title: Transdermal nitroglycerin for the treatment of preterm labor: a systematic review and metaanalysis.
abstract: 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.
  
  
  METHODS
  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); β2-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 β2-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.
  
  
  CONCLUSIONS
  Although transdermal nitroglycerin appears to be more effective than β2-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.
authors.affiliation: Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health and Human Services, Bethesda, MD, and Detroit, MI.
authors.forename: Agustín
authors.initials: A
authors.lastname: Conde-Agudelo
authors.forename: Roberto
authors.initials: R
authors.lastname: Romero
mesh_terms: D000279:Administration, Cutaneous; D058666:Adrenergic beta-2 Receptor Agonists / Q000008:administration & dosage*; D005260:Female; D006801:Humans; D008278:Magnesium Sulfate / Q000008:administration & dosage*; D009543:Nifedipine / Q000008:administration & dosage*; D005996:Nitroglycerin / Q000008:administration & dosage*; D007752:Obstetric Labor, Premature / Q000188:drug therapy*; D011247:Pregnancy; D015149:Tocolytic Agents / Q000008:administration & dosage*
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; D015149:Tocolytic Agents; D008278:Magnesium Sulfate; D005996:Nitroglycerin; D009543:Nifedipine
keywords: magnesium sulfate; neonatal morbidity; nifedipine; nitric-oxide donor; preterm birth; tocolytic agent; β(2)-adrenergic receptor agonist
references.citation: Am J Obstet Gynecol. 2004 Sep;191(3):683-90
references.pmid: 15467526
references.citation: Pediatrics. 2013 Mar;131(3):548-58
references.pmid: 23400611
references.citation: Am J Obstet Gynecol. 2000 May;182(5):1173-83
references.pmid: 10819855
references.citation: Rev Bras Ginecol Obstet. 2009 Nov;31(11):552-8
references.pmid: 20084326
references.citation: Am J Obstet Gynecol. 1989 May;160(5 Pt 1):1117-23
references.pmid: 2786341
references.citation: Ann N Y Acad Sci. 1994 Sep 30;734:414-29
references.pmid: 7978942
references.citation: Mol Hum Reprod. 2009 Aug;15(8):507-12
references.pmid: 19528264
references.citation: Z Geburtshilfe Neonatol. 2001 Sep-Oct;205(5):189-94
references.pmid: 11727665
references.citation: Cochrane Database Syst Rev. 2012 Dec 12;12:CD003927
references.pmid: 23235600
references.citation: J Perinatol. 2000 Jan-Feb;20(1):27-33
references.pmid: 10693097
references.citation: Am J Obstet Gynecol. 1996 Oct;175(4 Pt 1):834-7
references.pmid: 8885731
references.citation: Lancet. 2008 Jan 5;371(9606):75-84
references.pmid: 18177778
references.citation: Med Wieku Rozwoj. 2000 Jul-Sep;4(3):307-16
references.pmid: 11093348
references.citation: Lancet. 2012 Jun 9;379(9832):2151-61
references.pmid: 22579125
references.citation: J Bone Joint Surg Am. 2012 Jul 18;94 Suppl 1:56-60
references.pmid: 22810449
references.citation: Am J Obstet Gynecol. 2006 Aug;195(2):484-7
references.pmid: 16707077
references.citation: Neurosci Biobehav Rev. 2012 Apr;36(4):1314-30
references.pmid: 22353425
references.citation: Am J Obstet Gynecol. 1999 Oct;181(4):822-7
references.pmid: 10521736
references.citation: BMJ. 2012 Oct 09;345:e6531
references.pmid: 23048012
references.citation: Am J Obstet Gynecol. 1997 Oct;177(4):819-24
references.pmid: 9369826
references.citation: BMJ. 2012 Oct 09;345:e6226
references.pmid: 23048010
references.citation: Lancet. 1994 Aug 20;344(8921):553; author reply 553-4
references.pmid: 7914652
references.citation: Cochrane Database Syst Rev. 2002;(3):CD002860
references.pmid: 12137661
references.citation: Am J Obstet Gynecol. 2007 Sep;197(3):325-6; author reply 326
references.pmid: 17826440
references.citation: Cochrane Database Syst Rev. 2002;(4):CD001060
references.pmid: 12519550
references.citation: Int J Gynaecol Obstet. 2004 May;85(2):165-7
references.pmid: 15099781
references.citation: J Obstet Gynaecol Can. 2010 Dec;32(12):1147-1152
references.pmid: 21176326
references.citation: Am J Obstet Gynecol. 2002 Sep;187(3):653-60
references.pmid: 12237643
references.citation: Am J Obstet Gynecol. 1998 Apr;178(4):862-6
references.pmid: 9579457
references.citation: Lancet. 2012 Jun 9;379(9832):2162-72
references.pmid: 22682464
references.citation: Am J Obstet Gynecol. 2007 Jan;196(1):4
references.pmid: 17240218
references.citation: Am J Obstet Gynecol. 1993 Jul;169(1):97-102
references.pmid: 8333483
references.citation: BMJ. 1998 Nov 7;317(7168):1309-12
references.pmid: 9804726
references.citation: Am J Obstet Gynecol. 2000 May;182(5):1191-9
references.pmid: 10819857
references.citation: Ann Intern Med. 2009 Aug 18;151(4):W65-94
references.pmid: 19622512
references.citation: Obstet Gynecol. 1999 Sep;94(3):403-8
references.pmid: 10472868
references.citation: Am J Obstet Gynecol. 2010 Dec;203(6):565.e1-6
references.pmid: 20817132
references.citation: BMJ. 2007 Apr 14;334(7597):786
references.pmid: 17403713
references.citation: JAMA. 2010 Mar 24;303(12):1180-7
references.pmid: 20332404
references.citation: BJOG. 2006 Dec;113 Suppl 3:17-42
references.pmid: 17206962
references.citation: Am J Obstet Gynecol. 2000 Jun;182(6):1477-82
references.pmid: 10871468
references.citation: Am J Obstet Gynecol. 2007 Jan;196(1):37.e1-8
references.pmid: 17240225
references.citation: Am J Obstet Gynecol. 1995 May;172(5):1577-84
references.pmid: 7755075
references.citation: BJOG. 2000 Sep;107(9):1182-3
references.pmid: 11002973
references.citation: Am J Obstet Gynecol. 1999 Dec;181(6):1432-7
references.pmid: 10601925
references.citation: JAMA. 2003 May 21;289(19):2554-9
references.pmid: 12759327
references.citation: Lancet. 1994 May 28;343(8909):1325-6
references.pmid: 7910325
references.citation: Curr Pharm Des. 2003;9(5):359-80
references.pmid: 12570814
references.citation: Am J Obstet Gynecol. 1993 Oct;169(4):1065-70
references.pmid: 8238121
references.citation: J Reprod Fertil. 1997 Jul;110(2):249-54
references.pmid: 9306978
references.citation: Am J Obstet Gynecol. 2012 Feb;206(2):119-23
references.pmid: 22177191
references.citation: Cochrane Database Syst Rev. 2012 Oct 17;10:CD007748
references.pmid: 23076936
references.citation: AACN Clin Issues. 2000 May;11(2):271-82
references.pmid: 11235436
references.citation: Am J Obstet Gynecol. 2007 Feb;196(2):119.e1-6
references.pmid: 17306647
references.citation: Am J Obstet Gynecol. 2000 May;182(5):1184-90
references.pmid: 10819856
references.citation: Am J Obstet Gynecol. 2000 Aug;183(2):513-4
references.pmid: 10942502
references.citation: BMJ. 2010 Aug 18;341:c3920
references.pmid: 20719825
references.citation: BMJ. 1997 Sep 13;315(7109):629-34
references.pmid: 9310563
references.citation: Am J Obstet Gynecol. 2012 Feb;206(2):108-12
references.pmid: 22118964
references.citation: Lancet. 2012 Feb 4;379(9814):445-52
references.pmid: 22244654
references.citation: Gynecol Endocrinol. 2001 Feb;15(1):34-42
references.pmid: 11293922
references.citation: Am J Obstet Gynecol. 2006 Apr;194(4):976-81
references.pmid: 16580286
references.citation: Am J Obstet Gynecol. 1997 Oct;177(4):742-5
references.pmid: 9369812
references.citation: Am J Obstet Gynecol. 2012 Feb;206(2):113-8
references.pmid: 22177186
references.citation: Cochrane Database Syst Rev. 2004 Oct 18;(4):CD004352
references.pmid: 15495104
references.citation: Am J Obstet Gynecol. 1993 Oct;169(4):960-4
references.pmid: 8238157
references.citation: Cochrane Database Syst Rev. 2005 Jul 20;(3):CD004452
references.pmid: 16034931
references.citation: Am J Obstet Gynecol. 2003 Apr;188(4):1046-51
references.pmid: 12712108
references.citation: Am J Obstet Gynecol. 1997 Oct;177(4):814-8
references.pmid: 9369825
references.citation: Am J Obstet Gynecol. 2011 Feb;204(2):134.e1-20
references.pmid: 21284967
references.citation: J Perinat Med. 2000;28(3):232-42
references.pmid: 10923308
references.citation: Am J Obstet Gynecol. 2009 Jun;200(6):627.e1-10
references.pmid: 19306963
references.citation: Br J Obstet Gynaecol. 1999 Jul;106(7):736-9
references.pmid: 10428533
references.citation: Lancet. 1994 Aug 20;344(8921):553; author reply 553-4
references.pmid: 7914651
references.citation: J Obstet Gynaecol Can. 2002 May;24(5):403-9
references.pmid: 12196860
references.citation: BMJ. 2003 Sep 6;327(7414):557-60
references.pmid: 12958120