Hearing loss in newborn infants with hypoxic ischaemic encephalopathy: protocol for a case–control study

Introduction

Hypoxic ischaemic encephalopathy (HIE), a condition where the brain does not receive adequate oxygen and/or blood flow just before, during or soon after birth, is associated with significant morbidity and mortality1 and has a worldwide occurrence of 3–5 per 1000 live births.2 HIE is clinically graded using the Sarnat grading system from 1 to 3, where stage 1 (mild) is characterised by hyperalertness, uninhibited reflexes, sympathetic effects and a normal electroencephalogram. Stage 2 (moderate) HIE features are obtundation, hypotonia, strong distal flexion and multifocal seizures. Electroencephalogram demonstrates a periodic pattern and is occasionally preceded by continuous delta activity. In stage 3 (severe) HIE, infants are stuporous and flaccid with suppressed brain stem and autonomic functions. The electroencephalogram is isopotential or has infrequent periodic discharges. The clinical grade of HIE along with other investigations such as electroencephalogram and neuroimaging are used for prognostication and counselling families.3 4

Therapeutic hypothermia (TH) for infants with moderate to severe HIE improves overall outcomes,5 6 and TH is considered standard practice for infants born ≥36 weeks’ gestation with HIE who meet certain criteria.7 Practically, this involves fulfilling three criteria. For criteria A, one of the following needs to be fulfilled: Apgar score of ≤5 at 10 min after birth; continued need for resuscitation, including endotracheal or mask ventilation, at 10 min after birth; acidosis defined as a pH≤7.00 and base deficit of ≥16 mmol/L in cord or baby’s blood gas sample within 60 min of birth. Criteria B includes moderate to severe encephalopathy on clinical assessment and at least one of the following: hypotonia, abnormal reflexes, absent or weak suck or clinical seizures. Once criteria A and B are met, criteria C where at least 30 min of amplitude integrate electroencephalogram recording demonstrating abnormal background electrical activity or seizures are necessary before commencing TH.

TH for infants reduces secondary injury at a cellular level.8 The most severe grade of HIE results in hypoxic injury, which is not limited to the vital organs such as the brain, heart and adrenals but includes other organs such as the kidneys, liver, bone marrow and skin. However, these organs respond differently to hypoxia, and injury to most organs is reversible once circulation is established.

Neurodevelopmental surveillance is the standard of care for newborn infants with grade 2 or higher HIE where motor development and other aspects including speech and development are monitored for the first few years.7 One of the pre-requisites for normal speech and language development is the ability to have normal hearing.

The ear is responsible for the initial encoding of acoustic input, and studies suggest that numerous changes occur after full-term birth. The mammalian ear is divided into three main parts: the outer ear, the middle ear and the inner ear. The outer ear funnels sound waves to the middle ear, an air-filled cavity in the temporal bone of the skull housing the malleus, incus and stapes, which form a chain connecting the tympanic membrane to the oval window. The cochlea in the inner ear converts these sound waves into electrochemical signals.9 The inner ear is supplied by the labyrinthine artery, an end artery branching from the inferior cerebellar artery.10 Cochlear blood flow is a function of cochlear perfusion pressure, which is the difference between mean arterial blood pressure and inner ear fluid pressure.11 Cochlea contains two types of sensory cells, namely the outer and inner hair cells. In utero, the hair cells mature during the third trimester but synaptic connections with the auditory nerve continue to mature after birth. Peripheral maturation of the auditory system can be studied non-invasively using otoacoustic emissions (OAEs). At birth, in contrast with the immature outer and middle ear, the inner ear is relatively more mature as characterised by OAEs.12

The cochlear hair cells critically depend on normal microcirculation13 and are also vulnerable to the effects of hypoxia and prone to injury.14 15 The extent of the injury to the hair cells in different grades of HIE is poorly understood. Fitzgerald and colleagues16 who examined a small cohort of HIE infants found hearing impairment in 9.5% of infants. Hamed et al who investigated a similar sized cohort found hearing loss in 8.8% of infants with HIE.17 Kadıoğlu Şimşek et al 18 noticed no difference in hearing screening failure rates in infants with different grades of HIE.

Cardiovascular parameters such as heart rate,19 heart rate variability20 and left ventricular output21 could be affected in newborn infants with HIE undergoing TH. A higher heart rate and reduction in heart rate variability have been shown to be associated with severe grades of HIE. Left ventricular output has been shown to change during and after TH.22 Given that myocardial dysfunction and consequently low left ventricular output are likely to be present with severe HIE, we speculate that multi-organ dysfunction and end-organ injury secondary to suboptimal perfusion are more common in newborn infants with severe HIE compared with mild HIE.

Methods and analysis

Ethics and dissemination

The study was reviewed and approved by the local research and innovation (R&I) department of the Homerton Healthcare NHS Foundation Trust. The study was approved by the Health and Care Research Wales (HCRW) Research Ethics Committee and Health Research Authority (HRA) (reference 21/HRA/4506). The data collected will be accessed by the chief investigator and the research team who are based at the Homerton University Hospital. Homerton R&I Department officers will have access to the study files for audit and quality control purposes.

The results of the study will be disseminated via multiple methods including but not limited to oral presentations at regional meetings, oral/poster presentations at national and international conferences and via social media. The chief investigator will ensure that the results are also published in peer-reviewed scientific journals, ideally open access for wider impact, in both online and print form, which will be valuable to parents, clinicians, policy makers and the wider research community.

Discussion

HIE remains a serious condition that is associated with potentially significant morbidity and mortality. Neurodevelopmental surveillance plays a key role in early targeted interventions in these high-risk infants including early audiologist input and speech and language therapy for those with hearing impairments. The study will provide the rates of hearing screening failure rates and confirmed hearing loss in infants with HIE, infants without HIE who receive intensive care plus antibiotics and stable infants in PNW who receive intravenous aminoglycosides, a well-known ototoxic agent. The results of this study will be of interest to a broad range of audiences, including neonatologists, general paediatricians, community paediatricians, audiologists, speech and language therapists, neurologists, researchers, policymakers and parents of infants with HIE. This information will also help in counselling parents of infants who do not receive intensive care but only intravenous antibiotics.

The newborn hearing screening programme has been fully implemented in the UK since March 200626 and always involves OAE. Some infants need further testing with AABR.27 Newborn hearing screening has a test sensitivity of >90% for bilateral moderate or greater permanent childhood hearing impairment.28 The hearing screening programme has resulted in a significant increase in timely audiologist referrals for infants below 6 months.28 Although the hearing screening programme has expedited audiology consultation, it is not without pitfalls. The newborn hearing screening programme will not identify infants with late-onset deafness and auditory neuropathy. In addition, infants who do not pass the initial newborn hearing screening test may be lost to follow-up due to a change in abode, psychosocial or other reasons.29 Practices that can mitigate these risks include the prompt identification of risk factors for late-onset hearing loss such as congenital infections such as cytomegalovirus, neurodegenerative disorders or trauma—all of which are scrutinised in the newborn hearing screening risk factor form that is completed for the newborn hearing screening prior to hospital discharge. Therefore, this study will only be able to provide data for the number of newborn infants who do not pass the hearing screening and the results of the subsequent confirmatory tests. This study design would not be able to identify infants with delayed onset hearing loss but can potentially provide data on infants who are lost to follow-up, although we believe this number is likely to be low due to robust primary care service provision.

The overall rates of permanent hearing loss may be similar to those found in small cohorts, but the results of this work will arm clinicians with robust data to accurately estimate the burden of hearing impairment in this high-risk cohort and therefore help clinicians in anticipatory guidance, targeting neurodevelopmental surveillance, signposting resources and in planning future clinical research trials in this very important area.

Conclusion

Hearing loss in infants with HIE potentially poses significant impact on speech and language development. Understanding the burden of this morbidity will aid clinicians, researchers and policymakers to provide vital resources and target early intervention to provide the best outcomes for this high-risk group of infants.