corticosteroids RESULT: The women of the two groups did not have any significant difference according to age, body mass index, primary Bishop Score, gestational age at the time of tocolytic therapy, history of abortion, vaginal or cesarean delivery and preterm labor. In more women in the NG group, delivery was postponed for 2 h (59 (98.3%) vs 48 (80%), P = 0.001), for 48 h (52 women (86.7%) vs 41 (68.3%), P = 0.016) and also for 7 days (47 (78.3%) vs 37 (61.7%), P = 0.046), than the women in the nifedipine group. Gestational age at the time of delivery was higher in the NG group (35.6 ± 1.9 vs 34.3 ± 2.05 weeks, P = 0.155), however, it was not statistically significant. Apgar score of minute 5, (P = 0.03) and neonatal weight (P = 0.04), were more and cesarean deliveries, neonatal intensive care unit (NICU) admission and duration of NICU stay were less in the NG group. Adverse effects were similar, minimal and negligible in both groups. CONCLUSION: The NG patch is a more effective method for preterm labor control than nifedipine with regard to minimal side effects. Journal of Perinatology advance online publication, 8 May 2014; doi:10.1038/jp.2014.77
INTRODUCTION Spontaneous preterm labor is an important complication of pregnancy and is the most common cause of neonatal mortality and morbidity. After passing through 34 weeks of gestation, these issues are decreased substantially.1,2 Because of the mentioned reasons, postponing delivery and treatment of premature contractions of the uterus are very important in order to give time for corticosteroids administration and intrauterine transfer of a premature fetus to a well-equipped hospital and neonatal intensive care unit (NICU). Different agents have been evaluated for this purpose, and up to now, there is no tocolytic with no side effects, which is fully perfect and comes with full efficacy. Various tocolytics are different with each other with regard to effectiveness, adverse effects and specific actions just on the uterus. Also their prices are different. β-adrenergic receptor agonists, magnesium sulfate, prostaglandin inhibitors, oxytocin antagonists, calcium channel blockers and nitric oxide donors all have been used for the treatment of preterm labor. One of the effective treatments for preterm labor is nifedipine, which is a calcium channel blocker and is accessible, not
expensive and safe,1,3 and has been proposed for arresting premature labor since late 1970s, and has been reported in different studies as an effective and safe treatment for preterm labor. This agent can inhibit preterm labor through lowering the calcium level in the uterus. The adverse effects mainly include hypotension, palpitation and headache. Nitric oxide (NO) donors are powerful relaxants of smooth muscles, which affect the uterus and vasculature.1,4–6 Studies7 have shown that NO is an important factor in controlling the cervix during its transition from pregnancy to the beginning of labor and in coordination with progestin, regulates the uterine quiescence and cervical stiffness. Reduction in NO production in the uterus is related to beginning of labor,7 whereas NO causes cervical ripening in cervix. Therefore, NO donors can have therapeutic effects as tocolytic agents. Their adverse effects include hypotension, headache, flushing, dizziness and dermal irritation.8 In a preliminary observational study, 50 mg trans-dermal patch of glyceril trinitrate was used in 10 women with cervical dilatation and preterm labor. Delivery was postponed for an average of 46.2 days without any serious side effects.9
1 Iran University of Medical Sciences, Department of Obstetrics & Gynecology, Akbarabadi Teaching Hospital, Tehran, Iran and 2Middlesex University, Business School, London, UK. Correspondence: Dr M Kashanian, Iran University of Medical Sciences, Department of Obstetrics & Gynecology, Akbarabadi Teaching Hospital, No 9, Mostaghimi Alley, Khajeh Nasir Toosi Avenue, Tehran 16117, Iran. E-mail: [email protected] Received 1 November 2013; revised 23 February 2014; accepted 24 March 2014
Nitroglycerin dermal patch and nifedipine treatment M Kashanian et al
2 The purpose of the present study was to compare nifedipine and nitroglycerin (NG) dermal patch for treatment of preterm labor and their side effects. With the best of available knowledge, there is only one study on the comparison of these two agents for prevention of preterm delivery, which is in Portuguese.10 METHODS Study was performed as a randomized clinical trial in the Akbarabadi Teaching Hospital, Tehran, Iran, between June 2010 and March 2011, on women who were admitted in the labor ward with the diagnosis of preterm labor. Inclusion criteria included gestational age between 26 and 34 weeks (according to a reliable last menstrual period and ultrasound confirmation of the first trimester), singleton pregnancy, at least four contractions during 20 min or eight contractions during 60 min plus cervical dilatation of >1 cm and cervical effacement of ⩾ 50%. Exclusion criteria included ruptured membrane, maternal and fetal indications for termination of pregnancy or conditions that in which, continuation of pregnancy was not beneficial such as hypertension, fetal distress, intrauterine fetal death, cervical dilatation of > 5 cm, known hypersensitivity to NG, tocolytic therapy during previous 24 h, vaginal bleeding, smoking, any systemic disorder or any drug use except ordinary supplementations such as iron or folic acid, fetal anomalies, known uterine anomalies, polyhydramnios, oligohydramnios,
intrauterine growth restriction and any sign or symptoms of chorioamnionitis. A sample size of 120 patients (60 in each group) was considered sufficient in order to obtain a power of 90% (α = 0.05,1 − β = 0.085) with a significance level of 5%. A written informed consent was obtained from all participants who were fully informed about the study. Institutional review board approval and institutional ethics committee approval was given to the study, which was also registered in the Iran Registry of Clinical Trial. (Trial registration number: IRCT201108262624N8) Eligible women (127) entered the study and were randomly grouped (by the investigator’s colleague); four parts, block random using sealed, sequentially distributed envelopes to which the letters A, B, C and D had been allocated: the letters A and C to the NG group and the letters B and D to the nifedipine group). The patients chose one of the envelopes, which were opened by the investigator’s colleague, and according to the letters, the groups of patients were determined. At first, in all eligible women, 500 CC normal saline was infused during 30 min and betamethasone, 12 mg every 24 h was prescribed intramuscularly up to two doses. Then, the women were randomly assigned in to the two groups. In the nifedipine group, nifedipine and in the NG group, NG was prescribed. Because the shapes of the two medicines were totally different, blinding was not performed, however, those assessing the outcomes, were blinded to group assignment.
Assessed for eligibility n=155
Excluded (n= 28)
Enrollment
Not meeting inclusion criteria (n=20) Refused to participate (n=7) Other reasons (n= 1)
Is it Randomized?
Allocated to intervention (NG) group (n= 63) Received allocated intervention (n=63)
Allocated to intervention (nifedipine) group (n= 64) Allocation
Did not receive allocated intervention
Did not receive allocated intervention
Lost to follow-up (n= 2)
Lost to follow-up (n=3)
Discontinued intervention (n=2)
Discontinued intervention (n=0)
Analyzed (n=60)
Analyzed (n=60) Excluded from analysis (n=0)
Figure 1.
Received allocated intervention (n=64)
18 Analysis
Excluded from analysis (n=0)
The consort E-flowchart.
Journal of Perinatology (2014), 1 – 5
© 2014 Nature America, Inc.
Nitroglycerin dermal patch and nifedipine treatment M Kashanian et al
3 Table 1.
The characteristic of the two groups
Characteristics
Nifedipine group n = 60
NG group n = 60
P-value
26.33 ± 6.37 27.01 ± 3.12 4.9 ± 1.4 31.4 ± 2.3 14 (32.2%)
24.31 ± 4.26 26.13 ± 5.34 5.2 ± 1.5 31.5 ± 1.9 8 (13.3%)
0.103 0.563 0.592 0.832 0.157
12 (20%) 13 (21.7%) 4 (6.7%)
6 (10%) 7 (11.7%) 3 (5%)
0.915 0.913 0.821
Age (years) mean ± s.d. BMI Primary Bishop score mean ± s.d. Gestational age at inclusion (weeks) mean ± s.d. Previous abortion Previous delivery N = 25 NVD CS Previous preterm delivery
Abbreviations: BMI, body mass index; CS, Caesarean section; NG, nitroglycerin; NVD, normal vaginal delivery.
Blood pressure was checked every 15 min for all women for a duration of 1 h and then their blood pressure was checked every 4 h. Then the contractions of the uterus were evaluated up to 2 h, and the women were followed up to 48 h, 7 days and up to delivery. The primary outcome was to postpone delivery for 48 h in order to have enough time for prescribing corticosteroids, but if the contractions were not stopped (o2 contractions during 20 min with short duration and low force) up to 2 h after the beginning of tocolytics, it was considered as failure of treatment and an alternative tocolytic was started. Also, recurrent episodes of contractions and preterm labor were managed with alternative tocolytics. In the NG group (n = 63), at first a 10 mg NG patch was applied and despite the continuation of contractions within 1 h, the second 10 mg patch was used, and in case of arrest of contractions, the second patch was not used. In the nifedipine group (n = 64), 10 mg (one capsule) nifedipine was prescribed, every 20 min up to maximum 4 doses. In the cases whose contractions had subsided, 20 mg (2 capsules), every 6 h up to 24 h, thence 20 mg every 8 h for the second 24 h and finally 10 mg every 8 h for the next 24 h were prescribed. In the cases of the continuation of contractions, or blood pressure o90/50 mm Hg, the administration of nifedipine was discontinued.11 In two cases, nifedipine was discontinued due to hypotension that occurred immediately after the beginning of the treatment and 60 women were monitored up to delivery (Figure 1). The other five women left the hospital (for financial reasons or personal problems) with their own request without staff permission and we lost to follow them. Therefore, they have not been considered for analysis. All women were followed up to delivery. The gestational age at the time of delivery, the number of women in whom delivery was postponed for 2 h, 48 h and 7 days were compared between the two groups. Also, NICU admission, duration of NICU stay and adverse effects of two agents including maternal hypotension, fetal bradycardia, headache, palpitation and tachycardia, neonatal Apgar score, neonatal weight and delivery rout were compared between the two groups. Data were analyzed using SPSS 18 software (SPSS, Chicago, IL, USA). The student's t-test, χ2-test and Mann–Whitney test were used for analysis. P-value of o0.05 was considered as significant.
(Table 3). Side effects of drugs in the two groups are shown in Table 4. Maternal blood pressure before intervention, in minutes 15, 30, 45 and 60 after intervention were not significantly different between the two groups, but at 120 min after intervention, blood pressure was less in the nifedipine group than in the NG group (98 ± 11 vs 102 ± 12 for systolic pressure and 67 ± 9 vs 68 ± 8 for diastolic pressure (P = 0.04). Also at 180 min after intervention, it was less in the nifedipine group (P = 0.02). It seems that low blood pressure is more prolonged in nifedipine than in the NG group. At the 4th hour after intervention, there was no difference between the groups with regard to blood pressure.
RESULTS Women (120) were evaluated in total (60 women in each group). The women of the two groups did not show significant difference according to age, gestational age at the beginning of study, body mass index and primary Bishop score (Table 1). The two groups did not have significant difference according to different parameters of the Bishop score (Table 2). Arrest of contractions for 2 h, 48 h and 7 days were significantly more in the NG group than in the nifedipine group (Table 3). Also, the number of cesarean deliveries in the NG group was less than in the nifedipine group (Table 3). Gestational age at the time of delivery, neonatal Apgar score were more in the NG group (Table 3). NICU admission, duration of NICU stay and hypotension were less in the NG group
DISCUSSION In the present study, NG could arrest uterine contractions significantly better than nifedipine and the adverse effects were minimal. At the same time, NICU admission and duration of NICU stay in these groups were less than the nifedipine group. There was a 1.3-week difference between groups. Although not statistically significant, this may have influence on neonatal outcomes. In 1996, Rowlands et al.,9 for the first time, in a study on 10 women, showed beneficial effects of trans-dermal NG for postponing delivery in preterm labor. In a study by Smith et al.,8 trans-dermal NG was compared with placebo, and NG’s effect on neonatal outcome was evaluated.
© 2014 Nature America, Inc.
Table 2.
Different parameters of the Bishop score in the two groups
Characteristics Cervical consistency Soft Medium Firm Position Posterior Medium Anterior Station (minus) mean ± s.d. Effacement % mean ± s.d. Cervical Dilatation
P-value
Nifedipine group n = 60
NG group n = 60
33 (55%) 26 (43.33%) 1 (1.66%)
49 (81.6%) 10 (16.66%) 1 (1.66%)
0.8
15 (25%) 19 (31.66%) 26 (43.33%) 2.7 ± 0.7
7 (11.66%) 20 (33.33%) 33 (55%) 2.7 ± 0.7
0.286
63.8 ± 22.8
64.7 ± 19.7
0.386
2.1 ± 0.8
2.1 ± 0.7
0.759
0.9
Abbreviation: NG, nitroglycerin.
Journal of Perinatology (2014), 1 – 5
Nitroglycerin dermal patch and nifedipine treatment M Kashanian et al
4 Table 3.
Treatment outcome in the two groups
Results
Nifedipine group n = 60
NG group n = 60
P-value
48 (80%) 41 (68.3%) 37 (61.7%) 34.3 ± 2.05 30 (50%) 7.7 ± 1.7 21.41 ± 22.18 2357.41 ± 857.12 30 (50%)
59 (98.3%) 52 (86.7%) 47 (78.3%) 35.6 ± 1.9 17 (29%) 8.5 ± 0.9 8.43 ± 15.15 2634.39 ± 584.09 21 (35%)
o0.001 0.016 0.046 0.155 0.015 0.03 0.03 0.04 0.09
Arrest of contractions for 2 h n (%) Arrest of contractions for 48 h n (%) Postpone delivery for 7 days n (%) Gestational age at delivery (weeks) mean ± s.d. Cesarean delivery n (%) Apgar Score minute 5 mean ± s.d. Duration of NICU stay (day) mean ± s.d. Neonatal weight (gram) mean ± s.d. NICU admission n (%) Abbreviations: NG, nitroglycerin; NICU, neonatal intensive care unit.
Table 4.
The adverse effects of the two groups
Adverse effects Headache Hypotension BPo100/70 mm Hg Hot flash Hypotension led to stop of treatment Fetal bradycardia FHR o120 Maternal tachycardia Dermal irritation (erythema)
Nifedipine group n = 60 4 (6.66%) 14 (23.33%) 0 (0%) 2 (3.33%) 0 0 (0%) 0 (0%)
NG group n = 60 3 (5%) 9 (15%) 2 (3.33%) 0 (0%) 0 0 (0%) 3 (5%)
Abbreviations: BP, blood pressure; FHR, fetal heart rate; NG, nitroglycerin.
They concluded that neonatal mortality and morbidity was decreased because of prolongation of pregnancy. In another study that compared ritodrine and glyceril trinitrate,12 it was shown that glyceril trinitrate has less adverse effects than ritodirine and is safer, but the study did not show significant difference for acute tocolysis. Another study,4 has evaluated the effect of trans-dermal NG on 30 pregnant women with the complain of preterm labor who were in their 27 to 34th week of their pregnancy. A reduction has been reported in uterine contractions in all women without any effects on fetal heart rate and cardiotocography. In contrast, in a meta- analysis in 2002,13 five clinical trials, which have been performed on NG effects for delaying delivery and improvement of neonatal outcome in cases of threatened preterm labor, were evaluated. This study reported no improvement in neonatal outcome and delaying delivery. The authors concluded that at the present time, evidence are not enough to support routine use of NO donors for treatment of threatened preterm labor. A study, which compared intravenous terbutalin and intravenous NG for acute intrapartum resuscitation and also evaluated the maternal homodynamic, reported that terbutalin is a more effective tocolytic with less effects on maternal blood pressure, however, there was no difference between the two medications for intrauterine resuscitation during labor.5 In the other study,6 ritodrine and trans-dermal glyceril trinitrate were compared for their effects on fetus and mother. They reported that with the therapeutic amount that is necessary for tocolysis, NG has minimal effects on blood pressure, pulse rate and fetal heart rate, and these effects are less than vascular adverse effects of intravenous ritodrine. Therefore, NG is a safer drug for women with preterm labor. Journal of Perinatology (2014), 1 – 5
Also, the other study14 showed that trans-dermal patch of NG is effective and safe and reduces the poor neonatal outcome with prolongation of pregnancy duration. Improvement of pregnancy outcome and neonatal conditions are dependent on gestational age, which can be obtained by prolongation of pregnancy and corticosteroids administration.15 Probably, with the same mechanism, NG has shown the ability to reduce the dysmenorrheal pain,16 also, it is more effective than placebo for treatment of preterm labor, however, in comparison with magnesium sulfate and ritodrine, it has not been shown that it is more effective.16 With regard to very high expenses of NICU stay for preterm neonates, and very high expenses of neonatal morbidity and mortality due to preterm delivery, using a trans-dermal NG patch can reduce these expenses and improve neonatal outcome.17 With the best of available knowledge, there are limited studies on comparison of these two agents for prevention of preterm delivery. We could find just one study in Portuguese (but the abstract is in English),10 and in this study, these two agents showed similar results and efficacy in inhibiting preterm delivery for 48 h. Although nifedipine is an effective and safe tocolytics with minimal side effects (such as headache and hypotension), NG showed more tocolysis and less-adverse effects, therefore, it can be considered as an important tocolytic; however, more studies are necessary to confirm this conclusion, and if this superiority can be confirmed, NG can be suggested as first line of the treatments for preterm labor. An important limitation of the present study is the fact that the study was not double-blind and placebo controlled, therefore, it is suggested to perform more double-blind, placebo controlled, randomized clinical trials on this significant issue. CONFLICT OF INTEREST The authors declare no conflict of interest.
ACKNOWLEDGEMENTS Trial registration number and registry website: IRCT201108262624N8.
REFERENCES 1 Cunninghan FG, Leveno KJ, Bloom SL, Hauth JC, Rouse DJ, Spong CY. Williams Obstetrics 23rd edn MC Graw Hill Medical: New York, NY, USA, 804–8312010. 2 Kam KY, Lament RF. Developments in the pharmaco therapeutic management of spontaneous preterm labor. Expert Opin Pharmacother 2008; 9(7): 1153–1168. 3 Kashanian M, Akbarian AR, Soltanzade M. Atosiban and nifedipine for the treatment of preterm labor. Int J Gynaecol Obstet 2005; 91(1): 10–14. 4 Leszczynska-Gorzelak B, Laskowska M, Marciniak B, Oleszczuk J. Nitric oxide for treatment of threatened preterm labor. Int J Gynaecol Obstet 2001; 73(3): 201–206.
© 2014 Nature America, Inc.
Nitroglycerin dermal patch and nifedipine treatment M Kashanian et al
5 5 Pullen KM, Riley ET, Waller SA, Taylor L, Caughey AB, Druzin ML et al. Randomized comparison of intravenous terbutalin VS nitroglycerin for acute intra partum fetal resuscitation. AM J Obstet Gynecol 2007; 1974(414): e1–e6. 6 Black RS, Lees C, Thompson C, Pickles A, Campbell S. Maternal and fetal cardio vascular effects of trans dermal glyceril trinitrate and intravenous ritodrine. Obstet Gynecol 1999; 94(4): 572–576. 7 Chawalisz K, Garfield RE. Role of nitric oxide in the uterus and cervix; implications for the management of labor. J Perinat Med 1998; 26(6): 448–457. 8 Smith GN, Walker MC, Ohlsson A, O’ Brien K, Windrim R. Canadian preterm labor nitroglycerin trial group Randomized double – blind placebo controlled trail of trans dermal nitroglycerin for preterm labor. Am J Obstet Gynecol 2007; 196(1): 37e 1–38e. 9 Rowlands S, Trudinger B, Visva-Lingam S. Treatment of preterm cervical dilatation with glyceryl trinitrate a nitric oxide donor. Aust N Z J Obstet Gynaecol 1996; 36(4): 377–810. 10 Amorim MM, Lippo LA, Costa AA, Coutinho IC, Souza AS. Transdermal nitroglycerin versus oral nifedipine administration for tocolysis: a randomized clinical trial. Rev Bras Ginecol Obstet 2009; 31(11): 552–558.
© 2014 Nature America, Inc.
11 King JF, Flenady V, Papatsonis D, Dekker G, Carbo B. Calcium channel blockers for inhibiting preterm labor, a systematic review of the evidence and protocol for administration of nifedipine. Aust N Z J Obstet Gynecol 2003; 43(3): 192–198. 12 Lees CC, Lojacono A, Thompson C, Danti L, Black RS, Tanzi P et al. Glyceryl trinitrate and ritodrine in tocolysis: an international multicenter randomized study. GTN, Preterm Labor Investigation Group. Obstet Gynecol 1999; 94(3): 403–408. 13 Duckitt K, Thomton S. Nitric oxide donors for the treatment of preterm labor. Cochrane Database Syst Rev 2002; (3): CD002860. 14 Sheikh S, Sheikh AH, Akhter S, Isran B. Efficacy of trans dermal nitroglycerin in idiopathic preterm labor. J Pak Med Assoc 2012; 62(1): 47–50. 15 Smith GN, GUO Y, Wen SW, Walker MC. Canadian Preterm Labor Nitroglycerin Trial Group Secondary analysis of the use of trans dermal nitroglycerin for preterm labor. Am J Obstet Gynecol 2010; 203(6): 565.e1–565.e6. 16 Morgan PJ, Kung R, Tarshis J. Nitroglycerin as a uterine relaxant: a systematic review. J Obstet Gynaecol Can 2002; 24(5): 403–409. 17 Guo Y, Longo CJ, Xie R, Wen SW, Walker MC, Smith GN. Cost - effectiveness of trans dermal nitroglycerin use for preterm labor. Value Health 2011; 14(2): 240–246.
Journal of Perinatology (2014), 1 – 5
ORIGINAL ARTICLE
Comparison between nitroglycerin dermal patch and nifedipine for treatment of preterm labor: a randomized clinical trial M Kashanian1, Z Zamen1 and N Sheikhansari2 OBJECTIVE: Preterm labor and delivery are of the most important complications of pregnancy and have a major role in neonatal mortality and morbidity. Management of preterm labor and prevention from preterm delivery in order to lower these risks have always been under serious concern. The purpose of this study was to compare the effect of nifedipine and nitroglycerin (NG) dermal patch for taking control of preterm labor. STUDY DESIGN: The study was performed as a randomized clinical trial on women who had been admitted in the hospital diagnosed with preterm labor. In one group, the NG dermal patch and in the other group, nifedipine was prescribed. Then the women of the two groups were followed up to delivery and were compared according to arrest of labor for 2 h, 48 h, 7 days, gestational age at the time of delivery and their adverse effects. The primary outcome was to postpone delivery for 48 h in order to have enough time for prescribing corticosteroids RESULT: The women of the two groups did not have any significant difference according to age, body mass index, primary Bishop Score, gestational age at the time of tocolytic therapy, history of abortion, vaginal or cesarean delivery and preterm labor. In more women in the NG group, delivery was postponed for 2 h (59 (98.3%) vs 48 (80%), P = 0.001), for 48 h (52 women (86.7%) vs 41 (68.3%), P = 0.016) and also for 7 days (47 (78.3%) vs 37 (61.7%), P = 0.046), than the women in the nifedipine group. Gestational age at the time of delivery was higher in the NG group (35.6 ± 1.9 vs 34.3 ± 2.05 weeks, P = 0.155), however, it was not statistically significant. Apgar score of minute 5, (P = 0.03) and neonatal weight (P = 0.04), were more and cesarean deliveries, neonatal intensive care unit (NICU) admission and duration of NICU stay were less in the NG group. Adverse effects were similar, minimal and negligible in both groups. CONCLUSION: The NG patch is a more effective method for preterm labor control than nifedipine with regard to minimal side effects. Journal of Perinatology advance online publication, 8 May 2014; doi:10.1038/jp.2014.77
INTRODUCTION Spontaneous preterm labor is an important complication of pregnancy and is the most common cause of neonatal mortality and morbidity. After passing through 34 weeks of gestation, these issues are decreased substantially.1,2 Because of the mentioned reasons, postponing delivery and treatment of premature contractions of the uterus are very important in order to give time for corticosteroids administration and intrauterine transfer of a premature fetus to a well-equipped hospital and neonatal intensive care unit (NICU). Different agents have been evaluated for this purpose, and up to now, there is no tocolytic with no side effects, which is fully perfect and comes with full efficacy. Various tocolytics are different with each other with regard to effectiveness, adverse effects and specific actions just on the uterus. Also their prices are different. β-adrenergic receptor agonists, magnesium sulfate, prostaglandin inhibitors, oxytocin antagonists, calcium channel blockers and nitric oxide donors all have been used for the treatment of preterm labor. One of the effective treatments for preterm labor is nifedipine, which is a calcium channel blocker and is accessible, not
expensive and safe,1,3 and has been proposed for arresting premature labor since late 1970s, and has been reported in different studies as an effective and safe treatment for preterm labor. This agent can inhibit preterm labor through lowering the calcium level in the uterus. The adverse effects mainly include hypotension, palpitation and headache. Nitric oxide (NO) donors are powerful relaxants of smooth muscles, which affect the uterus and vasculature.1,4–6 Studies7 have shown that NO is an important factor in controlling the cervix during its transition from pregnancy to the beginning of labor and in coordination with progestin, regulates the uterine quiescence and cervical stiffness. Reduction in NO production in the uterus is related to beginning of labor,7 whereas NO causes cervical ripening in cervix. Therefore, NO donors can have therapeutic effects as tocolytic agents. Their adverse effects include hypotension, headache, flushing, dizziness and dermal irritation.8 In a preliminary observational study, 50 mg trans-dermal patch of glyceril trinitrate was used in 10 women with cervical dilatation and preterm labor. Delivery was postponed for an average of 46.2 days without any serious side effects.9
1 Iran University of Medical Sciences, Department of Obstetrics & Gynecology, Akbarabadi Teaching Hospital, Tehran, Iran and 2Middlesex University, Business School, London, UK. Correspondence: Dr M Kashanian, Iran University of Medical Sciences, Department of Obstetrics & Gynecology, Akbarabadi Teaching Hospital, No 9, Mostaghimi Alley, Khajeh Nasir Toosi Avenue, Tehran 16117, Iran. E-mail: [email protected] Received 1 November 2013; revised 23 February 2014; accepted 24 March 2014
Nitroglycerin dermal patch and nifedipine treatment M Kashanian et al
2 The purpose of the present study was to compare nifedipine and nitroglycerin (NG) dermal patch for treatment of preterm labor and their side effects. With the best of available knowledge, there is only one study on the comparison of these two agents for prevention of preterm delivery, which is in Portuguese.10 METHODS Study was performed as a randomized clinical trial in the Akbarabadi Teaching Hospital, Tehran, Iran, between June 2010 and March 2011, on women who were admitted in the labor ward with the diagnosis of preterm labor. Inclusion criteria included gestational age between 26 and 34 weeks (according to a reliable last menstrual period and ultrasound confirmation of the first trimester), singleton pregnancy, at least four contractions during 20 min or eight contractions during 60 min plus cervical dilatation of >1 cm and cervical effacement of ⩾ 50%. Exclusion criteria included ruptured membrane, maternal and fetal indications for termination of pregnancy or conditions that in which, continuation of pregnancy was not beneficial such as hypertension, fetal distress, intrauterine fetal death, cervical dilatation of > 5 cm, known hypersensitivity to NG, tocolytic therapy during previous 24 h, vaginal bleeding, smoking, any systemic disorder or any drug use except ordinary supplementations such as iron or folic acid, fetal anomalies, known uterine anomalies, polyhydramnios, oligohydramnios,
intrauterine growth restriction and any sign or symptoms of chorioamnionitis. A sample size of 120 patients (60 in each group) was considered sufficient in order to obtain a power of 90% (α = 0.05,1 − β = 0.085) with a significance level of 5%. A written informed consent was obtained from all participants who were fully informed about the study. Institutional review board approval and institutional ethics committee approval was given to the study, which was also registered in the Iran Registry of Clinical Trial. (Trial registration number: IRCT201108262624N8) Eligible women (127) entered the study and were randomly grouped (by the investigator’s colleague); four parts, block random using sealed, sequentially distributed envelopes to which the letters A, B, C and D had been allocated: the letters A and C to the NG group and the letters B and D to the nifedipine group). The patients chose one of the envelopes, which were opened by the investigator’s colleague, and according to the letters, the groups of patients were determined. At first, in all eligible women, 500 CC normal saline was infused during 30 min and betamethasone, 12 mg every 24 h was prescribed intramuscularly up to two doses. Then, the women were randomly assigned in to the two groups. In the nifedipine group, nifedipine and in the NG group, NG was prescribed. Because the shapes of the two medicines were totally different, blinding was not performed, however, those assessing the outcomes, were blinded to group assignment.
Assessed for eligibility n=155
Excluded (n= 28)
Enrollment
Not meeting inclusion criteria (n=20) Refused to participate (n=7) Other reasons (n= 1)
Is it Randomized?
Allocated to intervention (NG) group (n= 63) Received allocated intervention (n=63)
Allocated to intervention (nifedipine) group (n= 64) Allocation
Did not receive allocated intervention
Did not receive allocated intervention
Lost to follow-up (n= 2)
Lost to follow-up (n=3)
Discontinued intervention (n=2)
Discontinued intervention (n=0)
Analyzed (n=60)
Analyzed (n=60) Excluded from analysis (n=0)
Figure 1.
Received allocated intervention (n=64)
18 Analysis
Excluded from analysis (n=0)
The consort E-flowchart.
Journal of Perinatology (2014), 1 – 5
© 2014 Nature America, Inc.
Nitroglycerin dermal patch and nifedipine treatment M Kashanian et al
3 Table 1.
The characteristic of the two groups
Characteristics
Nifedipine group n = 60
NG group n = 60
P-value
26.33 ± 6.37 27.01 ± 3.12 4.9 ± 1.4 31.4 ± 2.3 14 (32.2%)
24.31 ± 4.26 26.13 ± 5.34 5.2 ± 1.5 31.5 ± 1.9 8 (13.3%)
0.103 0.563 0.592 0.832 0.157
12 (20%) 13 (21.7%) 4 (6.7%)
6 (10%) 7 (11.7%) 3 (5%)
0.915 0.913 0.821
Age (years) mean ± s.d. BMI Primary Bishop score mean ± s.d. Gestational age at inclusion (weeks) mean ± s.d. Previous abortion Previous delivery N = 25 NVD CS Previous preterm delivery
Abbreviations: BMI, body mass index; CS, Caesarean section; NG, nitroglycerin; NVD, normal vaginal delivery.
Blood pressure was checked every 15 min for all women for a duration of 1 h and then their blood pressure was checked every 4 h. Then the contractions of the uterus were evaluated up to 2 h, and the women were followed up to 48 h, 7 days and up to delivery. The primary outcome was to postpone delivery for 48 h in order to have enough time for prescribing corticosteroids, but if the contractions were not stopped (o2 contractions during 20 min with short duration and low force) up to 2 h after the beginning of tocolytics, it was considered as failure of treatment and an alternative tocolytic was started. Also, recurrent episodes of contractions and preterm labor were managed with alternative tocolytics. In the NG group (n = 63), at first a 10 mg NG patch was applied and despite the continuation of contractions within 1 h, the second 10 mg patch was used, and in case of arrest of contractions, the second patch was not used. In the nifedipine group (n = 64), 10 mg (one capsule) nifedipine was prescribed, every 20 min up to maximum 4 doses. In the cases whose contractions had subsided, 20 mg (2 capsules), every 6 h up to 24 h, thence 20 mg every 8 h for the second 24 h and finally 10 mg every 8 h for the next 24 h were prescribed. In the cases of the continuation of contractions, or blood pressure o90/50 mm Hg, the administration of nifedipine was discontinued.11 In two cases, nifedipine was discontinued due to hypotension that occurred immediately after the beginning of the treatment and 60 women were monitored up to delivery (Figure 1). The other five women left the hospital (for financial reasons or personal problems) with their own request without staff permission and we lost to follow them. Therefore, they have not been considered for analysis. All women were followed up to delivery. The gestational age at the time of delivery, the number of women in whom delivery was postponed for 2 h, 48 h and 7 days were compared between the two groups. Also, NICU admission, duration of NICU stay and adverse effects of two agents including maternal hypotension, fetal bradycardia, headache, palpitation and tachycardia, neonatal Apgar score, neonatal weight and delivery rout were compared between the two groups. Data were analyzed using SPSS 18 software (SPSS, Chicago, IL, USA). The student's t-test, χ2-test and Mann–Whitney test were used for analysis. P-value of o0.05 was considered as significant.
(Table 3). Side effects of drugs in the two groups are shown in Table 4. Maternal blood pressure before intervention, in minutes 15, 30, 45 and 60 after intervention were not significantly different between the two groups, but at 120 min after intervention, blood pressure was less in the nifedipine group than in the NG group (98 ± 11 vs 102 ± 12 for systolic pressure and 67 ± 9 vs 68 ± 8 for diastolic pressure (P = 0.04). Also at 180 min after intervention, it was less in the nifedipine group (P = 0.02). It seems that low blood pressure is more prolonged in nifedipine than in the NG group. At the 4th hour after intervention, there was no difference between the groups with regard to blood pressure.
RESULTS Women (120) were evaluated in total (60 women in each group). The women of the two groups did not show significant difference according to age, gestational age at the beginning of study, body mass index and primary Bishop score (Table 1). The two groups did not have significant difference according to different parameters of the Bishop score (Table 2). Arrest of contractions for 2 h, 48 h and 7 days were significantly more in the NG group than in the nifedipine group (Table 3). Also, the number of cesarean deliveries in the NG group was less than in the nifedipine group (Table 3). Gestational age at the time of delivery, neonatal Apgar score were more in the NG group (Table 3). NICU admission, duration of NICU stay and hypotension were less in the NG group
DISCUSSION In the present study, NG could arrest uterine contractions significantly better than nifedipine and the adverse effects were minimal. At the same time, NICU admission and duration of NICU stay in these groups were less than the nifedipine group. There was a 1.3-week difference between groups. Although not statistically significant, this may have influence on neonatal outcomes. In 1996, Rowlands et al.,9 for the first time, in a study on 10 women, showed beneficial effects of trans-dermal NG for postponing delivery in preterm labor. In a study by Smith et al.,8 trans-dermal NG was compared with placebo, and NG’s effect on neonatal outcome was evaluated.
© 2014 Nature America, Inc.
Table 2.
Different parameters of the Bishop score in the two groups
Characteristics Cervical consistency Soft Medium Firm Position Posterior Medium Anterior Station (minus) mean ± s.d. Effacement % mean ± s.d. Cervical Dilatation
P-value
Nifedipine group n = 60
NG group n = 60
33 (55%) 26 (43.33%) 1 (1.66%)
49 (81.6%) 10 (16.66%) 1 (1.66%)
0.8
15 (25%) 19 (31.66%) 26 (43.33%) 2.7 ± 0.7
7 (11.66%) 20 (33.33%) 33 (55%) 2.7 ± 0.7
0.286
63.8 ± 22.8
64.7 ± 19.7
0.386
2.1 ± 0.8
2.1 ± 0.7
0.759
0.9
Abbreviation: NG, nitroglycerin.
Journal of Perinatology (2014), 1 – 5
Nitroglycerin dermal patch and nifedipine treatment M Kashanian et al
4 Table 3.
Treatment outcome in the two groups
Results
Nifedipine group n = 60
NG group n = 60
P-value
48 (80%) 41 (68.3%) 37 (61.7%) 34.3 ± 2.05 30 (50%) 7.7 ± 1.7 21.41 ± 22.18 2357.41 ± 857.12 30 (50%)
59 (98.3%) 52 (86.7%) 47 (78.3%) 35.6 ± 1.9 17 (29%) 8.5 ± 0.9 8.43 ± 15.15 2634.39 ± 584.09 21 (35%)
o0.001 0.016 0.046 0.155 0.015 0.03 0.03 0.04 0.09
Arrest of contractions for 2 h n (%) Arrest of contractions for 48 h n (%) Postpone delivery for 7 days n (%) Gestational age at delivery (weeks) mean ± s.d. Cesarean delivery n (%) Apgar Score minute 5 mean ± s.d. Duration of NICU stay (day) mean ± s.d. Neonatal weight (gram) mean ± s.d. NICU admission n (%) Abbreviations: NG, nitroglycerin; NICU, neonatal intensive care unit.
Table 4.
The adverse effects of the two groups
Adverse effects Headache Hypotension BPo100/70 mm Hg Hot flash Hypotension led to stop of treatment Fetal bradycardia FHR o120 Maternal tachycardia Dermal irritation (erythema)
Nifedipine group n = 60 4 (6.66%) 14 (23.33%) 0 (0%) 2 (3.33%) 0 0 (0%) 0 (0%)
NG group n = 60 3 (5%) 9 (15%) 2 (3.33%) 0 (0%) 0 0 (0%) 3 (5%)
Abbreviations: BP, blood pressure; FHR, fetal heart rate; NG, nitroglycerin.
They concluded that neonatal mortality and morbidity was decreased because of prolongation of pregnancy. In another study that compared ritodrine and glyceril trinitrate,12 it was shown that glyceril trinitrate has less adverse effects than ritodirine and is safer, but the study did not show significant difference for acute tocolysis. Another study,4 has evaluated the effect of trans-dermal NG on 30 pregnant women with the complain of preterm labor who were in their 27 to 34th week of their pregnancy. A reduction has been reported in uterine contractions in all women without any effects on fetal heart rate and cardiotocography. In contrast, in a meta- analysis in 2002,13 five clinical trials, which have been performed on NG effects for delaying delivery and improvement of neonatal outcome in cases of threatened preterm labor, were evaluated. This study reported no improvement in neonatal outcome and delaying delivery. The authors concluded that at the present time, evidence are not enough to support routine use of NO donors for treatment of threatened preterm labor. A study, which compared intravenous terbutalin and intravenous NG for acute intrapartum resuscitation and also evaluated the maternal homodynamic, reported that terbutalin is a more effective tocolytic with less effects on maternal blood pressure, however, there was no difference between the two medications for intrauterine resuscitation during labor.5 In the other study,6 ritodrine and trans-dermal glyceril trinitrate were compared for their effects on fetus and mother. They reported that with the therapeutic amount that is necessary for tocolysis, NG has minimal effects on blood pressure, pulse rate and fetal heart rate, and these effects are less than vascular adverse effects of intravenous ritodrine. Therefore, NG is a safer drug for women with preterm labor. Journal of Perinatology (2014), 1 – 5
Also, the other study14 showed that trans-dermal patch of NG is effective and safe and reduces the poor neonatal outcome with prolongation of pregnancy duration. Improvement of pregnancy outcome and neonatal conditions are dependent on gestational age, which can be obtained by prolongation of pregnancy and corticosteroids administration.15 Probably, with the same mechanism, NG has shown the ability to reduce the dysmenorrheal pain,16 also, it is more effective than placebo for treatment of preterm labor, however, in comparison with magnesium sulfate and ritodrine, it has not been shown that it is more effective.16 With regard to very high expenses of NICU stay for preterm neonates, and very high expenses of neonatal morbidity and mortality due to preterm delivery, using a trans-dermal NG patch can reduce these expenses and improve neonatal outcome.17 With the best of available knowledge, there are limited studies on comparison of these two agents for prevention of preterm delivery. We could find just one study in Portuguese (but the abstract is in English),10 and in this study, these two agents showed similar results and efficacy in inhibiting preterm delivery for 48 h. Although nifedipine is an effective and safe tocolytics with minimal side effects (such as headache and hypotension), NG showed more tocolysis and less-adverse effects, therefore, it can be considered as an important tocolytic; however, more studies are necessary to confirm this conclusion, and if this superiority can be confirmed, NG can be suggested as first line of the treatments for preterm labor. An important limitation of the present study is the fact that the study was not double-blind and placebo controlled, therefore, it is suggested to perform more double-blind, placebo controlled, randomized clinical trials on this significant issue. CONFLICT OF INTEREST The authors declare no conflict of interest.
ACKNOWLEDGEMENTS Trial registration number and registry website: IRCT201108262624N8.
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Nitroglycerin dermal patch and nifedipine treatment M Kashanian et al
5 5 Pullen KM, Riley ET, Waller SA, Taylor L, Caughey AB, Druzin ML et al. Randomized comparison of intravenous terbutalin VS nitroglycerin for acute intra partum fetal resuscitation. AM J Obstet Gynecol 2007; 1974(414): e1–e6. 6 Black RS, Lees C, Thompson C, Pickles A, Campbell S. Maternal and fetal cardio vascular effects of trans dermal glyceril trinitrate and intravenous ritodrine. Obstet Gynecol 1999; 94(4): 572–576. 7 Chawalisz K, Garfield RE. Role of nitric oxide in the uterus and cervix; implications for the management of labor. J Perinat Med 1998; 26(6): 448–457. 8 Smith GN, Walker MC, Ohlsson A, O’ Brien K, Windrim R. Canadian preterm labor nitroglycerin trial group Randomized double – blind placebo controlled trail of trans dermal nitroglycerin for preterm labor. Am J Obstet Gynecol 2007; 196(1): 37e 1–38e. 9 Rowlands S, Trudinger B, Visva-Lingam S. Treatment of preterm cervical dilatation with glyceryl trinitrate a nitric oxide donor. Aust N Z J Obstet Gynaecol 1996; 36(4): 377–810. 10 Amorim MM, Lippo LA, Costa AA, Coutinho IC, Souza AS. Transdermal nitroglycerin versus oral nifedipine administration for tocolysis: a randomized clinical trial. Rev Bras Ginecol Obstet 2009; 31(11): 552–558.
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11 King JF, Flenady V, Papatsonis D, Dekker G, Carbo B. Calcium channel blockers for inhibiting preterm labor, a systematic review of the evidence and protocol for administration of nifedipine. Aust N Z J Obstet Gynecol 2003; 43(3): 192–198. 12 Lees CC, Lojacono A, Thompson C, Danti L, Black RS, Tanzi P et al. Glyceryl trinitrate and ritodrine in tocolysis: an international multicenter randomized study. GTN, Preterm Labor Investigation Group. Obstet Gynecol 1999; 94(3): 403–408. 13 Duckitt K, Thomton S. Nitric oxide donors for the treatment of preterm labor. Cochrane Database Syst Rev 2002; (3): CD002860. 14 Sheikh S, Sheikh AH, Akhter S, Isran B. Efficacy of trans dermal nitroglycerin in idiopathic preterm labor. J Pak Med Assoc 2012; 62(1): 47–50. 15 Smith GN, GUO Y, Wen SW, Walker MC. Canadian Preterm Labor Nitroglycerin Trial Group Secondary analysis of the use of trans dermal nitroglycerin for preterm labor. Am J Obstet Gynecol 2010; 203(6): 565.e1–565.e6. 16 Morgan PJ, Kung R, Tarshis J. Nitroglycerin as a uterine relaxant: a systematic review. J Obstet Gynaecol Can 2002; 24(5): 403–409. 17 Guo Y, Longo CJ, Xie R, Wen SW, Walker MC, Smith GN. Cost - effectiveness of trans dermal nitroglycerin use for preterm labor. Value Health 2011; 14(2): 240–246.
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