TABLE 1.

Characteristics of studies included in the systematic review

First author, year	Location	Inclusion/exclusion criteria	Gestational age (weeks), cervical dilatation/effacement, and frequency of uterine contractions at trial entry	Interventions (sample size)	Alternative tocolytic therapy
Nitroglycerin compared with placebo
Smith,56 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 minutes) after one 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,57 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 minutes) 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 β2-adrenergic-receptor agonists
Bisits,58 1998	Australia	Inclusion: women with singleton pregnancy in preterm labor (painful regular uterine contractions at <5-minute 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 removed. If uterine activity ceased, the patch was removed 12 hours later. If after this period further tocolytic treatment was indicated, one 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 minutes until the patient was completely weaned.	Albuterol in nitroglycerin group (15.4%)
Lees,59 1999	United Kingdom, Italy, Belgium, Germany, Thailand, and Indonesia	Inclusion: women with singleton or multiple pregnancy in preterm labor (at least three 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 one hour, there was no reduction in contraction frequency or strength, an additional patch was placed. Patches remained in place for full 24 hours, at the end of which 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 two 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,60 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 h, a second patch of 5 mg was placed. Depending on uterine activity, one 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 minute which was increased according to uterine contractions and tolerance to drug. After contractions ceased, patients received fenoterol (5 mg) + verapamil (40 mg) orally every 4–6 hours.	Not reported
Schleussner,61 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’ gestation.	Not reported
Bisits,62 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 pregnancies, 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 β2-adrenergic-receptors antagonists 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 one 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 β2 sympathomimetic treatment was commenced. Salbutamol or ritodrine (n = 116) according to local practice. No data on doses used.	β2-adrenergic-receptors agonists in nitroglycerin group (33.1%)
Lee,63 2004	South Korea	Inclusion: women with singleton pregnancy in preterm labor (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 increasing every 15 minutes until contractions were inhibited or side effects became intolerable (maximum dose, 200 μg/min).	Magnesium sulfate
Wani,64 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 retardation, 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 being 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,65 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 minute and then increased by 10 drops every 5–10 min until contractions ceased. Then tapered off slowly in next 12 hours. Both treatments were discontinued if contractions ceased for 24 hours or delivery occurred.	Not reported
Rekha,66 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 one 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,67 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 h, 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,68 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