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Ototoxicity in preterm infants: effects of genetics, aminoglycosides, and loud environmental noise

Journal of Perinatology volume 33, pages 3–8 (2013)Cite this article

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Abstract

Majority of hearing-loss cases with extremely preterm infants have no known etiology. There is a growing concern that the administration of aminoglycoside treatment in the noisy environment of the Neonatal Intensive Care Unit (NICU) may lead to hair-cell damage and subsequent auditory impairments. In addition, several mitochondrial DNA mutations are known to have been associated with aminoglycoside-induced hearing loss. This review provides a systematic analysis of the research in this area and elucidates the multifactorial mechanisms behind how mitochondrial DNA mutations, aminoglycosides and loud noise can potentiate ototoxicity in extremely preterm neonates. Recommended steps to minimize the risk of ototoxicity and improve clinical care for NICU infants are discussed.

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References

  1. Parmalee HP, Sigman MD . Perinatal Brain Development and Behavior 2nd edn vol. II. John Wiley and Sons: New York, 1983.

    Google Scholar 

  2. Rubel E . Auditory System Development vol. 53. Ablex: Camden, NJ, 1985.

    Google Scholar 

  3. Abrams RM, Gerhardt KJ . The acoustic environment and physiological responses of the fetus. J Perinatol 2000; 20: S31–S36.

    Article  CAS  Google Scholar 

  4. Birnholz JC, Benacerraf BR . The development of human fetal hearing. Science (New York, NY) 1983; 222: 516–518.

    Article  CAS  Google Scholar 

  5. Querleu D, Renard X, Boutteville C, Crepin G . Hearing by the human fetus? Sem perinatol 1989; 13: 409–420.

    CAS  Google Scholar 

  6. Gerhardt KJ, Abrams RM, Oliver CC . Sound environment of the fetal sheep. Am J obstet gynecol 1990; 162: 282–287.

    Article  CAS  Google Scholar 

  7. Querleu D, Renard X, Versyp F, Paris-Delrue L, Crepin G . Fetal hearing. Eur J Obstet Gynecol Reprod Biol 1988; 28: 191–212.

    Article  CAS  Google Scholar 

  8. Hepper PG, Shahidullah BS . Development of fetal hearing. Arch Dis Child 1994; 71: F81–F87.

    Article  CAS  Google Scholar 

  9. Crade M, Lovett S . Fetal response to sound stimulation: preliminary report exploring use of sound stimulation in routine obstetrical ultrasound examinations. J Ultrasound Med 1988; 7: 499–503.

    Article  CAS  Google Scholar 

  10. Fifer WP, Moon C . Auditory Experience in the Fetus. Telford: Caldwell, NJ, 1988; 175 pp.

    Google Scholar 

  11. Philbin MK, Gray L . Changing levels of quiet in an intensive care nursery. J Perinatol 2002; 22: 455–460.

    Article  Google Scholar 

  12. Pinheiro EM, Guinsburg R, Nabuco MA, Kakehashi TY . [Noise at the neonatal intensive care unit and inside the incubator]. Rev Latino-Am Enfermagem 2011; 19: 1214–1221.

    Article  Google Scholar 

  13. Levy GD, Woolston DJ, Browne JV . Mean noise amounts in level II vs level III neonatal intensive care units. Neonatal Netw 2003; 22: 33–38.

    Article  Google Scholar 

  14. Kent WD, Tan AK, Clarke MC, Bardell T . Excessive noise levels in the neonatal ICU: potential effects on auditory system development. J Otolaryngol 2002; 31: 355–360.

    Article  Google Scholar 

  15. American Academy of Pediatrics CoEH. Noise: a hazard for the fetus and the newborn. Pediatrics 1997; 100: 724–727.

  16. Als H, Butler S, Kosta S, McAnulty G . The Assessment of Preterm Infants’ Behavior (APIB): furthering the understanding and measurement of neurodevelopmental competence in preterm and full-term infants. Ment Retard Dev Disabil Res Rev 2005; 11: 94–102.

    Article  Google Scholar 

  17. Wachman EM, Lahav A . The effects of noise on preterm infants in the NICU. Arch Dis Child Fetal Neonatal Ed 2010; 96: F305–F309.

    Article  Google Scholar 

  18. Morton CC . Genetics, genomics and gene discovery in the auditory system. Hum Mol Genet 2002; 11: 1229–1240.

    Article  CAS  Google Scholar 

  19. Yoon PJ, Price M, Gallagher K, Fleisher BE, Messner AH . The need for long-term audiologic follow-up of neonatal intensive care unit (NICU) graduates. Int J Pediatr Otorhinolaryngol 2003; 67: 353–357.

    Article  Google Scholar 

  20. Ertl T, Hadzsiev K, Vincze O, Pytel J, Szabo I, Sulyok E . Hyponatremia and sensorineural hearing loss in preterm infants. Biol Neonate 2001; 79: 109–112.

    Article  CAS  Google Scholar 

  21. Morton NE . Genetic epidemiology of hearing impairment. Ann NY Acad Sci 1991; 630: 16–31.

    Article  CAS  Google Scholar 

  22. Pillers DM, Schleiss MR . Gentamicin in the Clinical Setting. Volta Rev 2005; 105: 205–210.

    Google Scholar 

  23. Clark R, Spitzer A . Antibiotics Used in the NICU. Neonatology Today 2006; 1: 1–10.

    Google Scholar 

  24. Chambers H, Sande MA . Antimicrobial Agents (Continued): The Aminoglycosideos. Macmillian Publishing: New York, 1995.

    Google Scholar 

  25. Matz GJ . Aminoglycoside cochlear ototoxicity. Otolaryngol Clin North Am 1993; 26: 705–712.

    CAS  PubMed  Google Scholar 

  26. Chambers H . The aminoglycosides 11th edn. McGraw Hill: New York, 2006.

    Google Scholar 

  27. Tran Ba Huy P, Manuel C, Meulemans A, Sterkers O, Amiel C . Pharmacokinetics of gentamicin in perilymph and endolymph of the rat as determined by radioimmunoassay. J Infect Dis 1981; 143: 476–486.

    Article  CAS  Google Scholar 

  28. Wang Q, Steyger PS . Trafficking of systemic fluorescent gentamicin into the cochlea and hair cells. J Assoc Res Otolaryngol 2009; 10: 205–219.

    Article  Google Scholar 

  29. Bernard PA . Freedom from ototoxicity in aminoglycoside treated neonates: a mistaken notion. Laryngoscope 1981; 91: 1985–1994.

    Article  CAS  Google Scholar 

  30. Darrouzet J, Limasobrinhoe DE . [the Internal Ear, Kanamycin and Acoustic Trauma. Experimental Study]. Rev Bras Cir 1963; 46: 120–134.

    CAS  PubMed  Google Scholar 

  31. Gannon RP, Tso SS, Chung DY . Interaction of kanamycin and noise exposure. J Laryngol Otol 1979; 93: 341–347.

    Article  CAS  Google Scholar 

  32. Ryan AF, Bone RC . Potentiation of kanamycin ototoxicity by a history of noise exposure. Otolaryngology 1978; 86: ORL-125–ORL-128.

    Article  Google Scholar 

  33. Ryan AF, Bone RC . Non-simultaneous Interaction of exposure to noise and kanamycin intoxication in the chinchilla. Am J Otolaryngol 1982; 3: 264–272.

    Article  CAS  Google Scholar 

  34. Vernon J, Brown J, Meikle M, Brummett RE . The potentiation of noise-induced hearing loss by neomycin. Otolaryngology 1978; 86: ORL-123–ORL-124.

    Article  Google Scholar 

  35. Dayal VS, Kokshanian A, Mitchell DP . Combined effects of noise and kanamycin. Ann Otol Rhinol Laryngol 1971; 80: 897–902.

    Article  CAS  Google Scholar 

  36. Collins PW . Synergistic interactions of gentamicin and pure tones causing cochlear hair cell loss in pigmented guinea pigs. Hear Res 1988; 36: 249–259.

    Article  CAS  Google Scholar 

  37. Tan CT, Hsu CJ, Lee SY, Liu SH, Lin-Shiau SY . Potentiation of noise-induced hearing loss by amikacin in guinea pigs. Hear Res 2001; 161: 72–80.

    Article  CAS  Google Scholar 

  38. Pye A, Collins P . Interaction between sound and gentamicin: immediate threshold and stereociliary changes. Br J Audiol 1991; 25: 381–390.

    Article  CAS  Google Scholar 

  39. Dodson HC, Bannister LH, Douek EE . The effects of combined gentamicin and white noise on the spiral organ of young guinea pigs. A structural study. Acta Otolaryngol 1982; 94: 193–202.

    Article  CAS  Google Scholar 

  40. Li H, Wang Q, Steyger PS . Acoustic trauma increases cochlear and hair cell uptake of gentamicin. PLoS One 2011; 6: e19130.

    Article  CAS  Google Scholar 

  41. Alles RM, Pye A . Cochlear damage in guinea pigs following contralateral sound stimulation with and without gentamicin. Br J Audiol 1993; 27: 183–193.

    Article  CAS  Google Scholar 

  42. Bhattacharyya TK, Dayal VS . Potentiation of cochlear hair cell loss by acoustic stimulus and gentamicin in the guinea pig. Anat Rec 1991; 230: 136–145.

    Article  CAS  Google Scholar 

  43. Fernandez EA, Ohlemiller KK, Gagnon PM, Clark WW . Protection against noise-induced hearing loss in young CBA/J mice by low-dose kanamycin. J Assoc Res Otolaryngol 2010; 11: 235–244.

    Article  Google Scholar 

  44. Brown JJ, Brummett RE, Fox KE, Bendrick TW . Combined effects of noise and kanamycin. Cochlear pathology and pharmacology. Arch Otolaryngol 1980; 106: 744–750.

    Article  CAS  Google Scholar 

  45. Brummett RE, Fox KE, Kempton JB . Quantitative relationships of the interaction between sound and kanamycin. Arch Otolaryngol Head Neck Surg 1992; 118: 498–500.

    Article  CAS  Google Scholar 

  46. Brown JJ, Brummett RE, Meikle MB, Vernon J . Combined effects of noise and neomycin. Cochlear changes in the guinea pig. Acta Otolaryngol 1978; 86: 394–400.

    CAS  PubMed  Google Scholar 

  47. Chen TJ, Chen SS, Lin CH, Hsieh YL . Synergestic effects of noise and aminoglycoside antibiotic (gentamicin) on auditory function in the gerbil. Kaohsiung J Med Sci 1997; 13: 407–416.

    CAS  PubMed  Google Scholar 

  48. Jauhiainen T, Kohonen A, Jauhiainen M . Combined effect of noise and neomycin on the cochlea. Acta Otolaryngol 1972; 73: 387–390.

    Article  CAS  Google Scholar 

  49. Marcotti W, van Netten SM, Kros CJ . The aminoglycoside antibiotic dihydrostreptomycin rapidly enters mouse outer hair cells through the mechano-electrical transducer channels. J Physiol 2005; 567: 505–521.

    Article  CAS  Google Scholar 

  50. Kroese AB, Das A, Hudspeth AJ . Blockage of the transduction channels of hair cells in the bullfrog’s sacculus by aminoglycoside antibiotics. Hear Res 1989; 37: 203–217.

    Article  CAS  Google Scholar 

  51. Li H, Steyger PS . Synergistic ototoxicity due to noise exposure and aminoglycoside antibiotics. Noise Health 2009; 11: 26–32.

    Article  CAS  Google Scholar 

  52. Alharazneh A, Luk L, Huth M, Monfared A, Steyger PS, Cheng AG et al. Functional hair cell mechanotransducer channels are required for aminoglycoside ototoxicity. PLoS One 2011; 6: e22347.

    Article  CAS  Google Scholar 

  53. Chen Y, Huang WG, Zha DJ, Qiu JH, Wang JL, Sha SH et al. Aspirin attenuates gentamicin ototoxicity: from the laboratory to the clinic. Hear Res 2007; 226: 178–182.

    Article  CAS  Google Scholar 

  54. Oesterle EC, Campbell S, Taylor RR, Forge A, Hume CR . Sox2 and JAGGED1 expression in normal and drug-damaged adult mouse inner ear. J Assoc Res Otolaryngol 2008; 9: 65–89.

    Article  Google Scholar 

  55. Ricci AJ, Crawford AC, Fettiplace R . Tonotopic variation in the conductance of the hair cell mechanotransducer channel. Neuron 2003; 40: 983–990.

    Article  CAS  Google Scholar 

  56. Li R, Xing G, Yan M, Cao X, Liu XZ, Bu X et al. Cosegregation of C-insertion at position 961 with the A1555G mutation of the mitochondrial 12S rRNA gene in a large Chinese family with maternally inherited hearing loss. Am J Med Genet A 2004; 124A: 113–117.

    Article  Google Scholar 

  57. Zhao L, Young WY, Li R, Wang Q, Qian Y, Guan MX . Clinical evaluation and sequence analysis of the complete mitochondrial genome of three Chinese patients with hearing impairment associated with the 12S rRNA T1095C mutation. Biochem Biophys Res Commun 2004; 325: 1503–1508.

    Article  CAS  Google Scholar 

  58. Bacino C, Prezant TR, Bu X, Fournier P, Fischel-Ghodsian N . Susceptibility mutations in the mitochondrial small ribosomal RNA gene in aminoglycoside induced deafness. Pharmacogenetics 1995; 5: 165–172.

    Article  CAS  Google Scholar 

  59. Fischel-Ghodsian N . Mitochondrial deafness mutations reviewed. Hum Mutat 1999; 13: 261–270.

    Article  CAS  Google Scholar 

  60. Hobbie SN, Akshay S, Kalapala SK, Bruell CM, Shcherbakov D, Bottger EC . Genetic analysis of interactions with eukaryotic rRNA identify the mitoribosome as target in aminoglycoside ototoxicity. Proc Natl Acad Sci USA 2008; 105: 20888–20893.

    Article  CAS  Google Scholar 

  61. Qian Y, Guan MX . Interaction of aminoglycosides with human mitochondrial 12S rRNA carrying the deafness-associated mutation. Antimicrob Agents Chemother 2009; 53: 4612–4618.

    Article  CAS  Google Scholar 

  62. Chinnery PF, Elliott C, Green GR, Rees A, Coulthard A, Turnbull DM et al. The spectrum of hearing loss due to mitochondrial DNA defects. Brain 2000; 123, Pt 1 82–92.

    Article  Google Scholar 

  63. Guan MX, Fischel-Ghodsian N, Attardi G . A biochemical basis for the inherited susceptibility to aminoglycoside ototoxicity. Hum Mol Genet 2000; 9: 1787–1793.

    Article  CAS  Google Scholar 

  64. Zhao H, Young WY, Yan Q, Li R, Cao J, Wang Q et al. Functional characterization of the mitochondrial 12S rRNA C1494T mutation associated with aminoglycoside-induced and non-syndromic hearing loss. Nucleic Acids Res 2005; 33: 1132–1139.

    Article  CAS  Google Scholar 

  65. Guan MX . Mitochondrial 12S rRNA mutations associated with aminoglycoside ototoxicity. Mitochondrion 2011; 11: 237–245.

    Article  CAS  Google Scholar 

  66. Ealy M, Lynch KA, Meyer NC, Smith RJ . The prevalence of mitochondrial mutations associated with aminoglycoside-induced sensorineural hearing loss in an NICU population. Laryngoscope 2011; 121: 1184–1186.

    Article  CAS  Google Scholar 

  67. White RD . Designing environments for developmental care. Clin Perinatol 2011; 38: 745–749.

    Article  Google Scholar 

  68. White RD . The newborn intensive care unit environment of care: how we got here, where we're headed, and why. Semin Perinatol 2011; 35: 2–7.

    Article  Google Scholar 

  69. Rao SC, Ahmed M, Hagan R . One dose per day compared to multiple doses per day of gentamicin for treatment of suspected or proven sepsis in neonates. Cochrane Database Syst Rev 2006; 9: CD005091.

    Google Scholar 

  70. Pacifici GM . Clinical pharmacokinetics of aminoglycosides in the neonate: a review. Eur J Clin Pharmacol 2009; 65: 419–427.

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Newborn Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    E Zimmerman & A Lahav

  2. Department of Pediatrics, Mass General Hospital for Children, Boston, MA, USA

    A Lahav

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  1. E Zimmerman
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  2. A Lahav
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Correspondence to A Lahav.

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Zimmerman, E., Lahav, A. Ototoxicity in preterm infants: effects of genetics, aminoglycosides, and loud environmental noise. J Perinatol 33, 3–8 (2013). https://doi.org/10.1038/jp.2012.105

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