Prospective Evaluation of Hearing Status in Neonatal Hyperbilirubinemia

Abstract

Elevated bilirubin levels in neonates are commonly seen both physiologically and in pathological conditions. There are few articles describing the effects of elevated bilirubin levels on the auditory system. The objectives of this paper was to study the prevalence of hearing impairment in neonates with hyperbilirubinemia and assess outcome/reversibility of hearing impairment in these neonates with follow-up hearing evaluation. This was a prospective single centre, case control study. Cases: neonates, total bilirubin levels >15 mg/dl. Controls: <15 mg/dl. Exclusion criteria included neonates with neonatal hypoxia, intrauterine infections, sepsis or meningitis, infants with a family history of hearing loss, low birth weight, ototoxic medications, external and middle ear pathology. Otoacoustic emission testing (OAE) was done at birth. Neonates who fail OAE were advised follow up with Brainstem Evoked Response Audiometry (BERA) after 2 months. Neonates having abnormal BERA waves were called for follow up at 6 months. Out of 57 cases, 3 had failed OAE and had normal BERA waves on follow up at 2 months. Out of 60 controls, 5 had failed OAE and follow up BERA for 3 patients were normal and 2 babies were lost to follow up. No statistical significance in hearing impairment in hyperbilirubinemia v/s normal babies was noted. Elevated bilirubin levels in the absence of any other risk factors may not show significant changes in the hearing screening. Some effect owing to the p value close to being significant in cases has been noted. The same may not contribute to permanent hearing impairment as first OAE changes may be transient and seem to revert with age.

Supplementary Information

The online version contains supplementary material available at 10.1007/s12070-023-04181-7.

Introduction

Infants with hearing problem have a prevalence of 1.3 per thousand and 0.62 per hundred in high-risk babies, respectively [1]. A hearing loss in up to 40% of newborns with jaundice is possible. Increased bilirubin production as a result of hemolytic diseases like red cell membrane defects which are inherited like (spherocytosis), hemolysis which is immune-mediated (Rh or ABO incompatibility), enzymatic defects of erythrocytes (deficiency of G6PD) and sepsis are mostly the frequent factors leading to indirect hyperbilirubinemia (pathologic). Furthermore, elevated hepatic metabolism, like as in cases of breastfeeding jaundice, and impaired metabolism (Gilbert’s syndromes and Crigler-Najjar), can result in hyperbilirubinemia [2]. The auditory nerve is the structure to be impacted by high bilirubin levels, followed by the cochlear nuclei in the brainstem, and higher neurological centres are last. Oto-Acoustic Emissions, which are a helpful screening tool for newborns and babies and can provide non-invasive measurements of physiological auditory function [1]. An accurate and unbiased electrophysiological technique for assessing ascending auditory systems is the Auditory Brainstem Response (ABR). It depends on capturing the auditory system’s electrical activity when it responds to the right sonic stimulation. In ABR, hearing loss is diagnosed based on analysis of latencies of the waves I, III, and V as well as inter-wave I-III, I-V, and III-V. Test which is most accurate for identifying hearing loss due to pathology in the retrocochlea is the auditory brainstem response test [3].

This study aims to understand the association of hearing impairment and hyperbilirubinemia, the reversibility of the BERA changes which would help in early detection of hearing impairment for rehabilitation and development of speech and language skill.

Materials and Methods

This is a prospective, case control study conducted in a tertiary care hospital in South India, involving the Department of ENT- Head and Neck Surgery, Paediatrics department and speech and audiology department. The study was conducted over a period of 16 months from June 2021 to September 2022. The children included in this study were babies delivered in the hospital who were divided into cases (Group A) and controls (Group B) based on their blood bilirubin levels. The sample size was determined to be 117 (p = 2.135, e = 3%). The inclusion criteria for group A (cases) was new-borns and infants who underwent healthy term delivery (more than 36 weeks old) with bilirubin levels more than 15 mg/dl. Group B (controls) included newborns and infants who underwent healthy term delivery (more than 36 weeks old) with bilirubin levels less than 15 mg/dl. Newborns with history of neonatal hypoxia, intrauterine infections, sepsis or meningitis, infants with a family history of hearing loss, low birth weight, ototoxic medications such as aminoglycosides, congenital malformations were excluded from the study.

The study was conducted after approval of the Institutional Ethics Committee and Clinical Trials Registry- India (registration number CTRI/2021/08/035944). This study was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.

Methodology: Neonates underwent otoscopic examination and screening using OAE after obtaining consent from the parents. If the OAE was present, they were considered as ‘pass’ and no further evaluation was done. For any abnormalities in OAE, BERA was done within 2 months of age as a part of diagnosis of hearing impairment and rehabilitation. This is adhering with the routine screening, diagnostic methods and follow up, being carried out for the neonates in the hospital. Assessment with BERA was again done at 6 months of age in neonates with hearing impairment to re-evaluate the prognosis of hearing function of the infants involved in the study. Reassessment at 6 months is also a part of the routine screening program in the hospital.

Observation and Results

The data collected were grouped into cases and controls based on bilirubin values. The prevalence of hearing loss among cases and controls were compared using IBM SPSS statistics software version 26 and Mann-Whitney U test and Chi-square/Fishers exact test were used to compare.

Out of 117 subjects recruited, 111 passed (94.9%) and 6 had absent OAE (5.1%) as depicted in Table 1.

Table 1.

First OAE results among subjects

	Frequency	Percent
PASS	111	94.9
REFER	6	5.1
Total	117	100.0

The total bilirubin levels among cases and controls was statistically compared as in Table 2. Mann-Whitney U test has been conducted to find out any statistically significant differences in total bilirubin levels between cases and controls and the result showed that there was a statistically significant difference (p < 0.001) between them.

Table 2.

Total bilirubin levels among cases and controls

	Group	N	Mean	Std. Deviation	p
Total bilirubin level	Cases	57	16.2475	1.36739	< 0.001, HS
	Controls	60	8.3047	3.59168

Mann-Whitney U test has been conducted to find out any statistically significant differences in total bilirubin levels between cases and controls and the result showed that there was a statistically significant difference (p < 0.001) between them

The role of gender and gestational age was analysed as in Table 3. Chi-square/Fishers exact test have been carried out to find out any statistically significant differences in gender and gestational age categories between cases and controls and the results revealed that there was a statistically significant difference in gestational age (p = 0.005) between cases and controls whereas no such significant differences showed with gender distribution (p = 0.893).

Table 3.

Comparison of gender and gestational age categories between cases and controls

Characteristics (n,%)	Cases (N = 57)	Controls (N = 60)	Total (N = 117)	P value
Gender:
Female	24 (42.1%)	26 (43.3%)	50 (42.7%)	0.893
Male	33 (57.9%)	34 (56.7%)	67 (57.3%)
Gestational Age:
36–36 + 6	17 (29.8%)	4 (6.7%)	21 (17.9%)	0.005
37–38 + 6	27 (47.4%)	36 (60.0%)	63 (53.8%)
39–40 + 6	13 (22.8%)	20 (33.3%)	33 (28.2%)

Chi-square/Fishers exact test have been carried out to find out any statistically significant differences in gender and gestational age categories between cases and controls and the results revealed that there was a statistically significant difference in gestational age (p = 0.005) between cases and controls whereas no such significant differences showed with gender distribution (p = 0.893)

The statistical analysis between the first OAE results in the cases and controls was done as shown in Table 4. First OAE findings have been categorized into Fail and Pass and Chi-square/Fishers exact test have been carried out to find out any statistically significant differences in first OAE categories between cases and controls but no statistically significant difference showed between them (p = 0.771).

Table 4.

Comparison of first OAE results among cases and controls

		Group
		Cases		Controls		Total
		Count	Column N %	Count	Column N %	Count	Column N %
First OAE	Fail	3	5.3%	5	8.0%	8	6.8%
	Pass	54	94.7%	55	92.0%	109	93.2%

First OAE findings have been categorized into Fail and Pass and Chi-square/Fishers exact test have been carried out to find out any statistically significant differences in first OAE categories between cases and controls but no statistically significant difference showed between them (p = 0.771)

Comparison of total bilirubin levels with first OAE outcome among cases and controls is shown in Table 5. Mann-Whitney U test has been conducted to find out any statistically significant differences in total bilirubin levels (mean) between first OAE findings among cases and controls. Results revealed that while there was a statistically significant difference (p = 0.054) between first OAE findings in cases, no such significant differences (p = 0.979) showed in control group.

Table 5.

Comparison of total bilirubin levels with first OAE outcome among cases and controls

	Cases (N = 57)			Controls (N = 60)
Blood Indice	First OAE = Pass (n = 54)	First OAE = Fail (n = 3)	P value	First OAE = Pass (n = 55)	First OAE = Fail (n = 5)	p value
	Mean ± S.D	Mean ± S.D		Mean ± S.D	Mean ± S.D
Total Bilirubin	16.17 ± 1.32	17.71 ± 1.66	0.054	8.31 ± 3.5	8.28 ± 4.95	0.979

Mann-Whitney U test has been conducted to find out any statistically significant differences in total bilirubin levels (mean) between first OAE findings among cases and controls. Results revealed that while there was a statistically significant difference (p = 0.054) between first OAE findings in cases, no such significant differences (p = 0.979) showed in control group

Comparison of BERA results and OAE findings among cases and controls is shown in Table 6. Newborns who failed OAE screening, the BERA was normal for all the neonates at 2-month follow-up both in cases and controls.

Table 6.

Comparison of BERA results and OAE findings among cases and controls

		Group
		Cases		Controls		Total
		Count	Column N %	Count	Column N %	Count	Column N %
BERA	NORMAL	3	100.0%	3	100.0%	6	100.0%
2nd OAE	pass	3	100.0%	3	100.0%	6	100.0%

Newborns who failed OAE screening, the BERA was normal for all the neonates at 2-month follow-up both in cases and controls

Discussion

Among developmental problems, one main factor for hearing loss, as well as cerebral palsy in children is kernicterus [4]. According to reports, the three main risk factors for hearing loss in infants are reduced birth weight, blood transfusion brought on by hyperbilirubinemia, and poor Apgar score assessed at first minute of delivery [5]. Hille et al. multivariate study of a national population showed that only severe asphyxia at birth (OR 1.7; 95% CI 1.0-2.7) less than 5 days of assisted ventilation (OR 3.6; 95% CI 2.1-6.0) were independent risk factors for hearing loss [6]. In the absence of other risk factors, there are very few studies in the literature that attempt to evaluate the impact of hyperbilirubinemia on hearing. The study conducted, prospectively evaluated hearing outcomes in neonates with and without hyperbilirubinemia over a period of 16 months (2021–2022) from a tertiary care center in south India.

There was no statistical significance showed with gender distribution (p = 0.893). In case group neonates were having lower gestational age and showed statistical significance (p = 0.005). Corujo- Santana et al. found that, 60% of full-term neonates and, premature ones 80% will suffer from hyperbilirubinemia within the one week of life. Jaundice at birth is a risk factor for hearing loss that is usually connected to other factors that could effect on the ability to hear synergistically [7]. Castillo et al. based their findings on a prospective cohort research including babies more than 35 weeks, mothers blood type O and/or Rh negative or positive antibody screen, and new-born were within 24 h old. The concentration of total serum bilirubin above the 95th percentile and above the 75th percentiles during the hospital admission are considered for severe hyperbilirubinemia, and so is phototherapy during the initial hospital stay. It was determined that younger gestational age, race of the mother and umbilical cord bilirubin is a useful predictor for developing severe hyperbilirubinemia after assessing the accuracy of the two tests and predictive performance (umbilical cord bilirubin and also titers of direct antigen) [5]. According to Muchowski et al., phototherapy should be started based on gestational age and risk factors because a younger gestational age and exclusive nursing are the two biggest risk factors for the development of hyperbilirubinemia [8].

In our study, OAE screening at birth was done and among cases 5.3% failed, where as in controls, 8%failed. There was no statistical significance between them (p = 0.771). In a case-control study including 60 new-borns, Ezzeldin Z et al. looked at the OAE results for each ear independently and discovered a statistical difference between the OAE results and the levels of bilirubin in the right ear (P-value = 0.103) and in the left ear (p = 0.028) [1]. Transient evoked otoacoustic emissions and evoked auditory brainstem responses were utilized in a retrospective analysis by Corujo-Santana et al. on 796 neonates who had hyperbilirubinemia at delivery. A total of 185 neonates (23.24%) had their evoked auditory brainstem responses recommended. However, in their investigation, half of the youngsters also had other risk factors, with exposure to ototoxic drugs being the most common [1]. In our study, results revealed that while there was no statistically significant difference (p = 0.054) between first OAE findings in cases, but as the value is close to 0.005, there could be some relation with levels of bilirubin and OAE findings in the case group. There is no such significant differences (p = 0.979) showed in control group. Besli et al. ‘s study of 41 term babies admitted to the hospital for indirect hyperbilirubinemia. Based on stable levels, patients without haemolysis were divided into three groups: total bilirubin levels 20 mg/dl, second group 20-24.9 mg/dl, and third group more than 25 mg/dl. The fourth group included patients with haemolytic illness and a total bilirubin level 20 mg/dl. The duration of exposure to high bilirubin levels and the high risk of hearing loss among the babies with severe hyperbilirubinemia may both contribute to t In our study, OAE screening at birth was done and among cases 5.3% failed, where as in controls, 8%failed. There was no statistical significance between them (p = 0.771). In a case-control study including 60 new-borns, Ezzeldin Z et al. looked at the OAE results for each ear independently and discovered a statistical difference between the OAE results and the levels of bilirubin in the right ear (P-value = 0.103) and in the left ear (p = 0.028) [1]. Transient evoked otoacoustic emissions and evoked auditory brainstem responses were utilized in a retrospective analysis by Corujo-Santana et al. on 796 neonates who had hyperbilirubinemia at delivery. A total of 185 neonates (23.24%) had their evoked auditory brainstem responses recommended. However, in their investigation, half of the youngsters also had other risk factors, with exposure to ototoxic drugs being the most common [1]. In our study, results revealed that while there was no statistically significant difference (p = 0.054) between first OAE findings in cases, but as the value is close to 0.005, there could be some relation with levels of bilirubin and OAE findings in the case group. There is no such significant differences (p = 0.979) showed in control group. Besli et al. ‘s study of 41 term babies admitted to the hospital for indirect hyperbilirubinemia. Based on stable levels, patients without haemolysis were divided into three groups: total bilirubin levels 20 mg/dl, second group 20-24.9 mg/dl, and third group more than 25 mg/dl. The fourth group included patients with haemolytic illness and a total bilirubin level 20 mg/dl. The duration of exposure to high bilirubin levels and the high risk of hearing loss among the babies with severe hyperbilirubinemia may both contribute to the development of bilirubin neurotoxicity [4].

In this study the BERA reports at 2 months were normal in all new-borns in the case and control group. A prospective, randomised research on 100 new-borns with ABR-assessed hearing was conducted by Mandour et al. 60 new-borns with a history of neonatal hyperbilirubinemia (greater than 17 mg/dl and also below 30 mg/dl) and 40 healthy infants were divided into the case group and the control group, respectively. According to age, each group was split into three categories: 0–6 months, 6–9 months, and 9–12 months. Age and the examined factors had a negative association with each other [9]. Between 3 and 24 h after delivery, Soni et al. found a statistically significant connection (p value 0.005) between rising bilirubin levels and changing BERA levels. 17.64% of infants discharged with isolated hyperbilirubinemia (> 20 mg/dl) had BERA abnormalities. BERA abnormalities were reversible in 61.61% of cases during follow-up at three months [10].

The Merits of our study is that it has a prospective design where in evaluation was performed at multiple predetermined time intervals to maintain uniformity. There was exclusion of other confounding factors which would contribute to hearing loss and the elevated bilirubin levels as a standalone factor was studied. The same equipment’s, were used to assess all the subjects in the study. We believe this study will help in awareness and education regarding neonatal hearing screening, which is often not strictly adhered to, in the Indian setup.

Conclusions

This prospective study did not show a statistical significance in hearing impairment among babies with hyperbilirubinemia on comparing with normal babies. Elevated bilirubin levels in the absence of any other risk factors for hearing loss, may not show significant changes in the hearing screening though they might have some effect owing to the p value close to being significant. The same may not contribute to permanent hearing impairment because the first OAE changes could be likely transient and they seem to revert with age.

Electronic Supplementary Material

Below is the link to the electronic supplementary material.

Funding

The authors have no financial or non-financial interests to disclose.

Declarations

Conflict of Interest

The authors do not have any potential conflicts of interest regarding this paper.

Informed Consent

Informed Consent was taken as approved by the institutional ethics committee and CTRI.

Research involving human participants and/or animals

The study was conducted after approval of the Institutional Ethics Committee and Clinical Trials Registry- India (registration number CTRI/2021/08/035944). This study was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.