围生期高危因素对早产儿脑干听觉功能的影响
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摘要
现代围生医学迅速发展,产科和新生儿重症监护技术提高的同时,早产儿存活率随之显著增加,但许多高危早产儿运动、认知及行为发育状况不容乐观,高危早产儿的神经发育结局令人担忧,因此预防和尽早评估神经系统缺陷成为临床工作的重点。围生期多种危险因素可以影响早产儿脑发育,引起脑损伤,导致长期严重的神经系统后遗症,而且这些损伤通常显著影响多个系统或功能,特别是影响脑干听觉系统的功能及发育。
晚期早产儿出生比率占全部早产儿的70%以上,人数众多。晚期早产儿虽然接近成熟,但发生各种围生期疾病和神经系统后遗症的风险仍较高,甚至会发生永久性脑损伤,如行为发育迟滞、心理成熟障碍、听力缺陷,并常易出现学龄期行为问题伴智力落后。因此晚期早产儿是不容忽视的早产儿亚群。本课题组以往研究证实：无围产期合并症的晚期早产儿中枢脑干听觉功能与足月儿相近,基本正常。然而,入住重症监护病房的高危晚期早产儿通常合并各种围生期疾病和并发症,可能导致脑损伤和神经系统后遗症或神经功能障碍,其脑干听觉功能是否正常目前尚不清楚。
支气管肺发育不良(Bronchopulmonary dysplasia, BPD)作为早产儿常见的肺部疾病,其导致的神经系统异常是早产儿最常见的远期并发症之一。BPD存活儿神经损伤和发育异常的发生率很高,已成为极早产儿神经发育缺陷的危险因素之一。本课题组既往研究发现：BPD患儿存在脑干听觉中枢功能障碍,在新生儿期及婴幼儿期,BPD早产儿脑干听觉功能发育延迟。因此,进一步研究并阐明BPD导致脑损伤以及功能恢复的时间窗对于促进BPD患儿临床诊疗,避免神经系统后遗症意义重大。
坏死性小肠结肠炎(Necrotizing enterocolitis, NEC)是早产儿常见的致死性胃肠道急症。大量远期随访研究显示NEC造成的影响远不止肠道损伤,更重要的是神经系统损伤,这已经引起众多学者的关注。NEC极易合并与脑损伤相关的诸多危险因素诸如：缺氧缺血、营养不良及感染等,导致神经系统功能障碍。然而NEC对新生儿脑干听觉功能及发育的影响,目前尚不清楚。如能较早了解NEC患儿发病阶段脑功能的异常及损伤程度,必然有助于早期干预,改善神经系统预后。
早产儿脑干听觉系统处于快速发育的关键时期,对脑损伤相关的各种有害因素高度易感,从而导致脑干听觉系统发育障碍或功能异常。听觉异常将导致患儿语言发育障碍,进而对认知能力甚至智力发育产生不良影响。因此,研究早产儿脑干听觉功能损伤的原因及机制有可能成为揭示未成熟脑损伤的一个重要的突破口。
脑干听觉诱发电位(Brainstem Auditory Evoked Response, BAER)是一种客观无创的电生理技术,可以床旁操作,反复检测,并提供反映脑干听觉功能状态和发育过程的客观依据。BAER对刺激参数如刺激速率和强度的变化很敏感,且对脑和神经的缺氧/缺血、炎症等损伤特别是灰、白质病变非常敏感,从而能够反映终末器官和脑损伤的状态,客观评估脑和神经系统功能的完整性。最大长度序列(Maximum Length Sequence, MLS)是先进的BAER技术,它可以将声音刺激的速率提高到1000/s以上或更高,从而比常规的BAER技术更易发现脑干听觉功能的异常,提高神经系统异常的检出率。
本研究一方面关注于早产儿中比例较大的群体即晚期早产儿,研究合并多种围生期疾病或者并发症的高危晚期早产儿的听觉脑干功能的情况。另一方面,本研究关注于较小胎龄的早产儿,在对早产儿进行危险因素分析后发现BPD、NEC是脑干听觉系统损伤的独立高危因素,由此进一步分别对这两部分患儿群体进行前瞻性的病例对照研究,探讨BPD和NEC对较小胎龄早产儿脑干听觉系统功能和发育的影响。
研究内容主要分为五部分。第一部分：应用MLS-BAER技术检测高危晚期早产儿在矫正胎龄足月时听觉脑干的功能异常,探讨是否高危晚期早产儿存在脑干听觉系统损伤；第二部分：回顾性分析早产儿在矫正胎龄足月前外周听阈的变化特点,以及矫正胎龄足月时脑干听觉功能损伤的高危因素,评价BPD、NEC是否是早产儿脑干听觉功能异常的独立危险因素；第三部分：随访检测和分析在矫正胎龄32周至足月的发育阶段内,BPD早产儿脑干听觉功能的异常及变化情况,研究BPD对早产儿在早产时期听觉脑干发育的影响；第四部分：应用常规BAER和MLS-BAER技术研究NEC对早产儿矫正胎龄足月时听觉脑干功能的影响。
第一部分高危晚期早产儿矫正胎龄足月时脑干听觉功能研究
目的：检测高危晚期早产儿在矫正胎龄足月时脑干听觉系统功能状态,探讨高危晚期早产儿听觉脑干系统损伤的电生理学变化。
方法：纳入合并各种围生期疾病的高危晚期早产儿68例,无围生期疾病的晚期早产儿对照35例和正常足月儿对照41例。在矫正胎龄足月时检测MLS-BAER,刺激速率为91、227、455、910/s,刺激强度为阈上40dB nHL。
结果：1)与足月儿对照比较：高危晚期早产儿的Ⅰ、Ⅲ波潜伏期及Ⅰ-Ⅲ波峰间期与正常足月儿无显著差异；然而V波潜伏期在较高刺激速率时较足月儿对照显著延长；Ⅰ-Ⅴ、Ⅲ-Ⅴ波峰间期在各个刺激速率均比正常足月儿对照显著延长；Ⅲ-Ⅴ/Ⅰ-Ⅲ峰间期比值在较高刺激速率时较足月对照显著增大。高危晚期早产儿的Ⅰ、Ⅲ、Ⅴ波振幅稍小于足月儿对照,Ⅴ/Ⅰ、Ⅴ/Ⅲ振幅比值稍大于足月儿对照,但振幅及振幅比值在组间均无显著差异。2)与低危晚期早产儿比较：高危晚期早产儿的Ⅰ、Ⅲ波潜伏期和Ⅰ-Ⅲ波峰间期均与低危晚期早产儿相似,统计学检验无显著差异。然而,在较高刺激速率下,高危晚期早产儿的V波潜伏期,Ⅲ-Ⅴ和Ⅰ-Ⅴ波峰间期均显著延长,Ⅲ-Ⅴ/Ⅰ-Ⅲ峰间期比值也显著增大。高危晚期早产儿的Ⅰ、Ⅴ波振幅较低危晚期早产儿稍减低,除Ⅰ波潜伏期在455/s时和V波潜伏期在227/s时有统计学差异外,其余参数在组间均无统计学差异；Ⅲ波振幅、Ⅴ/Ⅰ和Ⅴ/Ⅲ振幅比值与低危晚期早产儿也无显著性差异。
结论：合并围产期疾病的高危晚期早产儿存在脑干听觉功能损伤,而且主要存在于脑干听觉通路近中枢部分,外周部分影响不大。
第二部分高危早产儿外周听阈及脑干听觉功能异常的高危因素分析
目的：早产儿是神经损伤和发育缺陷的高危人群。通过分析高危早产儿外周听阈和MLS-BAER参数与各种围产期危险因素的关系,了解导致外周和中枢脑干听觉功能异常的独立危险因素。
方法：回顾性分析367例早产儿在矫正胎龄足月前各发育阶段(矫正胎龄32～42周)外周听阈的变化及特点,以及172例早产儿在矫正胎龄足月时(矫正胎龄37～42周)脑干听觉功能状态。应用多元线性回归分析外周听阈及MLS-BAER参数与围产期危险因素的相关性。
结果：1)外周听阈：随着生后发育和胎龄的增加,早产儿的外周听阈均值呈逐渐下降的趋势。孕龄偏小、出生体重偏轻的早产儿外周听阈更高。早产儿外周听阈异常主要表现为轻中度异常,在发育早期有少数严重异常的患者,随着胎龄增加,外周听阈异常比率逐渐减少。在矫正胎龄足月时,仅表现为轻度异常。各时期导致外周听阈异常的独立高危因素分别为：矫正胎龄26～32周,胎膜早破；矫正胎龄32～34周,呼吸暂停；矫正胎龄34～36周,机械通气日数；矫正胎龄36～42周,高胆红素血症、1分钟Apgar评分、机械通气日数。2)MLS-BAER参数：矫正胎龄足月时,BPD、NEC与代表脑干听觉功能近中枢部分的参数(V波潜伏期、Ⅲ-Ⅴ、Ⅰ-Ⅴ波峰间期以及Ⅲ-Ⅴ、Ⅰ-Ⅲ峰间期比值)极显著相关,而与代表近外周部分的参数(Ⅰ、Ⅲ波潜伏期和Ⅰ-Ⅲ波峰间期)不相关。BPD、NEC是脑干听觉系统神经功能损伤的独立危险因素。
结论：胎膜早破、高胆红素血症、呼吸暂停、机械通气、低Apgar评分为生后发育早期外周听阈异常的高危因素。BPD、NEC是早产儿至矫正胎龄足月时中枢脑干听觉功能损伤的高危因素。
第三部分支气管发育不良患儿脑干听觉功能发育研究
目的：随访研究新生儿期支气管肺发育不良(BPD)对早产儿未成熟脑发育和功能的影响,阐明BPD患儿听觉脑干发育特点,了解BPD患儿脑干听觉功能的异常和诱发电位特征性的改变,以及发生脑干听觉功能损伤和恢复的时间窗。
方法：对研究期间内纳入的早产儿每两周随访检测MLS-BAER(矫正胎龄32、34、36、38、40周),在矫正胎龄36周时明确BPD诊断,进行分组。本研究共纳入BPD患儿57例,低危早产儿对照47例和正常足月儿对照55例。
结果：1)外周听阈：新生儿期,BPD患儿外周听阈多数在正常范围,听阈异常多为轻度,仅少数表现为中度异常,无重度异常患儿。随着生后发育和矫正胎龄的增加,BPD患儿外周听阈均值不断下降,中重度异常的比率也逐渐减少,总的异常比率由32.5%下降至17.2%,轻中度异常比率也分别呈下降趋势。在矫正胎龄足月时,外周听阈异常全部表现为轻度,无中重度异常患儿。2)MLS-BAER参数：BPD患儿与低危早产儿对照相比,Ⅰ、Ⅲ波潜伏期及Ⅰ-Ⅲ波峰间期在各个胎龄阶段虽有延长,但组间均无显著性差异。在矫正胎龄32周,BPD患儿的Ⅴ波潜伏期,Ⅲ-Ⅴ、Ⅰ-Ⅴ波峰间期虽相对延长,但组间均无统计学差异；在矫正胎龄34周,BPD患儿的V波潜伏期,Ⅲ-Ⅴ、Ⅰ-Ⅴ波峰间期延长更明显,在较高刺激速率下显示统计学差异；在矫正胎龄36周,Ⅴ波、Ⅲ-Ⅴ波峰间期延长比矫正胎龄34周时更显著,在较低刺激速率即91/s时即表现出统计学差异,并随刺激速率增加,Ⅰ-Ⅴ波峰间期表现极显著差异；在矫正胎龄38～40周,V波潜伏期、Ⅲ-V波峰间期延长仍然明显,但与矫正胎龄36周相比,Ⅰ-Ⅴ波峰间期在组间的差异显著性程度降低。BPD患儿与足月儿相比,BPD患儿的Ⅰ、Ⅲ波潜伏期和Ⅰ-Ⅲ波峰间期均无显著差异；而Ⅲ-Ⅴ、Ⅰ-Ⅴ波峰间期在所有刺激速率下均显著延长,Ⅲ-Ⅴ/Ⅰ-Ⅲ峰间期比值在较高刺激速率下较足月儿对照显著增高。
结论：BPD影响早产儿在新生儿期脑干听觉系统的生长发育和功能成熟,早产合并BPD可以诱导或者加重脑损伤。在生后发育过程中,BPD主要影响脑干听觉通路近中枢部分的功能成熟及发育,而对外周部分影响不大。早产BPD患儿矫正胎龄足月前脑干听觉通路近中枢部更易受累,而且程度较为严重。矫正胎龄34周表现出显著脑干听觉系统损伤；矫正胎龄36周损伤仍然继续并且达到严重阶段,至矫正胎龄38周损伤仍然存在,但较前程度减轻；矫正胎龄40周脑干听觉功能已有一定程度恢复,但与同胎龄早产儿相比仍然有显著性差异。BPD患儿脑干听觉损伤和恢复的时间窗可能为临床诊疗和预后评估提供参考。
第四部分坏死性小肠结肠炎对矫正胎龄足月的早产儿脑干听觉功能的影响
目的：探讨坏死性小肠结肠炎(NEC)对于新生儿脑干听觉功能的影响。
方法：纳入早产NEC患儿37例,低危早产儿对照47例和正常足月儿对照38例。此外,8例近足月和足月NEC患儿也参与比较分析。所有新生儿均在矫正胎龄足月时进行常规BAER和MLS-BAER检测。
结果：1)外周听阈：除1例NEC患儿轻度升高外,其余均在正常范围。2)常规BAER:NEC早产儿的Ⅰ、Ⅲ波潜伏期,Ⅰ-Ⅲ波峰间期在各个刺激速率下均与两组对照无显著差异；然而V波潜伏期、Ⅲ-Ⅴ波峰间期在各个刺激速率下均较两组对照显著延长,Ⅲ-Ⅴ/Ⅰ-Ⅲ峰间期比值显著增大；Ⅰ-Ⅴ波峰间期在较高刺激速率下较低危早产儿显著延长,在所有刺激速率下较足月儿对照显著延长。NEC早产儿的各波振幅和振幅比值与两组对照基本无差异。3)MLS-BAER:在各个刺激速率下,NEC早产儿的Ⅰ、Ⅲ波潜伏期,Ⅰ-Ⅲ波峰间期均与低危早产儿对照无显著差异；然而V波潜伏期在较高刺激速率下显著延长；Ⅲ-Ⅴ、Ⅰ-Ⅴ波峰间期在各个刺激速率下均较早产儿对照显著延长；Ⅲ-Ⅴ/Ⅰ-Ⅲ峰间期比值在较高刺激速率下较早产儿对照显著增大。NEC早产儿Ⅰ、Ⅲ、Ⅴ波振幅和振幅比值均与早产儿对照无显著差异(除277/s时Ⅴ波振幅外)。与足月儿对照相比,在各个刺激速率下,早产NEC患儿Ⅰ、Ⅲ波潜伏期,Ⅰ-Ⅲ波峰间期与对照无显著差异；V波潜伏期、Ⅲ-Ⅴ、Ⅰ-Ⅴ波峰间期在各个刺激速率下均比足月对照显著延长,而且Ⅲ-Ⅴ/Ⅰ-Ⅲ峰间期比值显著增大。NEC早产儿的Ⅰ、Ⅲ、Ⅴ波振幅和振幅比值均与足月儿对照无显著差异。4)足月NEC患儿与正常足月儿相比,BAER及MLS-BAER各波潜伏期、波峰间期、峰间期比值、振幅及其振幅比值均无统计学差异。与常规BAER相比,MLS-BAER波形更易辨认,组间差异显著性更强,更易于发现轻微脑损伤。刺激速率为455/s的波形稳定,组间差异显著,应用该刺激频率进行检测所用的时间较传统BAER明显缩短,更适用于诊断早产儿听觉脑干损伤。
结论：与低危早产儿和正常足月儿相比,早产NEC患儿表现为神经传导延迟,代表脑干听觉通路近中枢部分的参数均显著异常,存在严重中枢脑干听觉功能损伤。而足月NEC患儿与正常足月对照相比各波参数无明显差异。NEC可导致早产儿脑损伤,而对足月儿脑干听觉功能影响不大：早产合并NEC可诱发或者加重脑损伤。MLS-BAER较常规BAER有更大优越性。
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 complications
Objective: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 weeks
Objective 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 Enterocolitis
Objective:To examine brainstem auditory function at term in preterm infants after NEC, and to understand the effect of NEC on immature auditory brainstem
Methods: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.
晚期早产儿出生比率占全部早产儿的70%以上,人数众多。晚期早产儿虽然接近成熟,但发生各种围生期疾病和神经系统后遗症的风险仍较高,甚至会发生永久性脑损伤,如行为发育迟滞、心理成熟障碍、听力缺陷,并常易出现学龄期行为问题伴智力落后。因此晚期早产儿是不容忽视的早产儿亚群。本课题组以往研究证实：无围产期合并症的晚期早产儿中枢脑干听觉功能与足月儿相近,基本正常。然而,入住重症监护病房的高危晚期早产儿通常合并各种围生期疾病和并发症,可能导致脑损伤和神经系统后遗症或神经功能障碍,其脑干听觉功能是否正常目前尚不清楚。
支气管肺发育不良(Bronchopulmonary dysplasia, BPD)作为早产儿常见的肺部疾病,其导致的神经系统异常是早产儿最常见的远期并发症之一。BPD存活儿神经损伤和发育异常的发生率很高,已成为极早产儿神经发育缺陷的危险因素之一。本课题组既往研究发现：BPD患儿存在脑干听觉中枢功能障碍,在新生儿期及婴幼儿期,BPD早产儿脑干听觉功能发育延迟。因此,进一步研究并阐明BPD导致脑损伤以及功能恢复的时间窗对于促进BPD患儿临床诊疗,避免神经系统后遗症意义重大。
坏死性小肠结肠炎(Necrotizing enterocolitis, NEC)是早产儿常见的致死性胃肠道急症。大量远期随访研究显示NEC造成的影响远不止肠道损伤,更重要的是神经系统损伤,这已经引起众多学者的关注。NEC极易合并与脑损伤相关的诸多危险因素诸如：缺氧缺血、营养不良及感染等,导致神经系统功能障碍。然而NEC对新生儿脑干听觉功能及发育的影响,目前尚不清楚。如能较早了解NEC患儿发病阶段脑功能的异常及损伤程度,必然有助于早期干预,改善神经系统预后。
早产儿脑干听觉系统处于快速发育的关键时期,对脑损伤相关的各种有害因素高度易感,从而导致脑干听觉系统发育障碍或功能异常。听觉异常将导致患儿语言发育障碍,进而对认知能力甚至智力发育产生不良影响。因此,研究早产儿脑干听觉功能损伤的原因及机制有可能成为揭示未成熟脑损伤的一个重要的突破口。
脑干听觉诱发电位(Brainstem Auditory Evoked Response, BAER)是一种客观无创的电生理技术,可以床旁操作,反复检测,并提供反映脑干听觉功能状态和发育过程的客观依据。BAER对刺激参数如刺激速率和强度的变化很敏感,且对脑和神经的缺氧/缺血、炎症等损伤特别是灰、白质病变非常敏感,从而能够反映终末器官和脑损伤的状态,客观评估脑和神经系统功能的完整性。最大长度序列(Maximum Length Sequence, MLS)是先进的BAER技术,它可以将声音刺激的速率提高到1000/s以上或更高,从而比常规的BAER技术更易发现脑干听觉功能的异常,提高神经系统异常的检出率。
本研究一方面关注于早产儿中比例较大的群体即晚期早产儿,研究合并多种围生期疾病或者并发症的高危晚期早产儿的听觉脑干功能的情况。另一方面,本研究关注于较小胎龄的早产儿,在对早产儿进行危险因素分析后发现BPD、NEC是脑干听觉系统损伤的独立高危因素,由此进一步分别对这两部分患儿群体进行前瞻性的病例对照研究,探讨BPD和NEC对较小胎龄早产儿脑干听觉系统功能和发育的影响。
研究内容主要分为五部分。第一部分：应用MLS-BAER技术检测高危晚期早产儿在矫正胎龄足月时听觉脑干的功能异常,探讨是否高危晚期早产儿存在脑干听觉系统损伤；第二部分：回顾性分析早产儿在矫正胎龄足月前外周听阈的变化特点,以及矫正胎龄足月时脑干听觉功能损伤的高危因素,评价BPD、NEC是否是早产儿脑干听觉功能异常的独立危险因素；第三部分：随访检测和分析在矫正胎龄32周至足月的发育阶段内,BPD早产儿脑干听觉功能的异常及变化情况,研究BPD对早产儿在早产时期听觉脑干发育的影响；第四部分：应用常规BAER和MLS-BAER技术研究NEC对早产儿矫正胎龄足月时听觉脑干功能的影响。
第一部分高危晚期早产儿矫正胎龄足月时脑干听觉功能研究
目的：检测高危晚期早产儿在矫正胎龄足月时脑干听觉系统功能状态,探讨高危晚期早产儿听觉脑干系统损伤的电生理学变化。
方法：纳入合并各种围生期疾病的高危晚期早产儿68例,无围生期疾病的晚期早产儿对照35例和正常足月儿对照41例。在矫正胎龄足月时检测MLS-BAER,刺激速率为91、227、455、910/s,刺激强度为阈上40dB nHL。
结果：1)与足月儿对照比较：高危晚期早产儿的Ⅰ、Ⅲ波潜伏期及Ⅰ-Ⅲ波峰间期与正常足月儿无显著差异；然而V波潜伏期在较高刺激速率时较足月儿对照显著延长；Ⅰ-Ⅴ、Ⅲ-Ⅴ波峰间期在各个刺激速率均比正常足月儿对照显著延长；Ⅲ-Ⅴ/Ⅰ-Ⅲ峰间期比值在较高刺激速率时较足月对照显著增大。高危晚期早产儿的Ⅰ、Ⅲ、Ⅴ波振幅稍小于足月儿对照,Ⅴ/Ⅰ、Ⅴ/Ⅲ振幅比值稍大于足月儿对照,但振幅及振幅比值在组间均无显著差异。2)与低危晚期早产儿比较：高危晚期早产儿的Ⅰ、Ⅲ波潜伏期和Ⅰ-Ⅲ波峰间期均与低危晚期早产儿相似,统计学检验无显著差异。然而,在较高刺激速率下,高危晚期早产儿的V波潜伏期,Ⅲ-Ⅴ和Ⅰ-Ⅴ波峰间期均显著延长,Ⅲ-Ⅴ/Ⅰ-Ⅲ峰间期比值也显著增大。高危晚期早产儿的Ⅰ、Ⅴ波振幅较低危晚期早产儿稍减低,除Ⅰ波潜伏期在455/s时和V波潜伏期在227/s时有统计学差异外,其余参数在组间均无统计学差异；Ⅲ波振幅、Ⅴ/Ⅰ和Ⅴ/Ⅲ振幅比值与低危晚期早产儿也无显著性差异。
结论：合并围产期疾病的高危晚期早产儿存在脑干听觉功能损伤,而且主要存在于脑干听觉通路近中枢部分,外周部分影响不大。
第二部分高危早产儿外周听阈及脑干听觉功能异常的高危因素分析
目的：早产儿是神经损伤和发育缺陷的高危人群。通过分析高危早产儿外周听阈和MLS-BAER参数与各种围产期危险因素的关系,了解导致外周和中枢脑干听觉功能异常的独立危险因素。
方法：回顾性分析367例早产儿在矫正胎龄足月前各发育阶段(矫正胎龄32～42周)外周听阈的变化及特点,以及172例早产儿在矫正胎龄足月时(矫正胎龄37～42周)脑干听觉功能状态。应用多元线性回归分析外周听阈及MLS-BAER参数与围产期危险因素的相关性。
结果：1)外周听阈：随着生后发育和胎龄的增加,早产儿的外周听阈均值呈逐渐下降的趋势。孕龄偏小、出生体重偏轻的早产儿外周听阈更高。早产儿外周听阈异常主要表现为轻中度异常,在发育早期有少数严重异常的患者,随着胎龄增加,外周听阈异常比率逐渐减少。在矫正胎龄足月时,仅表现为轻度异常。各时期导致外周听阈异常的独立高危因素分别为：矫正胎龄26～32周,胎膜早破；矫正胎龄32～34周,呼吸暂停；矫正胎龄34～36周,机械通气日数；矫正胎龄36～42周,高胆红素血症、1分钟Apgar评分、机械通气日数。2)MLS-BAER参数：矫正胎龄足月时,BPD、NEC与代表脑干听觉功能近中枢部分的参数(V波潜伏期、Ⅲ-Ⅴ、Ⅰ-Ⅴ波峰间期以及Ⅲ-Ⅴ、Ⅰ-Ⅲ峰间期比值)极显著相关,而与代表近外周部分的参数(Ⅰ、Ⅲ波潜伏期和Ⅰ-Ⅲ波峰间期)不相关。BPD、NEC是脑干听觉系统神经功能损伤的独立危险因素。
结论：胎膜早破、高胆红素血症、呼吸暂停、机械通气、低Apgar评分为生后发育早期外周听阈异常的高危因素。BPD、NEC是早产儿至矫正胎龄足月时中枢脑干听觉功能损伤的高危因素。
第三部分支气管发育不良患儿脑干听觉功能发育研究
目的：随访研究新生儿期支气管肺发育不良(BPD)对早产儿未成熟脑发育和功能的影响,阐明BPD患儿听觉脑干发育特点,了解BPD患儿脑干听觉功能的异常和诱发电位特征性的改变,以及发生脑干听觉功能损伤和恢复的时间窗。
方法：对研究期间内纳入的早产儿每两周随访检测MLS-BAER(矫正胎龄32、34、36、38、40周),在矫正胎龄36周时明确BPD诊断,进行分组。本研究共纳入BPD患儿57例,低危早产儿对照47例和正常足月儿对照55例。
结果：1)外周听阈：新生儿期,BPD患儿外周听阈多数在正常范围,听阈异常多为轻度,仅少数表现为中度异常,无重度异常患儿。随着生后发育和矫正胎龄的增加,BPD患儿外周听阈均值不断下降,中重度异常的比率也逐渐减少,总的异常比率由32.5%下降至17.2%,轻中度异常比率也分别呈下降趋势。在矫正胎龄足月时,外周听阈异常全部表现为轻度,无中重度异常患儿。2)MLS-BAER参数：BPD患儿与低危早产儿对照相比,Ⅰ、Ⅲ波潜伏期及Ⅰ-Ⅲ波峰间期在各个胎龄阶段虽有延长,但组间均无显著性差异。在矫正胎龄32周,BPD患儿的Ⅴ波潜伏期,Ⅲ-Ⅴ、Ⅰ-Ⅴ波峰间期虽相对延长,但组间均无统计学差异；在矫正胎龄34周,BPD患儿的V波潜伏期,Ⅲ-Ⅴ、Ⅰ-Ⅴ波峰间期延长更明显,在较高刺激速率下显示统计学差异；在矫正胎龄36周,Ⅴ波、Ⅲ-Ⅴ波峰间期延长比矫正胎龄34周时更显著,在较低刺激速率即91/s时即表现出统计学差异,并随刺激速率增加,Ⅰ-Ⅴ波峰间期表现极显著差异；在矫正胎龄38～40周,V波潜伏期、Ⅲ-V波峰间期延长仍然明显,但与矫正胎龄36周相比,Ⅰ-Ⅴ波峰间期在组间的差异显著性程度降低。BPD患儿与足月儿相比,BPD患儿的Ⅰ、Ⅲ波潜伏期和Ⅰ-Ⅲ波峰间期均无显著差异；而Ⅲ-Ⅴ、Ⅰ-Ⅴ波峰间期在所有刺激速率下均显著延长,Ⅲ-Ⅴ/Ⅰ-Ⅲ峰间期比值在较高刺激速率下较足月儿对照显著增高。
结论：BPD影响早产儿在新生儿期脑干听觉系统的生长发育和功能成熟,早产合并BPD可以诱导或者加重脑损伤。在生后发育过程中,BPD主要影响脑干听觉通路近中枢部分的功能成熟及发育,而对外周部分影响不大。早产BPD患儿矫正胎龄足月前脑干听觉通路近中枢部更易受累,而且程度较为严重。矫正胎龄34周表现出显著脑干听觉系统损伤；矫正胎龄36周损伤仍然继续并且达到严重阶段,至矫正胎龄38周损伤仍然存在,但较前程度减轻；矫正胎龄40周脑干听觉功能已有一定程度恢复,但与同胎龄早产儿相比仍然有显著性差异。BPD患儿脑干听觉损伤和恢复的时间窗可能为临床诊疗和预后评估提供参考。
第四部分坏死性小肠结肠炎对矫正胎龄足月的早产儿脑干听觉功能的影响
目的：探讨坏死性小肠结肠炎(NEC)对于新生儿脑干听觉功能的影响。
方法：纳入早产NEC患儿37例,低危早产儿对照47例和正常足月儿对照38例。此外,8例近足月和足月NEC患儿也参与比较分析。所有新生儿均在矫正胎龄足月时进行常规BAER和MLS-BAER检测。
结果：1)外周听阈：除1例NEC患儿轻度升高外,其余均在正常范围。2)常规BAER:NEC早产儿的Ⅰ、Ⅲ波潜伏期,Ⅰ-Ⅲ波峰间期在各个刺激速率下均与两组对照无显著差异；然而V波潜伏期、Ⅲ-Ⅴ波峰间期在各个刺激速率下均较两组对照显著延长,Ⅲ-Ⅴ/Ⅰ-Ⅲ峰间期比值显著增大；Ⅰ-Ⅴ波峰间期在较高刺激速率下较低危早产儿显著延长,在所有刺激速率下较足月儿对照显著延长。NEC早产儿的各波振幅和振幅比值与两组对照基本无差异。3)MLS-BAER:在各个刺激速率下,NEC早产儿的Ⅰ、Ⅲ波潜伏期,Ⅰ-Ⅲ波峰间期均与低危早产儿对照无显著差异；然而V波潜伏期在较高刺激速率下显著延长；Ⅲ-Ⅴ、Ⅰ-Ⅴ波峰间期在各个刺激速率下均较早产儿对照显著延长；Ⅲ-Ⅴ/Ⅰ-Ⅲ峰间期比值在较高刺激速率下较早产儿对照显著增大。NEC早产儿Ⅰ、Ⅲ、Ⅴ波振幅和振幅比值均与早产儿对照无显著差异(除277/s时Ⅴ波振幅外)。与足月儿对照相比,在各个刺激速率下,早产NEC患儿Ⅰ、Ⅲ波潜伏期,Ⅰ-Ⅲ波峰间期与对照无显著差异；V波潜伏期、Ⅲ-Ⅴ、Ⅰ-Ⅴ波峰间期在各个刺激速率下均比足月对照显著延长,而且Ⅲ-Ⅴ/Ⅰ-Ⅲ峰间期比值显著增大。NEC早产儿的Ⅰ、Ⅲ、Ⅴ波振幅和振幅比值均与足月儿对照无显著差异。4)足月NEC患儿与正常足月儿相比,BAER及MLS-BAER各波潜伏期、波峰间期、峰间期比值、振幅及其振幅比值均无统计学差异。与常规BAER相比,MLS-BAER波形更易辨认,组间差异显著性更强,更易于发现轻微脑损伤。刺激速率为455/s的波形稳定,组间差异显著,应用该刺激频率进行检测所用的时间较传统BAER明显缩短,更适用于诊断早产儿听觉脑干损伤。
结论：与低危早产儿和正常足月儿相比,早产NEC患儿表现为神经传导延迟,代表脑干听觉通路近中枢部分的参数均显著异常,存在严重中枢脑干听觉功能损伤。而足月NEC患儿与正常足月对照相比各波参数无明显差异。NEC可导致早产儿脑损伤,而对足月儿脑干听觉功能影响不大：早产合并NEC可诱发或者加重脑损伤。MLS-BAER较常规BAER有更大优越性。
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 complications
Objective: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 weeks
Objective 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 Enterocolitis
Objective:To examine brainstem auditory function at term in preterm infants after NEC, and to understand the effect of NEC on immature auditory brainstem
Methods: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.
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