Intervention Review

You have free access to this content

Nitric oxide donors for treating preterm labour

  1. Kirsten Duckitt1,*,
  2. Steve Thornton2,
  3. Oliver P O'Donovan3,
  4. Therese Dowswell4

Editorial Group: Cochrane Pregnancy and Childbirth Group

Published Online: 8 MAY 2014

Assessed as up-to-date: 1 DEC 2013

DOI: 10.1002/14651858.CD002860.pub2


How to Cite

Duckitt K, Thornton S, O'Donovan OP, Dowswell T. Nitric oxide donors for treating preterm labour. Cochrane Database of Systematic Reviews 2014, Issue 5. Art. No.: CD002860. DOI: 10.1002/14651858.CD002860.pub2.

Author Information

  1. 1

    Campbell River and District General Hospital, Campbell River, British Columbia, Canada

  2. 2

    University of Exeter Medical School and Peninsula College of Medicine and Dentistry, Exeter, UK

  3. 3

    South Devon Healthcare Trust, Department of Obstetrics and Gynaecology, Torquay, Devon, UK

  4. 4

    The University of Liverpool, Cochrane Pregnancy and Childbirth Group, Department of Women's and Children's Health, Liverpool, UK

*Kirsten Duckitt, Campbell River and District General Hospital, 375 - 2nd Avenue, Campbell River, British Columbia, V9W 3V1, Canada. kduckitt@doctors.org.uk.

Publication History

  1. Publication Status: New search for studies and content updated (no change to conclusions)
  2. Published Online: 8 MAY 2014

SEARCH

 
Characteristics of included studies [ordered by study ID]
Amorim 2009

MethodsRandomisation performed by opaque, sealed envelopes. Computer-generated, random-number sequence. Not blinded. Prospective power calculation. Intention-to-treat analysis.


ParticipantsBrazil. 50 pregnant women in preterm labour (defined as at least 4 contractions in 30 minutes, cervical dilatation at 4 cm and associated cervical changes of position, length, consistency or dilatation) between 24 and 34 weeks with a singleton pregnancy.


Interventions1. GTN patch 10 mg/24 hrs, 2nd patch added after 6 hrs if contractions had not reduced. If contractions settled, removed at 12 hrs; if not settled by 12 hrs, 250 mg subcutaneous terbutaline was given (n = 26).
2. Nifedipine (Adalat) 10 mg capsule sublingual, repeated after 30 minutes; and if contractions continued, 20 mg every 6 hrs (n = 24).


OutcomesPrimary outcome was time required to obtain effective tocolysis. Secondary outcomes were inhibition of labour within 12 hrs, time taken for tocolysis (up to 6 hrs), recurrence of labour within 24 hrs and premature birth within 48 hrs. Maternal adverse effects (headache; flushing; hypotension; nausea; tachycardia).


NotesComment that terbutaline was given to nitroglycerin group at 12 hrs if contractions had not reduced, but no comment on how often this was done.

All women got steroids but there is no mention of antibiotics.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComputer-generated sequence.

Allocation concealment (selection bias)Low riskEnvelopes sequentially numbered, sealed and opaque.

Blinding of participants and personnel (performance bias)
All outcomes
High riskNo blinding of participants, doctors or assessors. Feasible if used placebo patch with active tablet and vice versa.

Blinding of outcome assessment (detection bias)
All outcomes
High riskAs above.

Incomplete outcome data (attrition bias)
All outcomes
Low riskMissing outcome data balanced across intervention groups.

Selective reporting (reporting bias)Unclear riskInsufficient information to permit a judgement.

Other biasLow riskGroups appeared comparable at baseline.

Bisits 1998

MethodsUnclear how allocation sequence generated, but allocation sequence concealed using sealed, opaque envelopes. No blinding or power calculation.


ParticipantsAustralia. 26 pregnant women in preterm labour (defined as painful, regular contractions at < 5-minute intervals) with singleton pregnancies between 24-34 weeks' gestation with cervical dilation < 5 cm with intact or ruptured membranes.


Interventions(1) GTN patch 10 mg/24 hrs (n = 13).
(2) Intravenous albuterol at an initial rate of 25 micrograms/minute (n = 13).


OutcomesBirth within 24 hrs, birth within 7 days, birth at term, adverse drug reactions, plasma corticotrophin releasing hormone levels.


NotesTwo participants changed from GTN group to albuterol because of persistent contractions. No information on whether women got steroids and/or antibiotic therapy.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskUnclear how allocation sequence generated.

Allocation concealment (selection bias)Low riskAllocation sequence concealed using sealed, opaque envelopes.

Blinding of participants and personnel (performance bias)
All outcomes
High riskNo blinding.

Blinding of outcome assessment (detection bias)
All outcomes
High riskNo blinding.

Incomplete outcome data (attrition bias)
All outcomes
Low riskAll women randomised were included in the analysis.

Selective reporting (reporting bias)Unclear riskAssessment from published study report.

Other biasLow riskBaseline characteristics were described as similar.

Bisits 2004

MethodsRandomisation performed by opaque, sealed envelopes. Each centre had own local random-number sequence. Not blinded. Prospective power calculation. Intention-to-treat analysis.


ParticipantsAustralia, Singapore and Hong Kong. 238 pregnant women in preterm labour (defined as at least 2 contractions in 10 minutes and either positive fibronectin or ruptured membranes but cervical dilatation less than 5 cm) between 24 and 35 weeks with a singleton pregnancy.


InterventionsGTN patch 10 mg/24 hrs , 2nd patch added after one hr if contractions had not stopped. If contractions settled removed at 12 hours, if not settled by 2 hrs rescue treatment with β2 sympathomimetic treatment. (n = 121). The control group received β2 sympathomimetic treatment with either i.v. ritodrine or i.v. salbutamol depending on local practice.


OutcomesPrimary outcome was latency period (number of days from randomisation to birth). Secondary outcomes were maternal strength of contraction, adverse effects and neonatal outcome (short and long term).


Notes1/3 GTN rescued with β2 sympathomimetic.

No information on whether women got steroids and/or antibiotic therapy.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandom-number tables.

Allocation concealment (selection bias)Low riskEnvelopes sequentially numbered, sealed and opaque.

Blinding of participants and personnel (performance bias)
All outcomes
High riskParticipants and doctors not blinded. Feasible if placebo patch with active i.v. therapy and vice versa.

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskUnclear if outcome assessors blinded or not.

Incomplete outcome data (attrition bias)
All outcomes
Low riskMissing outcome data balanced across intervention groups and intention-to-treat analysis.

Selective reporting (reporting bias)High riskNot all of the studies pre-specified outcomes were reported.

Other biasLow riskGroups appeared comparable at baseline.

El-Sayed 1999

MethodsRandomisation by independent third party using envelope shuffling to generate allocation sequence. Concealment maintained by opaque, sealed envelopes. No blinding. No power calculation.


ParticipantsUSA. 30 pregnant women in preterm labour (defined as the occurrence of at least 2 contractions in 10 minutes, with cervical change or ruptured membranes) under 35 weeks' gestation with singleton or multiple pregnancies with cervical dilation less than 4 cm with intact or ruptured membranes.


Interventions(1) Nitroglycerin i.v. 100 microgram bolus then 1 microgram/kg/minute up to maximum of 10 micrograms/kg/minute (n = 16).
(2) Intravenous magnesium sulphate 4 g bolus, then 2 g/hr up to maximum of 4 g/hr (n = 14).


Outcomes12 hrs of successful tocolysis, maternal adverse effects (headache; dizziness; flushing; palpitations; hypotension), serial maternal BP and heart rate changes and fetal heart rate changes.


Notes1 woman in each group discontinued treatment because of adverse effects. All participants received hydration with Ringers lactate solution as well as randomised therapy. No information on whether women got steroids and/or antibiotic therapy.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskEnvelope shuffling.

Allocation concealment (selection bias)Low riskOpaque sealed envelopes.

Blinding of participants and personnel (performance bias)
All outcomes
High riskNo blinding.

Blinding of outcome assessment (detection bias)
All outcomes
High riskNo blinding.

Incomplete outcome data (attrition bias)
All outcomes
Low riskMissing outcome data balanced across intervention groups.

Selective reporting (reporting bias)Unclear riskAssessment from published study report.

Other biasLow riskGroups appeared similar at baseline.

Haghighi 2005

MethodsRandomised by sequential use of opaque, sealed envelopes numbered using random-number tables. Double blinding implied. No power calculation. No intention-to-treat analysis.


ParticipantsIran. 150 pregnant women in preterm labour (defined as more than 8 uterine contractions per hr that lasted longer than 30 seconds and progressive cervical dilatation z1 cm during a 3.5-h observation) between 33 and 36 weeks with a singleton pregnancy.


Interventions1. Isosorbide dinitrate sublingual tablet 5 mg, repeated every 30 minutes up to 40 mg or stop of contractions. 10 mg 1 hour after halt of contractions and every 6 hrs for 48 hrs (n = 75).

2. Placebo (n = 75).


OutcomesPrimary outcome was preterm birth. Secondary outcomes were adverse effects and Apgar scores.


NotesBoth groups first administered 50 mg i.v. of meperidine in 500 mL of Ringer solution over 30 minutes, followed by 100 mL per hr of the same for 3 hrs. No information on whether women got steroids and/or antibiotic therapy.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandom-number tables.

Allocation concealment (selection bias)Low riskEnvelopes sequentially numbered, sealed and opaque.

Blinding of participants and personnel (performance bias)
All outcomes
Low riskParticipants blinded, unclear re personnel.

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskUnclear whether assessors blinded or not.

Incomplete outcome data (attrition bias)
All outcomes
High riskOf the 81 women randomised to isosorbide dinitrate group, 6 were excluded for reasons that may have related to treatment allocation (hypotension).

Selective reporting (reporting bias)Unclear riskInsufficient information to permit a judgement.

Other biasUnclear riskLittle information on participant characteristics.

He 2002

MethodsRandomisation by computer. No blinding. No mention of power calculation or intention-to-treat analysis.


ParticipantsChina. 60 pregnant women in preterm labour (defined as contracting every 5-10 minutes lasting 30 seconds with cervix more than 2 cm dilated) between 28 and 37 weeks with intact membranes. No comment on multiple pregnancies. Not blinded. No power calculation mentioned and no intention-to-treat analysis mentioned.


Interventions1. GTN patch 5 mg/24 hrs with another patch added every hr until contractions stopped or 25 mg maximum dose reached. Patches changed every 24 hrs (n = 30).

2. Magnesium sulphate and salbutamol, no doses stated (n = 30).


OutcomesPercentage of women in whom contractions stopped, days delay of labour, pre and post-treatment corticotrophin releasing hormone levels.


NotesNo information on whether women got steroids and/or antibiotic therapy. Translated by Cochrane.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComputer-generated sequence.

Allocation concealment (selection bias)Unclear riskNot described.

Blinding of participants and personnel (performance bias)
All outcomes
High riskNo blinding.

Blinding of outcome assessment (detection bias)
All outcomes
High riskNo blinding.

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskInsufficient reporting of attrition and exclusions to permit judgement, e.g. number randomised not stated or no reasons for missing data provided.

Selective reporting (reporting bias)Unclear riskInsufficient information to permit a judgement.

Other biasUnclear riskNot addressed in translation.

Lees 1999

MethodsRandom lists prepared centrally used to generate allocation sequence. Randomisation was by random-permuted blocks, stratified by centre. Central randomisation and sealed envelopes then used to conceal allocation sequence. No blinding. Power calculation performed prospectively. Intention-to-treat analysis.


ParticipantsUK, Europe and Indonesia. 245 pregnant women in preterm labour (defined as painful, regular uterine contractions > 2 in 10 for 1 hr or more) between 24 and 36 weeks' gestation with singleton or multiple pregnancies with intact membranes.


Interventions(1) GTN patch 10 mg/24 hrs (46%) or 20 mg/24 hrs (54%) n = 120.
(2) i.v. ritodrine starting at 50 microgram/minute (n = 125).


OutcomesProlongation of pregnancy expressed as a percentage of the time from entry to 37 weeks, proportion of women who delivered the same day, next day, within 7 or 14 days and by 32, 34 and 37 weeks. Maternal adverse effects (headache; dizziness; palpitations; shortness of breath; nausea; tachycardia; chest pain/tightness; cessation of drug).


NotesOutcome data missing for 4.8% women. No information on whether women got steroids and/or antibiotic therapy.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandom lists prepared centrally used to generate allocation sequence.

Allocation concealment (selection bias)Low riskCentral randomisation and sealed envelopes then used to conceal allocation sequence.

Blinding of participants and personnel (performance bias)
All outcomes
High riskNo blinding.

Blinding of outcome assessment (detection bias)
All outcomes
High riskNo blinding.

Incomplete outcome data (attrition bias)
All outcomes
Unclear risk245 randomised, some loss to follow-up, 233/245 followed up to birth. There were missing data for adverse effects.

Selective reporting (reporting bias)Unclear riskAssessment from published study report.

Other biasUnclear riskBaseline characteristics were comparable. There some treatment cross-overs and some women did not receive treatment as planned or treatment was discontinued.

Schleussner 2001

MethodsRandomised. No blinding. No mention of power calculation or intention-to-treat analysis.


Participants50 pregnant women between 27 and 35 weeks. Germany.


Interventions1. GTN patches 0.4-0.8 mg/hr (n = 28).

2. Fenoterol 60-120 micrograms/hr (n = 22).


OutcomesPrimary outcomes were prolongation of pregnancy and neonatal outcome. Secondary outcomes were cervical ripening and maternal adverse effects.


NotesOnly abstract available in English.

No information on whether women got steroids and/or antibiotic therapy.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)High riskAllocation by hospital number.

Allocation concealment (selection bias)High riskAllocation on basis of hospital number.

Blinding of participants and personnel (performance bias)
All outcomes
High riskNo blinding. Different treatment regimens.

Blinding of outcome assessment (detection bias)
All outcomes
High riskNo blinding. Different treatment regimens.

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNot clear.

Selective reporting (reporting bias)Unclear riskAssessment from translated notes.

Other biasUnclear riskAssessment from translated notes.

Smith 1999

MethodsRandomisation with stratification by gestational age (< and > 30 weeks) and blocking in groups of 2 were performed before the study by the clinical investigations unit of the hospital. Sealed study envelopes coded with the randomisation number and used in order of randomisation number, contained the study patches, instructions for the nurses and bags to collect all used and unused patches. Therapy blinded to participant, doctor and outcome assessor although not to nurses who either peeled off the impermeable protective backing to use the active patch or kept the backing on if placebo was required. Both patches were covered with non-transparent tape so would appear similar to all participants. Intention-to-treat analysis. Designed as pilot study. Post-trial power calculation performed to determine numbers required for larger multi-centre trial.


ParticipantsCanada. 33 pregnant women in preterm labour (defined as evidence of cervical change over 1-2 hrs) between 24 and 34 weeks' gestation with singleton or twin pregnancies with intact membranes and cervical dilatation < 4 cm.


Interventions(1) GTN transdermal patch 9.6 mg/24 hrs for 48 hrs (n = 17).
(2) Placebo (n = 16).


OutcomesProlongation of pregnancy > 48 hrs, completed course of maternal steroids, adverse drug reactions.


NotesBoth groups also received a 1000 mL i.v. infusion of 0.9% saline over 1-2 hrs before randomisation applying the patch. Women received betamethasone and antibiotics at discretion of attending physician but numbers same in both groups.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandomisation by pharmacy using randomisation number.

Allocation concealment (selection bias)Low riskEnvelopes sequentially numbered, sealed and opaque.

Blinding of participants and personnel (performance bias)
All outcomes
Low riskParticipants and doctors blinded, not nurses who applied the patch.

Blinding of outcome assessment (detection bias)
All outcomes
Low riskOutcome assessors blinded.

Incomplete outcome data (attrition bias)
All outcomes
Low risk33 women randomised and all accounted for in the analysis. Intention-to-treat analysis.

Selective reporting (reporting bias)Unclear riskAssessment from published study report.

Other biasLow riskBaseline characteristics of groups appeared similar.

Smith 2007

MethodsWeb-based randomisation by independent company, stratified by centre and gestation with random-block sizes of 2, 4 or 6. Opaque envelopes. Double blinded. Prospective power calculation performed. Intention-to-treat analysis.


ParticipantsCanada.153 pregnant women in preterm labour (defined as 4 painful uterine contractions per 20 minutes and evidence of cervical change, i.e. change in Bishop score or Bishop score 6) between 24 and 32 weeks with a singleton pregnancy and intact membranes.


Interventions1. GTN patch 0.4 mg/hr, with another added 1 hr later if still labouring, patches replaced after 24 hrs (n = 74).

2. Placebo patch (n = 79).


OutcomesComposite outcome of serious neonatal morbidity and perinatal mortality, chronic lung disease, necrotising enterocolitis, grade III or i.v. intraventricular haemorrhage, periventricular leukomalacia, birth at less than 48 hrs, and before 28, 34, and 37 weeks' gestation, completion of course of corticosteroids.


NotesRecruitment stopped early due to unavailability of ritodrine. Many units switched to GTN patch as standard practice.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComputer-generated sequence.

Allocation concealment (selection bias)Low riskEnvelopes sequentially numbered, sealed and opaque.

Blinding of participants and personnel (performance bias)
All outcomes
Low riskParticipants and doctors blinded, not nurses who applied the patch.

Blinding of outcome assessment (detection bias)
All outcomes
Low riskOutcome assessors blinded.

Incomplete outcome data (attrition bias)
All outcomes
Low riskMissing outcome data balanced across intervention groups

Selective reporting (reporting bias)Low riskStudy protocol is available and all prespecified outcomes that are of interest have been reported in the pre-specified way.

Other biasUnclear riskStudy stopped early due to recruitment difficulties.

Szulc 2000

MethodsRandomised. Not blinded. No power calculation. Intention-to-treat analysis.


ParticipantsPoland. 60 pregnant women in preterm labour (defined as contracting 4/20, cervical shortening 60%) between 23 and 34 weeks with a singleton pregnancy and intact membranes.


Interventions1. GTN patch 10 mg/24 hrs , 2nd 5 mg patch added after 1 hr if contractions had not stopped. Replaced after 24 hrs (n = 30).

2. Fenoterol 1 mg and Isoptin 10 mg i.v., then 5 mg fenoterol and 40 mg Isoptin PO repeated 4-6 times per day (n = 30).


OutcomesMean prolongation of pregnancy, maternal adverse effects (headache; flushing; nausea; tachycardia; chest pain/tightness) and neonatal outcome.


NotesTranslated from Polish.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskRandomised coding.

Allocation concealment (selection bias)Unclear riskUnclear what method used.

Blinding of participants and personnel (performance bias)
All outcomes
High riskNo blinding.

Blinding of outcome assessment (detection bias)
All outcomes
High riskNo blinding.

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskInsufficient reporting of attrition or exclusions to permit judgement, e.g. number randomised not stated or no reasons for missing data provided.

Selective reporting (reporting bias)Unclear riskInsufficient information (assessment from translated notes).

Other biasUnclear riskOriginal article in Polish, assessment from translated notes.

Wani 2004

MethodsRandomisation by sequentially numbered, opaque envelopes. Not blinded. No power calculation. Intention-to-treat analysis.


ParticipantsUnited Arab Emirates. 132 pregnant women in preterm labour (defined as painful, regular contractions (> 20/hrs) and/or cervical dilatation of 2 cm or more) between 23 and 34 weeks with a singleton pregnancy and intact membranes.


InterventionsGTN patch 10mg/24 hrs, 2nd patch added after 1 hr if contractions had not stopped, replaced after 24 hrs (maximum 5 days) (n = 67).

i.v. ritodrine150 mg/minute with 50 mg increment until contractions ceased, a maximum dose of 350 mg/minute was reached or the occurrence of adverse effects (maximum 3 days) (n = 65).


OutcomesProlongation of pregnancy, neonatal outcome and maternal adverse effects (headache; palpitations; nausea; tachycardia; chest pain/tightness; cessation of drug).


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskRandomised but no mention of how sequence was generated.

Allocation concealment (selection bias)Low riskEnvelopes sequentially numbered, sealed and opaque.

Blinding of participants and personnel (performance bias)
All outcomes
High riskNo blinding.

Blinding of outcome assessment (detection bias)
All outcomes
High riskNo blinding.

Incomplete outcome data (attrition bias)
All outcomes
Low riskAll dropouts accounted for.

Selective reporting (reporting bias)Unclear riskInsufficient information to permit a judgement.

Other biasLow riskGroups appeared comparable at baseline.

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Bulgay-Moerschel 2008Not clear how many women assigned to each intervention group.

Clavin 1996Preliminary data. Denominator of total women randomised unclear. Author contacted. Data lost in Hurricane Katrina.

Groom 2000Letter, not RCT.

Hogberg 1998Does not include relevant comparisons as both groups received terbutaline as a tocolytic with 1 group having additional nitroglycerin and the other having terbutaline alone.

Leszczynska 2001Not RCT.

Pasargiklian 1983NO donor not used.

Rytlewski 2008Both intervention groups received standard tocolysis with MgSo4 and a B2 agonist. Later, 1 group received L-arginine, a NO precursor, or placebo.

 
Characteristics of studies awaiting assessment [ordered by study ID]
Simsek 2000

MethodsLittle information on study methods. Stated that women were "randomly selected" to receive 1 of the 2 treatments.

Participants24 women admitted to hospital with preterm labour with gestational age of 20-34 weeks.

InterventionsGlyceryl trinitrate (patches) or ritodrine HCL infusion.

Outcomes"The interval of therapy to birth was found to be 29.2+/-20.8 (mean+/-SD) in GTN and 18.0+/-16.2 (mean+/-SD) for the ritodrine HCL group."

NotesBrief abstract identified by search. We are seeking the full text article.

 
Comparison 1. Nitric oxide donors versus placebo or no treatment

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Prolongation of pregnancy greater than 48 hours2186Risk Ratio (M-H, Random, 95% CI)1.19 [0.74, 1.90]

 2 Birth prior to 37 completed weeks2Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

 3 Birth prior to 34 completed weeks1153Risk Ratio (M-H, Fixed, 95% CI)0.93 [0.61, 1.41]

 4 Birth prior to 28 completed weeks1153Risk Ratio (M-H, Fixed, 95% CI)0.50 [0.23, 1.09]

 5 Caesarean section133Risk Ratio (M-H, Fixed, 95% CI)0.47 [0.14, 1.57]

 6 Any adverse drug reactions2186Risk Ratio (M-H, Fixed, 95% CI)1.49 [1.14, 1.94]

 7 Headache1153Risk Ratio (M-H, Fixed, 95% CI)1.95 [1.31, 2.90]

 8 Dizziness1153Risk Ratio (M-H, Fixed, 95% CI)1.60 [0.60, 4.28]

 9 Flushing1153Risk Ratio (M-H, Fixed, 95% CI)0.90 [0.43, 1.89]

 10 Hypotension1153Risk Ratio (M-H, Fixed, 95% CI)1.20 [0.49, 2.95]

 11 Completion of course of maternal steroids2186Risk Ratio (M-H, Fixed, 95% CI)1.04 [0.90, 1.20]

 12 Death unrelated to congenital abnormalities2Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    12.1 In utero
1153Risk Ratio (M-H, Fixed, 95% CI)0.36 [0.01, 8.59]

    12.2 In first 28 days of life
2186Risk Ratio (M-H, Fixed, 95% CI)0.43 [0.06, 2.89]

   12.3 After 28 days
00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 13 Intraventricular haemorrhage1153Risk Ratio (M-H, Fixed, 95% CI)2.14 [0.20, 23.06]

 14 Respiratory distress syndrome133Risk Ratio (M-H, Fixed, 95% CI)0.47 [0.14, 1.57]

 15 Chronic lung disease1153Risk Ratio (M-H, Fixed, 95% CI)0.15 [0.02, 1.21]

 16 Birthweight (grams)133Mean Difference (IV, Fixed, 95% CI)327.0 [-272.13, 926.13]

 17 (Non-prespecified) Composite outcome: serious infant morbidity or mortality1153Risk Ratio (M-H, Fixed, 95% CI)0.29 [0.08, 1.00]

 
Comparison 2. Nitric oxide donors versus any betamimetic

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Prolongation of pregnancy greater than 24 hours2264Risk Ratio (M-H, Fixed, 95% CI)0.94 [0.82, 1.08]

 2 Prolongation of pregnancy greater than 48 hours3420Risk Ratio (M-H, Fixed, 95% CI)0.96 [0.87, 1.05]

 3 Prolongation of pregnancy greater than 7 days5679Risk Ratio (M-H, Random, 95% CI)1.03 [0.92, 1.15]

 4 Prolongation of pregnancy greater than 14 days2365Risk Ratio (M-H, Random, 95% CI)1.07 [0.82, 1.39]

 5 Birth prior to 37 completed weeks5679Risk Ratio (M-H, Random, 95% CI)0.73 [0.50, 1.05]

 6 Birth prior to 34 completed weeks2365Risk Ratio (M-H, Random, 95% CI)0.71 [0.36, 1.42]

 7 Birth prior to 32 completed weeks1233Risk Ratio (M-H, Fixed, 95% CI)1.00 [0.54, 1.85]

 8 Caesarean section2283Risk Ratio (M-H, Fixed, 95% CI)0.87 [0.53, 1.43]

 9 Adverse effects1132Risk Ratio (M-H, Fixed, 95% CI)0.45 [0.30, 0.68]

 10 Headache3349Risk Ratio (M-H, Random, 95% CI)4.35 [0.91, 20.71]

 11 Dizziness1191Risk Ratio (M-H, Fixed, 95% CI)1.55 [0.26, 9.06]

 12 Palpitations2323Risk Ratio (M-H, Fixed, 95% CI)0.06 [0.01, 0.30]

 13 Shortness of breath2217Risk Ratio (M-H, Fixed, 95% CI)0.09 [0.02, 0.46]

 14 Nausea3349Risk Ratio (M-H, Fixed, 95% CI)0.47 [0.22, 0.98]

 15 Tachycardia2323Risk Ratio (M-H, Fixed, 95% CI)0.03 [0.01, 0.10]

 16 Chest pain/tightness2323Risk Ratio (M-H, Fixed, 95% CI)0.12 [0.02, 0.64]

 17 Adverse effects leading to treatment cessations1132Risk Ratio (M-H, Fixed, 95% CI)0.05 [0.00, 0.86]

 18 Maternal pulmonary oedema1191Risk Ratio (M-H, Fixed, 95% CI)0.34 [0.01, 8.34]

 19 Death unrelated to congenital abnormalities1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    19.1 In utero
1191Risk Ratio (M-H, Fixed, 95% CI)0.34 [0.01, 8.34]

    19.2 In first 28 days of life
1191Risk Ratio (M-H, Fixed, 95% CI)2.06 [0.19, 22.38]

   19.3 After 28 days
00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 20 Use of mechanical ventilation1132Risk Ratio (M-H, Fixed, 95% CI)0.42 [0.11, 1.54]

 21 Chronic lung disease1238Risk Ratio (M-H, Fixed, 95% CI)1.03 [0.43, 2.51]

 22 Admission of infant to neonatal intensive care unit2181Risk Ratio (M-H, Fixed, 95% CI)0.50 [0.31, 0.80]

 23 Birthweight2182Mean Difference (IV, Fixed, 95% CI)440.39 [237.35, 643.44]

 
Comparison 3. Nitric oxide donors versus magnesium sulphate

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Headache130Risk Ratio (M-H, Fixed, 95% CI)2.41 [0.99, 5.87]

 2 Dizziness130Risk Ratio (M-H, Fixed, 95% CI)3.06 [0.76, 12.40]

 3 Flushing130Risk Ratio (M-H, Fixed, 95% CI)0.15 [0.04, 0.54]

 4 Palpitations130Risk Ratio (M-H, Fixed, 95% CI)0.44 [0.04, 4.32]

 5 Hypotension130Risk Ratio (M-H, Fixed, 95% CI)7.94 [0.46, 135.65]

 
Comparison 4. Nitric oxide donors versus any calcium channel blocker

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Prolongation of pregnancy greater than 48 hours150Risk Ratio (M-H, Fixed, 95% CI)0.97 [0.77, 1.21]

 2 Headache150Risk Ratio (M-H, Fixed, 95% CI)3.69 [0.87, 15.69]

 3 Flushing150Risk Ratio (M-H, Fixed, 95% CI)1.85 [0.18, 19.08]

 4 Hypotension150Risk Ratio (M-H, Fixed, 95% CI)0.31 [0.03, 2.76]

 5 Nausea150Risk Ratio (M-H, Fixed, 95% CI)0.62 [0.11, 3.37]

 6 Tachycardia150Risk Ratio (M-H, Fixed, 95% CI)0.31 [0.01, 7.23]

 
Comparison 5. Nitric oxide donors versus combination of tocolytics

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Prolongation of pregnancy greater than 48 hours160Risk Ratio (M-H, Fixed, 95% CI)1.13 [0.91, 1.39]

 2 Caesarean section160Risk Ratio (M-H, Fixed, 95% CI)1.5 [0.47, 4.78]

 3 Headache160Risk Ratio (M-H, Fixed, 95% CI)13.0 [3.38, 49.96]

 4 Flushing160Risk Ratio (M-H, Fixed, 95% CI)0.17 [0.04, 0.68]

 5 Nausea160Risk Ratio (M-H, Fixed, 95% CI)1.5 [0.47, 4.78]

 6 Tachycardia160Risk Ratio (M-H, Fixed, 95% CI)0.05 [0.01, 0.32]

 7 Chest pain/tightness160Risk Ratio (M-H, Fixed, 95% CI)0.08 [0.00, 1.31]