pediatrics
March 2000, VOLUME105 /ISSUE 3

# Adverse Effects of Fetal Cocaine Exposure on Neonatal Auditory Information Processing

1. Susan M. Potter, PhD*,
2. Philip R. Zelazo, PhD*,
3. Dale M. Stack, PhD, and
4. Apostolos N. Papageorgiou, MD§
1. From the *Department of Psychology and Research Institute, McGill University and Montreal Children's Hospital, Montreal, Canada; the
2. Departments of Psychology (and Centre for Research in Human Development), Concordia University and Montreal Children's Hospital, Montreal, Canada; and the
3. §Departments of Neonatology and Pediatrics, Sir Mortimer B. Davis Jewish General Hospital, Montreal, Canada.

## Abstract

Background. Studies with animals have shown that in utero exposure to cocaine interferes with fetal brain development by disrupting the processes of neuronal proliferation, differentiation, and migration, often leading to subsequent neurobehavioral deficits. However, studies with humans have produced inconsistent findings. Although neurobehavioral abnormalities have been observed among cocaine-exposed infants in several studies and in some cases dose-response effects have been found, the specific neurobehaviors affected vary from one study to the next. Researchers studying the effects of fetal cocaine-exposure are faced with many difficult challenges. For example, women who use cocaine typically use other substances in addition to cocaine, many of the methods available for identifying cocaine-exposed neonates are not reliable, and the available methods for assessing cocaine-exposed newborns may not be sufficiently sensitive to detect the subtle effects of cocaine on the developing central nervous system. Despite these difficulties, there is a growing body of research that suggests that fetal cocaine exposure is associated with subsequent language deficits among children exposed in utero. However, it is virtually impossible to disentangle the effects of the impoverished environments in which these children are often raised from the effect, if any, of fetal cocaine exposure. To determine the effects of fetal cocaine exposure independent of postnatal environmental effects, cocaine-exposed neonates would ideally be tested within the first few weeks of birth, and to identify early risks for subsequent language delay, well-researched auditory information processing measures could be used.

Objective. The purpose of the present study was to assess the effects of fetal cocaine exposure on neonatal auditory information processing ability. To overcome limitations of some previous studies on the neuroteratogenic effects of cocaine, such as unreliable subject identification techniques, inadequate control over confounding variables, and questionable measures of central nervous system integrity, a valid measure of auditory information processing was used in a rigorous, case-control design.

Method. Newborn information processing was assessed using habituation and recovery of head-turning toward an auditory stimulus across the 3 phases of the procedure: familiarization, novelty, and dishabituation. During the familiarization phase, the infant orients and habituates to a repeated word; during the novelty phase, the infant recovers head-turning to a novel word and subsequently habituates to this word; and during the dishabituation phase the infant displays renewed head-turning to the return of the original stimulus. Testing takes ∼20 minutes. This procedure has been shown previously to discriminate among infants at high-, moderate-, and low-risk for subsequent developmental delay. Twenty-five cocaine-exposed and 25 nonexposed control neonates, identified by meconium analysis, urine analysis, and/or maternal self-report, were tested on the auditory information processing procedure. The majority of infants were tested within the first few days of birth. Cocaine-exposed and control neonates were matched on birth weight, gestational age, Apgar scores, age at testing, and socioeconomic status as reflected by household income. Mothers were matched on age, weight gain, cigarette smoking, and alcohol consumption.

Results. Fetal cocaine exposure was associated with impaired auditory information processing. Both cocaine-exposed and nonexposed control neonates oriented to the familiarization stimulus, but cocaine-exposed neonates displayed impaired habituation. Moreover, cocaine-exposed neonates did not recover or habituate to the novel stimulus or dishabituate to the return of the familiarization stimulus. Whereas nonexposed, control infants exhibited high levels of turning away from the familiarization stimulus during habituation (implying boredom), followed by high levels of turning toward the novel stimulus, indicating recovery of attention, the cocaine-exposed infants turned randomly. Clearly, auditory information processing of cocaine-exposed infants was impaired, despite the fact that they exhibited the same overall number of head-turns and the same high level of positive state as the nonexposed infants.

Conclusions. The results imply that cocaine is a neuroteratogenic agent that impairs auditory information processing ability during the newborn period. Cocaine-exposed neonates exhibited a response pattern that is consistent with slower speed of auditory information processing. These deficits were observed within the first few days of birth, before adverse postnatal environmental influences could exert their effect. Moreover, the case-control design increased the probability that the observed information processing deficits were due primarily to the direct effects of fetal exposure to cocaine and not other prenatal factors. However, the long-term implications of these findings for the development of the infant/child are not known and must be addressed in follow-up studies.

• cocaine
• neonate
• information processing
• habituation
• novelty responsiveness
• Abbreviations:
CNS =
central nervous system
NBAS =
Neonatal Behavioral Assessment Scale
BW =
birth weight
GA =
gestational age
FTII =
Fagan Test of Infant Intelligence
SES =
socioeconomic status as reflected by household income
WG =
mother's pregnancy weight gain
CARE =
extent of prenatal care
BE =
benzoylecgonine
• The number of pregnancies complicated by maternal use of cocaine increased dramatically during the 1980s and early 1990s.1 Although estimates of the number of newborns exposed to cocaine prenatally in the United States vary widely depending on the geographical region sampled and the screening methods used, prevalence rates range from ∼1% in suburban and rural areas2 ,3 to >30% in some urban areas,4 with a nationwide average in the order of 10%. Canadian prevalence rates are similar, with 3% of neonates testing positive for prenatal cocaine exposure in suburban Toronto and 12.5% in urban Toronto.5Cocaine can penetrate the placenta and accumulate in the fetal brain at concentrations up to 4 times greater than those observed in plasma.6 Furthermore, prenatal cocaine-exposure has been shown by animal studies to disrupt fetal central nervous system (CNS) development by interfering with the processes of neuronal proliferation, migration, and differentiation.7–9 Fetal cocaine-exposure also leads to significant alterations in brain activity among laboratory animals10 ,11 and there is an emerging consensus among some researchers that fetal cocaine exposure in humans may lead to subtle but significant deficits in children, particularly with behaviors necessary for academic success.12 However, the effects of fetal cocaine-exposure on the development of the CNS in human infants are not clear and many studies to date have been subject to a variety of methodologic limitations.

In early studies using the Neonatal Behavioral Assessment Scale (NBAS),13 cocaine-exposed infants exhibited a variety of neurobehavioral impairments relative to control infants. However, the specific NBAS cluster scores affected differed across studies. This lack of consistency in results may be related to differences among studies in the control over confounding factors,14 ,15 with some studies not controlling for factors such as birth weight (BW) and gestational age (GA),16 ,17 neurologic insults,16–18 and obstetric complications.16Maternal cigarette smoking was also often not considered in the research design or data analysis of studies assessing the risks of fetal cocaine exposure.19 ,20 Impairments on the NBAS may be more likely among infants whose mothers smoked cigarettes during pregnancy.21–24 The results of more recent and better-controlled studies have yielded inconsistent results with some studies finding adverse effects of fetal cocaine exposure on some NBAS scores during the first month of life25–33 and others reporting no adverse effects.34–36 The most common findings on the NBAS were cocaine-associated disturbances on measures assessing state regulation.16–18 25–30 ,32 ,33

The NBAS may not be sufficiently sensitive to detect subtle cognitive disturbances which may be associated with abnormal development of the CNS among cocaine-exposed neonates. The NBAS includes measures of orientation and habituation to an initial stimulus, but Zelazo and colleagues37 demonstrated that it is response to change, ie, recovery of responding and habituation to novelty after habituation to an initial stimulus, that has the greatest sensitivity and validity for identifying neonates at risk for subsequent developmental delays. The NBAS does not measure response to change. A large series of carefully controlled studies using the auditory information processing procedure developed by Zelazo and colleagues38–43 has demonstrated that newborn infants orient and habituate to an auditory stimulus and recover responding to novelty with little variability across studies. Habituation and recovery to novelty in infancy correlate with measures of intellectual competence in childhood, suggesting that these measures assess infant central processing44 ,45 (see “Reference 45” for direct experimental tests of competing interpretations). Delayed mental ability results in decreased speed of processing on measures of infant information processing.37 ,46 If cocaine interferes with normal CNS development, decreased speed of processing may be evident on measures of habituation and recovery during the neonatal period.

Existing studies assessing the effects of fetal cocaine-exposure on information processing ability in infancy have used visual stimuli and yielded inconclusive results.47–50 Mayes and colleagues47 reported that although cocaine-exposed infants were more likely to fail to begin a visual habituation and novelty responsiveness task, those that completed the task did not differ from controls on habituation or response to novelty. Struthers and Hansen48 used the Fagan Test of Infant Intelligence (FTII) to study the effects of prenatal cocaine exposure on infant visual information processing. Overall, FTII scores were significantly lower among the drug-exposed infants relative to controls, with 17 of the 36 drug-exposed infants scoring in the at-risk range compared with only 3 of the 26 controls. However, only 47% of the drug-exposed sample were exposed to cocaine and not amphetamines, a number of the mothers had also used significant quantities of alcohol, marijuana, and opiates, and cigarette use was not documented. In one well-controlled, longitudinal study, Jacobson and colleagues49 found that heavy cocaine use early in pregnancy was related to poorer recognition memory and visual information processing as measured by the FTII. Alessandri and colleagues,50 however, failed to find deficits in novelty responsiveness or information processing in their study of 8-month-old cocaine-exposed infants. At present, there are no studies of which we are aware that have assessed information processing during the early neonatal period and none in which auditory stimuli were used.

Several studies have reported language impairments51–58and attentional problems59 on follow-up assessments of children exposed to cocaine in-utero, supporting the notion that cocaine may adversely affect the development of higher cortical processes. A recent meta-analysis revealed that cocaine has a significant detrimental effect on the receptive and expressive language abilities of children exposed prenatally, as well as a small but significant adverse effect on IQ.60 However, studies on the effects of prenatal cocaine exposure on subsequent language development of the child are often subject to methodologic problems such as lack of control groups, retrospective designs, small sample sizes, maternal polydrug use, nonblind examiners, and lack of control over confounding factors. For this reason, the results of such studies should be interpreted with caution. Because maternal cocaine use is generally associated with a host of other biological and environmental risk factors for disturbances in children's cognitive development, such as multiple substance use, lack of prenatal care, poverty, and child neglect, it is difficult to isolate prenatal cocaine exposure as the singular cause of impaired language development. Nevertheless, there is a growing body of data51–58 to suggest that prenatal cocaine-exposure may be associated with disturbances in language development.

If fetal cocaine exposure is associated with impaired language development, it may be more appropriate to assess auditory rather than visual information processing in early infancy to evaluate possible intrauterine influences. The relative contributions of intrauterine cocaine exposure and postnatal environment to later cognitive development are virtually impossible to disentangle retrospectively. However, if language impairments are a result of disturbances in fetal brain development among children exposed to cocaine in utero, then such disturbances may be detectable at birth using tests of auditory information processing.

In the present study, the information processing procedure developed by Zelazo and colleagues37–43 ,45 was used to assess newborn central processing of auditory stimuli. It was hypothesized that cocaine exposure in utero can alter neurologic development and this may be detected at birth by abnormal auditory information processing. Specifically, it was hypothesized that cocaine-exposed neonates would be less likely than nonexposed neonates to respond to stimulus change after habituation to a previously presented stimulus.

## METHODS

The procedures followed in this study were in accordance with the ethical standards of the Canadian and American Psychological Associations, and were approved by the institutional review boards of the Sir Mortimer B. Davis Jewish General Hospital, Montreal Children's Hospital, and McGill University. Mothers on the postpartum ward were approached about participating in the study and the nature of the study was explained in detail, including the fact that if they admitted to using cocaine or if cocaine was detected by biological assay that we would be required to report this to Social Services. All cocaine users who agreed to participate were already known to Social Services and were being followed by a social worker at the time of delivery. Signed informed consent forms were obtained from each mother before testing her infant. Each mother was aware that she was free to withdraw from the study at any time and that this would in no way affect her care at the hospital or her treatment by Social Services, and that, with the exception that drug use must be reported, all data obtained in the course of the study would be kept confidential.

### Participants

Twenty-five cocaine-exposed and 25 nonexposed control neonates, matched in a case-controlled design, were tested on an auditory information processing procedure. Neonates with brain hemorrhages or any other clear neurologic insults (such as hydrocephalus, spina bifida, seizures) were excluded and all infants had 5-minute Apgar scores of 7 or greater. Preterm infants were not excluded but cocaine-exposed and control infants were matched on GA and BW. Prenatal exposure to cocaine was determined by maternal self-report obtained through a questionnaire about drug use during pregnancy completed by the mother after the delivery of her infant (n = 21 positive self-reports), meconium analysis (n = 8 positive samples), and/or 1 cocaine-positive urine sample from the infant (n = 16 positive samples). Because urine analysis can detect only recent cocaine use (within a few days) and self-reports of no drug use may be unreliable, it was important that all control infants had negative meconium analysis results to increase the likelihood that cocaine-exposed infants were not inadvertently included in the control group. Because positive urine tests for cocaine and/or maternal self-reports of cocaine use were deemed to be reliable indicators of prenatal cocaine use, where 1 of these indicated cocaine use, a lack of meconium analysis results was not considered problematic.

### Implications

Clearly, fetal exposure to cocaine may have negative implications for the cognitive abilities of infants, particularly auditory information processing and receptive and expressive language development. However, the findings of the present study are limited to the newborn period, and it is possible that the auditory information processing deficits are transient. The infant brain demonstrates remarkable plasticity and once free from exposure to cocaine, recovery of function may occur. It is also possible that the auditory processing deficits are a more permanent reflection of CNS impairment that occurred in utero. Well-controlled, long-term follow-up studies are warranted to determine if performance on the auditory information processing procedure is predictive of later cognitive competence, particularly language abilities.

## ACKNOWLEDGMENTS

The research was supported in part by grants from the Stairs Fund, Department of Psychology, McGill University and the Levinschi Foundation to P. R. Zelazo; Medical Research Council of Canada studentship, and Natural Sciences and Engineering Research Council of Canada grant to S. M. Potter.

We thank the nursing staff of the SMBD Jewish General and St. Mary's hospitals, along with Froma Schulman, Grace Valiante, Marthe Bonin, Caroline Reid, and Peta Leclerc for their assistance with this project, and the parents and infants in the Montreal community who gave their time. Special thanks to Doug Lewis of the United States Drug Testing Laboratories for his advice and kind contribution towards the meconium analysis.