Sub-optimal function of the auditory brainstem in term infants with transient low Apgar scores

Clinical Neurophysiology 118 (2007) 1088–1096 www.elsevier.com/locate/clinph

Sub-optimal function of the auditory brainstem in term infants with transient low Apgar scores Ze D. Jiang b

a,b,*

, Xiu Xu a, Dorothea M. Brosi b, Xiao M. Shao a, Andrew R. Wilkinson

b

a Children’s Hospital, Fudan University, Shanghai, China Neonatal Unit, Department of Paediatrics, University of Oxford, John Radcliffe Hospital, Headington, Oxford OX3 9DU, United Kingdom

Accepted 28 January 2007

Abstract Objectives: To assess functional integrity of the auditory brainstem in neonates with transient low Apgar scores. Methods: Forty-two term infants were studied with brainstem auditory evoked response (BAER) using the maximum length sequence during the first month of life. All had transient low Apgar scores but no clinical signs of hypoxic-ischaemic encephalopathy (HIE). Results: The latencies of BAER waves I and III in these infants were similar to those of age-matched normal controls at all click rates (91/s, 227/s, 455/s and 910/s) during the period studied. Wave V latency was increased at 910/s on day 1 (P < 0.01), but did not differ from that in the controls on any other days. I–V interval was increased significantly at 455/s and 910/s on day 1 (P < 0.01 and 0.001) and day 3 (P < 0.05 and 0.01). On days 5 and 7, BAER wave latencies and intervals were similar to those in the controls. On day 30, all latencies and intervals reached the values in the controls. No abnormalities were seen in BAER wave amplitude variables on any days. Conclusions: Neonates with transient low Apgar scores but without HIE had a significant increase in I–V interval at very high click rates on the first three days of life. Significance: Brainstem auditory function is sub-optimal during the first few days in neonates with transient low Apgar scores. Ó 2007 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. Keywords: Hypoxia; Perinatal brain damage; Neonatal auditory abnormality; Auditory brainstem evoked response; Evoked potentials; Maximum length sequence; Apgar score

1. Introduction The Apgar score was developed more than a half century ago to denote the condition of newborn infants during the first critical minutes after birth, to identify those who require resuscitation at birth, and to evaluate change in the condition of infants over the first minutes of life (Apgar, 1953). In spite of its various limitations, the Apgar score continues to be the most widely collected index of immediate postnatal health for newborn infants (Hegyi

*

Corresponding author. Present address: Neonatal Unit, Department of Paediatrics, University of Oxford, John Radcliffe Hospital, Headington, Oxford OX3 9DU, United Kingdom. Tel.: +44 1865 221364; fax: +44 1865 221366. E-mail address: [email protected] (Z.D. Jiang).

et al., 1998; Schmidt et al., 1988). It has assisted doctors in observing several clinical signs simultaneously (heart rate, respiration, muscle tone, reflex irritability and colour) in making clinical decisions. Recent studies further confirm the value of the Apgar score for the assessment of newborn infants, and suggest that the Apgar scoring system remains relevant for the prediction of neonatal survival (Casey et al., 2001; Papile, 2001). In neonatal audiology, a low Apgar score has been regarded as one of the major perinatal indicators associated with peripheral auditory impairment in infants (Joint Committee on Infant Hearing, 1995, 2000). Newborn infants who have a depressed Apgar score are more likely to develop peripheral auditory impairment when they grow up. However, it is not clear whether infants who have a low Apgar score, particularly those who are not associated with clinical signs of hypoxic-ischaemic encephalopathy (HIE),

1388-2457/$32.00 Ó 2007 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.clinph.2007.01.018

Z.D. Jiang et al. / Clinical Neurophysiology 118 (2007) 1088–1096

have any central auditory impairment, which may not be detected by conventional examinations. We have previously studied brainstem auditory evoked responses (BAERs) using conventional averaging techniques (i.e. conventional BAER) in term newborn infants who have a transient low Apgar score but no clinical signs of HIE in order to detect any abnormalities in central auditory function (Jiang et al., 2005b). The results suggest that except for maturational change, no abnormalities were found in the BAER on any days after birth. It seems that infants with a transient low Apgar score do not have central auditory impairment. However, it cannot be excluded that these infants may have sub-optimal auditory function or sub-clinical auditory impairment, which cannot be detected by conventional BAER. In order to detect any such impairment we have recently studied the auditory brainstem in these infants using the maximum length sequence BAER, which have proven to be a valuable test to improve the detection of auditory neuropathology in newborn infants (Jiang et al., 2000, 2003, 2005a, 2006; Wilkinson and Jiang, 2006). The maximum length sequence BAER was recorded during the first week of life to explore any possible dynamic change in functional integrity of the auditory brainstem, and then at one month for short-term outcome. 2. Methods 2.1. Subjects Study group: There were 42 newborn infants (24 male and 18 female) who had an Apgar score 67 at 1 min (n = 27) and/or 5 min (n = 15) but P8 at 10 min, recruited from the Neonatal Unit, Children’s Hospital of Fudan University, Shanghai. None had any clinical signs of HIE, e.g. hypotonia with reduced or no spontaneous movements, increased threshold for primitive reflexes, lethargy or comatose, absence or very weak suck and requirement of tube feeds, or seizures), and other signs of hypoxia, including frequent depression and failure of breathing spontaneously at birth (Levene, 2001; Levene and Evans, 2005; Volpe, 2001). Gestational age ranged between 37 and 42 weeks (39.2 ± 1.5 weeks), and birthweight between 2450 and 4550 g (3302 ± 501 g). Infants were excluded if he or she had congenital malformation, congenital or perinatal infection of the central nervous system (e.g. neonatal meningitis) and intrauterine growth retardation, ototoxic drugs, and hyperbilirubinaemia, which may cause sensorineural auditory impairment (Joint Committee on Infant Hearing, 1995, 2000; Wilkinson and Jiang, 2006). None of the subjects had perinatal history of anesthesia or maternal drugs that may depress the fetus, which may cause a low Apgar score. Control group: Forty healthy term infants (gestational age 37–41 weeks) served as controls. None had any major perinatal conditions or complications. Apgar scores in all controls were P8 at both 1 and 5 min. At the time of max-

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imum length sequence BAER testing, all had a monaural hearing threshold <20 dB nHL, determined by conventional BAER with 21/s clicks. In the study group the subjects were studied on days 1, 3, 5 and 7 after birth and then on day 30. Each subject was studied, as appropriate, between 2 and 4 times. The number of infants on each study day ranged between 21 and 34. The normal controls were studied on days 1–3 (first recording) and day 30 (second recording), respectively. Because of the ethical difficulty in recording the BAER on any other days during the first month of life, no other recordings were made in between the two recordings in these normal infants after discharge. This research was approved by the Central Oxford Research Ethics Committee and the Children’s Hospital Ethics Committee of Fudan University. Prior to study entry, informed consent was obtained from the parents of subjects and the paediatrician in charge. 2.2. BAER recording A Nicolet Bravo Evoked Potential System (Nicolet Biomedical Inc. Madison, WI, USA) was used to record and analyse the maximum length sequence BAER. As described before, the subjects lay supine in the cot during the recording (Jiang et al., 2003, 2005a). Three gold-plated disk electrodes were placed, respectively, at the middle forehead (positive), the ipsilateral earlobe (negative) and the contralateral earlobe (ground). Prior to the placement of electrodes the skin was gently and thoroughly cleaned so that the impedance between any two electrodes was kept as low as possible (<5 kX). The auditory meatus was inspected to avoid collapse of the meatal lumen and cleaned of any blockage by vernix and wax. Rarefaction clicks of 100-ls were delivered monaurally through a TDH 39 headphone. Care was taken to prevent the headphone from collapsing the ear canal. Recording of the maximum length sequence BAER was started after the subject fell asleep naturally, often after a feed. No sedatives were used. The left ear was tested in all subjects. The maximum length sequence BAER was recorded with clicks at 91–910/s and 60 dB nHL. Those who had a BAER threshold >20 dB nHL were also tested at higher intensities so that the data of maximum length sequence BAER central components in the study group could be compared with those of the normal controls at the same hearing level, i.e. P40 dB above the threshold of each subject. Duplicate recordings were made in response to each stimulus condition to examine reproducibility. The clicks were presented in the sequence of 91/s, 227/s, 455/s and 910/s in the first run, equivalent to a minimum interpulse interval (the duration of the sequence) of 11.1, 4.4, 2.2 and 1.1 ms, respectively. A reverse sequence was used in the second run. Brain responses evoked to the clicks were amplified and filtered at 100–3000 Hz. If the data exceeded 91% of the sensitivity parameter setting (51 lV), that sweep (artefact)

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was automatically rejected by the system. Sampling was manually discontinued whenever there were excessive muscle artefacts on the monitoring oscilloscope. Each run included averaged brain responses to 1500 clicks. The sweep duration was 24 ms. It is known that peripheral hearing impairment affects the measurement of central BAER components, resulting in amplitude reduction and latency prolongation. During the period of study, 5 of the infants with a low Apgar score but without signs of HIE had a slightly elevated threshold (25 or 30 dB nHL) on various days. In order to compare the maximum length sequence BAER data between the study and control groups at the same intensity level (P40 dB) above the threshold of each subject, a click intensity of 70–80 dB nHL was used to record the maximum length sequence BAER in these infants. One infant had a threshold 40 dB nHL on day 3 and another 45 dB on day 7, which were probably due to transient middle ear dysfunction – a common middle ear disorder in newborn infants (Stockard and Curran, 1990). The data from the two infants were excluded to minimize the potential effect of significant peripheral impairment on BAER central components and assess central function more accurately. 2.3. Data analysis All quantitative analyses of maximum length sequence BAER variables in the study group were based on the data, as described above, collected at the click intensity P40 dB above the threshold of each subject. Measurement of maximum length sequence BAER variables was carried out blind to the medical history and clinical data of each subject. The latencies and amplitudes of waves I, III, and V were measured. I–V, I–III and III–V interpeak intervals and the interval ratio of III–V and I–III (or III–V/I–III interval ratio) were calculated. The amplitude ratios of V/I and V/III were also calculated. In the maximum length sequence BAER, III–V complex was the most easily identifiable portion of the waveform. In newborn infants, the down slope of wave I is often significantly affected by wave II, resulting in considerable

variability in the amplitude of wave I and in turn in V/I amplitude ratio. Therefore, the amplitude of wave I was measured from its peak to the lowest trough between waves I and III, which is more reliable. The amplitude of wave III was measured from the lowest trough between waves I and III to the peak of wave III while the amplitude of wave V was made from the positive peak to the negative trough immediately after the peak (Jiang et al., 2000; Lasky, 1997). The measurements of each maximum length sequence BAER variables from two replicated recordings to each stimulus condition were averaged for data analyses. As mentioned above, no recordings were made in between days 1–3 and day 30 in the normal infants due to the ethical difficulty in recording the BAER on any other days during the first month of life. Thus, the data of the infants with a low Apgar score on days 1, 3, 5 and 7 were compared with those of the normal controls on days 1–3. The data in the study group on day 30 were compared with those of the controls on the same day 30. Mean and standard deviation of each BAER variable at each stimulus condition were compared between the infants with a low Apgar score and the normal controls using analysis of variance (ANOVA). Differences between groups were assessed by a post hoc Tukey test. The level of significance in probability was 0.05. Regression analysis of the relationship between maximum length sequence BAER measurements and click rate was performed. 3. Results Tables 1–4 present means and standard deviations (SDs) of various variables in the maximum length sequence BAER at different rates of clicks during the first month of life in both the infants with a transient low Apgar score but without clinical signs of HIE and the normal controls. Fig. 1 shows sample recordings of the maximum length sequence BAER in a normal infant (A) and an infant with a transient low Apgar score (B). Fig. 2 shows changes in I– V interval, the main BAER variable that reflects brainstem auditory function, at different rates of clicks on different days after birth.

Table 1 Means and standard deviations (SDs) of maximum length sequence BAER variables at 91/s (P40 dB above BAER threshold) during the first month of life BAER variables

I (ms) III (ms) V (ms) I–III (ms) III–V (ms) I–V (ms) III–V/I–III ratio V/I ratio V/III ratio

NC d1-3

LA d1

LA d3

LA d5

LA d7

LA d30

NC d30

Mean

SD

Mean

SD

Mean

SD

Mean

SD

Mean

SD

Mean

SD

Mean

SD

2.41 5.30 7.58 2.88 2.29 5.16 0.80 1.46 0.94

0.15 0.22 0.31 0.18 0.20 0.27 0.08 0.57 0.45

2.44 5.31 7.61 2.88 2.31 5.19 0.80 1.27 0.88

0.21 0.23 0.24 0.15 0.12 0.17 0.06 0.54 0.40

2.40 5.32 7.63 2.91 2.31 5.23 0.80 1.98 0.88

0.23 0.36 0.37 0.20 0.15 0.25 0.07 1.15 0.28

2.35 5.27 7.53 2.85 2.25 5.10 0.79 1.63 1.01

0.12 0.31 0.36 0.13 0.16 0.21 0.08 0.50 0.26

2.38 5.23 7.45 2.81 2.26 5.07 0.80 1.42 0.76

0.13 0.18 0.29 0.15 0.14 0.24 0.05 0.89 0.25

2.37 5.15 7.32 2.78 2.18 4.96 0.78 1.20 0.77

0.24 0.28 0.29 0.12 0.18 0.26 0.06 0.44 0.30

2.34 5.18 7.31 2.80 2.13 4.94 0.76 1.37 0.96

0.13 0.24 0.17 0.13 0.15 0.23 0.06 0.50 0.28

NC, normal controls; LA, low Apgar; d, day(s) (the same is applied to Tables 2–4).

Z.D. Jiang et al. / Clinical Neurophysiology 118 (2007) 1088–1096

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Table 2 Means and standard deviations (SDs) of maximum length sequence BAER variables at 227/s BAER variables

NC d1-3 Mean

SD

Mean

SD

Mean

SD

Mean

SD

Mean

SD

Mean

SD

Mean

SD

I (ms) III (ms) V (ms) I–III (ms) III–V (ms) I–V (ms) III–V/I–III ratio V/I ratio V/III ratio

2.59 5.64 8.20 3.05 2.57 5.62 0.85 1.53 0.84

0.16 0.23 0.25 0.19 0.18 0.22 0.09 0.79 0.27

2.59 5.66 8.25 3.09 2.58 5.67 0.84 1.32 0.85

0.20 0.25 0.29 0.15 0.13 0.21 0.05 0.62 0.40

2.55 5.57 8.21 3.02 2.63 5.66 0.88 2.08 0.99

0.21 0.36 0.36 0.22 0.13 0.27 0.07 1.21 0.61

2.50 5.59 8.08 2.99 2.50 5.50 0.84 1.65 0.80

0.17 0.33 0.39 0.21 0.10 0.29 0.04 0.88 0.29

2.55 5.50 8.02 2.91 2.55 5.46 0.86 1.51 0.86

0.13 0.25 0.36 0.19 0.12 0.28* 0.05 0.69 0.37

2.50 5.42 7.88 2.92 2.46 5.37 0.84 1.24 0.74

0.24 0.27 0.22 0.14 0.14 0.21 0.05 0.33 0.30

2.50 5.44 7.91 2.94 2.42 5.37 0.83 1.59 1.04

0.10 0.13 0.19 0.15 0.14 0.22 0.06 0.54 0.26

*P

LA d1

LA d3

LA d5

LA d7

LA d30

NC d30

< 0.05 in ANOVA for comparison between infants with a low Apgar score on day 7 (LA d7) and normal term controls on days 1–3.

3.1. Wave latencies and interpeak intervals On day 1, the latencies of BAER waves I and III in the infants with a low Apgar score but no HIE were similar to those in the controls on days 1–3 at all click rates 91–910/s, without any significant differences (Tables 1–4). Wave V latency tended to be increased at higher rates and differed significantly from the controls at the highest 910/s (P < 0.01, Table 4). As click rate was increased, I– V interval in the infants with a low Apgar score was increased more than that in the controls. The interval differed significantly between the two groups at 455/s (P < 0.01) and 910/s (P < 0.001, Tables 3 and 4, Fig. 2). III–V intervals also tended to increase at the two very high rates and differed significantly from those in the controls at 910/s (P < 0.01, Tables 3 and 4), although the change in I–III interval was less significant. III–V/I–III interval ratio in the infants with a low Apgar score was similar to that in the controls at all click rates (Tables 1–4). On day 3, the latencies of waves I and III in the infants with a low Apgar score tended to be decreased in comparison with those on day 1, and did not differ from those in the controls at any rates. Wave V latency did not show any apparent change, but no longer differed significantly from that in the controls at 910/s

(Tables 1–4). All intervals in the infants with a low Apgar score did not show any further major changes (Tables 1–4). I–V interval still differed significantly from that in the controls at the very high rates (455 and 910/s, P < 0.05 and 0.01, Fig. 2). III–V intervals showed similar change at the two click rates (P < 0.01 and 0.01, Tables 3 and 4). No significant change was seen in I–III interval and III–V/I–III interval ratio at any rates (Tables 1–4). On day 5, wave I latency in the infants with a low Apgar score did not show any apparent change, compared with that on day 3. Wave III and V latencies tended to decrease at all rates of clicks and were similar to the values in the controls (Tables 1–4). I–V interval was decreased towards the values in the controls at all click rates, and no longer differed significantly from the controls at 455 and 910/s of clicks (Tables 1–4, Fig. 2). Both I–III and III–V intervals were decreased slightly. On day 7, wave I latency in the infants with a low Apgar score did not show any further changes, but wave III and V latencies were decreased further. All latencies were slightly shorter than those in the controls. Similarly, all interpeak intervals in the infants with a low Apgar score were decreased slightly further. I–V interval did not differ significantly from that in the controls at any rates, except at 227/ s at which the interval was shorter than that in the controls

Table 3 Means and standard deviations (SDs) of maximum length sequence BAER variables at 455/s BAER variables

NC d1-3 Mean

SD

Mean

SD

Mean

SD

Mean

SD

Mean

SD

Mean

SD

Mean

SD

I (ms) III (ms) V (ms) I–III (ms) III–V (ms) I–V (ms) III–V/I–III ratio V/I ratio V/III ratio

2.71 5.91 8.77 3.19 2.86 6.06 0.91 1.81 0.97

0.17 0.24 0.23 0.21 0.18 0.21 0.09 0.85 0.29

2.66 5.93 8.86 3.28 2.92 6.22 0.90 1.80 1.06

0.22 0.30 0.33 0.16 0.15 0.22** 0.06 0.97 0.56

2.63 5.83 8.83 3.20 2.99 6.19 0.95 2.06 1.09

0.22 0.34 0.39 0.21 0.15** 0.26* 0.09 1.44 0.85

2.63 5.82 8.74 3.12 2.92 6.05 0.93 1.67 0.89

0.14 0.29 0.35 0.20 0.14 0.26 0.09 0.70 0.35

2.64 5.73 8.65 3.09 2.91 6.01 0.93 1.65 0.88

0.12 0.19 0.34 0.18 0.18 0.27 0.09 0.88 0.42

2.61 5.67 8.51 3.11 2.83 5.95 0.91 1.33 0.93

0.15 0.28 0.23 0.20 0.19 0.27 0.06 0.29 0.40

2.62 5.75 8.53 3.13 2.73 5.86 0.87 1.68 1.03

0.08 0.20 0.22 0.16 0.15 0.22 0.06 0.53 0.19

*P

LA d1

LA d3

LA d5

LA d7

LA d30

NC d30

< 0.05, **P < 0.01 in ANOVA for comparison between infants with a low Apgar score on day 1 and day 3 (LA d1 and LA d3) and normal term controls on days 1–3.

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Table 4 Means and standard deviations (SDs) of maximum length sequence BAER variables at 910/s BAER variables

NC d1-3

LA d1

LA d3

LA d5

LA d7

LA d30

NC d30

Mean

SD

Mean

SD

Mean

SD

Mean

SD

Mean

SD

Mean

SD

Mean

SD

I (ms) III (ms) V (ms) I–III (ms) III–V (ms) I–V (ms) III–V/I–III ratio V/I ratio V/III ratio

2.77 5.96 8.81 3.18 2.87 6.05 0.91 1.90 0.96

0.16 0.23 0.24 0.19 0.25 0.25 0.07 1.19 0.38

2.71 5.97 8.98 3.26 3.00 6.27 0.93 2.02 1.10

0.20 0.27 0.25* 0.15 0.20* 0.17** 0.09 1.22 0.83

2.66 5.92 8.92 3.26 3.00 6.26 0.92 1.74 0.76

0.20 0.33 0.36 0.20 0.15* 0.23* 0.08 0.88 0.28

2.73 5.88 8.84 3.15 2.97 6.11 0.94 1.37 0.85

0.14 0.27 0.27 0.22 0.14 0.22 0.10 0.55 0.56

2.69 5.85 8.74 3.11 2.93 6.04 0.93 2.04 0.83

0.10 0.19 0.31 0.21 0.17 0.26 0.08 1.18 0.28

2.66 5.75 8.64 3.17 2.84 6.01 0.88 1.67 1.11

0.15 0.20 0.16 0.16 0.13 0.23 0.08 0.46 0.37

2.67 5.87 8.62 3.20 2.74 5.93 0.86 1.90 1.09

0.09 0.19 0.23 0.15 0.15 0.20 0.06 1.31 0.40

*

P < 0.01, **P < 0.001 in ANOVA for comparison between infants with a low Apgar score on day 1 and day 3 (LA d1 and LA d3) and normal term controls on days 1–3.

(P < 0.05, Table 2, Fig. 2). No significant changes were seen in III–V/I–III interval ratio on either day 5 or day 7 (Tables 1–4).

On day 30, all wave latencies in the infants with a low Apgar score were decreased further in comparison with those on day 7, which was slightly more significant for the later waves than for the earlier waves (Tables 1–4). The latencies of waves I, III and V all reached the values in the controls on day 30. Both I–V and III–V intervals were also decreased further in comparison with those on day 7, although the differences did not reach statistical significance (Tables 1–4). All intervals and III–V/I–III interval ratio in the infants with a low Apgar score on day 30 did not show any significant differences from the controls on the same day (Tables 1–4, Fig. 2). 3.2. Wave amplitude variables During the first week of life, the infants with a low Apgar score did not show any significant and consistent

6.8

** *

I-V interval (ms)

6.3

** ** *

NC d1-3

LA d1

LA d3 5.8

* LA d5 5.3 LA d7 4.8 LA d30

NC d30

4.3 91

Fig. 1. Sample recordings of the maximum length sequence BAER in a normal infant (a) and an infant with a transient low Apgar score (b) on day 1 after birth. There were no differences in the waveforms of the maximum length sequence BAER between the two infants at 91 and 227/ sec clicks. However, at 455/s and 910/s wave V latency and I–V and particularly III–V intervals are longer in the infant with a transient low Apgar score than in the normal infant.

227

455

910

Click Rate (/s)

Fig. 2. Means and standard deviations of I–V interval at different repetition rates of click stimuli (P40 dB above BAER threshold) during the first month of life. *P < 0.05, **P < 0.01, ***P < 0.001 in ANOVA for comparison between infants with a low Apgar score on day 1 and day 3 (LA d1 and LA d3) and normal term controls on days 1–3.

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changes in the amplitudes of waves I, III and V at any rates of clicks. None of the amplitudes differed significantly from those of the normal controls on any days. V/I amplitude ratio in the infants with a low Apgar score was generally similar to that in the controls at most rates of clicks, and did not show any systematic changes at different rates during the first month, although there was some variation (Tables 1–4). This was also the case of V/III amplitude ratio (Tables 1–4). By the end of the first month, both V/I and V/III amplitude ratios in the infants with a low Apgar score were slightly smaller than the controls at some rates. 3.3. Click rate-dependent changes Similar to those in the controls, from day 1 to day 7 and on day 30 all wave latencies and interpeak intervals in the infants with a low Apgar score were increased with the increase in the rate of clicks. A one-tailed t test of the slopes of latency-rate functions was carried out for each maximum length sequence BAER variable to determine whether the slopes of the linear latency- and interval-rate functions were consistently different from zero. All these functions in both the infants with a low Apgar score and the controls were positively and significantly greater than zero at the 0.05 level or better on all days studied. The slope of I–V interval-rate function in the infants with a low Apgar score was slightly steeper than in the controls on days 1 and 3, but this difference did not reach statistical significance. All amplitudes of waves I, III and V in the infants with a low Apgar score were reduced with the increase in click rate on all days studied. The amplitude-rate function in these infants did not differ significantly from that in the controls for any wave amplitudes. Similar to the controls, neither V/I nor V/III amplitude ratios in the infants with a low Apgar score correlated significantly with the rate of clicks on any days studied. 4. Discussion 4.1. Sub-optimal auditory function in the brainstem during the first few days of life in term infants with a transient low Apgar score but without HIE HIE is the clinical marker of cerebral tissue that has been subjected to severe hypoxic-ischaemic damage, which may result in perinatal mortality or permanent neurodevelopmental disability (Volpe, 2001). We have previously studied dynamic changes in the maximum length sequence BAER in newborn infants who had a prolonged low Apgar score and clinical signs of HIE (Jiang et al., 2003). All wave latencies and interpeak intervals were increased significantly at 91–910/s of clicks on day 1 after birth, and were increased further on day 3. Thereafter, the latencies and intervals were decreased progressively. On days 5 and 7, wave V latency and all intervals were still

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significantly increased in comparison with those in the controls. These dynamic changes were more significant at higher rates of clicks than at lower rates. On day 30, I–V and III–V intervals were still increased slightly, although all wave latencies were decreased to normal values. These results indicate that hypoxic-ischaemic damage to the auditory brainstem persists during the first week after birth, with a peak on day 3, recovers progressively thereafter, and largely returns to normal by the end of the first month. In contrast, the present study found no major abnormalities in the maximum length sequence BAER in the infants who had a transient low Apgar score but no clinical signs of HIE. On day 1, only wave V latency was significantly increased at the highest rate 910/s and I–V interval was significantly increased at 455 and 910/s. On day 3, these abnormalities tended to improve, although I–V interval was still increased at these very high rates. Thereafter, none of the maximum length sequence BAER variables showed any abnormalities. These results suggest that auditory function in the brainstem is sub-optimal during the first 3 days of life in infants who have a low Apgar score but no clinical signs of HIE. Thus, compared to those with both a low Apgar score and clinical signs of HIE (Jiang et al., 2003), the infants with a transient low Apgar score but without clinical signs of HIE only have minor abnormalities in the auditory brainstem. After the first 3 days of life, with the increase in postnatal age all wave latencies in maximum length sequence BAER in the infants with a transient low Apgar score were decreased progressively. The decrease was slightly more significant for the more central components than for the more peripheral components. I–V interval was also decreased with the increase in postnatal age. These changes can be interpreted as a maturational change in the auditory brainstem. We found that all wave latencies and intervals in the maximum length sequence BAER in the infants with a transient low Apgar score reached the normal values by the end of the first month. This suggests that the abnormalities in the auditory brainstem in these infants return to normal much sooner than those with both a low Apgar score and clinical signs of HIE (Jiang et al., 2003), and that the short-term outcome is generally favourable. The rate-dependent changes in I–V interval in our infants with a low Apgar score but without signs of HIE were slightly more significant than in the normal controls on days 1 and 3, and maximum length sequence BAER abnormalities occurring only at very higher rates of clicks. The rate-dependent changes in the BAER primarily reflect neural processes concerning the efficacy of central synaptic transmission, as well as neural synchronisation and metabolic status of auditory neurons in the brainstem following the presentation of a physiological/temporal challenge (Ken-Dror et al., 1987; Jiang et al., 2002). It appears that the infants who have a low Apgar score have a slight decrease in the efficacy of central synaptic transmission or a decreased ability of central neurons to recover in time

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to transmit the next stimulus-evoked response during the first few days of life. 4.2. Possible cause of sub-optimal brainstem auditory function in infants with a transient low Apgar score Hypoxia is known to be a risk factor to the neonatal brain and auditory function. Severe hypoxia occurs during the perinatal period often associated with ischaemia, i.e. perinatal hypoxia-ischaemia. Cerebral ischaemia causes disorders of cerebral blood flow and metabolism, resulting in brain tissue injury and cerebral edema, or HIE. Newborn infants who suffer severe perinatal hypoxia-ischaemia are at high risk of brain damage and often develop life-long sequelae, including auditory impairment (Borg, 1997; Hecox et al., 1981; Jiang and Tierney, 1996; Johnston et al., 2001; Levene, 2001; Levene and Evans, 2005; Volpe, 2001; Wilkinson and Jiang, 2006). On the other hand, much less is known with regard to the influence of a less severe degree of perinatal hypoxia on the neonatal brain and auditory function. A major course of a low Apgar score is perinatal hypoxia or hypoxia-ischaemia with encephalopathy (i.e. HIE). Prolonged, significant low Apgar score may imply possible ongoing hypoxia-ischaemia, while a transient low Apgar score may be associated with a less severe degree of perinatal hypoxia, with no ischaemia. In addition to perinatal hypoxia or hypoxia-ischaemia, a low Apgar score can be caused by some perinatal conditions or problems. These include maternal drugs or anesthesia, laryngeal inhibition (e.g. due to aspiration of a small amount of amniotic fluid or by oronasopharyngeal-laryngeal stimulation from suction catheters), and prematurity in preterm infants. In the present study, none of the subjects had perinatal history of anesthesia or maternal drugs. All were full term infants. Therefore, the low Apgar score in our subjects was most likely to be caused by or related to short-term perinatal hypoxia which was not severe enough to result in clinical signs of encephalopathy. Our results suggest that transient less severe hypoxia may cause sub-optimal function in the auditory brainstem or sub-clinical auditory abnormalities during the first three days of life in newborn infants. 4.3. Maximum length sequence technique can improve the detection of sub-optimal neural function Earlier studies showed that the increase in the repetition rate of acoustic stimuli while recording the BAER may improve the detection of auditory impairment (Freeman et al., 1991; Gerling and Finitzo-Hieber, 1983; Hecox et al., 1981; Paludetti et al., 1983; Pratt et al., 1981). We have also studied the effect of click rate on the BAER in infants, and found that the increase in click rate can improve the detection of brain damage and brainstem or central auditory impairment in some clinical situations (Jiang, 1999; Jiang et al., 2001, 2002, 2004a,b; Wilkinson and Jiang, 2006). However, conventional averaging tech-

nique imposes a rate limit of about 100/s, which restricts the ability of the method of increasing click rate to improve early detection of auditory abnormalities. By comparison, the maximum length sequence technique can present acoustic stimuli at much higher rates (up to 1000/s or even higher) than is possible using conventional BAER which has a rate limit of about 100/s (Eysholdt and Schreiner, 1982; Jiang et al., 1999, 2000, 2003, 2005a, 2006; Jirsa, 2001; Lasky, 1994, 1997; Lina Granade et al., 1994; Picton et al., 1992). The higher rates provide a much greater physiological/temporal challenge to auditory neurons in the brainstem, potentially enhancing the detection of neuropathology. The maximum length sequence BAER has been used by some investigators to study sensorineural auditory impairment (Lina Granade et al., 1994). More recently, Jirsa (2001) reported that the maximum length sequence BAER appears to be useful in the assessment of auditory processing disorders. Over the last several years, we have tried to explore the value of the maximum length sequence BAER in early detection of brain damage and central auditory impairment in high-risk infants. Our studies have revealed that the maximum length sequence BAER is a valuable method to detect brain damage and central auditory impairment in newborn infants with some perinatal conditions or problems (Jiang et al., 2000, 2003, 2005a, 2006). It can improve the ability of BAER to detect early brain damage. Abnormalities in the maximum length sequence BAER were predominantly seen in infants who had severe perinatal problems that may either directly or indirectly damage the neonatal brain. The abnormalities generally became more significant as the rate of clicks was increased. In infants after perinatal hypoxia-ischaemia, who had both a low Apgar score and HIE, the dynamic changes in the maximum length sequence BAER during the first month of life were more dramatic at higher rates (Jiang et al., 2003). We also found that the results of the maximum length sequence BAER were often correlated well with clinical conditions. Therefore, the high rates provided by the maximum length sequence technique can improve the diagnostic value of the BAER for early brain damage and auditory impairment/abnormalities. In infants who had a transient low Apgar score but no clinical signs of HIE, our previous study in conventional BAER did not find any abnormalities during the first week of life and at one month (Jiang et al., 2005b). In the present study of the maximum length sequence BAER, however, I– V interval, the major BAER variable that reflects central conduction, was significantly increased at very high rates of clicks (455/s and 910/s) during the first 3 days of life, although these infants did not show any clinical signs of HIE. The abnormalities could not be demonstrated at the rates lower than 455/s. Therefore, the maximum length sequence BAER elicited at very high rates can detect some abnormalities that cannot be demonstrated by conventional BAER, improving the detection of sub-optimal auditory function or sub-clinical auditory abnormalities.

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4.4. Implications of the minor abnormalities in the maximum length sequence BAER in infants with a low Apgar score but without HIE Over the last half century, the Apgar score has been widely used as an indicator of immediate newborn condition to guide appropriate delivery room management and intervention. Understanding of whether infants who have a transient low Apgar score but no clinical signs of HIE are associated with any degree of brain damage and auditory impairment/abnormalities is of clinical importance as to whether any intervention is needed for such infants. The present study found no major abnormalities in brainstem auditory function in these infants. However, our findings in the maximum length sequence BAER do suggest that there is sub-optimal function in the auditory brainstem during the first three days after birth. Therefore, we cannot exclude the possibility of sub-clinical auditory impairment/ abnormalities during the first few days of life in infants who have a transient low Apgar score but no clinical signs of HIE. These infants may need to be observed with proper care. In a broader sense, the transient abnormalities in maximum length sequence BAER in infants with a low Apgar score also suggest that there may be transient neurological abnormalities in some of high-risk infants who do no show any obvious signs of brain damage or neurological abnormalities. Early detection of such abnormalities may provide useful information for clinical management of these infants. Therefore, we recommend that whenever there is a possibility to perform BAER testing, preferably maximum length sequence BAER, as a routine examination in high-risk infants, it should be done at least once during the first few days after birth to detect any transient abnormalities. Acknowledgements This work is supported by Defeating Deafness, WellChild Trust and Wellcome Trust, UK, and Chun-Hui Scheme of Education Ministry, China. We particularly thank the medical staff of the Neonatal Unit of the Children’s Hospital, Fudan University, Shanghai, for their enthusiastic support and assistance in recruitment of subjects and collecting data. References Apgar V. A proposal for a new method of evaluation of the newborn infant. Curr Res Anesth Analg 1953;32:260–7. Borg E. Perinatal asphyxia, hypoxia, ischemia and hearing loss. An overview. Scand Audiol 1997;26:77–91. Casey BM, McIntire DD, Leveno KJ. The continuing value of the Apgar score for the assessment of newborn infants. N Engl J Med 2001;344:467–71. Eysholdt U, Schreiner C. Maximum length sequences – a fast method for measuring brainstem evoked responses. Audiology 1982;21:242–50. Freeman S, Sohmer H, Silver S. The effect of stimulus repetition rate on the diagnostic efficacy of the auditory nerve-brain-stem evoked response. Electroencephalog Clin Neurophysiol 1991;78:284–90.

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