The Effect Of Perinatal Risk Factors On The Function Of Auditory Brainstem In Preterm Infants

With the rapid development of modern perinatal medicine, neonatal intensive care is greatly improved. The survival rate of premature infants sustained significantly growth. However, some of the preterm infants have movement, cognitive and behavioral defects, and the outcome is not optimistic. Therefore, early prevention and assessment of neurological defects become the focus of neonatal medicine. Many risk factors may influence the immature brain in preterm infants during perinatal period of growth and development, causing brain damage, and even leading to serious long-term neurological sequelae. Those damage and sequelae often involve in multiple systems including the auditory system.Late preterm births account for over70%of overall preterm births. Late preterm infants are more vulnerable than term infants to perinatal risk factors,multiple perinatal complications and neurological disabilities, i.e. developmental disorders, psychological retardation, and hearing deficiencies, etc. Many of those neurodevelopmental disorders can evolve into permanent brain damage and prone to behavior problems in school-age with mental retardation. The late preterm infants are subsets of premature infants which require considerable attention. Our previous studies showed that, the late preterm infants without any perinatal complications had similarly normal central auditory function to normal term infants. However, those late preterm infants who are enrolled into intensive care ward often suffer many combined perinatal complications and neural disorders, which may result in brain injury or neurodevelopmental disturbance. Up to now, little is known about the function of brainstem auditory in these high-risk late preterm infants.Bronchopulmonary dysplasia (BPD) is a very common chronic respiratory disease in very premature infants. the survivors of BPD have high incidence of neurologic impairment and developmental deficits, such that BPD has become one of the risk factors for neural dysplasia in premature infants. Our past research showed: Infants with BPD have brainstem auditory dysfunction. During the childhood or neonatal period, the development of brainstem auditory system is disruppted in those BPD survivors with premature birth. Finding out the time window between intimidate of injuries and functional recover in auditory brainstem, is very important and will ultimately help to clinical diagnosis, management, and prevention of neurological sequelae for BPD survivors.Necrotizing Enterocolitis (NEC) is one of the most common and fatal gastrointestinal emergency in very premature infants. A large number of long term follow-up studies showed the impact of NEC on preterm infants is more than intestinal damage, and more importantly, is injury of the central nervous system. NEC has now attracted much attention of scholars. NEC often combines with risk factors, such as prematurity, hypoxic-ischemia, malnutrition and infection, etc., many of which associated with brain injury, leading to dysfunction of the nervous system. However, little is known about the effect of NEC on auditory brainstem function and neurodevelopment. Early detection of cerebral dysfunction and estimation of its severity, will ultimately help to early intervention and improve the prognosis of the centrals nervous system.During the crucial period of rapid neurodevelopment in infancy, the auditory brainstem system in preterm infants is highly susceptible to various harmful factors, resulting in structure damage or neural dysfunction. Abnormal auditory perception will cause the language developmental disturbance in children with hearing disorders, and thus have an adverse effect on cognitive ability and intelligence development. Studying the causes and mechanisms of brainstem auditory dysfunction in preterm infants may make breakthrough in the research of immature brain injury.Brainstem auditory evoked potentials (i.e. Brainstem Auditory Evoked Response, BAER) is an objective and noninvasive electrophysiological technique, with easy access to bedside actions, repeated testing, non-traumatic, and provides objective evidence of brainstem auditory function and neurodevelopment information. BAER is very sensitive to the changes of stimulus intensity and click rate, many pathologic insultsin the course of brain damage due to hypoxia/ischemia and inflammation, especially gray and white matter lesions, so as to reflect the state of the effector organ and brain damage, providing an objectively assessment of brain and nervous system function.Maximal length sequence (MLS) BAER is a relatively new technique, which can increase acoustic stimuli at much higher repetition rates (up to1000clicks per second or even higher), providing a much stronger physiological challenge to brainstem, so that it is easier to detect functional abnormalities’of auditory brainstem system. The current research focused on the effect of perinatal risk factors on the function development of auditory brainstem in immature infants with varies perinatal disorders and complications, performed by MLS-BAER technology. This study contains fiveparts:Part Ⅰ is to study the functional status of high-risk late preterm infants with perinatal complications performed by MLS-BAER. Part Ⅱ is a retrospective study, observing dynamic changes of BAER threshold in neonatal period, investigating the high risk factors related to peripheral hearing and brainstem functional injuries, evaluating whether BPD and NEC are independent risk factors to auditory brainstem dysfunction. Part Ⅲ is to explore the auditory brainstem function in very preterm infantsduring neonatal period (between the age of32and42postconceptional weeks), and to study the effect of BPD on brainstem development in immature infants. Part Ⅳ is to detect the auditory function of preterm infants after NEC, by using traditional BAER and MLS-BAER, and get the message of influence of NEC on preterm infants.Part Ⅰ:Brainstem auditory function at term in preterm infants with perinatal complicationsObjective:To examine whether late preterm infants with perinatal problems are at risk of brainstem auditory impairment.Methods:68high-risk late preterm infants (gestation34-36weeks) with perinatal problems or conditions were studied at term using MLS-BAER. The controls were41normal term infants and37low-risk late preterm infants.Results:Compared with normal term infants, the high-risk late preterm infants demonstrated a significant abnormal increase in MLS-BAER variables that mainly reflect more central function of the brainstem auditory pathway, including wave Ⅴ latency, Ⅲ-Ⅴvand Ⅰ-Ⅴ interpeak intervals, and Ⅲ-Ⅴ/Ⅰ-Ⅲ interval ratio. The abnormalities were more significant at higher than at lower click rates. The slopes of MLS BAER-rate function for these variables were increased. Compared with low-risk late preterm infants, the high-risk infants showed similar, though slightly less significant, abnormalities, mainly a significant increase in Ⅲ-Ⅴ and Ⅰ-Ⅴ intervals.Conclusion:MLS-BAER components that mainly reflect central function of the auditory brainstem were abnormal at term in high-risk late preterm infants. More central regions of the auditory brainstem are impaired in high-risk late preterm infants, which is mainly caused by associated perinatal problems or conditions.Part Ⅱ:Risk factors for functional impairment of auditory brainstem in preterm infants with perinatal complications Objective:Preterm infants are at high-risk of neurodevelopmental impairment and later disabilities. To gain deeper understanding of neurologic impairment mechanism, we employed traditional BAER and MLS BAER to determine which risk factors related to peripheral hearing and neurological impairment in preterm infants with various perinatal complications in neonatal period and term age.Methods:We respectively analyzed the records of BAER threshold in367cases, and MLS-BAER parameters in172cases of preterm infants with various perinatal diseases and complications detected during neonatal period between the age of32and42postconceptional weeks, performed by multivariate linear regression analysis.Results:1) BAER threshold:peripheral auditory threshold showed a declining trend as postnatal age increasing. Smaller the gestational age, lighter the birth weight, higher the peripheral auditory threshold in these preterm infants. Majority premature infants had mild abnormalities in peripheral auditory threshold. There were several cases showed severe abnormalities during early phase of growth and development. The numbers of infants with abnormal threshold gradually decreased with the increase of postconceptional age. The independent risk factors associated with impairment in peripheral auditory threshold were:premature rupture of membranes during the age between26and32postconceptional weeks; apnea during the age between32and34postconceptional weeks; during the age between34and36postconceptional weeks, duration using mechanical ventilation, hyperbilirubinemia and1-minute Apgar score; duration using mechanical ventilation during the age between36and42postconceptional weeks.2) MLS-BAER:Multiple regression analysis for repeated measure data showed that BPD and NEC were independent risk factors for wave V latency, Ⅰ-Ⅴ interpeak interval, Ⅲ-Ⅴinterpeak interval and Ⅲ-Ⅴ/Ⅰ-Ⅲ interval ratio, which represent central function of auditory brainstem. At any acoustic rate of MLS-BAER, the standard partial regression coefficients of BPD and NEC were greater than the other risk factors.Conclusion:apnea, mechanical ventilation, low Apgar score were independent postnatal risk factors for peripheral auditory threshold impairment in preterm infants during early neonatal period. BPD and NEC were the most important independent risk factors for functional impairment of auditory brainstem in preterm babies at term equivalent age.Part Ⅲ:Auditory brainstem function in very preterm infants with bronchial dysplasia at the age between32and42postconceptional weeksObjective To explore the effect of BPD on the development and function in very premature infants, clarify the features of auditory brainstem development in infants with BPD, and find out the time window of cerebral injuries and functional recover in auditory brainstem.Methods:To access the effect of BPD on auditory brainstem maturation,57very preterm infants with BPD but no other major perinatal complications or problems were examined by using MLS-BAER at the age of32,34,36,38,40postconceptional weeks. The records were annualized and compared with47low risk preterm infants without any perinatal complications and55normal term infants.Results:1) BAER threshold:During the neonatal period, most of BAER threshold in BPD infants were in normal range. Abnormalities were mainly mild. A few were moderate. No severe anomalies were detected. With the increase of postconceptional age, peripheral auditory threshold continued to decline in infants with BPD, incidence of severe anomalies gradually reduced, overall incidence of abnormalities dropped from32.5to17.2percent, and so did the incidence of mild abnormalities. At term equivalent age, all abnormalities of infants with BPD were mild. Neither moderate nor severe abnormalities were detected in infants with BPD.2) Compared with preterm controls, Ⅰ and Ⅲ wave latencies and Ⅰ-Ⅲ interpeak interval in infants with BPD had no significant difference with preterm controls. At the age of32postconceptional weeks, Ⅴ wave latency, Ⅲ-Ⅴ and Ⅰ-Ⅴ interpeak intervals in infants with BPD were relative longer and significant different with preterm controls at higher stimulate rates. At the age of34postconceptional weeks, the V wave latency, Ⅲ-Ⅴ and Ⅰ-Ⅴ interpeak intervals were significant longer than preterm controls at higher stimulus rate. At the age of36postconceptional weeks, the V wave latency and Ⅲ-Ⅴ interpeak interval were significantly longer than those at the age of34postconceptional weeks at all click rates. As the stimulus rate increasing, Ⅰ-Ⅴ interpeak interval in infants with BPD showed more significant difference with preterm controls; At the age of38-40postconceptional weeks, wave V latency and Ⅲ-Ⅴ interpeak interval were still significant, but severity of which was smaller than those at the age of36postconceptional weeks. Compared with normal term controls, the Ⅰ and Ⅲ wave latency and Ⅰ-Ⅲ interpeak intervals in infants with BPD did not show significantly difference. Whereas the Ⅲ-Ⅴ, Ⅰ-Ⅴ interpeak intervals at all stimulus rates were significantly longer, and Ⅲ-Ⅴ/Ⅰ-Ⅲ interval ratio was significantly higher than term controls.Conclusion:The results suggested impairment of brainstem function in very preterm infants with BPD, resulting in delayed auditory brainstem maturation. During postnatal development, BPD may affected the maturation and development in central parts of brainstem auditory pathway with little effect on peripheral ones. The central component of auditory brainstem pathway was more vulnerable to impairment in preterm infants with BPD. The impairment in central part was more severe than that in peripheral components. Infants with BPD showed a significant injuries in auditory system since corrected age of34weeks. The insult continued and reached most severity at corrected age of36weeks. At corrected age of38weeks, the injury is still going on, but did not much severe than that at corrected age of36weeks. At corrected age of40weeks, the function of auditory brainstem has been somewhat recovered but still had significant difference with preterm controls.Part Ⅳ:Auditory brainstem function at term of preterm infants after Necrotizing EnterocolitisObjective:To examine brainstem auditory function at term in preterm infants after NEC, and to understand the effect of NEC on immature auditory brainstemMethods:Traditional BAER and MLS-BAER were performed at term equivalent age in37preterm infants after NEC. The results were compared with those in47healthy preterm and38normal full-term infants. In addition, the records of8full-term or near term infants after NEC were also involved in comparative analyses.Results:1) No statistically significant difference was found in BAER threshold between the infants after NEC and the normal controls.2) Traditional BAER:The latencies of waves Ⅰ and Ⅲ in the preterm infants after NEC were similar with those in two control groups, with no statistical significance. However, wave Ⅴ latency and Ⅲ-Ⅴ interpeak interval were significantly longer, and Ⅲ-Ⅴ/Ⅰ-Ⅲ interval ratio was significantly larger than in two control groups at all click rates. The Ⅰ-Ⅴ interval in infants after NEC was also significantly longer than in preterm controls at higher click rates, and than in term controls at all click rates. All wave amplitude in infants after NEC tended to be smaller than in the twocontrolgroups, but the differences did not reach statistical significance.3) MLS-BAER:The latencies of waves Ⅰ and Ⅲ, and Ⅰ-Ⅲ interpeak interval in the preterm infants after NEC did not significant differ with preterm controls. However, wave Ⅲ-Ⅴand Ⅰ-Ⅴ interpeak interval were significantly longer than in the preterm controls at all click rates. The V interval in infants after NEC was also significantly longer at higher click rates.Ⅲ-Ⅴ/Ⅰ-Ⅲ interval ratio was significantly larger than in preterm controls at all click rates. The wave Ⅰ, Ⅲ, and Ⅴ amplitudes and amplitude ratios did not significantly differ with preterm infants except wave Ⅴ amplitude at277/s click rate. Compared with term controls, the latencies of waves Ⅰ, Ⅲ and Ⅰ-Ⅲ in the preterm infants after NEC did not significantly different with term controls. The wave Ⅴ latency, Ⅲ-Ⅴand Ⅰ-Ⅴ intervals were significantly longer, and Ⅲ-Ⅴ/Ⅰ-Ⅲ interval ratio was larger in infants after NEC than in the term controls at all click rates. All wave amplitude and amplitude ratios did not significantly differ with term controls.4) All latencies, interpeak intervals and amplitudes in term infants with NEC did not significantly differ with normal term controls.Conclusion:Compared with those in preterm and term controls, those BAER and MLS-BAER variables reflecting central auditory function were significantly longer in premature infants after NEC than in preterm and term controls, suggesting somewhat delay of neural conduction. The results indicated central part of brainstem auditory pathway were injured in immature infants after NEC. On the other hand, term infants after NEC had almost normal BAER and MLS-BAER. Therefore, NEC had negative influence on auditory brainstem system in preterm infants, but not in term infants. Immature combined with NEC can induce or exacerbate cerebral injury of preterm infants.