http://informahealthcare.com/jmf ISSN: 1476-7058 (print), 1476-4954 (electronic) J Matern Fetal Neonatal Med, Early Online: 1–5 ! 2014 Informa UK Ltd. DOI: 10.3109/14767058.2014.936375
ORIGINAL ARTICLE
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Sensorineural hearing loss in very low birth weight infants with histological chorioamnionitis Stefania Vedovato1,2, Angela Lo Iacono3, Carla Morando1, Agnese Suppiej4, Eva Orzan5, Daniele Trevisanuto2, Silvia Visentin3, Francesco Cavallin6, Silvia Chiarelli7, and Vincenzo Zanardo2 1
Department of Pediatrics, Neonatal Intensive Care Unit, San Bortolo Hospital, Vicenza, Italy, 2Pediatric Department, Medical School, University of Padua, Azienda Ospedaliera Padova, Padua, Italy, 3Department of Gynaecology and Reproductive Science, Padua University, Italy, 4Department of Paediatrics, Child Neurology and Clinical Neurophysiology, Padua University, Italy, 5Department of Otolaryngology and Audiology, IRCCS Burlo Garofalo, Trieste, Italy, 6Independent Statistician, Padua, Italy, and 7Department of Oncological and Surgical Sciences (Section of Pathology), Padua University, Italy Abstract
Keywords
Objective: Histological chorioamnionitis (HCAM) has been associated with inflammatory diseases of preterm infants. Recently we have observed that it increased the risk of speech delay and hearing loss. So the aim of this study was to evaluate the relationship between sensorineural hearing loss (SNHL) of VLBW infants and HCAM. Methods: We performed an observational study on VLBW infants admitted to the NICU of Padua. Each patient with HCAM was matched with one control without HCAM. All infants underwent hearing screening before discharge by means of automated transient–evoked otoacustic emissions and automated auditory brainstem responses, which were repeated at 3 and 6 months of age with tympanometry measurement. Incidence of SNHL at 6 months of age was compared in the 2 groups and risk factors for hearing loss were studied. Results: Two of 77 (2.6%) newborns with HCAM e 6/73 (8.2%) without it presented SNHL at 6 months of corrected age (p ¼ 0.16). Multivariable logistic regression analysis identified surgical ligation of patent ductus arteriosus (PDA) as independent predictors of SNHL (OR: 5.75, 95% CI 1.34–24.84, p ¼ 0.02), whereas the effect of HCAM on SNHL was only near to statistical significance level. Conclusions: Surgical ligation of PDA is associated with an increased risk of SNHL in VLBW infants, regardless of HCAM.
Chorioamnionitis, hearing screening, preterm infants
Introduction In the last decades, survival of extremely premature and low birth weight infants has improved thank to advances in perinatal and neonatal treatment. On the other hand, it has led to new social and health problems related to the high risk of neurological sequelae [1]. One of the possible disability is sensory-neural hearing loss (SNHL) whose prevalence is 1–3 in 1000 healthy newborns [2], but it is much higher (2–4 in 100 live births) in preterm infants. Among these, very low birth weight infants (VLBWI) are considered at high risk of hearing impairment even if the rate of SNHL is difficult to establish because of the use of different methods for testing as well as different gestational ages at test and different definitions of SNHL. The literature reports a variable incidence of 0.8–8% among extremely low birth weight Address for correspondence: Stefania Vedovato, Neonatal Intensive Care Unit, Department of Pediatrics, San Bortolo Hospital, Viale Rodolfi 37, 36100 Vicenza, Italy. Tel: +39.0444.75.26.84. E-mail: [email protected]
History Received 1 March 2014 Revised 19 May 2014 Accepted 15 June 2014 Published online 11 July 2014
infants [3,4]. In addition to prematurity, many risk factors are involved in the pathogenesis of SNHL: hyperbilirubinemia requiring exchange transfusion, culture-positive sepsis, use of ototoxic drugs, hypoxia, asphyxia, prolonged need for ventilation, bronchopulmonary dysplasia (BPD), PDA ligation [5–9], loud environmental noise [10]. and the interaction between these factors has been demonstrated. Thus, in the ‘‘2007 Position Statement of Join Committee on Infant Hearing’’, neonatal intensive care of more than 5 days has been considered a risk indicator associated with hearing loss, and audiological monitoring has been recommended for this population regardless of gestational age [11]. However, HCAM has been implicated in the pathogenesis of brain damage in VLBW infants [12]. HCAM is the acute inflammatory response of both the mother and fetus to extracellular microorganisms that gain access to the gestational sac [13]. It leads to activation of the cytokines network which can induce preterm labor and cause the fetal inflammatory response syndrome (FIRS). FIRS has been associated to inflammatory diseases of preterm infants,
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increasing the risk of neonatal sepsis and meningitis, BPD and cerebral palsy [14,15]. Recently we have observed that VLBW infants with HCAM present an increased risk of speech delay and hearing loss at 18 months of age [16]. The role of chorioamnionitis in the pathogenesis of SNHL has never been studied. Considering that the inner ear concludes its development toward the 25th week of gestation [17], we hypothesized that inflammation cascade of HCAM could interfere with the delicate developmental phase of the cochlea. So the aim of this study was to evaluate the relationship between SNHL and HCAM in VLBW infants. The secondary objective was to perform a risk analysis for SNHL considering the risk factors for hearing impairment [5–10].
Methods This is a prospective study on VLBW infants with histological chorioamnionitis, born at the Obstetrics and Gynecology Department in Padua and admitted to the Neonatal Intensive Care Unit of Padua University, between 2001 and 2010. Each patient with HCAM was matched with one control without HCAM, of the same gestational age ± 1 week and born in the same year to minimize changes in care practices. The incidence of SNHL was determined at 6 months of corrected age and compared in the 2 groups. The placentas of all neonates included in the analysis were examined by an experienced pathologist, according to the Guidelines of the College of American Pathologists [18]. Placental histological examination included a minimum of three cross-sections of the umbilical cord taken from fetal and placental side of the umbilical cord, three membrane rolls and a sample of the chorionic plate. The inflammatory findings at histology were recorded and accounted for the worst area scored, as previously reported [15], according to the classification of Redline [13]. Exclusion criteria were major congenital malformations or craniofacial malformations. The following characteristics were obtained from the medical record of patients: maternal clinical data, antenatal administration of steroids, type of birth (vaginal or cesarean section), birth weight, Apgar Score (AS) at 1 and 5 minutes, RDS defined as the need for supplemental oxygen and ventilation support with the characteristic radiographic findings; mechanical ventilation for more than 5 days; BPD defined as need for supplemental oxygen at 36 postmenstrual weeks [19], postnatal administration of steroids according to our protocol (dexamethasone: 0.2 mg/kg/die 3 days then 0.1 mg/kg/die 4 days, after the second week of life) [20], culture proven sepsis or clinically suspected sepsis (C-reactive protein 48 mg/L and 2 clinical criteria), distinguishing early (572 hours of life) from late sepsis (472 hours of life); presence of PDA requiring medical treatment only or ligation; intraventricular hemorrhage (IVH); necrotizing enterocolitis (NEC) requiring surgery; retinal surgery; gentamicin administration; exchange transfusion [5–11]. All infants underwent blinded standard hearing screening. Hearing screening evaluated physiological responses to sound originating from different levels of auditory pathway: cochlear function was tested by oto-acoustic emissions (OAEs) while electrical responses of the early auditory pathway were
J Matern Fetal Neonatal Med, Early Online: 1–5
evaluated by auditory brainstem response (ABR). The first test records emission of acoustic energy by the cochlea in response to sound. OAEs are normally classified by the method of recording: transient evoked otoacoustic emissions (TEOAE) and distortion product otoacoustic emission (DPOAE). All newborns after 35 corrected gestational weeks and before discharge performed audiological screening programme by two tests: automated transient evoked otoacoustic emissions (A-TEOAE) and automated auditory brainstem responses (A-ABRs). Both tests have been made with the same instrument AccuScreen PROÕ which was calibrated daily before its use and once a year by the manufacturer. Results were considered negative if A-TEOAE and A-ABR for both ears were ‘‘PASS’’. Otherwise, infants underwent audiological evaluation within 3 months with DPOAE and A-ABRs. Middle ear function were assessed by 226 Hz frequency tympanometry and by the acoustic reflex threshold performed by Tympanometer GSI 33 which had been calibrated twice a year by manufacturer technical personnel. If these evaluations questioned the presence of hearing deficit, diagnostic ABR was performed. On the basis of its results, the patient underwent audiological assessment within 6 months of corrected age. All infants resulting ‘‘PASS’’ at standard hearing screening before discharge were evaluated at 6 months of corrected age with clinical examination (otoscopy), bilateral DPOAE, timpanometry measurement, A-ABRs. All tests were completed by experienced, certified, pediatric audiologist of the Pediatric Audiology Unit, Department of Otorhinolaryngology and Otosurgery of Padua University, who was blinded to placental histology, in an environment that assured reliable measurements. SNHL was defined as a unilateral or bilateral hearing threshold higher than 25 dB HL for at least two of the frequencies tested (from 500 to 4000 Hz). Conductive HL was diagnosed in children with normal bone conduction threshold (520 dB) and air-bone gap 15 dB averaged over 0.5, 1 and 2 kHz [20]. Sensorineural hearing loss was classified as follows: absent (average tone loss 0–20 dBHL), mild (average tone loss 21–40 dBHL), moderate (1st degree: average tone loss 41–55 dBHL, 2nd degree: average tone loss 56–70), severe (1st degree: average tone loss 71–80 dBHL, 2nd degree: average tone loss 81–90 dBHL), very severe (1st degree: average tone loss 91–100 dBHL, 2nd degree: average tone loss 101–110, 3rd degree: average tone loss 111–119) and total hearing loss (average tone loss 4120 dBHL) [21]. Informed consent was obtained from the parents. The study was approved by the local institutional review board. Statistical analysis Continuous data were expressed as Median and Interquartile Range (IQR). Categorical data were compared using Fisher’s test and continuous data using Wilcoxon Mann–Whitney test. A logistic regression model was estimated to identify the independent predictors of hearing loss; Apgar scores and use of postnatal steroids were not included in model estimation because they were considered indicators of most severe illness of infants with SNHL and not possible independent risk factors. A p value less than 0.05 was considered significant. Statistical analysis was performed using R 2.12 software
Hearing loss in newborn
DOI: 10.3109/14767058.2014.936375
(R Development Core Team (2010); R: A language and environment for statistical computing; R Foundation for Statistical Computing, Vienna, Austria, ISBN 3-90005107-0).
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Results Two-hundred and four VLBW infants were enrolled: 102 with HCAM (cases) and 102 without HCAM (controls). The 2 groups were comparable for gestational age: 27 gestational weeks (median 26–30) versus 28 (median 26–30), p ¼ 0.70; birth weight: 1047 grams (median 800–1380) versus 880 (median 700–1235), p ¼ 0.06; sex: M/F 55/47 versus 52/50, p ¼ 0.78; Apgar Score 53 at 1 minute: 7.8% versus 9.8%, (p ¼ 0.77); Apgar Score 55 at 5 minutes: 5.8% versus 5.8% (p ¼ 0.98); prenatal steroids: 84.3% versus 78.4% (p ¼ 0.37), while they were different for vaginal delivery: 26.4% versus 7.8% (p ¼ 0.0006), pre-eclampsia: 0.9% versus 8.8% (p ¼ 0.01), incidence of intrauterine growth restricted (IUGR) newborns [22]: 4.9% versus 27.4% (p ¼ 0.0001) and preterm labor: 79.4% versus 37.2% (p50.0001). Of 204 neonates enrolled, 11 (2 cases and 9 controls) died before discharge and 43 (23 cases and 20 controls) were lost to follow-up at 6 months. Thus 150 (73.5%) infants were considered for statistical analysis. In the final sample, the two groups were still comparable for gestational age: median 27 (interquartile range 26–31) versus 28 (interquartile range 26–29), p ¼ 0.66. Among these, 2 newborns with HCAM (2.6%) and 6 without HCAM (8.2%) presented bilateral SNHL (p ¼ 0.16) at 6 months of corrected age and 6 of them required intervention with hearing aids. Furthermore 9 cases (11.6%) and 2 controls (2.7%) presented conductive hearing loss at 6 months of corrected age. At univariate analysis SNHL was significantly associated with lower Apgar Score at the 1 minute (median 2 versus 7, p ¼ 0.002), lower Apgar Score at 5 minutes (median 6.5 versus 8, p ¼ 0.003), Apgar Score 53 at 1 minute (p ¼ 0.002), postnatal steroids administration (p ¼ 0.02) and PDA surgical ligation (p ¼ 0.03; Tables 1 and 2) Multivariable logistic regression analysis identified surgical ligation of patent ductus arteriosus as independent predictors of SNHL (OR: 5.75, 95% CI 1.34–24.84, p ¼ 0.02; Table 3). The effect of HCAM on SNHL was only near to statistical significance level (p ¼ 0.08).
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previous observational study on the neurodevelopmental outcome (5.7%), in which we found that newborns with HCAM compared with newborns without it presented a higher occurrence of hearing loss requiring hearing aids and speech delay at 18 months [16]. In the present study, incidence of SNHL was comparable in the patients with or without HCAM (2.6% versus 8.2%; p ¼ 0.16). The univariate analysis showed that lower Apgar Score at 1 and 5 minutes, postnatal steroids administration and PDA surgical ligation were significantly associated with SNHL, whereas the effect of HCAM on SNHL was only near to statistical significance level (p ¼ 0.08). Also Coeraad at al. observed that newborns admitted to the NICU and affected by hearing loss had a lower Apgar Score at 1 min [8]. While Hille et al. found a relationship between hearing loss and severe birth asphyxia in a population of preterm infants530 gestational weeks [23]. Low AS is an indicator of perinatal hypoxia and, in animal models, it has been shown that cochlear hail cells are sensitive to prolonged mild hypoxia [24]. Adequate oxygenation and perfusion are essential for normal cochlear function even if there is not a stated threshold level of hypoxia Table 2. Univariate analysis of sensorineural hearing loss (SNHL).
Risk factors HCAM Sex (M versus F) Apgar Score 10 53 Apgar Score 50 55 RDS HFO ventilation Mechanical ventilation 45 days BPD (36 wks) Postnatal steroids PDA (medical treatment) PDA (surgical ligation) IVH ROP NEC requiring surgery Early Sepsis Late Sepsis Exchangetransfusion Gentamicin administration Retinal surgery
SNHL in infants without risk factor (%)
p valuex
(2.6) (8.9) (30.8) (33.3) (6.5) (13) (10.2)
6/73 (8.2) 1/71 (1.4) 4/137 (2.9) 6/142 (2.8) 0/27 5/127 (3.9) 2/91 (2.2)
0.16 0.07 0.002 – 0.35 0.11 0.06
4/52 (7.7) 3/13 (23.1) 5/61 (8.2) 4/25 (16) 1/24 (4.2) 4/51 (7.8) 2/5 (40) 2/43 (4.7) 4/40 (10) 0/0 7/138 (5.1) 0/2
4/98 (4.1) 5/137 (3.7) 3/89 (3.4) 4/125 (3.2) 7/126 (5.6) 4/99 (4) 6/145 (4.1) 6/107 (5.6) 4/110 (3.6) 8/150 1/12 (8.3) 8/148 (5.4)
0.45 0.02 0.27 0.03 0.99 0.44 – 0.99 0.21 – 0.50 –
SNHL in infants with risk factor (%) 2/77 7/79 4/13 2/6 8/123 3/23 6/59
In this study, the overall prevalence of hearing loss was 5.3%. This is consistent with literature (2–4%) and with our
F: female; M: male; RDS: respiratory distress sindrome; HFO: high frequency oscillatory BPD: bronchopulmonary displasia; PDA: patent ductus arteriosus; IVH: intraventricular haemorrhage; ROP: retinopathy of prematurity; NEC: necrotizing enterocolitis. Data presented are numbers (percentages). xFisher test.
Table 1. Univariate analysis of sensorineural hearing loss (SNHL).
Table 3. Multivariate logistic regression analysis of sensorineural hearing loss (SNHL).
Discussion
No SNHL
SNHL
N 142 8 Gestational age 27 (26–30) 26 (25–29) Apgar Score 1 min 7 (5–8) 2 (1–4) Apgar Score 5 min 8 (7–9) 6.5 (4.5–7) Birth Weight (g) 945 (780–1310) 760 (598–1380) Total NICU stay (days) 52 (31–85) 80 (55–110)
p value # – 0.16 0.002 0.003 0.30 0.07
Data presented are median (interquartile range). #Wilcoxon Mann– Whitney test.
Risk factors HCAM (cases/controls) PDA surgical ligation versus medical treatment Sex (M/F): Mechanical ventilation 45 days Length of stay in NICU
p value
OR (95% C.I.)
0.08 0.02
– 5.76 (1.34–24.84)
0.10 0.28 0.72
– – –
HCAM: histological chorioamnionitis; F: female; M: male; PDA: patent ductus arteriosus.
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at which hearing is at risk. Moreover there is a different susceptibility of the patients which probably depends on concomitant risk factors associated to hypoxia (like hyperventilation and alkalinisation) [4]. Besides we observed a correlation between postnatal steroids administration and SNHL. Postnatal steroids are currently used at low-dose to improve clinical course of ventilator-dependent premature babies. Considering randomized, controlled trials of dexamethasone to prevent or treat BPD reported since late 1990s, the 2010 American Academy of Pediatrics statement concluded that therapy with high-dose dexamethasone cannot be recommended because of increased risk of cerebral palsy and neurodevelopmental delay. Moreover, in newborns treated with low-dose dexamethasone, an increase in adverse neurodevelopmental outcomes has not been reported even if there is insufficient evidence to make a recommendation regarding this treatment [25,26]. In our study, 3 of 8 infants with SNHL were treated with postnatal steroids according to our protocol [20], and the univariate analysis demonstrated that dexamethasone was associated with SNHL (p ¼ 0.02). Dexamethasone treatment has been shown to alter hippocampal synaptic plasticity and associative memory formation in later life [27]. Furthermore, in many studies it increases the risk of cerebral palsy [28], so an effect on auditory pathway can be postulated even if the pathogenesis is not clear. Finally we found that PDA surgical ligation is associated with SNHL. This is comparable to literature findings. PDA surgical ligation has been previously reported as a risk factor for mild/moderate or severe/profound permanent SNHL [9], and for neurosensory impairment in extremely low-birthweight infants [29]. The relationship is not clear but perioperative or intraoperative events such as hypothermia, cardiorespiratory instability, or exposure to anesthetic drugs have been postulated as possible explanations [29]. The association between SNHL and PDA ligation has also been confirmed by multivariable logistic regression analysis (OR: 5.75, 95% CI 1.34–24.84, p ¼ 0.02) even if the low prevalence of SNHL and the small sample size of this study are the main limit for this analysis. This study has however some limits. First, 21% of enrolled newborns and 14% of ‘‘REFER’’ newborns were lost to follow up at 6 months. Our percentages of ‘‘lost to follow up’’ are consistent with previous studies which reported a 13–14%, [30]. but a post-hoc analysis power calculation revealed a power of 0.33. Thus the low prevalence of SNHL prevents us from drawing robust conclusions. Secondly, we have considered a long period of time (2001– 2010), during which care practices may have been partly changed. That is why we matched patients of the same gestational age and born in the same year to minimize this bias. Thirdly premature infants are at risk of delayed onset and progressive hearing loss and according to JCIH guidelines audiological screening has to be continued up to 3 years of age to better describe the incidence of hearing loss in this population. In conclusion, in this study, surgical ligation of patent ductus arteriosus was identified as independent predictor of SNHL in VLBW infants. The effect of HCAM on SNHL could not be decisively assessed due to the low prevalence of
J Matern Fetal Neonatal Med, Early Online: 1–5
SNHL. Further follow up studies should be conducted to confirm the findings of the present study.
Acknowledgements We thank the audiologist Maria De Benedittis and the nurse Michela Scalco for their contributions in the collection of data and in the writing of the manuscript.
Declaration of interest The authors report no declarations of interest.
References 1. Marlow N, Wolke D, Bracewell MA, Samara M; for the EPICure Study Group. Neurologic and developmental disability at six years of age after extremely preterm birth. N Engl J Med 2005;352:9–19. 2. Fortnum HM, Summerfield AQ, Mashall DH, et al. Prevalence of permanent childhood hearing impairment in the United Kingdom and implication on universal neonatal hearing screening: questionnaire based ascertaintment study. BMJ 2001;323:536–40. 3. Fawke J. Neurological outcomes following preterm birth. Semin Fetal Neonatal Med 2007;12:374–82. 4. Cristobal R, Oghalai JS. Hearing loss in children with very low birth weight: current review of epidemiology and pathophysiology. Arch Dis Child Fetal Neonatal Ed 2008;93:F462–8. 5. Casano RA, Johnson DF, Bykhovskaya Y, et al. Inherited susceptibility to aminoglycoside ototoxicity: genetic heterogeneity and clinical implications. Am J Otolaryngol 1999;20:151–6. 6. De Vries LS, Lary S, Whitelaw AG, Dubowitz LM. Relationship of serum bilirubin levels and hearing impairment in newborn infants. Early Hum Dev 1987;15:269–77. 7. Olusanya BO. Newborns at risk of sensorineural hearing loss in low-income countries. Arch Dis Child 2009;94:227–30. 8. Coenraad S, Goedegebure A, van Goudoever JB, Hoeve LJ. Risk factors for sensorineural hearing loss in NICU infants compared to normal hearing NICU controls. Int J Pediatr Otorhinolaryngol 2010;74:999–1002. 9. Robertson CM, Howarth TM, Bork DL, Dinu IA. permanent bilateral sensory and neural hearing loss of children after neonatal intensive care because of extreme prematurity: a thirty-year study. Pediatrics 2009;123;e797–807. 10. Zimmerman E, Lahav A. Ototoxicity in preterm infants: effects of genetics, aminoglycosides, and loud environmental noise. J Perinatol 2013;33:3–8. 11. Committee on Infant Hearing. Year 2007 position statement: principles and guidelines for early hearing detection and intervention programs. Pediatrics 2007;120:898–921. 12. Shatrov JG, Birch SC, Lam LT, et al. Chorioamnionitis and cerebral palsy: a meta-analysis. Obstet Gynecol 2010;116:387–92. 13. Redline RW. Inflammatory responses in the placenta and umbilical cord. Semin Fetal Neonatal Med 2006;11:296–301. 14. Yoon BH, Romero R, Park JS, et al. The relationship among inflammatory lesions of the umbilical cord (funisitis), umbilical plasma interleukin 6 concentration, amniotic fluid infection, and neonatal sepsis. Am J Obstet Gynecol 2000;183:1124–9. 15. Zanardo V, Vedovato S, Cosmi E, et al. Preterm premature rupture of membranes, chorioamnion inflammatory scores and neonatal respiratory outcome. BJOG 2010;117:94–8. 16. Suppiej A, Franzoi M, Vedovato S,. Neurodevelopmental outcome in preterm histological chorioamnionitis. Early Hum Dev 2009;85: 187–9. 17. Rodriguez K, Shahl R, Kenna M. Anomalies of the middle and inner ear. Otoryngol Clin N Am 2007;40:81–96. 18. Langston C, Kaplan C, Macpherson T, et al. Practice guideline for examination of the placenta. Arch Pathos Lab Med 1997;121: 449–76. 19. Ehrenkranz RA, Walsh MC, Vohr BR, et al; National Institutes of Child Health and Human Development Neonatal Research Network. Validation of the national institutes of health consensus definition of bronchopulmonary displasia. Pediatrics 2005;116: 1353–60.
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DOI: 10.3109/14767058.2014.936375
20. Durand M, Mendoza ME, Tantivit P, et al. A randomized trial of moderately early low-dose dexamethasone therapy in very low birth weight infants: dynamic pulmonary mechanics, oxygenation, and ventilation. Pediatrics 2002;109:262–8. 21. International Bureau for Audiophonology [Internet]. Recommendations CT2 classification. BIAP Recommendation n 02/1 bis: audiometric classification of hearing impairments. October 1996. Available from: http://www.biap.org/index.php? option¼com_content&view¼article&id¼5%3Arecommandationbiap-021-bis&catid=65%3Act-2-classification-des-surdites&Itemid ¼19&lang¼en. 22. Cosmi E, Fanelli T, Visentin S, et al. Consequences in infants that were intrauterine growth restricted. J Pregnancy 2011;2011: Article ID 364381, 6 pages. 23. Hille ET, van Straaten HI, Verkerk PH; Dutch NICU Neonatal Hearing Screening Working Group. Prevalence and independent risk factors for hearing loss in NICU infants. Acta Paediatr 2007;96: 1155–8. 24. Sawada S, Mori N, Mount RJ, Harrison RV. Differential vulnerability of inner and outer hair cell systems to chronic mild hypoxia and glutamate ototoxicity: insights into the cause of auditory neuropathy. J Otolaryngol 2011:30:106–14.
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25. Watterberg KL; American Academy of Pediatrics. Committee on Fetus and Newborn. Policy statement – postnatal corticosteroids to prevent or treat bronchopulmonary dysplasia. Pediatrics 2010;126: 800–8. 26. AAP Committee on Fetus and Newborn. Postnatal corticosteroids to treat or prevent chronic lung disease in preterm infants. Pediatrics 2002;109:330–8. 27. Huang CC, Lin HR, Liang YC, Hsu KS. Effects of neonatal corticosteroid treatment on hippocampal ynaptic function. Pediatr Res 2007;62:267–70. 28. Barrington KJ. The adverse neuro-developmental effects of postnatal steroids in the preterm infant: a systematic review of RCTs. BMC Pediatr 2001;1:1. 29. Kabra NS, Schmidt B, Roberts RS, et al; Trial of Indomethacin Prophylaxis in Preterms Investigators. Neurosensory impairment after surgical closure of patent ductus arteriosus in extremely low birth weight infants: results from the Trial of Indomethacin Prophylaxis in Preterms. J Pediatr 2007;150:229–34. 30. Ari-Even Roth D, Hildesheimer M, Maayan-Metzger A, et al. Low prevalence of hearing impairment among very low birthweight infants as detected by universal neonatal hearing screening. Arch Dis Child Fetal Neonatal Ed 2006;91:F257–62.
ORIGINAL ARTICLE
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Sensorineural hearing loss in very low birth weight infants with histological chorioamnionitis Stefania Vedovato1,2, Angela Lo Iacono3, Carla Morando1, Agnese Suppiej4, Eva Orzan5, Daniele Trevisanuto2, Silvia Visentin3, Francesco Cavallin6, Silvia Chiarelli7, and Vincenzo Zanardo2 1
Department of Pediatrics, Neonatal Intensive Care Unit, San Bortolo Hospital, Vicenza, Italy, 2Pediatric Department, Medical School, University of Padua, Azienda Ospedaliera Padova, Padua, Italy, 3Department of Gynaecology and Reproductive Science, Padua University, Italy, 4Department of Paediatrics, Child Neurology and Clinical Neurophysiology, Padua University, Italy, 5Department of Otolaryngology and Audiology, IRCCS Burlo Garofalo, Trieste, Italy, 6Independent Statistician, Padua, Italy, and 7Department of Oncological and Surgical Sciences (Section of Pathology), Padua University, Italy Abstract
Keywords
Objective: Histological chorioamnionitis (HCAM) has been associated with inflammatory diseases of preterm infants. Recently we have observed that it increased the risk of speech delay and hearing loss. So the aim of this study was to evaluate the relationship between sensorineural hearing loss (SNHL) of VLBW infants and HCAM. Methods: We performed an observational study on VLBW infants admitted to the NICU of Padua. Each patient with HCAM was matched with one control without HCAM. All infants underwent hearing screening before discharge by means of automated transient–evoked otoacustic emissions and automated auditory brainstem responses, which were repeated at 3 and 6 months of age with tympanometry measurement. Incidence of SNHL at 6 months of age was compared in the 2 groups and risk factors for hearing loss were studied. Results: Two of 77 (2.6%) newborns with HCAM e 6/73 (8.2%) without it presented SNHL at 6 months of corrected age (p ¼ 0.16). Multivariable logistic regression analysis identified surgical ligation of patent ductus arteriosus (PDA) as independent predictors of SNHL (OR: 5.75, 95% CI 1.34–24.84, p ¼ 0.02), whereas the effect of HCAM on SNHL was only near to statistical significance level. Conclusions: Surgical ligation of PDA is associated with an increased risk of SNHL in VLBW infants, regardless of HCAM.
Chorioamnionitis, hearing screening, preterm infants
Introduction In the last decades, survival of extremely premature and low birth weight infants has improved thank to advances in perinatal and neonatal treatment. On the other hand, it has led to new social and health problems related to the high risk of neurological sequelae [1]. One of the possible disability is sensory-neural hearing loss (SNHL) whose prevalence is 1–3 in 1000 healthy newborns [2], but it is much higher (2–4 in 100 live births) in preterm infants. Among these, very low birth weight infants (VLBWI) are considered at high risk of hearing impairment even if the rate of SNHL is difficult to establish because of the use of different methods for testing as well as different gestational ages at test and different definitions of SNHL. The literature reports a variable incidence of 0.8–8% among extremely low birth weight Address for correspondence: Stefania Vedovato, Neonatal Intensive Care Unit, Department of Pediatrics, San Bortolo Hospital, Viale Rodolfi 37, 36100 Vicenza, Italy. Tel: +39.0444.75.26.84. E-mail: [email protected]
History Received 1 March 2014 Revised 19 May 2014 Accepted 15 June 2014 Published online 11 July 2014
infants [3,4]. In addition to prematurity, many risk factors are involved in the pathogenesis of SNHL: hyperbilirubinemia requiring exchange transfusion, culture-positive sepsis, use of ototoxic drugs, hypoxia, asphyxia, prolonged need for ventilation, bronchopulmonary dysplasia (BPD), PDA ligation [5–9], loud environmental noise [10]. and the interaction between these factors has been demonstrated. Thus, in the ‘‘2007 Position Statement of Join Committee on Infant Hearing’’, neonatal intensive care of more than 5 days has been considered a risk indicator associated with hearing loss, and audiological monitoring has been recommended for this population regardless of gestational age [11]. However, HCAM has been implicated in the pathogenesis of brain damage in VLBW infants [12]. HCAM is the acute inflammatory response of both the mother and fetus to extracellular microorganisms that gain access to the gestational sac [13]. It leads to activation of the cytokines network which can induce preterm labor and cause the fetal inflammatory response syndrome (FIRS). FIRS has been associated to inflammatory diseases of preterm infants,
2
S. Vedovato et al.
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increasing the risk of neonatal sepsis and meningitis, BPD and cerebral palsy [14,15]. Recently we have observed that VLBW infants with HCAM present an increased risk of speech delay and hearing loss at 18 months of age [16]. The role of chorioamnionitis in the pathogenesis of SNHL has never been studied. Considering that the inner ear concludes its development toward the 25th week of gestation [17], we hypothesized that inflammation cascade of HCAM could interfere with the delicate developmental phase of the cochlea. So the aim of this study was to evaluate the relationship between SNHL and HCAM in VLBW infants. The secondary objective was to perform a risk analysis for SNHL considering the risk factors for hearing impairment [5–10].
Methods This is a prospective study on VLBW infants with histological chorioamnionitis, born at the Obstetrics and Gynecology Department in Padua and admitted to the Neonatal Intensive Care Unit of Padua University, between 2001 and 2010. Each patient with HCAM was matched with one control without HCAM, of the same gestational age ± 1 week and born in the same year to minimize changes in care practices. The incidence of SNHL was determined at 6 months of corrected age and compared in the 2 groups. The placentas of all neonates included in the analysis were examined by an experienced pathologist, according to the Guidelines of the College of American Pathologists [18]. Placental histological examination included a minimum of three cross-sections of the umbilical cord taken from fetal and placental side of the umbilical cord, three membrane rolls and a sample of the chorionic plate. The inflammatory findings at histology were recorded and accounted for the worst area scored, as previously reported [15], according to the classification of Redline [13]. Exclusion criteria were major congenital malformations or craniofacial malformations. The following characteristics were obtained from the medical record of patients: maternal clinical data, antenatal administration of steroids, type of birth (vaginal or cesarean section), birth weight, Apgar Score (AS) at 1 and 5 minutes, RDS defined as the need for supplemental oxygen and ventilation support with the characteristic radiographic findings; mechanical ventilation for more than 5 days; BPD defined as need for supplemental oxygen at 36 postmenstrual weeks [19], postnatal administration of steroids according to our protocol (dexamethasone: 0.2 mg/kg/die 3 days then 0.1 mg/kg/die 4 days, after the second week of life) [20], culture proven sepsis or clinically suspected sepsis (C-reactive protein 48 mg/L and 2 clinical criteria), distinguishing early (572 hours of life) from late sepsis (472 hours of life); presence of PDA requiring medical treatment only or ligation; intraventricular hemorrhage (IVH); necrotizing enterocolitis (NEC) requiring surgery; retinal surgery; gentamicin administration; exchange transfusion [5–11]. All infants underwent blinded standard hearing screening. Hearing screening evaluated physiological responses to sound originating from different levels of auditory pathway: cochlear function was tested by oto-acoustic emissions (OAEs) while electrical responses of the early auditory pathway were
J Matern Fetal Neonatal Med, Early Online: 1–5
evaluated by auditory brainstem response (ABR). The first test records emission of acoustic energy by the cochlea in response to sound. OAEs are normally classified by the method of recording: transient evoked otoacoustic emissions (TEOAE) and distortion product otoacoustic emission (DPOAE). All newborns after 35 corrected gestational weeks and before discharge performed audiological screening programme by two tests: automated transient evoked otoacoustic emissions (A-TEOAE) and automated auditory brainstem responses (A-ABRs). Both tests have been made with the same instrument AccuScreen PROÕ which was calibrated daily before its use and once a year by the manufacturer. Results were considered negative if A-TEOAE and A-ABR for both ears were ‘‘PASS’’. Otherwise, infants underwent audiological evaluation within 3 months with DPOAE and A-ABRs. Middle ear function were assessed by 226 Hz frequency tympanometry and by the acoustic reflex threshold performed by Tympanometer GSI 33 which had been calibrated twice a year by manufacturer technical personnel. If these evaluations questioned the presence of hearing deficit, diagnostic ABR was performed. On the basis of its results, the patient underwent audiological assessment within 6 months of corrected age. All infants resulting ‘‘PASS’’ at standard hearing screening before discharge were evaluated at 6 months of corrected age with clinical examination (otoscopy), bilateral DPOAE, timpanometry measurement, A-ABRs. All tests were completed by experienced, certified, pediatric audiologist of the Pediatric Audiology Unit, Department of Otorhinolaryngology and Otosurgery of Padua University, who was blinded to placental histology, in an environment that assured reliable measurements. SNHL was defined as a unilateral or bilateral hearing threshold higher than 25 dB HL for at least two of the frequencies tested (from 500 to 4000 Hz). Conductive HL was diagnosed in children with normal bone conduction threshold (520 dB) and air-bone gap 15 dB averaged over 0.5, 1 and 2 kHz [20]. Sensorineural hearing loss was classified as follows: absent (average tone loss 0–20 dBHL), mild (average tone loss 21–40 dBHL), moderate (1st degree: average tone loss 41–55 dBHL, 2nd degree: average tone loss 56–70), severe (1st degree: average tone loss 71–80 dBHL, 2nd degree: average tone loss 81–90 dBHL), very severe (1st degree: average tone loss 91–100 dBHL, 2nd degree: average tone loss 101–110, 3rd degree: average tone loss 111–119) and total hearing loss (average tone loss 4120 dBHL) [21]. Informed consent was obtained from the parents. The study was approved by the local institutional review board. Statistical analysis Continuous data were expressed as Median and Interquartile Range (IQR). Categorical data were compared using Fisher’s test and continuous data using Wilcoxon Mann–Whitney test. A logistic regression model was estimated to identify the independent predictors of hearing loss; Apgar scores and use of postnatal steroids were not included in model estimation because they were considered indicators of most severe illness of infants with SNHL and not possible independent risk factors. A p value less than 0.05 was considered significant. Statistical analysis was performed using R 2.12 software
Hearing loss in newborn
DOI: 10.3109/14767058.2014.936375
(R Development Core Team (2010); R: A language and environment for statistical computing; R Foundation for Statistical Computing, Vienna, Austria, ISBN 3-90005107-0).
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Results Two-hundred and four VLBW infants were enrolled: 102 with HCAM (cases) and 102 without HCAM (controls). The 2 groups were comparable for gestational age: 27 gestational weeks (median 26–30) versus 28 (median 26–30), p ¼ 0.70; birth weight: 1047 grams (median 800–1380) versus 880 (median 700–1235), p ¼ 0.06; sex: M/F 55/47 versus 52/50, p ¼ 0.78; Apgar Score 53 at 1 minute: 7.8% versus 9.8%, (p ¼ 0.77); Apgar Score 55 at 5 minutes: 5.8% versus 5.8% (p ¼ 0.98); prenatal steroids: 84.3% versus 78.4% (p ¼ 0.37), while they were different for vaginal delivery: 26.4% versus 7.8% (p ¼ 0.0006), pre-eclampsia: 0.9% versus 8.8% (p ¼ 0.01), incidence of intrauterine growth restricted (IUGR) newborns [22]: 4.9% versus 27.4% (p ¼ 0.0001) and preterm labor: 79.4% versus 37.2% (p50.0001). Of 204 neonates enrolled, 11 (2 cases and 9 controls) died before discharge and 43 (23 cases and 20 controls) were lost to follow-up at 6 months. Thus 150 (73.5%) infants were considered for statistical analysis. In the final sample, the two groups were still comparable for gestational age: median 27 (interquartile range 26–31) versus 28 (interquartile range 26–29), p ¼ 0.66. Among these, 2 newborns with HCAM (2.6%) and 6 without HCAM (8.2%) presented bilateral SNHL (p ¼ 0.16) at 6 months of corrected age and 6 of them required intervention with hearing aids. Furthermore 9 cases (11.6%) and 2 controls (2.7%) presented conductive hearing loss at 6 months of corrected age. At univariate analysis SNHL was significantly associated with lower Apgar Score at the 1 minute (median 2 versus 7, p ¼ 0.002), lower Apgar Score at 5 minutes (median 6.5 versus 8, p ¼ 0.003), Apgar Score 53 at 1 minute (p ¼ 0.002), postnatal steroids administration (p ¼ 0.02) and PDA surgical ligation (p ¼ 0.03; Tables 1 and 2) Multivariable logistic regression analysis identified surgical ligation of patent ductus arteriosus as independent predictors of SNHL (OR: 5.75, 95% CI 1.34–24.84, p ¼ 0.02; Table 3). The effect of HCAM on SNHL was only near to statistical significance level (p ¼ 0.08).
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previous observational study on the neurodevelopmental outcome (5.7%), in which we found that newborns with HCAM compared with newborns without it presented a higher occurrence of hearing loss requiring hearing aids and speech delay at 18 months [16]. In the present study, incidence of SNHL was comparable in the patients with or without HCAM (2.6% versus 8.2%; p ¼ 0.16). The univariate analysis showed that lower Apgar Score at 1 and 5 minutes, postnatal steroids administration and PDA surgical ligation were significantly associated with SNHL, whereas the effect of HCAM on SNHL was only near to statistical significance level (p ¼ 0.08). Also Coeraad at al. observed that newborns admitted to the NICU and affected by hearing loss had a lower Apgar Score at 1 min [8]. While Hille et al. found a relationship between hearing loss and severe birth asphyxia in a population of preterm infants530 gestational weeks [23]. Low AS is an indicator of perinatal hypoxia and, in animal models, it has been shown that cochlear hail cells are sensitive to prolonged mild hypoxia [24]. Adequate oxygenation and perfusion are essential for normal cochlear function even if there is not a stated threshold level of hypoxia Table 2. Univariate analysis of sensorineural hearing loss (SNHL).
Risk factors HCAM Sex (M versus F) Apgar Score 10 53 Apgar Score 50 55 RDS HFO ventilation Mechanical ventilation 45 days BPD (36 wks) Postnatal steroids PDA (medical treatment) PDA (surgical ligation) IVH ROP NEC requiring surgery Early Sepsis Late Sepsis Exchangetransfusion Gentamicin administration Retinal surgery
SNHL in infants without risk factor (%)
p valuex
(2.6) (8.9) (30.8) (33.3) (6.5) (13) (10.2)
6/73 (8.2) 1/71 (1.4) 4/137 (2.9) 6/142 (2.8) 0/27 5/127 (3.9) 2/91 (2.2)
0.16 0.07 0.002 – 0.35 0.11 0.06
4/52 (7.7) 3/13 (23.1) 5/61 (8.2) 4/25 (16) 1/24 (4.2) 4/51 (7.8) 2/5 (40) 2/43 (4.7) 4/40 (10) 0/0 7/138 (5.1) 0/2
4/98 (4.1) 5/137 (3.7) 3/89 (3.4) 4/125 (3.2) 7/126 (5.6) 4/99 (4) 6/145 (4.1) 6/107 (5.6) 4/110 (3.6) 8/150 1/12 (8.3) 8/148 (5.4)
0.45 0.02 0.27 0.03 0.99 0.44 – 0.99 0.21 – 0.50 –
SNHL in infants with risk factor (%) 2/77 7/79 4/13 2/6 8/123 3/23 6/59
In this study, the overall prevalence of hearing loss was 5.3%. This is consistent with literature (2–4%) and with our
F: female; M: male; RDS: respiratory distress sindrome; HFO: high frequency oscillatory BPD: bronchopulmonary displasia; PDA: patent ductus arteriosus; IVH: intraventricular haemorrhage; ROP: retinopathy of prematurity; NEC: necrotizing enterocolitis. Data presented are numbers (percentages). xFisher test.
Table 1. Univariate analysis of sensorineural hearing loss (SNHL).
Table 3. Multivariate logistic regression analysis of sensorineural hearing loss (SNHL).
Discussion
No SNHL
SNHL
N 142 8 Gestational age 27 (26–30) 26 (25–29) Apgar Score 1 min 7 (5–8) 2 (1–4) Apgar Score 5 min 8 (7–9) 6.5 (4.5–7) Birth Weight (g) 945 (780–1310) 760 (598–1380) Total NICU stay (days) 52 (31–85) 80 (55–110)
p value # – 0.16 0.002 0.003 0.30 0.07
Data presented are median (interquartile range). #Wilcoxon Mann– Whitney test.
Risk factors HCAM (cases/controls) PDA surgical ligation versus medical treatment Sex (M/F): Mechanical ventilation 45 days Length of stay in NICU
p value
OR (95% C.I.)
0.08 0.02
– 5.76 (1.34–24.84)
0.10 0.28 0.72
– – –
HCAM: histological chorioamnionitis; F: female; M: male; PDA: patent ductus arteriosus.
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S. Vedovato et al.
at which hearing is at risk. Moreover there is a different susceptibility of the patients which probably depends on concomitant risk factors associated to hypoxia (like hyperventilation and alkalinisation) [4]. Besides we observed a correlation between postnatal steroids administration and SNHL. Postnatal steroids are currently used at low-dose to improve clinical course of ventilator-dependent premature babies. Considering randomized, controlled trials of dexamethasone to prevent or treat BPD reported since late 1990s, the 2010 American Academy of Pediatrics statement concluded that therapy with high-dose dexamethasone cannot be recommended because of increased risk of cerebral palsy and neurodevelopmental delay. Moreover, in newborns treated with low-dose dexamethasone, an increase in adverse neurodevelopmental outcomes has not been reported even if there is insufficient evidence to make a recommendation regarding this treatment [25,26]. In our study, 3 of 8 infants with SNHL were treated with postnatal steroids according to our protocol [20], and the univariate analysis demonstrated that dexamethasone was associated with SNHL (p ¼ 0.02). Dexamethasone treatment has been shown to alter hippocampal synaptic plasticity and associative memory formation in later life [27]. Furthermore, in many studies it increases the risk of cerebral palsy [28], so an effect on auditory pathway can be postulated even if the pathogenesis is not clear. Finally we found that PDA surgical ligation is associated with SNHL. This is comparable to literature findings. PDA surgical ligation has been previously reported as a risk factor for mild/moderate or severe/profound permanent SNHL [9], and for neurosensory impairment in extremely low-birthweight infants [29]. The relationship is not clear but perioperative or intraoperative events such as hypothermia, cardiorespiratory instability, or exposure to anesthetic drugs have been postulated as possible explanations [29]. The association between SNHL and PDA ligation has also been confirmed by multivariable logistic regression analysis (OR: 5.75, 95% CI 1.34–24.84, p ¼ 0.02) even if the low prevalence of SNHL and the small sample size of this study are the main limit for this analysis. This study has however some limits. First, 21% of enrolled newborns and 14% of ‘‘REFER’’ newborns were lost to follow up at 6 months. Our percentages of ‘‘lost to follow up’’ are consistent with previous studies which reported a 13–14%, [30]. but a post-hoc analysis power calculation revealed a power of 0.33. Thus the low prevalence of SNHL prevents us from drawing robust conclusions. Secondly, we have considered a long period of time (2001– 2010), during which care practices may have been partly changed. That is why we matched patients of the same gestational age and born in the same year to minimize this bias. Thirdly premature infants are at risk of delayed onset and progressive hearing loss and according to JCIH guidelines audiological screening has to be continued up to 3 years of age to better describe the incidence of hearing loss in this population. In conclusion, in this study, surgical ligation of patent ductus arteriosus was identified as independent predictor of SNHL in VLBW infants. The effect of HCAM on SNHL could not be decisively assessed due to the low prevalence of
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SNHL. Further follow up studies should be conducted to confirm the findings of the present study.
Acknowledgements We thank the audiologist Maria De Benedittis and the nurse Michela Scalco for their contributions in the collection of data and in the writing of the manuscript.
Declaration of interest The authors report no declarations of interest.
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