Prenatal Drug Exposure and Drug-Abusing Environments

Research Findings from September, 2004 Director's Report

This section lists selected summaries from NIDA funded research projects that investigate the consequences of prenatal drug exposure. The summaries provided were selected from recent issues of the Director's Report to the National Advisory Council on Drug Abuse. For a more comprehensive listing of NIDA funded projects see the Director's Report.

Prenatal Cocaine Exposure and Behavioral Tolerance

Repeated exposure to cocaine during sensitive periods of forebrain development produces specific, long-lasting changes in the structure and function of maturing neural circuits. Similar regimens of drug exposure in adult animals with mature, homeostatically regulated nervous systems produce neuroadaptations that appear to be quite different in nature and magnitude. In a recent paper, Dr. Pat Levitt and his associate, Dr. Gregg Stanwood, Vanderbilt University School of Medicine, report that specific adaptive changes in neural signaling and/or circuitry that occur in response to repeated exposure to psychostimulants are highly dependent upon the maturational state of the brain. Their studies were designed to investigate the ability of cocaine to induce behavioral sensitization and/or tolerance following repeated administration of cocaine to pregnant rabbits during the period of peak differentiation within the rabbit cerebral cortex (embryonic day 16-25). Offspring and the mothers were later tested following acute administration of amphetamine challenge. The offspring, having received cocaine during the prenatal sensitive period, showed profound behavioral tolerance to the amphetamine challenge. In contrast, the mothers of these offspring, who received cocaine at the same dose and duration, and experienced the same period of withdrawal, exhibited robust behavioral sensitization. Stanwood, G.D. and Levitt, P. Repeated I.V. Cocaine Exposure Produces Long-lasting Behavioral Sensitization in Pregnant Adults, But Behavioral Tolerance in their Offspring. Neuroscience 122, pp. 579-583, 2003.

The Effects of Prenatal Cocaine Exposure on Reversal Learning Using a Simple Visual Discrimination Task in Rhesus Monkeys

Dr. John Chelonis and colleagues at the University of Arkansas and the National Center for Toxicological Research report behavioral effects of prenatal exposure to cocaine in adult rhesus monkeys. At ages 1.5 and 3.0 the monkeys had undergone extensive behavioral testing involving a large battery of tasks that correlate with IQ in humans and had failed to exhibit any behavioral deficits. When tested as adults, however, data suggest possible deficits in behavioral adaptation to changing contingencies. At age 7, after the monkeys had been performing an operant conditional discrimination task based on color and response position for six years, the discrimination rules for reinforcement were reversed. This reversal in the reinforcement rules led to impairment in performance compared to monkeys that had not been prenatally exposed to cocaine. In some cases, the impairment was still evident two and a half years after the reversal when the observations were terminated, thus suggesting that the deficit may be permanent. When these animals learned the initial discrimination six years prior, they did not exhibit any impairment in acquiring the discrimination. The reversal task, of course, is more demanding because it involves extinction of the old behavior and acquisition of new behavior incompatible with the old. This work could have implications for research on prenatal cocaine exposure in humans. Based on the authors prior age-related work with these same monkeys showing that adults are 10-30 times more sensitive to dopaminergic challenges than are young monkeys, the authors suggest that some effects of prenatal cocaine may not be manifest until certain neurotransmitter systems are fully functional. Alternatively, the authors raise the possibility that had the reversal procedure been implemented at an earlier age, the same deficit may have occurred. Chelonis, J.J., Gillam, M.P. and Paule, M.G. The Effects of Prenatal Cocaine Exposure on Reversal Learning Using a Simple Visual Discrimination Task in Rhesus Monkeys. Neurotoxicology and Teratology, 25, pp. 437-447, 2003.

Emotion Regulation and Behavior During a Separation Procedure in 18-month-old cocaine-and-other-drug-exposed Children

Dr. Linda Mayes and colleagues at Yale University report that among toddlers prenatally exposed to cocaine, both maternal and child impairment was observed during a maternal-child separation procedure. The researchers observed 78 18-month old toddlers and their mothers before, during and after a play period during which a stranger entered the playroom and subsequently the mother left for approximately 3-minutes. Three groups of mother-child dyads from an ongoing longitudinal study were studied: those prenatally exposed to cocaine and other drugs (n= 26), those exposed to other drugs including alcohol, tobacco, and/or marijuana but not cocaine (n= 26), and those not exposed to any drugs prenatally (n= 26). All three groups are a very high-risk sample characterized by extreme poverty, adversity, and environmental instability. Upon separation from the mothers, the toddlers from the cocaine group did not show heightened reactivity, but rather showed the least level of reactivity. This effect was unrelated to various measures of maternal psychological functioning, other drug use, or by demographic or perinatal differences. During the mother-child reunion following the separation, the mothers in the cocaine group exhibited significantly less emotional engagement than the non-drug using mothers, an effect related to alcohol use among mothers in the cocaine group. The cocaine-exposed toddlers upon reunion exhibited less positive emotional engagement with their mothers compared to toddlers from the non-drug-using group. This effect was mediated by the mother's low level of emotional engagement and by a lower birth weight status in the cocaine group. Molitor, A., Mayes, L.C. and Ward, A. Emotion Regulation and Behavior During a Separation Procedure in 18-month-old cocaine-and-other-drug-exposed Children. Development and Psychopathology, 15, pp. 39-54, 2003.

Developmental Trajectories of Cocaine-and-other-drug Exposed and Non-cocaine-exposed Children

Dr. Linda Mayes and colleagues at Yale University report data on the effects of prenatal cocaine exposure on the developmental trajectory of mental and motor performance, as measured by the Bayley Scales of Infant Development-II, in children assessed bi-yearly from age 3 months to age 36 months. Three groups of children in an ongoing longitudinal study were studied: those prenatally exposed to cocaine and other drugs (n= 265), those exposed to other drugs including alcohol, tobacco, and/or marijuana but not cocaine (n= 66), and those not exposed to any drugs prenatally (n= 129). All three groups are a very high-risk sample characterized by extreme poverty, adversity, and environmental instability. Dr. Mayes and her colleagues found that the Bayley motor index indicated a decline in motor performance across time in all three groups. The decline was greater in the cocaine-exposed group, though not statistically significant. The Bayley mental index also indicated a decline across age, but only to 24 months. Although the rate of mental performance decline, i.e., the trajectory, did not differ among the groups, the cocaine-exposed children had lower mental performance scores than those in the other two groups at each age level. These data indicate that impoverished cocaine- and non-cocaine-exposed children develop along the same trajectories in the mental and motor domains, but that cocaine-exposed children exhibit delays in mental development relative to the non-cocaine-exposed children. Mayes, L.C., Cicchetti, D., Acharyya, S. and Zhang, H. Developmental Trajectories of Cocaine-and-other-drug exposed and Non-cocaine-exposed Children. Journal of Developmental and Behavioral Pediatrics, 24, pp. 1-13, 2003.

Prenatal Marijuana Exposure and Academic Achievement at Age 10 Years

University of Pittsburgh researchers have reported their latest findings from a longitudinal cohort study of children exposed to marijuana in utero. In this study, women were interviewed about their substance use at the end of each trimester of pregnancy, and at multiple times during the child's development. The children were assessed on physical, emotional, and cognitive development at 8 and 18 months, and at 3, 6, 10, 14, and 16 years postpartum. This report provides findings on academic achievement at age 10 (606 children were assessed), using the Wide Range Achievement Test-Revised (WRAT-R), the reading comprehension subtext of the Peabody Individual Achievement Test-Revise (PIAT-R), and teacher reports of child performance in school. As a group, the women were of lower socioeconomic status, high-school-educated, light-to-moderate users of marijuana and alcohol, and equally distributed in terms of race/ethnicity (Caucasian and African-American). Exposure to one or more marijuana joints per day during the first trimester predicted deficits in WRAT-R reading and spelling scores, and a lower rating on the teachers' evaluations of the children's performance. These associations existed when home environment, race/ethnicity, socioeconomic status, and other prenatal substance exposure were controlled. However, these associations were mediated by effects of first-trimester marijuana exposure on the children's symptoms of depression and anxiety. Second-trimester marijuana use was associated with reading comprehension and underachievement. Exposure to alcohol during the first and second trimesters predicted poorer teacher ratings of overall school performance, whereas second-trimester binge drinking predicted lower reading scores. There was no interaction between prenatal marijuana and alcohol exposure. Each was an independent predictor of aspects of academic performance. The investigators compared their findings to those of the other cohort study of prenatal marijuana exposure reported in the literature, and they discussed possible reasons for differences in findings on school performance between the two studies. The investigators also discuss the limitations of the analyses and of the generalizability of the findings. Goldschmidt, L., Richardson, G.A., Cornelius, M.D., and Day, N.L. Prenatal Marijuana and Alcohol Exposure and Academic Achievement at Age 10. Neurotoxicology and Teratology, 26, pp. 521-532, 2004.

Cognitive Outcomes of Preschool Children with Prenatal Cocaine Exposure

Researchers at Case Western Reserve University report that 4-year-old children who were exposed to cocaine in utero scored significantly lower on some specific measures of intelligence than did children who were not exposed to the drug in utero. The two groups did not differ on overall, verbal, and performance IQ scores, although exposed children were less likely to have above-average overall IQ. The study results also suggest that mentally stimulating home environments may positively affect brain development and lessen prenatal effects of cocaine. At 4 years of age, 190 cocaine-exposed and 186 nonexposed children were assessed using the Wechsler Preschool and Primary Scales of Intelligence-Revised. This test revealed that exposed children had lower scores than nonexposed children in the specific areas of information, arithmetic, and object assembly (reflecting visual-spatial skills). In arithmetic skills, cocaine-exposed boys had lower scores than girls and nonexposed boys. The researchers also compared two groups within the cocaine-exposed children, i.e., 148 cocaine-exposed children living with their biological mothers or other relatives, and 42 cocaine-exposed children living in adoptive or foster care. They found that 25 percent of cocaine-exposed children living with their mothers or relatives had overall IQ scores lower than 70, compared with only 10 percent of cocaine-exposed children in adoptive or foster care. The researchers report that caregivers in the adoptive and foster homes were better educated, and had better vocabulary and intelligence test scores than the caregivers who were family members. Additional findings indicated that adoptive or foster care was associated with a lower rate of mental retardation in the cocaine-exposed children, despite the fact that these children had been exposed to twice as much cocaine while in utero, and that the cocaine-exposed children in the more stimulating environments had IQ scores that were similar to those of nonexposed children. The findings of this study are consistent with and expand on other preschool cocaine-exposure studies that show specific (but not global) IQ deficits. The results also emphasize how important it is to examine childrearing environments when assessing developmental progress of drug-exposed children, and they also provide optimism that interventions may be effective for children who are affected by prenatal cocaine exposure. Singer, L.T., Minnes, S., Short, E., et al. Cognitive Outcomes of Preschool Children with Prenatal Cocaine Exposure. JAMA, 291(20), pp. 2248-2456, 2004.

Developmental Outcomes of 2-Year Old Cocaine-Exposed Children Relative to their Childrearing Environments

Researchers conducting a longitudinal study in Atlanta with children exposed to cocaine in utero have reported on analyses that examine the role of caregiving environments for these children. The investigators note that the few previous studies examining whether type of care affects the development of exposed children have been inconsistent in their findings. The current analyses focused on cognitive and social-emotional outcomes of 2-year-old cocaine-exposed toddlers. Forty-nine of 83 cocaine-exposed children were reared in parental care, and 34 were reared in non-parental care (resulting from voluntary and involuntary relinquishment of care. Findings indicated that, in general in this sample, nonparental caregivers had more economic resources, experienced less psychological distress, and provided more stimulating and responsive home environments than did birth parents who continued to care for their cocaine-exposed children. The children in nonparental care performed better in several developmental domains. Also reported was the fact that within the group of nonparental caregivers, nonkin caregiving was different from kin caregiving, and was associated with different child outcomes. The investigators discuss the challenges and methodological limitations of doing these kinds of analyses (e.g., defining who is a primary caregiver in families where children are cared for by numerous adults in the course of a day or week is very difficult). They also point out that findings from these kinds of analyses, which are being reported in the literature with increasing frequency, underscore the importance of considering the specifics of the caregiving context when evaluating the potential developmental impact of prenatal cocaine exposure. Such analyses also should provide guidance for interventions to prevent or ameliorate negative developmental outcomes. Brown, J.V., Bakeman, R., Coles, C.D., Platzman, K.A., and Lynch, M.E. Prenatal Cocaine Exposure: A Comparison of 2-Year-Old Children in Parental and Nonparental Care. Child Development, 75(4), pp. 1282-1295, 2004.

Maternal Substance Use Patterns During Pregnancy and Infant Growth Parameters at Birth

Maternal cocaine use during pregnancy has been associated with decreased growth parameters in multiple previous studies. Women who use cocaine often use other substances as well (e.g., alcohol and tobacco, both of which have been shown to have effects on birth weight). A recent publication from the Maternal Lifestyle Study (MLS) reported on how patterns of cocaine, alcohol, tobacco, and marijuana use during pregnancy were related to infant birth weight, length, and head circumference in a sample of 651 mothers and their infants. Because cocaine use has been associated with preterm delivery, only term pregnancies were evaluated for this report. The MLS is a multisite longitudinal study of in utero drug exposure that is jointly funded by NICHD and NIDA. It is the largest study of its type. Histories of substance use were obtained for the 3-month period before pregnancy and the three trimesters of pregnancy. Patterns of use were categorized for each substance as consistently high, moderate, or low/none, and increasing or decreasing. The effects on growth parameters were analyzed in multivariate linear regression analyses, with adjustment for clinical site, maternal age, prepregnancy weight, multidrug use, and socioeconomic status. Detailed results of use patterns and growth parameters are reported in the publication. Overall, with adjustments made for confounders, including multi-drug use, patterns of tobacco use during pregnancy were associated with deficits in birth weight, length, and head circumference, whereas cocaine use was linked to deficits in birth weight and head size. In addition, birth weight, length, and head circumference were significantly greater among infants born to women who used no drugs compared to women with any cocaine, opiate, alcohol, tobacco, or marijuana use during pregnancy. The investigators emphasize that a clinical implication of the study is the importance of curtailing use during pregnancy of illicit drugs as well as alcohol and tobacco. Shankaran, S., Das, A., Bauer, C.R., et al. Association between Patterns of Maternal Substance Use and Infant Birth Weight, Length, and Head Circumference. Pediatrics, 114(2), pp. e226-e234, 2004.

Immune System Parameters and Clinical Morbidity in Infants Exposed to Drugs and HIV in Utero

Recently published data from the Women and Infants Transmission Study (WITS) reported on associations between maternal drug use during pregnancy and lymphocyte subsets and clinical morbidity in uninfected infants born to HIV-infected mothers. WITS is a multi-site longitudinal study of the health of HIV-infected mothers and their children, as well as mother-to-child HIV transmission. It is jointly supported by NIAID, NICHD, and NIDA. The outcomes of HIV-exposed but uninfected infants is a major focus within WITS. The current report presents findings for infants through 2 years of age. The definition of drug use during pregnancy included use of cocaine, methadone, heroin, and other opiates. History of illness and clinical findings were recorded using standardized collection instruments for medical history and medical chart abstraction. Measurement of immune system parameters (CD4, CD8, CD19, NK cell lymphocyte percentage and absolute numbers) utilized standard laboratory procedures. A total of 401 of the 1436 uninfected infants were born to drug-using mothers. Infants born to drug-using mothers had lower gestational age and birth weight, and lower CD4 lymphocyte percentage over the first 4 months of life after adjusting for covariates and higher natural killer lymphocyte percentage. The clinical significance of the lower CD4 percentage and higher NK cell level remain unclear. The investigators suggest that future studies evaluating immunologic parameters in HIV-exposed but uninfected infants should control for the effect of drug exposure. They also indicate that additional research that includes functional assays of lymphocyte cell populations is needed in order to evaluate effects of drug exposure on immune function in addition to phenotype, whether such effects are transient or persist over time, and whether there is any clinical significance of such findings. Neu, N., Leighty, R., Adeniyi-Jones, S., et al. Immune Parameters and Morbidity in Hard Drug and Human Immunodeficiency Virus-Exposed but Uninfected Infants. Pediatrics, 113(5), pp. 1260-1266, 2004.