Am J Perinatol 2013; 30(07): 529-536
DOI: 10.1055/s-0032-1329684
Review Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Prevention of Respiratory Distress Syndrome in Preterm Infants by Antenatal Ambroxol: A Meta-Analysis of Randomized Controlled Trials

Zhi-Qun Zhang
1   Department of Neonatology, Hangzhou First People's Hospital, Zhejiang, China
,
Qian-Qian Wu
1   Department of Neonatology, Hangzhou First People's Hospital, Zhejiang, China
,
Xian-Mei Huang
1   Department of Neonatology, Hangzhou First People's Hospital, Zhejiang, China
2   Department of Pediatrics, Hangzhou First People's Hospital, Zhejiang, China
,
Hui Lu
1   Department of Neonatology, Hangzhou First People's Hospital, Zhejiang, China
› Author Affiliations
Further Information

Publication History

26 April 2012

21 August 2012

Publication Date:
10 December 2012 (online)

Abstract

Objective To evaluate the efficacy and safety of antenatal ambroxol as a preventive therapeutic of respiratory distress syndrome (RDS) in preterm infants.

Methods Randomized controlled trials of antenatal ambroxol treatment for RDS in preterm infants published up to March 2012 were downloaded from the Cochrane Library, PubMed, EMBASE, Science Citation Index, and Google Scholar databases. Data were evaluated for homogeneity and analyzed by the Cochrane Collaboration's RevMan software.

Result Twelve trials involving a total of 1335 premature infants were selected for meta-analysis. Neonatal RDS was lower in the ambroxol-treated group than in the groups treated with placebo (risk ratio [RR] = 0.38, 95% confidence interval [CI]: 0.24 to 0.59) or corticosteroids (RR = 0.49, 95% CI: 0.31 to 0.78). The ambroxol-treated group had lower risk of neonatal infection than the corticosteroid-treated group (RR = 0.36, 95% CI: 0.18 to 0.73).

Conclusions In cases of inevitable preterm birth, antenatal ambroxol is recommended over corticosteroids to prevent neonatal RDS. However, further research is necessary to determine the optimal treatment dosages and regimens of antenatal ambroxol to achieve consistent superior results over corticosteroids.

Funding

This work was supported by Hangzhou Science and Technology Development Project, grant number 20110833B02.


 
  • References

  • 1 Miracle X, Di Renzo GC, Stark A, Fanaroff A, Carbonell-Estrany X, Saling E. Coordinators of World Associatin of Perinatal Medicine Prematurity Working Group. Guideline for the use of antenatal corticosteroids for fetal maturation. J Perinat Med 2008; 36: 191-196
  • 2 Jobe AH. Pulmonary surfactant therapy. N Engl J Med 1993; 328: 861-868
  • 3 Henderson-Smart DJ, Wilkinson A, Raynes-Greenow CH. Mechanical ventilation for newborn infants with respiratory failure due to pulmonary disease. Cochrane Database Syst Rev 2002; (4) CD002770
  • 4 Sweet DG, Carnielli V, Greisen G , et al; European Association of Perinatal Medicine. European consensus guidelines on the management of neonatal respiratory distress syndrome in preterm infants—2010 update. Neonatology 2010; 97: 402-417
  • 5 Wapner R, Jobe AH. Controversy: antenatal steroids. Clin Perinatol 2011; 38: 529-545
  • 6 Disse BG, Ziegler HW. Pharmacodynamic mechanism and therapeutic activity of ambroxol in animal experiments. Respiration 1987; 51 (Suppl. 01) 15-22
  • 7 Allegra L, Bossi R, Braga P. Influence of surfactant on mucociliary transport. Eur J Respir Dis Suppl 1985; 142: 71-76
  • 8 Robertson B. Pharmacological stimulation of surfactant secretion and surfactant replacement. Eur J Respir Dis Suppl 1985; 142: 63-70
  • 9 Pfeifer S, Zissel G, Kienast K, Müller-Quernheim J. Reduction of cytokine release of blood and bronchoalveolar mononuclear cells by ambroxol. Eur J Med Res 1997; 2: 129-132
  • 10 Fabbri L, Pauwels RA, Hurd SS. GOLD Scientific Committee. Global strategy for the diagnosis, management and prevention of chronic obstructive pulmonary disease: GOLD Executive Summary updated 2003. COPD 2004; 1: 105-141 ; discussion 103–104
  • 11 Poole PJ, Black PN. Oral mucolytic drugs for exacerbations of chronic obstructive pulmonary disease: systematic review. BMJ 2001; 322: 1271-1274
  • 12 Zhang ZQ, Huang XM, Lu H. [Ambroxol for the prevention of respiratory distress syndrome in preterm infants: a meta analysis]. Zhongguo Dang Dai Er Ke Za Zhi 2010; 12: 858-863
  • 13 Vytiska-Binstorfer E, Salzer H, Simbruner G. [Ambroxol in comparison with betamethasone for the stimulation of antepartal lung maturity. A clinical double-blind study]. Zentralbl Gynakol 1986; 108: 220-229
  • 14 Chen XQ, Wu SH, Guo XR, Zhou XY. Effects of antenatal application of ambroxol and glucocorticoid on lung morphometry and signal transduction of bone morphogenetic protein in the fetal rat. Mol Med Report 2012; 6: 63-68
  • 15 Seifart C, Clostermann U, Seifart U , et al. Cell-specific modulation of surfactant proteins by ambroxol treatment. Toxicol Appl Pharmacol 2005; 203: 27-35
  • 16 Wirtz HR. [Effect of ambroxol on surfactant secretion and synthesis in isolated type II alveolar cells]. Pneumologie 2000; 54: 278-283
  • 17 Sun B, Rider E, Ikegami M, Jobe A. Antenatal ambroxol effects on surfactant pool size and postnatal lung function in preterm ventilated rabbits. Biol Neonate 1992; 62: 55-62
  • 18 Dani C, Grella PV, Lazzarin L, Rubaltelli FF. Antenatal ambroxol treatment does not prevent the respiratory distress syndrome in premature infants. Eur J Pediatr 1997; 156: 392-393
  • 19 Luerti M, Lazzarin A, Corbella E, Zavattini G. An alternative to steroids for prevention of respiratory distress syndrome (RDS): multicenter controlled study to compare ambroxol and betamethasone. J Perinat Med 1987; 15: 227-238
  • 20 Moher D, Liberati A, Tetzlaff J, Altman DG. PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 2009; 6: e1000097
  • 21 Higgins JPT, Green S , Eds. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available at: www.cochrane-handbook.org . Accessed July 11, 2012
  • 22 Heytmanek G, Salzer H, Vityska-Binstorfer E , et al. [Ambroxol versus betamethasone for the promotion of antepartum lung maturity in pathological pregnancies]. Wien Klin Wochenschr 1990; 102: 443-448
  • 23 Kimya Y, Küçükkömürcü S, Ozan H, Uncu G. Antenatal ambroxol usage in the prevention of infant respiratory distress syndrome. Beneficial and adverse effects. Clin Exp Obstet Gynecol 1995; 22: 204-211
  • 24 Laoag-Fernandez JB, Fernandez AM, Maruo T. Antenatal use of ambroxol for the prevention of infant respiratory distress syndrome. J Obstet Gynaecol Res 2000; 26: 307-312
  • 25 Wauer RR, Schmalisch G, Menzel K , et al. The antenatal use of ambroxol (bromhexine metabolite VIII) to prevent hyaline membrane disease: a controlled double-blind study. Int J Biol Res Pregnancy 1982; 3: 84-91
  • 26 Lee ES, Kim KA, Shin SM, Koh MW, Lee TH. The preventive effect of neonatal administration of ambroxol on the neonatal respiratory distress syndrome. Yeungnam University Journal of Medicine 1999; 16: 52-59
  • 27 Salzer H, Weidinger H, Simbruner G, Vytiska-Binstorfer E. [Ambroxol versus betamethasone for stimulating antepartal lung maturity—a multicenter study]. Z Geburtshilfe Perinatol 1986; 190: 49-59
  • 28 Wolff F, Ponnath H, Wiest W. [Induction of fetal lung maturation using ambroxol and betamethasone. Results of an open multicenter study]. Geburtshilfe Frauenheilkd 1987; 47: 19-25
  • 29 Lv YC, Chen LG, Li P. Antenatal ambroxol usage in the prevention of premature infant respiratory distress syndrome. Chinese Journal of Birth Health and Heredity 2005; 13: 79-80
  • 30 Zhou J, Duan T, Yan XL. Effect of antenatal Ambroxol versus Dexamethasone on NRDS prevention in PPROM. Chin J Perinat Med 2006; 9: 157-160
  • 31 Marinov B, Jekova N, Andreeva A, Hitrova S. [Antenatal ambroxol administration for prevention of respiratory distress syndrome in preterm infants: preliminary report]. Akusherstvo i Ginekologiia (Sofia) 2011; 50: 17-22
  • 32 Lazzarin A, Luerti M, Uberti-Foppa C, Zavattini G, Rossi A, Tornaghi R. Polymorphonuclear leucocytes functions from premature infants after prevention of respiratory distress syndrome with betamethasone and ambroxol. Biol Res Pregnancy Perinatol 1984; 5: 130-134
  • 33 Luerti M, Spagnolo D, Zavattini G, Bianchi C, Barbera AG, Corbella E. Cord blood prolactin and thyroid hormone levels after antenatal administration of betamethasone or ambroxol for prevention of respiratory distress syndrome (RDS). Biol Res Pregnancy Perinatol 1984; 5: 124-129
  • 34 Disse BG. The pharmacology of ambroxol—review and new results. Eur J Respir Dis Suppl 1987; 153: 255-262
  • 35 Wauer RR, Schmalisch G, Hammer H, Buttenberg S, Weigel H, Huth M. Ambroxol for prevention and treatment of hyaline membrane disease. Eur Respir J Suppl 1989; 3: 57S-65S
  • 36 Wauer RR, Schmalisch G, Böhme B, Arand J, Lehmann D. Randomized double blind trial of Ambroxol for the treatment of respiratory distress syndrome. Eur J Pediatr 1992; 151: 357-363
  • 37 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
  • 38 Lazzarin A, Capsoni F, Luerti M , et al. Immunological characteristics of preterm neonates after prophylaxis of NRDS. In: Vignali M, Cosmi EV, Luerti M, , eds. Diagnosis and Treatment of Fetal Lung Immaturity. Milan, Italy: Masson; 1986: 134-139
  • 39 Gené R, Poderoso JJ, Corazza C , et al. Influence of ambroxol on amoxicillin levels in bronchoalveolar lavage fluid. Arzneimittelforschung 1987; 37: 967-968
  • 40 Kallapur SG, Kramer BW, Moss TJ , et al. Maternal glucocorticoids increase endotoxin-induced lung inflammation in preterm lambs. Am J Physiol Lung Cell Mol Physiol 2003; 284: L633-L642
  • 41 Paleari D, Rossi GA, Nicolini G, Olivieri D. Ambroxol: a multifaceted molecule with additional therapeutic potentials in respiratory disorders of childhood. Expert Opin Drug Discov 2011; 6: 1203-1214
  • 42 Whitelaw A, Thoresen M. Antenatal steroids and the developing brain. Arch Dis Child Fetal Neonatal Ed 2000; 83: F154-F157
  • 43 Peltoniemi OM, Kari MA, Lano A , et al. Two-year follow-up of a randomised trial with repeated antenatal betamethasone. Arch Dis Child Fetal Neonatal Ed 2009; 94: 402-406
  • 44 Wapner RJ, Sorokin Y, Mele L , et al; National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. Long-term outcomes after repeat doses of antenatal corticosteroids. N Engl J Med 2007; 357: 1190-1198