INTRODUCTION:

Amikacin has been shown to have significant ototoxicity in adults (4.6–24%), with cochlear toxicity affecting those treated for longer and with a history of previous aminoglycoside exposure, although a number of these patients also had high peak and trough levels. Vestibulotoxicity was reported in very few patients (0.65%).

Animal studies have shown that concentration and duration of Amikacin may cause hearing loss by increasing perilymph Amikacin levels. Severe hearing loss is reported in 1–3% of babies who had been admitted to neonatal units, 10-times the prevalence of those not admitted to neonatal units.^[1]At an approximate half of the NICU admissions receive at least one antimicrobial agent and sepsis was the most common reason for its administration.^[2] Neonatal sepsis is characterized by systemic signs of infection and accompanied by bacteremia in the first month of life. Amikacin was the most commonly prescribed antimicrobial agent followed bymeropenem.^[3] Regular clinical examination of the neonates cannot diagnose the hearing impairment in them. In such cases severe hearing loss may be diagnosed only at 18 to 24 months of life and mild to moderate hearing loss may not be identified until 48 months of infants life. This will have a devastating and deleterious effect on the development of newborn infants. Reduced auditory inputs badly affects the growth of auditory nervous system and can negatively impact the speech. It will result in decreased listening and spoken language skills, academic success and psychosocial interaction. Late identification of hearing impairment will delay in development of effective communication skills which will affect the overall quality of life of the affected neonates. Hence the need to have hearing assessment for the neonates and appropriate audiologic rehabilitation , as necessary cannot be over emphasised.^[4] Healthy and term babies are at lower risk of developing hearing loss while premature babies who require intensive care are at a higher risk of developing hearing loss. Some of the features that make them more prone to hearing loss that are described in the literature are craniofacial malformations, congenital anomalies, premature birth, weight <1500g, hyperbilirubinemia, bacterial meningitis, low APGAR score, syndromes with hearing loss, growth retardation, neonatal seizure, neonatal sepsis, maternal rubella, family history of hearing loss and hydrocephalus. Apart from these, admission to the NICU, exposure to ototoxic drugs, mechanical ventilation >5 days and ambient sound levels are significant contributors or predisposing factors.^[5] In our study hearing assessment was done using Brainstem Evoked Response Audiometry (BERA) test. Babies who had poorly formed waves (I, III and V) at 85 dB or more were considered to have an impairment and recommended to have a repeat BERA after 3 months. In this study we evaluated the prevalence of ototoxicity in neonates needing Amikacin use in a tertiary neonatal unit setting and also the associated risk factors in a setting where in facilities for measuring Amikacin levels are limited.

MATERIALS AND METHODS:

Study design: Retroprospective observational study, conducted over a period of one year of which data collection was for 8 months. Retrospective data was collected from January 2018 to August 2018 and prospective data from September 2018 to April 2019. A standard data collection form was prepared. Data collection form includes gestational age, sex, term of neonates, lab parameters, dose and duration of Amikacin therapy, about other ototoxic medications, type of hearing impairment etc. The data of the patients were collected through the Amrita Healthcare Information System (AHIS) and from the medical records.

Study subjects: Neonates who were admitted to the NICU and were on amikacin therapy, satisfying the inclusion and exclusion criteria were selected for the study.

Inclusion criteria

· All newborns admitted to the neonatal ICU, who are on amikacin therapy

Exclusion criteria

· Neonates with craniofacial malformation and middle ear infections

· Neonates who were lost to follow up or neonates whose medical records were unavailable during the period of study

· Neonates who have not had a BERA test done

· Family history of deafness

Sample size for the study was calculated using the following formula

n= [z²_1-α/2.p(1-p)]÷ d²

where

n- sample size

p – expected proportion

d - relative precision

z_1-α/2 - value of desired confidence interval

p- 60% ^[6]

d- 20%

z_1-α/2- 95%

The minimum number of patients required was calculated to be 256 as per the equation. A total of 260 patients were included in the study.

Ethical statement: The study protocol was approved by the Institutional Ethics Committee (IEC-AIMS- 2018-PHARM-172) before the enrolment of patients. An informed consent was obtained from the parents of the neonates.

Statistical analysis: Statistical analysis was performed by IBM SPSS version 20.0 software. Categorical variables are expressed using frequency and percentage. To test the statistical significance of the association of categorical variables with hearing impairment, Chi square test was used.

RESULTS:

In this study among the total of 260 neonates, 188 (72.3%) neonates were inborn and 72 (27.7%) were outborn and male patients (58%) were predominant. 224 (86.4%) patients were born as singletons, 32 (12.3%) were twins and the rest of the 4 (1.5%) were born as one amongst triplets. Majority of the patients were single born.Considering the gestational age, 48 (18.4%) of them were born before 32 weeks of gestational age, 111( 42.6%) were born in between 32 to 37 weeks and 101 (39%) were born after 37 weeks of gestational age. The mean gestational age was found to be 35.16 ± 3.58 weeks. Regarding the nature of term of neonates, 160 (61%) of them were preterm patients and remaining 100 (39%) were term patients.Based on the birth weight, 22 (8.5%) of them were in the extremely low birth weight (ELBW - <1) group, 37 (14.2%) in the very low birth weight (VLBW – 1to 1.5) group, 94 (36.1%) in the low birth weight group(LBW- 1.5 to 2.5) and 107(21.2%) in the normal birth weight (>2.5) group. Mean birth weight of the sample population was found to be 2.24 ± 0.85 kg. 74 (28.5%) were small for gestational age(SGA), 183(70.4%) were appropriate for gestational age(AGA) and 3(1.2%) were large for gestational age(LGA). Majority of the sample population ,226(87%) did not have intrauterine growth retardation (IUGR) while 34 (13%) of them were IUGR. 65 (25%) of them were born by normal vaginal delivery (NVD), 13(5%) by assisted delivery (AD, 47 (18.1%) by elective LSCS (El.LSCS) and 135 (51.9%) by emergency LSCS (Em. LSCS). The mean length of hospital stay was found to be 20.71 ± 20.18 days and 177 (68%) of them had a hospital stay of less than 20 days while 83 (32%) of the had a hospital stay of more than 20 days. 20 (7.7%) had an APGAR score of ≤ 4 at 1 minute and 11(4.2%) had an APGAR score of ≤ 6 at 5 minutes. Only 16 (6.2%) had some genetic anomalies and the remaining 244 (93.8%) had no genetic issues. With respect to the Amikacin therapy, 220 (84.6%) patients had only a single course of Amikacin , 29 (11.2%) had two courses of Amikacin and 11 (4.2%) patients had three courses of Amikacin therapy during the hospital stay. In the study population of neonates, 232(89.2%) of them had a creatinine value ≤ 1 mg/dl whereas only 28 (10.8%) of them had CRP > 1 mg/dl. Majority had a creatinine value in the normal range. 161 (62%) patients had hyperbilirubinemia and were on phototherapy while 99 (38%) of them did not had hyperbilirubinemia.. The comorbidities taken into consideration were meningitis and seizures. Among the whole sample population, 7 (2.7%) of them had meningitis and 13(5%) had seizures during their hospital stay. 176 (67.3% ) of them needed respiratory support during their hospital stay while 84 (34%) of them did not need any respiratory support during their hospital stay.Among the 176, 143 (54.6%) were on non invasive ventilation and 33 (12.7%) were on invasive ventilation. Mean duration of respiratory support (invasive and noninvasive) is 12.14 ± 16.56 days. 153 (58.8%) of them were not any other ototoxic medications.34(13.1%) of them were on Furosemide therapy, 19(7.3%) of them on Meropenam therapy and (7(2.7%) of them on Vancomycin therapy.37(14.2%) of the had a combination of Furosemide and Meropenam. 3(1.2%) were on a combination of Meropenam and Vancomycin. 7(2.7%) were treated with Furosemide, Vancomycin and Meropenam.

The prevalence of hearing impairment in the study sample was found to be 11.2% (29/260). Among the 29 patients who had hearing impairment, 10(34.5%) of them were diagnosed with bilateral impairment and 19(65.5%) of them with unilateral impairment. Among the 29 patients with hearing impairment, only 16 of them had repeat hearing assessment done by the end of this study. In those 16 patients, 8 (50%) of them showed an hearing impairment and the remaining 8 (50%) had normal test results.

Association of variables with hearing impairment

Association of demographics of sample with hearing impairment

Variable	Category	Hearing impairment		P value
Variable	Category	Yes n (%)	No n (%)	P value
Place of birth	Inborn (188)	19(10.1)	169(89.9)	0.385
Place of birth	Outborn (72)	10(13.9)	62(86.1)	0.385
Multiplicity of birth	Single (224)	22(9.8)	202(90.2)	0.1
	Twin (32)	7(21.9)	25(78.1)
	Triplet (4)	0	4(100)
Gestational age	< 32 weeks (50)	6 (12)	44 (88)	0.318
	32 to 37 weeks (115)	16 (13.9)	99(86.1)
	>37 weeks (95)	7(7.4)	88(92.6)
Gender	Female (108)	10(9.3)	98(90.7)	0.549
Gender	Male (152)	19(12.5)	133(87.5)	0.549
Birth weight	< 1 kg (22)	2 (9.1)	20 (90.9)	0.138
	1 to 1.5 kg (37)	8 (21.6)	29 (78.4)
	1.5 to 2.5 kg (96)	11 (11.5)	85(88.5)
	>2.5 kg (105)	8 (7.6)	97(92.4)
Mode of delivery	NVD (65)	3 (4.6)	62(95.4)	0.158
	AD (13)	2(15.4)	11(84.6)
	El.LSCS (47)	4(8.5)	43(91.5)
	Em.LSCS (135)	20(14.8)	115(85.2)
Length of stay	< 20 days (177)	16(9)	161(91)	0.139
Length of stay	>20 days (83)	13(15.7)	70(84.3)	0.139

Association of risk factors with hearing impairment

Variable	Category	Hearing Impairment		p value
Variable	Category	Yes n (%)	No n (%)	p value
APGAR at 1	≤4 (20)	4 (20)	16(80)	0.255
APGAR at 1	>4 (240)	25(10.4)	215(89.6)	0.255
APGAR at 5	≤6 (11)	2(18.2)	9(81.8)	1.0
APGAR at 5	>6 (249)	27 (10.8)	222(89.2)	1.0
Genetic anomalies	Yes (16)	7(43.8)	9 (56.3)	0.001
Genetic anomalies	No (244)	22(9.0)	222(91.0)	0.001
1^st course of Amikacin therapy
Sepsis	Yes (63)	5(8.1)	57(91.9)	0.490
Sepsis	No (198)	24(12.1)	174(87.9)	0.490
CRP	<1 (62)	11(17.7)	51(82.3)	0.067
CRP	≥1 (198)	18(9.1)	180(90.9)	0.067
Blood culture report	Positive (17)	0	17(100)	0.231
Blood culture report	Negative (243)	29(11.9)	214(88.1)	0.231
Amikacin dose in kg/mg	15 (171)	17(9.9)	154(90.1)	0.411
Amikacin dose in kg/mg	18 (89)	12(13.5)	77(86.5)	0.411
Amikacin daily frequency	Q 24 H (167)	17(10.2)	150(89.8)	0.477
	Q 36 H (72)	8(11.1)	64(88.9)
	Q 48 H (21)	4(19)	17(81)
Amikacin duration	≤5 (219)	25(11.4)	194(88.6)	1.0
Amikacin duration	>5 (41)	4(9.8)	37(90.2)	1.0
2^nd episode of amikacin use
Sepsis	Yes (27)	3(11.1)	24(88.9)	0.370
Sepsis	No (13)	3(23.1)	10(76.9)	0.370
Blood culture report	Positive (20)	3(15)	17(85)	1.0
Blood culture report	Negative (20)	3(15)	17(85)	1.0
Amikacin dose in mg/kg	15 (37)	6(16.2)	31(83.8)	1.0
Amikacin dose in mg/kg	18 (3)	0	3(100)	1.0
Amikacin daily frequency	Q 24 H (29)	6(20.7)	23(79.3)	0.262
	Q 36 H (10)	0	10(100)
	Q 48 H (1)	0	1(10
Amikacin duration	≤5 (19)	3(15.8)	16(84.2)	1.0
Amikacin duration	>5 (21)	3(14.3)	18(85.7)	1.0
Creatinine	≤1 (232)	25 (10.8)	207(89.2)	0.531
Creatinine	>1 (28)	4 (14.3)	24(85.7)	0.531
Hyperbilirubinemia and phototherapy	Yes (161)	19(11.8)	142(88.2)	0.840
Hyperbilirubinemia and phototherapy	No (99)	10(10.1)	89(89.9)	0.840
No. of phototherapy lights	One (5)	2(40)	3(60)	0.214
	Two (147)	16(10.9)	131(89.1)
	Three (6)	1(16.7)	5(83.3)
	Four (3)	0	3(100)
Exchange Transfusion	Yes (1)	0	1(100)	1.0
Exchange Transfusion	No (259)	29(11.2)	230(88.8)	1.0
Appropriateness of size with gestational age	SGA (74)	13(17.6)	61(82.4)	0.104
	AGA (183)	16(8.7)	167(91.3)
	LGA (3)	0	3(100)
IUGR	Yes (34)	6(17.6)	28(82.4)	0.238
IUGR	No (226)	23(10.2)	203(89.8)	0.238
Meningitis	Yes (7)	1(14.3)	6(85.7)	0.567
Meningitis	No (253)	28(11.1)	225(88.9)	0.567
Seizures	Yes (13)	3(23.1)	10(76.9)	0.166
Seizures	No (247)	26(10.5)	221(89.5)	0.166
Respiratory support	None (84)	6 (7.1)	78(92.8))	0.334
	Non invasive (143)	18 (12.6)	125 (87.4)
	Invasive (33)	5 (15.2)	28(84.8)
Duration of respiratory support	≤12 (129)	12(9.3)	117(90.7)	0.572
Duration of respiratory support	>12 (46)	6(13)	40(87)	0.572
Ototoxic drugs	Yes (107)	14(13.1)	93(86.9)	0.429
Ototoxic drugs	No (153)	15(9.8)	138(90.2)	0.429
Amikacin + Furosemide	Yes(77)	8(10.4)	69(89.6)	1.0
Amikacin + Furosemide	No(180)	21(11.5)	162(88.5)	1.0
Amikacin + Meropenam	Yes(66)	9(13.6)	57(86.4)	0.498
Amikacin + Meropenam	No(194)	20(10.3%)	174(89.7)	0.498
Amikacin + Vancomycin	Yes(17)	1(5.9)	16(94.1)	0.703
Amikacin + Vancomycin	No(243)	28(11.5)	215(88.5)	0.703

Various factors have been taken into consideration to establish a relationship with hearing impairment. Among them genetic anomalies showed a significant relationship with hearing impairment (p value 0.001) and CRP value during the 1^st episode of amikacin therapy had shown border line significance( p value 0.067).

DISCUSSION:

Aminoglycosides are broad-spectrum, bactericidal antibiotics that are commonly prescribed for children, primarily for infections caused by gram-negative pathogens. Among the various aminoglycosides available, Amikacin is the aminoglycoside of choice in the neonatal intensive care unit (NICU) where my study was done. It is often used as first line empirical therapy when suspecting bacterial infections in neonates, in combination with Ampicillin. Aminoglycosides have a narrow therapeutic index, and their use may result in toxicity (namely ototoxicity and nephrotoxicity); thus for courses lasting for more than 2–3 days in duration, their serum concentration must be monitored to ensure efficacy and avoid excessive pre dose (trough) concentrations. Micromedex Neofax Essentials 2014 was used as the reference for dosing regimen for the use of Amikacin in our NICU. The doses of Amikacin used were 15mg/kg and 18 mg/kg with the frequencies of administration being 24 hourly, 36 hourly and 48 hourly based on the gestational age at birth and postmenstrual Age (PMA; equivalent to Geststional Age + Postnatal age) as determinants of the dose and frequency regimen of Amikacin that a baby would qualify to receive. PMA is classified as ≤ 29 weeks( where postnatal days can be 0 to 7 days, 8 to 28 days or ≥ 29 days) 30 to 34 weeks (where postnatal days can be 0 to 7 days or ≥ 8 days) and ≥ 35 weeks (where postnatal day can be any).^[7]

The prevalence of Amikacin induced ototoxicity in neonates was found to be 11.2% in our study (29 out of 260). Among these 29, only 16 had a followup BERA and rest were lost to follow up. Of the 16, only 8 of them showed persistent hearing impairment at the 3 months BERA which needed some audiological intervention. This is a much lower value as compared to the study done by Shoaib et al^[8] , where 60% of the study population had profound hearing impairment .Similarly in a study conducted by Deirde et al^[9], 59% of the neonatal population on Amikaicn therapy had demonstrated hearing impairment. In both these studies, the sample population ( n=60 and n=55 respectively) were significantly lower compared to our study (n = 260).

The other variables which could produce a cumulative effect for Amikacin associated ototoxicity that were included in our study were the demographic details, APGAR scores, genetic anomalies, duration of Amikacin therapy, hyperbilirubinemia and related therapies, comorbidities (meningitis and seizures), lab parameters such as CRP and creatinine value, ventilation, use of other ototoxic medications (Furosemide, Vancomycin, Meropenam).

Among the demographic characteristics, place of birth (inborn/out born) were taken into consideration.It was found that neonates who were out born had a higher prevalence (13.9%) of hearing impairment among the total of 29 sample who had hearing impairment although this difference did not achieve statistical significance.This high rate could be due to a difference in dosing regimens, concomitant use of other ototoxic medications or exposure to other risk factors while in the outside hospital.

In our study male population was found to have a slightly higher percentage (12.5%) of hearing impairment compared to females (9.3%). The study conducted by Muddasir et al^[10] also found out male gender to be a significant risk factor. While in the study done by Ehsan et al, gender was not found to be a risk factor.

In our study, regarding the gestational age and birthweight, preterm(< 37 weeks) and low birth weight(<2.5 kg) was found to be clinically significant factors of hearing impairment. Similarly in the study done by Bhagya et al^[11] it was observed that infants exposed to risk factors like preterm delivery and low birth weight are prone for some hearing abnormality. Similar results were obtained from the study of Ehsan et al^[12] , where gestational age and birth weight was significantly associated with hearing loss. Low birthweight and prematurity are also factors that are linked to each other. The prevalence of failed hearing screening in neonates with VLBW is significantly higher than in neonates with normal birth weight because they experience higher rates of transient middle ear fluid accumulation and conductive hearing loss. This temporary hearing loss usually resolves within weeks of discharge from the hospital. The extent to which VLBW alone increases the prevalence of sensorineural hearing impairment in the early neonatal period remains unclear. However, these patients are commonly exposed to other risk factors for hearing loss such as ototoxic drugs, hypoxia and hyperbilirubinaemia, which may lead to early or delayed-onset sensorineural hearing loss as well as progression of a mild pre-existing sensorineural hearing loss years after hospital discharge. The causes of hearing loss in very preterm infants may differ from those in more mature children as, in parallel with other neurological structures, the period between 20 and 33 weeks of gestation is one of rapid fetal audiological development.

Length of hospital stay also showed some clinical significance with hearing impairment.Those with duration of hospital stay more than 20 days showed a higher percentage of hearing loss. In a study done by Ehsan et al, length of stay was found to be a significant risk factor. The reason for prolonged hospital stay to be a risk factor for hearing impairment could be the prolonged exposure of neonates to factors like ventilation, ototoxic medications, chances of getting infections.

Genetic anomalies had showed a significant association with hearing impairment (P value = 0.001) in our study . Among the total of 16 population who had genetic issues 43.8 % of them had hearing impairment. Genetic abnormalities is usually due to the mutations in the gene. These mutations could also be responsible for the abnormal functioning of the ear.

In our study, value of CRP (mg/dl) during the 1^st course of Amikacin therapy had shown a border line significance (P value =0.067) with hearing impairment. A higher CRP is indicative of an infection and this could probably be the reason for the significance. In the study done by Satoko et al^[13], they found that a high CRP (≥10 mg/dl) showed a positive relationship with hearing loss.

A low APGAR score ( ≤4 at 1^st minute) even though not statistically significant, had shown some relation with hearing loss.20% of the total population with low APGAR were found to have impairment while only 10.4 % of the total population with higher APGAR showed impairment. Even though low APGAR is an established factor, different studies have shown different results. Katarzyn et al^[14] established that low APGAR score is a significant risk factor of hearing loss in preterm, near term and term babies. However in the study by Jayaprabha et al, no significant association was found between the them. Low Apgar score may also be a sign of central nervous system impairment. Thus, impaired development of the central nervous system, including infections or hemorrhages in the fetal brain, may affect Apgar score at birth and also be associated with hearing loss.

In our study, neonates who were small for their gestational age (SGA) and having intrauterine growth retardation (IUGR) had higher rate of impairment (17.6%) than those belonging to the group, appropriate for gestational age (AGA) (8.7%).

Babies having comorbidities such as meningitis and seizures had a higher percentage of hearing impairment in our study . 14.3% of the total population with meningitis had impairment while only 11.1% of the total population without meningitis had impairment. Similar trends were noted in babies who have been diagnosed as having seizures 23.1% patients with seizures had impairment while only 10.5 % without seizures had impairment.

Literature suggest hearing loss develops early in the course of bacterial meningitis. Meningitis being an infection of the lining of the brain and spinal cord, the sense organs of hearing and balance are especially sensitive to this infection. Studies have suggested that the auditory nerves and the cochlea are most likely to be affected. There is also evidences about lesions of the brainstem or higher centres. In the study by Muddasir et al, meningitis was found to be an independent risk associated with hearing impairment (P value = 0.008). While in the study by Ni et al^[15], meningitis was not established as a significant risk factor (P value =0.204)

In our study, among the patients who were on other ototoxic medications (Furosemide,Vancomycin, Meropenam) 13.1% of them had a transient hearing impairment but in the population who were not on other ototoxic medications (furosemide, vancomycin, meropenam) only 9.8 % had impairment. Furosemide use leads to reversible hearing loss by blocking ion transport within stria vascularis in cochlea. It also increases the rate of aminoglycoside-induced permanent hearing impairment. Even at lower doses they can induce transient hearing loss. Vancomycin appears to have only a minor ototoxicity, administering it along with Amikacin can potentiate its adverse effect. Vancomycin induced ototoxicity is thought to involve dose dependant intracellular oxidative damage which leads to the loss of cochlear sensory hair cells resulting in high frequency hearing loss. Both vancomycin and furosemide affects the cochlear part of the ear. Similarly in the study conducted by Zamani et al^[16], the use of ototoxic medications was found to be a significant risk factor ( P value <0.05). But in the study conducted by Jayaprabha et al^[17], it was found that the use of ototoxic medications has no significant relationship with hearing impairment.

Among the additional risk factors considered in the study for hearing impairment, only the presence of genetic anomalies showed statistical significance and CRP values showed some borderline significance. Some of the factors had a clinical correlation with hearing impairment.

The study duration was limited. More valid results could have been obtained if the study were conducted at least for a period of one year with more patients.Since the study was carried out only in a single centre, the results cannot be generalized.Medication history of those patients referred from other hospitals were not available and maternal history of the sample population were not considered.

CONCLUSION:

The prevalence of Amikacin induced ototoxicity in neonates admitted to the neonatal intensive care unit was found to be 11.2%.Among the risk factors taken into consideration, only the presence of genetic anomalies showed a strong association with hearing impairment whilst an increased CRP had shown a tendency towards statistical significance. As genetic abnormalities have shown a significant relationship with hearing impairment, Amikacin use in such neonates should be done so with caution and appropriate monitoring.

Even though statistical relationship was not established, factors such as male gender, low birth weight, preterm, length of hospital stay, low APGAR score and the use of ototoxic medications had some correlation with hearing impairment. Number of neonates diagnosed with hearing impairment was further lower on repeat BERA during follow up.

Aminoglycosides are a mainstay of treatment in neonates especially for sepsis in NICU, empirically or in definitive therapy. Even though use of Amikacin and presence of other factors have an established relationship with ototoxicity (shown as hearing loss), it was found that those factors did not significantly affect the neonatal population in this study. Several studies have emphasised the use of Amikacin under careful TDM followed by dose adjustments.

REFERENCES:

1. Kent A, Turner MA, Sharland M et al. Aminoglycoside toxicity in neonates: something to worry about?. Expert Rev. Anti Infect. Ther 2014;12: 319–31.

2. Khan SN and Joseph S: Appropriate Use of Antibiotics for the Management of Sepsis in Neonates. International Journal of Pharmaceutical Science and Research. 2012; 3(7): 1928-1934

3. Gandraa S, Uriab GA, Murkic S, Singh SK et al. Point prevalence surveys of antimicrobial use among eight neonatal intensive care units in India: 2016. Available from : URL : https:// www.elsevier.com/locate/ijid

4. Gouri ZUH, Sharma D, Berwal PK et al. Hearing impairment and its risk factors by newborn screening in north-western India. Matern Health Neonatol Perinatol 2015; 1:17

5. Olusanyaa BO, Luxona LM, Wirzb SL et al. Benefits and challenges of newborn hearing screening for developing countries. Int. J. Pediatr. Otorhinolaryngol 2004; 68: 287—305.

6. Ahmed S, Waqas M, Manzoor T, Basheer F.Hearing Assessment with BERA in Infants who had Received Amikacin. Pakistan Journal of Otolaryngology 2014;30:47-49

7. Micromedex Neofax Essentials 2014

8. Ahmed S, Waqas M, Manzoor T, Basheer F. Pakistan Journal of Otolaryngology 2014;30:47-49

9. Engler D, Schellack N, Naude A, Gous A. A pilot study on the use of Amikacin in neonates:who should be monitored for ototoxicity ?. Southern African Journal of Infectious Disease 2016;30:72-76.

10. Maqbool M, Najar BA, Gattoo I, Chowdhary J. Screening for hearing impairment in high risk neonates: a hospital based study. J Clin Diagn Res 2015;9:18-21

11. Maqbool M, Najar BA, Gattoo I, Chowdhary J. Screening for hearing impairment in high risk neonates: a hospital based study. J Clin Diagn Res 2015;9:18-21

12. Alaee E, Sirati M, Taziki MH et al. Risk Factors for Sensorineural Hearing Loss Among High-Risk Infants in Golestan Province, Iran in 2010 – 2011.Iran Red Crescent Med J 2015; 17: e20419

13. Yoshikawa S, Ikeda K, Kudo T, Kobayashi K. The effects of hypoxia, premature birth, infection, ototoxic drugs,circulatory system and congenital disease on neonatal hearing loss. Auris Nasus Larynx .2004;31: 361–368.

14. Seniuk KW, Greczka G, Dabrowski P, Harris JS, Mazela J. Hearing impairment in premature newborns -Analysis based on the national hearing screening database in Poland. PLoS ONE 2017; 12:

15. Maharani N L P, Haksari E L, Artana W D. Risk factors for hearing loss in neonates. Paediatr. Indones 2015; 55

16. Zamani A, Daneshjou K, Ameni A, Takand J. Estimating the incidence of neonatal hearing loss in high risk neonates.Acta Med Iran 2004;42:176-180

17. Sathyabhama J, Karat A. A study on neonatal hearing loss using transient evoked otoacoustic emissions. J. Evolution Med. Dent. Sci 2016;5:871-75.

Received on 27.08.2019 Modified on 22.09.2019

Research J. Pharm. and Tech 2020; 13(3): 1467-1473.

DOI: 10.5958/0974-360X.2020.00268.1