PEDIATRICS Vol. 113 No. 2 February 2004, pp. 357-360
Abnormal Auditory Brainstem Response Among Infants With Prenatal Cocaine Exposure
Mary Anne Tan-Laxa, MD*,
Consolacion Sison-Switala, MD*,
William Rintelman, PhD
and
Enrique M. Ostrea, Jr, MD*
* Department of Pediatrics, Hutzel Hospital, Wayne State University School of Medicine, Detroit, Michigan
Department of Audiology, Wayne State University, Detroit, Michigan
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ABSTRACT
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Objective. To determine the auditory brainstem response (ABR) patterns in infants with prenatal cocaine exposure as detected by meconium analysis.
Methods. Meconium drug analysis was done on term infants who were at risk for antenatal illicit drug exposure. Infants who tested positive for cocaine served as the exposed group; those who tested negative served as control subjects. An ABR was done on the infants within 6 days of life. Absolute latencies at 40 and 70 decibels (dB) of waves I, III, and V and interpeak latencies between I and III, III and V, and I and V were measured.
Results. Among 58 infants in the study, 21 (35.6%) were positive, by meconium analysis, for cocaine and 5 (8.5%) were positive for cannabinoids. Four infants tested positive for cocaine, although their mothers denied illicit drug use. There was a significant difference in mean maternal age, gravidity, parity, birth weight, and head circumference among cocaine-exposed versus nonexposed infants. The ABR from cocaine-positive infants showed significantly prolonged mean absolute latencies in both ears as compared with nonexposed infants: right ear at 40 dB III (4.823 vs 4.447 milliseconds), 40 dB V (7.400 vs 6.968 milliseconds), 70 dB I (2.111 vs 1.631 milliseconds), and 70 dB III (4.122 vs 3.821 milliseconds); left ear at 40 dB III (4.820 vs 4.444 milliseconds), 40 dB V (7.460 vs 6.860 milliseconds), 70 dB I (2.063 vs 1.741 milliseconds), 70 dB III (4.026 vs 3.656 milliseconds), and 70 dB V (6.568 vs 6.258 milliseconds). The interpeak latency was not significantly different except in 1 cocaine-positive infant: left ear at 40 dB III to V (2.667 vs 2.417 milliseconds).
Conclusion. The ABR in neonates who are exposed prenatally to cocaine shows prolonged absolute peak latencies compared with nonexposed neonates and may indicate compromise of the auditory system from gestational exposure to cocaine that will need additional audiologic follow-up. Meconium analysis can more accurately detect the infants who are at risk.
Key Words: auditory brainstem response • cocaine • drug abuse • infant of drug-dependent mother • drug use during pregnancy
Abbreviations: ABR, auditory brainstem response • dB, decibels • nHL, normal hearing level • SD, standard deviation
There is a growing concern regarding the effects of prenatal cocaine exposure on the developing fetus as a result of the increasing number of pregnant women who use cocaine.1 Numerous studies have shown that prenatal cocaine exposure is associated with a variety of neurobehavioral and electrophysiologic abnormalities.2–7 However, knowledge on the effects of maternal cocaine abuse on the neonatal auditory system function is limited. Although prolonged absolute and interpeak component latencies in the auditory brainstem response (ABR) have been demonstrated in cocaine-intoxicated animals,8–10 reports in newborn infants have been few and inconsistent. In 3 reports, abnormal ABR patterns were observed11–13 among cocaine-exposed infants, whereas in 1 report,14 such deficits were not seen. However, common to these studies was the use of maternal history and/or urine drug screen to identify cocaine exposure in the infants, and it is likely that many of the cocaine-exposed infants were not appropriately detected and labeled as control infants. Meconium drug analysis is a sensitive test to detect antenatal exposure of the infants to cocaine.15–17 This is the first study to determine ABR patterns in a cohort of infants with prenatal cocaine exposure as detected by meconium analysis.
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METHODS
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Meconium drug analysis, by enzyme immunoassay, as previously described,15,16 was done on 58 term infants with risk factors for antenatal illicit drug exposure viz, maternal history of illicit drug (55.2%), limited or no prenatal care (36.2%), maternal alcohol use (6.9%), and teenage pregnancy (1.7%). Infants who tested positive for cocaine served as the cocaine-exposed group; infants with negative results served as the control. Exclusion criteria included infants who were small for gestational age and the presence of any risk factor for hearing impairment in the neonatal period as defined by the 1994 Joint Committee on Infant Hearing.17
The infants underwent a complete physical examination, including an otologic examination. ABR was performed after consent was taken, within 6 days of life, by a trained technician under the supervision of an audiologist using a Grason-Stadler Model 55 BAEP unit in a prefabricated sound-treated test room (IAC, Model 403, New York, NY). The stimuli were 100-microsecond rarefaction clicks delivered monaurally via an insert earphone. Click intensity was expressed in decibels (dB) regarding normal hearing level (dB nHL) whereby 0 dB is the average behavioral click threshold of young adult listeners. The infant’s scalp was cleaned with an alcohol swab, and Omniprep redux was applied to lower electrode impedance. Grass EC-2 cream served as the conducting medium. Electrical activity was recorded via silver-silver chloride electrodes with vertex-to-ipsilateral mastoid configuration. The ground electrode was placed on the contralateral mastoid. Responses were averages over 2048 click presentations with 2 repetitions at 70 dB nHL and 40 dB nHL in each ear. Bioelectrical activity was amplified (300 000x) and digitally filtered (150–2000 Hz) at a sampling interval of 20 microseconds. Absolute latencies at 40 and 70 dB of waves I, III, and V and interpeak latencies between I and III, III and V, and I and V were measured by a single audiologist who was blinded to the type of drug exposure of the subjects. The criteria for normal hearing was defined as the presence of wave III and/or V at 40 dB. The criteria used for a hearing disorder were distorted wave form morphology, absent waves, or prolonged absolute latencies or interwave latencies of waves I to V. An abnormally prolonged latency is a latency that is >2 standard deviations (SDs) above a normative group’s average.
Power Analysis
Power was calculated on the basis of the mean (SD) of the absolute and interpeak latencies (milliseconds) of ABR measurements in newborn infants. For a calculated mean population difference (between cocaine exposed and nonexposed) in ABR latencies of 0.3 milliseconds, an SD difference of 0.1 milliseconds, an 
= .05, and 2-tailed analysis, we have a power of 0.98 for a sample size of 10 per group.
Data Analysis
Data in this report are expressed as mean ± SD or as percentages. Statistical analysis was performed using SPSS for Windows 10.0.5 (SPSS Inc, Chicago, IL). Two-tailed, unpaired t tests were used to test the differences between group means of independent samples. Fisher exact test was used to determine the difference in group proportions. Correlation among continuous variables was determined using the Pearson correlation test. Statistical significance was set as P < .05 for all analyses.
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RESULTS
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Fifty-eight infants were included in the study: 21 (35.6%) were positive and 37 (62.7%) were negative for cocaine; 5 (8.5%) were positive for cannabinoids. No opiate was detected. There were 4 infants who tested positive for cocaine but whose mothers denied the use of illicit drugs and 7 (30%) infants whose mothers admitted to cocaine use during pregnancy but had negative meconium test. On the basis of the meconium analysis, the infants were grouped into cocaine exposed (N = 21) or cocaine negative (N = 37). There was a significant (P < .05) difference in mean maternal age (29.2 vs 23.7), gravidity >3 (90.5% vs 51.4%), parity >3 (52.4% vs 27%), birth weight (2881 vs 3182 g), and head circumference (32.98 vs 33.78 cm) among cocaine-positive compared with cocaine-negative groups. There was no significant difference in the 2 groups in maternal cesarean section rate; history of alcohol use; and gestational age, length, race, gender, and grouped 1- and 5-minute Apgar scores.
The ABRs of cocaine-positive infants (based on meconium analysis) showed significantly (P < .05) prolonged absolute latencies in both ears as compared with cocaine-negative infants (Table 1). Prolonged interpeak latency was not significantly different in the 2 groups except in 1 infant who was positive for cocaine with left ear at 40 dB III to V (2.667 vs 2.417 milliseconds; P < .05; Table 2). There was no significant correlation between birth weight and the 24 ABR variables except for the absolute latency at 70 dB for peak 1 (P = .04) in the non–cocaine-exposed infants. Because 7 infants who tested negative for cocaine by meconium analysis had a positive maternal history of cocaine use, the data were also analyzed excluding these 7 infants from the cocaine-negative group. The results of comparing ABR differences were essentially similar to those shown in Tables 1 and 2 except for an additional significant increase in latency in the right ear (70 dB) at peak V (6.611 ± 0.407 vs 6.296 ± 0.511; P < .03) in the cocaine-exposed infants. However, the significant increase in interpeak latency in the left ear (40 dB) at waves III to V was not seen. The data were further analyzed including these 7 infants into the cocaine-positive group. Again, the results were essentially similar to those shown in Tables 1 and 2 except for an additional significant increase in latency in the right ear (70 dB) at peak V (6.596 ± 0.491 vs 6.296 ± 0.511; P < .03) in the cocaine-exposed infants. However, neither the increase in absolute latency in the right ear (70 dB) at peak III nor the increase in interpeak latency in the left ear (40 dB) at waves III to V were seen.
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TABLE 1. ABR Absolute Latencies in Cocaine-Exposed (N = 21) Versus Nonexposed (N = 37) Infants as Determined by Meconium Analysis
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TABLE 2. ABR Interpeak Latencies in Cocaine-Exposed (N = 21) Versus Nonexposed (N = 37) Infants as Determined by Meconium Analysis
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Five infants were positive for cannabinoids, but 3 were also positive for cocaine. Because of the small number of infants (n = 2) who were positive only for cannabinoid, it was not possible to observe from this study the effects of exposure to cannabinoid, alone, on the ABR of the infants.
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DISCUSSION
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The measurement of ABR is the best screening method to evaluate the auditory system in the neonatal period. The brainstem potentials reflect stimulus-related electrical activity generated from the auditory nerve and brainstem nuclei. Therefore, a normal ABR is dependent on both an intact peripheral hearing mechanism and an auditory brainstem.
In this study, the ABRs from neonates who were exposed prenatally to cocaine showed significantly prolonged (P < .05) absolute latencies in both ears as compared with nonexposed infants (Table 1). The prolonged absolute peak latencies in most of the potentials reflect an abnormality in the peripheral auditory system (middle ear, cochlea, and auditory nerve). Prolonged interpeak latency was also demonstrated in 1 infant who was positive for cocaine (Table 2). The prolonged interpeak latency reflects delayed or desynchronized transmission of auditory information along the brainstem auditory pathway (cochlear nucleus or higher).
It is possible that prenatal exposure to cocaine may have a direct and indirect effect on the neonatal auditory system resulting in abnormal ABR pattern. Animal studies8–10 have shown that cocaine has a direct toxic effect on the organ of Corti or its embryonic precursor, the otic placode, and can cause damage during certain critical periods of prenatal development, resulting in prolonged absolute latencies. In human studies,11–13 it was shown that cocaine induced an acutely toxic effect on the brainstem auditory neurons, causing impairment in synaptic efficiency and prolongation of the interpeak latencies.14 Conversely, Carzoli et al15 reported no apparent effect of maternal cocaine use during pregnancy on the developing auditory system in otherwise healthy, term infants.
The abnormalities in the fetal auditory system may also be secondary to cocaine effects on the maternal circulation. Cocaine prevents the reuptake of norepinephrine at the nerve endings and results in an excess of circulating catecholamines. The vasoconstrictive effects of cocaine on the uterine vessels can result in placental insufficiency and ischemic/hypoxic injury to the developing brain and the brainstem auditory system, which is particularly sensitive to oxygen deprivation. The damage of the cochlear nuclei, the inferior colliculus, other brainstem nuclei, and the cochlea has been demonstrated in hypoxic-ischemic insults.16
One of the known effects of maternal cocaine abuse is low birth weight or intrauterine growth retardation in the fetus.17,18 Impaired fetal growth and undernutrition can also affect brainstem maturation as a result of delayed myelination and result in abnormal ABR.19 In weanling rats, fetal undernutrition has resulted in prolonged neural conduction velocity caused by disturbed myelin synthesis or fewer oligodendrocytes.20 In this study, there was a significant difference in mean birth weight (2881 vs 3182 g; P < .05) of cocaine-exposed infants compared with nonexposed infants. However, we did not observe a significant correlation between birth weight and ABR latencies.
The multiplicity of factors, described above, on cocaine effect on the auditory system may explain the variations in clinical reports of cocaine effect on the hearing test in newborn infants.11–15 Other factors may also be influential, such as the timing of cocaine exposure during pregnancy, the amount of exposure to cocaine, the effect of other drugs such as opiate or alcohol or other neurotoxicants, and the susceptibility of the sensorineural organs of hearing at various stages of gestation, which, singly or additively, can lead to different cocaine effects on the auditory system.
In previous studies that demonstrated the adverse effects of cocaine exposure on the ABR of the infants, the cocaine exposure in the infants was determined by maternal history and/or urine drug screen.11–13 Because these are not accurate methods of detecting drug exposure, it is likely that some of the cocaine-exposed infants were not detected appropriately and may also explain the variations in observed effects of cocaine exposure on the infants’ ABR in the various studies. Conversely, meconium analysis is a sensitive tool to detect antenatal exposure of infants to illicit drugs, including cocaine.21,22 This is the first study to demonstrate ABR abnormalities in infants who were exposed prenatally to cocaine using meconium analysis for drug detection. Four infants in this study were born to mothers who denied illicit drug use during pregnancy yet they tested positive for cocaine. Conversely, there were 7 infants whose mothers admitted to cocaine use during pregnancy but whose meconium tested negative for cocaine (false negative). This situation may occur when there is inadequate amount of meconium sampled for testing or cocaine use in the mother is limited only to the first trimester of pregnancy.23 Nonetheless, exclusion of these 7 infants with false-negative meconium test from the nonexposed group or their inclusion into the cocaine-positive group still showed ABR abnormalities that were essentially similar to those seen among the groups of cocaine-exposed/nonexposed infants determined only by meconium analysis (Tables 1 and 2). Five infants tested positive for cannabinoids; 3 of them also tested positive for cocaine. Because of the small sample size of the group that was exposed to cannabinoids alone, it was not possible from this study to determine the effects of cannabinoid on the ABR of the infants.
Although meconium testing has a high sensitivity because of the wide window of gestational exposure that it can monitor in the fetus, it also has limitations, particularly because it can detect exposure only after the first trimester of pregnancy. This limitation may partly explain some of the inconsistencies reported on cocaine effect on the central versus peripheral pathways of hearing.
It remains to be determined whether the ABR abnormalities in the infants are transient or permanent, as no follow-up ABR studies were done. However, many of the ABR abnormalities in cocaine-exposed infants are probably not permanent because these abnormalities reflect developmental or maturational problems rather than permanent injury from cocaine. Nonetheless, infants who are born to cocaine-abusing mothers should be considered at high risk for auditory system dysfunction and may need follow-up to determine the persistence and potentially long-term effects of the neonatal ABR abnormalities. The early detection of hearing loss and appropriate intervention may improve the speech, language, and cognitive development in this group of infants.
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CONCLUSION
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The ABR in neonates who are exposed prenatally to cocaine shows prolonged absolute peak latencies compared with nonexposed neonates. Such abnormalities may indicate neurodevelopmental compromise of the auditory system from gestational exposure to cocaine that needs additional audiologic and neurologic follow-up. Meconium analysis can more accurately detect these infants who are at risk.
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FOOTNOTES
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Received for publication Jan 10, 2003; Accepted May 8, 2003.
Reprint requests to (E.M.O.) Department of Pediatrics, Hutzel Hospital, 4707 St Antoine, Detroit, MI 48201. E-mail: eostrea{at}med.wayne.edu
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PEDIATRICS (ISSN 1098-4275). ©2004 by the American Academy of Pediatrics
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ABSTRACT
METHODS
