Abstract
Objective. Little is known about the neurophysiologic effects of prenatal cocaine/crack use. The aim of this study, designed to overcome methodologic limitations of previous research, was to investigate the effects of prenatal cocaine use on electroencephalographic (EEG) sleep patterns, a marker of central nervous system development.
Methods. In a longitudinal study of prenatal cocaine/crack exposure, women were interviewed at the end of each trimester about cocaine, crack, alcohol, tobacco, marijuana, and other drug use. Two-hour paper- and computer-generated EEG sleep recordings were obtained on a sample of the full-term infants on the second day of life and at 1 year postpartum. Eligible newborns were full-term, had received no general anesthesia, and had a 5-minute Apgar score >5. All infants whose mothers used one or more lines of cocaine during their first trimester or any crack (n = 37) were selected. A comparison group was chosen randomly from the group of women who did not use cocaine or crack during their pregnancy (n = 34).
Results. Women who used cocaine/crack during the first trimester were older, less educated, less likely to be working, and used more tobacco, alcohol, marijuana, and other illicit drugs than women who did not use cocaine/crack during the first trimester. There were no differences in infant birth weight, length, head circumference, or gestational age between the two exposure groups. After controlling for the significant covariates, prenatal cocaine exposure was associated with less well developed spectral correlations between homologous brain regions at birth, and with lower spectral EEG power values at 1 year of age. Prenatal alcohol, marijuana, and tobacco use were found to affect state regulation and cortical activities.
Conclusions. These results indicate that the neurotoxic effects of prenatal cocaine/crack use can be detected with quantitative EEG measures.
- CNS =
- central nervous system •
- EEG =
- electroencephalographic •
- qEEG =
- quantitative electroencephalography •
- EMG =
- electromyogram •
- REM =
- rapid eye movement
The development of the central nervous system (CNS) in the fetus exposed to a potential neurotoxin is an important concern. Electroencephalographic (EEG) sleep patterns can be used to assess cerebral maturation and neurophysiologic organization of the developing CNS.1 This is of particular interest because some studies have reported that gestational cocaine exposure affects the development of the CNS. For example, a number of authors have reported that cocaine exposure results in decreased head circumference at birth.2–5 A case report has suggested that prenatal cocaine exposure affects fetal behavioral state, which reflects brain organization.6 Research protocols have found that prenatal cocaine exposure is associated with changes on the Brazelton Neonatal Behavioral Assessment Scale.7–11 In our own research, we have reported that prenatal cocaine exposure affects reflexes, motor maturity, and autonomic stability in the newborn.12
Neurophysiologic measures also suggest that the development of the CNS may be affected by prenatal cocaine exposure. In case reports, exposure has been associated with neonatal seizures,13 EEG background disturbances,14 and evoked response abnormalities.15 Legido et al16 compared polydrug-exposed infants to a comparison group of siblings of victims of sudden infant death syndrome whose mothers did not use drugs during pregnancy. EEGs conducted at an average age of 4 weeks (range, 1–9 weeks) showed that the exposed infants had an earlier age of onset of slow wave sleep, a sign of accelerated brain maturity. The groups did not differ in the number of EEG abnormalities. In pneumocardiographic studies, polydrug-exposed infants had more total awake time, less total sleep time, and more arousals during active sleep than did nonexposed infants.17 There were no differences in quiet sleep or active sleep. DiPietro et al18 used the Brazelton Neonatal Behavioral Assessment Scale to define the state of the infant. Newborns exposed to cocaine prenatally spent less time asleep and more time in a drowsy state compared with infants who were not exposed during gestation.
These reports of neurophysiologic differences attributable to prenatal cocaine exposure must be interpreted with caution because none controlled for the covariates of substance use. Research has demonstrated that women who use drugs during pregnancy, whether cocaine, crack, alcohol, or other illicit drugs, differ significantly from women who do not. Cocaine/crack use in pregnant women is associated with the use of other substances such as tobacco, alcohol, marijuana, and other illicit drugs, as well as with poor nutrition, inadequate prenatal care, and an unstable lifestyle with few social supports.19 These differences are, in themselves, risk factors for poorer pregnancy outcomes. Previous research has shown that prenatal alcohol, marijuana, and tobacco affect neurophysiologic development.20–26 Therefore, it is important to assess the effects of prenatal cocaine use in studies that have a comparison group to allow for stronger causal inferences, and that can statistically adjust for other behaviors associated with substance use and for other factors which affect the outcome.
One study that did control for other correlates of use compared infants exposed predominantly to crack and infants who were not exposed during gestation on a polygraph at 2 weeks of age.27 After controlling for the covariates of cocaine use, prenatal cocaine exposure was associated with decreased active sleep and increased indeterminate sleep. There was no effect on quiet sleep. Additional studies are needed to identify more clearly the relationship between neurophysiologic development and cocaine/crack exposure during gestation.
The present report is from an ongoing prospective study of prenatal substance use. The outcome is the development of the CNS, assessed by EEG/polysomnographic (EEG sleep) studies at birth and at 1 year postpartum. The EEG has been a useful instrument in the assessment of trends in functional brain maturation. Studies of EEG development traditionally include descriptions of changes in frequency and power with age, with reliance on pattern recognition of analog recordings. More recently, with the advent of computerization, quantitative EEG (qEEG) analyses are being used to more precisely characterize changes in frequency and power. Power characterizes cerebral activity as a reflection of neuronal aggregates in a specific region of the brain. Similar spectral measures compare cerebral activity across different areas of the brain (ie, coherence).28–30
The study was composed of a sample of women who attended an urban prenatal clinic. They represented a general population sample rather than a sample of women in drug treatment, or of infants with neurologic problems. Women were interviewed at set times during pregnancy to reduce recall bias. Cocaine and crack use were assessed during each trimester of pregnancy. Data were collected on demographic factors, medical history, lifestyle and environment of the mothers, allowing for the identification of and statistical adjustment for confounding variables.
METHODS
Study Design
The cohort from which this subsample was selected was a sample of women and infants who were participating in a longitudinal investigation of the effects of prenatal cocaine/crack use. Women were recruited for the study between March 1988 and December 1992. In the larger cohort, women who were at least 18 years of age were initially interviewed when they came for prenatal care during their 4th or 5th prenatal month. Ninety percent of those approached agreed to participate. Medical chart reviews of a random sample of women who refused to participate indicated that only 5% had a history of drug use during the current pregnancy.
Written consent was obtained for both mothers and infants according to guidelines established by the University of Pittsburgh's Institutional Review Board for Biomedical Research and by the Research Review and Human Experimentation Committee of Magee-Womens Hospital. A Confidentiality Certificate, obtained from the Department of Health and Human Services, assured participants that their responses could not be subpoenaed.
During the initial interview, information was obtained about the use of cocaine and crack in the year before pregnancy and during the first trimester, as well as the use of tobacco, alcohol, marijuana, and other illicit substances during the same time periods. All women who reported any cocaine or crack use during the first trimester were enrolled in the longitudinal study. The next woman interviewed who reported no cocaine or crack use during the year before pregnancy and during the first trimester was also enrolled. Of the women initially interviewed, 325 (18%) met the inclusion criteria and were enrolled into the study.
Women selected into the study were interviewed at 7 months about their substance use during the second trimester. At 24 hours after delivery, they were asked about third trimester substance use. Demographic, environmental, lifestyle, and psychologic characteristics were assessed at each phase.
Information regarding pregnancy, labor, and delivery conditions was abstracted from the medical charts by study nurses after the physical examination of the newborn was completed. Pregnancy, labor, and delivery conditions were classified using common obstetrical complication schemes as guidelines.31–33 For example: pregnancy conditions included anemia, maternal infections, hypertension, and abnormal bleeding during pregnancy; labor conditions included precipitous labor, induction, pitocin augmentation, and premature labor; and delivery conditions included anesthesia, meconium stained fluid, nuchal cord, cesarean section, and forceps delivery.
All infants underwent comprehensive physical examination, generally within 24 to 48 hours of delivery, by study nurse clinicians who were unaware of prenatal exposure status. The infants' length, head, and chest circumference were measured. Gestational age, as measured by a modification of the Dubowitz assessment,34 was also assessed. Birth weight and Apgar scores were transcribed from the medical records.
At 1 year postpartum, the mothers were interviewed about their current substance use, demographic, psychologic, and lifestyle characteristics. Infants received a physical examination and were assessed with the Bayley Scales of Infant Development.35
Study Participants
A subsample of women was selected from the larger study to participate in the EEG sleep substudy. All women who used one or more lines per day of powder cocaine during the first trimester and all women who used crack during the first trimester were selected for the substudy (n = 37). A sample of women who did not use cocaine or crack at any time during pregnancy was also selected as a comparison group (n = 34). Infants were eligible for the neonatal EEG sleep study if they met the following criteria: 38 to 42 weeks gestation; no general anesthesia; and a 5-minute Apgar score >5. These criteria resulted in a sample of 71 newborns who received EEG sleep studies 24 to 36 hours after birth. There were no HIV-positive mothers or infants in this sample.
In the EEG sleep subsample, 45% of the infants were male. The average gestational age was 40.3 weeks and mean Apgar scores were 7.8 and 9.0 at 1 and 5 minutes, respectively. The mean birth weight was 3272 g (range, 2230–4240 g), the mean length was 50 centimeters (range, 44–55 cm), and the mean head circumference was 34 cm (range, 32–39 cm). Eight infants were delivered by cesarean section.
The mothers of the selected infants were, on average, 26 years old (range, 18–41 years), 39% were white, and 61% were African-American. Women were of lower socioeconomic status, with a mean family income of $657 per month (range, $182-$2800) and an average educational level of 12 years (range, 9–16 years). Fourteen percent were married at initial enrollment and 46% worked and/or went to school during the first trimester. During the first trimester, 52% of the 71 women used cocaine/crack. During the second and third trimesters, 14% and 23% used cocaine/crack, respectively. All of the women who were using cocaine/crack during the second and third trimesters also used these drugs during the first trimester. That is, no one started using during the second or third trimester. The majority of use was crack rather than the powdered form of cocaine. Of the women who used cocaine and/or crack, 67%, 80%, and 88% used crack during the first, second, and third trimesters, respectively. The rest of the users were powder cocaine users.
At 1 year postpartum, 57 infants returned for EEG sleep studies, representing 80% of the EEG sleep sample seen at birth. The average age at the 1-year follow-up was 14 months (range, 12–21 months). There were no differences in demographic characteristics or prenatal substance use between the women who did and did not return for the 1-year sleep study.
Substance Use Measurement
For each substance, women were asked about the usual, maximum, and minimum quantity and frequency of use. In addition, we used a technique we have developed to enhance the accuracy of reporting first trimester substance use.36 Women usually do not change their substance use patterns until after they have confirmed their pregnancy, which often does not occur until late in the first trimester. We asked women about their substance use during the time periods from conception to recognition, and from recognition to the diagnosis of the pregnancy to get a more accurate measure of first trimester use. We also asked whether their use during these time periods was more like what they had reported for before pregnancy use or more like their reported first trimester use. This allowed calculation of substance use during each month of the first trimester and a weighted estimate of the average daily use for the first trimester. For second and third trimester use, women reported use for the entire trimester.
Interviewing was the method of choice to collect detailed information regarding the timing and pattern of cocaine/crack use, especially during the first trimester. The most commonly used test, urine screening, reflects use only during a short period of time.37 ,38 In addition, laboratory measures cannot give an estimate of the pattern of use, information which is critical in evaluating the effect of a potential neurotoxin. We did, however, have access to medical record data for the women who were screened for clinical purposes. In fact, 100% of the women who had a positive urine screen for cocaine when tested by the hospital were identified by our study interview as users. By contrast, 49% of the women who told us they used cocaine/crack, and who were screened, had a negative screen. Thus, our interview detected more cocaine/crack use than did the toxicology screen, demonstrating that drug use information can be reliably obtained when interviews are well-constructed and interviewers are carefully selected and trained.
Procedures for Recording and Scoring Infant EEG Sleep
A 2-hour EEG sleep recording was obtained 24 to 36 hours postpartum and repeated at 1 year of age. Neonatal recordings were obtained on swaddled infants who were placed in a prone position ∼1 hour after a morning feeding. Newborn male infants were studied before circumcision. All 1-year-old infants were fed and changed before the study. EEG sleep recordings were conducted in a quiet, environmentally-controlled room designated for neonatal and infant sleep studies.
Neonatal and infant sleep EEGs were recorded using a Nihon Kohden (Palo Alto, CA), Model 4200, 21-channel polygraph. Sixteen channels were designated for EEG monitoring. Five channels recorded additional physiologic measures; 1 channel recorded submental electromyogram (EMG), 2 channels monitored eye movement activity, right and left eye outer canthi, offset slightly above and below the eye to optimize visualization of both horizontal and vertical eye movements. The remaining 2 channels recorded cardiorespiratory measures (cardiopneumograph). Electrode placement for the recordings followed the standard international 10/20 system, with modifications as recommended for neonates.39 All recordings were obtained at a paper speed of 15 mm/s and low linear filter settings of 0.3 Hz (EEG), 0.03 Hz (electrocardiogram and eye movements), and 0.1 Hz (EMG). EEG sensitivity was 7 μ/mm at the beginning of the recording and was adjusted as necessary. Throughout the recording period, behavioral observations were noted on the recording paper by the EEG technologist. Observations included eyes open, eyes closed, eye movements, body movements, jerks and twitches with indication of body parts involved, startle, sucking movements, vocalizations, and respiratory irregularities such as sighs and pauses in the infant who seemed quiet. Environmental noises were noted to differentiate evoked from spontaneous arousals.
The EEG sleep recordings were scored independently by an electroencephalographer who was not aware of the exposure status of these infants. Recordings were scored for EEG state, rapid eye movements (REMs), arousals, and body movements using 1-minute scoring epochs. Scoring was based on operational definitions using representative neonatal EEG samples of each of the above areas. Standardized definitions for awake, active, and quiet sleep states in the neonate20 and REM, non rapid eye movement, and wake states in the 1-year-olds were used.40 Additional sleep behaviors, including indeterminate or transitional sleep, arousals, and phasic REM activity, sleep efficiency, maintenance, and cycle length, were also included.41
The data from each 2-hour sleep study were digitized to analyze spectral physiologic measures during a visually identified epoch of an EEG sleep state, or throughout the entire recording. For this assessment, recordings were from 11 cerebral electrodes that yielded 14 channels of EEG activity. Data were sampled at 80 samples/s. For statistical analysis, mean values for the 6 spectral EEG measures were computed for each minute of EEG sleep state and throughout the entire recording. These included total EEG (0.5–22 Hz), EMG (0.5–32 Hz), δ band frequencies (0.5–3 Hz), θ band (4–8 Hz), α band (8–13 Hz), and β frequency band (14–22 Hz).
Mathematically, the digitized data were analyzed using a Kaiser window function, and the time series were transformed into the frequency domain using a fast fourier transform program algorithm.42 The values computed for each frequency band were squared and stored as individual data points. Average spectral energies for each minute of recording were computed by averaging the spectra across the 14 channels for each frequency band. A summary of the spectral energies for the entire EEG recording was computed by averaging the minute by minute values for each frequency throughout the entire recording time.
Spectral correlations were computed between pairs of EEG channels.42 All possible pairs of the 14 channels of EEG were investigated, resulting in a total of 91 pairs which were averaged for the entire recording period. These numbers were then summarized into interhemispheric and sagittal measures by regions.
Statistical Analyses
Definition of Variables Describing Cocaine/Crack Use
Cocaine/crack use was expressed as the average daily grams of cocaine/crack for the first trimester. A dichotomous variable (use/no use) was also defined to describe use for each of the 3 trimesters. Average daily use of cocaine/crack was not used as a continuous variable for the second and third trimesters because the number of users in these trimesters was small (10 and 16, respectively).
Definition of Variables Describing EEG Sleep
It was necessary because of the small sample size and the large number of EEG sleep measures to reduce the outcomes in the analyses to a smaller number. In the absence of a body of literature, we selected this first list of potential outcomes based on the experience we have had with other teratogens and with the clinical EEG. These measures, shown in Table 4, have been associated with other neurotoxic exposures, including alcohol, tobacco, and marijuana, in previous research by our group.20 In addition, these measures have been shown to be associated with immaturity in the development of the CNS of the fetus on EEG sleep studies on normal and premature newborns.41 ,42 These reductions in the number of outcomes allowed the analyses to estimate type I error more accurately and reduced the problems associated with multiple comparisons. With a sample size of 71, an α level of 0.05, and a medium effect size, the power to detect an effect was 0.84.
Regression Analyses for Outcomes at Birth*
Sleep states coded from the visual analysis included the assessment of awake time, active, quiet, and indeterminate sleep.41These were expressed as the percent of time the infant spent in each state during the 2-hour sleep recording. REMs were defined as the average number of occurrences per minute. Body movements and arousals were defined as the average number of occurrences per minute for active and quiet sleep separately. Cycle length was defined as the number of minutes from the beginning of the first segment of quiet sleep until the beginning of the next quiet sleep segment.
Spectral δ, θ, α, and β energies were defined as the averaged energies within each band throughout the entire recording. Spectral correlations were the comparisons of quantitative EEG measures between pairs of EEG channels (ie, T3C3/C4T4; FP1C3/FP2C4) for each minute and then averaged across the total recording.
Data Analysis and Hypothesis Testing
As a first step, the distributions of all independent and dependent variables were examined using scatter plots and descriptive statistics. Outliers were identified and examined. Transformations were used when a distribution was determined to be not normal. If normality could not be achieved through transformations, nonparametric tests were used.
Characteristics that differentiated users and nonusers of cocaine/crack were identified using bivariate analyses, including Student'st test, χ2, or Mann-Whitney rank sum test, based on whether the comparisons were of continuous, categorical, or nonparametric data, respectively. Data reduction was done by examining the correlations between variables.
Stepwise regression was used to explore the relationship between cocaine/crack use at each trimester and the EEG sleep outcome measures. Analyses were done for the first trimester using cocaine/crack both as a continuous and a dichotomous variable. For second and third trimester, use was dichotomized as use/no use.
Before selection of the final model, the distribution of the residuals was examined for normality and variables in the model were checked for multicollinearity. Influential points were identified using Cook's distance measure.43 Two influential points were identified for the analysis of the birth data and were excluded from the birth regressions. Two different points were identified and excluded from the analyses of the 1-year data.
In a second analysis, we assessed the effects of patterns of use across pregnancy. Three groups were defined: 1) abstainers: women who did not use cocaine/crack in the first trimester and did not use in the third trimester; 2) discontinued: women who used cocaine/crack in the first trimester, but did not use in the third trimester, and 3) continued: women who used cocaine/crack in both the first and third trimesters. An analysis of covariance was used to compare these groups. The group means were adjusted for the variables that were significant predictors of the specific outcome in the regression analyses.
RESULTS
Descriptive Analyses
As shown in Table 1, women who used cocaine/crack during the first trimester were significantly older, less educated, and less likely to be working or going to school than were the women who did not use first trimester. First trimester users had significantly higher gravidity and more pregnancy conditions compared with first trimester nonusers. There were no significant differences in race, marital status, family income, parity, weight gain during pregnancy, number of prenatal visits, adequacy of prenatal care,44 or labor or delivery conditions between the groups. Women who used cocaine/crack during the first trimester reported using significantly more tobacco, alcohol, and marijuana during the first trimester than did the first trimester nonusers. There were also significant differences between the groups in the use of other illicit drugs, such as amphetamines and barbiturates, during the first trimester.
Maternal Characteristics Associated With First Trimester Cocaine/Crack Use
Women who used cocaine/crack during the third trimester were less likely to be white, had less education, lower family incomes, were less likely to be married, and had more pregnancies than women who did not use cocaine in the third trimester (Table 2). Third trimester users had significantly fewer prenatal visits and more pregnancy conditions than women who did not use cocaine/crack in the third trimester. There were no significant differences in age, work/school status, parity, weight gain during pregnancy, adequacy of prenatal care, or labor or delivery conditions between the groups. Women who used cocaine/crack third trimester also used more tobacco, alcohol, and other illicit drugs during the third trimester than women who did not use cocaine/crack third trimester. There was no significant difference in third trimester marijuana use between the groups.
Maternal Characteristics Associated With Third Trimester Cocaine/Crack Use
In this sample of full-term infants, offspring of mothers who were cocaine/crack users during the first trimester did not differ from infants of women who were not first trimester users on gestational age, birth weight, length, head circumference, percent low birth weight (<2500 g), or percent small-for-gestational-age, defined as birth weight less than 10th percentile for gestational age (Table 3). There were also no differences between the groups in 1-year growth parameters. There were no differences in the birth or 1-year outcomes between offspring of women who used cocaine/crack during the third trimester and those who did not use third trimester.
Infant Characteristics Associated With First Trimester Cocaine/Crack Use
There were no recorded episodes of apnea during the neonatal period. No electrographic seizures, with or without coincident clinical seizure behaviors, were noted at either age. No differences between the groups were observed in excessive sharp-wave transients, electrographic background abnormalities, or dysmaturity of EEG sleep patterns. No child had electrographic or polysomnographic evidence of state discordance by visual inspection.
Multivariate Analyses
After examining the pairwise correlations between sociodemographic characteristics and maternal substance use with the outcomes, the following variables were selected as covariates in the stepwise regression model. For the analysis of the birth data, gender, race, gestational age, income, and prenatal alcohol, marijuana, cigarette, and other illicit drug use were entered into the regression model. For the outcomes at 1 year, gender, race, infant's age, mother's age, number of infant hospitalizations, and the prenatal substance use variables were selected. A stepwise regression procedure was used to investigate the effects of maternal cocaine/crack use at each trimester adjusted for sociodemographic covariates and for maternal alcohol, marijuana, and cigarette use. Significance was defined as P< .05 (2-tailed).
At birth, first and third trimester cocaine/crack use both predicted decreased spectral correlations between homologous areas of the brain. Second trimester cocaine/crack use predicted a reduction in spectral δ energies (Table 4). None of the other outcome variables was significantly associated with cocaine/crack exposure during gestation. At 1 year of age, third trimester cocaine/crack use predicted a reduction in spectral δ and θ energies (Table 5).
Regression Analysis for Outcomes at 1 Year*
Effects of other prenatal substance use were also found. At birth, prenatal tobacco exposure significantly predicted decreased active sleep, quiet sleep, and REM, and increased indeterminate sleep, body movements during active and quiet sleep, and arousals during quiet sleep. At 1 year, prenatal tobacco exposure significantly predicted increased indeterminate sleep and arousals during active sleep.
At birth, prenatal alcohol use was a significant predictor of increased time awake, body movements during active and quiet sleep, cycle length, and θ, α, and β energies. At 1 year, prenatal alcohol use was associated with decreased indeterminate sleep and δ energies and with increased REM and spectral correlations. At birth, prenatal marijuana use significantly predicted increased θ energies and spectral correlations and decreased α energies. Prenatal marijuana use significantly predicted increased arousals during active sleep and decreased β energies at 1 year of age.
Group Analyses
To reduce the likelihood of type I error, this analysis was limited to those outcomes for which cocaine use was a significant predictor in the regression analysis. Analysis of covariance was used to assess the effect of the pattern of cocaine/crack use throughout pregnancy. The three groups, previously defined in the data analysis section, were the abstainers, discontinuers, and continuers. Outcomes were the spectral correlations and δ energies at birth and δ and θ energies at 1 year. The means were adjusted for the covariates that were significant in the regression analyses (Table 6). There was a significant difference in θ energies across the groups, with offspring of women who used cocaine/crack throughout pregnancy having the lowest θ energies at 1 year. However, it is not possible to determine from this pattern whether first trimester use or continuous exposure is more critical in causing the decrease. There were nonsignificant trends toward greater effects on the remaining outcome measures among the offspring of women who used cocaine/crack throughout pregnancy.
Group Analyses for Significant Regression Findings*
DISCUSSION
In this longitudinal study of prenatal cocaine exposure, qEEG measures were obtained at birth and 1 year of age. This is a unique cohort of children whose mothers were identified through a prenatal clinic at an obstetrical hospital, rather than a specialty clinic or program in which maternal drug abuse was being treated. Quantity, frequency, and pattern of substance use were obtained at three defined time points during pregnancy.
Infants with prenatal cocaine exposure displayed less well developed spectral correlations between homologous brain regions at birth, and lower spectral EEG power values in the lower frequency ranges at 1 year of age. These effects of prenatal cocaine exposure were significant after controlling for the covariates of cocaine use.
It is difficult to compare these results to those of other researchers because most of the previous studies did not control for the covariates of cocaine use.13–18 One study that did control for extraneous variables found prenatal cocaine use to be associated with decreased active sleep and increased indeterminate sleep.27 The absence of significant effects in our study on visually-analyzed sleep measures may reflect differences in sample characteristics, levels of drug exposure, and age at assessment between the two studies. However, the absence of visually-observed EEG abnormalities does not exclude the possibility that differences might be detected on qEEG measures.
Studies of qEEG power and coherence can document developmental trends in functional brain maturation. Such qEEG studies provide evidence for multiple stages of cerebral maturation on both a bihemispheric, hemispheric, and regional basis. Neuroanatomic studies, such as cross-sectional studies of skull size, cortical thickness and volume, and nerve cell densities, provide further evidence that brain maturation may have a regional specificity as well as areas of peaks and plateaus with respect to neuronal maturation.30 ,45 ,46Changes in the spectral power of the EEG may also reflect differences in the mass organization and excitability of particular groups of neurons.47 Changes in the spectral power in particular regions, such as the frontal lobes, across maturation may reflect reorganization of the brain in that region. Coherence has been related to the density of white matter axons in the short- and long-fiber networks of these axons. The strength and number of these axonal connections are reflected by coherence values.47 Coherence of the EEG recorded from electrode sites at different locations may reflect the degree to which the axons connect between these regions.
Our results demonstrate that there are effects of cocaine/crack exposure on qEEG at birth and at 1 year of age. The findings of lower spectral correlations suggest that infants exposed to cocaine possess fewer interhemispheric neuronal connections at birth. This may indicate fewer connections in utero or a delay in cortico-cortical interconnections. At 1 year of age, infants exposed prenatally to cocaine have fewer neuronal aggregates reflected as lower spectral power during sleep. Cocaine-exposed and nonexposed infants did not differ on the characteristics measured by visual polysomnographic measures, such as sleep architecture, continuity, and phasic measures (ie, active, quiet, and indeterminate sleep percentages, arousals, movements, and REMs). Thus, the effect of cocaine seems to be specific to the expression of interhemispheric synaptic connections and neuronal aggregates, as expressed at the cortical surface.
These differences in qEEG may reflect a direct effect of cocaine in utero, as Regalado et al27 have also suggested. Cocaine alters catecholaminergic neurotransmission.48 Chronic prenatal cocaine exposure may influence neurophysiologic organization through changes in different neurotransmitter pools which interact during sleep. This interpretation is further supported by findings of altered neurobehavioral processes (ie, habituation and orientation) during the waking state in cocaine-exposed infants, behaviors which may also be mediated by similar neurotransmitter populations.10 ,11 ,49 Several researchers have also suggested that cocaine disturbs CNS development by inhibiting in vitro neuronal growth and differentiation50 ,51 and in vivo corticogenesis and gliogenesis.52 ,53 These structural changes would affect brain function and may represent the anatomic underpinnings of the effects we have detected.
The findings of lower spectral EEG correlations at birth and lower spectral power at 1 year of age illustrate the altered functional brain maturation that began in utero and continued during the first postnatal year. An important next step is to investigate whether these abnormal brain patterns are related to abnormal development. An association between altered qEEG/sleep state measures and lower developmental scores in later infancy has been described for healthy preterm samples.54 ,55 Dawson et al56 reported that frontal lobe functioning, measured by the EEG, was associated with increased emotional arousal. This is important in light of studies which have found that attention and emotional regulation are affected by prenatal cocaine exposure.57 ,58 Future analyses of this data will address whether the observed differences in EEG patterns are related to different developmental patterns in infants exposed to cocaine.
By contrast to the effects of prenatal cocaine exposure, prenatal alcohol, marijuana, and tobacco exposure affect a more diverse number of neuronal networks at both subcortical and cortical levels, resulting in alterations in state regulation and/or cortical activities. The findings for these substances confirm previously published results,20 as well as provide new insight. Prenatal alcohol exposure affects neonatal state regulation, and is expressed as an increased number of arousals, body movements, and transitional sleep periods.20 In the present analysis, increased levels of arousal are seen in the greater wakefulness at birth. This is quantitatively expressed as greater spectral power at higher EEG frequencies; the infants require more time to complete a sleep cycle.
The effects of prenatal marijuana exposure on neonatal state regulation that were reported earlier20 were not confirmed in these analyses. The effects of prenatal tobacco use in this current analysis included increased arousals, motility, and transitional sleep periods, which we earlier observed as attributable to prenatal marijuana exposure. In this study, both marijuana and tobacco exposure were associated with increased arousals at 1 year of age.
This study represents an improvement over previous research because of its prospective design, a sufficient number of study participants, the use of statistical control for the covariates of prenatal substance use, and the use of qEEG measures. Women enrolled in this study represent a community-based sample: they were not recruited from drug treatment programs. The sample is most representative of women who use early in pregnancy and then stop using. The results are not generalizable to women who use cocaine/crack, alcohol, or marijuana throughout pregnancy because few of the women in this study continued to use throughout pregnancy. In addition, all women received at least some prenatal care by their fifth month of pregnancy. The number of visits and the adequacy of prenatal care was measured, thus allowing for control of the differing amount of prenatal care by level of cocaine use. All women were interviewed at the same time points and at frequent intervals to minimize recall bias. The interview techniques have been used in several previous studies of substance use in pregnancy and have been shown to be reliable and valid.59–61
A potential limitation of this study is that drug screening was not used. It is possible that some women who used drugs denied use on the interview and were classified as nonusers. However, although urine screening has been shown to identify some women who deny use on interview, it is also unable to detect many women who use. And as we reported, our interviewing identified a much higher percentage of users than did urine screening. Although it would be beneficial to have both self-report and urine screens on all study participants, that was not feasible in this study. Detailed, confidential interviewing close to the time of use remains an effective way to identify users and to characterize the quantity and pattern of use, as well as to obtain information about other substances such as alcohol, marijuana, and tobacco.19
The results indicate that prenatal cocaine exposure affects the development and functioning of the CNS, as demonstrated by lower spectral correlations at birth and lower spectral EEG power values at 1 year of age. These results are subtle. There are no direct clinical applications and the long-term consequences of such changes are unknown. They do, however, cause concern because they may indicate an effect of gestational exposure to cocaine and crack which may affect the development and subsequent functioning of the developing CNS. Many of these children go home to a less than optimal environment, whether because of substance use in the household or of other detrimental factors such as lack of financial and social resources. The combination of negative factors may magnify the effects of these changes. It is important to replicate these findings and to evaluate the long-term effects of these subtle changes.
ACKNOWLEDGMENTS
This research was supported by the National Institute on Drug Abuse Grant DA05460 (G. Richardson, Principal Investigator).
We wish to thank the staff of the Maternal Health Practices and Child Development Project and of the Developmental Neurophysiology Laboratory at Magee-Womens Hospital, especially Marquita Beggarly for her assistance with data collection and Doris Steppe for her assistance with data analysis.
Footnotes
- Received July 14, 1998.
- Accepted June 4, 1999.
Reprint requests to (G.A.R.) Western Psychiatric Institute and Clinic, 3811 O'Hara St, Pittsburgh, PA 15213. E-mail: gar+@pitt.edu
An earlier version of this article was presented at the Association of Professional Sleep Societies; June 1993; Los Angeles, CA.
REFERENCES
- Copyright © 2000 American Academy of Pediatrics
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