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Am J Perinatol 2011; 28(1): 057-066
DOI: 10.1055/s-0030-1262512
© Thieme Medical Publishers

Calcium Channel Blockers for the Management of Preterm Birth: A Review

Anwar H. Nassar1 , Joelle Aoun1 , Ihab M. Usta1
  • 1Department of Obstetrics and Gynecology, American University of Beirut Medical Center, Beirut, Lebanon
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Publication History

Publication Date:
16 July 2010 (online)

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ABSTRACT

Preterm birth continues to be the leading cause of perinatal morbidity and mortality. A wide range of tocolytics have been utilized for the management of preterm labor. Calcium channel blockers, namely nifedipine, gained popularity as tocolytics due to the oral route of administration, availability of immediate- and slow-release preparations, the low incidence of maternal adverse effects associated with their use, and the fact that they are inexpensive. This article reviews the available literature on the clinical utility of calcium channel blockers for acute and maintenance tocolysis with special emphasis on potential adverse effects, the most appropriate dose/regimen, and contemporary practice patterns among obstetricians. There are no randomized, placebo-controlled studies demonstrating the benefit of nifedipine in preterm labor. A suggested tocolytic protocol would be to start with the lowest dose of oral immediate-release nifedipine. For the first 48 hours thereafter, all attempts should be made not to exceed 60-mg daily doses.

KEYWORDS

Calcium channel blockers - tocolysis - preterm labor - adverse effects - dose

REFERENCES

  • 1 Martin J A, Hamilton B E, Sutton P D Centers for Disease Control and Prevention National Center for Health Statistics National Vital Statistics System et al. Births: final data for 2005.  Natl Vital Stat Rep. 2007;  56 1-103
    PubMedGoogle Scholar
  • 2 Roberts D, Dalziel S. Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth.  Cochrane Database Syst Rev. 2006;  3 CD004454
    PubMedGoogle Scholar
  • 3 ACOG Committee on Practice Bulletins—Obstetrics . ACOG practice bulletin. Management of preterm labor. Number 43, May 2003.  Int J Gynaecol Obstet. 2003;  82 127-135
    CrossrefPubMedGoogle Scholar
  • 4 King J F, Flenady V, Papatsonis D, Dekker G, Carbonne B. Calcium channel blockers for inhibiting preterm labour; a systematic review of the evidence and a protocol for administration of nifedipine.  Aust N Z J Obstet Gynaecol. 2003;  43 192-198
    CrossrefPubMedGoogle Scholar
  • 5 Anotayanonth S, Subhedar N V, Garner P, Neilson J P, Harigopal S. Betamimetics for inhibiting preterm labour.  Cochrane Database Syst Rev. 2004;  4 CD004352
    PubMedGoogle Scholar
  • 6 Crowther C A, Hiller J E, Doyle L W. Magnesium sulphate for preventing preterm birth in threatened preterm labour.  Cochrane Database Syst Rev. 2002;  4 CD001060
    PubMedGoogle Scholar
  • 7 Lamont R F. The pathophysiology of pulmonary oedema with the use of beta-agonists.  BJOG. 2000;  107 439-444
    CrossrefPubMedGoogle Scholar
  • 8 Tocolytic Drugs for Women in Preterm Labour .Clinical Guideline No. 1(B). Royal College of Obstetricians and Gynecologists, 2002. Available at: http://www.rcog.org.uk/files/rcog-corp/GT1BTocolyticDrug2002revised.pdf Accessed December 28, 2009
    PubMedGoogle Scholar
  • 9 Mercer B M, Merlino A A. Society for Maternal-Fetal Medicine . Magnesium sulfate for preterm labor and preterm birth.  Obstet Gynecol. 2009;  114 650-668
    CrossrefPubMedGoogle Scholar
  • 10 Fox N S, Gelber S E, Kalish R B, Chasen S T. Contemporary practice patterns and beliefs regarding tocolysis among U.S. maternal-fetal medicine specialists.  Obstet Gynecol. 2008;  112 42-47
    CrossrefPubMedGoogle Scholar
  • 11 Costantine M M, Weiner S J. Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network . Effects of antenatal exposure to magnesium sulfate on neuroprotection and mortality in preterm infants: a meta-analysis.  Obstet Gynecol. 2009;  114 (2 Pt 1) 354-364
    CrossrefPubMedGoogle Scholar
  • 12 Nayler W G, Poole-Wilson P. Calcium antagonists: definition and mode of action.  Basic Res Cardiol. 1981;  76 1-15
    CrossrefPubMedGoogle Scholar
  • 13 Hearne A E, Nagey D A. Therapeutic agents in preterm labor: tocolytic agents.  Clin Obstet Gynecol. 2000;  43 787-801
    CrossrefPubMedGoogle Scholar
  • 14 Nakajima H, Hoshiyama M, Yamashita K, Kiyomoto A. Effect of diltiazem on electrical and mechanical activity of isolated cardiac ventricular muscle of guinea pig.  Jpn J Pharmacol. 1975;  25 383-392
    CrossrefPubMedGoogle Scholar
  • 15 Braunwald E. Mechanism of action of calcium-channel-blocking agents.  N Engl J Med. 1982;  307 1618-1627
    CrossrefPubMedGoogle Scholar
  • 16 Papatsonis D N, Bos J M, van Geijn H P, Lok C A, Dekker G A. Nifedipine pharmacokinetics and plasma levels in the management of preterm labor.  Am J Ther. 2007;  14 346-350
    CrossrefPubMedGoogle Scholar
  • 17 Bussey H I, Talbert R L. Promising uses of calcium-channel blocking agents.  Pharmacotherapy. 1984;  4 137-143
    PubMedGoogle Scholar
  • 18 Kaul A F, Osathanondh R, Safon L E, Frigoletto Jr F D, Friedman P A. The management of preterm labor with the calcium channel-blocking agent nifedipine combined with the beta-mimetic terbutaline.  Drug Intell Clin Pharm. 1985;  19 369-371
    PubMedGoogle Scholar
  • 19 Ulmsten U, Andersson K E, Wingerup L. Treatment of premature labor with the calcium antagonist nifedipine.  Arch Gynecol. 1980;  229 1-5
    CrossrefPubMedGoogle Scholar
  • 20 Abenhaim H A, Tremblay V, Tremblay L, Audibert F. Feasibility of a randomized controlled trial testing nifedipine vs. placebo for the treatment of preterm labor.  J Perinat Med. 2007;  35 301-304
    CrossrefPubMedGoogle Scholar
  • 21 Bracero L A, Leikin E, Kirshenbaum N, Tejani N. Comparison of nifedipine and ritodrine for the treatment of preterm labor.  Am J Perinatol. 1991;  8 365-369
    Article in Thieme ConnectPubMedGoogle Scholar
  • 22 Kupferminc M, Lessing J B, Yaron Y, Peyser M R. Nifedipine versus ritodrine for suppression of preterm labour.  Br J Obstet Gynaecol. 1993;  100 1090-1094
    PubMedGoogle Scholar
  • 23 García-Velasco J A, González González A. A prospective, randomized trial of nifedipine vs. ritodrine in threatened preterm labor.  Int J Gynaecol Obstet. 1998;  61 239-244
    CrossrefPubMedGoogle Scholar
  • 24 Mawaldi L, Duminy P, Tamim H. Terbutaline versus nifedipine for prolongation of pregnancy in patients with preterm labor.  Int J Gynaecol Obstet. 2008;  100 65-68
    CrossrefPubMedGoogle Scholar
  • 25 Ferguson II J E, Dyson D C, Schutz T, Stevenson D K. A comparison of tocolysis with nifedipine or ritodrine: analysis of efficacy and maternal, fetal, and neonatal outcome.  Am J Obstet Gynecol. 1990;  163 (1 Pt 1) 105-111
    PubMedGoogle Scholar
  • 26 Jannet D, Abankwa A, Guyard B, Carbonne B, Marpeau L, Milliez J. Nicardipine versus salbutamol in the treatment of premature labor. A prospective randomized study.  Eur J Obstet Gynecol Reprod Biol. 1997;  73 11-16
    CrossrefPubMedGoogle Scholar
  • 27 Koks C A, Brölmann H A, de Kleine M J, Manger P A. A randomized comparison of nifedipine and ritodrine for suppression of preterm labor.  Eur J Obstet Gynecol Reprod Biol. 1998;  77 171-176
    CrossrefPubMedGoogle Scholar
  • 28 Weerakul W, Chittacharoen A, Suthutvoravut S. Nifedipine versus terbutaline in management of preterm labor.  Int J Gynaecol Obstet. 2002;  76 311-313
    CrossrefPubMedGoogle Scholar
  • 29 Papatsonis D N, Van Geijn H P, Adèr H J, Lange F M, Bleker O P, Dekker G A. Nifedipine and ritodrine in the management of preterm labor: a randomized multicenter trial.  Obstet Gynecol. 1997;  90 230-234
    CrossrefPubMedGoogle Scholar
  • 30 Tsatsaris V, Papatsonis D, Goffinet F, Dekker G, Carbonne B. Tocolysis with nifedipine or beta-adrenergic agonists: a meta-analysis.  Obstet Gynecol. 2001;  97 (5 Pt 2) 840-847
    CrossrefPubMedGoogle Scholar
  • 31 Al-Omari W R, Al-Shammaa H B, Al-Tikriti E M, Ahmed K W. Atosiban and nifedipine in acute tocolysis: a comparative study.  Eur J Obstet Gynecol Reprod Biol. 2006;  128 129-134
    CrossrefPubMedGoogle Scholar
  • 32 Kashanian M, Akbarian A R, Soltanzadeh M. Atosiban and nifedipin for the treatment of preterm labor.  Int J Gynaecol Obstet. 2005;  91 10-14
    CrossrefPubMedGoogle Scholar
  • 33 King J F, Flenady V J, Papatsonis D N, Dekker G A, Carbonne B. Calcium channel blockers for inhibiting preterm labour.  Cochrane Database Syst Rev. 2003;  1 CD002255
    PubMedGoogle Scholar
  • 34 Larmon J E, Ross B S, May W L, Dickerson G A, Fischer R G, Morrison J C. Oral nicardipine versus intravenous magnesium sulfate for the treatment of preterm labor.  Am J Obstet Gynecol. 1999;  181 1432-1437
    CrossrefPubMedGoogle Scholar
  • 35 Glock J L, Morales W J. Efficacy and safety of nifedipine versus magnesium sulfate in the management of preterm labor: a randomized study.  Am J Obstet Gynecol. 1993;  169 960-964
    PubMedGoogle Scholar
  • 36 Lyell D J, Pullen K, Campbell L et al.. Magnesium sulfate compared with nifedipine for acute tocolysis of preterm labor: a randomized controlled trial.  Obstet Gynecol. 2007;  110 61-67
    CrossrefPubMedGoogle Scholar
  • 37 Nassar A H, Usta I M. Magnesium sulfate compared with nifedipine for acute tocolysis of preterm labor: a randomized controlled trial.  Obstet Gynecol. 2007;  110 1170-1171, author reply 1171
    PubMedGoogle Scholar
  • 38 Papatsonis D N, Kok J H, van Geijn H P, Bleker O P, Adèr H J, Dekker G A. Neonatal effects of nifedipine and ritodrine for preterm labor.  Obstet Gynecol. 2000;  95 477-481
    CrossrefPubMedGoogle Scholar
  • 39 Thornton J. The drugs we deserve.  BJOG. 2003;  110 969-970
    PubMedGoogle Scholar
  • 40 Moutquin J M, Sherman D, Cohen H et al.. Double-blind, randomized, controlled trial of atosiban and ritodrine in the treatment of preterm labor: a multicenter effectiveness and safety study.  Am J Obstet Gynecol. 2000;  182 1191-1199
    CrossrefPubMedGoogle Scholar
  • 41 Worldwide Atosiban versus Beta-agonists Study Group . Effectiveness and safety of the oxytocin antagonist atosiban versus beta-adrenergic agonists in the treatment of preterm labour.  BJOG. 2001;  108 133-142
    CrossrefPubMedGoogle Scholar
  • 42 Gaunekar N N, Crowther C A. Maintenance therapy with calcium channel blockers for preventing preterm birth after threatened preterm labour.  Cochrane Database Syst Rev. 2004;  3 CD004071
    PubMedGoogle Scholar
  • 43 Carr D B, Clark A L, Kernek K, Spinnato J A. Maintenance oral nifedipine for preterm labor: a randomized clinical trial.  Am J Obstet Gynecol. 1999;  181 822-827
    CrossrefPubMedGoogle Scholar
  • 44 Sayin N C, Varol F G, Balkanli-Kaplan P, Sayin M. Oral nifedipine maintenance therapy after acute intravenous tocolysis in preterm labor.  J Perinat Med. 2004;  32 220-224
    CrossrefPubMedGoogle Scholar
  • 45 Lyell D J, Pullen K M, Mannan J et al.. Maintenance nifedipine tocolysis compared with placebo: a randomized controlled trial.  Obstet Gynecol. 2008;  112 1221-1226
    CrossrefPubMedGoogle Scholar
  • 46 Thornton J G. The quality of randomised trials of tocolysis.  BJOG. 2006;  113 (Suppl 3) 93-95
    PubMedGoogle Scholar
  • 47 Harake B, Gilbert R D, Ashwal S, Power G G. Nifedipine: effects on fetal and maternal hemodynamics in pregnant sheep.  Am J Obstet Gynecol. 1987;  157 (4 Pt 1) 1003-1008
    PubMedGoogle Scholar
  • 48 Holbrook Jr R H, Lirette M, Katz M. Cardiovascular and tocolytic effects of nicardipine HCl in the pregnant rabbit: comparison with ritodrine HCl.  Obstet Gynecol. 1987;  69 83-87
    PubMedGoogle Scholar
  • 49 Parisi V M, Salinas J, Stockmar E J. Fetal vascular responses to maternal nicardipine administration in the hypertensive ewe.  Am J Obstet Gynecol. 1989;  161 1035-1039
    PubMedGoogle Scholar
  • 50 Matsuda Y, Ikenoue T, Matsuda K et al.. The effect of nicardipine on maternal and fetal hemodynamics and uterine blood flow in chronically instrumented pregnant goats.  Asia Oceania J Obstet Gynaecol. 1993;  19 191-198
    CrossrefPubMedGoogle Scholar
  • 51 Blea C W, Barnard J M, Magness R R, Phernetton T M, Hendricks S K. Effect of nifedipine on fetal and maternal hemodynamics and blood gases in the pregnant ewe.  Am J Obstet Gynecol. 1997;  176 922-930
    CrossrefPubMedGoogle Scholar
  • 52 Ducsay C A, Thompson J S, Wu A T, Novy M J. Effects of calcium entry blocker (nicardipine) tocolysis in rhesus macaques: fetal plasma concentrations and cardiorespiratory changes.  Am J Obstet Gynecol. 1987;  157 1482-1486
    PubMedGoogle Scholar
  • 53 Giles W, Bisits A. Preterm labour. The present and future of tocolysis.  Best Pract Res Clin Obstet Gynaecol. 2007;  21 857-868
    CrossrefPubMedGoogle Scholar
  • 54 Ferguson II J E, Dyson D C, Holbrook Jr R HJ, Schutz T, Stevenson D K. Cardiovascular and metabolic effects associated with nifedipine and ritodrine tocolysis.  Am J Obstet Gynecol. 1989;  161 788-795
    PubMedGoogle Scholar
  • 55 Childress C H, Katz V L. Nifedipine and its indications in obstetrics and gynecology.  Obstet Gynecol. 1994;  83 616-624
    CrossrefPubMedGoogle Scholar
  • 56 Oei S G. Calcium channel blockers for tocolysis: a review of their role and safety following reports of serious adverse events.  Eur J Obstet Gynecol Reprod Biol. 2006;  126 137-145
    CrossrefPubMedGoogle Scholar
  • 57 Oei S G, Oei S K, Brölmann H A. Myocardial infarction during nifedipine therapy for preterm labor.  N Engl J Med. 1999;  340 154
    CrossrefPubMedGoogle Scholar
  • 58 Bal L, Thierry S, Brocas E, Adam M, Van de Louw A, Tenaillon A. Pulmonary edema induced by calcium-channel blockade for tocolysis.  Anesth Analg. 2004;  99 910-911
    CrossrefPubMedGoogle Scholar
  • 59 Vaast P, Dubreucq-Fossaert S, Houfflin-Debarge V et al.. Acute pulmonary oedema during nicardipine therapy for preterm labour, report of five cases.  Eur J Obstet Gynecol Reprod Biol. 2004;  113 98-99
    CrossrefPubMedGoogle Scholar
  • 60 Hodges R, Barkehall-Thomas A, Tippett C. Maternal hypoxia associated with nifedipine for threatened preterm labour.  Br J Obstet Gynaecol. 2004;  111 380-381
    PubMedGoogle Scholar
  • 61 Verhaert D, Van Acker R. Acute myocardial infarction during pregnancy.  Acta Cardiol. 2004;  59 331-339
    CrossrefPubMedGoogle Scholar
  • 62 van Veen A J, Pelinck M J, Pampus M G, Erwich J J. Severe hypotension and fetal death due to tocolysis with nifedipine.  Br J Obstet Gynaecol. 2005;  112 509-510
    PubMedGoogle Scholar
  • 63 van Geijn H P, Lenglet J E, Bolte A C. Nifedipine trials: effectiveness and safety aspects.  Br J Obstet Gynaecol. 2005;  112 79-83
    CrossrefPubMedGoogle Scholar
  • 64 Abbas O M, Nassar A H, Kanj N A, Usta I M. Acute pulmonary edema during tocolytic therapy with nifedipine.  Am J Obstet Gynecol. 2006;  195 e3-e4
    PubMedGoogle Scholar
  • 65 Nassar A H, Ghazeeri G, Usta I M. Nifedipine-associated pulmonary complications in pregnancy.  Int J Gynaecol Obstet. 2007;  97 148-149
    CrossrefPubMedGoogle Scholar
  • 66 Carbonne B, Papatsonis D N, Flenady V J, Dekker G A, King J F. Comment on the article: “Acute pulmonary oedema during nicardipine therapy for premature labour. Report of five cases”.  Eur J Obstet Gynecol Reprod Biol. 2005;  120 119-120
    PubMedGoogle Scholar
  • 67 Psaty B M, Heckbert S R, Koepsell T D et al.. The risk of myocardial infarction associated with antihypertensive drug therapies.  JAMA. 1995;  274 620-625
    CrossrefPubMedGoogle Scholar
  • 68 Parasuraman R, Gandhi M M, Liversedge N H. Nifedipine tocolysis associated atrial fibrillation responds to DC cardioversion.  BJOG. 2006;  113 844-845
    PubMedGoogle Scholar
  • 69 Impey L. Severe hypotension and fetal distress following sublingual administration of nifedipine to a patient with severe pregnancy induced hypertension at 33 weeks.  Br J Obstet Gynaecol. 1993;  100 959-961
    PubMedGoogle Scholar
  • 70 Chan L W, Sahota D S, Yeung S Y et al.. Side-effect and vital sign profile of nifedipine as a tocolytic for preterm labour.  Hong Kong Med J. 2008;  14 267-272
    PubMedGoogle Scholar
  • 71 de Heus R, Mol B W, Erwich J J et al.. Adverse drug reactions to tocolytic treatment for preterm labour: prospective cohort study.  BMJ. 2009;  338 b744
    CrossrefPubMedGoogle Scholar
  • 72 Read M D, Wellby D E. The use of a calcium antagonist (nifedipine) to suppress preterm labour.  Br J Obstet Gynaecol. 1986;  93 933-937
    PubMedGoogle Scholar
  • 73 Nassar A H, Abu-Musa A A, Awwad J, Khalil A, Tabbara J, Usta I M. Two dose regimens of nifedipine for management of preterm labor: a randomized controlled trial.  Am J Perinatol. 2009;  26 575-581
    Article in Thieme ConnectPubMedGoogle Scholar
  • 74 Juon A M, Kühn-Velten W N, Burkhardt T, Krähenmann F, Zimmermann R, von Mandach U. Nifedipine gastrointestinal therapeutic system (GITS) as an alternative to slow-release for tocolysis—tolerance and pharmacokinetic profile.  Eur J Obstet Gynecol Reprod Biol. 2008;  140 27-32
    CrossrefPubMedGoogle Scholar
  • 75 Khan K, Zamora J, Lamont R F et al.. Safety concerns for the use of calcium channel blockers in pregnancy for the treatment of spontaneous preterm labour and hypertension: a systematic review and meta-regression analysis.  J Matern Fetal Neonatal Med. 2010;  February 25 (Epub ahead of print)
    PubMedGoogle Scholar
  • 76 Norwitz E R, Bahtiyar M O, Sibai B M. Defining standards of care in maternal-fetal medicine.  Am J Obstet Gynecol. 2004;  191 1491-1496
    CrossrefPubMedGoogle Scholar
  • 77 Cook C M, Peek M J. Survey of the management of preterm labour in Australia and New Zealand in 2002.  Aust N Z J Obstet Gynaecol. 2004;  44 35-38
    CrossrefPubMedGoogle Scholar
  • 78 Hui D, Liu G, Kavuma E, Hewson S A, McKay D, Hannah M E. Preterm labour and birth: a survey of clinical practice regarding use of tocolytics, antenatal corticosteroids, and progesterone.  J Obstet Gynaecol Can. 2007;  29 117-130
    PubMedGoogle Scholar
  • 79 Klauser C K, Briery C M, Magann E F, Martin R W, Chauhan S P, Morrison J C. Tocolytic preference for treatment of preterm labor.  J Miss State Med Assoc. 2007;  48 35-38
    PubMedGoogle Scholar

Anwar H NassarM.D. 

American University of Beirut Medical Center

P.O. Box 113-6044/B36, Hamra 110 32090, Beirut, Lebanon

Email: an21@aub.edu.lb

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