Children of Addiction: Research, Health, and Public Policy Issues(Garland Reference Library of Social Science)

CHILDREN OF ADDICTION CHILDREN OF ADDICTION RESEARCH, HEALTH, AND PUBLIC POLICY ISSUES EDITED BY HIRAM E.FITZGERALD ...

Author: Hiram E. Fitzgerald | Barry M. Lester | Barry S. Zuckerman

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CHILDREN OF ADDICTION

CHILDREN OF ADDICTION RESEARCH, HEALTH, AND PUBLIC POLICY ISSUES EDITED BY

HIRAM E.FITZGERALD BARRY M.LESTER BARRY S.ZUCKERMAN

ROUTLEDGEFALMER NEW YORK & LONDON/2000

Published in 2000 by RoutledgeFalmer 29 West 35th Street New York, NY 10001 Published in Great Britain by RoutledgeFalmer 11 New Fetter Lane London EC4P 4EE This edition published in the Taylor & Francis e-Library, 2003. RoutledgeFalmer is an imprint of the Taylor & Francis Group Copyright © 2000 by Hiram E.Fitzgerald, Barry M.Lester, and Barry S.Zuckerman All rights reserved. No part of this book may be reprinted or reproduced or utilized in any form or by any electronic, mechanical, or other means, now known or hereafter invented, including photocopying and recording, or in any information storage or retrieval system, without permission in writing from the publisher. Library of Congress Cataloging-in-Publication Data Children of addiction: research, health, and public policy issues/edited by Hiram E. Fitzgerald, Barry M.Lester, Barry S.Zuckerman. p. cm.—(Garland reference library of social science; 1486. Source books on education) Includes bibliographical references and index. ISBN 0-8153-3899-6 (alk. paper) 1. Children of alcoholics. 2. Children of narcotic addicts. 3. Alcoholics— Family relationships. 4. Parents—Drug use. I. Fitzgerald, Hiram E. II. Lester, Barry M. III. Zuckerman, Barry S. IV. Garland reference library of social science; v. 1486. V. Garland reference library of social science. Source books on education (Unnumbered) HV5132 .C47 2000 362.29'13–dc21 00–024777 ISBN 0-203-90460-5 Master e-book ISBN

ISBN 0-203-90464-8 (Adobe eReader Format)

Contents

Preface Contributors List of Tables and Figures Chapter 1

Chapter 2

Chapter 3

Chapter 4

Chapter 5

vii xi xiii

Are There Dose Effects of Prenatal Cocaine Exposure on Children’s Bodies and Brains? Deborah A.Frank, Marilyn Augustyn, Mark Mirochnick, Tripler Pell, and Barry S.Zuckerman

1

Prenatal Cocaine Exposure and Child Outcome: From Research to Public Policy Linda L.LaGasse and Barry M.Lester

29

Parenting and Parent-Child Relationships in Families Affected by Substance Abuse Sydney Lynn Hans

45

Assessing Vulnerability to Moderate Levels of Prenatal Alcohol Exposure Sandra W.Jacobson and Joseph L.Jacobson

69

The Teratologic Model of the Effects of Prenatal Alcohol Exposure Nancy L.Day and Gale A.Richardson

91

v

vi

Chapter 6

Contents

The Clinical and Social Ecology of Childhood for Children of Alcoholics: Description of a Study and Implications for a Differentiated Social Policy Robert A.Zucker, Hiram E.Fitzgerald, Susan K.Refior, Leon I.Puttler, Diane M.Pallas, and Deborah A.Ellis

109

Chapter 7

American Indian Children of Alcoholics Paul Spicer and Candace Fleming

143

Chapter 8

Alcohol and Drug Use among African-American Youth H.Elaine Rodney

165

Chapter 9

Substance Use and Abuse Outcomes in Children of Alcoholics: From Adolescence to Young Adulthood Laurie Chassin and Aaron Belz

193

Author Index

217

Subject Index

231

Preface

Proceedings of the Third Society for Research on Child Development Round Table: Children of Addiction

Alcoholism is the most common form of substance abuse in the United States, with at least 28 million children exposed prenatally or postnatally to alcoholabusing parents or other caregivers. Of the 7 million children under 18 who are exposed to alcohol, approximately 679,000 are younger than 2 years of age, and 1,555,000 are between 2 and 5 (cf. Fitzgerald, Puttier, Mun, & Zucker, 2000). Recent epidemiological analyses indicate that prevalence for an alcohol dependence diagnosis as defined by the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders, 4th edition (1994) decreases with age at drinking onset. The later the onset, the less likely that the individual will ever have a diagnosis of alcohol dependence. Prevalence rates have increased in the past decade at the same time that the age of first use has decreased to about 12 (Grant & Dawson, 1997). When one adds prenatal and postnatal exposure to cocaine, opioids, and other drugs into the substance abuserisk equation, one is forced to conclude that exposure to substance-abusing parents and/or other adults is a setting event that places children at high risk for the intergenerational transmission of substance abuse and related forms of psychopathology (Fitzgerald, Davies, & Zucker, in press; Zucker, Fitzgerald, & Moses, 1995). The third SRCD Round Table brought together individuals from nine major research centers, each of which focuses on some aspect of the intergenerational impact of exposure to substance-abusing parents. The first five chapters address issues related to prenatal exposure to alcohol and/or other drugs and its impact of postnatal growth and development. In Chapter 1, Deborah Frank, Marilyn Augustyn, Mark Mirochnic, Tripler Pell, and Barry Zuckerman at Boston Medical Center review evidence that links prenatal exposure to cocaine to brain and behavioral outcomes. They point out that tracing the route from prenatal exposure to postnatal outcome is difficult vii

viii

Preface

because a standardized method for quantifying prenatal exposure is not yet in use, many effects may be dose dependent, and exposure is always linked to the individual characteristics of the mother-fetus dyad (i.e., exposure takes place in a dynamic system). One way to try to understand diversity in research outcomes is to identify normative elements across studies that vary in sampling characteristics, sample sizes, cultural contexts, and research methodologies. In Chapter 2, Linda LaGasse and Barry Lester at Women’s and Infants’ Hospital and Brown University describe a database that has been constructed to code all published studies of cocaine exposure in an effort to isolate normative trends as well as identify critical individual differences that may better predict the boundaries of the route from prenatal exposure to postnatal outcome. Such databases allow for meta-analytic scans that dampen the methodological limitations of individual studies, while simultaneously providing sufficient statistical power to identify the critical predictors of postnatal outcomes. Such findings can then lead to replication studies testing specific hypotheses that emerge from such meta-analyses. In Chapter 3, Sydney Hans discusses her research at the University of Chicago that focuses on the quality of parenting given to infants who are exposed prenatally to opioids. She raises crucial issues related to parenting. For example, do infants who have been exposed prenatally to drugs differ from nonexposed infants with regard to the quality of parenting they receive postnatally? Stressing the biology-environment transactions now recognized by all developmental sciences, Hans attempts to tease out the relative contributions to infant outcomes made by prenatal exposure to drugs and postnatal exposure to the caregiving environment. In Chapter 4, Sandra and Joseph Jacobson at Wayne State University address issues related to what traditionally has been referred to as fetal alcohol effects. The work they describe homes in on a critical question: Do levels of exposure that are insufficient to produce fetal alcohol syndrome influence the etiology of such problems as attention deficit, learning disorder, language delay, and poor self-regulation that often are difficult to diagnose during the birth-to-3 age period? Moreover, if such effects can be linked to prenatal exposure to alcohol, what are the critical variables that modulate the expression of such social, cognitive, and behavior problems? In the final chapter to address prenatal exposure, Nancy Day and Gale Richardson at the Univeristy of Pittsburgh School of Medicine discuss the implications of the teratologic model for research with humans and especially with children. The teratologic model posits direct effects from prenatal exposure. In contrast, a developmental model accepts both direct and indirect effects due to the dynamic system in which fetal exposure to teratogens takes place. Their work suggests that both the teratologic and developmental models help us understand the effects of prenatal exposure on prenatal and postnatal development. The final four chapters address issues related to the etiology of alcoholism. In Chapter 6, Robert Zucker, Hiram Fitzgerald, Susan Refior, Leon Puttier,

Preface

ix

Diane Pallas, and Deborah Ellis address a wide range of issues related to the social ecology of the alcoholic environment in which children are reared and their risk for various pathological outcomes. Drawing on data from the Michigan State University-University of Michigan Longitudinal Study, they raise important questions concerning etiologic models of psychopathology, at least with respect to familial alcoholism. What are the longterm consequences of differential patterns of exposure to parental alcoholism and co-active forms of psychopathology? What role do such co-active forms of parental psychopathology as antisocial personality and depression play in structuring risk for the intergenerational transmission of substance abuse and psychopathology? How does one factor the dynamics of developmental change into etiologic models of psychopathology? Such questions are especially relevant for populations for whom etiologic issues are poorly understood. In Chapter 7, Paul Spicer and Candace Fleming, investigators at the National Center for American Indians and Alaska Natives, draw attention to a wide range of issues related to alcohol abuse and dependence among American Indians. They note that established epidemiologic morbidity and mortality rates for alcohol-specific effects among American Indians has detracted from studies of within-tribe and between-tribe variation in such risk factors. Moreover, insufficient attention to etiology has detracted from identifying etiologic factors that are common to all populations, such as parental violence and spouse and/or child abuse, and those that may be specific to American Indian cultures. From their anthropological perspective, preventive intervention programs directed at American Indians must be informed by the cultural context of Indian drinking, while simultaneously taking into account the destructive effects of alcohol abuse and individual and family life. In Chapter 8. Elaine Rodney describes her research at Prairie View A & M University and in the Midwest on alcohol and drug use among AfricanAmerican youth. Her extensive studies of alcohol and drug use among AfricanAmerican children, youth, and young adults provide additional support for the necessity of taking cultural variation into account in etiologic studies. Finally, in Chapter 9. Laurie Chassin and Aaron Belz, drawing on data from the Adult and Family Development Project at Arizona State University, illustrate the significant role that alcoholism plays in risk for alcohol and drug use independent of associated forms of parental psychopathology. Moreover, they stress the fact that the dynamics of alcoholism show great variation from one individual to another and from one family to another. This heterogeneity challenges investigators to identify the critical mediators and moderators that affect developmental pathways that either maintain risky environments and/or risky behaviors (Fitzgerald et al., 2000) and lead to poor outcomes or provide a resilience structure that substantially reduces risk for intergenerational problems related to alcohol use. Readers searching for definitive answers concerning the etiology of alcoholism will find few of them in this volume. Indeed, a key purpose of the

x

Preface

round tables was to identify the questions that should structure the research, health care, and policy agenda for children of poverty (Fitzgerald, Lester, & Zuckerman, 1995), children of color (Fitzgerald, Lester, & Zuckerman, 1999), and children of addiction (current volume). The round tables were endorsed by the Executive Committee of the Society for Research in Child Development through its Liaison to Pediatrics initiative. They were financially sponsored by the Irving B.Harris Foundation, an organization that has provided broad support to issues related to research, health, and policy impacts on infants, children, and their families. We are deeply indebted to both the SRCD and the Irving B.Harris Foundation for the success of these round tables. Finally, we also thank the participants in this final round table discussion for their dedication to the task and for their amazing stamina through 9 hours of discussion. Hiram E.Fitzgerald Barry M.Lester Barry S.Zuckerman August, 1999 REFERENCES Fitzgerald, H.E., Lester, B.M., & Zuckerman, B. (1995). Children of poverty: research, health, and policy issues. New York: Garland. Fitzgerald, H.E., Lester, B.M., & Zuckerman, B. (1999). Children of color: research, health, and policy issues. New York: Garland. Fitzgerald, H.E., Davies, O.H., & Zucker, R.A. (in press). Growing up in an alcoholic family: Structuring pathways for risk aggregation and theory-driven intervention. In R.MacMahon & R.dev.Peters (Eds.), Thirtieth Banff conference on behavior science: children of disordered parents. New York: Kleuwer. Fitzgerald, H.E., Puttier, L.I., Mun, E.-Y., & Zucker, R.A. (2000). Prenatal and postnatal exposure to parental alcohol use and abuse. In J.D.Osofsky & H.E. Fitzgerald (Eds.), WAIMH Handbook of infant mental health: Vol. 4 Infant mental health in groups at high risk (pp. 124–159). New York: Wiley. Grant, B.F., & Dawson, D.A. (1997). Age of onset of alcohol use and its association with DSM-IV alcohol abuse and dependence: Results from the National Longitudinal Alcohol Epidemiologic Survey. Journal of Substance Abuse, 9, 103–110. Zucker, R.A., Fitzgerald, H.E., & Moses, H, (1995). Emergence of alcohol problems and the several alcoholisms: A developmental perspective on etiologic theory and life course trajectory. In D.Cicchetti & D.Cohen (Eds.), Manual of developmental psychopathology: Vol. 2. Risk, disorder, and adaptation (pp. 677–711). New York: Wiley.

Contributors

Marilyn Augustyn Boston Medical Center Aaron Belz, Ph.D. Arizona State University Laurie Chassin, Ph.D. Arizona State University Nancy L.Day, MPH, Ph.D. University of Pittsburgh School of Medicine Deborah A.Ellis, Ph.D. Wayne State University Hiram E.Fitzgerald, Ph.D. Michigan State University Candace Fleming, Ph.D. National Center for American Indians & Alaska Natives Deborah A.Frank, M.D. Boston Medical Center Sydney Lynn Hans, Ph.D. University of Chicago Sandra W.Jacobson, Ph.D. Wayne State University Joseph L.Jacobson, Ph.D. Wayne State University xi

xii

Linda L.LaGasse, Ph.D. Women’s & Infants’ Hospital Barry M.Lester, Ph.D. Women’s & Infants’ Hospital Mark Mirochnick, M.D. Boston Medical Center Diane M.Pallas, MA Central Michigan University Tripler Pell, M.Sc. Boston Medical Center Leon I.Puttier, Ph.D. University of Michigan Susan K.Refior, MSW University of Michigan Gale A.Richardson, Ph.D. University of Pittsburgh School of Medicine H.Elaine Rodney, Ph.D. Prairie View A & M University Paul Spicer, Ph.D. National Center for American Indians & Alaska Natives Robert A.Zucker, Ph.D. University of Michigan Barry S.Zuckerman, MD Boston University School of Medicine

Contributors

Tables and Figures

Table 1.1 Table 1.2 Figure 2.1 Figure 2.2 Table 2.1 Table 2.2 Table 3.1 Table 3.2 Table 3.3 Table 3.4 Table 3.5 Table 4.1 Table 4.2 Table 4.3 Table 4.4 Figure 4.1

Table 4.5

Research Implications for Selected Interview Formats for Assessing Alcohol and Illicit Substance Use Human Studies Addressing Cocaine Dose Effects of Prenatal Exposure Systems approach to the effects of prenatal cocaine Sample size of exposed and comparison groups Neurobehavioral Measures Societal Burden of Prenatal Cocaine Exposure Parenting Behavior of Opioid and Comparison Group Mothers over the First 2 Years of Life Psychosocial Risk Factors for Opioid and Comparison Groups Parenting Behavior Correlated with Maternal Drug Use and Psychosocial Risk Factors for Entire Sample Correlations between Parenting Behavior and Child Development at 24 Months for Opioid Group Only Caregiving Patterns of Children at Age 10 Effects of Pregnancy Drinking on the Bayley Scales Effects of Maternal Drinking on Bayley Scale Scores Number of Infants Performing in Bottom 10th Percentile by Pregnancy Drinking Level Drinking Levels in Ounces of Absolute Alcohol per Day and Standard Drinks per Day Dose-response relations for Bayley MDI and PDI, adjusted for potential confounders. Group ns are shown in parentheses. Effects of Drinking on Infant Cognitive Outcome xiii

6 13 31 34 35 38 50 51 53 54 56 70 71 72 74

75 77

xiv

Figure 4.2

Table 4.6 Table 4.7 Figure 4.3 Table 4.8 Table 4.9

Table 6.1 Table 6.2

Table 6.3

Table 6.4 Figure 6.1 Figure 6.2 Table 6.5

Table 6.6

Figure 9.1

Tables and Figures

Dose-response relations for two measures of speed of processing, adjusted for potential confounders. Group ns are shown in parentheses. Thresholds at Which Neurobehavioral Effects Were Seen for the Seattle Cohort Thresholds at Which Neurobehavioral Effects Were Seen for the Detroit Cohort Number of women drinking alcohol at least 1 day per week. Drinking Patterns during Pregnancy Relation of Pregnancy Drinking to Incidence of Functional Impairment in Infants Born to Younger and Older Mothers Lifetime (and 12-Month) Prevalence of DSM-III-R Disorders (Estimated U.S. Population Rates) Estimated Number and Percentage of Children in the Household Who Had One or More Parents Dependent on Alcohol, by Children’s Ages Estimated Number and Percentage of Children in the Household Who Had One or More Parents Dependent on Alcohol, and/or Illicit Drugs, by Children’s Ages Design and Basic Protocol of the Michigan State University-University of Michigan Longitudinal Study Recruitment flow for court alcoholic protocol (involving six district courts in four counties). Recruitment flow for community canvass to locate control and community alcoholic families. Social Visibility of Parental Alcoholism and Family Psychosocial Adaptation during the Early Child-Rearing Years (Children at Ages 3 to 5) Correlations Between Census Tract Indicators of Economic Attainment and Social Disorganization and Alcoholism Discovery Rates in Those Tracts. Variations as a Function of Social Visibility of the Alcoholism. Growth model predicting adolescent’s initial substance use (intercept) and growth over time in substance use (slope). Standardized path coefficients are shown.

79 80 81 82 83

85 111

112

113 120 121 122

123

126

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CHILDREN OF ADDICTION

CHAPTER 1

Are There Dose Effects of Prenatal Cocaine Exposure on Children’s Bodies and Brains? DEBORAH A.FRANK MARILYN AUGUSTYN MARK MIROCHNICK TRIPLER PELL BARRY S.ZUCKERMAN

Over the past decade, the study of the possible effects of prenatal cocaine exposure on child outcome has become increasingly sophisticated. The field emerged in the midst of a national controversy over “crack babies” and “pregnant addicts.” Popular opinion predicted the emergence of a “biologic underclass” of cocaine-exposed children. In large part, the public’s early apprehensions stemmed from the social associations of illicit drug use with criminality and a variety of gender and racially biased assumptions (Daniels, 1997; Neuspiel, 1996). Throughout the 20th century, cocaine use has not only been illegal, but associated in the public mind with deviancy, violence, and uncontrolled sexuality, particularly among African Americans (Neuspiel, 1996). In the scientific world, these social meanings were reflected in implicit assumptions that any amount of exposure to cocaine in pregnancy would have negative effects on the infant. In contrast, in the early literature on prenatal alcohol exposure, there was sustained controversy as to whether “social use” (i.e., level of use that is socially acceptable in nonpregnant adults) of alcohol in pregnancy—in the absence of maternal alcoholism—had negative effects on child outcomes (Forrest & Florey, 1991). The social associations of illicit drug use have continued to impact scientific research negatively through discriminatory public policies and increasingly punitive judicial law. For example, mothers are less likely to report drug use to researchers and health providers for fear of imprisonment and loss of child custody (Roberts, 1991). In spite of ongoing public controversy, the scientific community has gradually developed a more balanced and informed approach to the study of illicit drug exposure in utero. Investigators are now addressing the problems posed by the 1

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Children of Addiction

interaction of possible drug dose effects with a variety of pharmacologic, biologic, and social variables (Frank, Augustyn, & Zuckerman, 1998). At various levels of cocaine exposure, these variables may confound, mediate, or moderate drug effects. However, despite these advances in research, there remain intrinsic methodological constraints in human studies. For example, it is still difficult to ascertain whether cocaine and other psychoactive substance exposures have occurred at all. Even more complex is the problem of determining gestational timing of exposure and the acute and cumulative doses to which the fetus was exposed. Understanding these constraints will facilitate an informed interpretation of available data and future study designs. The goals of this chapter are twofold. First, the methodologic problems entailed in defining dose in studies of prenatal cocaine exposure in humans will be summarized. Established standards for evaluating dose of alcohol exposure will be used to illustrate the difficulties generic to the field of the effects of prenatal psychoactive substance exposure on child outcome. Second, available published data will be reviewed that link various definitions of dose of cocaine exposure with neonatal and later outcomes. IDENTIFICATION OF COCAINE DOSE A critical component of any study investigating the effects of prenatal drug use on infants is identification of drug-exposed and unexposed infants. An ideal method would not only identify all exposed infants but also reveal the magnitude and pattern of exposure. Unfortunately, ascertainment of drug use during pregnancy has proven to be difficult and complex in the absence of such a method. Currently, there are two classes of techniques available to ascertain exposure: maternal interview and biologic assays. Both techniques fall far short of an ideal method. Maternal Interview Many different methods, all with intrinsic limitations, have been used in research projects to identify human prenatal cocaine exposure. The first is ascertaining substance exposure based on maternal interviews conducted by clinicians and noted in medical records. This method has been proven to be imprecise, consistently identifying many fewer users than other methods. In two recent comparisons of maternal self-report with biologic assays, only 1/4 of mothers with positive biologic assays for illicit substances admitted prenatal drug use to obstetric clinicians (Kline, Schittini, Levin, & Susser, 1998; Ostrea, Brady, Gause, Raymundo, & Stevens, 1992). Respondents are more likely to acknowledge cocaine use under research conditions, where trained interviewers offer stringent assurances of

Are There Dose Effects of Prenatal Cocaine Exposure?

3

confidentiality (Frank et al., 1988; Richardson, Hamel, Goldschmidt, & Day, 1993). However, even under research conditions, maternal self-report is limited. Maternal self-report is lower than actual usage because of both denial (common among all substance-abusing populations) (Saitz, Mulvey, Plough, & Samet, 1997) and maternal fears of the consequences of admitting to illicit drug use, which may include the loss of child custody (Chavkin, Breitbart, Elimah, & Wise, 1998; Roberts, 1991). Hingson et al. (1986) have demonstrated that a disproportionate number of pregnant women are reluctant to admit to illicit (as compared to toxic although legal) drug use. In that study, mothers in a research project were administered a structured interview designed to determine prenatal drug use. Those mothers who were told that their urine samples would be tested for drug and alcohol use had an increased rate of reporting marijuana use but not alcohol and tobacco use. Even when aware of urine testing, significant numbers of drug-using pregnant women will deny use. Thus, reliance on selfreport alone may cause enough misclassification of drug-exposed infants to obscure clinically important differences between drug exposed and unexposed infants (Zuckerman et al., 1989). Some investigators have found that mothers respond more readily (and possibly more accurately) to questions about substance use before the recognition of pregnancy (Sampson, Bookstein, & Barr, 1994). By tacitly implying that the mothers’ substance use ceased once pregnancy was identified, this strategy obviates any possibility of using maternal report to quantify fetal substance exposure in the later stages of pregnancy, when potential detrimental effects on fetal growth are most likely to be found (Chasnoff, Griffith, MacGregor, Drikes, & Burns, 1989). Conversely, researchers in separate samples in Detroit (Jacobson et al., 1991) and Pittsburgh (Ernhart, Morrow-Tlucak, Sokol, & Martier, 1988) found that mothers acknowledge higher levels of alcohol use when questioned 1 or more years after the index pregnancy than they reported when they were asked prospectively during the pregnancy. The levels of use reported prospectively during pregnancy were more strongly associated with infant outcome in the Detroit sample (Jacobson et al., 1991). Although these findings could be due to recall bias, they may otherwise show that rank ordering of use is a more useful tool in identifying the relationship between exposure and outcome than attempting to quantify absolute amounts of exposure. Asking about use prior to recognition of pregnancy or asking well after the child’s birth may reduce the social pressure on the mothers to minimize reported substance use. Nevertheless, this approach has uncertain implications for predictive validity when compared with repeated interviews obtained during pregnancy or even single interviews conducted immediately postpartum. Measures that were developed for quantifying alcohol use have served as the models for documenting illicit drug exposure. One measure is the QuantityFrequency (Q-F) index of Strauss and Bacon (1953), which has been modified by Mulford and Miller (1960). This tool uses the average amount per drinking

4


occasion as the measure of quantity but makes no distinction between patterns of drinking behavior. Thus, two people with extremely different drinking habits (for example, one binging on specific occasions and the other drinking moderately over a prolonged period) could achieve the same average quantity. These differing patterns of use could have widely disparate implications for maternal and fetal blood alcohol levels and potential fetal effects. A second index, developed by Cahalan and Cisin (1967), is the VolumeVariability Index, which attempts to compare binge versus more frequent but less heavy drinking and holds the volume constant. The basic technique of this index entails a two-step operation: (a) to classify each respondent according to average daily volume and (b) to divide each of several daily-volume groups into subgroups according to how the daily intake varies. The latter scale is able to differentiate people who drink moderate amounts of alcoholic beverages regularly (in terms of each episode of consumption) from those who binge intermittently. This issue is further complicated when pregnant adolescents are included in the research. For adolescents, sociologic as well as physiologic criteria are used to demarcate standard measures. In one recent study (Midanik, Zahn, & Klein, 1998), pregnant adolescents younger than 20 years old were considered “at risk” if they drank five or more drinks on a single occasion at least once a month. Meanwhile, pregnant women above the age of 20 were defined as “at risk” if they drank five or more drinks on a single occasion at least twice a month. In this instance, a narrow demarcation of age significantly altered the criteria used to define “at risk” groups. In epidemiologic studies, there are two major classification systems for rank ordering alcohol use. The first, used by the Department of Health and Human Services, defines drinking as light (up to one drink per occasion), moderate (more than one to three drinks), or heavy (more than three drinks). Frequency in this scheme is classified as light (less than 15 occasions per month), moderate (15 to 21 occasions per month), and heavy (21 or more occasions). Volume is classified as light (fewer than 21 drinks per month), moderate (22 to 29 drinks per month), and heavy (30 or more drinks per month) (Ashley et al., 1994). A second classification system was developed for the 1988 National Health Interview Survey. This system used a weekly rather than monthly interval, defining light as fewer than 7 drinks per week, moderate as 7 to 13 drinks a week, and heavy as 14 or more drinks per week. Jacobson and Jacobson (1994), in a study of prenatal alcohol exposure, further subdivided these categories into “very light” (up to 3.49 drinks a week) and “very heavy” (28 or more drinks a week) consumption. In the Jacobson and Jacobson sample, while there was no increased incidence in functional impairments (test scores less than the 10th percentile) at levels of exposure below seven drinks a week, even “very light” exposure had statistically significant effects on mean Bayley Mental Developmental Index scores. This suggests that patterns of drinking that are


5

not of health or functional concern for nonpregnant adults may have fetal effects. There are other measures (such as CAGE, DRUG CAGE, and TWEAK) (Russell, 1994) that do not measure frequency or quantity at all but seek only to elicit evidence of tolerance and negative health or social consequences for the adult substance user (which presumably occurs at different exposure doses for different individuals). These instruments probably detect use only at levels well above most postulated thresholds for fetal effects. A recent study (Stoler et al., 1998) demonstrated that two or more physiologic markers of alcohol use, measured in maternal blood during pregnancy, were more predictive of infant outcome than mothers’ self-report on the TWEAK (Russell et al., 1996). The lack of standardization of potency and purity of illegal drugs further detracts from the usefulness of self-report. Even if a respondent is willing within the limits of memory to make every effort to provide an accurate account of her illicit substance use during pregnancy, the substance that she has used may vary from day to day, from place to place, or from year to year. Moreover, illicit drugs may be shared among a group of users, so that the amount ingested by any one user on a given occasion is difficult to estimate. In contrast, self-report of use of legal psychoactive substances such as ounces of wine or beer or number of cigarettes permits more accurate calculations of the average amount of alcohol or nicotine to which child and mother were exposed, regardless of where or when the substance was used. There is no such standardization for purity or potency in “lines” or “rocks” of cocaine. The composition and potency of Colombian cocaine may have changed in unpredictable ways by the time it is sold on the street in Columbus, Ohio. Moreover, respondents may be completely unaware of potential contaminants that have been introduced into illegal drugs, contaminants that may have active toxic effects of their own. Regardless of the accuracy of report of the dose ingested by the mother, the dose of substance transmitted to the fetus may be difficult to estimate accurately, depending on genetic variability in maternal and fetal metabolism of the drug and physiologic variability in placental detoxification and blood flow (Polin & Fox, 1992; Potter et al., 1994; Simone, Derewlany, Oskamp, Knie, & Koren, 1994). Still, self-report should never be omitted from research on prenatal cocaine exposure because it also offers some unique advantages. First, clinical interviewing by a skilled interviewer is less biased than selective urine screening in clinical settings, which may be based on provider expectation of drug use rather than actual drug use (Chasnoff, Landress, & Barnett, 1990; Kline et al., 1997). Second, maternal report is the only way to ascertain lifetime use prior to conception or use in very early pregnancy before the pregnant woman presents herself to a health care setting. Self-report also identifies route of drug administration and whether the drug is used in a “binge” pattern (Ward, Haney, Fischman, & Foltin, 1997). Self-report can delineate patterns of simultaneous or sequential psychoactive substance use (e.g., cocaine and alcohol use), which

6


also may have important physiologic implications (Perez-Reyes, 1994). Selfreport is the only method that can detect use outside the time windows when biologic markers are valid. Urine reflects use only in the past 72 hours and meconium after 20 weeks of pregnancy. Furthermore, self-report instruments are cost-effective and readily available, and in medical or mental health settings they provide an opportunity for the mother to discuss with a clinician the potential benefits of and strategies for reducing or eliminating drug consumption. There is currently no gold standard interview for estimating dose of cocaine exposure in pregnancy. Most of the standard self-report screening measures have been developed for clinical use for adult, nonchildbearing populations and are designed to identify “problem use” of alcohol or addiction to illegal drugs. These measures have been primarily validated in samples of users in advanced stages of drug or alcohol dependence who may be manifesting psychosocial or medical sequelae for the adult user. However, data on prenatal alcohol effects (Jacobson & Jacobson, 1994) suggest that negative effects of prenatal exposure to psychoactive substances may be seen on infant outcomes at levels of use far lower than those associated with DSM diagnoses of substance use disorders (Spitzer, Williams, Gibbon, & First, 1992). Table 1.1 expands on standard interview formats for ascertaining alcohol and illicit substance use. In the study of illicit drug exposure in utero, a consensus has yet to evolve in defining what is “heavy” use for a pregnant woman, definitions that may differ from those accepted for other adults. As quantities of cocaine are not nationally standardized, frequency of use is established more easily than quantity. For this reason, uniform frequency and quantity measures are more difficult to derive for cocaine than for alcohol research. Table 1.1 Research Implications for Selected Interview Formats for Assessing Alcohol and Illicit Substance Use


7

continued

8


Table 1.1 (Continued)

Biologic Assays Supplementing interview data with biologic markers has been shown to enhance identification of newborns exposed to cocaine in utero (Chasnoff et al., 1990; Kline et al., 1997; Ostrea, Brady, Gause, Raymundo, & Stevens, 1992; Zuckerman et al., 1989). Biologic assays can be performed by using a variety of analytic techniques applied to a range of biologic substrates. Immunoassays provide rapid and sensitive methods of detecting the presence of drugs and their metabolites in biologic matrices. The most commonly used immunoassay techniques are radioimmunoassay and enzyme immunoassay.


9

Radioimmunoassay is a highly sensitive test that can detect low concentrations of drugs and metabolites and has been widely used in research settings. The disadvantages of radioimmunoassay are the need for expensive equipment, the use of radiolabeled materials, and the need to batch specimens into large runs. Enzyme immunoassay (either enzyme multiplied immunoassay technique or fluorescence polarization immunoassay) has the benefit of not involving radioactive materials. It is also able to screen individual samples for panels of drugs or large numbers of samples for single drugs. However, all immunoassay techniques have the drawback of cross-reaction with other substances, and confirmatory testing with chromatographic techniques is often performed. Chromatographic techniques, such as high-performance liquid chromatography (HPLC) and gas chromatography-mass spectrometry (GCMS), are extremely specific but expensive and time-consuming to perform. They also require sophisticated equipment and highly skilled personnel. Chromatographic techniques are generally used to confirm positive tests found by other techniques and are obligatory for forensic drug testing. Many clinical studies rely solely on immunoassay techniques and do not use confirmatory testing, running the risk of false-positive results. However, while chromatographic techniques are extremely specific, false negatives may result if the methodology does not look for all the significant metabolites of the drug (Lewis, Moore, & Leitkin, 1994b). Until recently, the most widely used biologic matrix for cocaine exposure in clinical or research settings was maternal or infant urine, obtained either during pregnancy or at the time of delivery (Osterloh & Lee, 1989). The use of urine assay facilitates the identification of infant effects. In a study conducted by our research group, the use of maternal urine assay greatly enhanced the classification of users and nonusers. In fact, without maternal urine assay, the cocaine effect on infant size at birth would not have been identified because so many users would have been misclassified as nonusers (Zuckerman et al., 1989). Urine is easily obtained from adults and contains most drugs and/or their metabolites in high concentrations. Most commonly used drugs of abuse can be detected in urine for several days after use. However, a few drugs, including phenobarbital, cannabinoids, and phencyclidine, can be detected for 2 weeks or longer after use (Vega, Kolody, Hwang, & Noble, 1993). The exact duration of the length of time a drug and/or its metabolites can be detected in urine will depend on the amount and frequency of use as well as on the lower limit of detection of the assay being used (Ambre et al., 1988). Cocaine metabolites appear in maternal and infant urine for only approximately 24 to 72 hours after the last dose. Thus, if a mother does not provide a urine sample relatively close to the time of drug use, her use will not be identified (Halstead, Godolphin, Lockitch, & Segal, 1988). Despite its widespread use in screening for drug use, urine has several limitations: (a) difficulty in obtaining adequate specimens from infants; (b) varying concentrations of drugs and metabolites,

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which are dependent on the subject’s state of hydration; and (c) the relatively brief period of detection after use for most drugs. In addition, urine assays are not useful for identification of dose of drug exposure (Callahan et al., 1992). For these reasons, testing of alternative biologic matrices has been investigated, including maternal and infant hair and infant meconium. A few studies have used assays of umbilical cord blood, but the collection requires sufficiently controlled conditions in the delivery room as to obviate usefulness in large epidemiological studies (Winecker et al., 1997). Several other biologic substances have been assayed for the presence of drugs and/or metabolites, including amniotic fluid and newborn gastric aspirates (Garcia, Romero, Garcia, & Ostrea, 1996). Cocaine metabolites were detected in the amniotic fluid of three of six women admitting to third-trimester cocaine use, but amniotic fluid is too difficult to obtain to be commonly used (Casanova et al., 1994). Fetuses swallow amniotic fluid in utero, and cocaine and benzoylecgonine can be detected in gastric aspirates collected immediately after birth (Garcia et al., 1996). Use of maternal or neonatal hair (Graham, Koren, Klein, Schneiderman, & Greenwald, 1989; Koren, 1995) to identify drug exposure, whether prenatal or otherwise, has been a matter of controversy (Baumgartner, Jones, Baumgartner, & Black, 1979; Kidwell & Blank 1995). The mechanism of drug transfer into hair is not known, but it may involve transfer from the bloodstream during hair matrix formation and/or from sweat or sebaceous excretions later incorporated into the hair structure. Drugs and metabolites remain until the hair is cut. In addition to illicit drugs, hair can be assayed for nicotine and cotinine to assess tobacco exposure (Pichinci et al., 1995). Hair analysis has been shown to be more sensitive than urine assay. In a recent study of maternal hair analysis, 59.8% of study women had positive hair assays for cocaine, and only 19.9% had positive urine samples (Kline et al., 1997). Hair analysis was specific as well. More than 90% of mothers who admitted to cocaine use within 6 months of delivery had positive hair samples (Kline et al., 1997). In a direct comparison of infant urine, meconium, and hair analysis, meconium analysis by GCMS and hair analysis by radioimmunoassay were equally sensitive, detecting between 75% and 80% of cocaine-exposed infants; immunoassay of urine detected only 38% (Callahan et al., 1992). Although some researchers suggest that segmenting maternal hair is a reliable way to identify exposure over time (Kline et al., 1997), other investigators working with nonpregnant samples have found that rates of appearance of radioactive-labeled cocaine show wide individual variability (Henderson, Harkey, Zhou, Jones, & Jacob, 1996). In addition, hair assays may inadvertently create ethnic and age biases in research data, such that dose of exposure may be underestimated in fair-haired samples. Hair with high concentrations of melanin binds cocaine metabolites more readily than blond or white hair (Reid, O’Connor, & Crayton, 1994). Environmental


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contamination may be reflected in assays of adult hair, contamination that cannot be completely removed by washing techniques (Joseph, Tsai, Su, Tsao, & Cone, 1997). Cosmetic treatments of hair have also been shown to alter drug concentration in that hair (Welch, Sniegoski, Allgood, & Habram, 1993). Therefore, the use of maternal hair for identifying timing and amount of illicit cocaine exposure during pregnancy must be considered approximate at best. However, Chiriboga, Brust, Bateman, and Hauser (1999) have found that concentration of cocaine metabolites in maternal hair correlates in a doserelated fashion with neonatal neurologic findings. Fetal hair has been considered by some to be a more promising medium than maternal hair in that the issues of cosmetic interference and environmental contamination do not apply. In utero hair formation begins during the last 3 to 4 months of gestation, and drugs or metabolites deposited in hair during the third trimester can be detected for as long as 4 to 5 months after birth (Graham et al., 1989). Although hair analysis requires a sample of hair only the thickness of a pencil lead, mothers may be reluctant to allow their newborn’s hair to be cut. Infant hair does not identify exposure before the second trimester, when fetal hair begins to grow, and does not have 100% congruence with other measures. However, one study of dose effects of prenatal cocaine use has correlated concentration of cocaine metabolites in fetal hair with fetal head growth (Sallee et al., 1995). Meconium drug analysis has been shown to be more sensitive than urine drug testing in identifying infants with prenatal drug exposure (Callahan et al., 1992). Drugs and drug metabolites excreted into fetal bile are secreted directly into the intestine. Alternatively, drugs and their metabolites may be excreted into the amniotic fluid via the fetal kidney as urine, swallowed by the fetus, and then deposited in the intestine. Meconium can be collected easily and noninvasively and has higher concentrations of drugs and their metabolites than urine (Ostrea, Brady, Parks, Asensio, & Naluz, 1989). Meconium acts as a reservoir for drugs used during pregnancy and their metabolites, providing a longer window of detection than urine, although the pattern and intensity of maternal drug use needed to produce a positive meconium drug assay has not yet been precisely established (Casanova et al., 1994; Ostrea, 1994a). Meconium assay has been shown to be a more sensitive method than urine assays for detecting prenatal drug exposure. In one study of 20 infants born to mothers admitting prenatal cocaine, opiate, or cannabinoid use, meconium assays were positive for all infants, but only 37% had positive urine assays (Ostrea et al., 1989). In another study, meconium assay was positive in 77% of infants born to mothers admitting prenatal cocaine use (Mirochnick, Frank, Cabral, Turner, & Zuckerman, 1995). Because meconium can be collected noninvasively from discarded diapers, it is the best methodology for use in large-scale screening studies (Ostrea et al., 1992). Meconium assay has also

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been shown to provide a marker for the intensity of prenatal cocaine use, with higher concentrations of the cocaine metabolite benzoylecgonine in meconium correlating in a dose-response fashion with decreased fetal growth as well as impaired newborn motor activity and regulation of state (Mirochnick et al., 1995; Tronick, Frank, Cabral, Mirochnick, & Zuckerman, 1996; DelaneyBlack et al., 1996). Meconium assay for nicotine metabolites can be used to determine fetal exposure to tobacco; assay for cocaethylene, a metabolite of cocaine and alcohol, will assess concurrent fetal exposure to these drugs (Lewis et al., 1994; McCance, Price, Kosten, & Jatlow, 1995). One limitation of meconium drug testing is that exposure to alcohol alone cannot be assessed. Although some investigators have reported that drug metabolites can be excreted into meconium as early as 15 prenatal weeks (Ostrea, Knapp, et al., 1994), others have not been able to show any accumulation in infants of known users until 3 weeks prior to delivery (Casanova et al., 1994). Meconium is still a controversial medium for measuring dose of cocaine exposure; in clinical settings, the cocaine concentration may be altered by admixture of infant urine that contains cocaine metabolites from recent maternal use (Rosengren et al., 1993). Nevertheless, in several studies, meconium has proved useful for a heuristic rank ordering of exposure (Delaney-Black et al., 1996; Mirochnick et al., 1995; Tronick et al., 1996). Neither meconium assay nor other biologic markers currently available permit a precise determination of threshold and dose response or gestational timing of exposure. DOSE OF PRENATAL COCAINE EXPOSURE AND CHILD OUTCOMES IN HUMAN SAMPLES Before the construct of dose was applied in the study of prenatal cocaine effects, there was little consistency in detection of cocaine effects on any outcome except infant gestational age and size at birth (which were found to be depressed in most studies) (Frank, Augustyn, & Zuckerman, 1998; Frank, Bresnahan, & Zuckerman, 1993). Even when studies were performed with confound control and masked examiners, findings varied widely. The effects of prenatal exposure did not show consistent patterns of association with neurobehavior during the neonatal period, development and behavior during infancy and early childhood, risks of sudden infant death, central nervous system structures, or somatic abnormalities. Table 1.2 summarizes the findings of human studies that address the issue of dose of prenatal exposure to cocaine, specifically in relation to perinatal outcomes, neonatal behavior, and outcomes in infancy and early childhood. In many regards, the findings of these studies of dose have been inconsistent and difficult to interpret. In large part, this may be due to their differing methods of measuring level of exposure and whether level of exposure was identified


13

by biologic markers as well as by self-report. Four studies that use the Neonatal Behavioral Assessment Scale (NBAS) (Brazelton, 1984) to assess outcome (Richardson et al., 1993; Delaney-Black et al., 1996; Eyler, Behnke, Conlon, Woods, & Wobie, 1998b; Tronick et al., 1996) utilize some estimation of dose of prenatal cocaine exposure. Each study employs a different method of dose estimation: Delaney-Black et al. (1996) perform continuous correlation with concentration of cocaine metabolites in meconium; Tronick et al. (1996) rank exposure ordinally by a combination of meconium metabolites and number of self-reported days of cocaine use; Eyler et al. (1998b) define dose as mean dollars per day spent on cocaine throughout pregnancy; and Richardson et al. (1996) define dose by the use of one or more lines of cocaine a day during the first trimester of pregnancy. There is a negative cocaine dose effect on the NBAS state regulation measure in three of these four studies (Delaney-Black et al., 1996; Tronick et al., 1996; Eyler et al., 1998b). Interestingly, two of these studies (Delaney-Black et al., 1996; Eyler et al., 1998b) found no such effect when cocaine exposure was analyzed as a dichotomous exposed-unexposed variable. This suggests that inconsistency in other studies of NBAS findings may reflect obfuscation of the cocaine effect when lighter and heavier users are considered as part of a single, homogeneous group. Table 1.2 Human Studies Addressing Cocaine Dose Effects of Prenatal Exposure

continued

14 Table 1.2 (Continued)



15

continued




17

continued




19

The data on whether there is a dose effect of prenatal cocaine exposure on cranial ultrasound outcomes are more difficult to interpret, especially when varying measures of dose exposure are considered. Behnke et al. (1998) found no relationship between maternal cocaine use and cranial ultrasound findings when pregnancy dose was defined as dollars per day. This finding was present despite the fact that, in the same sample, this measure was related to birth length, head circumference, and state regulation on the NBAS. In contrast, we recently reanalyzed a data set in which there was no difference among 241 term infants in ultrasound lesions if they were categorized only as cocaine exposed or unexposed (Frank, McCarten, Cabral, Levenson, & Zuckerman, 1992). However, when level of dose exposure was considered, the findings changed. An increased risk for Grade I intraventricular hemorrhage was found only among the most heavily cocaine exposed (top quartile by days of selfreported use or concentration of cocaine metabolites in meconium), where the odds of such a hemorrhage were 3.88 (95% confidence interval 1.45, 10.35, two-tailed p=.007) compared with unexposed after covariate control (including cigarettes, alcohol, and marijuana) (Frank, McCarten, Robson, Mirochnick, Cabral, Park, & Zuckerman, 1999). The more lightly exposed did not differ from unexposed. A cocaine dose relationship with cranial ultrasound findings must be considered tentative until replicated because two available studies have contradictory results. The effects of level of prenatal cocaine exposure after the neonatal period have been explored in four reports (from three samples), all of which determine dose solely by maternal self-report (Alessandri, Bendersky, & Lewis, 1998; (Hurt et al., 1997; Jacobson, Jacobson, Sokol, Martier, & Chiodo, 1996).

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Jacobson et al. (1996) reported negative effects of heavier exposure on infant information processing measured by the Pagan Test of Infant Intelligence but not on scores on the Bayley Scales of Infant Development at 13 months. In this same sample, the investigators found higher cocaine exposure associated with more rapid responsiveness on a visual expectancy paradigm. After control for maternal behavior and medical and environmental risk, Bendersky and Lewis (1998) noted that heavily exposed (defined as 2 or more days a week of use in pregnancy), 4-month-old infants showed less joy during en face play and less ability to recover from stress than lightly or unexposed infants. In the same cohort, no dose effect was found on a novelty habituation task or on Bayley II scores at 8 months, but there was a difference between heavily cocaine-exposed children and unexposed on mental development index (MDI) scores at 18 months (Alessandri et al., 1998). In contrast, Hurt et al. (1997) did not find any relationship between quartile of days of self-reported cocaine use and Wechsler Preschool and Primary Scale of Intelligence-Revised scores at 48 months. On the other hand, available research has also revealed important consistencies, helping to substantiate the real effects (or noneffects) of cocaine exposure in utero. Currently, available human research suggests that, after confound control, there is a cocaine dose effect on neonatal size at birth. As Table 1.2 shows, the more heavily exposed infants in any sample are smaller in all parameters than those less heavily exposed, whether heavy exposure is reflected by maternal self-report or hair analysis, neonatal hair analysis, meconium, or a combination of meconium and self-report. In addition, there is consistency in the three studies that have evaluated dose effects on neonatal behavior (Chiriboga et al., 1999; Delaney-Black et al., 1996; Eyler et al., 1998b; Richardson et al., 1993; Tronick et al., 1996). Less optimal state regulation is associated with heavier cocaine exposure, whether defined by meconium assay, self-report, or a combined measure (although other behavioral findings are not consistently dose related from study to study) (Eyler et al., 1998b; Delaney-Black et al., 1996; Tronick et al., 1996). When considered together, these studies demonstrate the importance of methods of measuring dose of cocaine exposure in determining infant effects. As shown in Table 1.2, it is striking that every study that uses a biologic method of quantifying level of cocaine exposure (whether the matrix is meconium, infant hair, or maternal hair, alone or in combination with self-report) identified dose effects. However, those that used self-report without biologic markers found effects only in some instances Although biologic markers cannot be used to precisely quantify exposure for individuals, they can be used to aggregate populations into exposure groups that allow the delineation of dose effects.


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CONCLUSIONS The popular perception is that any prenatal exposure to cocaine is almost certainly associated with devastating effects on the neonate. However, these data suggest that most potentially detrimental effects, including neonatal size (Mirochnick et al., 1995), neonatal behavior (Tronick et al., 1996), and central nervous system lesions (Frank et al., 1999) of prenatal cocaine exposure occur disproportionately among the heaviest users. Although this dose effect requires further replication, it parallels findings in research on alcohol and cigarette exposure (Jacobson & Jacobson, 1994). In addition, the precision of dose quantification in humans for cocaine is not yet adequate for statements to be made regarding whether the pattern of the effect is continuous or whether there is an actual threshold beyond which effects occur. Great caution must be exercised in drawing health education and public policy conclusions from available information regarding dose. For instance, several studies define heavy users as those who use more than twice a week, but this is a not a true threshold. One cannot be sure that less frequent use would not have detrimental effects. In addition, dose may vary throughout pregnancy; most investigators find that women’s use decreases as the pregnancy progresses (Richardson et al., 1993). It is not yet known whether the primary determinant of adverse outcome is cumulative dose, which is only approximately reflected in meconium (Maynard, Amoruso, & Oh, 1991) or neonatal or maternal hair (Chiriboga et al., 1999; Koren, 1995; Lewis et al., 1994b) or maximum dose used on a single occasion, which usually occurs earlier in pregnancy and may not be reflected in available biologic markers. Even if a standardized mode of quantifying prenatal cocaine exposure develops, the phenomenon of dose response is not always straightforward. Simple linear models (the more exposure, the worse the outcomes) may not be adequate to describe the actual relationships, which may be nonlinear or even paradoxical (some is worse than none or a lot) (Decoufle & Boyle, 1997). Moreover, the possible explanations for such paradoxical effects are various, including biologic and social mechanisms. For example, higher cocaine dose may produce greater placental vasoconstriction with less metabolite transferred to the fetus (Potter et al., 1994). One could speculate that repeated use might upregulate enzymatic pathways of detoxification, decreasing effects with higher cumulative use (Bailey, 1997; Simone et al., 1994). There is also the question of a “healthy user” effect, with women with better overall health tolerating higher doses than women with other adverse health conditions that may place the fetus at risk (Decoufle & Boyle, 1997). There are also potential social mediators of paradoxical dose effects. For instance, women with better education or more economic resources may obtain more doses of an illicit drug. This phenomenon has been described in Jamaica, where, compared with

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infants of nonusers, infants of heavy marijuana users had more optimal behavioral findings at 1 month of age (Dreher, Nugent, & Hudgins, 1994). In the United States, because heavier users and their infants may be more readily detected by clinicians, they may be given preferential access to compensatory services such as maternal drug treatment or infant developmental intervention—leading to a more optimal outcome long term than infants exposed to a lower dose who receive no compensatory care (Hofkosh et al., 1995; Olds, Henderson, & Tatelbaum, 1994). As these areas evolve, defining dose and documenting biologic and social variables that confound, mediate, or moderate dose effects will continue to pose major challenges. REFERENCES Alessandri, S.M., Bendersky, M., & Lewis, M. (1998). Cognitive functioning in 8- to 18month old drug-exposed infants. Developmental Psychology, 34 (3), 565–573. Ambre, J. (1988). The urinary excretion of cocaine and metabolites in humans: A kinetic analysis of published data. Journal of Analytical Toxicology, 12 (6), 301–306. Ashley, M.J., Ferrence, R., Room, R., Rankin, J., & Single, E. (1994). Moderate drinking and health: Report of an international symposium. Canadian Medical Association Journal, 151, 809–828. Bailey, D.N. (1997). Cocaine and cocaethylene binding to human placenta in vitro. American Journal of Obstetrics and Gynecology, 177 (3), 527–531. Baumgartner, A.M., Jones, P.F., Baumgartner, A.W., & Black, T.C. (1979). Radioimmunoassay of hair for determining opiate-abuse histories. Journal of Nuclear Medicine, 20, 748–752. Behnke, M., Eyler, F.D., Conlon, M., Wobie, K., Woods, N.S., & Gumming, W. (1998). Incidence and description of structural brain abnormalities in newborns exposed to cocaine. Journal of Pediatrics, 132, 291–294. Bendersky, M., & Lewis, M. (1998). Arousal modulation in cocaine-exposed infants. Developmental Psychology, 34, 555–564. Brazelton, T.B. (Ed.). (1984). Neonatal behavioral assessment scale (2nd ed.). London: Spastics International. Burkett, G., Yasin, S., Palow, D., Lavoie, L., & Martinez, M. (1994). Patterns of cocaine bingeing: Effect on pregnancy. American Journal of Obstetrics and Gynecology, 171, 372–379. Cahalan, D., & Cisin, H. (1967). American drinking practices: Summary of finding from a national probability sample. Quarterly Journal of Studies in Alcohol, 28, 642– 656. Callahan, C.M., Grant, T.M., Phipps, P., Clark, G., Novack, A.H., Streissguth, A.P., & Raisys, V.A. (1992). Measurement of gestational cocaine exposure: Sensitivity of infants’ hair, meconium, and urine. Journal of Pediatrics, 120, 763–768.


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Eyler, F.D., Behnke, M., Conlon, M., Woods, N.S., & Wobie, K. (1998b). Birth outcome from a prospective, matched study of prenatal crack/cocaine use: ii. Interactive and dose effects on neurobehavioral assessment. Pediatrics, 101 (2), 237–241. Forrest, F., & Florey, C. (1991). Reported social alcohol consumption during pregnancy and infants’ development at 18 months. British Medical Journal, 303 (6793), 22– 26. Frank, D.A., Augustyn, M., & Zuckerman, B. (1998). Neonatal neurobehavioral and neuroanatomic correlates of prenatal cocaine exposure: Problems of dose and confounding. Annals of the New York Academy of Sciences, 846, 40–49. Frank, D.A., Bresnahan, K., & Zuckerman, B. (1993). Maternal cocaine use: Impact on child health and development. Advances in Pediatrics, 40, 65–99. Frank, D.A., McCarten, K., Cabral, H., Levenson, S.M., & Zuckerman, B. (1992). Cranial ultrasound in term newborns: Failure to replicate excess abnormalities in cocaine exposed [abstract]. Pediatric Research, 31, 247A. Frank, D.A., McCarten, K., Robson, C.D., Mirochnick, M., Cabral, H., Park, H., & Zuckerman, B. (1999). Level of prenatal cocaine exposure and neonatal ultrasound findings. Pediatrics, 104, 1101–1105. Frank, D.A., Zuckerman, B., Amaro, H., Aboagye, K., Bauchner, H., Cabral, H., Fried, L., Hingson, R., Kayne, H., & Levenson, S.M. (1988). Cocaine use during pregnancy: Prevalence and correlates. Pediatrics, 82, 888–895. Garcia, D.C., Romero, A., Garcia, G.C., & Ostrea, E.M. (1996). Gastric fluid analysis for determining gestational cocaine exposure. Pediatrics, 98, 291–293. Graham, K., Koren, G., Klein, J., Schneiderman, J., & Greenwald, M. (1989). Determination of gestational cocaine exposure by hair analysis. Journal of the American Medical Association, 262, 3328–3330. Halstead, A.C., Godolphin, G.W., Lockitch, G., & Segal, S. (1988). Timing of specimens is crucial in urine screening of drug dependent mothers and infants. Clinical Biochemistry, 21, 59–61. Henderson, G.L., Harkey, M.R., Zhou, C., Jones, R.T., & Jacob, P. (1996). Incorporation of isotopically labeled cocaine and metabolites in human hair: 1. Dose-response relationships. Journal of Analytical Toxicology, 20, 1–12. Hingson, R., Zuckerman, B., Amaro, H., Frank, D.A., Kayne, H., Sorenson, J.R., Mitchell, J., Parker, S., Morelock, S., & Timperi, R. (1986). Maternal marijuana use and neonatal outcome: Uncertainty posed by self-reports. American Journal of Public Health, 76, 667–669. Hofkosh, D., Pringle, J.L., Wald, H.L., Swital, J., Hinderliter, S.A., & Hamel, S.C. (1995). Early interactions between drug involved mothers and infants. Archives of Pediatrics and Adolescent Medicine, 149, 665–672. Hurt, H., Malmud, E., Betancourt, L., Braitman, L.E., Brodsky, N., & Giannetta, J. (1997). Children with in utero cocaine exposure do not differ from control subjects on intelligence testing. Archives of Pediatrics and Adolescent Medicine, 151, 1237– 1241. Jacobson, J.L., & Jacobson, S.W. (1994). Prenatal alcohol exposure and neurobehavioral


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CHAPTER 2

Prenatal Cocaine Exposure and Child Outcome From Research to Public Policy LINDA L.LAGASSE BARRY M.LESTER

For the past 15 years, the problem of cocaine use by pregnant women and its effects on developing children has been a major focus of research, treatment, and public policy in the United States. It is also an issue that has been the subject of much debate and controversy and one that has taught us some interesting lessons. It is hard to describe the sentiment that ripped through this country when cocaine use by pregnant women became identified as a public health concern. This came about because of the availability of crack, a potent and cheap form of cocaine that resulted in a resurgence of cocaine use among all levels of society, including women of childbearing age. It was immediately described as an epidemic and generated anger and disgust at these women for the “damage” they were inflicting on their unborn children. How could they? How dare they? The fact that cocaine is an illegal substance made it easier for society to act out its anger by using the courts and the child welfare system to remove infants from their mothers and prosecute mothers under child abuse and neglect statutes. We created a generation of “boarder babies,” newborn infants languishing in hospitals while placement decisions were being made. Instead of viewing substance abuse by pregnant women as a mental health problem and focusing on treatment, prevention, and intervention, society stigmatized these women and treated them as criminals. DATABASE OF PUBLISHED STUDIES Despite early reports suggesting that prenatal cocaine exposure had devastating effects on the developing child, findings from the literature continue to show an inconsistent pattern of results. Concerns about this literature led us to develop for the Robert Wood Johnson Foundation a computerized database of the published literature of studies of prenatal cocaine exposure and child 29

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development outcome in order to provide a systematic analysis and description of the characteristics and findings from these studies. The Nature of the Problem Most studies aim to determine the terotologic effects of in utero cocaine exposure on child outcome. However, we know that cocaine use occurs in a context of polydrug use, risky environments, medical problems, and comorbidity with psychiatric problems. As illustrated in Figure 2.1, all these factors influence child outcome. Thus, to summarize the overall results of prenatal cocaine exposure on neurobehavioral outcomes, we need to evaluate the methodology of each study, including whether and how the investigators dealt with confounding factors. For our database, we review studies of four categories of neurobehavior: behavior, neurological function, and physiological or neurochemical measures. We further subdivide behavioral outcomes into 15 domains (later shown in Table 2.1). The first report from this database was published in 1996 as part of a National Institute on Drug Abuse (NIDA) monograph (Lester, LaGasse, Freier, & Brunner, 1996) and was based on 50 studies that met the inclusion criteria (listed later). In our second report (Lester, LaGasse, & Brunner, 1997), the database was expanded to 76 studies that met the inclusion criteria. Our most recent review includes 101 studies in the database published from 1985 through August 1997. Method The method includes quarterly literature searches through Medline and Psyclit. Each article is reviewed to determine eligibility for inclusion in the final database, contingent on the criteria described. Information from the articles is then abstracted, coded, and entered into the database. Variables are defined that represent either characteristics of the study, such as sample size and the method of drug detection, or behavioral outcomes such as an IQ score. Summary statistics are then generated across studies. Criteria for Inclusion Seven criteria are used to identify studies to be included in the final database: (a) cocaine use during pregnancy, (b) human subjects, (c) neurobehavioral measures, (d) original research, (e) inclusion of control or comparison group, (f) statistical analysis of data, and (g) publication in a peer-reviewed or refereed journal.

Prenatal Cocaine Exposure and Child Outcome

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Figure 2.1 Systems approach to the effects of prenatal cocaine

Identification of Drug Use An essential part of study methodology is how drug use during pregnancy is determined. The database shows that the most common methods used to detect maternal use of cocaine during pregnancy are history (including self-report) and/ or toxicology analysis of urine, meconium, or hair. Most studies do not rely on a single index; 76% of the studies used some combination of these methods. The most common combination was urine and self-report, which was used in 65% of the studies with multiple indices. The meconium assay provides a record of drug use from approximately 20 weeks gestational age, in contrast to the urine assay, which provides only a 72-hour record of drug use. However, most of these studies were conducted before the meconium assay was in widespread use. Meconium was used in 8 studies, 7 of which also used self-report. In sum, most studies include more than one means of identification of drug use, but few include meconium analysis, which provides greater confidence not only in identifying cocaine users but also in assuring a nonusing comparison group. Confounding Factors The current cocaine database indicates there are three classes of confounding factors: polydrug use, social and demographic factors, and medical and health status. Polydrug Use It is now well established that cocaine is seldom used alone (Lester et al., 1997). The most commonly reported companion drugs of cocaine are alcohol (72% of

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cocaine-exposed groups in the 101 studies) and nicotine (73%), followed by marijuana (59%) and heroin or methadone (42%). However, other drugs such as amphetamines, central nervous system (CNS) depressants, phencyclidine (PCP), and hallucinogens are present in 2% to 19% of the cocaine-exposed groups. Only 13% of the studies reported a cocaine-only sample. Unfortunately, many studies of cocaine exposure failed to account for poly drug use, calling into question claims of unique cocaine effects. For example, 23% of the 101 studies did not mention alcohol use, 25% did not mention nicotine use, 38% did not mention opiate use, and 36% did not mention marijuana use. Social Demographics The unique effects of prenatal drug exposure on development is even more difficult to separate from the impact of disadvantaged environments. Most of the current research findings are based on predominantly low socioeconomic status (SES) families on public assistance. In addition, the typical participant in these studies is black, single, a high school graduate, and between 26 and 30 years old. Can it be assumed that this profile describes the population of cocaine users? One problem with this assumption is that the preponderance of low SES, black, single women on welfare may be more reflective of the type of samples available to the investigators, such as convenience samples from drug treatment centers or clinics, rather than samples selected from the broader population. Particular groups of women were poorly represented, including Hispanic mothers, middle-class mothers, and teenage mothers. Further, many studies fail to describe social demographic information: 22% fail to describe race, 31% do not describe educational level, and 59% fail to describe SES; even fewer describe receipt of public assistance and marital status. Finally, it should be noted that the social and demographic characteristics typically described in the cocaine studies are status or index variables of social risk (e.g., SES or race) that provide little understanding of the process by which social and environmental risk compromises development. Possible risk factors that more closely represent process or direct impact on the child that are rarely reported in this database include family composition, stability of caretakers, mental illness of caretakers, foster care, neighborhood quality, and the level of violence surrounding the child. Medical and Health Status The first generation of research studies on prenatal cocaine exposure reported devastating medical outcomes (e.g., congenital malformation, apnea, sudden infant death syndrome [SIDS], perinatal cerebral infarction), but these findings have been called into question by recent, better controlled studies (see Lutiger, Graham,


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Einarson, & Koren, 1991 for a meta-analysis of medical findings; Lester & Tronick, 1994; Mayes, Granger, Bornstein, & Zuckerman, 1992). Although cocaine is unlikely to cause severe medical problems, the most replicated findings suggest that cocaine exposure is associated with increased genitourinary malformations, shorter gestational age, smaller head circumference, shorter birth length, and lower birthweight. However, recent findings have not replicated the association of cocaine exposure with birthweight or genitourinary malformations (Bauer, 1999). Unlike polydrug and social-demographic risk factors, cocaine exposure may, in fact, contribute to greater risk of medical complications. The dilemma for researchers is whether to treat adverse medical factors as outcomes, as possible mediators of developmental outcomes (Jacobson, Jacobson, Sokol, Martier, & Chiodo, 1996), or as confounding factors that obscure the question of cocaine’s unique effect on development. Intervention Effects on Child Outcome Finally, given the high-risk nature of this population, it would be reasonable to expect that many of the infants and mothers in these studies are receiving intervention services. Although intervention may affect the outcome of the child, information about intervention provided to the child or the mother was mentioned in only 37% of the studies. Sample Size Limitations Sample size is a critical issue in interpreting the results of these studies. Most studies are based on relatively small sample sizes. Small sample sizes are problematic in two ways: (a) many observed cocaine effects are subtle and can be missed if the study does not have enough subjects (i.e., low power); (b) cocaine use occurs in a multiple-risk context that requires large samples to use multivariate statistical approaches for control of confounding and mediator variables. The relationship between subtle effects and sample size can be easily explained by effect size. Effect size is described in terms of standard deviation units and is typically classified as small (.75 SD) (Cohen, 1988). In order to detect a small effect, a minimum of 80 subjects per group is necessary. Medium effect sizes can be detected with samples of 30 to 80 subjects. Only large effects can be detected with samples of fewer than 30. As shown in Figure 2.2, only a third of the studies in the database are large enough to detect subtle cocaine effects. This suggests that there may be effects of cocaine that are real but have not been observed because of too few subjects. In addition, the sample size of many studies restricts the number of covariates that could be included in the analysis. Without the ability to control for polydrug, medical, and social factors, the potential teratogenic effects of cocaine cannot be determined.

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Figure 2.2 Sample size of exposed and comparison groups

Neurobehavioral Outcome Table 2.1 shows the neurobehavioral measures used in the studies, including the number of times each measure was used and if statistically significant cocaine effects were found. It is apparent from this table that the range of measures used has been wide, with few measures used across studies. The most frequently used measures—the Neurobehavioral Assessment Scale (NBAS), the Neonatal Intensive Care Unit Network Neurobehavioral Scale (NNNS), and stress abstinence measures—as expected, pertain to early infancy. The NBAS-NNNS does show cocaine effects in 17 of 19 studies. Abstinence or withdrawal effects were reported in 12 of 21 studies and may be related to the additional effects of opiates as a confounding variable. It is also interesting that 6 of 12 studies using measures of developmental level such as the Bayley Scales did not find cocaine effects. By contrast, measures of more subtle function such as temperament showed cocaine effects in 8 of 13 studies and attention in 7 of 8 studies. With older children, 4 of 9 language studies and 3 of 7IQ studies showed cocaine effects. Database Summary To summarize, the initial outcry about the devastating effects of prenatal cocaine exposure on child development has not been validated, but we cannot rule out subtle effects that increase vulnerability in children already immersed in highrisk environments. Our literature review indicates that our knowledge base is virtually confined to early infancy, with a striking absence of long-term followup studies.


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Table 2.1 Neurobehavioral Measures (n=101)

The neurobehavioral findings are scattered across a wide array of measures, most of which have been used in only a few studies. There is a clear need for measures to be used across studies in order to determine if there is a consistent pattern of findings. There is also a question as to how measures are selected; few appear to have been theoretically or hypothesis-driven, and some measures may be too gross to detect the subtler effects that have been attributed to cocaine. Other factors, such as high attrition rates in longitudinal studies, failure to control for examiner blindness, and intervention effects, further cloud interpretation of the findings. In sum, findings are limited and compromised by methodological problems that mitigate any conclusions about whether or how prenatal cocaine exposure affects child outcome. LESSONS FROM THE PAST As described previously (Lester & Tronick, 1994), there is a certain déjà vu associated with the study of prenatal cocaine exposure. The study of prenatal influences and insults on child development is a much-studied area, and it

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might be useful to consider cocaine exposure as a special case of this larger problem. In this way, we can learn from the past as well as define what is unique about this particular problem. The study of preterm infants provides a good model. Starting in the 1950s with the National Perinatal Collaborative Study of some 20,000 pregnancy and delivery outcomes, substantial effort was devoted to the “effects of prematurity” (Niswander & Gordon, 1972). The prevailing Zeitgeist at that time was that being born prematurely was a form of biologic insult likely to affect CNS development and the long-term outcome of the child. As supporting evidence, studies showed that premature infants were overrepresented in many populations of abnormal outcomes, including cerebral palsy and mental retardation (Lilienfeld & Parkhurst, 1951; Pasamanick & Knobloch, 1966). The second generation of studies of the effects of preterm birth told a different story. We were reminded that the evidence (even if it was true) that preterm infants were overrepresented among the handicapped population was based largely on retrospective data. Prospective longitudinal studies began to show that when preterm infants were followed from birth, most developed normally. Studies such as the Kauai study showed that, in fact, it was the environments of these children that was predictive of their developmental outcome, rather than their medical status at birth (Werner, Bierman, & French, 1971). We also learned that preterm infants were not a homogeneous group. As babies began to survive at lower and lower birthweights, the medical community distinguished between low birth weight (1,500 to 2,500 g) and very low birthweight (

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