Objective
The purpose of this study was to evaluate the efficacy and safety of transdermal nitroglycerin as a tocolytic agent in women with preterm labor.
Study Design
We conducted a systematic review and metaanalysis of randomized controlled trials.
Results
Thirteen studies were included (1302 women) comparing transdermal nitroglycerin vs placebo (2 studies; n = 186); β 2 -adrenergic receptor agonists (9 studies; n = 1024); nifedipine (1 study; n = 50); and magnesium sulfate (1 study; n = 42). There were no significant differences between transdermal nitroglycerin and placebo for delivery within 48 hours of the initiation of treatment or at <28, <34, or <37 weeks of gestation, adverse neonatal outcomes, and neurodevelopmental status at 24 months of life. Nevertheless, 1 study found a marginally significant reduction in the risk of a composite outcome of major neonatal morbidity and perinatal death (3/74 [4.1%] vs 11/79 [13.9%]; relative risk, 0.29; 95% confidence interval, 0.08–1.00). When compared with β 2 -adrenergic receptor agonists, transdermal nitroglycerin was associated with a significant reduction in the risk of preterm birth at <34 and <37 weeks of gestation, admission to the neonatal intensive care unit, use of mechanical ventilation, and maternal side effects. There were no significant differences between transdermal nitroglycerin and nifedipine and magnesium sulfate in delivery within 48 hours of treatment and pregnancy prolongation, respectively. Overall, women who received transdermal nitroglycerin had a higher risk of headache.
Conclusion
Although transdermal nitroglycerin appears to be more effective than β 2 -adrenergic receptor agonists, the current evidence does not support its routine use as a tocolytic agent for the treatment of preterm labor. Further double-blind placebo-controlled trials are needed.
In 2010, an estimated 15 million babies (range, 12.3–18.1 million) were born preterm, which was 11.1% of all live births worldwide, ranging from approximately 5% in several European countries to 18% in some African countries. In 2011, the preterm birth rate in the United States was 11.7%, which currently is one of the 10 countries with the highest number of preterm births and accounts for 42% of all preterm births in the developed world. Preterm birth is now the second most common cause of death in children younger than 5 years of age, after pneumonia, and is the leading cause of neonatal death worldwide. In addition, preterm birth contributes to long-term growth impairment and substantial long-term morbidity such as cognitive, visual, and learning impairments.
Approximately 40-45% of preterm births follow spontaneous preterm labor. Tocolytic therapy continues to be the focus of treatment of preterm labor to allow the administration of antenatal corticosteroids to improve fetal lung maturity and to transfer the mother to a tertiary care facility with a neonatal intensive care unit (NICU). The ideal tocolytic agent should be specific to the common pathway of parturition (activated in the specific patient), easy to administer, effective in the prevention of preterm birth, and able to improve neonatal outcomes with few maternal, fetal, and neonatal side effects and without long-term adverse effects. A wide variety of agents have been used to suppress uterine contractions, which include β 2 -adrenergic receptor agonists, magnesium sulfate, cyclooxygenase inhibitors, calcium channel blockers, oxytocin-receptor antagonists, and nitric oxide donors. Currently, there is no clear first-line tocolytic agent, although a recent metaanalysis suggested that nifedipine appears to meet several characteristics of an ideal tocolytic agent.
Nitric oxide, a potent relaxant of smooth muscle, is possibly involved in maintaining uterine quiescence during pregnancy. Nitroglycerin, a nitric-oxide donor, has been shown to produce a significant decrease in the contractility of human myometrium from pregnant and nonpregnant women in vitro. In 1994, Lees et al reported that transdermal nitroglycerin patches suppressed uterine contractions in all 20 episodes of preterm labor that occurred in 13 consecutive women who were enrolled in a pilot study and suggested that this nitric-oxide donor could be an effective and safe tocolytic agent. Transdermal nitroglycerin has the attraction of simplicity of administration, potential effectiveness, low cost, and few side effects. However, the use of transdermal nitroglycerin for the management of preterm labor has been and continues to be the subject of debate and controversy. The most recent update of the Cochrane review regarding transdermal nitroglycerin for the treatment of preterm labor included 4 randomized controlled trials that involved a total of 436 patients. This review concluded that there was insufficient evidence to support the routine administration of nitric-oxide donors (mainly transdermal nitroglycerin) in the treatment of preterm labor. However, the literature searches in which this review was based were performed in 2002. Subsequent randomized controlled trials evaluating transdermal nitroglycerin have been published; consequently, reassessment of the efficacy and safety of this agent is justified.
The objective of this systematic review and metaanalysis was to evaluate the efficacy and safety of transdermal nitroglycerin as a tocolytic agent in patients with preterm labor.
Materials and Methods
This study was conducted following a prospectively prepared protocol and reported according to the Preferred Reporting Items for Systematic Reviews and Metaanalyses guidelines for metaanalyses of randomized controlled trials.
Literature search
Searches were performed in Medline, Embase, CINAHL, and LILACS (all from inception to Oct. 31, 2013), the Cochrane Central Register of Controlled Trials ( http://www.mrw.interscience.wiley.com/cochrane/cochrane_clcentral_articles_fs.html ; 1960 to Oct. 31, 2013), ISI Web of Science ( http://www.isiknowledge.com ; 1960 to Oct. 31, 2013), Research Registers of ongoing trials ( www.clinicaltrials.gov , www.controlled-trials.com ; www.centerwatch.com ; www.anzctr.org.au ; http://www.nihr.ac.uk , and www.umin.ac.jp/ctr ), and Google scholar with the use of a combination of keywords and text words related to nitroglycerin , preterm labor , and tocolysis . To locate additional publications, we reviewed proceedings of international society meetings of maternal-fetal and reproductive medicine as well as international meetings on preterm birth and tocolysis, and bibliographies of identified studies and review articles. For studies with multiple publications, the data from the most complete report were used and supplemented if additional information appeared in other publications. The language of publication was not restricted.
Study selection
We included randomized controlled trials in which transdermal nitroglycerin was used for tocolysis in patients with preterm labor compared with placebo, no treatment, or alternative tocolytic agents. Trials were excluded in the following circumstances: (1) if they were quasi-randomized; (2) if they evaluated nitroglycerin for tocolysis administered intravenously, sublingually, or orally; or (3) if they evaluated the use of transdermal nitroglycerin for other obstetric or medical conditions such as the improvement of implantation or pregnancy rates in women who underwent assisted reproductive technologies, uterine relaxation in attempted external cephalic version or inverted uterus, acute intrapartum fetal resuscitation, facilitation of fetal extraction of preterm infants during cesarean delivery, and prevention or management of preeclampsia, intrauterine growth restriction, placental abruption, and angina during pregnancy, among others. Published abstracts alone were excluded if additional information on methodologic issues and results could not be obtained. All published studies that were deemed suitable were retrieved and reviewed independently by the 2 authors to determine inclusion. Disagreements were resolved through discussion. Authors of selected studies were contacted to complement data on trial methods and/or outcomes.
Outcome measures
The prespecified primary outcomes were delivery within 48 hours and 7 days of treatment, delivery at <34 and <37 weeks of gestation, perinatal death, neonatal morbidity (respiratory distress syndrome, intraventricular or intracerebral hemorrhage, necrotizing enterocolitis, neonatal sepsis, and admission to NICU), and neurodevelopmental status at ≥12 months of age. Secondary outcomes included the interval between trial entry and delivery, gestational age at birth, delivery at <32 and <28 weeks of gestation, recurrent preterm labor, maternal adverse events, discontinuation of treatment because of adverse events, birthweight, fetal bradycardia and tachycardia, other neonatal morbidities, and the use of mechanical ventilation.
Assessment of risk of bias
Study quality assessment was conducted according to a tool recommended by the Cochrane Collaboration that considers 7 items: (1) random sequence generation, (2) allocation concealment, (3) blinding of participants and personnel, (4) blinding of outcome assessment, (5) incomplete outcome data, (6) selective reporting, and (7) other bias. Review authors’ judgments were categorized as “low risk” of bias, “high risk” of bias, or “unclear risk” of bias. The risk of bias in each included trial was assessed individually by the 2 investigators, and discrepancies were resolved through discussion.
Data extraction
Using a standardized data abstraction form, the 2 authors independently extracted data from each article on study characteristics (randomization procedure; concealment allocation method; blinding of providers, patients, and outcome assessors; completeness of outcome data for each outcome; and intention-to-treat analysis), participants (inclusion and exclusion criteria; definition of preterm labor; cervical dilation and effacement at trial entry; gestational age at randomization; number of women randomly assigned; baseline characteristics; and country and date of recruitment), details of intervention (aim; loading and maintenance dose; route, duration and retreatment; use of alternative tocolytic therapy; and routine administration of antenatal corticosteroids), and outcomes (number of outcome events and/or mean ± SD for each outcome). In an attempt to obtain additional data, we contacted 5 authors by e-mail of whom only 1 responded. Disagreements regarding extracted data were resolved by discussion between the authors.
Statistical analysis
Statistical analyses were performed according to the guidelines of the Cochrane Collaboration. Outcomes were analyzed on an intent-to-treat basis. If this was not clear from the original article, then we carried out reanalysis when possible. If no evidence of a substantial difference in study populations, interventions, or outcome measurements was found, a metaanalysis was performed. For dichotomous data, we calculated the summary relative risk (RR) with 95% confidence interval (CI). For continuous data, we used the mean difference if outcomes were measured in the same way among trials or standardized mean difference (with 95% CI) if the same outcome was measured in a variety of ways.
Four prespecified subgroup analyses were performed to compare transdermal nitroglycerin with placebo, β 2 -adrenergic receptor agonists, magnesium sulfate, and nifedipine. The subgroup analyses that compared transdermal nitroglycerin vs cyclooxygenase inhibitors or oxytocin-receptor antagonists were not performed because trials that addressed these comparisons were not identified. Additional subgroup analyses were planned to assess primary outcomes according to several characteristics (definition of preterm labor, cervical dilation at trial entry, dose of transdermal nitroglycerin, status of membranes, plurality, gestational age at trial entry, study setting, maintenance therapy, use of alternative tocolytic therapy, and antenatal corticosteroid therapy); however, these were not undertaken given the small number of studies that were included in each comparison and because of insufficient data.
Heterogeneity of the results among studies was tested with the quantity I 2 , which describes the percentage of total variation across studies that is due to heterogeneity rather than chance. A value of 0% indicates no observed heterogeneity, whereas I 2 values of ≥50% indicate a substantial level of heterogeneity. A fixed-effects model was used to pool data across studies if substantial statistical heterogeneity was not present. If I 2 values were ≥50%, a random effects model was used to pool data across studies if causes of heterogeneity could not be determined and if the average treatment effect was considered clinically meaningful. A sensitivity analysis that included only trials having adequate concealment allocation and were double masked was planned to explore the impact of study quality on the effect size for the primary outcomes. This analysis was not performed because only 1 of the included studies was truly double masked. However, we undertook a sensitivity analysis for the comparison of transdermal nitroglycerin vs β 2 -adrenergic receptor agonists by including only studies with adequate concealment of allocation.
The number needed to treat (NNT) for benefit or harm (with 95% CI) was calculated for the outcomes for which there was a statistically significant reduction or an increase in risk difference based on control event rates in the included studies. We assessed publication and related biases visually by examining the symmetry of funnel plots and statistically by using the Egger test. A probability value of < .1 was considered to indicate significant asymmetry.
Analyses were performed with the Review Manager (RevMan; version 5.1.7; The Nordic Cochrane Centre, København, Denmark) and StatsDirect (version 2.7.9; StatsDirect Ltd, Cheshire, UK).
Results
We identified 431 studies in our literature search and considered 33 of them to be potentially eligible ( Figure 1 ). Thirteen studies, which included 1302 women, met the inclusion criteria: 2 studies evaluated transdermal nitroglycerin vs placebo ; 9 studies evaluated transdermal nitroglycerin vs β 2 -adrenergic receptor agonists (3 studies used ritodrine ; 2 studies used fenoterol ; 1 study each used salbutamol, albuterol, isoxsuprine, and ritodrine or salbutamol ), and 1 each evaluated transdermal nitroglycerin vs nifedipine and transdermal nitroglycerin vs magnesium sulfate. One study that primarily evaluated transdermal nitroglycerine vs ritodrine also assessed transdermal nitroglycerine vs placebo in 2 hospitals that did not routinely use any tocolytics. Data on child neurodevelopmental outcomes for 2 trials were reported in 2 additional publications. Moreover, 1 author provided additional unpublished data for 1 trial.
The main characteristics of the studies included in our review are summarized in Table 1 . Two studies were conducted in Canada ; 2 studies were conducted in European countries ; 5 studies were conducted in Asian countries ; 1 study each was conducted in Australia and Brazil ; and the remaining 2 were multicenter studies conducted in 9 countries. The sample size ranged from 26 to 236 women (median, 60 women). Preterm labor was defined as the presence of uterine contractions with evidence of cervical changes in 9 trials. One study included patients with or without cervical changes ; 2 studies did not include cervical changes in the diagnosis of preterm labor ; and 1 study did not report on the definition of preterm labor. All but 1 study were limited to women with intact membranes. Only 2 trials included women with multiple gestations. Standard maternal and fetal contraindications to tocolysis were reported as exclusion criteria in most included studies. The gestational age at inclusion varied from 23-36 weeks. The minimum gestational age at trial entry ranged from 23–28 weeks, and the maximum ranged from 32–36 weeks. Most studies included women from 24-34 weeks of gestation.
| First author, year | Location | Inclusion/exclusion criteria | Gestational age (wks), cervical dilatation/effacement, and frequency of uterine contractions at trial entry | Interventions (sample size) | Alternative tocolytic therapy |
|---|---|---|---|---|---|
| NITROGLYCERIN COMPARED WITH PLACEBO | |||||
| Smith, 1999 | Canada | Inclusion: women with singleton or twin pregnancy in preterm labor (change in the Bishop score over an initial period of saline infusion) and intact membranes. Exclusion: rupture of membranes, any maternal condition such as significant antepartum hemorrhage or fetal condition necessitating immediate delivery, suspicion of fetal anomalies or intrauterine fetal death, multiple gestation greater than twins, cervical dilatation >4 cm, treatment with another tocolytic agent within 24 hours, previous enrollment in the trial, known sensitivity to nitroglycerin, and failure to give consent. | 24-34; mean Bishop score at randomization was 6.8 ± 2.1 and 6.3 ± 2.6 for nitroglycerin and placebo groups, respectively. No data on frequency of uterine contractions at trial entry. | Nitroglycerin (n = 17): one 10 mg/24 h (0.4 mg/h) transdermal patch was applied to the skin of the abdomen. If the uterus was still actively contracting (4 contractions per 20 min) after 1 hour of application of the first patch, or there was evidence of ongoing cervical change, a second patch, in addition to the first, was placed in the same manner. Placebo (n = 16): the impermeable protective backing of the nitroglycerin patch which prevented contact between skin and drug reservoir was not removed, and the patch was placed on the woman’s abdomen. Twenty-four hours after initiation of treatment, the patches were replaced with the same number of patches for a further 24 hours of treatment. | None of the subjects in either arm received any other tocolytic at any time. |
| Smith, 2007 | Canada | Inclusion: women with singleton pregnancy in preterm labor (at least 4 painful uterine contractions per 20 min and evidence of cervical change [change in the Bishop score or Bishop score >6]) and intact membranes. Exclusion: any maternal/fetal condition necessitating delivery, multiple gestation, rupture of membranes, intrauterine fetal death, treatment with tocolytics within 24 hours, lethal fetal anomaly, cervical dilatation >5 cm, previous enrollment in the trial, sensitivity to nitroglycerin, or failure to give consent. | 24-32; no data on cervical dilatation and effacement, and frequency of uterine contractions at trial entry. | Nitroglycerin (n = 74): one 10 mg/24 h (0.4 mg/h) transdermal patch was applied to the skin of the abdomen. If there was ongoing uterine activity (4 contractions per 20 min) or evidence of further cervical change 1 hour after placement of the first study patch, one additional study patch was placed. Placebo (n = 79): similar placebo patch. Twenty-four hours after initiation of treatment, the patches were replaced with the same number of patches for a further 24 hours of treatment. | None of the subjects in either arm received any other tocolytic at any time. |
| NITROGLYCERIN COMPARED WITH β 2 -ADRENERGIC-RECEPTOR AGONISTS | |||||
| Bisits, 1998 | Australia | Inclusion: women with singleton pregnancy in preterm labor (painful regular uterine contractions at <5-min intervals) and intact membranes. Exclusion: multiple pregnancy, intrauterine infection, severe fetal distress, rapidly progressing labor, advanced cervical dilatation (>5 cm), active vaginal bleeding, and the presence of contraindications to nitrate therapy or albuterol. | 24-34; no data on cervical dilatation and effacement, and frequency of uterine contractions at trial entry. | Nitroglycerin (n = 13): one 10 mg/24 h (0.4 mg/h) transdermal patch was applied to the skin of the upper abdomen and replaced, if necessary, every 24 hours. If no decrease in uterine contractility was noted after 1 hour, a second patch was applied. If there was still no decrease in uterine activity after another hour, the patient received intravenous albuterol and the patch was removed. If uterine activity ceased, the patch was removed 12 hours later. If after this period further tocolytic treatment was indicated, 1 patch could be placed on the abdomen every 24 hours. Albuterol (n = 13): 25 μg/min intravenously. The infusion rate was subsequently titrated against uterine activity and maternal heart rate. If uterine contractions ceased, the infusion rate was halved every 30 min until the patient was completely weaned. | Albuterol in nitroglycerin group (15.4%) |
| Lees, 1999 | United Kingdom, Italy, Belgium, Germany, Thailand, and Indonesia | Inclusion: women with singleton or multiple pregnancy in preterm labor (at least 3 painful, uterine contractions every 10 min for more than 1 hour with or without cervical change) and intact membranes. Exclusion: hypotension, major fetal congenital abnormality, non reassuring fetal cardiotocography, antepartum hemorrhage, placenta previa, rupture of membranes, chorioamnionitis, cervical suture in situ, unexplained pyrexia, urinary tract infection, contraindication to nitrates or β-agonists, and previous treatment with tocolytics in current pregnancy. | 24-36; no data on cervical dilatation and effacement, and frequency of uterine contractions at trial entry. | Nitroglycerin (n = 113): one 10 mg/24 h (0.4 mg/h) transdermal patch was applied to the skin of the abdomen. If, after 1 hour, there was no reduction in contraction frequency or strength, an additional patch was placed. Patches remained in place for a full 24 hours, at which time they were removed. Ritodrine (n = 120): 50 μg/min intravenously. The rate of administration was titrated to the woman’s contractions and increased according to local guidelines. Treatment was terminated after cessation of contractions for 24 hours, or progress of labor to delivery. In 2 hospitals that did not use any tocolytics routinely, a double-masked placebo controlled trial was done: Nitroglycerin (n = 7): two patches applied per 24 hours with a maximum duration of 48 hours. Placebo (n = 5): similar placebo patch. | Cross over to other treatment (6% in each group) |
| Szulc, 2000 | Poland | Inclusion: women with singleton pregnancy in preterm labor (at least four uterine contractions every 20 min with effacement ≥80% or cervical dilatation up to 3 cm), no contraindications to tocolysis, and intact membranes. Exclusion: not reported. | 23-34; no data on cervical dilatation and effacement, and frequency of uterine contractions at trial entry. | Nitroglycerin (n = 30): one 10 mg/24 h (0.4 mg/h) transdermal patch was applied to the skin of the lower abdomen. If contractions persisted after 1 hour, a second patch of 5 mg was placed. Depending on uterine activity, 1 additional patch was placed at 24 hours. Fenoterol (n = 30): 1 mg plus verapamil (10 mg) in 500 ml of 5% dextrose solution at a rate of 10-30 drops per min which was increased according to uterine contractions and tolerance to the drug. After contractions ceased, patients received fenoterol (5 mg) + verapamil (40 mg) orally every 4-6 hours. | Not reported |
| Schleussner, 2001 | Germany | Inclusion: women with singleton pregnancy in preterm labor (at least three uterine contractions every 30 min with Bishop score ≥3), maternal age ≥18 years, and intact membranes. Exclusion: multiple pregnancy, preterm rupture of membranes, chorioamnionitis, placenta previa, abruption placentae, antepartum hemorrhage, contraindication to nitroglycerin or β-agonists, and inclusion in other study. | 27-35; mean Bishop score, sonographic cervical length, and cervical funneling at trial entry was 4.5 ± 1.2, 2.3 ± 0.8, and 51%, and 4.7 ± 1.4, 2.4 ± 0.9, and 62% for nitroglycerin and control groups, respectively. Mean uterine activity was 6 contractions per 30 min in both groups. | Nitroglycerin (n = 57): two 10 mg/24 h (0.8 mg/h) transdermal patches were applied to the skin of the periumbilical area. Fenoterol (n = 61): 60-120 μg/h plus magnesium sulfate (1.2 g/h) and verapamil (0.6-1.4 mg/h) intravenously or oral metoprolol (47.5 mg/d). The doses of the study medications were halved after 24 hours without contractions and stopped after 48 hours without contractions. Then, all women from both arms received magnesium aspartame oral 300 mg/d until 35 weeks of gestation. | Not reported |
| Bisits, 2004 | Australia, Singapore, and Hong Kong | Inclusion: women with singleton pregnancy in preterm labor (at least two uterine contractions every 10 min) with positive cervicovaginal fetal fibronectin or ruptured membranes. Exclusion: multiple pregnancy, chorioamnionitis, cervical dilatation ≥5 cm, a history of hypotension, and a negative cervicovaginal fetal fibronectin in the presence of intact membranes. | 24-35; mean cervical dilatation at trial entry was 0.71 and 0.63 cm for nitroglycerin and β 2 -adrenergic-receptor agonists groups, respectively. | Nitroglycerin (n = 120): one 10 mg/24 h (0.4 mg/h) transdermal patch was placed on the skin of the anterior chest wall. If contractions did not settle in 1 hour, then 1 additional patch was placed. If the contractions settled, the patch was left on for 12 hours and then removed. If the contractions did not settle after 2 hours of nitroglycerin treatment, they were then removed and β 2 sympathomimetic treatment was initiated. Salbutamol or ritodrine (n = 116) according to local practice. No data on doses used. | β 2 -adrenergic-receptors agonists in nitroglycerin group (33.1%) |
| Lee, 2004 | South Korea | Inclusion: women with singleton pregnancy in preterm labor (≥4 uterine contractions in 20 min or at least 8 in 60 min and cervical dilatation >1 cm) and intact membranes. Exclusion: premature rupture of membranes, fetal malformation, preeclampsia, hypotension, non-reassuring fetal cardiotocography, chorioamnionitis, placenta previa, urinary tract infection, history of maternal cardiovascular disease, and hypersensitivity or contraindication to study drugs. | 24-34; no data on cervical dilatation and effacement, and frequency of uterine contractions at trial entry. | Nitroglycerin (n = 24): one 5 mg/24 h (0.2 mg/h) transdermal patch was applied to the skin of the abdomen, followed by an additional patch after 1 hour if contractions continued. Patches were left on for 24 hours and then removed. Ritodrine (n = 35): 25 μg/min intravenously was increased every 15 min until contractions were inhibited or side effects became intolerable (maximum dose, 200 μg/min). | Magnesium sulfate |
| Wani, 2004 | United Arab Emirates | Inclusion: women in preterm labor (no definition provided), intact membranes, no vaginal bleeding, and no cardiovascular disease. Exclusion: abnormal fetal cardiotocography, intrauterine infection, rupture of membranes, fetal death, severe intrauterine growth restriction, antepartum hemorrhage with hemodynamic instability, and cervical dilatation >4 cm. | 23-34; no data on cervical dilatation and effacement, and frequency of uterine contractions at trial entry. | Nitroglycerin (n = 67): one 10 mg/24 h (0.4 mg/h) transdermal patch was applied to the skin of the abdomen, followed by an additional patch after 1 hour if contractions continued. Patches were replaced after 24 hours. Ritodrine (n = 65): 150 μg/min intravenously increasing by 50 μg/min every 10 minutes until contractions ceased, a maximum dose of 350 μg/min was reached or the occurrence of side effects. After cessation of contractions, a minimal dose of ritodrine was continued to maintain suppression of uterine activity. Treatment was continued for at least 24 hours after cessation of contractions, nitroglycerin was used for up to 5 days and ritodrine for a maximum of 3 days. Recurrence of preterm labor was treated as randomized. | Not reported |
| Latif, 2010 | India | Inclusion: women with singleton pregnancy in preterm labor (>20 uterine contractions per hour documented by external tocography, and/or cervical dilatation ≥2 cm) and intact membranes. Exclusion: multiple pregnancy, premature rupture of membranes, known contraindications to tocolytics, and treatment with tocolytics in current pregnancy. | 28-36; among women allocated to receive nitroglycerin, 70% had a cervical dilatation >1 cm and 80% had 2-4 uterine contractions per minute at trial entry. The corresponding values among women allocated to receive salbutamol were 77% and 77%, respectively. | Nitroglycerin (n = 30): one 10 mg/24 h (0.4 mg/h) transdermal patch was applied to the skin of the abdomen, followed by an additional patch after 1 hour if there was no reduction in contraction frequency or intensity. Patches were left in place for 24 hours. Salbutamol (n = 30): 5 mg in 500 ml of 5% dextrose solution. The infusion was started at a rate of 10 drops per min, increased by 10 drops every 5-10 min until contractions ceased and then tapered off slowly in the next 12 hours. Both treatments were discontinued if contractions ceased for 24 hours or delivery occurred. | Not reported |
| Rekha, 2012 | India | Inclusion: women with singleton pregnancy in preterm labor (≥4 uterine contractions in 20 min or at least 8 in 60 min, cervical dilatation >1 cm, and effacement ≥80%). Exclusion: active labor, preterm premature rupture of membranes, chorioamnionitis, severe hypertension, eclampsia, antepartum hemorrhage, fetal distress, severe intrauterine growth restriction, lethal congenital anomaly, intrauterine death, and sensitivity or contraindication to tocolysis. | 24-36; no data on cervical dilatation and effacement, and frequency of uterine contractions at trial entry. | Nitroglycerin (n = 50): one 10 mg/24 h (0.4 mg/h) transdermal patch was applied to the skin of the anterior abdominal wall. If, after 1 hour, there was no reduction in uterine activity, an additional 10 mg/24 h patch was placed and both patches were continued for 24 hours. Twenty-four hours after initiation of treatment, the patches were replaced with the same number of patches for a further 24 hours of treatment. Isoxsuprine (n = 50): 10 mg intramuscularly every 8 hours until 24 hours of uterine relaxation, thereafter 10 mg orally every 8 hours for 7 days. | Not reported |
| NITROGLYCERIN COMPARED WITH NIFEDIPINE | |||||
| Amorim, 2009 | Brazil | Inclusion: women with singleton pregnancy in preterm labor (≥4 uterine contractions in 30 min with a duration ≥30 seconds and cervical changes) and intact membranes. Exclusion: premature rupture of membranes, preeclampsia, diabetes, placental abruption, fetal malformation, and previous treatment with tocolytics. | 24-34; median (range) cervical dilatation and number of uterine contractions per 10 min at trial entry was 2 (2-4) cm and 3 (2-4), respectively. | Nitroglycerin (n = 26): one 10 mg/24 h (0.4 mg/h) transdermal patch was applied to the skin of arm or forearm. If contractions persisted after 6 hours, a second patch of 10 mg was placed (maximum dose of 20 mg/24 h). Nifedipine (n = 24): 10 mg sublingually repeated after 30 min. Then 20 mg orally every 6 hours for at least 24 hours. | Terbutaline |
| NITROGLYCERIN COMPARED WITH MAGNESIUM SULFATE | |||||
| Mirteimoori, 2009 | Iran | Inclusion: women with singleton pregnancy in preterm labor (≥4 uterine contractions in 20 min with cervical dilatation <4 cm and effacement ≥80%), and intact membranes. Exclusion: placenta previa, abruptio placentae, hypertension, fetal growth restriction, fetal abnormality, chorioamnionitis, and a history of recurrent vaginal bleeding, urinary tract infection, sensitivity or contraindication to nitrates or magnesium sulfate, rupture of the membranes, and renal insufficiency. | 27-36; no data on cervical dilatation and effacement, and frequency of uterine contractions at trial entry. | Nitroglycerin (n = 21): one 5 mg/24 h (0.2 mg/h) transdermal patch was applied to the skin of the upper abdomen. No additional patches were placed. Magnesium sulfate (n = 21): 4-g bolus then 2 g/h until suppression of uterine contractions. | Not reported |
Overall, nitroglycerin dosing regimens were similar across the trials. Ten studies used one 10-mg/24-h (0.4 mg/h) transdermal patch that was applied to the skin of the abdomen, anterior chest wall, arm, or forearm. One study used two 10-mg/24-h (0.8 mg/h) transdermal patches, and 2 studies used one 5-mg/24-h (0.2 mg/h) transdermal patch. In 10 studies, 1 additional patch was placed if contractions persisted after 1 hour of the application of the first patch. In 1 study, a second patch was applied if contractions persisted after 6 hours. No additional patches were placed in the remaining 2 studies. In 6 studies, 1 additional patch was placed at 24 hours after the initiation of treatment. One study used transdermal nitroglycerine for up to 5 days after the cessation of contractions. Verapamil or metoprolol was used for suppression of the tachycardia that was caused by fenoterol in 2 studies that compared transdermal nitroglycerin with this β 2 -adrenergic receptor agonist. Moreover, magnesium sulfate was added to the fenoterol infusion in one of these studies. The use of alternative tocolytic therapy was mentioned explicitly in 5 studies. In 2 studies, none of the subjects in either arm received any other tocolytic at any time. The use of alternative tocolytic therapy was not reported in the remaining 6 studies. Six trials reported the administration of antenatal corticosteroids for most women who were enrolled. The use of antenatal corticosteroids was not reported in the remaining 7 trials. The main primary outcome measures were interval between trial entry and delivery (7 studies), delivery within 48 hours (5 studies) and 7 days of treatment (5 studies), and delivery at <37 weeks of gestation (4 studies).
Figure 2 shows the risk of bias in each included study. Nine studies had adequate generation of allocation sequence, and 8 studies reported adequate concealment of allocation. Blinding of the intervention was not performed in any of the 11 studies that evaluated transdermal nitroglycerin vs any other tocolytic, and masking assessment of outcomes was not reported in 10 of these trials. Of the 2 trials that evaluated transdermal nitroglycerin vs placebo, only 1 trial was actually double-blinded and placebo-controlled. In the remaining study, true placebo patches were not available, and the nursing staff who applied the patches were not blinded to the treatment. However, we judged that assessment and measurement of most outcomes included in our review are considered objective in nature and were not likely to be influenced by a lack of blinding. All studies had an adequate handling of incomplete outcome data; 10 studies were free of suggestion of selective outcome reporting. Eight studies appeared to be free of other sources of bias. The study by Smith et al was stopped early because of feasibility issues after 158 women were recruited (26% of the original sample size was calculated). Six trials met ≥5 criteria; 3 trials met 4 criteria, and the remaining 4 trials met <3 criteria.
Transdermal nitroglycerin vs placebo
Two trials, with a total of 186 women, compared transdermal nitroglycerin with placebo. There were no significant differences between transdermal nitroglycerin and placebo for delivery within 48 hours of the initiation of treatment or at <28, <34, or <37 weeks of gestation or gestational age at birth ( Table 2 ). Maternal side effects that were due to study medication were significantly more common among women who were allocated to transdermal nitroglycerin rather than placebo (67% vs 45%; RR, 1.49; 95% CI, 1.14–1.94; NNT for harm, 5; 95% CI, 2–16). In addition, 1 trial reported that headache and local irritation were significantly more frequent among women in the transdermal nitroglycerin group than among women in the placebo group. No statistically significant differences were seen for flushing, dizziness, hypotension, and fetal bradycardia.
| Outcome | Number of trials | Events/total (n/N) or total number (N) | Relative risk or mean difference (95% CI) | I 2 (%) | |
|---|---|---|---|---|---|
| Nitroglycerin | Placebo | ||||
| Pregnancy | |||||
| Delivery within 48 hours of treatment | 2 | 24/91 | 31/95 | 0.80 (0.51–1.24) | 6 |
| Preterm birth at <28 weeks of gestation | 1 | 8/74 | 17/79 | 0.50 (0.23–1.09) | NA |
| Preterm birth at <34 weeks of gestation | 1 | 26/74 | 30/79 | 0.93 (0.61–1.41) | NA |
| Preterm birth at <37 weeks of gestation | 2 | 37/81 | 41/84 | 0.68 (0.19–2.43) | 52 |
| Gestational age at birth | 2 | 91 | 95 | 1.1 (–0.5 to 2.7) | 0 |
| Any maternal side effect | 2 | 61/91 | 43/95 | 1.49 (1.14–1.94) | 0 |
| Headache | 1 | 42/74 | 23/79 | 1.95 (1.31–2.90) | NA |
| Flushing | 1 | 11/74 | 13/79 | 0.90 (0.43–1.89) | NA |
| Local irritation | 1 | 10/74 | 3/79 | 3.56 (1.02–12.43) | NA |
| Dizziness | 1 | 9/74 | 6/79 | 1.60 (0.60–4.28) | NA |
| Hypotension | 1 | 9/74 | 8/79 | 1.20 (0.49–2.95) | NA |
| Fetal bradycardia | 1 | 7/74 | 2/79 | 3.74 (0.80–17.41) | NA |
| Perinatal and neonatal | |||||
| Birthweight, g | 1 | 17 | 16 | 327 (–272 to 926) | NA |
| Respiratory distress syndrome | 1 | 3/17 | 6/16 | 0.47 (0.14–1.57) | NA |
| Necrotizing enterocolitis | 2 | 1/91 | 2/95 | 0.67 (0.11–4.07) | 27 |
| Grade III/IV intraventricular hemorrhage | 1 | 2/74 | 1/79 | 2.14 (0.20–23.06) | NA |
| Periventricular leukomalacia | 1 | 0/74 | 2/79 | 0.21 (0.01–4.37) | NA |
| Chronic lung disease | 1 | 1/74 | 7/79 | 0.15 (0.02–1.21) | NA |
| Perinatal death | 2 | 1/91 | 4/95 | 0.34 (0.05–2.13) | 0 |
| Composite of neonatal morbidity/perinatal mortality | 1 | 3/74 | 11/79 | 0.29 (0.08–1.00) | NA |
| Child developmental performance total score at 1-year follow-up | 1 | 55 | 56 | 3.3 (–15.1 to 21.7) | NA |
| Child developmental performance total score at 2-year follow-up | 1 | 42 | 41 | 16.6 (–7.5 to 40.6) | NA |
There were no significant differences among the groups for the risk of major adverse perinatal/neonatal outcomes and neurodevelopmental status at 12 and 24 months of age. Nevertheless, the study by Smith et al found a marginally significant reduction in the risk of a composite outcome (occurrence of ≥1 of chronic lung disease, necrotizing enterocolitis, grade 3 or 4 intraventricular hemorrhage, periventricular leukomalacia, and perinatal death) in the transdermal nitroglycerin group compared with the placebo group (4% vs 14%; RR, 0.29; 95% CI, 0.08–1.00).
Transdermal nitroglycerin vs β 2 -adrenergic receptor agonists
This subgroup analysis included data from 9 trials with a total of 1024 women. Compared with women who received β 2 -adrenergic receptor agonists, patients who received transdermal nitroglycerin had a statistically significant reduction in the risk of preterm birth at <34 weeks of gestation (20% vs 28%; RR, 0.71; 95% CI, 0.51–0.99; I 2 = 47%; NNT for benefit, 12; 95% CI, 7–362) and preterm birth at <37 weeks of gestation (44% vs 57%; RR, 0.76; 95% CI, 0.60–0.96; I 2 = 67%; NNT for benefit, 7; 95% CI, 4–44; Table 3 ). A significant increase in the interval between trial entry and delivery (mean difference, 1.4 days; 95% CI, 0.7–2.0; I 2 = 49%) and birthweight (mean difference, 331 g; 95% CI, 67–595; I 2 = 53%) was also shown. No differences were seen in the risk of delivery within 48 hours and 7 days of the initiation of treatment.
| Outcome | Number of trials | Events/total (n/N) or total number (N) | Relative risk or mean difference (95% CI) | I 2 (%) | |
|---|---|---|---|---|---|
| Nitroglycerin | β 2 -agonists | ||||
| Pregnancy | |||||
| Delivery within 48 hours of treatment | 7 | 90/461 | 77/477 | 1.18 (0.91–1.53) | 28 |
| Delivery within 7 days of treatment | 7 | 140/450 | 140/455 | 1.00 (0.83–1.20) | 47 |
| Preterm birth at <34 weeks of gestation | 3 | 45/230 | 65/235 | 0.71 (0.51–0.99) | 44 |
| Preterm birth at <37 weeks of gestation | 7 | 199/450 | 258/455 | 0.76 (0.60–0.96) | 67 |
| Pregnancy prolongation | 3 | 148 | 161 | 1.4 (0.7–2.0) | 49 |
| Maternal tachycardia | 5 | 3/265 | 166/277 | 0.03 (0.01–0.07) | 0 |
| Headache | 7 | 169/335 | 33/351 | 5.92 (2.04–17.22) | 82 |
| Hypotension | 2 | 10/74 | 0/85 | 30.24 (1.86–492.7) | NA |
| Flushing | 3 | 16/137 | 48/141 | 0.35 (0.22–0.57) | 34 |
| Palpitations | 4 | 7/268 | 125/273 | 0.07 (0.03–0.13) | 39 |
| Nausea/vomiting | 6 | 21/285 | 39/301 | 0.57 (0.35–0.94) | 0 |
| Chest pain | 5 | 1/272 | 30/288 | 0.10 (0.03–0.33) | 0 |
| Dyspnea | 2 | 1/107 | 16/110 | 0.09 (0.02–0.46) | 0 |
| Pulmonary edema | 2 | 0/144 | 1/147 | 0.34 (0.01–8.34) | NA |
| Dizziness | 2 | 7/151 | 16/158 | 0.59 (0.12–2.78) | 58 |
| Discontinuation of treatment because of adverse effects | 3 | 19/237 | 39/246 | 0.52 (0.31–0.86) | 45 |
| Fetal tachycardia | 3 | 0/121 | 11/130 | 0.08 (0.01–0.61) | 0 |
| Perinatal and neonatal | |||||
| Birthweight, g | 2 | 121 | 123 | 331 (67–595) | 53 |
| Respiratory distress syndrome | 2 | 4/104 | 12/108 | 0.35 (0.12–1.04) | 0 |
| Necrotizing enterocolitis | 1 | 10/120 | 10/116 | 0.97 (0.42–2.24) | NA |
| Intracerebral/intraventricular hemorrhage | 2 | 4/174 | 11/174 | 0.37 (0.12–1.12) | 0 |
| Neonatal sepsis | 1 | 0/54 | 4/58 | 0.12 (0.01–2.16) | NA |
| Retinopathy of prematurity | 1 | 1/54 | 0/58 | 3.22 (0.13–77.34) | NA |
| Chronic lung disease | 1 | 9/120 | 9/116 | 0.97 (0.40–2.35) | NA |
| Perinatal death | 4 | 5/335 | 12/336 | 0.44 (0.16–1.18) | 0 |
| Admission to the neonatal intensive care unit | 3 | 32/171 | 58/173 | 0.57 (0.40–0.81) | 0 |
| Use of mechanical ventilation | 3 | 6/171 | 16/173 | 0.38 (0.15–0.95) | 0 |
| Patent ductus arteriosus | 1 | 3/120 | 10/116 | 0.29 (0.08–1.03) | NA |
| Griffiths mental development total score at 18 months of age <2 SD of the mean | 1 | 5/58 | 4/54 | 1.16 (0.33–4.11) | NA |
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