National Institute on Drug Abuse

RESEARCH

MONOGRAPH SERIES

Methodological

Issues in

Controlled

Studies on Effects

of Prenatal

Exposure to Drug

Abuse

U.S. Department of Health and Human Services • Public Health Service • National Institutes of Health

114
Methodological Issues in

Controlled Studies on

Effects of Prenatal

Exposure to Drug Abuse

Editors:

M. Marlyne Kilbey, Ph.D.

Khursheed Asghar, Ph.D.

Research Monograph 114

1991

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES

Public Health Service

Alcohol, Drug Abuse, and Mental Health Administration

National Institute on Drug Abuse

5600 Fishers Lane

Rockville, MD 20857
Associate Editors, NIDA

NORA CHIANG, Ph.D. JOHN W. SPENCER, Ph.D.

Medications Development Division Division of Clinical Research

LYNDA ERINOFF, Ph.D. PUSHPA V. THADANI, Ph.D.

Division of Preclipical Research Division of Preclinical Research

CORYL L. JONES, Ph.D.

Division of Epidemiology and

Prevention Research

CORA LEE WETHERINGTON, Ph.D.

Division of Clinical Research

ACKNOWLEDGMENT

This monograph is based on the papers and discussion from a technical

review on “Methodological Issues in Controlled Studies on Effects of Prenatal

Exposure to Drugs of Abuse” held on June 8-9, 1990, in Richmond, VA. The

review meeting was sponsored by the National Institute on Drug Abuse and

cosponsored by the National Institute of Child Health and Human Development.

COPYRIGHT STATUS

The National Institute on Drug Abuse has obtained permission from the

copyright holders to reproduce certain previously published material as noted in

the text. Further reproduction of this copyrighted material is permitted only as

part of a reprinting of the entire publication or chapter. For any other use, the

copyright holder’s permission is required. All other material in this volume

except quoted passages from copyrighted sources is in the public domain and

may be used or reproduced without permission from the Institute or the authors.

Citation of the source is appreciated.

Opinions expressed in this volume are those of the authors and do not

necessarily reflect the opinions or official policy of the National Institute on Drug

Abuse or any other part of the U.S. Department of Health and Human Services.

The U.S. Government does not endorse or favor any specific commercial

product or company. Trade, proprietary, or company names appearing in this

publication are used only because they are considered essential in the context

of the studies reported herein.

NIDA Research Monographs are indexed in the Index Medicus. They are

selectively included in the coverage of American Statistics Index, BioSciences

Information Service, Chemical Abstracts, Current Contents, Psychological

Abstracts, and Psychopharmacology Abstracts.

DHHS publication number (ADM)91-1837

Printed 1991

ii
Preface

Prenatal exposure to drugs of abuse, now a public health concern of national

importance, has adversely affected the lives of hundreds of thousands of babies

born each year in the United States to drug-dependent mothers. The cost of

providing intensive care to drug-exposed infants can be enormous. The cost of

care and treatment of one infant could exceed $100,000 depending on the

severity of sickness. Many infants born to drug-abusing mothers do not remain

with the parents, and their placement outside the home excessively burdens the

resources of the Nation’s foster care provider agencies. The National Institute

on Drug Abuse (NIDA) has assumed a lead role in supporting research to

identify the prenatal effects of drugs of abuse on the behavioral, intellectual,

and physical development of these infants and to determine the effects of drug

abuse on reproductive outcome in the addicted mother. Moreover, NIDA is

increasingly emphasizing research related to the prevention and treatment of

developmental anomalies, which eventually would help reduce the suffering

caused by this menace in the lives of babies, families, and society at large.

Methodological difficulties and the existence of confounding variables have

been impeding progress in reaching the research goals identified above.

Clearly, to deal with special problems of drug dependence, interaction and

collaboration among different disciplines need to be engendered. Interaction is

needed between those who have been studying human development for many

years and those who are experienced in dealing with the problems associated

with drug dependence. Therefore, NIDA sponsored two research technical

reviews that focused on the experimental design issues inherent in research

into the effects of prenatal exposure to drugs of abuse. The purpose of the

technical reviews was to bring together panels of eminent researchers to

consider how meaningful data can be best obtained and how to identify the

kinds of research questions that can be addressed competently, given the

current technological limitations.

This monograph presents the proceedings of the first NIDA technical review

related to the conduct of controlled studies on the effects of prenatal exposure

to drugs of abuse. Held June 8-9, 1990, at the Richmond Marriott in Richmond,

VA, the technical review was cosponsored by the National Institute of Child

iii
Health and Human Development. The following NIDA staff members

participated in its planning and served as associate editors of this monograph:

M. Marlyne Kilbey, Ph.D., Cochair (Dr. Kilbey served as Science Adviser to the

Director of NIDA during calendar year 1989); Khursheed Asghar, Ph.D.,

Cochair; Nora Chiang, Ph.D.; Lynda Erinoff, Ph.D.; Coryl L. Jones, Ph.D.; John

W. Spencer, Ph.D.; Pushpa V. Thadani, Ph.D.; and Cora Lee Wetherington,

Ph.D.

We wish to express our appreciation of substantial advice and input provided in

the planning of the technical review by the following NICHD staff members:

Linda Wright, MD.; Danuta Krotoski, Ph.D.; and Marlan Willinger, Ph.D.

The second technical review, related to epidemiological, prevention, and

treatment research on the effects of prenatal drug exposure on women and

their children, was held July 25-26, 1990, at the Sheraton Inner Harbor Hotel In

Baltimore, MD. The proceedings of this technical review are scheduled for

publication in another NIDA monograph.

M. Marlyne Kilbey, Ph.D.

Chair

Department of Psychology

Wayne State University

Detroit, Ml 48202

Khursheed Asghar, Ph.D.

Chief

Basic Sciences Research Review Branch

Office of Extramural Program Review

National Institute on Drug Abuse

Parklawn Building, Room 10-42

5600 Fishers Lane

Rockville, MD 20857

iv
Contents

Page

Preface vii

M. Madyne Kilbey and Khursheed Asghar

Session: Detection and Quantification of Prenatal

Drug Exposure in Infants

Drug Exposure to the Fetus—The Effect of Smoking 1

Betty R. Kuhnert

Pharmacokinetic Correlates of Fetal Drug Exposure 18

C. Lindsay DeVane

Discussion: Methodological Issues in Controlled Studies on Effects

of Prenatal Drugs 37

Hazel H. Szeto

Session: Assessment of Pregnancy Outcome

Selected Methodologic Issues in Investigations of Prenatal Effects

of Cocaine: Lessons From the Past 45

Barry Zuckerman

Methodological Issues in Studying Cocaine Use in Pregnancy:

A Problem of Definitions 55

lra J. Chasnoff

v
Use of Birth Defects Monitoring Programs for Assessing the Effects

of Maternal Substance Abuse on Pregnancy Outcomes 66

M. Louise Martin and Larry D. Edmonds

Discussion: Methodologic Issues in Assessment of

Pregnancy Outcomes 84

Ronald A. Chez

Session: Assessment of Status of the Newborn

What We Can Learn From the Status of the Newborn 93

T. Berry Brazelton

Neurobehavioral Organization of the Newborn:

Opportunity for Assessment and Intervention 106

Heidelise Als

Substance Abuse in Pregnancy: Effects on Cardiorespiratory

Function in the Infant 117

Eduardo Bancalari

The Effect of Cocaine on Developing HumanBrain 128

Barry E. Kosofsky

Discussion: Assessing Status of the Newborn 144

Edward Z. Tronick

Session: Measurement of Drug-Induced Physical and

Behavioral Delays and/or Abnormalities: A General Framework

Measurement of Drug-Induced Physical and Behavioral Delays and

Abnormalities in Animal Studies: A General Framework 148

Sheldon B. Sparber

Regulatory Disorders I: Clinical Perspectives 165

Stanley I. Greenspan

Regulatory Disorders II: Psychophysiologic Perspectives 173

Stephen W. Porges and Stanley I. Greenspan

Discussion: Measurement of Drug-Induced Physical and Behavioral

Delays and Abnormalities—A General Framework 182

Joseph L. Jacobson

vi
Session: Measurement of Drug-Induced Physical and

Behavioral Delays and/or Abnormalities: (A) Physiology

and (B) Neuroendocrinology

Postnatal Development of Cardiac and Respiratory Control

Following Prenatal Drug Exposure 187

Ronald M. Harper

Endocrine Function as a Target of Perinatal Drug

Effects: Methodologic Issues 206

Cynthia Kuhn, Diane Ignar, and Rolf Windh

Discussion: Neuroteratology of Cocaine Relationship

to Developing Monoamine Systems 233

Jean M. Lauder

Session: Measurement of Drug-Induced Physical and

Behavioral Delays and/or Abnormalities: (C) Learning

and Cognition and (D) Social Bonding/Emotional

and Development

Assessment of Teratogenic Effects on Cognitive and

Behavioral Development in Infancy and Childhood 248

Joseph L. Jacobson and Sandra W. Jacobson

New Methodologies for Evaluating Residual Brain Damage In

Infants Exposed to Drugs of Abuse: Objective Methods for

Describing Movements, Facial Expressions, and

Communicative Behaviors 262

Edward Z. Tronick, Marjorie Beeghly, Linda Fetters,

and M. Katherine Weinberg

Rationale and Methodologies for Developing Nonhuman

Primate Models of Prenatal Drug Exposure 291

Stephen J. Suomi and J. Dee Higley

Discussion: Measurement of Drug-Induced Delays in Learning

and Cognition and Social and Emotional Development 303

Sheldon B. Sparber

vii
Session: Tracking Drug Effects Over the Lifespan

Following Drug-Exposed Infants Into Middle Childhood:

Challenges to Researchers 310

Sydney L. Hans

Patterns of Growth and Development in Narcotic-Exposed Children 323

Marta H. Lifschitz and Geraldine S. Wilson

Integrity of Psychopathology Diagnoses Across the Lifespan 340

Patricia Cohen and Judith S. Brook

Discussion: Drug Effects—A Search for Mechanisms 352

Barry Zuckerman

List of NIDA Research Monographs 363

viii
Drug Exposure to the Fetus—The

Effect of Smoking

Betty R. Kuhnert

INTRODUCTION

Drugs are commonly abused in today’s society. Often, they are abused by

young women—frequently, the same young women who have unplanned

pregnancies. Assessing the extent of exposure of the fetus to drugs of abuse

and determining the effects of prenatal drugs on infant outcome are extremely

difficult. The ideal study for obtaining this information would require knowledge

of how much of a drug or drugs the mother took during pregnancy in order to

correlate the exact amount of fetal drug exposure to neonatal outcome

measures. This chapter presents general issues involved in assessing fetal

drug exposure and reviews recent work on fetal exposure to tobacco smoke.

ASSESSING FETAL DRUG EXPOSURE

The first issue in an ideal study for assessing fetal drug exposure concerns

measuring drug exposure. What is measured? Simply measuring the amount

of drug ingested is not always enough because metabolites of some drugs also

may cause adverse effects on the fetus. For example, meperidine (a narcotic

analgesic) has an active metabolite, normeperidine, which actually causes more

respiratory depression than the parent compound (Miller and Anderson 1954;

Golub et al. 1988). Thus, in this case, both the parent compound and the active

metabolite should be measured. Marijuana, for example, contains hundreds of

ingredients and produces hundreds of metabolites (Szeto, this volume).

Rapidly metabolized drugs are another issue. Such drugs as 2-chloroprocaine,

a local anesthetic, are rapidly metabolized primarily by plasma esterases,

probably plasma cholinesterases. In vitro, the half-life of this drug is measured

in seconds (O’Brien et al. 1979). Cocaine is predominately metabolized by

hepatic enzymes but is also partially metabolized by these esterases. The

cocaine half-life in humans is usually less than 1 hour (Kloss et al. 1984;

Stewart et al. 1979; lnaba et al. 1978; Jatlow et al. 1979). When the drug is

1
unstable in the plasma, appropriate amounts of enzyme inhibitor must be added

to the blood sample at the time of collection. In the case where the half-life of

the drug is very short, a stable metabolite is usually measured (O’Brien et al.

1979; Kuhnert et al. 1980). Benzoylecgonine, a major metabolite of cocaine, is

usually measured for the indication of cocaine exposure (Stewart et al. 1979;

lnaba et al. 1978), and it has been described in one infant’s urine for a period of

several days (Chasnoff et al. 1986).

Measuring the drugs is often a problem because of the expense and the

problems with detection limits if some time has elapsed since the drug was

taken. Analytical methodologies can range from inexpensive immunoassay

techniques, for example, using radioimmunoassay (RIA) or enzyme

immunoassay (such as EMIT) for rapid screening, to sophisticated, timeconsuming but more specific and sensitive gas chromatography/mass

spectrometry for confirmation of nanogram or picogram levels of drugs. Other

commonly used assay methods include thin-layer chromatography (TLC), gasliquid chromatography (GLC), and high-performance liquid chromatography

(HPLC).

The next issue to consider is what sample should be measured. Ideally,

maternal blood samples and perhaps amniotic fluid samples should be

measured during pregnancy. At birth, cord blood tells only what drug is present

at that moment, not what is in the infant’s tissues (Kuhnert et al. 1979).

Neonatal urine can give a better indication of tissue levels, but only if the

collection bags can be kept on and the skin stays intact long enough to get

more than spot samples (Kuhnert et al. 1979). The rapid disappearance and

then fluctuation of phencyclidine in neonatal urine has been documented in this

way (Kuhnert et al. 1984). Maternal blood or urine taken at delivery also can be

very informative (Kuhnert et al. 1984). Finally, an adhesive transcutaneous

collection system that accumulates substances migrating from the blood to the

skin was recently reported for use in preterm infants (Murphy et al. 1990).

However, none of these samples will yield positive results unless drug exposure

has been recent.

Accordingly, other noninvasive techniques for identifying past drug exposure

have been suggested. Meconium from infants of drug-dependent mothers may

test positive for drug metabolites, despite negative neonatal urine samples

(Ostrea et al. 1989). Drug metabolites are thought to accumulate in meconium

throughout gestation by direct deposition from bile, ingestion of metabolites in

amniotic fluid, or both (Ostrea et al. 1989). Alternatively, benzoylecgonine has

been reported in neonatal hair (Graham et al. 1989). Thus, hair analysis also

may identify intrauterine exposure to drugs when maternal history is unclear or

samples of body fluids test negative. However, at present, there are no

2
generally accepted or standardized procedures for hair analysis for drugs of

abuse, and laboratory analysis of hair is both laborious and tedious (Bailey

1989).

The final issue is how to measure neonatal neurobehavioral outcome after drug

exposure. This remains controversial because many clinicians feel that the

classical Brazelton exam (Brazelton 1973) is too time consuming and the data

analysis required is too sophisticated if all of the confounding variables and

pharmacologic variables are considered (Kuhnert et al. 1985).

The following review illustrates how some of the various methodologic issues

can be dealt with in a study of the effect of smoking during pregnancy on

neonatal outcome.

EFFECT OF SMOKING ON NEONATAL OUTCOME

Background

It is well known that smoking during pregnancy is harmful (Surgeon General’s

Report 1979; Abel 1980). The effects range from lesions in the placenta to

abnormal behavior in the offspring (Kuhnert and Kuhnert 1985). The most

common sign of fetal tobacco syndrome is decreased birth weight (Nieburg

et al. 1985). But why cigarette smoking causes decreased birth weight,

particularly in older parturients, is not clear (Cnattingius et al. 1985; Wen et al.

1990). Carbon monoxide and nicotine are obviously harmful components of

cigarette smoke that may be related to decreased birth weight. Carbon

monoxide binds to hemoglobin to form carboxyhemoglobin and cause fetal

hypoxia, and nicotine causes a gamut of effects related to cholinergic agonists

and catecholamine release.

But there are other components of cigarette smoke, including lead (Cogbill and

Hobbs 1957), cadmium (Cd) (Lewis et al. 1972), and thiocyanate (SCN)

(Pettigrew and Fell 1972), that may harm the fetus. Both lead and SCN can

cause decreased birth weight. In addition, it has been suggested that cadmium

may share responsibility for the decreased birth weight of infants of smokers

(Webster 1978; Longo 1980). Smoking is the major source of cadmium in

nonpolluted areas.

The adverse effects of cadmium come from its similarity in structure to zinc (Zn)

and its ability to substitute for zinc in zinc-dependent enzymes, including alcohol

dehydrogenase. The inhibition of this enzyme by cadmium from cigarette

smoke may partially explain the reported potentiation of smoking on the effects

of alcohol use during pregnancy (Fried and Makin 1987; Gusella and Fried

3
1984). However, studies in humans (Roels et al. 1978; Lauwerys et al. 1978)

and animals (Parizek 1965; Levin and Miller 1980) have shown that very little

cadmium actually crosses the placenta. Cadmium actually accumulates in the

placenta and appears to be trapped there (Kuhnert et al. 1982; Van Hattum and

de Voogt 1981; Miller and Gardner 1981).

Hypothesis

Animal studies had suggested the possibility of a cadmium-zinc interaction

because low doses of cadmium resulted in growth retardation and

malformations that were very similar to the same patterns seen in experimental

zinc deficiency (Apgar 1985). It was thought that cadmium would induce the

formation of binding proteins in the placenta that might also trap zinc. Support

for this hypothesis came from the fact that many of the adverse effects of

smoking during pregnancy are also found in mothers who are zinc-deficient

during pregnancy (Jameson 1976; Lazebnik et al. 1988).

Methods

Testing the hypothesis in humans that smoking during pregnancy results In

a cadmium-zinc interaction that may lead to zinc deficiency necessitated

reliable quantification of the exposure to cigarette smoke. Fetal cadmium

levels could not be used as an index of exposure because cadmium does not

cross the placenta in proportion to the amount of smoking (Kuhnert et al. 1982).

Thiocyanate, with its long half-life, has been shown to be a marker that

correlates well with the number of cigarettes the mother smokes (Pettigrew et

al. 1977; Bottoms et al. 1982). Furthermore, fetal SCN correlates well with

maternal SCN (Bottoms et al. 1982).

The outcome measures included placental zinc, maternal and fetal measures of

zinc status, placental cadmium and maternal whole blood cadmium, and birth

weight (Kuhnert et al. 1987a). These variables had to be measured in the

mother to eliminate any effects attributable to maternal zinc status. All elements

were measured by sensitive atomic absorption spectrophotometry techniques.

The Cadmium-Zinc lnteraction

Maternal indices turned out to be similar between smoking and nonsmoking

groups (Kuhnert et al. 1987a, 1988a). This was particularly true for activity of

maternal alkaline phosphatase (a zinc-dependent enzyme) and levels of zinc in

plasma and red blood cells (RBCs). Thus, smoking did not appear to affect

maternal zinc status.

4
As shown in figure 1, maternal whole blood cadmium was 65 percent higher;

placental cadmium was 45 percent higher; and placental zinc was 10 percent

higher in smokers (Kuhnert et al. 1987a). All three fetal indices of zinc status

were significantly lower in the smoking group (figure 2) (Kuhnert et al. 1988a).

The finding that cord blood RBC zinc was 9 percent lower in infants of smokers

was in agreement with the hypothesis that smoking causes accumulated

placental cadmium that traps zinc and results in a zinc-deficient fetus.

FIGURE 1. Effect of smoking on whole blood cadmium, placental cadmium,

and placental zinc

SOURCE: Kuhnert et al. 1987a, copyright 1987, Mosby-Year Book

5
FIGURE 2. Effect of smoking on the assessment of fetal zinc status SEM)

SOURCE: Kuhnert et al. 1988a, copyright 1988, Wiley and Sons

The relationship between several indices of maternal and fetal zinc status also

was disrupted by smoking. The only significant correlation between maternal

and fetal indices of zinc status in nonsmokers was the weak positive

relationship between maternal and fetal RBC zinc (r=0.25); but, in smokers,

there was a weak negative correlation between maternal plasma zinc and cord

6
vein plasma zinc (r=-0.20). This finding again suggests that maternal zinc

stores are not as readily available to the fetus of the mother who smokes during

pregnancy.

The clinical outcome measure was birth weight. As expected, there were

significant differences in the means between the groups of smokers and

nonsmokers (Kuhnert et al. 1987a, 1988a). Infants of smokers were almost

400 g (1 lb) lighter at birth. Cord vein RBC zinc (CVRBCZn) and the ratio of

placental zinc to placental cadmium (Zn/Cd ratio) were positively related to birth

weight in the smoking group. The correlations were r=0.30, p<0.05, and r=0.31,

p<0.05, respectively. In contrast, maternal cadmium and SCN were negatively

related to birth weight, but only in smokers (r=-0.35, p<0.05 and r=-0.33,

p<0.05, respectively) (Kuhnert et al. 1987a, 1987b, 1988a). Furthermore, there

was a significant negative correlation between maternal plasma zinc and birth

weight in smokers (r=-0.29). The only significant correlation in the nonsmoking

group was a correlation between cord vein RBC zinc and birth weight (r=0.30)

(Kuhnert et al. 1988a). These data support the hypothesis that zinc is trapped

in the placenta and that maternal zinc is therefore unavailable for fetal growth in

smokers.

The relationship between cord vein RBC zinc and birth weight is more obvious

when the whole range of birth weights in both groups together is considered

(figure 3) (Kuhnert et al. 1988a). However, when this relationship is broken

down by smoking status, an alteration in smokers is obvious (figure 4). Infants

of nonsmokers always have higher cord vein RBC zinc levels for a given mean

birth weight, suggesting that the infants of smokers may be marginally zinc

deficient. That this is related to smoking is evident from the close relationship

between SCN, the index of smoking exposure, and fetal cord vein RBC zinc

(figure 5).

Maternal Age and Smoking

If the hypothesis of an interaction between zinc and cadmium were correct, one

would expect that placental zinc would correlate with placental cadmium,

especially since the Zn/Cd ratio correlated with birth weight. However, the

findings were not so clear cut. A correlation was found but only in multiparous

patients (r=0.41, p<0.01) (Kuhnert et al., in press). Why? The answer is related

to a similar unanswered question: Why are older pregnant smokers more at

risk for impaired fetal growth (Cnattingnius et al. 1985; Wen et al. 1990)?

Multiparous patients have been reported to be possibly deficient in some

essential trace elements, such as chromium (Hambidge and Rodgerson 1969),

but zinc stores were believed to be replenished after delivery (Rodriguez de la

7
FIGURE 3. Relationship between cord vein RBC zinc and birth weight

SOURCE: Kuhnert et al. 1988a, copyright 1988, Wiley and Sons

8
FIGURE 4. Effect of smoking on the relationship between cord vein RBC zinc

and birth weight

SOURCE: Kuhnert et al. 1988a, copyright 1988, Wiley and Sons

9
FIGURE 5. Relationship between SCN and cord vein RBC zinc

SOURCE: Kuhnert et al. 1988a, copyright 1988, Wiley and Sons

Nuez et al. 1981). However, when the various indices of zinc status were

examined in relation to age or parity, placental zinc levels decreased with

increased parity (figure 6) (Kuhnert et al. 1988b), and alkaline phosphatase

activity also decreased with age (r=-0.26, p<0.05). These results are consistent

with the depletion of body zinc stores with increasing parity and age.

On the other hand, placental cadmium increases with age and parity but only in

smokers (figure 7) (Kuhnert et al. 1988b). These results are consistent with the

10
FIGURE 6. Effect of smoking and parity on placental zinc (mean±SEM)

NOTE: For clarity, only half of the standard error bars are shown. Black

line=smokers; dashed line=nonsmokers.

SOURCE: Kuhnert et al. 1988b, copyright 1988, reprinted with permission from

the American College of Obstetricians and Gynecologists

10-year half-life of Cd in the body (Telisman et al. 1986). The results also agree

with information from autopsy tissues from smokers (Summer et al. 1986).

The relationship of the Zn/Cd ratio in the placenta with age and smoking status

is shown in figure 8. It is obvious that smokers always have lower ratios than

nonsmokers and that the ratio decreases with age. The Zn/Cd ratio was

previously shown to be related to birth weight (Kuhnert et al. 1987b). Thus, the

decrease in zinc with parity or age and the increase with cadmium in smokers

(i.e., the Zn/Cd ratio) provides a partial explanation for the finding that older

parturients are at higher risk for impaired fetal growth. It also attests to the

toxicity of cadmium.

11
FIGURE 7. Effect of smoking and parity on placental cadmium (mean±EM)

NOTE: For clarity, only half of the standard error bars are shown. Black

line-smokers; dashed line=nonsmokers.

SOURCE: Kuhnert et al. 1988b, copyright 1988, reprinted with permission from

the American College of Obstetricians and Gynecologists

CONCLUSION

It is well known that smoking results in smaller infants, but the mechanism has

been unclear, particularly in older women. Choosing the appropriate indicator

of exposure to cigarette smoke and accurately measuring the appropriate

outcome variables In the right samples with sensitive techniques has made it

possible to suggest that infants of smokers are smaller because they may be

marginally zinc-deficient. It also can be suggested that older parturients are at

increased risk of bearing infants with decreased birth weight due to an altered

placental zinc-to-cadmium ratio. Similar research strategies and methodologies

could be used to measure the effects of exposure to other drugs of abuse

during pregnancy.

12
FIGURE 8. Effect of smoking and age on the ratio of placental zinc to

placental cadmium

NOTE: Black line=smokers; dashed line=nonsmokers

SOURCE: Kuhnert et al. 1988b, copyright 1988, reprinted with permission from

the American College of Obstetricians and Gynecologists

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of 2-chloroprocaine in obstetric patients and their neonates after epidural

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Kuhnert, B.R.; Kuhnert, P.M.; Tu, A.S.L.; and Lin, D.C.K. Meperidine and

normeperidine levels following meperidine administration during labor. II.

Fetus and neonate. Am J Obstet Gynecol 133(8):909-914, 1979.

Kuhnert, B.R.; Kuhnert, P.M.; and Zarlingo, T.J. Associations between

placental cadmium and zinc and age and parity in pregnant women who

smoke. Obstet Gynecol 71(1):67-70, 1988b.

Kuhnert, B.R.; Linn, P.L.; and Kuhnert, P.M. Obstetric medication and neonatal

behavior—Current controversies. Clin Perinatol 12(2):423-439, 1985.

Kuhnert, P.M.; Kuhnert, B.R.; Bottoms, S.F.; and Erhard, P. Cadmium levels in

maternal blood, fetal cord blood, and placental tissues of pregnant women

who smoke. Am J Obstet Gynecol 142(8):1021-1025, 1982.

Kuhnert, P.M.; Kuhnert, B.R.; Erhard, P.; Brashear, W.T.; Groh-Wargo, S.L.;

and Webster, S. The effect of smoking on placental and fetal zinc status.

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the frequency distributions of the biological indices in maternal and umbilical

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pregnancy complications, and labor abnormalities. Am J Obstet Gynecol

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Levin, A.A., and Miller, R.K. Fetal toxicity of cadmium in the rat: Maternal vs.

fetal injections. Teratology 22:1-5, 1980.

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Longo, L.D. Environmental pollution and pregnancy: Risks and uncertainties

for the fetus and infant, Am J Obstet Gynecol 137(2):162-173, 1980.

Miller, J.W., and Anderson, H.H. The effect of N-demethylation on certain

pharmacologic actions of morphine, codeine, and meperidine in the mouse.

J Pharmacol Exp Ther 112:191-196, 1954.

15
Miller, R.K., and Gardner, K.A. Cadmium in the human placenta: Relationship

to smoking. (Abstract.) Teratology 23:51, 1981.

Murphy, M.G.; Peck, C.C.; Conner, D.P.; Zamani, K.; Merenstein, G.B.; and

Rodden, D. Transcutaneous theophylline collection In preterm Infants. Clin

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Nieburg, P.; Marks, J.S.; McLaren, N.M.; and Remington, P.L. The fetal

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and measurement of chloroprocaine, an ester-type local anesthetic. J Pharm

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16
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50066. Washington, DC: Supt. of Docs., U.S. Govt. Print. Off., 1979.

pp. 8.1-8.93.

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ACKNOWLEDGMENT

The research described here was supported in part by US. Public Health

Service, National Institutes of Health grants 5MO1-RR-00210, NO1-RR-8-2212,

RO1-HD-13359, and RO1-DAU-2903.

AUTHOR

Betty R. Kuhnert, Ph.D., M.B.A.

Associate Professor, Reproductive Biology

Perinatal Clinical Research Center

Cleveland Metropolitan General Hospital

Case Western Reserve University

3395 Scranton Road

Cleveland, OH 44109

Present title and address

Associate Director

Clinical Communications

Clinical Research and Development

Wyeth-Ayerst Research

P.O. Box 8299

Philadelphia, PA 19101

17
Pharmacokinetic Correlates of Fetal

Drug Exposure

C. Lindsay DeVane

INTRODUCTION

Essentially all drugs taken by a pregnant woman reach her fetus. The

consequences of fetal drug exposure may be inconsequential, disastrous, or, in

most cases, unknown. Pharmacokinetic studies attempt to quantitate the

degree of fetal drug exposure. Factors that determine the degree of fetal drug

exposure include maternal absorption, distribution, and elimination; bidirectional

placental transfer; placental disposition; and fetal distribution and elimination. A

major determinant of fetal relative to maternal drug exposure is the lipid

solubility of the drug or chemical of interest. Most xenobiotics possess sufficient

lipid solubility so that the placenta does not limit drug transfer to the fetus, and

fetal exposure becomes limited only by blood flow. Ironically, the neonatal

period may be associated with slower elimination of fetally received drugs

because of the abrupt cessation of maternal contributions to drug elimination at

the time of birth.

The accurate measurement of fetal exposure to a maternally administered drug

is crucial to establishing the relationship between maternal drug use and fetal

effects. This is a major objective of pharmacokinetic studies, along with

assessing the risk of potential fetal harm from xenobiotic exposure. In addition,

an important aim of pharmacokinetic studies is to predict drug exposure of the

fetus given a specific maternal exposure. This is important not only in

establishing thresholds that are associated with hazardous effects on the fetus

from maternal drug ingestion, but also in developing guidelines to treat the fetus

pharmacologically with appropriate maternally administered drug-dosage

regimens as medical science extends treatment to the preterm fetus (Cagnazzo

and D’Addario 1989).

With the advent of methodology for the specific and sensitive measurement of

plasma drug concentrations during the 1960s and 1970s there has been an

increased emphasis on pharmacokinetic studies of placental drug transfer (Nau

and Scott 1987). This chapter reviews problems and design considerations

18
inherent in conducting pharmacokinetic studies of fetal drug exposure and

potential methods for minimizing these obstacles in the analysis of data. The

focus is on neither animal nor human studies exclusively, but on general

principles involved in all studies of fetal drug exposure.

PROBLEMS IN PLACENTAL TRANSFER STUDIES

Factors Contributing to Intersubject Variability

The list below enumerates the potential factors contributing to intersubject

variation in fetal drug exposure. The degree of variability is often large, both

between and within individuals. Although it is generally assumed that variability

in pharmacological/toxicological response is the result of pharmacokinetics, it is

reasonable to assume that the pharmacodynamic response also may vary.

Much less is known about this source of variability in the toxicological response

to maternally administered drugs than about the sources of pharmacokinetic

variability.

Maternal factors

— Overall state of health

— Cardiovascular, renal, hepatic, and endocrine function

— Acid-base balance

— Concentration of plasma drug-binding proteins

— Presence or absence of plasma drug-binding displacers

— Gestational age

Fetal factors

— Gestational age

— Serum/plasma drug-binding proteins

— Hepatic and renal development

Other factors

— Input rate of drug and size of dose

— Functional state of placenta

The dynamic physiological status of the mother and fetus during pregnancy

results in changes in numerous plasma constituents, including the major

drug-binding proteins (Hytten and Chamberlain 1980). These changes directly

affect fetal drug exposure. Both albumin and alpha-1-acid glycoprotein

concentrations become reduced during the course of pregnancy. This effect

19
implies that highly protein-bound acidic and basic drugs may have an increased

free fraction or concentration. The mean change of albumin from the third

month of gestation to the ninth in 27 women was from 44±5 g/L to 32±5 g/L

(Haram et al. 1983). Alpha-1-acid glycoprotein changed from 0.72±0.21 to

0.50±24 g/L during pregnancy. The widely held assumption that only unbound

drug is able to pass the placenta predicts that a diffusion equilibrium can be

expected to exist at steady-state between free drug concentration in maternal

plasma and fetal plasma. Reduced maternal binding as a result of either the

presence of binding displacers or reduced binding proteins would allow more

free drug to pass the placenta. In addition, if drug binding is greater on the fetal

side when equliibrium of free drug across the placenta is established, then total

drug concentration would be greater in the fetal plasma, even though the free

concentration should be equivalent to that of the maternal side. This reasoning

is consistent with several observations of high-plasma diazepam and Ndesmethyldiazepam concentration in maternal and fetal plasma (Gamble et al.

1977; Hamar and Levy 1980; Kuhnz and Nau 1983).

Collection of Data at Appropriate Intervals

Human studies of fetal drug exposure are limited by ethical and practical

considerations. Generally, the data of many pharmacokinetic studies in

humans has provided descriptive information involving determinations of

maternal and fetal drug exposure at only a single time point. Ethical

considerations prohibit sampling from humans during pregnancy, except in a

few circumstances where the benefits of drug exposure are judged to outweigh

the risks of maternal drug administration. Often, pharmacokinetic studies

consist of data from a limited number of sample times for the determination of

when and how much of the drug is transferred to the fetus. Several researchers

have emphasized the inability to draw valid conclusions about the extent of fetal

drug exposure when samples are limited. For this reason, in vivo animal

models have become a major research tool. Depending on whether the fetal

drug plasma concentration is below, equal to, or greater than maternal plasma

drug concentration at the time of sampling, the conclusion reached that

placental transfer is either minimal or extensive could be very misleading. As

illustrated in figure 1, the concentration of cocaine in the fetal iamb exceeds that

in the pregnant ewe for approximately 4 minutes following an Intravenous (IV)

maternal cocaine dose (DeVane et al., in press). A single sample taken before

or after 4 minutes would suggest opposite conclusions about the degree of

placental passage of cocaine. Therefore, the area under the concentration-time

curve (AUC) has been used as a better index for drug exposure after a single

dose. it is important in the assessment of placental transfer to collect an

adequate number of samples to better define the extent of drug exposure.

Obviously, the ability to estimate pharmacokinetic parameters improves as the

number of data points increases.

20
FIGURE 1. Plasma concentration vs. time course of cocaine in a ewe and its

fetus following a 2 mg/kg IV bolus dose to the ewe

SOURCE: Data taken from DeVane et al., in press

In many studies, the time of sampling may occur randomly, either by necessity

or by temporary convenience. The number of observations may vary widely

between individuals. Also, depending on the drug or chemical of interest, the

emphasis may shift from single-dose situations to steady-state conditions. in

figure 2, the plasma concentrations of imipramine (IMI) (50 mg/day oral

administration) and its three major pharmacologically active metabolites in a

pregnant woman with panic disorder can be seen to remain relatively stable

during the final 3 months of gestation (Ware and DeVane 1990). Cord plasma

at delivery contained all four drugs, but in lower concentration than in maternal

plasma. These data also suggest a postdelivery change in desipramine (DMI)

disposition, with Increased concentration in both maternal plasma and breast

milk after delivery. Apart from documenting fetal drug exposure, only limited

21
FIGURE 2. Plasma concentrations of IMI and its three major metabolites

(DMI; 2-hydroxy-imipramine, 2-OH-IMI; 2-hydroxy-desipramine, 2-

OH-DMI) following 50 mg/day oral administration in a pregnant

woman, Concentrations are also shown for breast milk (BM) at

the time of delivery and from a sample of plasma obtained from

the infant’s cord blood (CP).

information from data of this type can be extrapolated to other pregnant women

receiving IMI therapy.

INTERSPECIES DIFFERENCES IN DRUG DISPOSITION

Active Metabolites

The assessment of fetal drug exposure is complicated by recognition that many,

if not most, drugs produce biologically active metabolites. Thus, measurement

of fetal drug exposure should include the contribution of pharmacologically

active metabolites. Figure 3 shows the maternal plasma and whole fetal

22
tissue concentrations of DMI, the demethylated metabolite of the tricyclic

antidepressant IMI, following an intraperitoneal (IP) injection of 30 mg/kg IMI to

pregnant rats (DeVane and Simpkins 1985). Following an oral dose, DMI is

extensively formed in humans by presystemic elimination of IMI in the liver.

Steady-state DMI concentrations usually exceed those of IMI during chronic

therapy. However, as shown in figure 2, there are exceptions to this

generalization, as plasma DMI was lower than was IMI during pregnancy. The

rapid appearance of DMI in the maternal rat plasma (figure 3) and parallel

decline in the fetus suggest both maternal formation of DMI and elimination with

equilibrium of drug distribution in the fetus. Even when human data are limited,

if combined with animal data, insight may be gained into fetal drug exposure

during gestation.

FIGURE 3. IMI and DMI concentrations in pregnant rat plasma (Mat. IMI; Mat.

DMI) and whole fetal tissues following IP administration of 30 mg/

kg IMI

23
The issue of active metabolites is further complicated by the fact that maternally

administered drugs may be biotransformed in several major sites, including the

maternal liver, placenta, and fetal liver. Renal clearance by the fetus is also

possible. By directly infusing cocaine into the fetal lamb, DeVane and

colleagues (in press) were able to measure ecgonine methylester and

benzoylecgonine, two major metabolites of cocaine, in the fetal circulation.

Their concentrations were higher than in the maternal circulation, implying

cocaine metabolism by the fetal liver.

More rigorous experiments are needed to define the precise contribution of fetal

metabolism to the overall fetal disposition of a maternally administered drug.

Although contribution of fetal drug clearance to the overall total body clearance

(including both fetal and maternal clearance) may be negligible (Levy 1981),

fetal clearance may account for a substantial portion of the total clearance of

the drug from the fetus. Szeto and colleagues (1982) found the fetal metabolic

clearance of methadone to be 21 to 51 percent of the total clearance of

methadone from the fetal compartment. These relatively high values may not

hold for other drugs or other species. This 2.4-fold range of fetal metabolic

clearance values also reflects the role of the fetus as a source of variability In

fetal drug exposure. A fetus may eliminate a drug rapidly, causing a rapid

decrease in fetal drug concentrations in some instances. Nevertheless, this

situation could result in fetal accumulation of metabolites; and, if these are not

rapidly transferred to the maternal circulation and excreted, considerable

teratogenicity could follow. Such a mechanism has been speculated to underlie

the teratogenetic effects of thalidomide (Juchau 1989).

The role of the placenta in drug disposition has been reviewed by Juchau

(1976). The in vitro-isolated perfused placenta has been used to assess the

extent of biotransformation of drugs by the human placenta.

Quantitative Differences In Metabolic Pathways

Comparison of different species is useful in assessing fetal drug exposure.

Figure 4 Includes data obtained from several investigations on the elimination

of cocaine, normalized for administered dose, in the pregnant rat (DeVane et al.

1989), dog (Kanter et al., submitted for publication), and pregnant sheep

(DeVane et al., in press). Comparison also is made with cocaine

concentrations calculated from pharmacokinetic parameters in humans, as

reported by Chow and coworkers (1985). Some differences can be appreciated

in the rate of cocaine’s elimination from plasma among these species. In

pregnant sheep, cocaine had a mean half-life of 5.0 minutes in the ewe and 4.3

minutes in the fetal lamb. Khan and coworkers (1987) attributed the rapid

clearance of cocaine in the sheep (mean half-life of 12.9 minutes) to pulmonary

24
FIGURE 4. Cocaine disposition in different species. Plasma concentrations

are shown for the pregnant rat (DeVane et al. 1989), dog

(Kanter et al., submitted for publication), pregnant ewe (DeVane

et al., in press), and human (Chow et al. 1985). The curve for

humans is calculated from mean pharmacokinetic parameters.

Concentrations have been normalized to a 3 mg/kg dose. Route

of administration was IP in rat and IV in all other species.

clearance not occurring in other species (half-life in humans of 48 minutes).

Although the ovine maternal-fetal model has been useful for studying several

drugs (Szeto 1982), the clearance pathways of cocaine in this species may

make it less suitable for studying fetal drug exposure of this particular drug of

abuse.

DeVane and colleagues (1989) found in rodent studies that the AUC for

norcocaine was only 3.1 percent of that of cocaine in maternal plasma;

however, norcocaine was present in substantial concentration in whole fetal

tissues compared with maternal plasma. The tissue concentration vs. time

25
curves of norcocaine in the fetal rat compared with those in maternal plasma

can be seen in figure 5. Thus, the near absence of a metabolite in the maternal

plasma cannot be taken as evidence of a lack of fetal metabolite exposure.

In contrast to the rodent data, DeVane and coworkers (in press) have been

unable to quantitate norcocaine in pregnant sheep using a high performance

liquid chromatography assay with a sensitivity of 1 ng/mL and cocaine doses up

to 4 mg/kg. However, norcocaine has been found in the urine of cocaineexposed infants (Chasnoff and Lewis 1988) suggesting that this metabolite is

potentially important in humans, Norcocaine has been found to have some of

the pharmacologic activity of cocaine (Hawks et al. 1975). Thus, interspecies

differences in drug disposition may be important considerations, both

quantitatively and qualitatively, in assessing the consequences of fetal drug

exposure.

FIGURE 5. Time course of norcocaine concentrations in maternal plasma and

fetal tissues of the fetal rat following a 30 mg/kg IP dose

26
EXPERIMENTAL REQUIREMENTS

Basic Considerations in Study Design

The fetal-drug-exposure problem is complicated by an uncertain knowledge of

how to best express fetal exposure and to compare exposure between drugs

and species. The area under the plasma or tissue concentration vs. time curve

Is widely believed to be an accurate representation of fetal exposure. DeVane

and colleagues (1991) found that the same mg/kg dose of phenobarbital and

phenytoin administered to rats resulted in an identical ratio of AUC in fetus to

AUC in maternal plasma (AUC-F/AUC-M) of 0.77. This finding suggests that

the rat fetus received an identical proportional exposure relative to the maternal

plasma concentration of either of these drugs. However, phenytoin has more

teratogenic potential than does phenobarbital when used as an anticonvulsant

by pregnant women. Thus, in terms of pharmacodynamic and toxicologic

implications, the free drug concentration should be considered rather than the

total drug in plasma (plasma protein bound plus free).

In the commonly used two-compartment pharmacokinetic model, where the

fetus has minimal ability to eliminate drugs, at steady-state the fetal plasma

concentration should be equal to the maternal plasma concentration when

referenced to free, nonprotein bound drug. Such models, discussed in more

detail below, also consider the maternal and fetal compartments to exist with

homogeneous drug distribution. However, this is a simplification, as neither

the fetus nor the mother behave as a homogeneous compartment. Table 1

shows AUC values found for various fetal tissues for different drugs

administered to pregnant Sprague-Dawley rats at a dose of 30 mg/kg. The

fetal drug distribution is both uneven and inconsistent between drugs. It

therefore appears that maternal and fetal tissue concentrations are dictated by

binding to tissue components, As suggested by differences in teratogenic

potential among drugs, most of this binding is probably nonspecific and

pharmacodynamically irreveiant. Nevertheless, the degree of fetal drug

exposure can be predicted by physiochemical properties of drugs. In figure 6,

the relationship between the AUC of the whole rat fetus to the AUC in the dam

strongly correlates with the logarithm of the octanol-water partition coefficient of

the administered drug (Leo et al. 1971). Several researchers have found

positive relationships between lipid solubility and biological activity (Kubinyi

1979; Manners et al. 1988).

As mentioned above, phenytoin and phenobarbital had the same relative fetal

exposure referenced to total maternal plasma concentration, although the

partition coefficient for phenytoin is greater. By taking literature values for free

drug concentration, the inset in figure 6 shows a much stronger relationship

27
TABLE 1. Fetal rat tissue exposure to various drugs*

Drug

Administered Whole Fetus

Tissue

Placenta Fetal Liver Fetal Brain

IMI

Phenytoin

Phenobarbital

Morphine

Cocaine

14.9 53.3

(7.5) (26.9)

57.7 74.6

(0.8) (1.0)

586.0 659.0

(0.8) (0.9)

12.9 141.0

(2.5) (27.0)

130.6 98.3

(3.3) (25.1)

32.9

(16.6)

90.2

(1.2)

495.0

(0.6)

135.0

(26.0)

81.3

(20.7)

33.5

(16.9)

67.6

(0.9)

390.0

(0.5)

23.8

(4.5)

5.6

(1.4)

*Values are AUC in mcg/mL hr following a dose of 30 mg/kg IP. AUC ratios to

maternal plasma appear in parentheses.

between fetal exposure when referenced to free plasma concentration in the

dam. In many cases, fetal drug exposure referenced to free drug concentration

will be unity, and differences between total (free and bound) drug in AUC ratios

may have little significance (Levy 1981). If this reasoning is correct, then future

studies should consider free drug concentration in maternal plasma as a

primary determinant of fetal drug exposure.

Idealized Data for Parameter Estimation

Ideally, the extent of fetal drug exposure given a maternal drug dose should be

known. Assessment of differences between single exposure and steady-state

conditions would be desirable, as would some evaluation of linearity. The

relative contribution of fetal clearance to maternal clearance should be

determined, as well as the separate contributions of fetal liver, renal, and

placenta processes. In addition, it would be desirable to know how

perturbations in the mother affect fetal drug exposure. These would include

changes in maternal serum constituents and other physiological changes that

normally occur during pregnancy (Hytten and Chamberlain 1980; Notarianni

1990) that affect the relative risk of fetal exposure at different times of

pregnancy.

28
FIGURE 6. The relationship between log octanol/water partition coefficient

(PC) and ratio of area under the fetal tissue concentration vs. time

curve (AUC-F) to maternal plasma concentration vs. time curve

(AUC-M) in rats after IP administration of several drugs. The

inset shows the relationship between PC and the AUC ratio for

calculated free concentration in maternal plasma (AUC-F/AUCM[f]).

Ultimately, fetal drug exposure must be related to pharmacological effects. In

doing so, effect-concentration pairs of data should be collected under

circumstances in which concentrations are both rising and falling in the maternal

organism, at steady-state. Because of the variability in fetal drug exposure,

sample size in animal studies needs to be adequate to define the extent of

variability. It should be ensured that sampling does not alter either the

pharmacokinetics or the pharmacodynamics of the drug. Ail active metabolites

should be measured. When appropriate in pharmacodynamic studies, the

effect of placebo should be determined. Route of administration can be

29
important for some drugs. Finally, factors contributing to intersubject variability

should be assessed.

METHODS FOR ANALYSIS OF PHARMACOKINETIC DATA

Descriptive Approach

The most common approach to analysis of pharmacokinetic data is descriptive,

including a history of maternal drug exposure, any pharmacokinetlc data that

may be available (such as plasma or urine drug/metabolite concentrations), and

any pharmacodynamic observations. This type of report is illustrated by the IMI

data described above (figure 2) (Ware and DeVane 1990).

Compartmental Models

Compartmental modeling is the classical approach to pharmacoklnetic analysis

of data. Figure 7 is a compartmental model proposed by Krauer and colleagues

(1980). A compartment consists of tissues that can be treated kinetically as a

homogenous unit. Generally, there is no physiological counterpart, as all

models are an approximation of biological systems. However, a model need

not be any more complex than required to serve the scientist’s function and

purpose.

Compartmental modeling fits exponential functions to a drug concentration time

curve. Tissues are lumped together and the body represented as one or more

large compartments, generally termed a central, or shallow, compartment and

peripheral, or deep, compartment(s). Following drug administration, rapid

equilibrium is reached between the tissues of central compartment and the

blood, while slow equilibrium is reached between tissues of the peripheral

compartment(s) and the blood.

The simplest maternal-fetal compartmental model would consist of a maternal

and a fetal unit. Consistent with observations that the human fetal liver can

metabolize various xenobiotics (Pacifici et al. 1987), elimination could occur

from both the maternal and the fetal compartments. An intercompartmental

clearance or rate constant describes the transfer of drug across the placenta.

Maternal and fetal plasma concentration versus time data are necessary to

derive estimates of all parameters of this model. Following separate constant

rate IV infusions to the mother and fetus, both the maternal and the fetal

steady-state free drug concentrations are measured. Experimental data for

several narcotic agonists have been obtained using this approach by Szeto and

colleagues (1982).

30
FIGURE 7. Maternal-fetal compartmental pharmacokinetic model consisting

of a maternal central and peripheral compartment and a placental

and fetal compartment. Rate constants (kii) describe transfer

between compartments or absorption into the central

compartment (ka).

Several disadvantages of compartment modeling are apparent. This empirical

approach does not describe a physiological system with large tissue-to-tissue

concentration differences as shown in table 1. Such models may be

inadequate if the drug has a specific target organ. Compartmental models do

not permit extrapolation from species to species. The volume of distribution and

transfer rate constants are based on mathematics rather than on actual

anatomy and physiology.

The assumption of compartmental models of kinetic homogeneity does not

mean that drug concentrations in all tissues of compartments are equal but,

instead, that any change in plasma concentration reflects a change in the

central compartment. Peripheral compartments are hybrids of several

physiological units. Tissues may be in the peripheral or central compartment,

depending on distribution properties of the drug. Drug elimination is assumed

to be first order, as are drug transfers between compartments. Whether a

distribution phase is apparent after rapid maternal drug administration depends

on the frequency with which blood samples are taken. The two or three

compartment models often fail, especially when several species are scaled, to

account for metabolites, or the administration of other drugs.

31
Physiological Models

In contrast to compartmental models, physiological models incorporate blood

flow, perfusion, organ size, and anatomical arrangement of all relevant organs.

Figure 8 illustrates the basic concept of a physiological model incorporating a

placental and fetal compartment. Literature values for organ size and blood

flow can be Incorporated with observed concentration data to fit the data to

equations. These models (Gabrielsson and Paazlow 1983; Gabrielsson and

Larsson 1987) have successfully predicted fetal exposure to maternally

administered morphine and salicylic acid in the rat.

Physiological pharmacokinetic models are far better than compartmental

models to identify sources of variability and to predict how such variability is

expressed in terms of fetal drug exposure. Obviously, the amount of data

necessary for physiological modeling far exceeds that for compartmental

modeling. Nevertheless, the use of physiologically based models represents

progress in developing insight into the sources of variability that affect placental

drug transfer and fetal drug exposure. However, once sources of variablity are

identified, the problem remains of assessing their significance in regard to

overall fetal health.

Combined Pharmacokinetic-Pharmacodynamic Models

The lack of pharmacologic response data in most pharmacokinetic studies of

placental transfer greatly limits the ability to utilize pharmawkinetic data. The

combined kinetic-effect models (Holford and Sheiner 1982; Schwartz et al.

1989) offer very attractive approaches for relating pharmacokinetic data on fetal

drug exposure with pharmacodynamic events. Theoretically, this approach is

capable of relating a concentration at an “effect” site with pharmacological

effects, but it has not yet been applied to studies of fetal drug exposure.

METHODS FOR MINIMIZING PROBLEMS IN PHARMACOKINETIC STUDIES

Obtaining Sufficient Data

Pharmacokinetic studies must be designed to obtain sufficient data to

characterize the maternal and fetal drug exposure. When only a few data

points are obtained, the estimates of kinetic parameters (half-life, clearance,

AUC) will be unreliable.

Obtaining serial blood or plasma samples is difficult or impossible in small

laboratory animals. For this reason, much information on placental transfer has

been obtained using the pregnant ewe (Szeto 1982). This preparation allows

32
FIGURE 8. Maternal-fetal physiological pharmacokinetic model.

Compartments are connected by blood flows (Q) between the

venous and arterial blood, with elimination by clearance (Cl) from

various organs and tissues.

cannulation of fetal blood vessels in order to serially collect simultaneous

blood samples from the fetus and the mother during transfer experiments.

In addition, the fetal lamb is not sacrificed and can be used in repeated

experiments, providing the additional advantage of being able to use a fetus as

its own control. This is a suitable model for application of the combined

pharmacokinetic-pharmacodynamic approach discussed above.

33
Extrapolating Pharmacokinetics Across Species

Drug disposition across species has been estimated frequently using body

weight (Mordenti 1986; Owens et al. 1987) after the relationships first described

by Adolph (1949). The studies of Boxenbaum (1982) and Dedrick and Bischoff

(1980) are notable for incorporating a time variable, maximum lifespan

potential, along with the physiological pharmacokinetic approach in relating the

clearance and protein binding of several drugs among different species. With

the increasing reports of values for fetal drug clearance, it may be possible to

use this approach to predict fetal drug exposure.

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mammals. Science 109:579-585, 1949.

Boxenbaum, H. Interspecies scaling, allometry, physiological time, and the

ground plan of pharmacokinetics. J Pharmacokinet Biopharm 10:201 -227,

1982.

Cagnazzo, G., and D’Addario, V., eds. The Fetus as Patient. Amsterdam:

Excerpta Medica, 1989.

Chasnoff, I.J., and Lewis, D.E. Cocaine metabolism during pregnancy. Pediatr

Res 23[Suppl]:257A, 1988

Chow, M.J.; Ambre, J.J.; Ruo, T.I.; Atkinson, A.A., Jr.; Bowsher, D.J.; and

Fischman, M.W. Kinetics of cocaine distribution, elimination, and

chronotropic effects. Clin Pharmacol Ther 38:318-324, 1985.

Dedrick, R.L., and Bischoff, K.B. Species similarities in pharmacokinetics. Fed

Proc 39:54-59, 1980.

DeVane, C.L.; Burchfield, D.J.; Abrams, R.M.; Miller, R.L.; and Braun S.B.

Disposition of cocaine in pregnant sheep. I. Dev Pharmacol Ther, in press.

DeVane, CL., and Simpkins, J.W. Pharmacokinetics of imipramine and its

major metabolites in pregnant rats and their fetuses following a single dose.

Drug Metab Dispos 13:438-442, 1985.

DeVane, CL.; Simpkins, J.W.; Miller, R.L.; and Braun, S.B. Tissue distribution

of cocaine in the pregnant rat. Life Sci 45:1271-1276, 1989.

DeVane, C.L.; Simpkins, J.W.; and Stout, S.A. Distribution of phenobarbital and

phenytoin in pregnant rats and their fetuses. Epilepsia 32:250-256, 1991.

Gabrielsson, J.L., and Larsson, K.S. The use of physiological pharmacokinetic

models in studies on the disposition of salicyclic acid in pregnancy. In: Hau,

H., and Scott, W.J., Jr., eds. Pharmacokinetics in Teratogenesis. Vol. II.

Boca Raton, FL: CRC Press, 1987. pp. 13-26.

Gabrielsson, J.L., and Paalzow, L.K. A physiological pharmacokinetic model for

morphine disposition in the pregnant rat. J Pharmacokinet Biopharm 11:147-

163, 1983.

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Gamble, J.A.S.; Moore, J.; Lamki, H.; and Howard, P.J. A study of plasma

diazepam levels in mother and infant. Br J Obstet Gynaecol 84:588-591,

1977.

Hamar, C., and Levy, G. Serum protein binding of drugs and bilirubin in

newborn infants and their mothers. Clin Pharmacol Ther 28:58-63, 1980.

Haram, K.; Augensen, K.; and Elsayed, S. Serum protein pattern in normal

pregnancy with special reference to acute-phase reactants. Br J Obstet

Gynaecol 90:139-145, 1983.

Hawks, R.L.; Kopin, I.J.; Colburn, R.W.; and Thoa, N.B. Norcocaine: A

pharmacologically active metabolite of cocaine found in brain. Life Sci

15:2189-2195, 1975.

Holford, N.H.G., and Sheiner, L.B. Kinetics of pharmacologic response.

Pharmacol Ther 16:143-166, 1982.

Hytten, F.E., and Chamberlain, G. Clinical Physiology in Obstetrics. Oxford,

England: Blackwell Scientific, 1980.

Juchau, M.R. Drug biotransformation reaction in the placenta. In: Mirkin, B.L.,

ed. Perinatal Pharmacology and Therapeutics. New York: Raven Press,

1976. pp. 29-39.

Juchau, M.R. Bioactivation in chemical teratogenesis. Annu Rev Pharmacol

Toxicol 29:165-187, 1989.

Kanter, R.J.; DeVane, CL.; and Epstein, M.L. Electrocardiographic and

electrophysiologic effects of very high-dose cocaine on dogs. Am J Cardiol,

submitted for publication.

Khan, M.; Gupta, P.K.; Cristie, R.; Nangia, A.; Winter, H.; Lam, F.C.; and

Perrier, D.G. Determination of pharmacokinetics of cocaine in sheep by

liquid chromatography. J Pharm Sci 76:39-43, 1987.

Krauer, B.K.; Krauer, F.; and Hytten, F.E. Drug disposition and

pharmacokinetics in the maternal-placental-fetal unit. Pharmacol Ther

10:301-328, 1980.

Kubinyi, H. Lipophilicity and biological activity. Arzneimittelforschung 29:1067-

1080, 1979.

Kuhnz, W., and Nau, H. Differences in in vitro binding of diazepam and Ndesmethyldiazepam to maternal and fetal plasma proteins at birth: Relation

to free fatty acid concentration and other parameters. Clin Pharmacol Ther

34:220-226, 1983.

Leo, A.; Hansch, C.; and Elkins, D. Partition coefficients and their uses. Chem

Rev 71:525-616, 1971.

Levy, G. Pharmacokinetics of fetal and neonatal exposure to drugs. Obstet

Gynecol 58(5, Suppl):9S-16S, 1981.

Manners, C.N.; Payling, D.W.; and Smith, D.A. Distribution coefficient, a

convenient term for the relation of predictable physico-chemical properties to

metabolic processes. Xenobiotica 18:331-350, 1988.

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Mordenti, J. Man versus beast: Pharmacokinetic scaling in mammals.

J Pharm Sci 75:1028-1040, 1986.

Nau, H., and Scott, W.J., Jr., eds. Pharmacokinetics in Teratogenesis. Vols. I

and II. Boca Raton, FL: CRC Press, 1987.

Notarianni, L.J. Plasma protein binding of drugs in pregnancy and neonates.

Clin Pharmacokinet 18:20-36, 1990.

Owens, S.M.; Hardwick, W.M.; and Blackall, D. Phencyclidine pharmacokinetic

scaling among species. J Pharmacol Exp Ther 242:96-101, 1987.

Pacifici, G.M.; Peng, D.; Bistoletti, P.; Mellgren, A.; and Rane, A. Morphine

glucuronidation in human fetal liver cultures and isolated hepatocytes. In:

Nau, H., and Scott, W.J., Jr., eds. Pharmacokinetics in Teratogenesis. Vol.

II. Boca Raton, FL: CRC Press, 1987. pp. 219-224.

Schwartz, J.B.; Verotta, D.; and Sheiner, L.B. Pharmacodynamic modeling of

verapamil effects under steady-state and nonsteady-state conditions.

J Pharmacol Exp Ther 251:1032-1038, 1989.

Szeto, H.H. Pharmacokinetics in the ovine maternal-fetal unit. Annu Rev

Pharmacol Toxicol 22:221-243, 1982.

Szeto, H.H.; Umans, J.G.; and Rubinow, S.I. The contribution of transplacental

clearances and fetal clearance to drug disposition in the ovine maternal-fetal

unit. Drug Metab Dispos 10:382-386, 1982.

Ware, M.R., and DeVane, C.L. Treatment of panic disorder during pregnancy

with imipramine. J Clin Psychiatry 51:482-484, 1990.

ACKNOWLEDGMENT

Preparation of this chapter was supported in part by National Institute of Child

Health and Human Development grant HD-14075 and National Institute on Drug

Abuse grant DA-05170.

AUTHOR

C. Lindsay DeVane, Pharm.D.

Professor of Pharmacy and Psychiatry

Department of Pharmacy Practice

University of Florida

Box J-486

Gainesville, FL 32610

36
Discussion: Methodological Issues in

Controlled Studies on Effects of

Prenatal Drugs

Hazel H. Szeto

INTRODUCTION

The primary concern in the use of both licit and illicit drugs during pregnancy is

the adverse effects that these drugs may produce on the developing fetus.

Over the past 10 years, there has been a dramatic increase in clinical and basic

research on the Impact of substance abuse on the fetus. These investigations

have progressed from simply determining if a certain drug “crosses the

placental barrier” and the adverse effects seen in the neonate to highly

sophisticated studies determining the mechanisms of drug action on the fetus.

Kuhnert and DeVane (this volume) allude to the fact that the placenta does not

serve as a barrier to exclude drugs from the fetus. This is particularly true for

drugs that are readily distributed to the central nervous system, as are the drugs

of abuse.

Kuhnert (this volume) proposes to correlate the extent of fetal drug exposure to

neonatal outcome measures. However, the extent of fetal drug exposure in the

human can be rather difficult to ascertain. Some of the difficulties have been

outlined by Kuhnert. Although the presence of drug or metabolites in cord

blood, amniotic fluid, or neonatal urine may indicate that the fetus has been

exposed to the drug at some time prior to sample collection, it does not reveal

the frequency of drug use nor the overall extent of fetal drug exposure

throughout gestation. The quantitation of drug or metabolites in meconium or

neonatal hair would certainly help in determining drug exposure for drugs that

are eliminated rapidly, but it does not provide any quantitative measure of the

extent of fetal drug exposure throughout gestation. Thus, even given adequate

analytical methods, the interpretation of such drug levels is still very limited.

The choice of compound to quantitate is also a problem, particularly for

exposure to either nicotine or marijuana smoke. Both these substances contain

a large number of ingredients besides the main pharmacological ingredient.

37
More than 60 cannabinoids have been identified in marijuana smoke, and it is

not known which of these is(are) the pharmacologically relevant compound(s).

To date, there has not been a good example of a correlation between the extent

of fetal drug exposure and neonatal outcome in the clinical setting as most of

the reports have attempted to correlate only the extent of reported drug use and

neonatal outcome.

DeVane (this volume) also addresses the need to relate fetal drug exposure

to pharmacodynamic effects. Furthermore, it was suggested that an

understanding of the pharmacokinetics of a drug in the maternal-fetal unit may

help in the interpretation of single time-point drug levels in the clinical setting. It

is quite obvious that detailed pharmacokinetics studies can only be obtained

using suitable animal models. DeVane points out the problems in interpreting

data from different species. Despite these difficulties, pharmacokinetics studies

in animal models have contributed significantly to the understanding of

maternal-fetal drug disposition. Some of the more important findings are

highlighted in this chapter.

MECHANISMS OF DRUG ACTION ON THE FETUS

First, the potential mechanisms by which maternal drug use may affect fetal

development must be addressed. Kuhnert and DeVane already have pointed

out that a drug may exert direct action on the fetus via placental drug transfer.

In this case, it can be assumed that the magnitude of adverse effect should be

a function of the extent of fetal drug exposure. However, a drug also may

adversely affect the fetus by indirect action on placental function, including

possible effects on placental perfusion and the diffusion of oxygen and nutrients

across the placental membranes (e.g., the well-known effects of cocaine on

maternal hemodynamics and uterine vascular resistance). Intravenous

administration of cocaine to maternal sheep produced dose-dependent

increases in maternal blood pressure and heart rate, decreases in uterine blood

flow, and fetal hypoxemia, tachycardia, and hypertension (Woods et al. 1987).

While the fetal tachycardia and hypertension are largely due to placental

transfer of cocaine and a direct action on the fetus, the hypoxemia was

secondary to the reduction in uterine blood flow. This was confirmed by direct

administration of cocaine to the fetus. Cocaine is thought to act on uterine

blood vessels by blocking reuptake of norepinephrine, thereby potentiating the

vasoconstrictive actions of norepinephrine. In this case, the magnitude of fetal

hypoxemia would be more a function of maternal drug levels than of fetal drug

levels; the reduction in uterine perfusion may reduce the distribution of cocaine

to the fetus, as its distribution is most likely flow-dependent.

38
A similar situation has been demonstrated in studies of the effects of tobacco

and marijuana smoking. Intravenous administration of nicotine to maternal

sheep increased fetal blood pressure, decreased fetal heart rate and fetal pO2

,

and suppressed fetal breathing movements (Manning et al. 1978). On the other

hand, direct administration of nicotine to the fetus induced a burst of fetal

breathing movements, no change in blood gases, and an increase In blood

pressure and heart rate. These findings suggest that the suppression of fetal

breathlng movements following maternally administered nicotine was most likely

due to fetal hypoxemia as a result of uterine vasoconstriction.

Introduction of marijuana smoke to pregnant sheep caused significant

reductions in maternal respiratory rate and arterial pO2

 (Clapp et al. 1986). This

maternal hypoxemia resulted in a significant reduction in fetal oxygen tension,

which remained depressed even after maternal pO2

 values had returned to

control levels. The prolonged reduction in fetal pO2 suggests that either

placental gas transfer or fetal oxygen consumption also was affected by

marijuana smoke inhalation. Therefore, although the extent of fetal drug

exposure Is important, fetal development also may be affected indirectly by the

drug’s action on placental function.

NEW FINDINGS ON MATERNAL-FETAL PHARMACOKINETICS OF DRUG

ABUSE

Some important findings have come from maternal-fetal pharmacokinetics

studies. First, it has been clearly demonstrated that all drugs studied to date

are distributed to the fetus with relative ease, although there are some

differences in their rate and extent of transfer. Ethanol is distributed very rapidly

between the mother and fetus, and maternal and fetal concentrations are

virtually superimposable up to 14 hours after 1-hour infusion of ethanol to the

mother (Brien et al. 1985). The placental transfer of most opioid drugs also was

found to be very rapid, with peak fetal blood levels occurring in less than 10

minutes (Szeto et al. 1978, 1981; Golub et al. 1986). The placental transfer of

cocaine also has been shown to be very rapid (Woods 1989). On the other

hand, the placental transfer of tetrahydrocannabinol (THC) following marijuana

smoke inhalation was found to be much slower, with peak fetal levels not seen

until 1.5 to 2 hours after smoke exposure (Abrams et al. 1985). The reason for

this apparently slow distribution of such an extremely lipid soluble compound is

not known, but it may be because of the extensive binding of THC to maternal

plasma proteins.

Another major finding from these pharmacokinetics studies is that the placenta

plays the major role in drug elimination from the fetus. For all drugs that have

been studied, the elimination half-life in the fetus is identical to that in the

39
mother, suggesting that elimination of these drugs from the fetus is largely

dictated by maternal elimination characteristics. This is in contrast to the old

Idea that the fetus may act as a “sink” for drugs because of inadequate drugelimination capacity. The immature drug-elimination system is only a problem

upon removal of the placenta, such as at the time of birth. This has been very

elegantly demonstrated for ethanol, where the decline in ethanol concentration

in the sheep fetus has been shown to be similar to that in maternal plasma but

is much slower in the newborn (Cumming et al. 1984).

Not only have recent studies revealed that the fetus does not act as a sink for

drugs, but also most studies have found that fetal plasma drug levels tend to be

significantly lower than maternal plasma levels, even at steady state after

continuous drug infusion (Szeto 1982). Pharmacokinetics modeling suggests

that this lack of equilibrium between mother and fetus can be explained only by

the presence of fetal drug elimination (Szeto et al. 1982a). Although early in

vitro metabolism studies in fetal rats indicated that the fetus has negligible

capacity to eliminate drugs, recent functional studies in the fetal lamb have

revealed varying degrees of renal and hepatic drug elimination (Szeto et al.

1979, 1980; Olsen et al. 1988). Drugs that are excreted renally can be found in

amniotic fluid (Szeto et al. 1979). There is even evidence that metabolites of

fetal origin such as morphine-3-glucuronide may accumulate in fetal plasma

because of their polar nature (Olsen et al. 1988).

Pharmacokinetics studies have clearly helped in understanding the factors that

determine the extent of fetal drug exposure. However, these findings also raise

further questions, some of which are addressed below.

QUESTIONS FOR FUTURE INVESTIGATION

1. Does the extent of fetal drug exposure change as a function of gestational

age? Pharmacokinetics modeling suggested that the extent of fetal drug

exposure depends on both placental and fetal clearance of the drug (Szeto

1982). For the same drug, placental clearance may be affected by

changes in plasma protein binding and placental perfusion. Gestational

age-dependent changes in plasma protein binding have been

demonstrated in both maternal and fetal plasma. For instance, it was found

that the extent of methadone binding in fetal plasma increases with

gestational age (Szeto et al. 1982b). Fetal binding was initially much lower

than maternal binding, but it increased significantly in the last 2 weeks of

gestation, reaching the level of maternal binding by the time of birth. How

would this affect drug distribution between the maternal and fetal

compartments throughout gestation? Placental perfusion also can change

throughout pregnancy. How would these changes affect the extent of fetal

40
2.

drug exposure? Would the effects depend on the degree of plasma protein

binding of the drug and on whether the distributlon is flow- or diffusionlimited? Although there has been much speculation on these issues, there

have not been any systematic studies addressing these points.

Furthermore, the extent of fetal drug exposure can be expected to change

with progressive maturation of fetal drug-elimination systems. The

contribution of fetal drug clearance to the overall clearance of methadone

from the fetal compartment has been found to increase throughout the third

trimester until 2 weeks prior to birth, while it remained constant for

morphine prior to birth (Szeto et al. 1982c). However, there has been no

longitudinal study of the extent of fetal exposure to any of the drugs of

abuse throughout pregnancy, and there have been no attempts to correlate

extent of fetal drug exposure to fetal drug-elimination capacity. This is

clearly an area that deserves more attention.

Although studies to date have clearly demonstrated the important role that

the placenta plays in the elimination of drugs from the fetal compartment,

what are the consequences of polar metabolites that are generated by the

fetus? The fetal-maternal clearance of these polar metaboiites can be

expected to be rather restricted. Morphine-3-glucuronide has been shown

to accumulate in fetal plasma following morphine administration to the

mother (Olsen et al. 1988); and there is some evidence that this metabolite

may be pharmacologically active. Another interesting case may be the

comparison of the extent of fetal drug exposure to heroin vs. methadone.

Heroin is hydrolyzed rapidly in plasma to 6-monoacetylmorphine and

morphine. Szeto and colleagues (1982c) showed that the extent of fetal

exposure to methadone is threefold higher than that to morphine because

of the lower placental clearance of morphine from mother to fetus due to its

relative lower lipophilicity. When heroin is administered to the mother, it

can be expected to be rapidly distributed to the fetus because of its lipid

solubility. Once in the fetal compartment, it may be rapidly hydrolyzed to 6-

monoacetylmorphine and morphine. Because of the relatively low placental

clearance of morphine, it may be expected to accumulate in the fetus.

Thus, the extent of fetal opiate exposure may be higher for heroin than for

methadone. This hypothesis needs to be tested.

3. What is the fate of drug or metabolites excreted into amniotic fluid? Will the

dynamics be different for lipid-soluble vs. polar compounds? Many

investigators have suggested that drugs in amniotic fluid are swallowed by

the fetus and undergo enterohepatic recirculation. The dynamics of this

potential pathway have not been investigated. Previous data suggest that

for lipid-soluble compounds, the majority of the drug is distributed back into

the maternal circulation via diffusion across the amnion (Szeto et al. 1978).

41
But what about polar metabolites such as morphine-3-glucuronide? How

much of this can be absorbed from the gastrointestinal tract in the fetus,

and is there any ß-glucuronidase activity? Although drug levels can be

readily determined in amniotic fluid samples obtained In humans durlng

amniocentesis, they can only be interpreted if there is a clear

understanding of the dynamics of drugs in this fluid compartment.

4. Some rather sophisticated compartmental models have been proposed for

the maternal-placental-fetal unit. Other researchers have even included the

amniotic fluid as a separate compartment. The number of unknown kinetic

constants and compartment volumes far exceeds the information that can

be obtained experimentally. To date, only a simple two-compartment

model (with mother and fetus each being treated as a homogenous

compartment) has been solved (Szeto et al. 1982a). New experimental

approaches would be necessary to make these more complicated models

worthwhile. Can it be done? What additional information would they

provide? And would the efforts be worth it?

5. The physiological modeling presented by DeVane (this volume) obviously

has many advantages because it does not assume that the mother and

fetus are homogenous compartments. However, the disadvantages are

that the blood flows to the various organs must be determined in the same

species, and it must be assumed that the drug that is being studied does

not change any of the flow parameters. This may be rather difficult

because many of the drugs of abuse tend to alter uterine-placental

perfusion. Furthermore, such a model would have to be further modified to

include drug elimination from the fetus and umbilical blood flows. As it

stands, this model puts heavy emphasis on the maternal side only,

disregarding the complexity of the fetal side. However, such models would

be extremely useful in predicting the effects of blood-flow changes on the

extent of fetal drug exposure.

6. Finally, Kuhnert and DeVane have indicated that the goal is to correlate the

extent of fetal drug exposure with pharmacodynamic responses in the

fetus. To date, there has been only one example where a clear correlation

between maternal-fetal pharmacokinetics and magnitude of fetal response

has been demonstrated. Pharmacokinetics studies in the pregnant ewe

have shown that the extent of fetal exposure to methadone is threefold

higher than with morphine (Szeto et al. 1982c). It has now been

demonstrated that the magnitude of neurobehavioral effects in the fetal

lamb is also three times greater following maternal methadone

administration compared with morphine administration (Umans and Szeto

42
1983). It would be important to obtain more experimental evidence such as

this to document a clear dose-response relationship in the fetus.

A final point concerns the development of tolerance upon chronic exposure to

many of the drugs of abuse. Tolerance has been demonstrated to develop

rapidly in the fetus with constant-rate administration of morphine to the mother

(Szeto et al. 1988). In such instances, any relationship between dose and

response would be expected to fall apart. Furthermore, intermittent drug

exposure also may result in intermittent withdrawal between doses (Umans and

Szeto 1985) and may have a detrimental impact on fetal development and

pregnancy outcome. Thus, the total impact of maternal drug abuse may be

very complicated and not solely dependent on the extent of fetal drug exposure.

REFERENCES

Abrams, R.M.; Cook, C.E.; and Davis, K.H., Niederreiher, K; and Szeto H.H.

Plasma THC in pregnant sheep and fetus after smoking a marijuana

cigarette. Alcohol Drug Res 6:361-369, 1985.

Brien, J.F.; Clarke, D.W.; Richardson, B.; and Patrick, J. Disposition of ethanol

in maternal blood, fetal blood, and amniotic fluid of third trimester pregnant

ewes. Am J Obstet Gynecol 152:583-590, 1985.

Clapp, J.F.; Wesley, M.; Cooke, R.; Pekala R.; and Holstein, C. The effects of

marijuana smoke on gas exchange in ovine pregnancy. Alcohol Drug Res

7:85-92, 1986.

Cumming, M.E.; Ong, B.Y.; Wade, J.G.; and Sitar, D.S. Maternal and fetal

ethanol pharmacokinetics and cardiovascular responses in near-term

pregnant sheep. Can J Physiol Pharmacol 62:1435-1439, 1984.

Golub, M.S.; Eisele, J.H.; and Anderson, J.H. Maternal-fetal distribution of

morphine and alfentanil in near-term sheep and rhesus monkeys. Dev

Pharmacol Ther 9:12-22, 1986.

Manning, F.A.; Walker, D.; and Feyerabend, C. The effect of nicotine on fetal

breathing movements in conscious pregnant ewes. Obstet Gynecol 52:563-

568, 1978.

Olsen, G.D.; Sommer, K.M.; Wheeler, P.L.; Boyea, S.R.; Michelson, S.P.; and

Cheek D.B.C. Accumulation and clearance of morphine-3-glucuronide in fetal

lambs. J Pharmacol Exp Ther 247:576-584, 1988.

Szeto, H.H. Pharmacokinetics in the ovine maternal-fetal unit. Ann Rev

Pharmacol Toxicol 22:221-243, 1982.

Szeto, H.H.; Mann, L.I.; Bhakthavathasalan, A.; Liu, M.; and luturrisi, C.E.

Meperidine pharmacokinetics in the maternal-fetal unit. J Pharmacol Exp

Ther 206:448-459, 1978.

43
Szeto, H.H.; Kaiko, R.F.; Clapp, J.F.; Larrow, R.W.; Mann, L.I.; and luturrisi,

C.E. Urinary excretion of meperidine by the fetal lamb. J Pharmacol Exp

Ther 209:244-248, 1979.

Szeto, H.H.; Clapp, J.F.; Larrow, R.W.; Inturrisi, C.E.; and Mann, L.I. Renal

tubular secretion of meperidine by the fetal lamb. J Pharmacol Exp Ther

213:346-349, 1980.

Szeto, H.H.; Clapp, J.F.; Larrow, R.W.; Hewitt, J.; luturrisi, C.E.; and Mann, L.I.

Disposition of methadone in the ovine maternal-fetal unit. Life Sci 28:2111-

2117, 1981.

Szeto, H.H.; Umans, J.G.; and Rubinow, S.I. The contribution of transplacental

clearances and fetal clearance to drug disposition in the ovine maternal-fetal

unit. Drug Metab Dispos 10:382-386, 1982a.

Szeto, H.H.; Umans, J.G.; Umans, H.R.; and McFarland, J.W. The relationship

between maternal and fetal plasma protein binding of methadone in the ewe

during the third trimester. Life Sci 30:1271-1279, 1982b.

Szeto, H.H.; Umans, J.G.; and McFarland, J.W. A comparison of morphine and

methadone disposition in the maternal-fetal unit. Am J Obstet Gynecol

143:700-706, 1982c.

Szeto, H.H.; Zhu, Y.S.; Cox, M.J.; Amione, J.; and Clare, S. Prenatal morphine

exposure and sleep-wake disturbances in the fetus. Sleep 11:121-130,

1988.

Umans, J.G., and Szeto, H.H. Precipitated opiate abstinence in utero. Am J

Obstet Gynecol 151:441-444, 1985.

Umans, J.G., and Szeto, H.H. Effects of opiates on fetal behavioral activity in

utero. Life Sci 33:639-642, 1983.

Woods, J.R. Pharmacokinetics of cocaine: Fetal lamb studies. Ann N Y Acad

Sci 1989.

Woods, J.R.T.; Plessinger, M.A.; and Clark, K.E. Effects of cocaine on uterine

blood flow and fetal oxygenation. JAMA 257:957-961, 1987.

AUTHOR

Hazel H. Szeto, M.D., Ph.D.

Associate Professor

Department of Pharmacology

Cornell University Medical College

1300 York Avenue

New York, NY 10021

44
Selected Methodologic Issues in

Investigations of Prenatal Effects of

Cocaine: Lessons From the Past

Barry Zuckerman

INTRODUCTION

The perinatal cocaine epidemic has emerged rapidly. In the most systematic

study to date on cocaine use during pregnancy, 18 percent of women receiving

prenatal care at Boston City Hospital used cocaine at least once during

pregnancy (Zuckerman et al. 1989a). Less systematic surveys at other

hospitals, mostly in urban settings, demonstrate somewhat lower rates.

However, because urine assessments conducted at delivery fail to identify

many women who used cocaine earlier in pregnancy, these rates may

somewhat underestimate the use of cocaine during pregnancy.

Pregnancies of women who use cocaine are at risk not only because of cocaine

use but because of poor nutrition; sexually transmitted diseases; use of

cigarettes, marijuana, alcohol, and other illicit drugs; and lack of prenatal care.

Understandably, as preliminary investigations indicate, infants born to mothers

who use cocaine have a high likelihood of low birth weight, microcephaly,

prematurity, neurobehavioral dysfunction, and rare but catastrophic events such

as cerebral vascular accidents, necrotizing enterocolitis, malformations, and

abruptio placentae. The association between cocaine and these outcomes has

biologic plausibility because of the known pharmacologic actions of cocaine.

However, with few exceptions, these early studies have significant

methodologic flaws that prevent meaningful conclusions regarding the

independent effect of cocaine use during pregnancy.

Information based on good science is needed to make sound clinical, public

health, and public policy decisions. Professionals and the media also have an

important responsibility to ensure the dissemination of accurate information. A

recent review of abstracts submitted for presentation at the annual meeting of

the Society for Pediatric Research (Koren et al. 1989) showed that it was much

more likely that a paper on cocaine use during pregnancy would be accepted

for presentation if there were positive findings between cocaine exposure and

45
adverse outcomes compared to a paper reporting negative findings. In the

media, cocaine-exposed babies are depicted as “addicted” when in fact a

withdrawal syndrome has not been documented. Untoward consequences of

this misinformation include a national adoption agency declaring that cocaineexposed infants are not adoptable. Clinical decisions are also adversely

effected. Early reports from a convenience sample of infants of cocaine-using

mothers suggest an extraordinarily high rate (15 percent) of sudden infant death

syndrome (SIDS) (Chasnoff et al. 1989). If this report were accurate, cocaineexposed infants would need to be maintained on home monitors. Resulting

increased maternal anxiety might lead in turn to self-medication with drugs and

difficulty in attachment. However, this report was not supported by the only

systematic investigation of prenatal cocaine exposure and SIDS, which showed

no increase in SIDS (Bauchner et al. 1988).

Scientific standards for investigations are well known and are not reviewed

extensively here. This chapter identifies selected methodologic issues that

have plagued investigations of the impact of prenatal use of drugs. These

methodologic problems are the lack or incomplete control of potentially

confounding variables, reliance on self-report in identifying drug users, and

use of biased samples. The importance of identifying intervening variables,

especially protective factors that influence outcome, also is emphasized.

LESSONS LEARNED FROM PRENATAL ALCOHOL RESEARCH

Attributing Cause

The original description of fetal alcohol syndrome (FAS) (Jones et al. 1973) was

based on very careful descriptions of the physical characteristics of the children.

However, the extent to which health habits and other characteristics of the

mothers were documented varied widely. This tendency to record the physical

characteristics of offspring more completely than maternal characteristics is also

found in many of the approximately 250 reported cases that sewed as a basis

for the development of criteria for FAS. Clinicians and investigators who believe

the key component to be alcohol may pay more attention to a mother’s alcohol

consumption than to her other habits.

Evidence from three lines of investigation has raised questions regarding the

specificity of alcohol as causing FAS (Zuckerman and Hingson 1986). First, the

facial dysmorphology that some investigators consider to be the most striking

aspect of FAS has been demonstrated to resemble the facial appearance of

children born to mothers with phenylketonuria (Lipson et al. 1981). Children of

epileptic women who used phenytoin (Dilantin) during pregnancy also have a

similar appearance (Hill 1976). The facial appearance of FAS may not be as

distinct as originally thought. In one study, one of seven experts on FAS could

46
not identify children with FAS based on pictures of their faces (Clarren et al.

1987).

Second, the similarity of appearance to infants exposed to the three agents

mentioned above is consistent with the results of studies using mice suggesting

that any teratogen exposure during the gastrulation stage of embryogenesis

can result in craniofacial, brain, and eye defects corresponding to those noted

in severe forms of FAS (Sulik 1984).

Third, factors other than alcohol have been associated with features compatible

with FAS (CFAS). Because FAS is rare, Hanson (Hanson et al. 1978)

developed criteria for classifying infants as CFAS in an attempt to identify an

association between lower levels of drinking and less extensive dysmorphology.

In the only study (Hingson et al. 1982) that attempts to identify any association

between CFAS and factors other than alcohol, 2.2 percent of 1,384 infants

examined had CFAS. When other confounding variables were controlled,

marijuana use during pregnancy, weight gain less than 5 pounds, and exposure

to x-rays increased the risk that an infant would be born with CFAS. In contrast,

there was no increased risk for women who averaged two or more drinks daily.

These three lines of investigations suggest that the dysmorphology of FAS may

reflect a common pathway of numerous agents or a combination of agents

rather than a specific teratogenic effect of alcohol. It is possible that the initial

naming of the syndrome for its hypothesized cause may have resulted in

the neglect of important research questions; investigators may be failing to

consider the influence of maternal health or other drug use. Thus, while initial

uncontrolled observations are important, the observer should describe in detail

not only the outcome but also all possible factors that may have independently

or synergistically contributed to that outcome.

A similar type of problem with causal attribution now can be seen in attributing

the neurobehavioral dysfunction of cocaine-exposed infants to withdrawal

(“crack-addicted babies”). Although neurobehavioral dysfunction has been

shown to be associated with prenatal cocaine exposure (Chasnoff et al. 1985),

a withdrawal syndrome has not been demonstrated. Other possible

explanations of neurobehavioral dysfunction include acute direct toxic effect

of cocaine on the central nervous system (CNS) (Mittleman et al. 1989)

neurotransmitter (especially norepinephrine) elevations (Ward et al. 1989), or

structural CNS damage (Dixon and Bejar 1989).

Confounding Variables

Efforts to identify and to confirm the effects of a single substance such as

cocaine are complicated because it is unusual for humans to use or to abuse

only one drug. Assessing the independent effect of any drug or health variable

47
requires carefully designed studies with samples large enough to allow

multivariate data analysis and statistical control for confounding variables.

Unless confounding variables are controlled, study findings may either

overestimate the magnitude of a specific substance or demonstrate a significant

association where none exists.

Two of the most frequently cited studies showing an association between small

amounts of alcohol consumption and lower birth weight did not control for

important potentially confounding variables. Little (1977) found that one ounce

of absolute alcohol (two drinks) per day consumed before pregnancy was

associated with an average decrease of 90 grams at birth weight. Drinking that

amount during months 5 to 8 of pregnancy was associated with a decrease of

160 grams at birth weight. The effects of maternal age, height, parity, cigarette

use, and gestational age and sex of the child were held constant through

regression analysis. However, other potentially important variables, including

maternal illness during pregnancy, prepregnancy weight, maternal weight gain,

and marijuana use, were not examined. A more recent study (Mills et al. 1984)

demonstrates that drlnking an average of one to two drinks per day reduced

infant birth weight by 83 grams. Although this study controlled many variables

and had fewer methodologic limitations than most studies, it did fail to control

for weight gain and marijuana consumption during pregnancy, The unexplored

variables in both studies may explain the small differences in birth weight.

This possibility is illustrated by data from a study conducted at Boston City

Hospital (Hingson et al. 1982). Infants whose mothers drank two or more drinks

per day weighed 220 grams less (p<.04) than infants whose mothers did not

drink alcohol during pregnancy. When confounding variables were controlled in

the statistical analysis, the birth weight difference was only 51 grams and was

not statistically significant. On the other hand, women who smoked marijuana

during pregnancy delivered infants who weighed 300 grams less than infants

of mothers who did not smoke marijuana. When confounding variables were

controlled, the weight was 105 grams less, but this difference remained

statistically significant. The role of marijuana may be critical because it is

frequently used by women who drink alcohol (Zuckerman et al. 1989a; Hingson

et al. 1982). The inconsistency of findings between alcohol consumption

and decreased birth weight compared with the consistency of findings

between cigarette smoking and lowered birth weight suggests that control for

confounding variables is one of many important methodologic problems

(Zuckerman and Hingson 1986; Stein and Kline 1983; Roman et al. 1988) in

investigations of alcohol consumption during pregnancy. Many studies that

control for potentially confounding variables do not demonstrate a significant

association between two or fewer drinks per day and lower infant birth weight

(Zuckerman et al. 1989a; Hingson et al. 1982; Marbury et al. 1983; Tennes and

Blackard 1980; Grisso et al. 1984; Kline et al. 1987).

48
Determining the independent effect of cocaine is also complicated by the

tendency of cocaine users to use other drugs and practice peer health behavior.

Thus, in one study (Zuckerman et al. 1989a), while Infants of mothers who had

a positive urine assay for cocaine during pregnancy were 400 grams smaller in

birth weight compared with infants of mothers who did not use cocaine, only 25

percent of the weight decrement could be attributed directly to cocaine. The

remainder was attributable to the effects of cigarettes and marijuana, other

drugs, and poor nutrition.

LESSONS FROM PRENATAL MARIJUANA RESEARCH:

THE VALIDITY OF SELF-REPORT

Studies in humans on the effect of smoking marijuana during pregnancy show

conflicting findings (Hingson et al. 1985). One possible explanation for the

inconsistency of study results is the reliance by these studies on maternal selfreport. In the absence of the ascertainment of marijuana use through a biologic

marker such as urine testing, the number of marijuana users may have been

underestimated and some users misclassified as nonusers. This could result in

obscuring significant associations between marijuana use and neonatal

outcomes.

Hingson and colleagues (1986) conducted an investigation to explore the

validity of self-reported marijuana use during pregnancy by randomly allocating

pregnant women into a group who were told their urine would be tested for

marijuana and another group not so tested. Women told that they would be

tested reported using more marijuana than did untested women. Moreover,

urine assays identified more women who used marijuana during pregnancy than

were willing to admit it in the interview, even after being told their urine would be

tested.

Based on this evidence, Zuckerman and coworkers (1989a) conducted an

investigation on the effect of marijuana use during pregnancy by identifying use

by both self-report and urine assay for marijuana. Of 1,226 women, 331 (27

percent) were classified as marijuana users on the basis of the interview, urine

assay, or both. After potentially confounding variables were controlled for, the

infants of women who had a positive urine assay for marijuana were found to

weigh 79 grams less at birth (p=.04) and to be .5 centimeters shorter (p=.02)

than the infants of nonusers. To determine whether this finding was

comparable with those of other investigations that did not use urine assays, the

multiple regression analyses were repeated with the use of marijuana based

solely on interview findings. Of the 202 women whose samples were positive

for marijuana, 53 denied using it. Thus, 16 percent (53 of 331) of the women

who did not report marijuana use were identified as users with the urine assay

alone. On the basis of self-report alone, these women were misclassified as

49
nonusers. When the same potentially confounding variables were controlled

for, infants of women who reported marljuana use weighed only 15 grams less

(p=.66) and were .37 centimeters shorter (p=.06) than the infants of those who

did not report use. These data support the importance of the use of biologic

markers to ascertain marijuana use and suggest that, without urine assays, the

number of marijuana users in previous studies may have been underestimated.

The misclassification of users as nonusers potentially obscures significant

relationships between marijuana use and fetal growth.

Zuckerman and colleagues (1989b) also have shown that women 19 years and

younger have a different rate of denial for marijuana (12 percent) compared with

cocaine (35 percent). This difference in underreporting was not seen for adult

pregnant women (17 percent for marijuana and 20 percent for cocaine),

indicating that adolescents may have different drug-specific attitudes as well as

different perceptions of the acceptability of reporting drugs. Thus, studies may

have different rates of underreporting because of varying proportions of young

women in the study.

LESSONS FROM PRENATAL COCAINE STUDIES: PROBLEM WITH

BIASED SAMPLES

An important methodologic problem common among the published reports

regarding cocaine use during pregnancy is the use of potentially biased

samples of cocaine-using pregnant women. Some studies recruit women from

special prenatal chemical dependency programs, whereas other studies identify

cocaine-exposed infants by testing the infant’s urine at birth. Testing urines at

birth may result in users (women who used during pregnancy but denied use

and had a negative urine because they did not use within 3 days of delivery)

being misclassified as nonusers. Some studies only evaluate urines of

newborns meeting certain clinical criteria, which potentially introduces an even

greater bias. Data from the Boston City Hospital study (Zuckerman et al.

1989a) provide an opportunity to explore this potential bias. Only 25 percent of

women who acknowledged cocaine use during pregnancy had a positive urine

at the time of delivery. Among women who self-reported use, those who had a

positive urine at the time of delivery were heavier users compared with women

users who did not have a positive urine at the time of delivery (table 1). Twentysix percent of women with a positive postpartum urine used daily compared

with 9 percent of users who had negative urine postpartum (p<.001). To

determine whether the findings of Zuckerman and colleagues’ study (1989a) in

which urines were collected prenatally and postpartum were comparable with

investigations that depend on urines from newborns (similar to maternal

postpartum urines), the multiple regression analysis was repeated with cocaine

exposure defined solely by positive postpartum urine assay. Women who had a

50
positive urine prenatally and a negative urine postpartum were thereby

misclassified as nonusers. When the same confounding variables were

controlled, infants of women with positive postpartum urines had a 23-percent

further decrease in birth weight (from 93 grams to 115 grams) compared with

published results. Bias could have been introduced in both directions. Women

with positive urines postpartum are heavier users, which could result in a

greater decrease in birth weight in the postpartum cocaine-exposed group.

This potentially could be counterbalanced by a decrease in birth weight among

the nonusing cocaine group because nonusers were misclassified as users.

This could result in decreasing the difference between the cocaine-exposed

and nonexposed group. Based on the data, the net effect shows a greater

detrimental effect in the postpartum cocaine-exposed group. Therefore, infants

who are identified at the time of birth only by positive urines represent the tip of

the iceberg and skew findings toward mothers who were more frequent cocaine

users and infants with lower birth weight.

TABLE 1. Comparison of frequency of cocaine use between women with

positive and negative urines postpartum (among self-reported

cocaine users)

Less Than Once 1to 3 Times 1to 2 Times 3 to 6 Times

Urines a Month (%) a Month (%) a Week (%) a Week (%) Daily (%)

Negative 44 17 20 10 9

(n=128)

Positive

(n=35)

11 11 32 20 26

P<.0001

It is important to note that even in the Boston City Hospital study, a significant

association was demonstrated only between women who had a positive urine

assay for cocaine and impaired fetal growth and smaller head circumference.

There was no significant association among women who reported use but had a

negative urine assay. These women were less frequent users. Also, had the

cocaine users been combined regardless of means of identification, a significant

association would not have been found between cocaine use during pregnancy

and poor fetal growth or smaller head circumference when confounding

variables are controlled.

51
Important biases also may be introduced in investigations of women

participating in special prenatal chemical-dependency programs. Women in

such programs may be different in the amount, type, chronicity, and variety of

drugs used; amount of prenatal care; use of Special Supplemental Food

Program for Women, Infants, and Children; and presence of other risk factors

compared with women who were not in such programs.

An example of a bias introduced from this type of convenience sample is initial

early reports of a 15-percent rate of SIDS among children born to known

cocaine-using mothers (Chasnoff et al. 1987). Data from the Boston City

Hospital study obtained from a general prenatal clinic population showed there

was no significant difference in the prevalence of infants with SIDS between

mothers who used cocaine during pregnancy compared with infants from the

same population whose mothers did not use cocaine (Chasnoff et al. 1989).

CONCLUSION

Initial observations of possible adverse effects of any drug used prenatally

should be followed by systematic investigations. Attention to methodologic

issues described in this chapter, other chapters in this volume, and wellaccepted scientific standards (Feinstein 1988) will improve the accuracy of

information generated from investigations of prenatal drug use. Limitations in

study design should be identified and their implications acknowledged.

Replication of study results with different populations and different methods

further assures the validity of the findings, for all studies will have some

limitations. Good clinical care and good public health policy depend on good

information.

REFERENCES

Bauchner, H.; Zuckerman, B.; McClain, M.; Frank, D.; Fried, L.; and Kayne, H.

Risk of sudden infant death syndrome among infants with in utero exposure

to cocaine. J Pediatr 13:831-834, 1988.

Chasnoff, I.J.; Burns, K.A.; and Burns, W.J. Cocaine use in pregnancy:

Perinatal morbidity and mortality. Neurotoxicol Teratol 9:291-293, 1987.

Chasnoff, I.J.; Burns, W.J.; Schnoll, S.H.; and Burns, K.A. Cocaine use in

pregnancy. N Engl J Med 313(11):666-669, 1985.

Chasnoff, I.J.; Hunt, C.E.; Kletter, R.; and Kaplan, D. Prenatal cocaine

exposure is associated with respiratory pattern abnormalities. AJDC

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Clarren, S.; Sampson, P.; Larsen, J.; Donnell, D.; Barr, H.; Bockstein, F.;

Martin, D.; and Streissguth, A.P. Facial effects of fetal alcohol exposure:

Assessments by photographs and morphometric analysis. Am J Med Gen

26:651-666, 1987.

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Dixon, S.D., and Bejar, R. Echoencephalographic findings in neonates

associated with maternal cocaine and methamphetamine use: Incidence and

clinical correlates. J Pediatr 115:770-778, 1989.

Feinstein, A.R. Scientific standards in epidemiologic studies of the menace of

daily life. Science 242:1257-1263, 1988.

Grisso, J.A.; Roman, E.; Inskip, H.; Varel, V.; and Donovan, J. Alcohol

consumption and outcome of pregnancy. J Epidemiol Community Health

38:232-235, 1984.

Hanson, J.W.; Streissguth, A.P.; and Smith, D.W. The effects of moderate

alcohol consumption during pregnancy on fetal growth and morphogenesis.

J Pediatr 92:457-460, 1978.

Hill, R.M. Fetal malformations and antiepileptic drugs. Am J Dis Children

130:923-925, 1976.

Hingson, R.; Alpert, J.; Day, N.; Dooling, E.; Kayne, H.; Morelock, S.; and

Zuckerman, B. Effects of maternal drinking and marijuana use on fetal

growth and development. Pediatrics 70:539-546, 1982.

Hingson, R.; Zuckerman, B.; Amaro, H.; Frank, D.; Kayne, H.; Sorenson, J.R.;

Mitchell, J.; Parker, S.; Morelock, S.; and Timperi, R. Maternal marijuana

use and neonatal outcome. Uncertainty posed by self-reports. Am J Pub

Health 76:667-669, 1986.

Hingson, R.; Zuckerman, B.; Frank, D.A.; Kayne, H.; Sorenson, J.R.; and

Mitchell, J. Effects on fetal development of maternal marijuana use during

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Symposium on Cannabis. Oxford, England: IRL Press, 1985.

Jones, K.L.; Smith, D.W.; Ulleland, C.N.; and Streissguth, A.P. Pattern of

malformation in offspring of chronic alcoholic women. Lancet 1:1267-1271,

1973.

Kline, J.; Stein, Z.; and Hutzler, M. Cigarettes, alcohol and marijuana: Varying

associations with birthweight. Int J Epidemiol 16:44-51, 1987.

Koren, G.; Graham, H.; Shear, H.; and Einarson, T. Bias against the null

hypothesis: The reproductive hazards of cocaine. Lancet 2(8677):1440-

1442, 1989.

Lipson, A.H.; Yu, J.S.; O’Halloran, M.T.; and Williams, R. Alcohol and

phenylketonuria. Lancet 1:717-718, 1981.

Little, R. Moderate alcohol use during pregnancy and decreased infant birth

weight. Am J Public Health 67:1154-1156, 1977.

Marbury, M.C.; Linn, S.; Monson, R.; Schoenbaum, S.C.; Stubblefield, P.G.;

and Ryan, K.J. The association of alcohol consumption with outcome of

pregnancy. Am J Public Health 73:1165-1168, 1983.

Mills, J.L.; Graubard, B.I.; Harley, M.S.; Rhoads, G.G.; and Berrendes, H.W.

Maternal alcohol consumption and birthweight. JAMA 252:1875-1879, 1984.

Mittleman, R.; Lofino, J.; and Hern, W. Tissue distribution of cocaine in a

pregnant woman. J Forensic Sci 34:481-486, 1989.

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Roman, E.; Beral, V.; and Zuckerman, B.S. Review of the relationship between

alcohol consumption and pregnancy outcome in humans. In: Kalter, H., ed.

Issues and Reviews in Teratology. Vol. 4. 1988. pp. 205-235.

Stein, Z., and Kline, J. Smoking, alcohol, and reproduction. Am J Public

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Sulik, K.K. Critical periods for alcohol teratogenesis in mice with special

reference to the gastrulation stage of embryogenesis. In: Mechanisms of

Alcohol Damage in Utero. Ciba Foundation Symposium 105. London:

Pittman, 1984. pp. 124-141,

Tennes, K., and Blackard, C. Maternal alcohol consumption, birthweight, and

minor physical anomalies. Am J Obstet Gynecol 138:774-780, 1980.

Ward, S.L.; Bautista, D.B.; Buckley, S.; Schuetz, S.; Wachsman, L.; Bean, X.;

and Warburton, D. Circulating catecholamines and adrenoreceptors in

infants of cocaine abusing mothers. Ann N Y Acad Sci 562:349-350, 1989.

Zuckerman, B.S.; Amaro, H.; and Cabral, H. The validity of self-reported

marijuana and cocaine use among pregnant adolescents. J Pediatr 115:812-

815, 1989b.

Zuckerman, B.; Frank, D.; Hingson, R.; Amaro, H.; Levenson, S.; Parker, S.;

Vinci, R.; Aboagye, K.; Fried, L.; Cabral, H.; Timperi, R.; and Bauchner, H.

Effects of maternal marijuana and cocaine use on fetal growth. N Engl J

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ACKNOWLEDGMENT

This work was supported by the Harris Foundation.

AUTHOR

Barry Zuckerman, M.D.

Professor of Pediatrics

Department of Pediatrics and Public Health

Boston University School of Medicine

Director

Division of Developmental and Behavioral Pediatrics

Boston City Hospital

Talbot 214

818 Harrison Avenue

Boston, MA 02118

54
Methodological Issues in Studying

Cocaine Use in Pregnancy: A Problem

of Definitions

Ira J. Chasnoff

INTRODUCTION

Rigorous clinical investigation is a tedious process, requiring strict attention to

methodologic details that can influence the ultimate outcome of the research.

Unfortunately, the difficulties inherent in working with any substance-abusing

population afflict the planning and implementation of most projects that hope to

evaluate the impact of maternal cocaine use on pregnancy and neonatal

outcome. In addition, the emotional, legal, and financial issues surrounding

drug use in general, and perinatal cocaine use in particular, have been reflected

in a flood of reports of drug-related effects, which, in some cases, have not

been substantiated through well-conceived, well-executed studies.

REVIEW OF HUMAN STUDIES

The earliest case report of cocaine use in pregnancy concerned two

pregnancies complicated by abruptio placentae (Acker et al. 1983). In 1985

Chasnoff and colleagues published the first clinical study of cocaine use in

pregnancy, in which outcomes of 23 infants were reported. Women were

enrolled prenatally and tracked with urine toxicologies throughout pregnancy.

One group of cocaine-using women also used opiates, and one group used

cocaine but not opiates. A third group of women used opiates but not cocaine,

and a fourth group of drug-free women was identified. No differences in birth

weight, length, head circumference, or Apgar scores were found, but abruptio

placentae and marked neurobehavioral deficiencies were noted in some of the

cocaine-exposed population, and in two of these infants genitourinary tract

anomalies also were found.

A small study by Madden and coworkers (1986) of eight infants who were

identified at birth because of their mothers’ positive urine toxicologies for

cocaine concluded that there was no evidence of negative effects on the

55
pregnancies or infants, but two women who also admitted to alcohol use had

small-for-gestational-age infants. No control group was used.

The outcome of 160 pregnancies in which women used cocaine were reported

by Bingol and colleagues in 1987. The women were identified through

questloning at delivery by a genetic counselor. Fifty mothers admitted to using

cocaine only; 110 women used multiple drugs, including cocaine; and a third

group of 340 drug-free women were identified. A single urine toxicology on the

infant at delivery was used to confirm placement in the appropriate study or

control group. The two groups of cocaine-using women generally had an

increased incidence of abruptio placentae with stillbirths, and their live-born

infants were of lower mean birth weight and head circumference; however, only

the first group was statistically different from the drug-free group. The infants in

the cocaine-only group also displayed an increased incidence of malformations

(three with central nervous system/cranial defects and two with cardiac

anomalies).

MacGregor and colleagues (1987) reported on 70 women who were identified

as cocaine users during the early prenatal period and were followed in a

program designed to deliver comprehensive services to substance-abusing

pregnant women. Twenty-four of the women used cocaine only, 20 used

cocaine and marijuana, 22 used cocaine and opiates, and 4 used cocaine plus

various other illicit substances. Seventy women selected from the general

obstetric clinic population served as drug-free controls. These women were

similar in several prenatal parameters, except that the cocaine-using women

had a significantly higher rate of alcohol use. The cocaine- and cocaine/

polydrug-exposed pregnancies showed a significant decrease in gestational

age and birth weight, with a significantly higher rate of premature labor and

delivery and of small-for-gestational-age infants. Comparison of the 24

cocaine-only-exposed pregnancies with the 46 cocaine/polydrug-exposed

pregnancies demonstrated no differences between the two groups’ outcomes.

In a study from California, Oro and Dixon (1987) reported 110 neonates

identified by retrospective interview at the time of delivery as having been

exposed to cocaine, methamphetamines, heroin, or methadone during the

pregnancy. Forty-five women served as controls, who were matched for

age, prenatal care, and race but not for cigarette or alcohol exposure. It was

found that the drug-exposed infants had a high incidence of prematurity and

intrauterine growth retardation and a significant decrease in gestational age,

birth weight, length, and head circumference. There was also a higher rate of

perinatal complications in the drug-using groups. Significant neurobehavioral

changes were documented in the drug-exposed groups using a drug-withdrawal

scoring system.

56
A series of smaller studies reported cocaine-using women ascertained

by various methods. Ryan and coworkers (1987) reported on 50 women

enrolled in a drug treatment program who were using cocaine plus heroin and

methadone and compared them with 50 women in the same program who were

using heroin and methadone but not cocaine and with 50 women who had no

history of drug use. Urine toxicologies were used to determine cocaine use, but

it is not clear if the drug-free controls had urines tested. The cocaine-exposed

infants demonstrated a significant decrease in birth weight, head circumference,

length, and Apgar scores compared with the control population.

Chouteau and colleagues (1988) identified 361 women at the time of delivery

who had had no prenatal care and divided them into two groups based on a

single urine toxicology at the time of delivery. One hundred forty-three women

had a positive urine for cocaine and 218 did not. Both groups had evidence for

a high rate of polydrug use, including alcohol and tobacco, but these factors

were not controlled for. There was no difference in the rate of abruptio

placentae between the two groups. The women with a positive urine toxicology

for cocaine, however, had a significantly higher rate of infants born prematurely

and at a birth weight less than 2,500 grams.

Cherukuri and coworkers (1988) identified a group of crack-using women when

they entered the hospital for delivery. Fifty-five women admitted having used

crack during the pregnancy, and they were compared with 55 women who

denied any crack use. Assignment to drug-using and control groups and

evaluation of substance use or abuse relied on recall history, and no urine

toxicologies were performed. There was a significant decrease in gestational

age and birth weight in the crack-identified group, and the authors concluded

that crack-exposed infants were 3.6 times more likely to be growth retarded and

2.8 times more likely to have a head circumference less than the 10th percentile

for gestational age.

Little and colleagues (1989) also relied on self-report to identify 53 cocaineexposed pregnancies. A group of 100 drug-free women was selected based on

self-report to serve as controls. Growth parameters of the cocaine-exposed

infants were significantly reduced, and an increased rate of malformations was

reported; however, the poiydrug use patterns of the drug-using women were not

considered in the analysis of data.

Chasnoff and coworkers (1989) evaluated 75 pregnancies, dividing them into

two groups: The first had used cocaine only in the first trimester (n=23), and

the second had used cocaine throughout the pregnancy (n=52). None of the

women used opiates. A third group of drug-free controls (n=40) was identified

to serve as comparison. All three groups of women had been ascertained in the

57
early prenatal period and had histories as well as urine toxicologies tracked

through the time of delivery. The drug-using women all had been referred for

drug abuse treatment into the hospltal-based center. The infants exposed to

cocaine throughout the pregnancy had a significantly reduced gestational age

and birth weight, length, and head circumference in addition to a significantly

higher rate of intrauterine growth retardation. Infants exposed in only the first

trimester had no reduction in gestational age and had normal growth

parameters. Both groups of infants, however, demonstrated significant

impairment in orientation, motor, and state-regulation neurobehaviors.

Regression analyses to evaluate effects of secondary drug use were not

performed, although the two cocaine-using groups were similar in their use of

alcohol and marijuana, and all three groups had similar patterns of cigarette

use.

Zuckerman and colleagues (1989) identified 1,226 pregnant women during the

prenatal period and evaluated the impact of cocaine and/or marijuana on

pregnancy outcome. Controlling for tobacco and alcohol effects, it was found

that cocaine use in 216 women was independently associated with decreased

birth weight and head circumference. Other complications of pregnancy were

not addressed.

Burkett and coworkers (1990) reviewed obstetric charts for 139 women who

were identified on voluntary self-report as cocaine users. Ninety-two percent of

the cocaine-using women used multiple drugs in addition to the cocaine. No

control or comparison group was used, but it was concluded that the cocaineusing women were at high risk for perinatal complications: More than 30

percent had a sexually transmitted disease; 63.9 percent had precipitous labor;

20.5 percent had meconium-stained fluid, 36 percent had infants weighing less

than 2,500 grams; and 32 percent of the infants were small for gestational age.

Placental abruptions were not assessed.

Thus, in reviewing the current scientific literature on the effects of cocaine on

pregnancy and neonatal outcome, it becomes evident that many of the

methodoiogic difficulties revolve around a lack of precision in the definition of

maternal drug use and the variables to be studied. In addition, other

complicating factors in pregnancy have not been assessed so that their

contribution to outcome variables could be determined.

DEFINITION OF THE POPULATION

The cocaine-using population is a chaotic one, prone to abrupt changes in

lifestyle and drug use patterns. Many studies suffer at inception with the lack of

a specific definition for the drug-using population to be evaluated. The pregnant

58
woman tends to identify cocaine as the primary drug of abuse, but further

investigation reveals the use of multiple other drugs, including marijuana,

alcohol, and heroin. In addition, this polydrug use pattern may vary widely

through the tenure of the pregnancy, with binge use of cocaine accompanied by

continuous or intermittent use of the other substances. Some research

(Madden et al. 1986; Cherukuri et al. 1988; Chouteau et al. 1988; Hume et al.

1989) identified the population under study as cocaine-using women but did not

delineate other drugs used. One study (Ryan et al. 1987) labeled the women

as cocaine abusers, but in actuality, all of the women were opiate users on

methadone maintenance who also used cocaine. Two studies (MacGregor et

al. 1987; Little et al. 1989) identified other drugs used by the cocaine-using

women in their populations but did not take these secondary drug use patterns

into account when analyzing the pregnancy outcome data. Some studies have

used comparison groups with similar patterns of secondary drug use (Chasnoff

et al. 1985, 1987, 1989; Bingol et al. 1987; Oro and Dixon 1987) but did not use

statistical analyses capable of determining the relative impact of the multiple

drugs. The relatively small number of subjects in these studies makes these

types of analyses difficult.

The timing of the identification of the population to be evaluated varies from one

study to the next along the prenatal and postpartum continuum. Studies by

several groups that identified women retrospectively at the time of delivery

(Cherukuri et al. 1988; Little et al. 1989; Burkett et al. 1990) relied on historical

recall by women to review drug use patterns. Other studies (Madden et al.

1986; Oro and Dixon 1987; Bingol et al. 1987; Chouteau et al. 1988) relied on a

single urine toxicology at the time of delivery to identify the “cocaine-using”

population. The lack of prospective evaluation impedes accurate ascertainment

of drug-using women, and one negative urine toxicology at the time of delivery

does not assure the drug-free status of the woman throughout the pregnancy.

Other research (Chasnoff et al. 1985, 1987, 1989; Ryan et al. 1987; MacGregor

et al. 1987; Frank et al. 1988; Hume et al. 1989; Zuckerman et al. 1989)

identified women during the prenatal period and tracked the women’s drug use

patterns throughout the pregnancy. These studies had the advantage of being

able to identify more specifically the patterns and timing of drug use, but they

still could not accurately ascertain the amount of drug used at each instance.

This aspect has particularly impeded the establishment of dose-effect

relationships for pregnancy complications associated with cocaine use.

The setting of the project also can affect the recruitment of study subjects and

thus the definition of the population under investigation. In some research

(Chasnoff et al. 1985, 1987, 1989; Ryan et al. 1987; MacGregor et al. 1987),

the groups studied were all women referred for drug abuse treatment services

59
within a hospital-based program. Thus, these study results cannot necessarily

be extrapolated to women who receive no prenatal care (and are therefore

probably more dysfunctional than those in treatment) or to women whose more

moderate or minimal use does not initiate referral into a substance abuse

treatment program. Zuckerman and colleagues (1989) identified women

receiving prenatal care but did not collect Information regarding past or present

drug abuse treatment.

Women identified as cocaine users in a community setting will receive

interventions that vary according to the whim of the individual practitioner. Only

pregnant women who are perceived to be at greatest risk from their substance

use will be referred to clinical research programs, again affecting the definition

of the population to be studied. These issues are especially pertinent given

recent evidence that cocaine use occurs at a significant rate in the middle-class

population of women seeking care in the private health care setting (Chasnoff et

al. 1990).

DEFINITION OF THE DRUG

The drug under study, although labeled “cocaine,” may take many forms and

may be used in different ways (inhaled, smoked, freebased, injected). The

concentration of cocaine may vary from one community to another and, in fact,

may vary within a community or over a particular timeframe, as in the 40 weeks

of pregnancy. Contaminants with which the cocaine is processed may in

themselves have an impact on pregnancy, although no studies have addressed

this issue. Economic realities for the pregnant woman also may influence the

frequency, timing, and purity of the cocaine she uses as well as the interim use

of other drugs.

The dose of cocaine used also can vary over a period of time for the individual.

As noted above, polydrug use patterns predominate among cocaine users, but

studies are often not designed to take this fact into account. One aspect of this

problem is that, at the national level, societal and political concerns have tended

to focus on one particular drug at a time. Research priorities are vulnerable to

these concerns, so that research proposals and articles accepted for publication

tend to focus on that one drug rather than the spectrum of substance use

and abuse in pregnancy. This further fragments attempts to understand the

interactive and/or additive effects of multiple drugs.

DEFINITION OF THE ENVIRONMENT

In studies of cocaine use in pregnancy, the most difficult problem to overcome

is that of other variables in the maternal and fetal environments. The biologic

60
outcome variables (e.g., frequency of low birth weight) may be affected by

nutritional factors, previous pregnancy history, and maternal health, to name a

few. The frequencies of congenital malformations are known to vary according

to maternal age, race, geographic location, and maternal health. If these

confounding variables are ignored, their presence in abnormal pregnancy

outcomes may be spuriously attributed to drug use simply because these highrisk women also were more likely to use drugs. Conversely, improper

consideration of these variables could obscure a drug effect if, for example, the

“control group” values are abnormal because of factors increasing risk.

Few of the cited studies thoroughly assessed any of these factors, although

some (Chasnoff et al. 1985, 1987, 1989; Bingol et al. 1987; Ryan et al. 1987;

MacGregor et al. 1987; Little et al. 1989; Zuckerman et al. 1989) used as

controls women from the same obstetric population as their study group to

reflect a similar socioeconomic background. Chasnoff and colleagues (1985,

1987, 1989) and Zuckerman and colleagues (1989) used weight gain during

pregnancy as a rough indicator of nutritional status, but no studies have

assessed the impact of violence on pregnancy outcome—an important aspect

of many of these women’s lives.

The genetic makeup of the woman and the efficiency at which the pregnant

woman may metabolize and excrete cocaine are other areas that could have a

profound influence on pregnancy and the fetus, but researchers are not even

close to understanding these issues. Differences in fetal susceptibility to drug

effects are also of prime importance to the expression of outcome, as has been

demonstrated in studies of discordant teratogenesis found in dizygotic twins

exposed to alcohol in utero (Christoffel and Salafsky 1975; Chasnoff 1985).

The mechanism underlying this difference in susceptibility could involve

discordance of fetal and placental vasculature (Fogel et al. 1965), different rates

of organogenesis with resultant differences in susceptibility to teratogenesis

at different times (Lenz 1966), or different rates of drug degradation and

elimination on the part of each fetus (Seppala et al. 1971). Whatever the

mechanism, it is clear that current debates regarding “threshold” amounts of

cocaine that can affect pregnancy outcome are futile, because individual fetal

susceptibility is an important yet unpredictable factor in the outcome of the fetus

passively exposed to the drug.

DEFINITION OF APPROPRIATE COMPARISON GROUPS

The most difficult aspect of developing comparison groups is assuring that the

women selected are in fact drug-free. Most studies (Bingol et al. 1987; Oro and

Dixon 1987; Chouteau et al. 1988; Cherukuri et al. 1988; Little et al. 1989;

Burkett et al. 1990) have relied on ascertainment of controls retrospectively at

61
the time of delivery, relying on a negative history or one negative urine

toxicology to define drug-free status. Cocaine use even 72 hours prior to

delivery would thus not show up in the urine toxicology but could well affect the

outcome of the pregnancy and the infant. Some researchers have stated that

the mistaken Inclusion of drug-using women in the drug-free comparison group

could obliterate significant differences for the cocaine-using group. However,

another way to look at this problem is that if cocaine-exposed neonates did not

get identified as drug-exposed because they were asymptomatic (as could have

happened in any of the studies just mentioned), their more “normal” outcome

could ameliorate the overall negative outcome of the cocaine-exposed group.

This speaks to the importance of prenatal identification of control subjects, so

that their drug-free status throughout pregnancy can be documented.

In addition, although a control group may be demographically similar to the

group under study, there is little one can do to control for the drug-seeking

environment in which most of the women under study live. Some studies (Little

et al. 1989; Burkett et al. 1990), when they have ascertained controls and study

populations at the time of delivery, have included women who had no prenatal

care, usually in the substance-using group. Thus, many women in the drugusing group will have had no prenatal care, whereas most of the women in the

drug-free group have had prenatal care—a major factor in predicting pregnancy

outcome.

DEFINITION OF APPROPRIATE OUTCOME MEASURES

Some of the inconsistency as to outcomes found in various studies may be

traced to inadequate appreciation of the biologic expression of cocaine’s action

on the pregnancy and the fetus. Through a review of the current literature, it

appears that cocaine has two modes of action. The first is the indirect effect of

cocaine mediated through its pharmacologic action, which causes maternal and

fetal vasoconstriction and tachycardia (Woods et al. 1987) and stimulates the

pregnant uterus to contract (Lederman et al. 1978). This stimulation of the

uterus results in the high rate of prematurity seen in these pregnancies. Other

fetal outcomes, especially growth retardation, microcephaly, and congenital

anomalies, are mediated through the intrauterine hypoxia and malnutrition

induced by the vasoconstriction (Woods et al. 1987). Thus, one does not see

malformations but does see evidence for fetal disruptions in pregnancies

complicated by cocaine use (Van Allen 1981; Hoyme et al. 1990).

On the other hand, the second mode of action is the direct effects of cocaine

induced by its interference with dopamine, norepinephrine, and serotonin

reuptake engender increased neurotransmission and central nervous system

irritability that may result in direct toxicity to the developing central nervous

62
system of the fetus. This would explain the variations in neurobehavior seen in

these infants and also is consistent with studies showing that maternal use of

cocaine in the first trimester only can still result in neurobehavioral deficiencies

in the newborn infant (Chasnoff et al. 1989). Thus, it would appear that the

indirect effects of cocaine could be ameliorated through intervention (i.e.,

cessation of the woman’s cocaine use in pregnancy resulting in a decreased

rate of obstetric complications). This is consistent with the work of Chasnoff

and coworkers (1989) and Zuckerman and coworkers (1989). However, it also

appears that cessation of cocaine use would not reverse the direct effects of

cocaine, resulting in toxicity to the fetal central nervous system. Methodologic

issues thus arise when techniques for identification of a study population

intermix women who used cocaine only early in pregnancy with women who

used cocaine throughout the pregnancy.

CONCLUSION

Although all the studies completed thus far have suffered from many of the

methodologic issues discussed here, they have been of great value in defining

key risk factors and general clinical outcome. With the information now

available, it appears safe to conclude that placental dysfunction due to

cocaine’s vasoconstrictive activity increases risk for intrauterine growth

retardation and prematurity; fetal disruption due to acute cocaine-induced

vascular compromise places the fetus at risk for structural anomalies; and

neurotoxicity due to cocaine’s action on monoaminergic neurons places the

infant at risk for neurobehavioral abnormalities. Given the extreme difficulty that

studies have in establishing experimental control over the myriad confounding

variables that can influence pregnancy outcome and the status of the child,

what are now needed are studies designed so that sophisticated analytical

techniques can be used to establish statistical control over the additive and/or

interactive effects of demographic and lifestyle characteristics that place the

cocaine-using pregnant woman and her child at risk.

REFERENCES

Acker, D.; Sachs, B.P.; Tracey, K.J.; and Wise, W.E. Abruptio placentae

associated with cocaine use. Am J Obstet Gynecol 146:220-221, 1983.

Bingol, N.; Fuchs, M.; Diaz, V.; Stone, R.K.; and Gromisch, D.S. Teratogenicity

of cocaine in humans. J Pediatr 110:93-96, 1987.

Burkett, G.; Yasin, S.; and Palow, D. Perinatai implication of cocaine exposure.

J Reprod Med 35:35-42, 1990.

Chasnoff, I.J. Fetal alcohol syndrome in twin pregnancy. Acta Genet Med

Gemellol (Roma) (34:229-232, 1985.

63
Chasnoff, I.J.; Burns, K.A.; and Burns, W.J. Cocaine use in pregnancy:

Perinatal morbidity and mortality. Neurotoxicol Teratol 9:291-293, 1987.

Chasnoff, I.J.; Burns, W.J.; Schnoll, S.H.; and Burns, K.A. Cocaine use in

pregnancy. N Engl J Med 313:666-669, 1985.

Chasnoff, I.J.; Griffith, D.R.; MacGregor, S.; Dirkes, K.; and Burns, K.A.

Temporal patterns of cocaine use in pregnancy, JAMA 261(12):1741-1744,

1989.

Chasnoff, I.J.; Landress, H.J.; and Barrett, M.E. The prevalence of illicit-drug or

alcohol use during pregnancy and discrepancies in mandatory reporting in

Pinellas County, Florida. N Engl J Med 322:1202-1206, 1990.

Cherukuri, R.; Minkoff, H.; Feldman, J.; Parekh, A.; and Glass, L. A cohort

study of alkaloid cocaine (“crack”) in pregnancy. Obstet Gynecol 72:147-

151, 1988.

Chouteau, M.; Namerow P.B.; and Leppert, P. The effect of cocaine abuse on

birth weight and gestational age. Obstet Gynecol 72:351-354, 1988.

Christoffel, K.K., and Salafsky, I. Fetal alcohol syndrome in dizygotic twins.

J Pediatr 87:963-967, 1975.

Fogel, B.J.; Nitkowsky, H.M.; and Gruenwald, P. Discordant abnormalities in

monozygotic twins. J Pediatr 66:64-72, 1965.

Frank, D.A.; Zuckerman, B.S.; Amaro, H.; Aboagye, K.; Bauchner, H.; Cabral,

H.; Fried, L.; Hingson, R.; Kayne, H.; Levenson, S.M.; Parker, S.; Reece, H.;

and Vinci, R. Cocaine use during pregnancy: Prevalence and correlates.

Pediatrics 82:888-895, 1988.

Hoyme, H. E.; Jones, K.L.; Dixon, S.D.; Jewett, T.; Hanson, J.W.; Robinson,

L.K.; Msall, M.E.; and Allanson, J.E. Prenatal cocaine exposure and fetal

vascular disruption. Pediatrics 85:743-747, 1990.

Hume, R.F.; O’Donnell, K.J.; Stanger, C.L.; Killam, A.P.; and Gingras, J.L. In

utero cocaine exposure: Observations of fetal behavioral state may predict

neonatal outcome. Am J Obstet Gynecol 161:685-690, 1989.

Lederman, R.P.; Lederman, E.; Work, B.A., Jr.; and McCann, D.S. The

relationship of maternal anxiety, plasma catecholamines, and plasma cortisol

to progress in labor. Am J Obstet Gynecol 132:495-500, 1978.

Lenz, W. Malformations caused by drugs in pregnancy. Am J Dis Child

112:99-105, 1966.

Little, B.B.; Snell, L.M.; Klein, V.R.; and Gilstrap III, L.C. Cocaine abuse during

pregnancy: Maternal and fetal implications. Obstet Gynecol 73:157-160,

1989.

MacGregor, S.N.; Keith, L.G.; Chasnoff, I.J.; Rosner, M.A.; Chisum, G.M.;

Shaw, P.; and Minogue, J.P. Cocaine use during pregnancy: Adverse

perinatal outcome. Am J Obstet Gynecol 157:686-690, 1987.

Madden, J.D.; Payne, T.F.; and Miller, S. Maternal cocaine use and effect on

the newborn. Pediatrics 77:209-211, 1986.

64
Oro, A.S., and Dixon, S.D. Perinatal cocaine and methamphetamine exposure:

Maternal and neonatal correlates. J Pediatr 111:571-578, 1987.

Ryan, L.; Ehrlich, S.; and Finnegan, L. Cocaine abuse in pregnancy: Effects

on the fetus and newborn. Neurotoxicol Teratol 9:295-299, 1987.

Seppaia, M.; Raiba, N.C.R.; and Tamminen, V. Ethanol elimination in a mother

and her premature twins. Lancet 1:1188-1189, 1971.

Van Allen, M.I. Fetal vascular disruption: Mechanisms and some resulting birth

defects, Pediatr Ann 10:219-233, 1981.

Woods, J.R.; Plessinger, M.A.; and Clark, K.E. Effect of cocaine on uterine

blood flow and fetal oxygenation. JAMA 257:957-961, 1987.

Zuckerman, B.; Frank, D.A.; Hingson, R.; Amaro, H.; Levenson, S.M.; Kayne,

H.; Parker, S.; Vinci, R.; Aboagye, K.; Fried, L.E.; Cabral, H.; Timperi, R.; and

Bauchner, H. Effects of maternal marijuana and cocaine use on fetal growth.

N Engl J Med 320:762-768, 1989.

AUTHOR

Ira J. Chasnoff, M.D.

Associate Professor of Pediatrics and Psychiatry

Northwestern University Medical School

President

National Association for Perinatai Addiction Research and Education

Suite 200

11 East Hubbard Street

Chicago, IL 60611

65
Use of Birth Defects Monitoring

Programs for Assessing the Effects of

Maternal Substance Abuse on

Pregnancy Outcomes

M. Louise Martin and Larry D. Edmonds

INTRODUCTION

Birth defects are the fifth leading cause of years of potential life lost before age

65 and are the leading cause of infant mortality; they are directly responsible for

21 percent of all infant deaths in the United States (Centers for Disease Control

1989).

From a public health perspective, studying the causes of birth defects and other

adverse pregnancy outcomes is important because some causes are entirely

preventable. Adverse pregnancy events influenced or caused by maternal

ingestion of alcohol, cocaine, and other licit and illicit substances are

preventable. To prevent those defects, however, researchers must know (1)

the kind and extent of adverse events that are due to a particular agent, (2) the

population that is susceptible, and (3) the overall impact of the agent on the

public’s health.

One way to gain this knowledge is through surveillance systems constructed

to monitor or survey birth defects and other adverse pregnancy outcomes. The

data gathered through such systems provide a unique source for generating

and testing hypotheses about congenital malformations and a variety of

maternal and environmental exposures. Data from birth defects surveillance

programs have been used to supplement information gained through clinical

studies, to test hypotheses generated through clinical studies, and to assess

local and national trends in health events for the purpose of correlating

changing health trends with shifts in cultural, social, and environmental

exposures.

For more than 20 years, the Division of Birth Defects and Developmental

Disabilities, Centers for Disease Control (CDC), has conducted two well-known

66
surveillance programs, the Metropolitan Atlanta Congenital Defects Program

(MACDP) and the national Birth Defects Monitoring Program (BDMP),

to monitor trends in the occurrence of congenital defects and for use in

epidemiological studies (Edmonds et al. 1981). Recently, data from these

programs have been used to examine maternal substance abuse and its effects

on the developing fetus.

Descriptive and epidemiological studies using birth defects surveillance systems

contribute significantly to understanding of the etiologies and patterns in birth

defect occurrence in populations. In addition, surveillance data gathered in a

properly monitored program act as early warnings of new teratogens in the

study population.

FUNCTIONS AND ATTRIBUTES OF SURVEILLANCE SYSTEMS

A good health surveillance system maximizes its resources by addressing many

needs of the community. The multiple functions of a strong surveillance system

constructed to monitor or survey birth defects and other adverse pregnancy

outcomes may include (1) developing baseline data so that rates of birth defects

and trends in defect rates can be calculated, (2) identifying geographic areas of

concern (areas where clusters of defects occur) that may warrant indepth

epidemiological investigation, (3) conducting etioiogic studies to identify causes

of birth defects, (4) planning and evaluating health care programs and services,

(5) identifying children in need of special services, and (6) supporting education

and advocacy for special health care needs.

The functions of a birth defects surveillance program and the appropriate use of

its data depend heavily on the program’s characteristics and methods. A good

surveillance system has several key characteristics: (1) It has more than one

function so that surveillance resources are maximized; (2) it has representative

(population-based) coverage so that information gained can be applied or

“generalized” to the public at large: (3) its diagnostic data are accurate and

precise; (4) its data are reported in a timely manner; (5) its personal identifiers

link maternal and paternal records so that cases of disease among infants or

events of interest can be followed or, when necessary, coupled with parental

exposures; (6) it has case ascertainment (which may require data from multiple

sources) that is comprehensive so that underreporting is minimized; (7) it

measures many reproductive outcomes; (8) its nosologic methods are

etiologicaliy meaningful; (9) it provides a large historic database for comparing

rates and for analyzing trends; (10) it can link birth defects data with exposure

data: (11) its methods of data collection make followup studies easy to do;

(12) its statistical analyses are appropriate; and (13) its patient records are kept

confidential.

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As the functions and attributes of surveillance systems vary, so too do the

quality of the data and the procedures for generating those data. Researchers

using any surveillance data must have a thorough knowledge of the quality of

these data to interpret them correctly and to extrapolate results. Researchers

reviewing scientific literature describing studies based on surveillance data

should be aware of the strengths and limitations inherent in the data.

DATA SOURCES FOR BIRTH DEFECTS SURVEILLANCE

Numerous data sources are employed in birth defects surveillance systems;

frequently, they include birth and death certificates, hospital discharge

summaries, special surveys of existing medical data, special clinic notes,

laboratory reports, parental interview data, and environmental data. Each

data source has its strengths and limitations. For example, birth and death

certificates are useful in that they provide complete coverage of a population of

study (thus reducing the likelihood of selection bias) and provide both infant

medical data and parental information (allowing correlation with selected

parental characteristics or exposures). They are less useful for surveillance

tasks that require rapid reporting (because of delay in processing) and for case

identification (since they generally have lower rates of case ascertainment and

have less complete or accurate information). Newborn hospital discharge

summaries are generally more complete and available more quickly than are

birth or death certificates, but they provide little or no maternal information. In

addition, because newborn hospital discharge data only cover the newborn

period, data on defects ascertained after that period are usually missing.

One important difference among data sources is in the quality of case

ascertainment. Table 1 illustrates this difference, showing a comparison of

rates of major birth defects by source of data.

TABLE 1. Rates of major birth defects by data source

Source of Data Rate Per 10,000 Births

Birth certificates (NCHSa

 1982-1983) 88.9

Newborn hospital discharge (BDMPb 1982-1985) 282.5

Mandatory hospital reporting (Nebraskac 1982-1985) 248.0

Linked data sources (Missourid 1982-1987) 336.0

Active hospital surveillance (MACDPe 1982-1987) 415.0

(Iowaf 1983-1986) 549.0

Physical examination of infant (CPPg

 1959-1965) 830.0

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aPublic use data tape documentation: Birth certificates, 1982-83. Hyattsville,

MD: National Center for Health Statistics (1983)

bBirth Defects Monitoring Program, Division of Birth Defects and Developmental

Disabilites, Center for Environmental Health and Injury Control, Centers for

Disease Control

c

 Nebraska Birth Defects Registry, Divlsion of Health Data and Statistical

Research, State Department of Health

dMissouri Division of Health Resources, Missouri Department of Division of

Health

eMetropolitan Atlanta Congenital Defects Program, Division of Birth Defects and

Developmental Disabilities, Center for Environmental Health and Injury

Control, Centers for Disease Control

f

 Iowa Birth Defects Registry, Iowa Health Registry, University of Iowa

Department of Pediatrics and the Department of Health

g

The Collaborative Perinatal Project of the Collaborative Study of Cerebral

Palsy, Mental Retardation, and Other Neurological and Sensory Disorders of

Infancy and Childhood, from the National Institute of Neurological Diseases

and Stroke, National Institutes of Health

BASIC DESIGN ISSUES IN BIRTH DEFECTS SURVEILLANCE

In surveying for birth defects generally and for those attributable specifically to

substances of abuse, researchers must understand the basic design issues

with which they must contend. For example, researchers must consider the

following:

1.

2.

3.

4.

5.

6.

Population at risk—Will the surveillance system “capture” this group?

Outcomes to include in the case definition—Are nosologic and data

collection methods suitable for finding cases as defined in the study?

Methods to use for case ascertainment—Are the data sources adequate to

capture defined cases from the appropriate populations?

Dilemma between the need for confidentiality and the need for personal

identifiers—Does the ability to link data sources or to track records over

time add significantly to the quality of the surveillance and to the data?

Data to collect and by what methods—Will the surveillance system provide

adequate descriptive data to facilitate study comparisons of interest?

Procedures for data coding, analysis, and reporting and the quality of data

resulting from these procedures—Do these have limitations that influence

the data quality adversely?

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7. Need for followup studies and the procedures for conducting followup—

Does the surveillance system facilitate or preclude followup studies?

METHODS OF CASE ASCERTAINMENT: ACTIVE AND PASSIVE SYSTEMS

Cases in birth defects surveillance systems are ascertained actively or

passively. In active surveillance, trained surveillance staff actively seek cases

in hospitals, clinics, or other facilities by systematically reviewing medical and

other health or social records. In some active surveillance systems, such as the

Collaborative Perinatal Project (Myrianthopoulus and Chung 1974), personnel

performed complete medical examinations of each case infant. In CDC’s

MACDP, multiple sources of information, such as vital records and medical

charts in obstetric and pediatric hospitals, cytogenetic laboratories, and genetics

clinics, are used to identify cases (Edmonds et al. 1981).

Active surveillance systems with multiple sources of existing medical data

include the following as their strengths: (1) reporting of defects is fairly

complete, (2) data are provided in a timely fashion, (3) diagnoses are generally

complete and accurate, (4) followup studies are possible, and (5) information is

collected and available on both the infant and the mother. The latter is

especially important for assessing influences on the infant because of maternal

conditions and exposures. Active surveillance systems, however, are limited in

that they are often expensive and because their high cost may limit their range

of catchment to small populations. In addition, because they are generally

based on small populations, it takes much time to generate adequate baseline

data for reliable prevalence rates and to detect and monitor trends.

In passive surveillance systems, cases are identified through reports submitted

to the surveillance program by staff in hospitals, clinics, or other health care

facilities. Those reporting the data may do so voluntarily or because they are

required to do so by law or regulation. CDC’s national BDMP is a passive

system; its information comes from hospital discharge data on newborns and is

provided voluntarily by the contributing hospitals. The data in other systems are

gathered through legislatively mandated reports of birth defects, through linked

data from multiple sources, and through vital statistics sources only (Flynt et al.

1987).

In general, the strengths of passive systems are that they can cover populations

from a larger geographic area and therefore have data on a greater number of

cases than do active systems, and they are less expensive to conduct and

manage. Passive systems are, however, limited more than active systems by

incomplete data, inadequate data for followup studies, and greater delays in

reporting data.

70
An important factor for researchers to consider when interpreting data derived

from these two types of surveillance systems is that the data, like the sources,

differ in how thoroughly cases are ascertained. Table 2 shows select birth

defects prevalence rates per 10,000 births by method of ascertainment.

Comparing two well-known passive systems with three reputable active

systems highlights that, in virtually all cases, active surveillance programs have

better systems for diagnosing and ascertaining cases of birth defects. Also

noteworthy is that ascertaining cases of apparent defects, such as anencephaly

and cleft lip and palate, is better in both active and passive systems than is

ascertaining cases with more covert malformations, such as congenital cardiac

and renal anomalies.

CHARACTERISTICS OF TWO BIRTH DEFECTS SURVEILLANCE SYSTEMS

We will use two well-known surveillance systems operated by CDC to discuss

the data used for assessing pregnancy outcomes. Table 3 is a comparison of

these two systems and shows that the active system (MACDP) has a smaller

population (about 1/20th the number of births reported to BDMP) and covers a

smaller geographic area (Metropolitan Atlanta versus the Nation as a whole).

MACDP reports data faster and has an extended period for diagnosing and

ascertaining cases (it includes infants up to 1 year of age rather than newborns

only). For most cases, the active system has a greater sensitivity and predictive

value positive than does the passive system; it contains maternal information,

and researchers can use its data more easily for followup studies. These

surveillance systems have been used to augment information derived from

clinical research on birth defects and other adverse pregnancy outcomes.

USE OF SURVEILLANCE SYSTEMS FOR ASSESSING RISK OF BIRTH

DEFECTS ARISING FROM MATERNAL SUBSTANCE ABUSE

BDMP

In 1974 CDC began BDMP, the first nationwide system for monitoring

congenital malformations. BDMP was to function primarily as an early warning

system to identify new teratogens in the population and to alert public health

officials to any changing trends in birth defects or unusual geographic

differences within participating areas of the United States.

CDC purchases hospital discharge data from two sources, the Commission on

Professional and Hospital Activities and the MacDonnell Douglas Hospital

Information Service (MDHIS). Annually through these data, CDC follows about

1 million births (25 percent of the total in the United States) from a nonrandom,

hospital-based sample of U.S. births. The information gathered is collected and

71
TABLE 2. Comparison of birth defect rates per 10,000 births by method of

ascertainment

Birth Defect

Passive Active

NCHSa BDMPb MACDPC lOWAd CBDMPe

Anencephaly

Spina bifida

Cleft lip +/-

cleft palate

Hypoplastic

left heart

1.5 2.9 3.3 3.9 3.3

3.2 4.8 6.6 7.3 7.1

5.9 9.1 9.9 12.1 11.1

0.3 0.8 3.2 3.8 3.0

Down’s syndrome 3.6 8.5 9.6 10.1 9.7

aPublic use data tape documentation: Birth certificates, 1982-83. Hyattsville,

MD: National Center for Health Statistics (1983)

bBirth Defects Monitoring Program (1982-1985). Division of Birth Defects and

Developmental Disabilities, Center for Environmental Health and Injury

Control, Centers for Disease Control

c

 Metropolitan Atlanta Congenital Defects Program (1983-1987), Division of

Birth Defects and Developmental Disabilities, Center for Environmental Health

and Injury Control, Centers for Disease Control

d

Iowa Birth Defects Registry, Iowa Health Registry, University of Iowa

Department of Pediatrics and the Department of Health

eCalifornia Birth Defects Monitoring Program (1983-1985). California

Department of Health Services

coded uniformly from hospital discharge data, making BDMP the largest single

set of uniformly collected and coded data on birth defects among U.S.

newborns.

From these data, CDC generates prevalence rates and maintains historic

databases from which trends in birth defects can be monitored. Data are

monitored quarterly, and trends in rates are evaluated by CUSUM methods for

statistical significance. Data also have been used for descriptive and

epidemiological studies.

Using a subset of these data, CDC has also generated a linked record system

that allows us to generate hypotheses concerning maternal exposures and

infant outcomes.

72
TABLE 3. Characteristics of two birth defects surveillance systems, Centers

for Disease Control

Characteristic MACDPa BDMPb

Population

Database

Time between birth

and report

Nosology

Precise diagnosis

Case definition

Sensitivity

PVPe

Ascertainment

Maternal data

Followup

35,000/year

1968-present

(609,000 births)

1-6 months 6-12 months

6 digit BPA/CDCc

Written description

Diagnosis in first year

90-100%

90-100%

Multiple source

Yes

Yes

1,000,000/year

1970-present

(19 million births)

ICD-9-CMd

ICD code

Newborn diagnosis

60-90%

45-100%

Newborn discharge

No

Difficult

aMetropolitan Atlanta Congenital Defects Program, Division of Birth Defects and

Developmental Disabilities, Center for Environmental Health and Injury

Control, Centers for Disease Control

bBirth Defects Monitoring Program, Division of Birth Defects and Developmental

Disabilities, Center for Environmental Health and Injury Control, Centers for

Disease Control

c

 British Paediatric Association/Centers for Disease Control; the coding is a

CDC modification of the BPA coding scheme

d

lCD-9-CM: International Classification of Diseases, 9th Edition, Clinical

Modification

ePredictive value positive

73
BDMP: Monitoring Trends. From BDMP-generated rates, we can follow birth

defect trends in time and place for large populations and geographic regions;

we can also make comparisons among rates for select groups of infants. Table

4 shows rates of selected defects among designated racial or ethnic groups in

the United States (Chavez et al. 1989). One syndrome routinely monitored is

fetal alcohol syndrome (FAS). Compared with the risk for FAS among white

infants, Hispanic infants have about the same risk, black infants have a sixfold

greater risk, American Indian infants have a 30-fold greater risk, and Asian

infants have one-third the risk. These data illustrate that monitoring trends of

defects among subgroups is epidemiologically rewarding; the groups identified

as being at increased risk can be targeted for prevention and intervention

programs; those with lower relative risks can be studied for behavioral,

physiological, and genetic factors that protect them from alcohol-related

adverse events.

BDMP and MDHIS: Linking Maternal and Infant Records. Since 1982 CDC

has accumulated discharge data on almost 3 million infants born in hospitals

that subscribe to MDHIS and on women who gave birth in those hospitals. To

TABLE 4. Rates (per 10,000 births) of major congenital malformations by

race/ethnicity, United States, 1981-86

Malformation Black

American

Hispanic Indian Asian White

Anencephaly 2.1 4.4 3.6 4.4 3.0

Patent ductus 49.9 20.7 33.5 25.1 26.5

arteriosus

Cleft palate/ 3.7 3.7 9.8 4.6 5.9

no cleft lip

Cleft lip +/- 4.4 8.6 17.5 12.9 9.7

cleft palate

FAS 6.0 0.8 29.9 0.3 0.9

Down’s syndrome 6.5 11.6 6.7 11.3 8.5

Total 179.9 144.4 222.0 157.8 189.8

SOURCE: Centers for Disease Control 1988

74
ensure patient confidentiality, no data have personal identifiers; this need for

confidentiality, however, limits the usefulness of the data because there is no

direct link between maternal and Infant records. To enhance the usefulness of

the data, yet continue to maintain patient confidentiality, CDC has developed a

probabilistic model for linking infant and maternal records anonymously. The

linking algorithm relies on a weighted scoring system that assigns numeric

values to demographic and clinical variables. Table 5 is a list of some of these

variables and the maximum scores assigned for concordance between the

infant and the imputed maternal record. The minimum score for considering a

pair as matching is seven. Each match is the best match that can be achieved

for the pair. Validation studies have shown that 98 percent of infants and

mothers match; 95 percent of these are true matches (Heuther 1990).

TABLE 5. Variables used to link maternal and infant records, BDMPa 1982-

present

Variable Score

ZIP Code 3

Race 2

Religion 2

Twin status 5

Prematurity status 2

Same pay source 1

Physician 1

Surgeon 1

Hours between admissions 4 (maximum)

Same discharge hour 6 (maximum)

a

From the Division of Birth Defects and Developmental Disabilities, Center for

Environmental Health and Injury Control, Centers for Disease Control

The authors have used this linked data set to examine pregnancy outcomes of

women with specific medical conditions and environmental exposures coded on

their hospital records when their infants were delivered. We have compared the

birth outcomes of mothers with the exposures of interest with the outcomes of

all mothers in the data set. Several examples illustrate how the data can be

used for different maternal exposures.

Maternal Lithium Use and Ebstein’s Anomaly. It had been suggested that

women taking lithium for manic-depressive disorder were at an increased risk of

having an infant with a rare cardiac defect, Ebstein’s anomaly. Edmonds and

75
Oakley (1990) reported on a case-control study conducted at CDC with BDMP

data. They identified 53 infants with cases of Ebstein’s anomaly coded on their

records and reviewed the medical records of these infants. They determined

that infants that had false-positive cases (6 miscoded and 13 coded “rule-out

Ebstein’s” for which diagnoses were never confirmed). Thirty-four infants had

confirmed cases. Edmonds and Oakley reviewed hospital and physician

records for those 34 infants and for 34 control Infants. No infants had mothers

with a reported exposure to lithium during pregnancy or history of manicdepressive disease. Edmonds and Oakley corroborated their findings using the

MDHIS maternal-infant linked data set: Of the 34 infants whose records

indicated they had Ebstein’s anomaly, none were born to the 88 women whose

records indicated they suffered from manic-depressive disorder.

Maternal Alcohol Dependence. Another example of how these data can be

used for maternal exposures is illustrated in table 6, which shows selected

outcomes for infants born to 276 mothers whose records had codes for alcohol

dependence. As might be expected, these infants were at a higher (1,110-fold)

risk of having FAS than were other infants whose records were in the data set.

Infants of alcohol-dependent mothers were also at a 12.6-fold higher risk of

having microcephaly and at a 5.3-fold higher risk of having oral clefts.

TABLE 6. Association of maternal alcohol dependence with selected birth

defects: Preliminary Data, BDMPa

Rates Per 10,000 Births

Birth Defect Exposed Overall Relative Risk

Microcephaly 36.2 2.9 12.6

FAS 1,775.4 1.6 1,110.0

Oral clefts 72.4 13.6 5.3

a

From the Division of Birth Defects and Developmental Disabilities, Center for

Environmental Health and Injury Control, Centers for Disease Control

Maternal Cocaine Dependence. We also have used the data set to look at

pregnancy outcomes of mothers whose records show they were cocainedependent at the time of delivery. Table 7 shows selected outcomes for infants

born to these mothers. These infants were 113 times more likely to have

microcephaly than were other infants with records in the data set. They were

also 154 times more likely to suffer from FAS, 24 times more likely to have an

atrial septal defect, and 3 times more likely to have a ventricular septal defect.

76
Interpreting data from this data set must proceed with caution: Record-linkage

systems, such as this, are enticing because they are relatively inexpensive,

provide large sample sizes, and can be useful for exposures that are difficult

to ascertain. They are limited, however, by the degree of accuracy and

completeness of the linkage, by concerns about breach of confidentiality, and

by the potential for misclassification of exposures. For this data set, in

particular, limitations also include (1) lack of data on stillborns, (2) lack of

detailed information on maternal conditions and therapies, and (3) diagnoses of

birth defects only through the newborn period. Despite the limitations, such

data sets are excellent for generating hypotheses but should be complemented

by followup studies of medical records,

TABLE 7. Association between maternal cocaine dependence and selected

birth defects: Preliminary Analysis, BDMPa

Birth Defect

Microcephaly

FAS

Ventricular septal defect

Atrial septal defect

Rates Per 10,000 Births

Exposed Overall Relative Risk

327.9 2.9 113.1

245.9 1.6 153.7

41.0 14.4 2.8

41.0 1.7 24.1

a

 From the Division of Birth Defects and Developmental Disabilities, Centers for

Disease Control

MACDP Surveillance Data

The MACDP is a collaborative effort between the CDC, the Georgia Mental

Health Institute, and Emory University School of Medicine. The MACDP, like

the BDMP, is multifunctional. It has two main objectives: (1) to monitor births of

malformed infants for changes in prevalence or other unusual patterns

suggestive of environmental influences and (2) to develop a case registry for

use (a) in epidemiological and genetic studies, such as descriptive

epidemiologic studies; (b) in generating and testing hypotheses; and (c) in

conducting case-control and family studies. Since 1967 the MACDP has

collected data systematically, including identification, demographic, clinical, and

diagnostic information as well as information prior maternal illnesses and

pregnancy history. Cases of birth defects are ascertained by reviewing

maternal and infant medical records from multiple sources, including birth

77
hospitals, pediatric hospitals, cytogenetic laboratories, specialty clinics, and vital

records. Data are analyzed quarterly, and trends in rates are evaluated by

CUSUM methods for statistical significance. An added component of the

MACDP is the Atlanta Case Control Study (described later). MACDP data have

been used extensively in descriptive studies of selected birth defects, including

trends in the clinical characteristics of infants with spina bifida (Adams et al.

1985), in the incidence of pyloric stenosis (Lammer and Edmonds 1987), in the

epidemiology of early amnion rupture spectrum (Garza et al. 1988), and in the

impact of prenatal diagnosis of Down’s syndrome, selected midline defect

associations, and warctation of the aorta (Martin et al. 1990). Using the

MACDP data, researchers are currently conducting two studies to explore an

association of selected birth defects and cocaine abuse during pregnancy.

Gastroschisis Cluster Investigation. The first study is a case-control study of

gastroschisis in the Atlanta metropolitan area. In 1988 CDC identified a cluster

of infants affected by gastroschisis by monitoring MACDP trends in birth

defects. During that year, 18 infants with gastroschisis were born when only 6

were expected. The observed-to-expected ratio was 3.0 (p=0.00004). Figure 1

shows the prevalence of gastroschisis-affected births in Atlanta from 1968

through 1988. Because cocaine use during pregnancy is believed to produce

vascular disruption defects, one of which may be gastroschisis, one hypothesis

FIGURE 1. Gastroschisis: Trends in repotted incidence among live births

and stillbirths: MACDP, January 1968-December 1988 (rates per

10,000 live births)

78
to be tested in this case-control study is that maternal use of cocaine in

pregnancy may be associated with the increase in gastroschisis. Mothers of

case and control infants are currently being interviewed concerning a variety of

exposures during pregnancy, including use of cocaine in its various forms and

routes of administration (Lynberg, manuscript in progress).

Trends In Vascular Disruption Defects. Because it has been reported that

the incidence of cocaine use among women of childbearing age has been

increasing in the United States (Miller et al. 1984; Johnston et al. 1987), we

hypothesized that if maternal cocaine use caused vascular disruption, then a

concomitant increase in the prevalence of these defects should occur. Martin

and colleagues (1990) used MACDP surveillance data to examine trends for

vascular disruption defects. The infants selected were born between January 1,

1968, and December 31, 1989, with vascular disruptions involving two or more

organ systems; defects of interest included gastroschisis, porencephaly,

intestinal atresia, renal agenesis/dysgenesis and other urinary anomalies, and

transverse limb reductions. Figure 2 shows the 3-year moving average of birth

prevalence of infants with vascular disruption defects in two or more organ

systems during the study period. Preliminary analysis for trends showed no

significant increase in births over the time period of study (Chi square for linear

trend=1.16, p=0.28). In addition, the relative risk (RR) was not significantly

different for race (RR for blacks [whites as referent]=0.68, 95 percent

confidence interval [CI]=0.42-1.11). Further analysis is under way. Although no

detectable “epidemic” of multiple vascular disruption defects has occurred in

Atlanta during the study period, further epidemiologic studies are clearly

indicated to establish whether cocaine is a human teratogen and, if so, to

evaluate patterns of birth defects related to its teratogenic effects.

Atlanta Birth Defects Case Control Study. The Atlanta Birth Defects Case

Control Study is a special component of the MACDP. Data for the Atlanta Birth

Defects Case Control Study were collected from parents of babies with cases of

major congenital anomalies and from a group of parents of randomly selected

control babies without birth defects. Case infants were ascertained through the

MACDP data for 1968 through 1980. Through computer-assisted telephone

interviews, MACDP data for case infants were supplemented with detailed

maternal interview data collected from 1982 through 1983. Nearly 5,000

mothers of case infants and more than 3,000 mothers of control infants

responded to questions regarding family history, demographics, health, and

maternal exposures (overall response rate 71 percent). Details of the studies

have been described elsewhere (Erickson et al. 1984).

Data from this case control study were used by Chavez and coworkers (1989)

to investigate the association between genitourinary tract malformations and

79
FIGURE 2. Three-year moving average, prevalence of two vascular

disruptions in infants, 1968-89

cocaine use during pregnancy. Among the case infants, 276 were identified

with urinary anomalies and 791 with genital anomalies; among a group of

control infants (frequency matched to case infants by race, hospital of birth, and

calendar quarter of birth), they found 2,630 with urinary anomalies and 2,965

with genital anomalies (table 8). Maternal cocaine use was defined as use at

any time from 1 month before pregnancy through the first 3 months of

pregnancy. Chavez and coworkers found a statistically significant association

between reported cocaine use and an increased risk for urinary tract defects.

Infants of mothers who admitted to cocaine use were at a 4.39-fold higher risk

of having urinary tract abnormalities (95 percent Cl: 1.12-17.24). No significant

association with genital organ defects was noted. This study was the first

80
population-based case-control study of maternal cocaine use and congenital

urogenital anomalies.

Several limitations of the Chavez and coworkers’ study are noteworthy: (1) The

number of urogenital anomalies identified among babies of cocaine-using

women was small; and the confidence limits, although excluding unity, were

wide. The results, as the investigators pointed out, should be viewed as

tentative until confirmed or refuted by larger studies. (2) Cocaine use was

classified on the basis of maternal self-report. Classifying maternal cocaine

exposure on the basis of self-report has been controversial and has led to

criticisms of exposure misclassification (Valanis et al. 1988; Zuckerman et al.

1989). (3) The prevalence of cocaine exposure during the study period (1968-

1980) is probably lower than exposure prevalence during the latter part of the

1980s; using 1968-1980 figures may cause researchers to underestimate

current drug use. (4) The study period predated “crack” cocaine; if different

routes of cocaine administration have different pathogenetic effects on the

developing fetus, those differences may not be reflected in the results of this

study.

SUMMARY

We have attempted to demonstrate that birth defects surveillance systems are

a unique adjunct to clinical research data on maternal exposures, including

substances of abuse. Surveillance system data reflect the experiences of the

populations from which they are drawn and the characteristics of the people in

TABLE 8. Association between maternal cocaine use and urogenital

anomalies in infants

Anomaly

All urinary

tract defects

Maternal No Maternal

Cocaine Cocaine

Use Use

Odds Ratio

Cases Controls Cases Controls (95% Cl)

3 7 273 2,630 4.39

(1.12-17.24)

All genital 4 8 787 2,965 2.26

organ defects (0.67-7.62)

SOURCE: Chavez et al. 1989

81
those populations. Sensitive systems may reveal trends in health status and

changes in behavioral, cultural, social, or environmental exposures. They can

be used to monitor changing trends, to identify clusters for investigation, to

generate and test hypotheses, and to conduct epidemiological studies.

For researchers to interpret data derived from surveillance systems

appropriately and wisely, they need a thorough knowledge of the data sources,

the data-collection procedures, and the intent of the surveillance systems.

Researchers using surveillance data should have a thorough understanding of

the quality of their data and the methodologic subtleties that bear on its

interpretation; researchers reviewing scientific literature based on surveillance

data should be aware of the strengths and limitations inherent in the data.

REFERENCES

Adams, M.M.; Greenberg, F.; Khoury, M.J.; Marks, J.S.; and Oakley G.P.

Trends in clinical characteristics of infants with spina bifida: Atlanta, 1972-

79. Am J Dis Child 139:514-517, 1985.

Centers for Disease Control. Contributions of birth defects to infant mortality—

United States, 1986. MMWR 38:633-635, 1989.

Chavez, G.F.; Cordero, J.F.; and Becerra, J.E. Leading major congenital

malformations among minority groups in the United States, 1981-1986.

JAMA 261:205-208, 1989.

Chavez, G.F.; Mulinare, J.; and Cordero, J.F. Maternal cocaine use during

early pregnancy as a risk factor for congenital urogenital anomalies. JAMA

262(6):795-798, 1989.

Edmonds, L.D.; Layde, P.M.; James, L.M.; Flynt, J.W.; Erickson, J.D.; and

Oakley, G.P. Congenital malformation surveillance: Two American systems,

Int J Epidemiol 10:247-252, 1981,

Edmonds, L.D., and Oakley, G.P. Ebstein anomaly and maternal lithium

exposure during pregnancy. (Abstract.) Proceedings of the Third

International Conference of Teratogen Information Services. Park City, UT:

Third International Conference of Teratogen Information Services, 1990.

Erickson, J.D.; Mulinare, J.; McClain, P.W.; Fitch, T.G.; James, L.M.; McClearn,

A.B.; and Adams, M.J. Vietnam Veterans’ Risks for Fathering Babies with

Birth Defects. Atlanta, GA: Centers for Disease Control, 1984.

Flynt J.W.; Norris, C.K.; Zaro, S.; Kitchen, S.B.; Kotler, M.; and Ziegler, A. State

Surveillance of Birth Defects and Other Adverse Reproductive Effects.

Atlanta, GA: Centers for Disease Control, 1987.

Garza, A.; Cordero, J.F.; and Mulinare, J. Epidemiology of early amnion rupture

spectrum of defects: Atlanta, 1968-1982. Am J Dis Child 142:541-544,

1988.

82
Heuther, C.A. “Qualitative Assessment of CDC’s Birth Defects Monitoring

Program Data Sets.” Centers for Disease Cntrol, Atlanta, GA, 1990.

Johnston, L.D.; O’Malley, P.M.; and Bachman, J.G. National Trends in Drug

Use and Related Factors Among American High School Students and Young

Adults, 1975-7986. National Institute on Drug Abuse. DHHS Pub. No.

(ADM)87-1539. Washington, DC: Supt. of Docs., U.S. Govt. Print. Off.,

1987.

Lammer, E.J., and Edmonds, L.D. Trends in pyloric stenosis incidence. J Med

Genet 24:482-487, 1987.

Martin, M.L.; Adams, M.M; and Mortensen, M.L. The descriptive epidemiology

of selected malformations of the aorta: Atlanta, 1970-1983. Teratology

42(3):273-283, 1990.

Miller, J.D.; Cisin, I.H.; and Gardner-Keaton, H. National Survey on Drug

Abuse: Main Findings 1982. National Institute on Drug Abuse. DHHS Pub.

No. (ADM)84-1263. Washington, DC: Supt. of Docs., U.S. Govt. Print. Off.,

1984.

Myrianthopoulos, N.C., and Chung, C.S. Report from the Collaborative

Perinatal Project: Congenital Malformations in Singletons: Epidemiologic

Survey. Birth Defects: Original Article Series, The National Foundation,

March of Dimes. New York: Stratton Intercontinental Medical Book Corp,

1974. pp. 1-59.

Valanis, B.; Waage G.; Dworkin, L.; and Romig, K. Prevalence of drug use

during pregnancy by source of data used. Am J Epidemiol 128:944, 1988.

Zuckerman, B.; Frank, D.A.; Hingson, R.; Amaro, H.; Levenson, S.M.; Kayne,

H.; Parker, S.; Vinci, R.; Aboagye, K.; Fried, L.E.; Cabral, H.; Timperi, R.; and

Bauchner, H. Effects of maternal marijuana and cocaine use on fetal growth.

N Engl J Med 320:762-768, 1989.

AUTHORS

M. Louise Martin, M.S., D.V.M.

Epidemiologist

Larry D. Edmonds, M.S., D.V.M.

Epidemiologist

Birth Defects and Genetic Diseases Branch

Division of Birth Defects and Developmental Disabilities

Center for Environmental Health and Injury Control

Centers for Disease Control

1600 Clifton Road, N.E., F-37

Atlanta, GA 30333

83
Discussion: Methodologic Issues in

Assessment of Pregnancy Outcomes

Ronald A. Chez

INTRODUCTION

Birth defects monitoring programs for assessing the effects of maternal

substance abuse on pregnancy outcome are aimed at enhancing the capacity

to prevent such outcomes. As reviewed by Martin and Edmonds (this volume),

appropriate surveillance systems feature at least 13 key characteristics and

methodologic attributes. The source of data remains the crux, however,

because of the strengths and weaknesses of each data source. An example is

estimating the rates of major birth defects. Using birth certificates as a source

of data provides a rate of one-tenth the rate of 830 per 10,000 births found on

physical examination during the first year of life. Examinations done as the

infant progresses through childhood and puberty yield an even higher rate.

Consideration of these basic design issues highlights the differences between

active and passive surveillance. In analyzing the strengths and weaknesses

of each method, accuracy is the dominant area of disparity. Contrasting the

Metropolitan Atlantic Congenital Defects Program, an active program that

examines children up to 1 year of age, with the National Birth Defects

Monitoring Program, a passive program, emphasizes their differences,

including sensitivity and predictive value (Martin and Edmonds, this volume).

Some fundamental questions related to design need to be addressed. Without

answers, an inability to recognize the presence of birth defects with any alacrity

will continue. The first question concerns how one recognizes birth defects.

Phocomelia was recognized rapidly because it was relatively rare and its

features were overt. In contrast, an increased incidence of urinary tract

disorders, cerebral palsy, mental retardation, or a number of other conditions

with multifactorial origins would have delayed or prevented recognition of the

causal relationship between phocomelia and thalidomide use in mothers.

Extend this notion to ask whether the maternal use of a teratogen resulting in a

modification of intellectual, psychological, sociological, or learning behaviors

84
would be identified. These disabilities may not be manifest until a child enters

school. Question also the likelihood of recognizing a teratogen resulting in a

marked increase in the incidence of carcinoma of the cervix, gallbladder

disease, or emphysema, all relatively common diseases.

The diethylstilbestrol (DES) exposure in pregnancy experience is similar to the

phocomelia example. Again, the rarity of the lesions (adenosis and carcinoma

of the vagina and changes in the anatomical and functional capacity of the

cervix and uterus) enhanced recognition of the causal relationship. If, Instead,

DES exposure had resulted In an increase of Infertility per se or menstrual

dysfunction or premature rupture of the membranes, most likely the role of DES

would not have been identified.

DATA DEFICIENCIES

The reliability of research data that depend on history-taking and physical

examination by direct-care health professionals is also questionable. There

are always deficiencies in creating a medical record, including the discharge

summary. Regardless of the time of day, the intellectual interest, the capacity

of the patient to communicate, and the curiosity and thoroughness of the

examiner, too many data are always lacking. Without a specifically trained and

focused investigator who has no clinical responsibility but to obtain data related

to causation to test a specific hypothesis, medical records will always be an

unsatisfactory source of data.

Also important is how the questions are asked to ensure that reliable data

are obtained. A relevant example relates to identification of alcohol use in

pregnancy. Questions related to quantity of alcoholic beverages consumed

daily are neither as sensitive nor as specific as those related to changes in the

woman’s tolerance to alcohol (Martier et al. 1990). Also, it is necessary to

be alert to pejorative connotations in the construct of the questions and to

prejudices that the questioner may manifest verbally and nonverbally. Finally,

the patient’s own perceptions of her behavior, local societal values, and the

stigma and guilt about the appropriate or correct answers will affect her

willingness, her candor, and the veracity of her responses.

Another consideration is the extent to which this research depends on patient

self-reports. Because this is a medicine-taking society, women who take overthe-counter medications may not think of them as medications and may not

include them in a drug history. Large numbers of women take nonprescription

appetite suppressants, antiemetics, tranquilizers, analgesics, antihistamines,

supplemental minerals, and vitamins periconceptionally (Piper et al. 1987).

Women also are exposed unwittingly to environmental toxins and pollutants,

85
both in the home and at work. Most are not recognized. In other words, during

embryogenesis, a human fetus has the potential to be exposed to a number of

exogenous agents, not all of which are recognized or remembered by its

mother.

There is a current debate in this country as to whether the use of

periconceptional multivitamins can decrease the incidence of neural tuba

defects. Competent clinical investigators have published exactly opposite

interpretations. One group, headed by Mills, indicates that multivitamins have

no value; the other group, headed by Milunsky, indicates that the Incidence can

be decreased by 75 percent (Mills et al. 1989; Milunsky et al. 1989). Both sets

of data were collected through recall of the patients’ use of vitamins: the timing

and manner of data collection are the dominant differences between these two

studies. This is a specific example of the varying effect of when in pregnancy

the interview (and therefore the self-reporting) is solicited. In this case, further

bias is probable because of the selective and focused memory of a mother

when a neural tube defect is found at birth or prenatally with ultrasound.

A separate issue relates to cross-sectional vs. longitudinal studies. Many

practical reasons exist for performing cross-sectional studies: without

longitudinal studies, however, it is not possible to evaluate the full spectrum of

physical, mental, intellectual, behavioral, and psychological functioning in those

exposed to possible toxins or teratogens. Major deterrents are the cost and the

logistics of such studies. An additional deterrent applies specifically to

substance abuse. Criminalization of substance abuse with punitive sanctions

has made anonymity a basic requirement of this research area. The additional

factors of a mobile society, the demands of tracking people through many years

of life, and the relatively low priority most people place on providing health

information to researchers, all make a longitudinal study seem a utopian,

unrealistic dream. Longitudinal and prospective are the two key words,

Innovative and creative research techniques are the challenge for this highpriority goal as is the development of viable, alternative methodologies.

Zuckerman (“Selected Methodologic Issues,” this volume) reported data

from a number of published studies that exemplify bias, sampling error, and

inappropriate conclusions. The lessons derive not only from cocaine, but also

from alcohol and marijuana research. The common threads are dependency on

self-reporting and the lack of biologic markers to quantify amount and duration

of drug exposure. Flexible laboratory monitoring is not available as it is for the

pregnant insulin-dependent diabetic woman. For that patient, a glucometer can

measure current plasma glucose levels daily. Data are recorded on a memory

chip that is reviewed when the patient returns to the office. Glycosylated blood

hemoglobin levels integrate information about blood glucose levels over 8 to 12

86
weeks. Glycosylated blood albumin levels provide similar information about

albumin integrated over 3 to 4 weeks. These biochemical markers decrease

dependence on the patient’s memory or reporting. The preliminary data

obtained from research on meconium analysis is an important advance in

quantifying past exposure to cocaine (Ostrea et al. 1988). A search for other

laboratory aids in the field of substance abuse is critical.

There is a temptation to evaluate data from the point of view of biologic

plausibility. Fetal alcohol syndrome is an example of not making this too strong

a test of credibility. Alcohol is used by all cultures and tribes. A high use rate of

wine and beer exists in Europe and this country, yet the estimates of adverse

outcome in alcoholic pregnancy in studies from the United States and Europe

have failed to show an incidence higher than 50 percent (Danis and Keith

1983). This suggests that there are moderating variables, including genetic

susceptibility, individual metabolism, and a threshold for anomalies.

Recent articles on allelic genes for alcoholism and differences in alcohol

dehydrogenase levels in women compared with men emphasize susceptibility

(Blum et al. 1990; Frezza et al. 1990); however, many authorities interdict any

alcohol ingestion during pregnancy. The data do not allow this extrapolation.

The data also do not define a universal threshold. The incidence of minor or

major anomalies can be shown to relate to the number of drinks per day, but

whether this number is two, four, or six remains in doubt. The challenge is to

define the specificity, the critical period, and the threshold for alcohol

teratogenicity (Ernhart et al. 1987).

A recent article dealt cogently with the prediction and risk of fetal hydantoin

syndrome (Buehler et al. 1990). The human fetus has a variable response

when exposed to hydantoin during pregnancy. The maternal ingestion of this

drug results in elevated levels of its toxic intermediary metabolites. These are

normally eliminated by epoxide hydrolase, whose activity level is regulated by

a single gene with two allelic forms. According to this preliminary study,

low epoxide hydrolase activity in the fetus of a woman taking phenytoin

monotherapy will result in clinical findings compatible with the fetal hydantoin

syndrome. In contrast, the syndrome will not manifest in a fetus with high

enzyme activity. This study is important because it will eventually help to

identify fetuses at increased risk when their mothers ingest hydantoin. It also

provides insight into a biologic basis for variations in fetal susceptibility similar to

the lack of universality of adverse impact that characterizes most teratogens.

CONFOUNDING VARIABLES

Investigations into the relationship between use or abuse of teratogens and

adverse perinatal outcome address cause and effect; yet in many studies, a

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number of potential wntributlng variables have not been examined. In terms of

epidemiologic principles, such investigations are asking about determinants or

etiologic factors on the causal pathway to consequences or outcomes. The

research problem is one of identifying and factoring the effects of mediating and

confounding variables and effect modifiers. Mediating variables, both as direct

and indirect determinants, affect the magnitude of the cause-and-effect

relationship. Effect modifiers are factors that modify the magnitude of the

determinant’s affect on outcome. Confounding variables, although they are not

on the direct line of cause and effect, can bias its strength by distorting the

apparent relationship.

In clinical obstetrics, the recurring examples that exemplify these principles are

intrauterine growth retardation and premature rupture of membranes/premature

labor. Consider the established determinants of intrauterine growth and

gestational duration. The major etiologic categories for intrauterine growth

retardation are maternal, placental, and fetal. Each of these divisions has

immunologic, genetic, chromosomal, endocrine, and infectious disease

subcategories. The direct variables include infant sex, racial and ethnic origin,

maternal height, prepregnancy weight, paternal height and weight, maternal

birth weight, parity, history of prior infant with low birth weight, gestational

weight gain, caloric intake, general morbidity, cigarette smoking, and alcohol

consumption (Kramer 1987). With regard to gestational duration, the direct

determinants that have been established are prepregnancy weight, prior history

of prematurity or cigarette smoking, and in utero DES exposure (Kramer 1987).

Other etiologic categories for preterm birth include personal demographic

features; maternal behaviors, including stress, work, fatigue, and intercourse;

and personal hygiene and environmental conditions, including inadequate

social support systems.

These long lists illustrate the difficulties in establishing a causal pathway for

either of these outcomes. The result is underestimated determinants,

misclassified effect modifiers, unrecognized outcomes, and undocumented

confounding variables. In this environment, valid conclusions cannot be

forthcoming.

The review of human studies by Chasnoff (this volume) helps identify

methodologic difficulties that fundamentally revolve around lack of consistency

in the definitions of cocaine use and adverse outcome. The narrow focus of

investigators when validating their hypotheses almost ensures that confounding

and mediating variables cannot be identified or recognized. Furthermore, the

polydrug use pattern of patients (including the use of nicotine, with its long list of

adverse pregnancy outcomes) is frequently not recognized because information

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about it is not sought and because many drugs cannot be identified in the

absence of biologic markers.

There can be uncertainty about the timing of a prenatal insult and subsequent

adverse pregnancy outcomes. The putative effects of a teratogen in pregnancy

can involve assaults to the egg or sperm prior to conception, conception itself

with mutagenicity, the embryo with teratogenicity, embryotoxicity via fetal

growth and development, and newborn morbidity. Identifying the time of impact

requires tracking of patients, This strategy, a variation of the longitudinal study,

is essential to the clarification of fetal abnormalities associated with drug use.

There is a finite period of human embryogenesis; however, this timeframe may

be too narrow. Freinkel (1980) has posited that hyperglycemia during the

second trimester has an adverse effect on subsequent intellectual, behavioral,

and psychological development in the offspring of a diabetic mother. It is known

that the central nervous system continues to develop throughout the fetal life

and on into infancy; that neuronal differentiation, axonal growth, synapse

formation, process elimination, and myelinization continue throughout postnatal

life for many months; and that some of the adverse impact of alcoholism on fetal

growth can be decreased by modifying drinking behaviors even as late as the

third trimester. It is also known that establishing positive health practices in

women with insulin-dependent diabetes mellitus and with epileptics using

antiseizure medications prior to conception will decrease the incidence of

congenital malformations, The establishment of dose-effect relationships for

pregnancy complications requires obtaining data from preconception to the

postnatal period.

This research also requires the use of short- and long-term biochemical and

biophysical laboratory markers. A woman who has a single exposure to

cocaine at term in an attempt to precipitate the onset of labor will have a

positive urine screen at delivery. As such, she will be labeled as a cocaine user

during pregnancy and her data will be incorrectly combined with that from

women with other patterns of cocaine use. Chasnoff (this volume) emphasizes

the importance of quantifying the insult. The inability to ascertain what is

actually being used by the patient is a major concern in identifying causation.

Additional confounding factors relate to route, frequency, duration, and timing of

use; to peak maximum blood levels; and to the purity of the substance used.

The same comments apply to identifying the impurities contaminating the

substance of abuse and their effect on the pregnancy. Such pharmawkinetic

questions constitute the crux of the dose-response relationships.

Another variable is the physiology and function of the placenta. Drugs of abuse

can cause placental dysfunction, either via modification of metabolic pathways

89
or by curtailing the vascular supply of substrates and oxygen to and from the

placenta. Moreover, the location of the implantation site of the placenta in the

uterus, the normal physiological senescence of the placenta late in pregnancy,

and the possibility of disease of the placenta (such as infection) are all

confounding variables that cannot be quantitated.

A necessary part of clinical research is to define an appropriate comparison

group, but what is really known about the people assigned to control groups?

The same questions of teratogen exposure, nutrition, confounding and

mediating variables, and lack of biologic markers all apply to the control

group. The factors that influence pregnancy outcome include social status,

psychological stress, genetic makeup, infection and environmental hazards,

health and physiologic state during pregnancy, childhood experiences,

sociocultural pattern, health practices, and motivation to seek and use prenatal

care.

Considering this long list of determinants, how likely is it that a control group

can be identified for valid comparison? In fact, in actual research, it is

extraordinarily difficult. The access to large numbers of women delivering in

maternity hospitals does not obviate this very specific research problem.

CONCLUSION

Researchers all suffer from the diseases of jumping to conclusions regarding

cause and effect, failing to recognize confounding variables, and depending

excessively on the validity of self-reporting. Researchers have difficulty in

obtaining unbiased samples and valid control groups and are more adept at

recognizing and differentiating adverse outcomes that are rare, affect overt

physical structures, and occur immediately, as opposed to more longterm problems that are not as visible. Solutions include development of new

methods of toxicologic testing for long- and short-term biologic markers, funding

of longitudinal studies to understand both immediate and long-term effects,

and attention to rigorous preparation of medical records. Before credible

intervention strategies can be devised, researchers must be able to understand

the vagaries of the dose-effect relationship. Therefore, it is necessary to dissect

the variations in human biology, biochemistry, physiology, and biophysics and

determine their genetic bases.

The fundamental question is, What proximal and distal causes result in proximal

and distal effects? In asking this, researchers must remain alert to identifying

and factoring mediating and confounding variables, as well as effect modifiers,

The conclusion is that no single factor will stand alone as a sufficient cause for

either an adverse or a healthy pregnancy outcome.

90
REFERENCES

Blum, K.; Noble, E.P.; Sheridan; P.J.; Montgomery; A.; Ritchie; T.;

Jagadelswaran; P.; Nogami; H.; Briggs; A.H.; and Cohn, J.B. Allelic

association of human dopamine D2 receptor gene in alcoholism. JAMA

263:2055-2060, 1990.

Buehler, B.A.; Delimont, D.; van Waes, M.; and Finnell, R.H. Prenatal

prediction of risk of the fetal hydantoin syndrome. N Engl J Med 322:1567-

1572, 1990.

Danis, R.P., and Keith, L. Fetal alcohol syndrome: Incurable but preventable.

Contrib Obstet Gynecol 21:57-68, 1983.

Ernhart, C.B.; Sokol, R.J.; Martier, S.; Moron, P.; Nadler, D.; Ager, J.W.; and

Wolf, A. Alcohol teratogenicity in the human: A detailed assessment of

specificity, critical period, and threshold. Am J Obstet Gynecol 156:33-39,

1987.

Freinkel, N. Of pregnancy and progeny. Diabetes 29:1023-1033, 1980.

Frezza, M.; di Padova, C.; Pozzato, G.; Terpin, M.; Bavaona, E.; and Lieber,

C.S. High blood alcohol levels in women: The role of decreased gastric

alcohol dehydrogenase activity and first-pass metabolism. N Engl J Med

322:95-99, 1990.

Kramer, M.S. Determinants of low birth weight: Methodologic assessment and

meta-analysis. Bull World Health Organ 65:663-737, 1987.

Martier, S.S.; Bottoms, S.F.; Sokol, R.T.; and Ager, J.W. Pregnancy risk

drinking: Optimized screening with tolerance. Soc Gynecol Invest Abst. No.

126. 167:31, 1990.

Mills, J.L.; Rhoads, G.G.; Simpson, J.L.; Cunningham, G.C.; Conley, M.R.;

Lassman, M.R.; Walden, M.E.; Depp, R.O.; and Hoffman, H.S. The absence

of a relation between the periconceptional use of vitamins and neural tube

defects. N Engl J Med 321:430-435, 1989.

Milunsky, A.; Jick, M.; Jick, S.S.; Bruell, C.L.; MacLaughlin, D.S.; Rothman,

K.J.; and Willett, W. Multivitamin/folic acid supplementation in early

pregnancy reduces the prevalence of neural tube defects. JAMA 262:2847-

2852, 1989.

Ostrea, E.M.; Asensio, D.; Naluz, A.; Semkowski, K.; Subramanian, M.; and

Abel, E.L. The detection of heroin, cocaine and cannabinoid metabolites in

the stools of infants of drug dependent mothers. In: Harris, L.S., ed.

Problems of Drug Dependence, 7987: Proceedings of the 49th Annual

Scientific Meeting, The Committee on Problems of Drug Dependence, Inc.

National Institute on Drug Abuse Research Monograph 81. DHHS Pub. No.

(ADM)88-1564. Washington, DC: Supt. of Docs., U.S. Govt. Print. Off.,

1988. p. 262.

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Piper, J.M.; Baum, C.; and Kennedy, D.L. Prescription drug use before and

during pregnancy in a Medicaid population. Am J Obstet Gynecol 157:148-

156, 1987.

AUTHOR

Ronald A. Chez, M.D.

Professor

Department of Obstetrics and Gynecology

University of South Florida

Suite 500

Four Columbia Drive

Tampa, FL 33606

92
What We Can Learn From the Status of

the Newborn

T. Berry Brazelton

Although there have been other epidemics of drug abuse (cocaine and alcohol

in the late 1930s alcohol in every recent decade, marijuana and heroin in the

1960s and 1970s) the most serious threat to young adults and their offspring—

multiple drug abuse—has been booming since the 1980s seriously affecting

the fetuses of these young adults and threatening the future of approximately

one-fifth of neonates born in the United States. New approaches are needed to

assess, study, and intervene with the adult and newborn victims of this

epidemic.

It has long been known that intrauterine influences affect the DNA and RNA

replication of the developing fetus. These effects can be seen in reduced head

circumference, linear growth, and birth weight. In turn, these effects influence

the neonate’s behavioral responses in significant ways. In a study in

Guatemala, Brazelton and colleagues (1977) were able to demonstrate that

poor intrauterine nutrition significantly affected the behaviors of the neonate in

ways that led to poorer maternal nurturing. In addition, postnatal malnutrition

became synergistic with prenatal undernutrition. The significantly poorer

outcome of these children at ages 6 to 7 years was predicted by their neonatal

behavior, because it affected the responses to them by their already

undernourished, overstressed mothers. To interrupt this cycle of poverty, which

repeats itself from one generation to another, the prenatal and perinatal periods

would be the target spots for intervention (figure 1).

The ponderal index (a ratio of weight to length) can be used to indicate fetal

malnutrition. Als and colleagues (1976) compared full-term infants underweight

for length (below the 10th percentile) and average weight for length at 1, 3, 5,

and 10 days of life on the Neonatal Behavioral Assessment Scale (NBAS)

(Brazefton 1984a). These normal, healthy, but underweight infants differed

from controls along behavioral dimensions that are particularly important for

caregiving, such as attractiveness, need for stimulation, and interactive and

motor processes. The groups also differed on reflexive behavior. Moreover, in

followup by telephone during the first few weeks of life of the underweight

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FIGURE 1. Synergistic model of the effects of prenatal malnutrition

infants, mothers reported difficulties in temperamental organization and

indications of psychosomatic reaction to stress. Neonatal behavior predicted

difficulties in state behavior in later infancy (as late as 9 months), such as

hypersensitivity to stimuli, rapid and distractible state changes, and increased

crying spells of long duration. Difficult newborns remained difficult throughout

infancy.

Lester and Zeskind examined infants who were below the third percentile on the

ponderal index and showed that these infants exhibited poorer performance

across all NBAS behavioral dimensions (Lester et al. 1976; Lester and Zeskind

1978). Correlations between the NBAS dimensions and the acoustic features

of babies’ cries indicated that poor NBAS scores were related to differences in

cry features. The cry of the underweight-for-length babies showed a higher and

more variable fundamental frequency and more harmonic distortion, in contrast

to the generally flat melody form of the cry of the full-weight infant. Cry features

and NBAS scores were highly related. Babies’ behavior and cry features

can reflect intrauterine stress. In a recent study, the NBAS clusters and

supplementary items were found to discriminate infants with atypical patterns of

fetal growth from infants with appropriate patterns of fetal growth (Lester et al.

1986).

94
Lester and Zeskind (1978) used multiple regression to determine the relative

contribution of six high-risk variables on factor scores of the NBAS. Low

attention scores were associated with low-birth-weight babies who were likely to

be the infants of younger mothers. Low Apgar scores were associated with

babies who scored lower on a temperament-arousal dimension. The 52 babies

of this study also were included in a study of 140 infants of low, average, and

high birth weight (Lester et al. 1976). Factor scores representing three

dimensions—attention, arousal, and temperament—were compared among the

three birth-weight groups with gestational age as a covariant. Both extremeslow and very high birth-weight babies—scored lower on attentional behavior

than did infants of average birth weight. Low-birth-weight males and high-birthweight females scored lower on arousal and temperament than did other sexby-birth-weight groups. Postmature as well as immature babies may be at risk

for attentional deficits and poor state control. There are 20 to 30 such studies

using the NBAS that demonstrate the effects on the neonate’s behavior of

intrauterine deprivation.

These studies point to the importance of assessing as carefully as possible the

evidence in the neonate of maturity and of intrauterine deprivation—due to

nutrition and addiction as well as to other teratogenic or infectious influences. A

careful assessment of maturity (e.g., gestational age) (Dubowitz and Dubowitz

1981), of deprivation (as reflected by a measure such as ponderal index), and

of intrauterine insults (a careful assessment of dysgenetic features, e.g., Smith’s

Atlas) needs to be added to any study of the pediatric and neurological

adequacy. Neurological evaluations alone have not been particularly fruitful in

demonstrating future developmental dysfunction in high-risk infants. Behavioral

assessments are recommended to identify subtler central nervous system

(CNS) and autonomic nervous system dysfunction that will affect babies and

their environment’s response to them.

In particular, alcohol and stress must be considered as significant covariants in

any study of the effects of multiple drug abuse on the fetus and on neonatal

behavior. A growing number of studies demonstrate these effects. For

example, infants born to alcohol-addicted mothers were first studied by

Streissguth and colleagues (1983). They examined the effects of intrauterine

alcohol exposure in a sample of 417 infants, who were examined once on the

NBAS between 9 and 35 hours after delivery. Data on maternal alcohol usage

were obtained by self-report during the fifth month of pregnancy. Factor

analysis yielded six factors that were entered into a multiple-regression analysis

as dependent variables. Maternal alcohol use in midpregnancy was related to

poorer habituation and to significantly lower arousal in newborns, even after

adjusting for maternal smoking and caffeine use, maternal age, and nutrition

during pregnancy; for sex and age of the infant; and for obstetric medication.

95
Alcohol levels in the mother do seem to affect the baby’s CNS, as reflected by

the infants behavior at birth.

The NBAS has been in development for 25 years. Its goal is to attempt to

establish the newborn’s relative contribution to the parent-infant interaction and

to the infant’s own future. The original purpose of the NBAS was to attempt to

record the dimensions of state—autonomic, motor, sensory-receptive, and

responsive—that were seen as integrative and interacting with each other in the

normal, healthy, full-term infant. The NBAS was seen not as a set of discrete

stimulus-response presentations, but as an interactive assessment in which

the adult participant played a major role, facilitating the performance and

organizational skills of the Infant. The hope was to establish the infant’s

capacities and limits in contributing to the caregiving environment. The

expectation was to gain a deeper understanding of the meaning of infant

behavior as it reflected relative contribution to these developmental lines. A

single assessment in the neonatal period was seen as only one, brief glimpse

into the continuum of the infant’s adjustment to labor, delivery, and new

environment. As such, it was expected to reflect the baby’s inborn

characteristics and the behavioral responses that had already been shaped by

the intrauterine environment. Repeated exams should demonstrate the infant’s

coping capacities and capacities for experiencing, integrating, and profiting

developmentally from the environment. Indeed, day-to-day change in

behaviors can be more predictive of the baby’s future functioning than any one

set of assessments (Lester et al. 1987). If recovery curves (that is, the infant’s

pattern of change from day to day) can be seen as evidence for coping with the

stress of labor and delivery and for the baby’s capacity for integrating new

environmental information, perhaps coping patterns in the neonatal period can

be seen as predicting future patterns of coping and learning.

CONTENT OF THE NBAS

The NBAS was published 18 years ago (Brazelton 1973). Recently, revisions

were made, and the experience of 10 years was summarized in the revision

(Brazelton 1984a). Four centers and eight authors contributed to the revised

edition. The scale is In use in more than 600 locations all over the world; 6

training centers have been established in the United States, 6 in Europe, and 1

in Israel; more than 125 published studies have appeared within the United

States and in crosscultural contexts. In these studies, the characteristics of the

NBAS have been explored, evaluated, and criticized.

FUTURE DIRECTIONS

Since it was first published, the NBAS has become the most widely used

neonatal behavioral assessment instrument, Its use as a research instrument

96
has been validated by many studies. It is a dynamic assessment, and it has

taken time to evaluate its psychometric properties. The scale has been shown

to have face validity as well as concurrent validity. Predictive validity seems to

depend on the changes seen in repeated tests, and the data so far suggest that

when repeated tests are used, predictive validity is achieved (Lester 1984;

Nugent and Sepkoski 1984; Lester et al. 1987).

The assessment is a global one rather than a test of any one or two systems in

the newborn. Because the scale is so widely used, the next effort will be to

collect and collate the data from the many studies in an attempt to establish a

normative database against which can be tested the many variables that

influence neonatal behavior. A multivariate analysis of prenatal factors is one

obvious technique. Understanding its use as a communicative system between

parents and a concerned professional, in order to provide intervention and/or an

understanding of the baby to enhance the parent-infant interaction, may be the

most important future goal for the NBAS. How does one use it best as a

communication system?

In working with the NBAS, several issues have become clear. An assessment

of the newborn presents an opportunity for looking forward into the baby’s

future and backward into his or her intrauterine experience. The intrauterine

influences that shape newborn behavior are becoming more and more

commonly recognized. The newborn’s behavior at birth is phenotypic, not

genotypic, in that complex behaviors are already shaped by influences in utero

that probably act in a synergistic fashion.

The NBAS has revealed the baby’s impressive capacity to actively seek stimuli

in an appropriate range for the level of stimulation the infant can tolerate. This

ability in the normal baby fits with Osofsky’s thesis (1976) that such a baby is

both readable and predictable for the caregiver. Expectable behavior makes it

more likely that the parent will nurture the infant appropriately.

EARLY INTERVENTION

The importance of assessing the behavioral repertoire of the infant as early as

possible has now been widely accepted (see additional items in Brazelton

1984a). Recognition of neurological difficulties in organizing response systems

that make it difficult for an infant to adjust to his or her environment would

facilitate an optimal outcome for babies. It has long been recognized that the

environment is an influence in improving or reinforcing potential deficits toward

optimal development in high-risk infants.

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Research in neurophysiology demonstrates the redundancy of neurological

pathways in the immature CNS (St. James-Roberts 1979). Some modes for

recovery are vicarious functioning, equipotentiality of redundant pathways,

behavioral substitution, regrowth and supersensitivity, diaschisis, and recovery

from trauma (St. James-Roberts 1979). Unassigned pathways can be captured

for substitution of function for damaged or impaired pathways if such pathways

are offered experiences from which they are able to learn. Behavioral

substitution for impaired sensory or motor areas is possible; for instance, a blind

infant uses highly sensitized auditory and tactile cues to replace the usual visual

cues. The concept of substitution of these unassigned pathways reinforces the

concept of plasticity In the immature nervous system, but these pathways must

be provided with information appropriate to them for organizing and learning

responses rather than disorganizing responses. For example, an impaired

brain is likely to be hypersensitive, and ordinary stimuli may be inappropriate or

disorganizing. Hence, a behavioral assessment that can identify individuated

stimuli, graded to produce positive responses in a hypersensitive individual,

might point to the kind of environmental stimuli that would lead toward

organization and learning for that baby’s future. The best use of the NBAS

might be to identify as early as possible the individual differences in receptivity

of such babies and to identify each baby’s capacity for receiving and using

environmental stimuli.

Standardization data for the NBAS has been difficult to establish because of

the subtle influences of different prenatal and perinatal variables that affect

neonatal behavior. The large data sets being collected need to be pooled and a

database established to explore questions about the effect of these variables on

the day-to-day behaviors of the newborn. Prenatal and perinatal variables are

likely to act in combination in affecting neonatal behavior; thus, multivariate

analytic techniques are appropriate.

One plan for use with multidrug-abused babies would be to collect data from

many locations in the United States where the NBAS is being used to study

some of the effects of single as well as multiple variables on neonatal behavior

and to work toward developing a national database. Because of the changing

nature of newborns’ behavior as they respond to labor, delivery, and the new

environment, patterns of change over repeated NBAS administrations are seen

as systematic and part of the developmental process. High test-retest stability

from day to day would be unlikely, and a norm is needed for each day with

normal, full-term infants within our U.S. culture. These norms would be

influenced by the conditions of each newborn nursery, and the variables

affecting them would need to be carefully established. In addition, such

prenatal influences as malnutrition, addiction, medication, and infection would

be synergistic but could be accounted for as interacting variables.

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In the second edition of the NBAS (Brazelton 1984b), nine supplementary items

were added, for use with the NBAS in the assessment of high-risk infants. It

became clear that the NBAS as originally designed was not an appropriate

assessment for premature infants before they reached 36 weeks gestational

age (Brazelton 1984b). Furthermore, its use with premature infants after 36

weeks necessitated items that could capture the range and quality of the

behavior exhibited by such sensitive, fragile infants. This led to the attempt to

develop a number of supplementary items for high-risk fragile infants, based on

items used in the Assessment of Preterm Infant Behavior (APIB) (Als et al.

1982a, 1982b) and the NBAS, Kansas version (Horowitz and Linn 1978).

These items attempt to summarize the quality of the baby’s responsiveness, the

cost to the baby of such responses, and the amount of input from the examiner

necessary to organize them. These items are used to reflect the lowered

thresholds and the high cost of responsiveness in fragile and at-risk infants.

The NBAS in its present form cannot be used before an infant is 36 weeks of

gestational age and/or until a fragile infant is off life supports and in room air.

Only examiners trained specifically to work with high-risk infants should use the

NBAS with these populations. These items have been successful in delineating

the recovery of these infants and provide a window into their current functioning,

indicated by the following categories:

1. Quality of alert responsiveness

2. Cost of attention

3. Examiner persistence

4. General irritability

5. Robustness and endurance

6. Regulatory capacities

7. State regulation

8. Balance of motor tone

9. Reinforcement value of the infant’s behavior

These items can help in understanding the unique behavioral patterns of the

premature or fragile infant (Brazelton 1984a).

In a study of high-risk infants, Tronick and colleagues (1985) found that these

additional items added significantly to the prediction of the fragile infant’s

outcome. These nine items can be revised and used at age 2 years to

establish subtle deficits in the quality of performance on such standardized

instruments as the Bayley (1969) and Ainsworth and colleagues (1978)

assessments.

Trained and reliable examiners need to collaborate after using the present form

of the NBAS and its additional items to adapt it to the fragile neonates of

99
multiple drug abusers. Ideally, the trained observers would have established

their reliability as NBAS examiners for fragile infants and would have been

trained in the sensitive observations of the APIB.

The concept of “best performances” used in the neonatal exam demands

training and flexibility In the examiner. It was originally conceived of as a way to

overcome subtle, uncontrollable environmental Influences and to reproduce

parental responses to an infant’s best achievements. If it is used by trained

examiners to help these babies achieve their best responses and if the

maneuvers, the latency, and the cost to examiner and baby are recorded

carefully, it will give insight into the techniques needed for intervention with

these babies. For example, fragile small-for-gestational-age (SGA) and preterm

infants need to be contained carefully. Then a stimulus is introduced from only

one modality at a time—visual, auditory, tactile, or kinesthetic. That stimulus

needs to be carefully geared to the baby’s threshold for responsiveness.

Unless it is, the baby’s threshold for taking In, processing, and using the usual

environmental stimuli is impaired. These babies, who had to adapt to repeated

intrauterine stress, are likely to be either very high or very low on such

measures as habituation to stimuli, to state changes, and to autonomic

demands. Their ability to adapt to internal demands for autonomic compliance

is likely to be restricted. Their ability adapted in utero to insults by shutting out

disturbing stimuli may make them appear either lethargic or hypersensitive and

extremely irritable. Their inability to handle state changes may be reflected in

extreme lability, switching from unreachable sleep to unreachable crying,

unable to respond to environmental stimuli, or difficult to move out of “hooked”

states (of sleep, apparent attention, crying). To differentiate the effects of

multiple drugs, including alcohol, and malnutrition on the neonate’s behavior will

be an enormous challenge. To then differentiate effects of withdrawal, of

permanent CNS impairment, and of more temporary CNS effects (such as

those of neurotransmitter disorders affected by these intrauterine influences

acting synergistically) will be the next challenge. These issues need to be

addressed to the best of the scientific community’s capacity—applying

standardized measures and intersite reliability to large, multisite samples.

The real goal for understanding the behavior and the underlying CNS and

autonomic functions of the neonate will be to plan early intervention programs

based on the knowledge gained from these assessments. To understand

the babies and their caregivers, they must be reached with supportive,

understanding interventions and followed with sensitive measurement

techniques that include and reward their caregivers for any developmental

gains, for these are difficult, fragile babies. What is learned about the

functioning of the nervous system and its potential for repair will more than

repay all the efforts to try to understand them. In addition, if it can be learned

100
how to salvage these mothers from their addiction and poor self-image by using

the behaviors of the baby, a whole new system will develop for outreach and

cooperative feedback for a besieged population. The cost of salvaging these

babies and their parents will be great, but if any can be salvaged, billions of

dollars will be saved—money that would be spent in educating and controlling

these children, whose fragility in infancy is likely to be predictive of disabled,

impulse-ridden adolescents in the future.

The parents of these drug-exposed newborns are usually the products of

poverty and hopelessness. Few other countries in the world have created the

kind of hopelessness and devastated self-image from being poor that exists

in the United States. The victims of this hopelessness and its attendant

depression turn to alcohol and polydrug abuse and even to unwanted

pregnancies. A punitive response to their addiction will destroy any opportunity

to reach them for prenatal care and prevention, for care during delivery, and for

care of their fragile offspring. On the other hand, a search for new models of

understanding and support for these addicted, depressed, hopeless women

might create a new system for outreach. A high goal would be to create fragileinfant centers and fragile-mother centers in parallel and in proximity, so that

babies could be stabilized safely and be introduced to their mothers, who had

managed to cease their drug abuse under the protection of these centers.

Returning these women to their environments will result In a return to their

addiction. The environment that an addicted parent will provide for a fragile

infant binds them both to failure. Because studies have demonstrated that

at-risk infants will have a significantly better chance at outcome if their

environments can be flexible and oriented to the child’s developmental needs,

the most important intervention for these infants’ future would be to provide safe

and nurturing environments.

What is the role of health professionals? For 20 years at Harvard Medical

School, the author has been tralning pediatricians and, more recently, nurse

practitioners and psychologists to work with families and infants as part of the

parent-infant system—this is where parental and infant outcome for all families,

high and low risk, can be affected (figure 2). Teaching or telling parents how to

parent is demeaning and carries with it a negative implication: “I know and you

don’t.” The best influence on parents would be that of nurturing support to find

their own best potential as parents. The model to use with addicted parents

would be to nurture them toward a solution to their addiction, using successful

parent-infant interaction as one of the ways of inducing recovery and as their

goal. As their infant’s behavior improved and as they went through their own

withdrawal and recovery, their potential for caring for their fragile infant would

be augmented by caring for them. If all of this could be achieved under the

cover of a safe environment, it could be ascertained which parents and which

101
SUPPORT, POINTING THEM TOWARD THEIR GOAL

FIGURE 2. Therapist forms an envelope for the family

infants would recover. A better future could then be predicted than is likely

under present conditions of discharge to their chaotic, addiction-prone

environments. The NBAS, a model for assessing the neonate’s behavior over

time, has been used with a high-risk group of babies (suffering from intrauterine

growth retardation) and both middle-class and lower class mothers (Nugent and

Brazleton 1989). The babies’ behaviors at 40, 42, and 44 weeks of age were

shared with their mothers. Lower class women barely participated until the third

observation, saying they didn’t trust the staff until the third visit. Only the

babies’ behavior was shared with one group, but mothering was also discussed

with the other. Both groups profited (unpublished data) see lists below.

Intervention Effects at 1 Month

IUGR effects on NBAS orientation (p<.02)

IUGR effects on NBAS motor organization (p<.0001)

IUGR effects on NBAS state regulation (p<.06)

Intervention effects on degree of improvement on NBAS habituation over first

month (p<.02)

Intervention effects on degree of improvement on NBAS orientation over first

month (p<.03)

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FIGURE 3. Variables that influenced premature babies’ outcome on the

Bayley 18-month MDI

Nutritional status, maternal interest, SES effects on NBAS motor behavior at

1 month (p<.003)

Nutritional status, maternal anxiety, SES effects on NBAS range of state at

1 month (p<.02)

Nutritional status, maternal anxiety, SES effects on NBAS state regulation at

2 months (p<.03)

Intervention Effects at 4 Months

SES effects on Bayley MDI (p<.02)

Nutritional status, maternal anxiety, SES effects on Bayley PDI (p<.01)

Nutritional status, clinician-mother relationship, SES effects on Bayley MDI

(p<.06)

The shared observation did affect both the mothers’ and the babies’ behavioral

outcome. The influence on maternal behavior was to affect their self-image and

to reduce maternal depression at 4 months. The babies’ behavior improved at

1 month on the NBAS in all parameters across the two groups. It was hoped

that the behavioral responsiveness of the neonates would give these depressed

young women an anchor toward their own recovery. Indeed, Lester and

103
coworkers (1984) evaluated the outcome at 18 months on the mental aspect of

the Bayley scale of 20 high-risk premature babies. SES had an r

2

 of .65. When

the neonates’ behavioral recovery was added over the 40- to 44-week period, a

predictive r

2

of .85 was obtained (figure 3).

The studies by Nugent and Brazelton (1989) and others in the literature have

been used to evaluate the effects of using behavioral responses of the newborn

to enhance the recovery of the parents of fragile infants. This model of

outreach has great potential.

REFERENCES

Ainsworth, M.D.; Blehar, M.C.; Waters, E.; and Wall, S. Patterns Of Attachment:

A Psychological Study of the Strange Situation. Hillsdale, NJ: Lawrence

Erlbaum, 1978.

Als, H.; Lester, B.M.; Tronick, E.; and Brazelton, T.B. Towards a research

instrument for the assessment of preterm infants’ behavior. In: Fitzgerald,

H.E.; Lester, B.M.; and Yogman, M.W., eds. Theory and Research in

Behavioral Pediatrics. New York: Plenum Press, 1982a. pp. 35-63.

Als, H.; Lester, B.M.; Tronick, E.; and Brazelton, T.B. Manual for the

assessment of preterm infants’ behavior (APIB). In: Fitzgerald, H.E.; Lester,

B.M.; and Yogman, M.W., eds. Theory and Research in Behavioral

Pediatrics. New York: Plenum Press, 1982b. pp. 65-132.

Als, H.; Tronick, E.; Adamson, L.; and Brazelton, T.B. The behavior of the full

term yet underweight newborn infant. Dev Med Child Neurol 18:590-602,

1976.

Bayley, N. Development of mental abilities. In: Mussen, P.H., ed. Manual of

Child Psychology. 3rd ed. New York: Wiley, 1969. pp. 1163-1209.

Brazelton, T.B. Neonatal Behavioral Assessment Scale. Philadelphia:

Lippincott, 1973.

Brazelton, T.B. Neonatal behavioral assessment scale. Monograph. No. 88

(rev. ed.). Philadelphia: Lippincott, 1984a.

Brazelton, T.B. Neonatal Behavioral Assessment Scale. 2d ed. London:

Spastics International Medical Publications, 1984b.

Brazelton, T.B.; Tronick, E.; Lichtig, A.; Lasky, R.; and Klein, R. The behavior of

the nutritionally deprived Guatemalan infants. Dev Med Child Neurol 19:344-

372, 1977.

Dubowitz, V., and Dubowitz, L. The neurological assessment of the preterm

and full term newborn infant. Dev Med Child Neurol 79:10-44, 1981.

Horowitz, F.D., and Linn, P.L. Use of the NBAS in research. In: Brazelton,

T.B., ed. Neonatal Behavorial Assessment Scale. Philadelphia: Lippincott,

1984. pp. 97-105.

104
Lester, B.M. Data analysis and prediction. In: Brazelton, T.B., ed. Neonatal

Behavioral Assessment Scale. Philadelphia: Lipplncott, 1984. pp. 85-97.

Lester, B.M.; Boukydis, C.Z.; Hoffman, J.; Censullo, M.; Zahr, L.; and Brazelton,

T.B. Behavioral and psychophysiological assessment of the preterm infant.

In: Lester, B.M., and Tronick, E., eds. In Defense of the Premature Infant:

The Limits of Plasticity. New York: Lexington Books, 1987.

Lester, B.M.; Emory, E.K.; Hoffman, S.L.; and Eltzman, D.V. A multivariate

study of the effects of high risk factors on performance on the Brazelton

Neonatal Assessment Scale. Child Dev 47:515-517, 1976.

Lester, B.M.; Garcia-CoIl, C.T.; Valcarcel, M.; Hoffman, J.; and Brazelton, T.B.

Effects of atypical patterns of fetal growth on newborn (NBAS) behavior.

Child Dev 57:11, 1986.

Lester, B.M.; Hoffman, J.; and Brazelton, T.B. The rhythmic structure of

mother-infant interaction in term- and preterm infants. Child Dev 56:15-28,

1984.

Lester, B.M., and Zeskind, P.S. Brazelton scale and physical size correlates of

neonatal cry features. Infant Behav Dev 1:393, 1978.

Nugent, J.K., and Brazelton, T.B. Preventive intervention with infants and

families. The NBAS Model. Infant Ment Health J 10:84-99, 1989.

Nugent, J.K., and Sepkoski, C. The training of NBAS examiners. In:

Brazelton, T.B., ed. Neonatal Behavioral Assessment Scale. 2d ed.

London: Blackwell, 1984. p. 324.

Osofsky, J. Neonatal characteristics and mother-infant interaction in two

observational studies. Child Dev 47:1138-1140, 1976.

St. James-Roberts, I. Neurological plasticity. In: Reese, H., and Lipsett, L.,

eds. Advances in Child Development. New York: Academic Press, 1979.

pp. 38-62.

Streissguth, A.D.; Barr, H.M.; and Martin, D.C. Maternal alcohol use and

neonatal habituation assessed with the Brazelton scale. Child Dev

54(5):1109-1118, 1983.

Tronick, E.; Scanlon, J.; and Scanlon, K. A comparative analysis of the validity

of several approaches to the scoring of the behavior of the preterm infant.

Infant Behav Dev 8:35, 1985.

AUTHOR

T. Berry Brazelton, M.D.

Professor

Department of Pediatrics

Harvard Medical School

23 Hawthorn Street

Cambridge, MA 02138

105
Neurobehavioral Organization of the

Newborn: Opportunity for Assessment

and Intervention

Heldelise Als

INTRODUCTION

Infants come into the world equipped with a repertoire of neurobehavioral

functional competencies that serve to adaptively regulate their own functioning

as well as the behavior of their caregivers-parents or other adults—thus

ensuring the input and feedback the infants need to support their own

development. When newborn behavior is disturbed by focal insult, difference in

neurobiologic substrate, difference in caregiver input, or any combination of

these, a disturbance or difference in self-regulatory and other regulatory

behavior is to be expected. Altered developmental interactive trajectories and

feedback loops may result.

Early assessment of the newborn’s neurobehavioral functioning, therefore, is

important to identify possible differences and to ameliorate if not prevent

subsequent cyclical maladaptations. Intrauterine exposure to drugs of abuse

appears to have varying effects on brain function of the fetus. Behavior is

seen as the infant’s prime expression of brain function and key route of

communication. Can the behavioral functioning of the newborn serve as a

reliable and accurate yardstick of drug exposure and as an opportunity for

appropriate intervention and amelioration?

Als and colleagues have developed methodologies for newborn behavioral

assessment to document individual behavioral regulation differences thought to

be brain based. So far, these methodologies have been tested on a population

of preterm and fullterm infants free of documented medical complications to

determine the degree of sensitivity of the instruments to subtle behavioral

differences due to presumed difference in neurosensory experience in utero

compared with extra utero. If documentation of the effects of such subtle input

differences were successful, clearly this would be promising for the assessment

of the effects of prenatal drug exposure and possibly for an approach to

106
functional amelioration of such effects. The following overview and discussion

of results are adapted from Als (1989a).

QUESTION 1: DO MEDICALLY HEALTHY PRETERMS SHOW

BEHAVIORAL MODULATION DIFFERENCES COMPARED WITH

FULLTERMS?

Behavioral Assessment

Two assessment methodologies were designed specifically to assess the

behavioral regulation and organizational differences between preterm and

fullterm infants. The first is an assessment of newborn behavioral organization

called the Assessment of Preterm Infants’ Behavior (APIB) (Als et al. 1982a,

1982b); the second is an experimental play paradigm called the Kangaroo-Box

Paradigm (Als and Berger 1986). Both were developed to assess the degree of

flexibility and modulation of behaviorally identified subsystems of functioning,

their interplay with each other, and their joint interplay with the environment.

The subsystems observed include the autonomic, motor, state, attentional

interactive, and self-regulatory systems, as well as the facilitation necessary to

support the infant’s regulation. These are assessed as the infant is brought

through a systematic sequence of manipulations or is observed in a standard

paradigm designed to bring out the infant’s current level of regulation.

The APIB was developed in an effort to extend the Brazelton Neonatal

Behavioral Assessment Scale (NBAS) (Brazelton 1984) to the behavior of

prematurely born infants and to assess the level of differentiation and

modulation of functioning. The APIB casts the maneuvers of the NBAS

into a graded sequence of increasingly vigorous environmental inputs

to systematically assess the infant’s threshold from organization to

disorganization. The differential cost to infants in handling and responding to

the maneuvers of the examination becomes a key feature of analysis. For

instance, some newborns may move from sleep state to alert state only with

accompanying respiratory irregularity consisting of respiratory pauses,

alternating with tachypneic episodes, accompanied by visceral upheaval, color

changes, and motoric hyperextension oscillating with flaccidity. Once achieving

an alert state, they may appear facially bland or even strained, with

acrocyanosis and poor respiratory stability, unable to focus consistently on a

stimulus and process the sensory input. After a fleeting episode of strained

alerting, they may move quickly to a motorically hyperaroused state

accompanied by tachypnea, from which they may be brought to a more

balanced level of modulated flexor tone with regular respirations only with great

difficulty. Yet they will visually track and follow a target through a 60-degree

angle. Other newborns, in contrast, will move easily from sleep to alert state

107
without autonomic instability or motoric disorganization. Once in alertness, they

maintain themselves there readily and focus on various stimuli with ease and

alacrity while their angle of visual excursion is also 60 degrees. Despite the

same visual orientatlon angle, the second group of infants would be considered

more well organized than the first along the differentiation and modulation

continuum of subsystems, and their scores on the autonomic, motor, state,

attentional, and self-regulatory systems, as well as on examiner facilitation,

would be lower, reflecting better behavioral organization and, therewith, a

difference in regulation as defined in the framework of the APIB.

The Kangaroo-Box Paradigm (K-Box) was developed to assess the strategies

and degree of overall subsystem modulation and differentiation exhibited by

infants at 9, 18, and 36 months, with a version available for the 5- to 8-year-old

range. By 9 months postterm, the infants’ world has expanded considerably.

Their mobility allows them to approach and leave situations, objects, and

persons in a very different way than they did earlier. They initiate interactions

and explorations beyond their immediate reach space, pursue objects and

persons locomotively, and structure situations by incorporating much larger

space frames and with more temporal flexibility than before. To assess

competence along comparable dimensions of subsystem differentiation and

modulation analogous to the newborn period as measured by the APIB, Als

constructed a paradigm that uses a transparent plexiglass box accessible

through a transparent mobile porthole latch door and containing a hopping,

windup kangaroo. The box is placed on the floor of a playroom. During the

observation, all other distractions (pictures, chair, etc.) are removed, and

mother and infant are asked to go into the room and play with the toy so that

“they both have a good time.” They are observed and videotaped with a twocamera split-screen system through one-way mirror walls for 6 minutes. Then

the kangaroo is placed back in the box, the latch door closed, and the mother is

asked to sit against the wall of the room looking at the infant but not interacting

in any way. The infant is observed in this Stillface situation for 6 minutes. Then

a 3-minute reunion is observed when the mother again is asked to play with the

infant. The K-Box challenges the infant’s cognitive, gross and fine motor, social

and affective capacities, and, for some more sensitive infants, even

physiological regulation, as the infant attempts to retrieve the kangaroo from the

box. It also provides an opportunity to observe the mother’s strategies in

facilitating and expanding the infant’s competence.

Als and Berger (1986) developed a scoring manual to score the infant’s

capacities during the Play and Stillface episodes along 21 dimensions on a

scale from 1 (minimum) to 5 (optimal). These include autonomic organization,

gross and fine motor organization, symmetry of tonus, movement and posture,

apparent cognitive functioning, language and vocal organization, affective

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organization, social-interactive organization, competence in play with the object,

competence in combining object play and social interaction, degree of selfregulation, degree of facilitation and structure necessary, and degree of

pleasure and pride displayed by the Infant. Attention is paid to autonomic

reactions, movements, tone, vocalizations, and facial expressions. And, as in

the APIB, the degree of flexibility, differentiation, and modulation of each

subsystem is measured as an index of competence and regulation. The

mother’s behavior also is scored on parallel scales.

The K-Box for the older children consists of a large plexiglass tower with three

tiers and varying degrees of difficulty of access to the windup toy inside two of

the plexiglass cubes making up the tower. As an aid to reaching the top level, a

footstool and various raking tools are provided. The kangaroo either can be

taken out or dropped through a latch door in the floor of the top cube to the

second level. Once on the second level, it needs to be pushed via one of the

several raking tools provided at the second level opening to fall to the ground

level; from there it can be obtained via the door, which opens with a key. The

second kangaroo sitting in the ground level cube can be obtained independently

of the first. Both can be obtained and incorporated into exploration of the

various possibilities of this apparatus.

At each of the different age levels the K-Box apparatus is designed to have

built-in, immediate demand characteristics, yet to allow for individual differences

in the order, sophistication, and complexity of its manipulation and use.

Because the total child is directly involved in the K-Box Paradigm rather than

only selected facets of the child’s functioning, it is expected to yield useful and

systematic information about the integration and modulation of overall

behavioral functioning.

Results

So far, Als and coworkers have studied and analyzed the behavior of 160

healthy preterm and fullterm infants who spanned the gestational age (GA)

continuum in relatively equal numbers from 26- to 32-week pre-preterm (PPT),

33- to 37-week preterm (PT), and 38- to 41-week fullterm (FT). All infants were

selected to be free of known neurological insult, including perlnatal asphyxia,

neonatal seizures, bronchopulmonary dysplasia, and intraventricular

hemorrhage, as well as free of necrotizing enterocolitis and sepsis. All infants

were appropriate for age in weight at birth; all were singletons and free of any

congenital abnormalities and infections. There were 48 FTs, 48 PTs, and

64 PPTs. All infants were studied with the APIB at 2 weeks after due date.

The results indicate that the six system variables (autonomic, motor, state,

attentional organization, self-regulation, and examiner facilitation) show strong

differences among FTs, PTs, and PPTs, with the strongest differences between

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FTs and the two preterm groups together, and fewer, yet significant, differences

between the PTs and PPTs. The PPTs are consistently the most reactive,

hypersensitlve, and disorganized. The PTs take a middle position, and the FTs

are the most well modulated and well differentiated. Thus, the APIB appears

very sensitive In identifying gestational age effects (Als et al., in press). The

robustness of the APIB in identifying GA group membership also was shown by

successful prospective classification of an earlier sample of 20 FTs and 20 PTs.

Ninety-five percent (38 of 40) of the infants were correctly classified as to GA

status on the basis of their APIB scores (Als et al. 1988a). Furthermore, three

reliable (tested on two independent split-half samples), behaviorally defined

clusters of infants were identified (Als et al. 1988b; Als et al., in press), with a

preponderance of PPTs in the most reactive group and a preponderance of FTs

in the most well-organized group. Brain electrical activity mapping (BEAM) data

(Duffy 1989) implicated primarily frontal lobe and right hemispheric functional

differences between the behaviorally defined clusters (Als et al. 1989; Duffy

1989; Duffy et al. 1990).

One-hundred forty-eight infants were restudied at 9 months after expected date

of confinement (EDC) using the Bayley Scales (Bayley 1969) and the K-Box

Paradigm; 73 of the infants were restudied at 3 years post-EDC with a

comprehensive neuropsychological battery as well as the K-Box Paradigm.

While the Bayley Scale Scores, Mental Development Index (MDI), and

Psychomotor Development Index (PDI) did not show GA differences, the K-Box

Paradigm elicited consistent differences in autonomic, gross and fine motor,

social interactive, affective, and spatial regulation (Als et al., in press).

Preliminary analyses of the data at age 3 years again showed few differences

on the standardized psychological assessments, yet the K-Box Paradigm

showed many highly significant GA group effects (autonomic regulation, gross

and fine motor modulation, social interactive and affective regulation, and

language functioning) (Als et al. 1990). Furthermore, three clusters of

neurobehavioral functioning again emerged on the basis of the K-Box data at

each of the age points. Cluster concordance from the newborn period to the

later age points was very good (Als et al., in press).

Aside from these findings, K-Box data on 14 healthy preterm (<34 weeks) and

14 healthy fullterm children from the earlier sample of 20 each have been

collected and analyzed at 5 years. The results showed striking group

differences in this paradigm in the face of only very small differences on

standardized cognitive assessments, and BEAM again implicated frontal and

right hemispheric functioning (Als et al. 1989; Duffy and Als 1988).

Thus, it appears that there is a profile of regulatory difficulties characteristic of

preterm infants reflecting lower GA at birth that can be documented from the

110
newborn period on and that shows consistency to age 3 years and perhaps to

age 5 years. It appears to encompass not only greater autonomic reactivity but

also poorer modulation of gross and fine motor functioning, poorer affective and

attentional regulation, with more static facial expression, narrowed affective

range, higher distractibility and perseveration, poorer modulation of transition

from one task aspect to another, and poorer articulation and expressive

language use in the face of normal overall intellectual capacity. These

differences were found in the absence of documented brain injury, indicating a

difference in neurobehaviorai organization possibly due to difference in sensory

experience and consequent brain function.

QUESTION 2: WILL THE COMPREHENSIVE MODIFICATION OF SENSORY

INPUT TO THE VERY EARLY BORN PRETERM INFANT (<32 WEEKS)

REDUCE DEVELOPMENTAL COMPROMISE?

Als (1986) developed an intervention approach that focuses on reduction of

purported stress behaviors and increase of self-regulatory behaviors of the

poorly modulated infant by modification of the physical environment in the

neonatal intensive care unit (e.g., shielding from overhead lighting and from

noise) and the caregiving practices of nurses and other professionals as well

as the parents interacting with the infant (e.g., provision of prone or sidelying

flexor position support by specially constructed buntings, nonnutritive sucking,

containment during medical procedures, sleep state regulation protection). A

training program in individualized observation and caregiving is available at

various centers (Boston, Tucson, Oakland, Raleigh). Focus is on the behavioral

observation of the infant, on designing an individualized care plan, and on

comprehensive implementation of developmental support in collaboration with

the parents.

This approach has been tested with encouraging results in two studies focusing

on very-low-birth-weight infants.

lnitial Study

Als and coworkers (1986) studied eight control infants in the course of 1 year,

conducting detailed behavioral observations on the infants every 10th day. In

the second year of the study, the same observations were applied to infants

who, in addition, received carefully designed individualized intervention, based

on the observations, from the primary nursing teams and their parents. All

infants were initially respirator-dependent and met stringent selection criteria

that put them at high risk for the development of bronchopulmonary dysplasia

(e.g., birthweight <1,250g; mechanical ventilation within 3 hours of delivery;

mechanical ventilation >24 hours in the first 48 hours at >.60 FiO2

 for >2 hours

111
(Cohen and Taeusch 1983); no chromosomal or other genetic anomalies; no

major congenital infections; no major maternal illness, including intrauterine

infections; no twins). The control and Intervention groups did not differ on any

other medical variables up to day 10, when intervention started, nor did they

differ on any demographic variables. The results of the study showed the

intervention group with a significantly decreased number of days on the

respirator, on supplemental oxygen, and on tube feeding (Als et al. 1986). The

children were subsequently studied at 4 weeks post-EDC with the APIB; at 3, 6,

9, and 18 months post-EDC with the Bayley Scales (Bayley 1969); at 9, 18, and

36 months post-EDC with the K-Box Paradigm (Als 1984); and at 36 months

post-EDC with the McCarthy Scales of Children’s Abilities (McCarthy 1972) the

Kaufman Assessment Battery for Children (K-ABC) (Kaufman and Kaufman

1983), and the Psychomotor Scale of the Bayley Scores (Bayley 1969). The

intervention infants were better modulated, as measured by the APIB systems

scores, in terms of motor system and self-regulation ability. Of the five body

signal parameters measured, the intervention group showed a significantly

lower incidence of motoric extension behavior, such as grimacing or arching.

They also showed a higher number of normal reflexes. Furthermore, the MDI

and PDI scores for the control and intervention groups at 3, 6, and 9 months

consistently showed the intervention infants scoring significantly above the

control infants. Thus, the intervention appears to have had a substantial impact

on both the mental and motor development of these infants (Als 1989b; Als et

al. 1986). The K-Box Paradigm at 9, 18, and 36 months (Als 1989b; Als et al.

1986; Als et al. 1991) showed that the intervention children performed

significantly better than the control infants. Furthermore, the initial advantage

of the intervention children was well maintained, while the control children

deteriorated over time on many of the parameters. All parent-child interaction

parameters significantly favored the intervention children and their parents.

This advantage also was demonstrated on the McCarthy Scales, the Bayley

Psychomotor Scale raw score, and K-ABC performance (Kaufman and

Kaufman 1983) at age 3 years. These results demonstrate that behavioral

modulation, by modification of sensory input, shows striking continuity in

behavioral improvement over time, at least to age 3 years.

Replication Study

Als and colleagues (1988c) replicated and extended this study to a larger

sample (18 control and 20 intervention infants) using similar selection criteria.

This time, the preterms were randomly assigned to the control and intervention

groups, with intervention starting in the first 24 hours after delivery. Intervention

infants were cared for by nursing teams trained in special behavior observation.

The results, which are currently available through 2 weeks after due date,

again showed striking medical improvement of the intervention infants, with

significantly reduced respirator stay, oxygen need, tube feeding, and

112
bronchopulmonary dysplasia and marked reduction in the incidence of

intraventricular hemorrhage (10 out of 18 controls; 1 out of 20 intervention

infants). Furthermore, length of hospital stay was significantly reduced, as was

hospital cost. At 2 weeks post-EDC, APIB scores and electrophysiological

functioning, as assessed with BEAM, again showed highly significant group

differences favoring the Intervention infants (Als et al. 1988c). The functional

advantage of the intervention infants is expected to last over time, as was seen

in the initial intervention study reported above.

SUMMARY

A functional model has been formulated that attempts to specify the behavioral

subsystems of functioning that exemplify in their respective interplay an infant’s

individuality of behavioral functioning in the manner in which they move from

stable to disorganized functioning and in the flexibility with which they maintain

organized functioning in the face of varied exogenous and endogenous events.

Based on this model, Als and colleagues have attempted to develop systematic

assessments, the APIB and the K-Box Paradigm, to quantify the degree of

differentiation and modulation of these behaviorally defined subsystems of

functioning. It is hypothesized that the differences documented via these

assessments are brain based (i.e., part of the child’s biological makeup, which

is influenced by the intrauterine and extrauterine environment, be it sensory

and/or drug exposure, and which shows a recognizable pattern along a

definable trajectory).

The studies reported to date employing these methodologies show the

following:

1.

2.

3.

Medically healthy preterm infants show a gradient of modulation differences

by GA group, with the earlier born infants showing much greater sensitivity,

reactivity, and lower threshold to disorganization. BEAM studies appear to

implicate primarily the frontal lobes and secondarily the right hemisphere.

Behavioral organizational group membership in the newborn period

predicts to neuropsychological functioning at later ages, with the lowthreshold-reactive newborns showing greater difficulty in motor and spatial

planning, social interactive modulation capacity, and attentional regulation.

Behavioral organizational functioning of the newborn, at least the early-born

preterm infant, appears to be modified and supported by individualized

caregiving based on the the infant’s own behavioral cues indicating sensory

thresholds to disorganization.

The brain of the newborn is the organ that orchestrates and influences all

aspects of functioning. The synactive model of development outlines access

113
avenues for the observation of that brain’s function via the behavior displayed

by the infant. Autonomic, motoric, state organizational, attentional, and selfregulatory capacities of the infant can be observed to identify succinctly and

specifically an individual infant’s thresholds to sensory input for selfmaintenance and for increasing differentiation. To take the next step in

differentiation, previously integrated and synchronized connections open up,

necessitating the temporary disorganization and dyssynchronization of

subsystems in their interplay. Then the subsystems realign and support each

other again at a more differentiated level of functioning. In this model, if stress

is too massive, as may be the case in disease and/or intrauterine drug

exposure, more differentiated realignment of subsystems may not be possible,

and maladaptive, costly realignment may occur at a more rigid, canalized level

of functioning. Detailed observation of the behavior of the infant is seen as an

opportunity to estimate and infer from the infant’s behavior how appropriate

comprehensive physical environments and caregiving can be provided to

support the rapid brain and behavioral development of the infant, even in the

face of insult.

It appears that medical and developmental management must be geared to the

individual infant’s sensory thresholds to prevent secondary consequences from

generalization of defect, akin to deprivation and subsequent active neuronal

suppression (Duffy et al. 1984), and to enhance compensatory strategies in

overcoming and integrating possible damage and insult into each infant’s

endogenously fuelled developmental trajectory. Only careful environmental

manipulation in controlled studies with sensitive outcome measures will provide

the answers.

REFERENCES

Als, H. “Manual and Scoring System for the Assessment of Children’s

Behavior: Kangaroo-Box Paradigm.” Unpublished manuscript, Children’s

Hospital, Boston, 1984.

Als, H. Synactive model of neonatal behavioral organization: Framework for

the assessment and support of the neurobehavioral development of the

premature infant and his parents in the environment of the neonatal intensive

care unit In: Sweeney, J.K., ed. The High-Risk Neonate: Developmental

Therapy Perspectives. New York: Hayworth Press, 1986. pp. 3-55.

Als, H. Continuity and consequences of behavior in preterm infants. In: von

Euler, C.; Forssberg, H.; and Lagercrantz, H., eds. Neurobiology of Early

Infant Behaviour. Wenner-Gren Center International Symposium Series, Vol.

55. Hampshire, England: Macmillan Press Ltd., 1989a. pp. 87-106.

Als, H. Self-regulation and motor development in preterm infants. In:

Lockman, J., and Hazen, N., eds. Action in Social Context; Perspectives on

Early Development. New York: Plenum Press, 1989b. pp. 65-97.

114
Als, H., and Berger, A. “Manual and Scoring System for the Assessment of

Infants’ Behavior: Kangaroo-Box Paradigm.” Unpublished manuscript.

Children’s Hospital, 1986.

Als, H; Duffy, F.H.; and McAnulty, G.B. Behavioral differences between preterm

and fullterm newborns as measured with the A.P.I.B. system scores: I. IBD

11:305-318, 1988a.

Als, H.; Duffy, F.H.; and McAnulty, G.B. The A.P.I.B., an assessment of

functional competence in preterm and fullterm newborns regardless of

gestational age at birth: II. IBD 11:319-331, 1988b.

Als, H.; Duffy, F.H.; and McAnulty, G.B. Neurobehavioral regulation disorder of

prematurity. IBD 13:159, 1990.

Als, H.; Duffy, F.H.; and McAnulty, G.B. Neurobehavioral competence in

healthy preterm and fullterm infants: Newborn period to nine months. Dev

Psychol, in press.

Als, H.; Duffy, F.H.; McAnulty, G.B.; and Badian, N. Continuity of

neurobehaviorai functioning in preterm and full-term newborns. In:

Bornstein, M., and Krasnegor, N., eds. Stability and Continuity in Mental

Development. Hillsdale, NJ: Lawrence Eribaum, 1989. pp. 3-28.

Als, H.; Lawhon, G.; Gibes, R.; Duffy, F.H.; McAnulty, G.B.; and Blickman, J.G.

Individualized behavioral and environmental care for the very low birth weight

preterm infant at high risk for bronchopulmonary dysplasia: Neonatal

intensive care unit and developmental outcome. Pedia 78:1123-1132, 1986.

Als, H.; Lawhon, G.; Gibes, R.; Duffy, F.H.; McAnulty, G.B.; and Biickman, J.G.

“Individualized Behavioral and Developmental Care for the VLBW Preterm

Infant at High Risk for Bronchopulmonary Dysplasia and lntraventricular

Hemorrhage. Study II NICU Outcome.” Paper presented at New England

Perinatai Association Annual Meeting, Woodstock, VT, 1988c.

Als, H.; Lawhon, G.; McAnulty, G.B.; Duffy, F.H.; and Gibes, R. “Developmental

Outcomes to Age Three Years of Early Behaviorally Based Care in the

NICU,” unpublished manuscript, 1991.

Als, H.; Lester, B.M.; Tronick, E.; and Brazelton, T.B. Towards a research

instrument for the assessment of preterm infants’ behavior. In: Fitzgerald,

H.E.; Lester, B.M.; and Yogman, M.W., eds. Theory and Research in

Behavioral Pediatrics. Vol. I. New York: Plenum Press, 1982a. pp. 35-63.

Als, H.; Lester, B.M.; Tronick, E.; and Brazelton, T.B. Manual for the

assessment of preterm infants’ behavior (APIB). In: Fitzgerald, H.E.; Lester,

B.M.; and Yogman, M.W., eds. Theory and Research in Behavioral

Pediatrics. Vol. I. New York: Plenum Press, 1982b. pp. 65-132.

Bayley, N. Manual for the Bayley Scales of Infant Development. New York:

Psychological Corporation, 1969.

Brazelton, T.B. Neonatal Behavioral Assessment Scale. Clinics in

Developmental Medicine, No. 88 (rev. ed.). Philadelphia: Lippincott, 1984.

Catto-Smith, A.G.; Yu, V.Y.H.; Bajuk, B.; Orgill, A.A.; and Astbury, J. Effect of

neonatal periventricular hemorrhage on neurodevelopmental outcome. Arch

Dis 60:8-11, 1985.

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Cohen, A., and Taeusch, H.W. Prediction of risk for bronchpulmonary

dysplasia. Am J Perinatol 1:21-22, 1983.

Duffy, F.H. Electrophysiological evidence for gestational age effects in infants

studied at term: A BEAM study. In: von Euler, C.; Forssberg, H.; and

Lagercrantz, H., eds. Neurobiology of Early Infant Behaviour. Wenner-Gren

Center lnternational Symposium Series, Vol. 55. Hampshire, England:

Macmillan Press Ltd., 1989. pp. 337-355.

Duffy, F.H., and Als, H. Neural plasticity and the effect of a supportive hospital

environment on premature newborns. In: Kavanagh, J.F., ed.

Understanding Mental Retardation. Research Accomplishments and New

Frontiers. Baltimore: Paul H. Brookes Publishing Co., 1988. pp. 179-206.

Duffy, F.H.; Als, H.; and McAnulty, G.B. Behavioral and electrophysiological

evidence for gestational age effects in healthy preterm and fullterm infants

studied two weeks after expected due date. Child Dev 61:1271-1286, 1990.

Duffy, F.H.; Mower, G.D.; Jensen, F.; and Als, H. Neural plasticity: A new

frontier for infant development. In: Fitzgerald, H.E.; Lester, B.M.; and

Yogman, M.W. eds. Theory and Research in Behavioral Pediatrics, Vol. Il.

New York: Plenum Press, 1984. pp. 67-96.

Kaufman, A.S., and Kaufman, N.L. Kaufman Assessment Battery for Children,

K-ABC. Circle Pines, MN: American Guidance Service, 1983.

McCarthy, D. Manual for the McCarthy Scales of Children’s Abilities. New

York: Psychological Corporation, 1972.

ACKNOWLEDGMENTS

The work described in this chapter was supported by grants to the author from

the National Institute of Child Health and Human Development (RO1 HD-18654,

RO1 HD-18761); the National Institute for Disability and Rehabilitation

Research (GO-08435063); the H.P. Hood Foundation; the Merck Family Fund;

the U.S. Department of Education, Handicapped Children’s Early Education

Program (H0-24590003); and a Mental Retardation Center Grant (P30 HD18655) to Joseph J. Volpe, M.D., Chairman, Department of Neurology,

Children’s Hospital, Boston.

AUTHOR

Heidelise Als, Ph.D.

Associate Professor of Psychology (Psychiatry)

Harvard Medical School

Director

Neurobehavioral Infant and Child Studies

Enders Pediatric Research Building, EN-029

Children’s Hospital

320 Longwood Avenue

Boston, MA 02115

116
Substance Abuse in Pregnancy:

Effects on Cardiorespiratory Function

in the Infant

Eduardo Bancalari

Substance abuse during pregnancy has become more prevalent in recent

years, but little is known about the short- and long-term effects on the infant.

Because of a possible increase in the incidence of sudden infant death

syndrome (SIDS) in infants born to substance-abusing mothers (ISAM), special

emphasis has been placed on the possible consequences of substance abuse

on the cardiorespiratory function of the offspring.

EFFECTS ON THE FETUS

Respiratory System

Respiratory activity in the fetus is intermittent and does not contribute to gas

exchange; however, many substances used during pregnancy may influence

respiratory adaptation and function after birth.

Fetal Breathing. A recent report described a markedly abnormal breathing

pattern in human fetuses of cocaine-abusing mothers. The pattern was

characterized by persistent rhythmic, hyperpneic, and regular breathing that

lasted up to 30 minutes (Gingras et al. 1989). Similar results have been

reported in fetal iambs acutely exposed to methadone (Szeto 1983). This

hyperactivity may be associated with a significant increase in fetal oxygen

consumption. In contrast to these findings, Richardson and colleagues (1984)

reported a depressed breathing response to CO2

 in human fetuses of chronic

methadone-exposed mothers. The different results may be due to the different

subjects and to the fact that the animals were only exposed to an acute dose of

methadone.

Maternal smoking during pregnancy is also associated with a reduction in fetal

breathing movements (Manning and Feyerabend 1976; Gennser et al. 1975).

This effect seems to be secondary to the increased nicotine levels in the fetus

and not to the increase in carboxyhemoglobin.

117
Lung Maturation. There is some evidence that substance abuse, especially of

opioids, during pregnancy may accelerate lung maturation through enzyme

induction and reduce the incidence of respiratory distress syndrome (RDS)

(Gluck and Kulovich 1973). On the other hand, substance abuse is associated

with an increased risk of premature delivery that offsets any possible beneficial

effect on lung maturation and increases the risk of RDS in drug-exposed infants

(Ostrea and Chavez 1979).

Meconium Aspiration. Many substances used during pregnancy, such as

cocaine and opioids, can interfere with placental gas exchange and may induce

fetal distress. They also may cause elimination of meconium into the amniotic

fluid, resulting in aspiration of this fluid into the lungs and meconium aspiration

syndrome in the newborn (Ostrea and Chavez 1979).

Cardiovascular System

Because most substances abused during pregnancy cross the placenta, the

cardiovascular effects on the fetus are similar to those observed in the mother.

Many recent studies have focused on the effects of cocaine because of its

increasing use and the severe cardiovascular effects it produces.

Experiments done in pregnant ewes (Moore et al. 1986; Woods et al. 1987,

1989) have demonstrated that intravenous injection of cocaine, in doses that

produce levels similar to those observed during human use, produce a

significant increase in maternal arterial blood pressure, with a decrease in

uterine blood flow. This effect lasts at least 15 minutes and is associated with

marked increase in catecholamine plasma concentration. The fetus also

responds with an increase in arterial blood pressure and heart rate and a

decrease in arterial PO2. When the fetus is injected directly, the change in

blood pressure and heart rate is smaller and there is no change in arterial blood

gases. This suggests that the latter is due to impaired placental gas exchange

secondary to the decreased uterine blood flow. The half-life of the drug

(between 12 and 13 minutes) was similar in both mother and fetus.

EFFECTS ON THE NEONATE

Respiratory System

Respiratory Adaptation After Birth. As mentioned earlier, because of its

effects on the fetus, abuse of such substances as opioids may increase or

decrease the incidence of RDS (Gluck and Kulovich 1973; Ostrea and Chavez

1979). The increased incidence of fetal asphyxia produced by substance abuse

also increases the risk of meconium aspiration syndrome in these infants

(Chappel 1972; Ostrea and Chavez 1979; Little et al. 1989).

118
Use of any drug that depresses central nervous system (CNS) function

increases the risk of neonatal respiratory depression and asphyxia at birth. This

is even more important if the substance interferes with placental gas exchange

and the infant had become hypoxic before birth (Gerhardt et al. 1977). On the

opposite side, infants with signs of withdrawal after prenatal exposure to heroin

can show respiratory irritability with hyperventilation and hypocapnia (Glass et

al. 1972).

Respiratory Control In Infancy. Several reports have suggested that the

incidence of SIDS is higher in ISAM (Chavez et al. 1989; Chasnoff et al. 1989).

Because of this, special emphasis has been placed on the possible effect of

substance abuse during pregnancy on the respiratory control mechanisms of

the infant.

Maternal Substance Abuse and SIDS. The mechanisms for the increased

risk of SIDS in ISAM is controversial because of the many confounding factors

associated with substance abuse that also may affect the risk of SIDS during

pregnancy. For example, Chavez and colleagues (1979) reported a fivefold

increased risk of SIDS in infants born to mothers who used different substances

during pregnancy. In this study, it is Impossible to separate the effect of each of

these drugs on the risk of SIDS because of the small number of subjects and

the lack of specific information. Moreover, premature infants with birth weights

under 1.9 kg, who have an increased risk for SIDS, were excluded from this

study. As in other studies, Chavez and colleagues found that ISAM who died

from SIDS expired at an earlier age than did the SIDS cases in the control

group (9.2 weeks vs. 13.8 weeks). Chasnoff and coworkers (1989) also

reported a high incidence of SIDS (15 percent) in infants of mothers who

used cocaine during pregnancy. This was a retrospective study without a

simultaneous nonexposed control group; the incidence of SIDS in a

methadone-exposed group used as control was 4 percent.

More recently, Bauchner and colleagues (1988) found a similar incidence of

SIDS (5.6 percent per thousand) in 175 infants exposed to cocaine in utero and

in 821 controls (4.9 percent per thousand). This study has the limitation of a

relatively small sample size and a low death rate (one infant) in the cocaineexposed group. As discussed by the investigators, to detect an increase in

SIDS to 10 percent per thousand with a power of 80 percent would require a

population of 680 women who used cocaine.

Other methodological limitations of this study, common to many other reports,

were (1) there was no distinction made on the severity of drug use or the period

during pregnancy when the fetus was exposed, (2) there was no control for the

possible use of other drugs, and (3) there is always a good chance of

underreporting of SIDS cases.

119
In conclusion, although there appears to be an association between maternal

substance abuse and an increased risk of SIDS, there is no clear causal

relationship; and larger study populations will be required to adjust for the many

confounders that may have an influence on SIDS.

Breathing Pattern. Several investigators have reported abnormal respiratory

patterns in ISAM. Because similar alterations have been reported in infants

with apparent life-threatening events (ALTE), it has been suggested that these

abnormalities in respiratory function may predispose these infants to SIDS.

Davidson Ward and coworkers (1986) evaluated the respiratory pattern in 27

ISAM (5 were exposed to opiates, 7 to phencyclidine, 3 to cocaine, and 12 to

multiple drugs) and compared the results with 43 nonexposed controls. ISAM

had more sleep time, more duration of apnea greater than 6 seconds, more

periodic breathing, higher respiratory rates, and lower heart rates than the

controls. Pneumograms were considered abnormal in 32 percent of ISAM in

contrast to 9.3 percent in the controls. With one exception, all abnormal

pneumograms in the ISAM group were detected during the first 2 months,

suggesting that the effect of drug exposure disappears with postnatal age. No

infant with abnormal pneumograms died of SIDS. This is in agreement with

other data in the literature demonstrating that pneumograms do not predict the

risk of SIDS in individual patients (Southall et al. 1986). Davidson Ward and

coworkers’ study (1986) also has the limitation of mixing the results of infants

exposed to different substances. Furthermore, the controls were not screened

to assure that, in fact, they were not exposed to drugs.

Recently, Chasnoff and colleagues (1989) also reported an increased incidence

of apnea density and prolonged apneic episodes in a group of 32 infants

exposed to cocaine in utero when compared to a group of 18 methadoneexposed infants. Although many confounding variables were equal in both

groups, this study did not include a group of normal nonexposed infants. The

abnormal respiratory pattern observed in the cocaine-exposed infants was

normalized with the administration of aminophylline. This finding stresses the

importance of evaluating these infants before they receive any intervention that

may influence their respiratory function.

Two studies (Bachman et al. 1990; Gibson et al. 1990) recently reported

alterations in respiratory pattern in infants born to mothers who used

amphetamines or opiates similar to those described in infants of cocaineabusing mothers.

Maternal smoking during pregnancy or after delivery increases the risk of

central apneas in the offspring (Toubas et al. 1986). The same investigators

120
found that maternal caffeine consumption was associated with an increased risk

of central and obstructive apneas in the infant. The mechanism for the caffeine

effect is not clear, but it may be related to an increased number of adenosine

receptors in the brain stem (Marangos et al. 1984). Smoking during pregnancy

interferes with fetal oxygenation, and this may result in impaired CNS function.

In these studies, it is difficult to separate the effects of prenatal smoking from

those of passive smoking after birth.

Ventilatory Response to Stimuli

One of the characteristics of respiratory control in the neonate is that the

ventilatory response to hypoxia is not sustained during the first few postnatal

days. In the premature infant, this abnormal response may last for several

weeks after birth.

Several publications have reported abnormal arousal and ventilatory responses

to hypoxia and hypercapnia in infants with ALTE (Shannon et al. 1977; Hunt

1981; Hunt et al. 1981; Graff 1986). This alteration may be responsible for the

severe apneic episodes observed in these infants.

Davidson Ward and colleagues (1989) compared arousal from sleep during

exposure to an inspired PO2

 of 80 mm Hg in a group of infants born to cocaineabusing mothers with a group of nonexposed controls. While control infants

were aroused in 89 percent of the trials, infants exposed to cocaine were

aroused in only 27 percent of the hypoxic exposures. This observation is

important because another study (Rodriguez et al. 1987) also described

abnormal hypoxic arousal in a group of infants with apnea of infancy, and

elevated serum epinephrine levels were found in these infants. Perrin and

coworkers (1984) found a significant increase in the concentration of dopamine

and noradrenalin in the carotid bodies of infants who died of SIDS. These

findings suggest that the elevated endogenous catecholamine levels may

interfere with the function of the carotid bodies and the ventilatory response to

hypoxia observed in some of these infants. It is likely that infants exposed to

cocaine in utero also have increased concentrations of circulating

catecholamines (Ritchie and Greene 1987), although no data are available in

human neonates. Weese-Mayer and colleagues (1990) also reported an

attenuation of the ventilatory response to hypoxia in newborn rabbits chronically

exposed to cocaine in utero. This study as well as those of Davidson Ward and

colleagues (1986, 1989) suggest that chronic prenatal cocaine exposure may

alter the central or peripheral mechanisms responsible for a normal ventilatory

and arousal response to hypoxia.

Olsen and Lees (1980) also described a depressed ventilatory response to

CO2

 in infants born to mothers receiving methadone during pregnancy. This

121
depression persisted for 15 to 31 days, suggesting that the effect was not

directly related to the blood methadone levels in the infant. The depression of

the response to CO2 did not influence basal ventilation, alveolar PCO2, or

oxygen consumption.

Chen and coworkers (1989) demonstrated an increased number of respiratory

pauses induced by a facial airstream stimulation in infants born to mothers who

used cocaine during pregnancy compared to nonexposed controls. However,

the ventilatory response to CO2

 was similar In both groups. These results also

support the theory that ISAM have an alteration in the integration of the

mechanisms that are responsible for a normal respiratory pattern after birth.

Cardiovascular System

Little information is available regarding the effects of substance abuse during

pregnancy on neonatal cardiovascular adaptation and function. Because of the

marked cardiovascular effects of cocaine in the adult, one study (van de Bor et

al. 1990a) evaluated the hemodynamic function during the first 2 postnatal days

in 15 full-term infants born to mothers who used cocaine during pregnancy.

Cocaine metabolites were present in the urine of all infants. When, on the first

postnatal day, the results were compared with a group of 22 normal

nonexposed infants (negative urine screen), the cocaine-exposed neonates had

lower stroke volume, lower cardiac output, and higher systemic blood pressures

than did the controls. These differences disappeared in the second day,

suggesting that the effect was due to the circulating cocaine rather than to a

more permanent derangement of the cardiovascular control mechanisms. The

observed changes were attributed to an increase in circulating catecholamines

secondary to the blocking of catecholamine reuptake receptors, but plasma

catecholamine levels were not measured.

The same investigators (van de Bor et al. 1990b) found an increased cerebral

blood flow velocity in full-term infants of mothers who abused cocaine during

pregnancy. This increase in arterial blood pressure and cerebral blood flow

may increase the risk of intracranial hemorrhage, especially in preterm infants.

Methodological Considerations

The evaluation of the respiratory pattern and respiratory control mechanisms in

infants is subject to a number of methodological difficulties. Some are related to

the selection of the subjects included in these studies and to the presence of

many confounding variables. Others are related to the instrumentation

available for the measurements; and, finally, some are due to errors that occur

in the analysis and interpretation of the data.

122
Subjects. In any evaluation of control of breathing it is crucial to consider the

gestational, postnatal, and conceptional age of the infants because the

respiratory pattern, reflexes, and the ventilatory response to hypoxia and

hypercepnia are markedly influenced by these factors. Also, because abuse of

many substances during pregnancy is associated with an increased rate of

premature birth and intrauterine growth retardation, it is critical to use control

groups with the same distribution of gestational age and weight as in the study

population.

The incidence of both perinatal asphyxia and infection also is increased in

ISAM, and both are additional confounders that may alter cardiopulmonary

function. In considering the effect of a substance used during pregnancy, it is

very important to establish as accurately as possible the duration and dose of

exposure, as well as the time during pregnancy when the substance was used.

It is also extremely difficult to eliminate the possibility of polydrug use and its

Interactive effect on the variables that are measured.

Poor nutrition, a common problem associated with substance-abusing mothers,

is a confounding variable that should not be overlooked because of its possible

effects on fetal growth and cardiorespiratory function. The history of previous

ALTE is also very important, because these episodes may be responsible for

some of the alterations in respiratory pattern observed later in these infants

that may otherwise be attributed to the drugs. Finally, one must also keep in

mind that substances that are used by the mother postnatally are frequently

transferred to the infant through breast-feeding and may have significant effects

on the variables being measured.

Methods and Instrumentation. A limitation of many studies that include

breathing patterns is that respiration is most commonly monitored by

transthoracic impedance. This signal alone Cannot differentiate between central

and obstructive apneas. To do this, it is necessary also to record airway flow

using a nasal thermistor, a pneumotachograph, a capnograph, or other device

capable of detecting airway flow. The problem with these devices is that they

may irritate the infant or may increase the respiratory deadspace or airway

resistance. Inductance plethysmography is a noninvasive method that can

provide more information on specific patterns of breathing. Because the

electrical properties of the electrodes and the skin changes over time,

impedance monitors characteristically change their output and the quality of the

respiratory signal within a relatively short period of time.

Among the challenges when evaluating respiratory or cardiovascular function in

the neonate or small infant is that the equipment must be noninvasive to

eliminate any risk and the need for sedation. Obviously, the infant does not

123
collaborate with the tests, and it is essential to obtain the measurements in an

environment that preserves normal physiologic functions as much as possible

and that avoids any stressful condition that may influence the measurements.

Ambient temperature, sound, light, feeding, tactile stimulation, posture, or any

physical activity may have a profound effect on cardiorespiratory function and

must be standardized.

Findings in studies of respiratory control are strongly influenced by sleep state.

Sleep or awake state or type of sleep is commonly defined only by the

respiratory and heart-rate pattern in the pneumogram. This method requires

subjective interpretation and may be influenced by equipment artifact. As much

as possible, sleep state must be controlled or adequately defined. This requires

the use of electroencephalograms, oculograms, and myograms that increase

the number of electrodes and instrumentation needed for the studies. In the

preterm infant, sleep state is frequently indeterminate and, even with the proper

instrumentation, it is difficult or impossible to define.

Analysis and lnterpretation of Data

Because of the subjective interpretation of pneumograms or other respiratory

tests, it is essential to include a simultaneous control group. The traces

must be read blindly by at least two experienced observers using clear,

preestablished criteria.

Another problem with cardiorespiratory data is that there is frequently a large

individual variability even in the normal population. This results in a wide

overlap of the data between normal and abnormal subjects and requires very

large populations to detect any differences.

When evaluating any physiologic function, it is important to differentiate

alterations that may result from the chronic prenatal exposure to a given

substance from the direct effect of the drug that remains in the circulation or in

the tissues of the infant for some time after birth. In other situations, the effects

of drug withdrawal are the ones that predominate, possibly influencing the

results.

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Van de Bor, M.; Walther, F.J.; and Sims, M.E. Increased cerebral blood flow

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Ann N Y Acad Sci 562:267-279, 1989.

AUTHOR

Eduardo Bancalari, M.D.

Professor

Department of Pediatrics, Obstetrics, and Gynecology

Director

Division of Neonatology

Department of Pediatrics

University of Miami

P.O. Box 016960

Miami, FL 33101

127
The Effect of Cocaine on Developing

Human Brain

Barry E. Kosofsky

INTRODUCTION

Central nervous system (CNS) development requires a complex orchestration

of genetic factors and environmental forces that direct brain maturation and

shape infant development in a reproducible yet individualized manner. There

are eight major stages in the development of each part of the brain: neural

plate induction, cell proliferation (neurons and glia), cell migration, cell

aggregation, neuronal maturation, neuronal connectivity (including

synaptogenesis), cell death, and process elimination (Cowan 1979). Volpe

(1987) divides human brain development into a proliferative phase (for neurons

2 to 4 months gestation and for glia 5 months gestation to 1 year postnatal), a

migratory phase (peak time 3 to 5 months gestation), and an organizational

phase (peak time 6 months gestation to several years postnatal). The

protracted timetable of CNS maturation affords a continuum of biologic

vulnerability to developing brain. Moreover, the developmental consequences

of a toxic CNS insult relate critically to the gestational timing of the exposure.

Evrard and colleagues (1989) distinguish two classes of CNS developmental

disorders: those occurring in the first half of gestation that affect cytogenesis

and histogenesis and those occurring during the second half of gestation that

affect brain growth and differentiation (figure 1). During the organizational

phase in the second half of gestation, progressive events (neuronal maturation,

connection formation, and synaptogenesis) and regressive events (cell death

and selective elimination of processes) critically shape the maturation of brain

circuitry. Toxic influences during this period may dramatically alter brain

development but may also alter the regressive events that underlie the capacity

of developing brain to compensate for injury. A pattern of metabolic maturation

must parallel normal brain development and may impose regional stage-specific

metabolic requirements and vulnerabilities.

Within this context of brain development, one must consider potential modes of

toxicity of cocaine on developing brain. The action of cocaine is mediated by

blocking the reuptake of the catecholamine neurotransmitters norepinephrine

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FlGURE 1. Schematic representation of the chronology of the main neocortical developmental events

SOURCE: Evrard et al. 1989, copyright 1989, Paul H. Brookes Publishing Company
and dopamine and the indoleamine serotonin at nerve terminals (Gold et al.

1985). The peripheral effects of cocaine are a catecholamine-induced increase

in sympathetic drive leading to vasoconstriction, hypertension, and tachycardia.

The central effects of cocaine derive from increased central aminergic drive

leading to CNS stimulation (Ritchie and Greene 1985). The mechanisms by

which maternal cocaine exposure may compromise fetal well-being have been

suggested by physiologic studies in pregnant sheep. In the model of the fetal

ewe, injection of cocaine into the pregnant mother leads to fetal blood levels

approximately one-eighth that of the mother, within 5 to 7 minutes of injection

(Woods et al. 1989). After single intravenous injections of cocaine comparable

to commonly abused doses (1 mg/kg), maternal heart rate and oxygenation

were stable, but maternal mean arterial pressure increased. Concomitant with

maternal hypertension was a 34-percent decrease in uterine blood flow from

catecholamine-mediated vasoconstriction of the uterine arteries (Woods et al.

1987). The fetal consequences of decreased uterine blood flow are reduced

oxygen delivery (hypoxemia), fetal hypertension, and tachycardia. The fetal

response to hypoxemia is release of endogenous catecholamines (Phillippe

1983). The fetal catecholamines and maternal catecholamines, which are

transmitted to fetus via the placenta, are circulating in high quantities in the

fetus because cocaine, which diffuses to the fetal circulation, prevents their

reuptake. These animal studies point to the following classes of potential

mechanisms whereby maternal cocaine abuse can compromise fetal brain

development:

1. Indirect (maternal) via catecholamine-mediated placental vascular

compromise with consequent fetal hypoxemia and/or ischemic injury

2. Direct (fetal) peripheral via catecholamine-mediated effects on fetal

vasculature

3. Direct (fetal) central via aminergic mechanisms

(a) Altering the integrity of aminergic transmitter systems secondary to

developmental perturbation of amine concentration and distribution in

fetal brain

(b) Altering the fidelity of aminergic signals, which may subserve atrophic

role in CNS maturation (Lauder 1988)

One central question is to establish whether cocaine is a behavioral teratogen

(Vorhees 1989), a drug capable of generating a reproducible alteration in

behavior consequent to fetal exposure. Grimm (1987) outlines four levels of

research at which one should consider a behavioral teratogen:

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Cognitive level—define the behavioral and cognitive deficit

Systems level—specify the brain structures and neurochemical systems that

subserve the behavioral or cognitive deficit

Developmental level—specify the time course of brain vulnerability to the

insult

Pharmacologic-physiologic level—specify the mechanism of action of the

teratogen

Part of the difficulty in establishing cocaine as a behavioral teratogen is that the

behavioral consequences of prenatal exposure to cocaine may not be evident

at birth but may appear as the behavioral repertoire of the developing child

matures. Therefore, one strives to identify antecedents of the behavioral

abnormality. One also strives to identify predictive markers (clinical, anatomic,

physiologic, or chemical) of the subsequent expression of the behavioral

anomaly. Implicit in this approach is a consideration of the role of genetic and

environmental factors that may alter the susceptibility to or expression of a

teratogenic effect.

This chapter reviews the clinical studies that consider the toxic effects of

cocaine on developing brain. These studies focus on perinatal growth

parameters, infant behavior and development, and neuroanatomic and

neurophysiologic assessments.

CLINICAL STUDIES: PERINATAL OUTCOME

Bingol and colleagues (1987) compared pregnancy outcome in 50 women and

their offspring who were exposed only to cocaine during gestation (as defined

by maternal history and newborn urine screening) and 50 non-drug-exposed

mother-infant pairs. Stillbirth rate was higher in mothers who abused cocaine

during gestation (8 percent, all related to abruptio plecentae, occurring shortly

after cocaine administration in all four mothers, p<0.001), but no differences

were found in the rate of spontaneous abortions. In infants with gestations of

37 weeks or longer who were exposed to cocaine in utero, birth weight, length,

and head circumference were decreased (p<0.001). An increased incidence of

major congenital malformations was reported in infants exposed to cocaine in

utero (10-percent incidence in cocaine-exposed infants vs. 2-percent incidence

in controls, p<0.01). The study did not evaluate the contribution of other

maternal characteristics and habits related to cocaine use that may adversely

influence pregnancy outcome.

Analysis of 1,776 consecutive deliveries in an urban labor and delivery unit by

Neerhof and colleagues (1989) compared perinatal outcome in 114 newborns

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exposed only to cocaine in utero (documented by positive maternal urine

screening and confirmed by history) with 88 randomly chosen unexposed

newborns (negative maternal history and urine screening). Cocaine-exposed

infants demonstrated shorter gestational age (GA) (mean GA=37.5 weeks in

cocaine-exposed vs. GA=39.0 weeks in controls), increased incidence of

preterm (less than 37 weeks) delivery (25 percent of cocaine-exposed infants

vs. 9 percent of controls), and an increased incidence of small-for-gestational

age infants (28 percent of cocaine-exposed infants vs. 7 percent of controls

were less than the 10th percentile for weight). Of note is the rapid increase in

incidence of mothers who had cocaine detected in their urine at delivery during

the time of the study: from 4 percent of mothers delivering between September

1, 1986, and March 1, 1987, to 12 percent of mothers delivering between

February 1, 1988 and August 1, 1988. Statistical comparisons between infants

exposed only to cocaine and controls were not made, and the independent role

of cocaine in influencing developmental outcome was not assessed.

Zuckerman and colleagues (1989) reported a prospective study of 1,226 innercity mothers who were followed by interview and urine screening for cocaine

and marijuana use during pregnancy. The large number of study participants

and careful study design allowed a multivariate regression analysis, which

clearly established the independent effect of cocaine exposure on fetal growth.

Infants of women who had a positive urine assay for cocaine weighed 93 grams

less (p<0.07), were 0.7 cm shorter (p=0.01), and had a 0.43 smaller head

circumference (p=0.01) compared with infants born to women who were

otherwise identical for age; prepregnancy weight and weight gain during

pregnancy; parity; prenatal visits; sexually transmitted diseases; and marijuana,

cigarette, alcohol, and opiate use. Additionally, these investigators established

that (1) there was no independent association of cocaine exposure with shorter

duration of gestation; (2) cocaine may have an additional indirect effect on fetal

growth mediated by maternal undernourishment (see below); (3) 25 percent of

women who used cocaine during pregnancy denied use when interviewed (they

were identified by the urine assay alone); and (4) multiple regression analyses

recalculated based on reporting alone showed no statistically significant

difference in fetal growth between infants born to mothers who reported cocaine

use compared with those who did not report use. The finding of dramatic

reduction in head circumference (.43 cm decrement) of newborns because of

the additional burden of maternal cocaine abuse during pregnancy is in sharp

contrast with their finding of “head sparing” in infants born to gestational

marijuana abusers and with the established principle regarding relative sparing

of head size with nutritional compromise during gestation (Ballabriga 1989).

Attention is thereby focused on the specific toxicity of cocaine exposure in

compromising fetal brain growth.

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The interpretation of studies that relate maternal cocaine habits with neonatal

outcome requires consideration of confounding biologic, methodologic, and

epidemiologic variables. As Neerhof and coworkers (1989) point out, drug

history alone identified fewer than 50 percent of the women who had positive

urine toxicologic screens at delivery. Conversely, urine screening at delivery

only identifies mothers who have abused cocaine in the 3 to 5 days prior to

delivery, despite slower cocaine metabolism because of lower plasma and

liver choiinesterase activity evident in pregnant women (and in newborns,

especially infants born prematurely) (Ecobichon and Stephens 1973). Errors in

proper identification of exposed as well as control infants yield erroneous

conclusions, as discussed above in the Zuckerman study (1989). Attempts to

provide more complete fetal drug-exposure profiles include serial, prospective

historic, and toxicologic screening. Other screening methods being developed

include analysis of neonatal meconium, from which cocaine metabolites

(benzoylecgonine) were isolated in higher concentration than in paired urine

samples (Ostrea et al. 1989). Because meconium is accumulated by a fetus

during gestation, such analysis may serve as an adjunct in providing an

expanded temporal profile of maternal drug intake during the second half of

gestation. Another approach evolving in toxicology is the determination of

cocaine use by analysis of deposition of cocaine metabolites in hair. Graham

and colleagues (1989) repotted a study of 21 adults wherein self-reported drug

histories correlated with amount of cocaine metaboiite contained in samples of

hair (when concurrent urine screening was negative). Hair samples from seven

neonates, four infants (2.5 to 3.5 months of age) and three toddlers (1 to 3

years), exposed to cocaine in utero (documented by maternal history) were

analyzed. All seven neonates, two out of four infants, and none of the toddlers

had evidence of benzoylecgonine in samples of hair, documenting the potential

usefulness of hair analysis in screening neonates (though loss of neonatal hair

renders the assay less sensitive as the infant develops). Because hair analysis

provides data on long-term rather than recent drug exposure, this technique

may supplement urine screening (and extend toxic analyses, should the method

provide semiquantitative results). The better defined the prenatal cocaine

exposure can be (amount of cocaine the fetus is exposed to, the gestational

timing of that exposure, and the route, frequency, and duration of drug

exposure), the more informative the perinatal and postnatal characterization of

the effect of drug exposure can be.

Whether cocaine exposure is a risk factor for development of congenital

malformations has been controversial. It has been speculated that such a

teratogenic effect of cocaine is a consequence of fetal vascular disruption

during organogenesis (Hoyme et al. 1990). However, to establish a causal role

for cocaine in producing a low-incidence event such as a particular major

congenital anomaly requires a well-designed statistical analysis of a large

cohort. This was accomplished by Chavez and colleagues (1989), who

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analyzed data from the population-based Atlanta Birth Defects Case-Control

Study and established an increased risk of all urinary tract anomalies in mothers

who reported cocaine use during the time from 1 month before the pregnancy

began through the first 3 months of pregnancy when compared with population

controls (adjusted odds ratio=4.81, 95-percent confidence interval 1.15-20.14).

The adjusted risk estimate includes consideration of potential confounding

variables (maternal age and education, cigarette smoking, alcohol intake, and

use of other illicit drugs) through a multiple logistic analysis. Clarification of

whether in utero cocaine exposure imparts an increased risk for other lowincidence outcomes (such as intestinal atresia, neural tube defects, necrotizing

enterocolitis, or sudden infant death syndrome) awaits large-scale

epidemiologic analysis.

One of the advantages of well-designed, large-scale, case-controlled or

prospective studies is the ability to perform statistical analyses to assess the

independent contribution imparted by exposure to cocaine in utero on a

particular outcome. The developmental outcome of children exposed to

cocaine prenatally also may be influenced by maternal characteristics (race,

age, gravity, parity, history of sexually transmitted diseases, socioeconomic

status), maternal habits during gestation (prenatal care, nutrition and weight

gain, cigarette smoking, alcohol consumption, other drug habits), and additional

factors that influence maternal-infant interactions (maternal education, maternal

depression/isolation/ stress, home life, including marital status and social

supports, continued drug habits).

The Boston City Hospital study (Zuckerman et al. 1989) helps to clarify the roles

such individual factors play in fetal growth, thereby extending the findings of

previous prenatal analyses. These investigators emphasized this point by

contrasting bivariate comparisons with findings of their multiple regression

analyses on the same data. Bivariate analysis suggested that maternal cocaine

use (vs. nonuse, as defined by maternal urine screening) caused a statistically

significant (p<0.05) decrease in GA and increase in congenital anomalies (three

minor or one major). After controlling for potentially confounding variables, the

results of regression analysis revealed no independent statistical association

of maternal cocaine use with shorter duration of gestation or with an increase

in congenital malformation (p=.10 for three minor anomalies or one major

anomaly). These investigators noted that women in their study with urine

assays positive for cocaine weighed less and gained less weight during

pregnancy than women with assays negative for cocaine. By repeating the

regression analysis of infant birth weight without independent consideration of

maternal pregnancy weight and pregnancy weight gain, the magnitude of the

effect of cocaine on lowering birth weight increased (from 93 grams to 137

grams). The implication is that cocaine has a direct effect on decreasing fetal

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weight, as well as an indirect effect via maternal undernutrition. In summary,

studies that relate maternal cocaine habits to fetal outcome must incorporate

toxicologic screens to supplement self-reported drug histories, must consider

the contribution of potentially confounding variables associated with maternal

cocaine abuse, and must strive to identify markers that will predict subsequent

developmental compromise.

CENTRAL NERVOUS SYSTEM

Studies on newborns and infants that focus on markers for CNS insult can

be divided into clinical studies (behavioral, neurologic, and developmental

assessments), electrophysiologic studies (analysis of electroencephalograms

[EEGs], and evoked potentials), and imaging studies (employing head

ultrasounds [HUSs], and computerized axial tomography [CAT] scans). The

lack of long-term studies of neuroiogic, developmental, behavioral, and growth

outcome in children exposed to cocaine in utero reflects the recent emergence

and appreciation of the problem and emphasizes the additional difficulties

involved in longitudinal followup of this disenfranchised population.

NEUROBEHAVIORAL OUTCOME

Chasnoff and colleagues (1989) showed that a group of women who abused

cocaine solely during the first trimester did not have the increased risk of

preterm delivery, risk of having low-birth-weight infants, or increased rates of

intrauterine growth retardation (IUGR) that were seen in a group of mothers

who abused cocaine throughout pregnancy. These investigators employed the

Brazelton Neonatal Behavioral Assessment Scale (NBAS), a standardized

assessment of the pattern of an infant’s state change in response to external

and internal stimuli. Infant performance on 28 standard items is reduced to

cluster scores reflecting global function, including habituation, orientation, motor

performance, range of state, regulation of state, autonomic regulation, and

reflexes. In Chasnoff and colleagues’ study, 7 out of 16 infants born to mothers

who abused cocaine solely during the first trimester as well as 8 out of 36

infants whose mothers abused cocaine throughout gestation were unable to

reach alert states and were thereby unable to attend to visual or auditory

stimuli. Cluster-score comparisons between cocaine-exposed infants and a

control population demonstrated significant impairment of orientation, motor

ability, state regulation, and a number of abnormal reflexes when tested

between 12 and 72 hours of life. The implication of altered NBASs in infants

exposed to cocaine solely during the first trimester is that the window of biologic

vulnerability of developing brain to cocaine for subsequent behavioral effects

may be very early in gestation. This first-trimester insult may be independent of

second- and third-trimester effects of cocaine on fetal growth.

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Neurologic and developmental followup of infants exposed to cocaine was

reported by Rosen and Johnson (1988). They followed three groups of

pregnant women prenatally: Multidrug abusers (70 percent were using cocaine

with marijuana and/or mild to moderate intake of alcohol, and 30 percent were

using marijuana with or without alcohol); mothers on methadone maintenance;

and mothers free of substance abuse (during the second and third trimesters,

screened by history, and with serial urine evaluations in a prenatal clinic

setting). At birth each infant had a neurologic evaluation. Neurologic

evaluation and administration of the Bayley Scales of Infant Development were

repeated at 6 months and at 12 months. At birth, infants of polysubstance

abusers (70 percent of whom abused cocaine) had a 10-percent incidence of

abnormalities on neurologic exam. Neurologic exam was suspect to abnormal

in 21 percent of these infants at 6 months (compared with 16 percent of

controls) and in 6 percent of these infants at 12 months (vs. 4 percent of

controls), with normal Bayley scores, both mental development index (MDI) and

psychomotor development index (PDI) reported at both time points.

Chasnoff and Griffith (1989) published in abstract form a 2-year followup of

developmental scores (Bayley) and growth parameters in 125 infants exposed

to cocaine during gestation compared with 40 infants born to drug-free women.

Cocaine-exposed infants displayed a statistically significant decrease in

weight through 12 months of age (p<0.05), with normalization thereafter, but

demonstrated smaller head circumferences at all time points evaluated (through

24 months). There were no differences in the Bayley Scales (MDI or PDI) at

any of the time points assessed.

Dixon (1989), in reviewing a population of infants born to mothers who abused

stimulants during pregnancy (cocaine and/or methamphetamine), noted that

three-fourths of exposed infants had development quotients of less than 100

during the first year, with areas of fine motor and visual motor coordination

showing the greatest delays, with age-related decremental performance.

Dixon has observed that infants exposed to cocaine may go through a

secondary “withdrawal phase of neurobehavioral disturbance” at 2 to 8 weeks,

characterized by irritability, hypertonia, diaphoresis, mild hyperthermia,

hyperphagia, and hyposomnia. The most severely impaired of the stimulantexposed children had overt neuroiogic deficits, including spastic quadriparesis,

hemiplegia, microcephaiy, global delay, and seizures. More prevalent were

developmental problems, including altered adaptive behaviors during the first

year of life and delayed acquisition of language skills during the second year of

life.

In a review of infants exposed to multiple drugs in utero (the majority exposed to

a combination that included cocaine), Howard (1989) emphasized the deviant

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psychologic behavior evident in the mood states and ability to experience

pleasure during the first 2 years of life. She studied the emotional response of

20 18-month-olds when separated from their parent figures and described that

three-fourths of these infants “remained unsettlingly neutral in their emotional

response throughout the period of observation.”

ELECTROPHYSIOLOGIC STUDIES

Doberczak and coworkers (1988) prospectively studied serial EEGs in 39

neonates born to mothers abusing only cocaine (as confirmed by maternal

history and urine screening of both mothers and newborn infants). Initial EEGs

during the first week of life were abnormal in 17 infants, characterized by bursts

of sharp waves and spikes, which were multifocal in 14 of 17 tracings. All initial

EEGs showed features of background discontinuity. Abnormal tracings did not

correlate with historical data on route or quantity of maternal cocaine use or with

severity of neurologic signs (34 out of 39 infants displayed greater muscle tone,

brisk deep tendon reflexes, irritability, or tremors, most evident on day 3). Of

the 17 initially abnormal EEGs, 5 were normal at 8 to 19 days, and no infant

tested had an abnormal EEG at 3 to 12 months. Of note, clinical seizures were

not observed in any of these infants.

Kramer and coworkers (1990) reported on 16 infants exposed only to cocaine in

utero (documented historically and confirmed by urine testing of both mothers

and newborn infants). All infants examined within hours of birth demonstrated

multiple stereotypic events considered to be seizures, in addition to excessive

startle, irritability, and tremulousness. Clinical classification of seizures were

subtle in 10 out of 16, tonic in 2 out of 16, clonic in 3 out of 16, and focal in 1

out of 16 subjects (the only infant to demonstrate focal lesions on computerized

tomography [CT] consisting of recent bihemispheric middle cerebral artery

[MCA] infarcts). Seven of 16 had ictal EEGs, confirming the diagnosis.

Seizures were poorly responsive to therapeutic levels of phenobarbital and

phenytoin, alone and in combination. Five out of 16 infants continued to have

seizures (generalized, tonic, or tonic-clonic) after 6 months of age. Although

only 2 infants had extensive developmental testing, the investigators’

impression, based on clinical examination, suggested that all 16 children

revealed delayed motor milestones, which improved with age.

Shih and colleagues (1988) performed brain stem auditory evoked responses

(BAERs) in 18 newborns (within 6 days of delivery) who were exposed to

cocaine in utero (documented by history and by maternal and neonatal urine

screening) and in 18 newborns whose mothers were drug free (documented by

history and confirmed in a few cases with urine screening). Infants exposed to

cocaine in utero were somewhat younger (GA=37 weeks vs. 38 weeks in

controls) and smaller (birth weight [BW]=2,600 g vs. 3,400 g in controls). They

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showed that wave V was prolonged, as was the I-V interpeak latency in the

80dB condition in the cocaine-exposed infants. Prolongation of the Ill-V

interpeak latency for the cocaine-exposed infants was evident in the 40dB

and 80dB testing conditions. Since that report, data generated by other

investigators, presented in abstract form (Salamy et al. 1990) have confirmed

these findings of delayed brain stem transmission time in cocaine-exposed

infants (as determined by positive infant or maternal toxicology reports).

However, when cocaine-exposed infants were evaluated 52 to 65 weeks

postconception (3 to 6 months of age), they were no longer statistically

distinguishable from control values. Of note, two abstracts (Carzoli et al. 1990;

Schwartz et al. 1990) described studies where BAERs were not affected by

cocaine exposure in utero.

Anday and coworkers (1989) examined the effect of in utero cocaine exposure

(by history and by maternal and fetal urine screening demonstrating cocaine

only) on auditory augmentation of the glabeiiar eyeblink (startle) days to weeks

postdelivery. Nineteen cocaine-exposed infants were compared with 19 control

infants matched for GA and BW (GA=35.0 in cocaine-exposed infants, 34.8

in controls; BW=2,139 g in cocaine-exposed infants, 2,222 g in controls).

Cocaine-exposed infants demonstrated a higher amplitude glabellar eyeblink

and a statistically significant increased augmentation of eyeblink when the

glabellar tap was accompanied by a tone (startle).

Dixon and colleagues (1987) reported alterations in visual evoked responses

(VERs) in 12 term neonates exposed to cocaine in utero (neonatal urine

screens positive at birth). Flash VERs were abnormal in 11 out of 12 infants

studied, including gross hemispheric asynchrony with major positive wave

component delays (n=1), abnormal latency of major wave forms (n=1), and no

interpretable response (n=5). Of note, 11 out of 12 infants demonstrated

abnormalitles in EEGs described as disturbances in state organization, excess

sharp wave activity, and bursts of theta activity. Cranial ultrasounds were

normal in all infants.

NEUROIMAGING STUDIES

Chasnoff and coworkers (1986) reported a perinatai cerebral infarct in a fullterm, average for gestational age (AGA) infant born to a mother who used

cocaine intranasally during the first 5 weeks of pregnancy, then abstained

throughout the rest of her pregnancy until 3 days before delivery (5 grams) and

on the day of delivery (1 gram, 15 hours prior to delivery) with maternal and

fetal urine positive for cocaine only (and nicotine in the mother). The infant

displayed mildly decreased right upper extremity muscle tone at birth, and at 16

hours of life demonstrated multiple right focal motor seizures (right leg and right

arm). CT scan done at 24 hours of life revealed a wedge-shaped left MCA

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distribution acute infarction. Followup CT scan at 3 1/2 months showed

extensive cortical tissue loss in the left frontoparietal region (MCA territory

distribution). Chasnoff and coworkers (1989) reported a perinatal infarction in

an infant born to a mother who abused cocaine in the 2 to 3 days before

delivery. Kramer and colleagues (1990) published the case of a full-term 2-dayold infant exposed to crack in utero (documented by history and by urine

screening of mother and infant) with the onset of tonic left-upper-extremity

seizures associated with variable eye deviation and irregular breathing pattern

on day two of life. CT scan revealed recent large bihemispheric MCA

distribution cortical infarctions. Dixon and coworkers (1989) reported two

infants exposed to cocaine in utero (documented on infant urine screening) who

sustained perinatal cerebral infarctions confirmed by CT.

Dixon and Bejar (1989) reported HUS findings on or before day 3 of life in 32

full-term, “well” neonates prenatally exposed only to cocaine (defined by infant

urine screening). Forty-one percent (13 out of 32) of cocaine-exposed infants

had abnormal HUS studies, including white-matter cavitation (15.6 percent),

white-matter densities (12.5 percent), acute infarction (6.3 percent),

intraventricular hemorrhage (12.5 percent), subarachnoid hemorrhage (12.5

percent), subependymal hemorrhage (12.5 percent), and ventricular

enlargement (12.5 percent). The white-matter cavities, 3-10 mm cystic lesions,

were in the frontal lobes and in the basal ganglion. These lesions are

suggestive of prior hemorrhagic or ischemic injury, with secondary white-matter

cavitation, whereas white-matter densities are suggestive of acute hemorrhage

or infarction. Forty-one percent of “well” neonates exposed to cocaine

prenatally had HUS lesions, suggesting prior or acute CNS structural injury.

These infants with ultrasonographically definable CNS lesions could not be

differentiated from infants with normal studies on clinical grounds (no alteration

in anthropometric measures or specific neurobehavioral markers such as the

NBAS). Dixon is employing additional imaging modalities to follow this

population to assess degree of cerebral atrophy (on CT scans) and maturation

of myelination (on magnetic resonance imaging scans) to confirm and extend

the HUS findings.

SYNTHESIS

The data reviewed suggest the following:

1. Infants born to mothers who abuse cocaine during gestation demonstrate

impaired fetal growth. This appears to be mediated through an indirect

effect of poor maternal nutrition and a direct effect of cocaine. The

independent contribution of cocaine is a .43 cm decrement in head

circumference of the newborn.

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2.

3.

4.

5.

6.

Newborns of mothers who abuse cocaine during gestation (including

women who limit their cocaine habits to the first trimester) demonstrate

altered behavior, as evidenced by abnormalities in state control

(abnormalities on the NBAS), with difficulties in orientation/alertness being

the most affected.

Electrophysiologic studies suggest that newborns exposed to cocaine in

utero evidence CNS dysmaturation; that is, they characterize the cocaineexposed infant as being younger than chronologic age by demonstration of

more immature patterns of electrophysiologic activity.

Normalization of electrophysiologic testing and of neurologic testing occurs

during the first year, except in a minority of patients who sustain significant

structural insults (large vessel distribution infarction) or perinatal asphyxia

(related to acute dramatic placental insufficiency as in abruptio placentae).

A significant fraction of children exposed to cocaine in utero show evidence

of focal structural CNS damage. Most of this group identified with abnormal

cranial imaging is otherwise indistinguishable on clinical grounds.

A persistent deficit may be evident in delayed language acquisition,

cognitive impairment, and/or behavioral abnormalities in some children

exposed to cocaine during gestation as they get older. A clearer

characterization of the deficits evident in these children and the extent and

role that in utero cocaine exposure contributes to these deficits remain to

be determined.

In considering some future directions, clinical questions can be formulated at

the four levels of analysis previously discussed (Grimm 1987):

1.

2.

3.

Pharmacologic/physiologic—what are the mechanisms by which cocaine

can exert a toxic effect on developing brain (chronic-placental insufficiency,

nutritional compromise, acute-focal vascular injury, perinatal asphyxia,

recurrent-hypoxic ischemic injury, disruption of aminergic systems and

signals)?

Developmental level—what are the factors that influence the individual

susceptibility (e.g., maternal and fetal genetic factors) and window of

biologic vulnerability (drug dose, frequency, quantity, duration, timing with

respect to gestational age) of developing brain to the toxic effects of

cocaine?

Systems level—what are the brain structures and neurochemical systems

that subserve the behavioral or cognitive deficit?

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Clinicoanatomic and clinicobiochemical correlations await the application of

more sensitive anatomic methods, such as magnetic resonance imaging,

and dynamic imaging methods, such as positron emission tomography

scanning, which allow in vivo assessment of individuals at multiple

developmental timepoints to assess anatomic, metabolic, and chemical

integrity of specific neuronal systems and structures.

4. Behavior/cognitive level—what behavioral and cognitive deficits are evident

in children exposed to cocaine in utero? When do these deficits become

evident? What tests are available (or can be developed) to assess these

deficits and to identify their antecedents? What role do postnatal factors

(e.g., environment) play in the expression of these deficits?

The challenge for the next phase of clinical research on the effects of cocaine

on developing brain is to design studies that will provide meaningful answers to

these questions at each level of analysis.

REFERENCES

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cocaine exposure on startle and its modification. Dev Pharmacol Ther

12:137-145, 1989.

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nutrition during brain development in humans. Dev Neurobiol 12:271-286,

1989.

Bingol, N.; Fuchs, N.; Diaz, V.; Stone, R.K.; and Gromisch, D.S. Teratogenicity

of cocaine in humans. J Pediatr 100(1):93-96, 1987.

Carzoli, R.P.; Hammer-Knisel, J.; and Houy, J. Evaluation of auditory evoked

response in infants of cocaine abusing mothers. Pediatr Res 27(4):240A,

1990.

Chasnoff, I.J.; Bussey, M.E.; Savich, R.; and Stack, C.M. Perinatal cerebral

infarction and maternal cocaine use. J Pediatr 108(3):456-459, 1986.

Chasnoff, I.J., and Griffith, D.R. Cocaine-exposed infants: Two year follow-up.

Pediatr Res 25(4):249A, 1989.

Chasnoff, I.J.; Griffith, D.R.; MacGregor, S.; Dirkes, K.; and Burns, K.A.

Temporal patterns of cocaine use in pregnancy. JAMA 261(12):1741-1744,

1989.

Chavez, G.F.; Mulinare, J.; and Cordero, J.F. Maternal cocaine use during

early pregnancy as a risk factor for congenital urogenital anomalies. JAMA

262(6):795-798, 1989.

Cowan, W.M. The development of the brain. Sci Am 241(3):112-134, 1979.

Dixon, S.D. Effects of transplacental exposure to cocaine and

methamphetamine on the neonate (specialty conference). West J Med

150(4):436-442, 1989.

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Dixon, S.D., and Bejar, R. Echoencephalographic findings in neonates

associated with maternal cocaine and methamphetamine use: Incidence and

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Dixon, S.D.; Coen R.W.; and Crutchfield, S. Visual dysfunction in cocaineexposed infants. Pediatr Res 21(4):359A, 1987.

Doberczak, T.M.; Shanzer, S.; Senie, R.T.; and Kandall, S.R. Neonatal

neuroiogic and electroencephalographic effects of intrauterine cocaine

exposure. J Pediatr 113(2):354-358, 1988.

Ecobichon, D.J., and Stephens, D.S. Perinatai development of human blood

esterases. Clin Pharmacol Ther 14(1):41-47, 1973.

Evrard, P.; de Saint-Georges, P.; Kadhim, H.J.; and Gadisseux, J.F. Pathology

of prenatal encephalopathies. in: Child Neurology and Developmental

Disabilities. Baltimore, MD: Paul H. Brookes Publishing Co., 1989. pp. 153-

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Gold, M.S.; Washton, A.M.; and Dackis, C.A. Cocaine abuse: Neurochemistry,

phenomenology, and treatment. In: Kozel, N.J., and Adams, E.H., eds.

Cocaine Use in America: Epidemiologic and Clinical Perspectives. National

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Graham, K.; Koren, G.; Klein, J.; Schneiderman, J.; and Greenwald, M.

Determination of gestational cocaine exposure by hair analysis. JAMA

262(23):3328-3330, 1989.

Grimm, V.E. Effect of teratogenic exposure on the developing brain: Research

strategies and possible mechanisms. Dev Pharmacol Ther 10:328-345,

1987.

Howard, J. Cocaine and its effects on the newborn. Dev Med Child Neurol

31:255-263, 1989.

Hoyme, H.E.; Jones, K.L.; Dixon, S.D.; Jewett, T.; Hanson, J.W.; Robinson,

L.K.; Msall, M.E.; and Allanson, J.E. Prenatal cocaine exposure and fetal

vascular disruption. Pediatrics 85(5):743-747, 1990.

Kramer, L.D.; Locke, G.E.; Ogunyemi, A.; and Nelson, L. Neonatal cocainerelated seizures. J Child Neurol 5(1):60-64, 1990.

Lauder, J.M. Neurotransmitters as morphogens. Prog Brain Res 73:365-387,

1988.

Neerhof, M.G.; MacGregor, S.N.; Retzky, S.S.; and Sullivan, T.P. Cocaine

abuse during pregnancy: Peripartum prevalence and perinatal outcome.

Am J Obstet Gynecol 161(3):633-638, 1989.

Ostrea, E.M.; Brady, M.J.; Parks, P.M.; Asensio, D.C.; and Naluz, A. Drug

screening of meconium in infants of drug-dependent mothers: An alternative

to urine testing. J Pediatr 115(3):474-477, 1989.

Phillippe, M. Fetal catecholamines. Am J Obstet Gynecol 146(7):840-855,

1983.

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Ritchie, J.M., and Greene, N.M. Cocaine. In: Gilman, A.G.; Goodman, L.S.;

Rall, T.W.; and Murad, F., eds. The Pharmacologic Basis of Therapeutics.

7th ed. New York: Macmillan, 1985. pp. 309-310.

Rosen, T.S., and Johnson, H.L. Drug-addicted mothers, their infants, and

SIDS. Ann N Y Acad Sci 89-95, 1988.

Salamy A.; Eldredge L.; and Anderson, J. Effects of cocaine on brainstem

transmission time in early life. Pediatr Res 27(4):254A, 1990.

Schwartz, D.; Morris, M.; Civitello, B.; Spydell, J.; and Anday E. Lack of effect

of in utero on auditory brainstem evoked potential. Pediatr Res 25:348A,

1990.

Shih, L.; Cone-Wesson, B.; and Reddix, B. Effects of maternal cocaine abuse

on the neonatal auditory system. Int J Pediatr Otorhinolaryngol 15:245-

251, 1988.

Volpe, J.J. Neurology of the Newborn. Philadelphia, PA: W.B. Saunders

Company, 1987.

Vorhees, C.V. Concepts in teratology and developmental toxicology derived

from animal research. Ann N Y Acad Sci 562:31-41, 1989.

Woods, J.R.; Plessinger, M.A.; and Clark, K.E. Effect of cocaine on uterine

blood flow and fetal oxygenation. JAMA 257(7):957-961, 1987.

Woods, J.R.; Plessinger, M.A.; Scott, K.; and Miller, R.K. Prenatal cocaine

exposure to the fetus: A sheep model for cardiovascular evaluation. Ann

N Y Acad Sci 562:267-279, 1989.

Zuckerman, B.; Frank, D.A.; Hingson, R.; Amaro, H.; Levenson, S.M.; Kayne,

H.; Parker, S.; Vinci, R.; Aboagye, K.; Fried, L.E.; Cabral, H.; Timperi, R.; and

Bauchner, H. Effects of maternal marijuana and cocaine use on fetal growth.

N Engl J Med 320(12):762-768, 1989.

AUTHOR

Barry E. Kosofsky, M.D., Ph.D.

Research and Clinical Fellow

Department of Neurology

Massachusetts General Hospital

Harvard Medical School

Fruit Street

Boston, MA 02114

143
Discussion: Assessing Status of the

Newborn

Edward Z. Tronick

In their presentation at the technical review, Als and Duffy combined

neurophysiologic and neurobehavioral assessments into a single paradigm (Als,

this volume). This approach provides critical information on the effects of

lesions on particular neurophysiologic systems and on the functional pathology

resulting from these lesions. Much of the work in this area lacks the latter

type of information. As a consequence, little is known about the functional

implications of lesions on the functional status of the newborn and child. If the

scientific and human implications of drug exposure are to be understood, it is

critical that their lead be followed. This means that future work with humans

must utilize the most sophisticated physiologic, neurologic, and behavioral

measures available.

Two of the best standardized assessments of newborn functioning are the

Assessment of Preterm Infants’ Behavior (APIB) (Als et al. 1982) and its

parent, the Neonatal Behavioral Assessment Scale (NBAS) (Brazelton 1984).

These scales evaluate the infant’s capacities in a number of domains such as

orientation, self-regulation, habituation, motor control, and autonomic regulation.

Both scales are useful in providing a first picture of the effects of substances of

abuse on these areas of functioning. These assessments, however, need to be

followed up with more sensitive and sophisticated tests to examine in detail

areas of potential compromise. For example, motor dysfunction as found on

the NBAS can be followed up with computerized forms of kinematic analysis

(Fetters and Todd 1987), and autonomic dysfunction can be followed up with

an analysis of vagal tone (Lester 1983; Porges and Greenspan, this volume).

Such techniques are more objective and sensitive than omnibus assessments.

In addition, they overcome the problems of the halo effects of an observer

coding an entire behavioral assessment.

The assessment of infant functioning must take three forms. Examiners should

elicit the infant’s optimal and typical performances as well as his or her coping

responses to stress. Each of these approaches reveals something different

about the organization of the infant’s behavior, and taken together, they are far

144
more informative than any one technique. Eliciting optimal performance, as

demanded by the NBAS, uncovers the infant’s underlying capacities when the

infant is given as much support as possible by the examiner. This approach

may be most useful in understanding whether there is underlying residual brain

damage. For example, this approach helps determine whether a drug-exposed

infant can follow an object with smooth movements when the examiner has

minimized other interfering factors and has brought the infant into his or her

best state of consciousness. Tests eliciting the infant’s typical performance, on

the other hand, assess the infant’s capacities under normal handling conditions.

This method may be particularly relevant for understanding the effects that

the infant has on his or her caregivers, who, after all, are not necessarily

experienced handlers of newborns. Stressful evaluations—sometimes called

provocative tests—examine the infant’s regulatory capacities for dealing with

disruptive events. These tests often bring out underlying problems that are not

evident during either optimal or typical assessment techniques. However, these

tests are not as specific as the other two approaches. Stressful evaluations

disrupt the infant’s capacity to maintain homeostasis and behavioral state,

which, in turn, may disrupt the infant’s other functional capacities.

As emphasized by Kosofsky (this volume), the assessment of infant functioning

must be carried out serially. Serial assessment is required because, first of all,

in a rapidly developing organism, such as the human infant, both the organism’s

capacities and its progressive change—the capacity to develop—must be

assessed to evaluate the infant’s status. Second, as in all developing

organisms, exposure to drugs at different times during prenatal development

has different effects. A critical study—in full recognition of the difficulties

inherent in conducting such a study—would mimic a dose-related animal study.

Such a study would evaluate the effects of drug exposure by examining

subgroups of women who have used only cocaine only at certain periods (e.g.,

women who used cocaine during the first trimester only, the first and second

trimesters, and so on with different drugs and periods of use).

Obviously, from all the research presented in this monograph, the human

populations studied are not groups of infants exposed to only one drug but

groups of infants that have been exposed to multiple toxic factors. This, as

Zuckerman (this volume) notes, makes simply labeling a group as cocaineexposed a misnomer at the very least. More than likely, this labeling for drug

of preference from a drug history or for drug of record from a toxicologic

assessment is deceptive and serves to distort understanding. Many steps need

to be taken to correct this. One possibility is to carry out a study that examines

the effects of cocaine exposure in a population in which other risk factors are

minimized. It should be possible to identify and study a group of newborns

whose mothers have middle to high incomes, good medical care, and good

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prenatal care, and are well educated but who have used cocaine prior to

pregnancy, in the first weeks of pregnancy before pregnancy was identified and

then stopped its use, in the first trimester, and so on. The work by Striessguth

and colleagues (Streissguth and Giunta 1990) is a start in this direction.

Whatever the nature of the effects of intrauterine exposure on the newborn, it

must be understood that the infant is an active participant and creator of his or

her own development. As argued elsewhere (Tronick 1987), infants have a

developmental agenda of engaging the inanimate and social environments with

Increasingly sophisticated forms of behavior. Successful engagement requires

normal brain functioning and a capacity to regulate homeostatic and behavioral

states. When the infant is unable to regulate homeostatic or behavioral states,

his or her ability to maintain engagement is disrupted. Similarly, disruptions of

a specific function will compromise the infant’s state and preclude engagement.

For example, if a drug-exposed infant’s visual capacities are compromised,

then visual stimuli will stress the infant and disrupt other aspects of his or her

behavioral organization. The assessment task, then, is not only to uncover

dysfunctions but also to evaluate how these dysfunctions will lead the infant to

further compromise his or her own development.

Drug exposure in utero is not a one-time insult. Rather, it is likely to lead to

significant compromises in the developmental capacity of the infant that go well

beyond the initial insult. To the extent that these problems can be uncovered,

appropriate regulation from the environment can facilitate the infants capacities

to self-correct and achieve normal development.

REFERENCES

Als, H.; Lester, B.M.; Tronick, E.Z; and Brazelton, T.B. Manual for the

assessment of preterm infants’ behavior (APIB). In: Fitzgerald, H.E.; Lester,

B.M.; and Yogman, M.W., eds. Theory and Research in Behavioral

Pediatrics. Vol. 1. New York: Plenum, 1982.

Brezelton, T.B. Neonatal Behavioral Assessment Scale. 2d ed. London:

Spastics International Medical Publications, 1984.

Fetters, L., and Todd, J. Quantitative assessment of infant reaching

movements. J Mot Behav 19:147-166, 1987.

Lester, B.M. A method for study of change in neonatal behavior. In: Brazelton,

T.B., and Lester, B.M., eds. Infants at Risk: Assessment and Intervention.

New York: Elsevier, 1983.

Streissguth, A., and Giunta, C. “Subject Recruitment and Retention With

Special Reference to Population-Based Prospective Studies of Pregnant

Women and Their Offspring: A Nonintervention Model.” Paper presented at

146
the NIDA Technical Review Meeting on “Methodological Issues in

Epidemiological, Prevention, and Treatment Research on Drug-Exposed

Women and Their Children,” Baltimore, MD, June 25-26, 1990.

Tronick, E.Z. The Neonatal Behavioral Assessment Scale as a biomarker of the

effects of environmental agents on the newborn. Environ Health Perspect

74:185-189, 1987.

AUTHOR

Edward Z. Tronick, Ph.D.

Associate Professor of Pediatrics

Harvard Medical School

Chief

Child Development Unit

The Children’s Hospital

300 Longwood Avenue

Boston, MA 02115

147
Measurement of Drug-Induced

Physical and Behavioral Delays and

Abnormalities in Animal Studies:

A General Framework

Sheldon B. Sparber

INTRODUCTION

A technical review centered around methodological issues related to

experimental design and interpretation of data derived from studies on the

developmental effects of exposure of infrahuman species to drugs might seem

out of place in 1990. After all, one might imagine that there have been clear

and unambiguous demonstrations that drug exposure during development (i.e.,

in utero, during the postnatal developmental period, and perhaps exposure of

the gamete prior to fertilization) adversely affects physical and/or behavioral

parameters (and occasionally their underlying biological substrates) often

enough to accept such phenomena without question. Unfortunately, great

ambiguity exists. The key word is “exposure.” Accepting the notion that any

behavioral teratogenic or dysfunctional effect in offspring of pregnant subjects

administered a drug is the consequence of the drug acting directly on the

developing organism can be misleading. Most drugs have the potential to

cause indirect effects by virtue of their capacity to:

Cause hypoxic, ischemic, and possibly metabolic hypoxia or hypercapnia by

suppressing respiration, causing severe vasoconstriction, or interfering with

metabolic processes.

Induce malnutrition or undernutrition by suppressing food intake or altering

metabolic activity in pregnant dams (or during postnatal development).

Cause severe distress due to pain or inflammation at the site of injection

because of intrinsic properties (e.g., vasoconstriction) or physical-chemical

properties of the drug or its vehicle (e.g., pH, insolubility).

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Induce dependence, which itself may not compromise normal developmental

processes. However, consequences of withdrawal in utero or postnatally

may be more responsible for potential dysfunction than exposure per se.

It may not matter whether a dysfunction outcome of exposure of the fetus or

neonate is direct or indirect, if the agent of use or abuse is used by the pregnant

woman in a similar manner and route, and with relative doses similar to those

chosen by animal experimenters for their subjects. A cerebrovascular accident

(CVA), premature delivery with major complications, obvious dysmorphia, or

severe dysfunction in the child is no less important if caused by an indirect

rather than a direct drug effect. If these clinical outcomes can be mimicked in

the animal laboratory, such studies may offer insight into the prognosis for such

children and may help researchers understand the cause of the affliction so that

prevention or effective intervention strategies could be tried experimentally or

used in the clinic. However, as discussed below, by observations, it is illogical

to conclude that, in the absence of dysmorphia or obvious pathophysiological

consequences, there must be more subtle and insidious consequences of

exposure (direct or indirect) to much lower doses. Vorhees (1986) almost

argues such a case and, in his otherwise very good historical treatment of the

field of behavioral teratology, points to the leads derived from studies on the

dysmorphic effects of excessive vitamin A, salicylates, or other drugs, which

may produce behavioral teratogenic effects at doses that do not cause

anatomical changes or gross neurological symptoms. It is obvious that in the

case of salicylates or other drugs, pregnant women (or fetuses) need not be

exposed, if not absolutely necessary. However, it obviously is imprudent to

suggest that vitamin A, or even oxygen, which at excessive exposure levels are

toxic or potentially teratogenic, be eliminated from the pregnant woman’s diet or

environment.

In the case of most of the drugs of abuse that have been studied in animals,

the incidence of physical deformities (i.e., dysmorphia) attributable to drug

exposure is low. This is probably consistent with the clinical consensus.

Nevertheless, experimental protocols in behavioral teratology too often have

assumed that exposure should be only, or mainly, during periods of specific

organ developmental spurts (i.e., organogenesis). Thus, x-irradiation, large

doses of vitamin A, glucocorticoids, or other substantial insults are able to

induce structural deformities within organ systems that are undergoing cell

division and growth at their greatest rate during time of the insult. This design

may be inappropriate for functional teratology studies, and limiting exposure

to a specific stage in developing subjects could result in inappropriate

interpretations of data. Multiple factors should dictate experimental designs of

animal studies, the most reasonable and logical ones being related to the

149
probable manner in which the human fetus and/or developing child will be

exposed. Several of these factors are discussed below.

There are many ways to compromise behavioral pharmacology/toxicology

animal studies. These include the use of purchased, timed-pregnant subjects,

instead of attempting to breed four to five times as many females as are

ultimately needed, so that reasonably equal numbers of drug-exposed litters are

delivered at the same time. Not only is there a chance that excessive stress

during shipment of pregnant subjects may be responsible (entirely or in part) for

postnatal effects of interest to the investigator (Peters 1990) but it is also

possible that drug-inducible subtle dysfunctional effects may be masked by a

potentially greater effect of the stress that may attend shipping pregnant dams

under noncontrollable conditions. An associated problem is that of having to

start drug treatment some time after receiving pregnant subjects because they

were not bred in the laboratory—thereby missing an opportunity to expose

experimental embryos even prior to implantation (if not prior to fertilization of the

egg), which also may be more consistent with “modeling” human exposure.

Another reason why an experimenter may choose to start treatment of pregnant

subjects after implantation, even if laboratory bred, is because treatment of

dams earlier during pregnancy with the dose(s) chosen may not be compatible

with ovulation, normal implantation rates, and/or the successful outcome

of pregnancies that result in 90 to 100 deliveries of viable offspring. Such

a success rate is necessary if one wishes to determine if a drug insult is

potentially able to cause, directly or indirectly, long-lasting or permanent socalled dysfunctional effects in offspring exposed during development. In utero

or neonatal death, runting, or dysmorphia are sufficient indices to conclude that

the dose, route, time, or the interactive effects of all three are incompatible with

the normal growth and survival of offspring, but viable offspring are necessary

to study potential subtle dysfunction. It is the responsibility of the animal

experimenter to design and carry out prospective studies that approximate as

closely as possible the conditions and dosing schema that mimic human drug

abuse patterns, with the many identifiable variables that must be controlled.

Thus, data can be correctly interpreted and can be used for meaningful medical,

social, and regulatory policy decisions,

Basically, animal experiments using a drug as an independent variable can

be classified broadly into two categories. The first category asks questions

about whether exposure to illicit drugs in utero modifies developmental

processes. The second asks questions about the mechanisms that cause such

modifications. However, it would be premature to focus on the issue of whether

a sensitive period (Bateson 1987) exists for a drug-induced structural or

functional abnormality or to search for a mechanism—biobehavioral,

150
biochemical, or otherwise—before establishing that there is an unequivocal

reason to do so. For example, if an investigator wished to determine the

importance of GABAergic neurotransmission on the development of sleep-wake

cycles, or so-called state regulation, perhaps barbiturates or benzodiazepines

could be incorporated into the experimental protocol, along with agents that

“selectively” alter GABA synthesis, alter metabolism, or act as antagonists or

inverse agonists at one or more of the GABA receptors, if such drugs were

available. It also would be necessary to determine if the biochemical and

physiological “machinery” were present and functional during the particular

stage of development of interest, because most drugs suppress or amplify

function that already exists. It would not be a well-designed study if cocaine,

phencyclidine, methadone, or a host of other drugs were used because these

drugs do not have sufficiently selective GABAergic actions to be used as tools

to ask the experimental questions posed.

On the other hand, if it can be established that something related to cocaine

exposure during development interferes with normal sleep-wake cycles or

state regulation in utero or during the neonatal period, it may be of interest

to determine the importance of GABAergic neurotransmission for such

observations, if it were previously established that this transmitter is pivotal in

regulating such phenomena. However, if there were no evidence that state

regulation shifts associated with cocaine exposure are acutely dangerous (e.g.,

are associated with sleep apnea or sudden infant death syndrome [SIDS]) or

may be long-term markers for or potential causes of long-lasting dysfunction

after exposure to cocaine during development, investing significant resources

(intellectual, financial, or otherwise) to study cocaine in this manner may be

wasteful, even though the technological feasibility can be demonstrated or is

the forte of a particular laboratory.

The material introduced above can be summarized and extended in the

following way.

PURPOSES OF THE EXPERIMENTAL PROGRAM

An experimental program should ask fundamental questions about

developmental processes that can be modified selectively by drugs. In these

cases drugs are used, first, as tools to alter biochemical variables, such as

general metabolic processes (e.g., streptozocin to selectively destroy pancreatic

b cells, thereby causing hypoinsulinemic diabetes mellitus). Second, drugs are

used to alter nervous system communication by interfering with a specific class

of neurotransmitters (e.g., alpha-methyl-p-tyrosine to inhibit syntheses of

catecholamines or 6-OH-dopamine to selectively destroy one or more subtypes

of catecholamine cells). In instances where 6-OH-dopamine type neurotoxins

151
are to be used, it is important to know about the species differences in the rate

of development of the blood-brain barrier to such agents. This in turn will

dictate the route of administration and/or the need to use selective reuptake

blockers in conjunction with 6-OH-dopamine. Third, drugs are used to

determine If so-called critical or sensitive periods exist during development

when a selective insult may or may not cause (directly or indirectly)

developmental delays or functional abnormalities.

An experimental program also should ask if administration of drugs to pregnant

animals, developing animals postnatally, or in ova (for oviviparous species)

directly or indirectly causes developmental delays or functional abnormalities,

In these cases, the animal subjects and their various biochemical, physiological,

and/or behavioral processes should be used as tools to determine if therapeutic

doses of drugs (e.g., maintenance doses of methadone or treatment of

infectious diseases with antiviral or antibiotic agents) are potentially toxic or

teratogenic and to determine if and to what extent nonmedical use of or

detoxification from (i.e., withdrawal) prescribed or self-administered drugs is

potentially toxic or teratogenic. The subjects also should be used to search for

effective intervention strategies for alternative pharmacotherapy as substitutes

for drugs that are legally administered or illicit (e.g., contaminated with other

potentially toxic agents or of unknown concentration and, therefore, potency).

Under some circumstances, in the future it may be necessary to maintain a

pregnant woman on a drug to treat a pathophysiological condition and

coadminister another drug (agonist or antagonist) to the fetus to prevent or

reverse effects of the mother’s therapeutic agent. The obverse possibility also

may be a goal. Animal research may be directed at establishing the efficacy

and safety of such procedures,

Another purpose of the experimental program may depend on the goals of the

investigator, the physical and financial resources available, the nature of the

database on which the program is built, and the availability of appropriate

technology. These factors usually do not operate to influence such programs

individually but often operate in concert. Before questions relating to

fundamental mechanisms underlying desirable or undesirable developmental

effects of drugs are asked, it should be ascertained if such effects in an animal

model have been observed under conditions that appropriately model actual or

projected human exposure and if enough is known about the pharmacological

and/or toxicological properties of the experimental drug(s) in terms of its action

in mature subjects. For example, a drug class that causes severe respiratory

depression and/or vasoconstriction may affect a developing subject indirectly

by causing dangerous degrees of ischemia, hypertension, hypoxia, and/or

hypercapnia. Such knowledge is important and should be appropriately

considered. Pregnant women may self-administer toxic doses of cocaine,

152
which in turn can cause severe vasoconstriction, leading to hypertension and

fetal hypoxia, thereby affecting development indirectly. It therefore would be

valid to use such high doses of cocaine in experimental animals and/or to study

effects of similar degrees of fetal hypoxia, hypercapnia, and/or hypertension.

However, to use high doses of cocaine to induce fetal hypoxia, or in other

ways cause placental or fetal vasoconstriction to study the potential effects of

low doses of cocaine, may be as inappropriate as using low doses of cocaine

to study potential consequences of fetal hypoxia, hypertension, and

vasoconstriction or maternal hypertension and placental vasoconstriction. Just

as cocaine may have proconvulsant as well as anticonvulsant properties,

depending on the dose and situation (Russell and Stripling 1985, different

doses may produce different effects, including no noteworthy effect, and animal

developmental experiments should be designed to evaluate this range of

outcomes. It is obvious that doses of cocaine that produce CVAs and/or

convulsions in animals or humans threaten survival and are detrimental to

normal development and function. Fortunately, most cocaine-exposed infants

do not seem to have had a CVA and are not hemiplegic or epileptic. They may

or may not suffer long-term functional impairment directly attributable to passive

cocaine exposure. Polydrug abuse on the part of the mother, poor nutritional

status, lack of appropriate parenting, or other early experience factors may be

more important determinants of the social and cognitive development and

function of most “crack babies” than drug exposure per se. Large-scale, welldesigned, retrospective clinical studies employing sophisticated multivariate and

multiple-regression analyses, combined with well-designed prospective human

and animal studies in which a few variables are manipulated and/or adequately

controlled for, will be needed to determine the extent of damage suffered by

these children and its long-term consequence.

Questions have been raised about the safety of methadone treatment for

pregnant women and their offspring. However, the toxicologic effects of

methadone in animals have resulted from the use of high doses. Such doses,

often given only once a day (in spite of the fact that its duration of action and

plasma t1/2 are not sufficient to induce and maintain a stable degree of

dependence in a rat given the drug so infrequently), cause respiratory

depression, often leading to death in a significant number of pregnant

experimental subjects. Studies using these dosing regimens have not taken

into account fundamental principles of pharmacology and specific knowledge

already available to the investigator about the nature of methadone’s relatively

short duration of action in rats (i.e., relative to humans) and its acute toxicity,

and their findings are not applicable to women in methadone treatment

programs. Women enrolled in maintenance programs who become pregnant

are already tolerant to many of methadone’s acutely toxic or potentially

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teratogenic effects, such as its effects upon the endocrinium. Such tolerance of

the endocrinium may have allowed them to ovulate and become pregnant to

begin with, after stabilization on methadone.

At a time of limited resources, which include financial restrictions, inadequate

numbers of trained individuals, and pressures of inadequate time, investigators

and funding agencies must choose whether to study a particular agent in great

detail or to study several agents in lesser detail for safety and efficacy. Each

philosophy has its merits and drawbacks. If the goal of the funding agency

or investigator is to determine safety, at otherwise efficacious doses, it is

counterproductive to study the molecular, cellular, or behavioral mechanisms of

developmental toxicity of excessively large doses. Too little attention has been

paid to questions relating to why treatment of pregnant or developing subjects

has led to the many published reports of developmental delays and/or

behavioral abnormalities. In other words, it should be determined if it is

necessary to administer what often turns out to be overtly toxic doses of drugs

(i.e., lethal or capable of inducing severe morbidity) in order to observe more

subtle (i.e., behavioral teratogenic) effects. Also to be determined is whether

such observations are sufficient to conclude that, if it were possible to study the

appropriate numbers of subjects or if sufficiently sensitive measures were used,

behavioral consequences of insult during development also would have been

observed after lower doses. Such a philosophy is not embraced often enough

and denies the existence of threshold doses or concentrations of drugs, below

which there might be pharmacological efficacy with little or no toxicity.

Investigators are generally unaware of the number and quality of experiments or

clinical observations that do not result in noteworthy (i.e., published) results.

Such information would be extremely helpful in interpreting the reliability and

frequency of congenital anomalies in relation to the number of women and

children exposed to drugs. A recent report in the December 16, 1989, issue of

Lancet titled “Bias Against the Null Hypothesis: The Reproductive Hazards of

Cocaine” (Koren et al. 1989) is enlightening. These authors reviewed all the

abstracts submitted for presentation at the meeting of the Society of Pediatric

Research during a 10-year period (1980-1989). Only 1 of 9 (11 percent) was

accepted from those reporting no adverse effects of exposure to cocaine,

whereas 28 of 49 (57 percent) abstracts reporting adverse effects were

accepted for presentation. The studies that were “negative” and not accepted

for presentation verified cocaine use more often and generally had larger

sample sizes. Koren and colleagues argue convincingly that such a bias, in

the face of perceived teratogenic potential, may be responsible for excessive

numbers of women who have used cocaine sparingly during pregnancy

requesting termination by abortion. The authors go on to suggest that “it is the

duty of editorial boards, scientific committees, and funding agencies to

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acknowledge this serious bias and to indicate clearly that research results are

not more important if they are positive.” They also suggest that such “bias by

journals, scientific societies, and funding agencies against negative results may

have far-reaching detrimental effects. . . . This bias may lead scientists to

massage or misrepresent data to obtain positive results.”

The question of whether to study one or relatively few agents in greater

detail, compared with studying more agents in lesser detail, deserves some

discussion. One could easily be misled into believing that it is valid to

generalize between agents of the same class, if a few are studied in great

detail. This would be axiomatic if it could be agreed that all drugs of a class

differed only in their potency, for example, and not in their selectivity.

Unfortunately, the real world of pharmacology is not so ideal. Some drugs that

are classified broadly, based on therapeutic or illicit use, are structurally

dissimilar and/or have different actions or affinities for receptors other than

those to which they owe their therapeutic (or illicit) use. Amphetamine and

cocaine, for example, may owe their abuse liability to similar actions on a

specific central nervous system (CNS) function, but they also do not share

many properties (e.g., the ability to inhibit monoamine oxidase), nor are they

metabolized the same way, to the same products. Furthermore, amphetamine

is not metabolized by rats and humans in the same way, and if a metabolite

rather than a parent compound is responsible for one or more developmental

effects, generalizing from cocaine to amphetamine vis-a-vis developmental

effects in rats may be just as inappropriate as generalizing about

amphetamine’s developmental effects in rats to its effects in humans without

taking such factors into account.

METHODOLOGICAL ISSUES

The material above raises some philosophical issues that should be considered

by experimentalists prior to carrying out developmental drug studies with

animals. Following is a discussion of some methodological issues that speak

specifically to some of the concerns raised and to identify some ways to control

for identifiable and unidentifiable sources of variation that can contribute to or

be responsible for postnatal effects associated with drug exposure. In some

instances, identification of a secondary or tertiary effect may be important for

entirely different reasons. For example, significant anorexia coupled with

behavioral activation associated with cocaine or amphetamine administration

may lead to in utero and/or postnatal undernutrition. The undernutrition in turn

may be responsible for one or more structural (e.g., neuroanatomical) or

functional perturbations in “exposed” offspring. If similar nutritional deficiencies

attend human abuse of these drugs by pregnant women, the observation of

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such an effect in experimental animals is consistent with the protocol

approximating human use of cocaine and its consequences.

It also may be the case that an undernourished dam or fetus is more or less

vulnerable to other actions of the drug that caused the undernutrition. For these

and other reasons it would be important to control for the compromised

nutritional status by inducing a similar degree of undernutrition via a nondrug

procedure. A dose of drug given to the undernourished drug-experiencing dam

and the undernourished drug-naive dam should result in the same drug

concentrations in fetuses (and/or pregnant dams). Either pharmacokinetic

experiments can be used to this end or a sufficiently wide range of doses can

be given to pregnant dams fully nourished (i.e., ad lib fed) and to

undernourished dams, the assumption being that similar pharmacokinetic

factors would hold, for example, in a dam on free food given a higher dose of

drug and a dam on a drug-induced restricted diet given a lower dose of drug.

The null hypothesis being tested experimentally in this case would be that

undernourished pregnant dams and/or their offspring are more (or less)

vulnerable to an acutely toxic or congenital effect.

One of the major problems with such a drug study is that protective

mechanisms are available to the fetus and, whereas a pregnant dam may gain

considerably less weight as a result of drug treatment or restricted access to

food, the neonate may be born of normal weight in a normal-size litter. Even

when prenatal drug exposure is not a factor, the relationship between shortand long-term structural consequences and between structural and functional

consequences is not clear. (See, for example, Bedi [1987] and the discussion

that follows Bedi’s presentation.)

The issue becomes even more complicated when treatment with drugs (or

spontaneous withdrawal) postnatally is accompanied by retarded growth or

undernutrition. This dilemma is faced by practically every experimentalist

studying the in utero developmental effects of opiates (and drugs administered

via milk or via injection of neonates). Because a considerable degree of CNS

development continues into the first few years of human postnatal life, it is

sometimes necessary to manipulate rodents for 1 to a few weeks postnatally in

order to “model” the human condition. In the literature, different stages of

development of various parts of the CNS of different species are compared.

For example, the cerebellum (and to some extent parts of the limbic system)

shows substantial development postnatally in the rat. Therefore, the CNS

effects of drug treatment during development, which also is somehow

associated with retarded somatic growth of the neonate, should be interpreted

with caution. There also should be an attempt to determine experimentally if

the undernutrition (and/or associated stresses) may be responsible for the

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presumed direct drug effect, especially if children exposed passively to the

experimental drug when it is used by their pregnant mothers or while they

are nursing do not experience protracted undernutrition or experience any

undernutrition at all. One to several weeks of undernutrition in the rat

represents a considerably greater fraction of their lifespan than several weeks

of drug-induced or withdrawal-induced undernutrition in the human neonate.

Besides, lower maintenance doses of methadone, swaddling, and supplemental

parenteral feeding, if necessary, can be used to prevent or attenuate

withdrawal-induced effects in the human neonate. Nevertheless, practically

every animal study in which opiates are administered to pregnant rodents has

reported significant postnatal runtings of exposes pups. A critical review of the

literature (Lichtblau and Sparber 1984) as well as our own experiments have led

me to believe that most effects on growth are secondary to neonatal withdrawal

(or toxicity of milk-borne opiates). Moreover, Sparber and Lichtblau (1983)

have demonstrated that it is not necessary for neonatal rats to be exposed to

opiates and opiate withdrawal during development for them to be differentially

sensitive to opiates later in life, an effect that has been interpreted by others to

be proof of a selective, direct opiate action. It is sufficient for nondrug subjects

to experience very similar degrees of neonatal undernutrition, which include

reductions in brain weight and protein and nucleic acid concentrations similar to

those reported to be associated with perinatal opiate exposure (Sparber and

Lichtblau 1983). The juxtaposition of my discussion about the need to control

for such a source of variation in studies with drugs and the difficulties

encountered by experimentalists interested in developmental effects of

undernutrition per se on later CNS function is amply demonstrated by a recent

study from my laboratory in which Tonkiss and colleagues (1988) found

dramatically different changes in the brain parameters mentioned above in two

cohorts that were rendered “undernourished” via two different postnatal

manipulations. In both cases, body weight and length on postnatal day 10, at

the time nutritional rehabilitation was started, were identically reduced, about 35

percent and 17 percent, respectively. However, the manipulation that restricted

access to milk by forming excessively large litters (i.e., 20/litter) relatively

spared effects on the CNS. The other procedure (i.e., intermittent starvation by

giving the litters to nonlactating foster “aunts”) caused dramatically greater CNS

effects than did the large litter procedure (Tonkiss et al. 1988). Indeed, when

these groups were tested in adulthood for their ability to express acute

dependence on morphine, a divergence of effects again emerged (Cohen et al.,

in press).

There also is available a means by which the potential deleterious, long-term

consequences of opiate withdrawal can be studied without having to expose the

developing subject to opiates. Several drugs, including isobutylmethyixanthine

(IBMX), are capable of inducing a withdrawal syndrome in animals that is

157
virtually Indistinguishable from true opioid-type withdrawal. This quasi-morphine

withdrawal syndrome (QMWS) can be prevented by opiates, worsened by the

opioid antagonist naloxone, and attenuated by cionidine, which also attenuates

opiate withdrawal in humans and rats (Collier et al. 1981; Gold et al. 1978;

Kleven and Sparber 1989; Meyer and Sparber 1976). By administering IBMX to

rat pups, one should be able to study consequences of postnatal withdrawal

without the “confounding” effect of exposure to opiates. The same can be said

of exposure to withdrawal in utero, which we have reported to be more

detrimental than continued exposure to otherwise nontoxic maintenance doses

of the long-acting opiate I-a-acetylmethadol (for review see Sparber et al.

1986). Neal and Sparber (1991) and Neal and coworkers (1991) have found

evidence that mild QMWS during the neonatal period can cause significant

retardation in learning or performing autoshaped operant behavior and can

attenuate the expression of acute morphine withdrawal in adulthood. The dose

of IBMX administered over a few days during the neonatal period did not cause

significant weight loss compared with controls. This means that it is not

necessary to experience undernutrition similar to that often experienced by

opiate-dependent pups undergoing severe withdrawal. it is sufficient to

experience the stress of withdrawal and its attending biological consequences,

whatever they may be, to show long-lasting behavioral changes and differential

responsiveness to opiates in adulthood.

The results of these studies do not demonstrate that opiates cannot cause

similar or different behavioral or functional teratogenic effects, but they do

demonstrate ways in which one can design studies with appropriate methods to

control for secondary effects and/or uncover, at one or another level of analysis,

the mechanism of action whereby exposure to drugs during development can

affect function later in life.

I have chosen not to review the many arguments regarding when and when not

to use fostering and cross-fostering procedures, when it may be appropriate to

use more than one male and one female offspring from each outbred litter of

treated subjects, and why the litter should be used as the experimental unit for

statistical analyses of birth weight, eye opening, and other such variables that

are highly correlated within a litter. There have been adequate discussions and

reviews on these issues (e.g., see Abbey and Howard 1973), and I would

counsel investigators developing expertise in developmental biology and

behavioral teratology to seek advice and collaborations with knowledgeable

scientists and statisticians in planning studies. It is a pity when several personyears are spent only to discover that the data are useless because of poor

planning and wrong assumptions.

158
The question of which sex of the offspring to study for congenital effects of

exposure to drugs (or any other insult) is not now as important a problem as it

has been. It is now known that many of the effects (direct or indirect) of drugs

on transmitters, trophic factors, sex, and giucocorticoid or mineraiocorticoid

steroids can modify organizational processes (Lauder 1983) leading to sexrelated or -dependent structural and functional congenital effects. Sexual

dimorphic outcomes of stress, drug manipulations, or other manipulations of

pregnant subjects (Sparber 1974; McGivern et al. 1984; Meyerson et al. 1988)

make it mandatory that offspring of both sexes be studied. It is possible to miss

or misinterpret functional teratogenic actions of such manipulations if, as has

been the case In the past, only one sex (usually males, because of their

propensity for generating less variable data) is studied. There may be

opposite effects of drug treatment or stress during development on function or

responsiveness to drug challenge in adult male and female offspring (Kinsley et

al. 1988).

The recent interest in cocaine-exposed or so-called “crack babies” has resulted

in comparisons of routes of administration in nonpregnant and/or pregnant

experimental subjects, usually rats. It is a given that pregnant rats should

not be injected intraperitoneally with drugs because of multiple potentially

confounding effects, including the possibility of direct intrauterine injection,

locally large concentrations leading to great visceral vasoconstriction and

diffusion of drug unevenly across uterine walls, and so forth. Subcutaneous

administration of cocaine can lead to severe necrotic lesions and ulcerations at

the injection site (Bruckner et al. 1982; Dow-Edwards et al. 1989). It may be

difficult to induce identical lesions, systemic hypertension in the dam, and/or

vasoconstriction of placental vessels with other “control” agents such as

epinephrine and norepinephrine. However, if the subcutaneous route is to be

chosen for developmental drug studies, such controls are mandatory for

determining if the cocaine is producing any functional teratogenic effects directly

on the fetus or if stress of pain or other indirect actions of the cocaine are

responsible. Cocaine generally is self-administered intranasally, intravenously,

by smoking it, or by chewing leaves, It is reasonably well absorbed after oral

gavage. Inducing and achieving comparable fetal and/or maternal blood or

brain levels of cocaine and its major metabolites should lead to comparable

behavioral effects in the pregnant dam and/or her offspring if caused by cocaine

and not an epiphenomenon because of factors that are not clinically relevant.

Establishing equivalence of exposure by the least stressful means for the large

numbers of subjects required for developmental studies should be the initial

goal of every program studying cocaine’s action. If it is not plausible to have

pregnant dams self-administer cocaine intravenously, dosing schedules of

cocaine, using other routes, should attempt to bracket the dose and duration of

self-administration data available from the literature.

159
For example, Pickens and Thompson (1968) reported that rats would selfadminister about 6 mg/kg/hr intravenously over a 14-hour period of access to

0.25-3.00 mg/kg/infusion. By administering oral doses of 15 mg/kg/3.5 hr, three

times daily as a low dose and 45 mg/kg/3.5 hr, three times daily as a high dose,

Sparber and Kubak (1989) posited that such bracketing of the self-administered

doses reported by Pickens and Thompson would be a reasonable schedule for

treatment of pregnant rats with doses that approximated what they would have

self-administered over 12± hours. Nonpregnant female rats treated in this way

showed operant behavioral suppression 1/2 hour after treatment with a second

daily high dose, after a few days, no effect after the low dose, and no effect 3

hours after the high dose, before their next oral gavage. Sparber and Kubak

(1989) demonstrated that the cocaine had a behavioral effect in nonpregnant

females shortly after several days of oral administration of the high dose (i.e.,

there was some evidence of cumulative toxic effects when spaced about 3

hours apart over a 4- to 5-day period). Cocaine was administered orally to

pregnant rats that had been habituated to oral gavage with water prior to mating

(to reduce or eliminate stress of the procedure) during the last trimester of

pregnancy. A 12-percent reduction in weight gain by the last day of treatment

(gestation day 20) was the only obvious drug-induced effect observed in the

pregnant dams given the high dose (i.e., 145 mg/kg/day over 9 to 12 hours).

Seven days of treatment with the low dose (45 mg/kg/day) did not affect this

measure. No maternal mortality or fetal mortality was evident prior to or at birth.

Such a cohort, therefore, satisfies some of the requirements set forth previously

in this chapter for examining the possibility that exposure to cocaine during late

in utero life can cause congenital dysfunction of the CNS manifested as longlasting behavioral or neurochemical changes, relative to control offspring.

Because of the potential for indirect effects being responsible for treatment

outcome, or because placental, uterine, and other physiological and anatomical

differences of great magnitude exist between the rodent and human species, it

is important to carry out comparative studies with more than one infrahuman

species to assess the potential generalities of observations. The cost of

procuring and maintaining adequate numbers of primates for such studies

seems impractical and prohibitively high. My laboratory has been using the

developing domestic chicken embryo, fetus, and chicken for comparative,

parallel functional teratogenic studies. They are inexpensive, come with an

enormous database from experimental embryologists and poultry scientists, are

a renewable domesticated resource, and offer the advantage of being able to

study, even in ova, biochemical and behavioral variables associated with

exposure to drugs and other chemicals. Direct injection into the yolk, near the

embryo (chorioallantois) or via other routes can be easily accomplished,

depending on age of exposure, solubiiity of agent, and other factors (Seran and

Sparber 1988). Developmental pharmacologists and functional teratologists

160
might consider this species, along with a suitable rodent species, for

comparative experiments. Their phyiogenetic diversity would support the notion

that drug effects observed in the altricial mammalian (rodent), as well as in the

precocial avian (chick), if fundamentally similar, should generalize to most other

vertebrates, including humans (see Sparber et al. 1986 for a more extensive

review of such comparative studies).

Last, I would like to touch on the issue of when to study exposed offspring and

how long they should be studied. I have no difficulty with the premise that

behavioral development and drug effects on behavioral development are

important experimental topics. Developmental psychobiology has a long

tradition, and much can be learned much from its practitioners about

experimental design, statistical analyses, and early experience factors that

might interact with drug treatment to produce apparent behavioral teratogenic

effects. I am most concerned with the idea that demonstrating early postnatal

behavioral differences between drug-exposed and appropriate control offspring

is sufficient to conclude that such effects predict permanent dysfunction. To

accept this is to assume that there are no residual drug or withdrawal effects of

a transient nature or that plasticity, rehabilitation, and other forms of “catch-up”

cannot be expected. I also believe that it is mandatory that lifespan, or at least

long-term (i.e., to 1- to 2-year) studies be carried out with rats and comparative

long-term studies with other special species before one can conclude that there

is no functional teratogenic effect of exposure to a particular insult during

development. The aging process itself may unmask heretofore unrecognized or

delayed effects (Kolta et al. 1990; Meaney et al. 1988; Robbins et al. 1978).

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ACKNOWLEDGMENT

The preparation of this document and the research carried out in the author’s

laboratory described herein were supported in part by US. Public Health

Service grants DA-01880, DA-04979, T32DA-07097, and HD-20111.

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AUTHOR

Sheldon B. Sparber, Ph.D.

Professor

Department of Pharmacology, Psychiatry, and Psychology

University of Minnesota

435 Delaware Street, S.E.

Minneapolis, MN 55455

164
Regulatory Disorders I: Clinical

Perspectives

Stanley I. Greenspan

There is growing evidence that the effects of maternal prenatal substance

abuse on the developing fetus and the newborn infant are often indirect. Rather

than causing a specific physical or behavioral deficit, in many instances the

infant’s capacity for using sensory, motor, language, cognitive, or affective

systems for healthy adaptation is compromised. Depending on the type of drug,

pattern of usage (including pattern during various phases of pregnancy),

physical status of the mother (including her overall health and underlying

susceptibilities), as well as clinical conditions, one may see different types of

compromises in various aspects of the infant’s adaptive capacity and potential.

To understand the impact of prenatal substance abuse, this chapter presents a

new construct that focuses on the infant’s adaptive capacities. To be useful,

however, this construct must be highly specific in the way it organizes

understanding of these indirect compromises to the adaptation of the central

nervous system. In the context of behaviors and interactions between the infant

and his or her caregivers, the proposed construct will have certain advantages

over existing constructs that attempt to look at the infant’s innate capacities or

interactive behaviors.

For example, although an important and valuable literature exists on

“temperament” as a way of capturing the infant’s innate tendencies, most such

research relies on parental reports of the infant’s capacities, rather than on

“hands-on” assessment of the infant. In addition, most temperament constructs

tend to assume a general tendency within the infant toward such global

behaviors as introversion, extraversion, shyness, inhibition, outgoingness, and

so forth. These global behavioral tendencies may be secondary to highly

specific, hands-on, verifiable infant tendencies such as tactile or auditory

sensitivity or motor tone and motor planning difficulties.

As another example, there is a growing literature on attachment (e.g., Ainsworth

et al. 1974) and types of attachment difficulties using an experimental paradigm

that focuses on the infant’s reaction to a “strange situation.” While this

165
important body of work relates problems in later childhood to qualities of the

infant-caregiver attachment pattern in infancy, it ignores the infant’s individual

differences in terms of physical and maturational differences as an important

component of the infant’s adaptive capacities.

The model suggested in this chapter focuses on three important parameters of

the infant’s behavior: (1) the infant’s individual sensory, motor, cognitive

(including language), and affective differences; (2) infant-caregiver interaction

patterns; and (3) the caregiver-family and related cultural patterns. To look at

these variables in a highly specific manner, it has been useful to develope a

construct of regulatory disorders (Greenspan 1989, 1991). While the caregiverinfant relationship and family patterns are certainly not new ways of thinking

about infant and child behavior, this construct is a potentially useful clinical and

research model. It looks at the back-and-forth influence of highly specific,

verifiable constitutional and maturational factors on interactive and family

patterns (and vice versa). It also looks at the influence of these factors and

each of six developmental phases in relationship to later developmental and

psychopathologic disorders.

A regulatory disorder is a disturbance in the expected processes of regulation

that enable an infant to adapt to his or her own physical individual differences

and to the environment, including caregivers. The infant’s regulatory processes

that may be compromised include:

1.

2.

3.

4.

The ability to take in, modulate, discriminate, and comprehend impersonal

sensory and sensory affective experience. This ability is in evidence as

part of the infant’s capacity to attend to the world.

The ability to employ his or her developing motor system, language

capacities, and affective gestures to adaptively influence his or her

impersonal and interpersonal world.

The ability to accomplish 1 and 2 above as part of a calm, regulated state,

compared with states of hypoarousal or hyperarousal or excitability.

The ability to accomplish 1, 2, and 3 above in the context of increasingly

complex levels of organization, each of which adds demands and new

adaptive or coping capacities to the infant’s functional abilities. These

increasingly complex levels of organization include:

a. The ability to attend to multisensory affective experience and at the

same time organize a calm, regulated state and experience pleasure.

b. The ability to engage a caregiver with pleasure and evidence affective

preference for a caregiver.

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c. The ability to initiate and respond to two-way presymbolic gestural

communication.

d. The ability to organize chains of two-way communication (opening and

closing many circles of communication in a row), maintain

communication across space, integrate affective polarities, and

synthesize an emerging behavioral prerepresentational organization of

self and other.

e. The ability to represent (symbolize) affective experience (e.g., pretend

play, functional use of language). It should be noted that this ability

calls for higher level auditory and verbal sequencing ability.

f. The ability to create representational (symbolic) categories and

gradually build conceptual bridges between these categories.

This ability creates the foundation for such basic personality functions

as reality testing, impulse control, self/other representational

differentiation, affect labeling and discrimination, stable mood, and a

sense of time and space that allows for logical planning. It should be

noted that this ability rests not only on complex auditory and verbal

processing abilities but also on visual-spatial abstracting capacities.

It is important to note that each of these new organizational levels puts demand

on the infant to organize new types of experience. For example, engaging the

animate world or caregivers and becoming emotionally involved and dependent

on human relationships demand that the infant adjust to the unpredictable

behaviors, mood shifts, and frustrations of a real person. While infants can

bang a block on the floor and reliably hear a sound, they may not get back a

vocalization or receive a hug every time they vocalize or reach out invitingly with

their arms. When infants learn to use words and can form an internal picture of

their mother, they rely on the word and the picture to convey certain internal

feeling states such as security. The language and symbolic mechanisms

underlying this representational ability initially may not be as reliable as

mother’s continuing physical (and tactile) presence. Auditory or verbal

sequencing difficulties or sensory hyperreactivity or hyporeactivity in any

modality can easily compromise such emerging symbolic capacities. Yet, at the

same time, the ability to engage as well as the ability to represent or symbolize

experience provide great flexibility and new adaptive range for the growing

infant. In this respect, each new level of organization is, indeed, a “doubleedged sword.”

In considering the infant’s capacity for regulation and the various ways it can be

compromised, it is important to look at the processes that influence regulation,

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On one side of the equation are the infant’s constitutional and maturational

patterns. On the other side Is the infant’s environment, including caregivers,

family, community, and culture. These influences, however, are mediated

through the caregiver-infant relationship, which is the learning ground for the

infant. Here the infant either does or does not learn how to negotiate each

of the six levels of organization outlined in point 4 above. To picture this,

maturational and constitutional characteristics would be on the left; caregiver,

family, and cultural patterns on the right; the caregiver-infant relationship in

the middle; and the six levels of organization that the relationship attempts to

negotiate would be under the caregiver-infant relationship. For each of these

six levels, it is critical to understand the role of specific constitutional and

maturational characteristics and specific caregiver, family, and cultural patterns.

To specify the constitutional and maturational characteristics that should be

observed, the following list may prove helpful:

Sensory reactivity, including hyporeactivity and hyperreactivity in each

sensory modality (tactile, auditory, visual, vestibular, olfactory)

Sensory processing in each sensory modality (e.g., the capacity to decode

sequences, configurations, or abstract patterns)

Sensory-affective reactivity and processing in each modality (e.g., the ability

to process and react to degrees of affective intensity in a stable manner)

Motor tone

Motor planning

A new instrument to clinically assess aspects of sensory functions in a reliable

manner has been developed and is available (DeGangi and Greenspan 1988,

1989; DeGangi et al. 1988). At the same time, the characteristics of the

environment that relate to these constitutional and maturational characteristics

also can be systematized, as can characteristics of the parent-infant or

caregiver-infant relationship as it relates to the six levels of organization, A

discussion of these issues can be found elsewhere (Greenspan 1989).

BRIEF CASE ILLUSTRATION

The mother of an infant 7 1/2 months old worried that “he cries any time I try to

leave him, even for a second. If I’m not standing right next to him when he is

sitting on the floor, he cries and I have to pick him up. He’s a tyrant. He’s

waking up four times a night and is a fussy eater. He eats for short bursts

[breastfeeding] and then stops eating. I’m feeding him all the time.”

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The mother was feeling cornered, controlled, manipulated, and bossed around.

Her baby was like [my term] a “fearful dictator.” She said, “That’s the perfect

way to describe him.” The father was impatient with the mother; he felt that she

indulged the baby too much. He was getting “fed up,” because she had no time

for him.

The mother was frightened of aggression and was dependent on her own

mother. She wanted her baby to be happy (meaning no crying or discomfort),

and it made her “shake” to think that he could be uncomfortable. The father, an

angry sort of person, took the opposite approach—a “John Wayne,” tough-it-out

strategy. In interactions with the baby, each showed his or her characteristic

pattern.

The infant was very interactive and sensitive to every emotional nuance. As he

came into the room, he immediately caught my eye. We exchanged smiles and

motor gestures. He interacted with his parents with smiles, coos, and motor

movements. Father intruded somewhat. He would roughhouse until the baby

would cry, put the baby down, and then roughhouse again. Mother, in contrast,

was ever so gentle, but she had long silences between her vocalizations.

During her long silences, the baby would rev up, get more irritable, and start

whining. He whined with the mother and cried fearfully with the father. Even

before he could finish his motor gestures or vocalizations, his mother moved in

and picked him up, gave him a rattle, or spoke for him. In this way, she

undermined his initiative. Even while whining, however, he was interactive.

Physical examination showed this baby to be sensitive to loud noises, as well

as to light touch on the arms, legs, abdomen, and back. He had a mild degree

of low motor tone and was posturally insecure. He was not yet ready to crawl.

From a regulatory perspective, babies who are constitutionally most worrisome

are those who are oversensitive to the normal sounds and sensations of the

environment yet have poor control over their motor systems. Because of their

motor immaturity, they cannot do much to correct their sensitivities themselves.

They are passive victims of their own sensory and motor systems,

Mother, terribly frightened of her own and her infant’s potential assertiveness,

was not able to help her baby learn assertive coping because she was so

overprotective. At the same time, however, she was undernurturing, evidenced

most notably in the empty spaces in the rhythm of her speech. She was not

silent consciously. She wanted to do everything possible for her baby, but her

own depression and anxiety kept her from having a securing or soothing vocal

or gestural rhythm. The spaces in her vocal pattern conveyed a sense of

emotional emptiness. At the same time, father was impatient and moved in too

quickly. The baby was being challenged from all sides.

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Related to the mother’s patterns were worrisome fantasies that her baby

would be sick and not survive. These were related to anger at her own very

ambivalent mother. Behind father’s John Wayne approach was his relationship

to his own austere, tough-guy father. Father had been taught to “control” his

needs and longings very early in life.

In terms of mastering the first developmental challenge of shared attention

and engagement, the infant’s constitutional and maturational patterns did not

compromise development. This was an attentive, engaged baby. But at the

second developmental stage, intentional communication and assertiveness,

this baby was a passive reactor. He was not learning to initiate two-way

communication, to be assertive, and to take charge of his interactions. His low

motor tone was compromising his ability to control his motor movements. His

sensory hyperreactivity was compromising his ability to regulate sensation. He

was frequently overloaded by the basic sensations of touch and sound. At the

same time, he was not receiving support from his mother through nurturing and

rhythmic, self-initiating, fostering caretaking. Father obviously was not

supporting assertive communication either. The maturational patterns and the

family patterns played themselves out through the caregiver-infant interactions.

This family required therapeutic work on a number of fronts at once. The

infant’s special constitutional maturational patterns was discussed. Hands-on

practice helped the parents help their baby be attentive and calm. Also

addressed were how to play with the baby; how to get in front of him and help

him to take more initiative; how to help mother be more patient, waiting for him

to finish what he started; and how to support initiative (e.g., to put something in

front of the baby while the baby was on his tummy in order to motivate him to

crawl and reach). The mother was assisted in putting more affect into her voice

and to increase the rhythm and speed of her vocalizations; we worked on

getting the father to be more gentle. Other matters explored were the parents’

own feelings about the interactions—the father’s background, the mother’s fear

of her own assertiveness and of her baby being injured, and their own

associated family patterns.

Gradually, the baby began to sleep through the night and became more

assertive and less clinging and fearful. He also became happier. Because he

was slow to reach his motor milestones, an occupational therapist began to

work with him and to give the parents advice on motor development and

normalizing his sensory overreactivity. In 4 months, this infant was functioning

in an age-appropriate manner with a tendency toward a cautious but happy and

assertive approach to life’s developmental challenges.

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CHILDREN WITH SEVERE REGULATORY PROBLEMS

Some children who come in for treatment present with severe communication

problems, sensory underreactivity and overreactivity and processing difficulties,

motor delays, and “autistic features,” with the diagnosis of pervasive

developmental disorder or atypical development. Such children often have

problems at all the developmental levels described earlier—attention,

engagement, two-way gestural communication, and the symbolization of

emotions.

At each developmental level there are problems on all fronts-family,

maturation, and interaction. The constitutional problems with sensory reactivity

and processing (of a severe nature, especially auditory-verbal processing),

motor tone and motor planning, family system problems, parent-child interaction

problems, and the parents’ own reactions and fantasies about the child

undermine attending, forming relationships, being intentional, and using words

or complex symbols and gestures to convey needs or desires. Treatment

involves a comprehensive approach. Often, with these children, however,

professionals may try to work with splinter skills at the symbolic level and not

enough with the regulatory difficulties and the early levels of engagement,

shared attention, and gestural interactions. Play therapy four times a week that

focuses on all developmental levels, occupational therapy twice a week (for

some children), speech therapy twice a week, parent counseling once or twice a

week, and a psychoeducational program half days, five times a week are

elements of a comprehensive program.

With such a program, many children who have been treated in the past few

years have done remarkably well, better than one would have expected at the

start. Within 6 months, for example, withdrawn preschoolers are comfortable

with dependency and closeness, seeking out their parents, and learning to

be intentional. Within 1 year, they are beginning to symbolize affect and to

become comfortable with peers. Over time, specific severe learning disabilities

become the focus of treatment as the pervasive emotional difficulties improve

compared with children where the focus is on controlling behavior and splinter

skills. Working comprehensively on the underlying regulatory difficulties and

their associated emotional patterns leads to children having greater warmth and

spontaneity.

For each case, one must pinpoint the family system dynamics, the parents’

fantasies, the baby’s constitutional-maturational contributions, and the

caregiver-child interactions for each developmental level: attention and

engagement, two-way communication, shared meanings, and emotional

thinking.

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CONCLUSION

The infant and child’s ability for “regulation” can be viewed in the context of the

infant’s sensory, motor, interactive, and family patterns. Each of these variables

in turn, can, be viewed in the context of several developmental-emotional levels

of functioning. The model of regulation and regulatory disorders provides a

construct that is sensitive to an infant’s individual differences, family, and

environmental patterns, on the one hand, and his or her emerging adaptive and

psychopathological patterns on the other hand. It provides a bridging construct

between genetic, prenatal, perinatal, or early developmental variables and later

developmental outcomes. This type of construct may be particularly useful for

understanding the developmental course of conditions where multiple etiological

factors interact with one another or where the impact of certain etiological

factors is part of a dynamic system. In this respect, the model suggested here

may prove especially valuable for conceptualizing the impact of substance

abuse on development. It also has implications for constructing a

comprehensive treatment approach that can work with the multiple intervening

variables that influence the course of development.

REFERENCES

Ainsworth, M.; Bell, S.M.; and Stayton, D. Infant-mother attachment and social

development: Socialization as a product of reciprocal responsiveness to

signals. In: Richards, M., ed. The Integration of the Child into a Social

World. Cambridge, England: Cambridge University Press, 1974.

DeGangi, G.A., Berk, R.A.; and Greenspan, S.I. The clinical measurement of

sensory functioning in infants. A preliminary study. Phys Occupat Ther

Pediatr 8(2/3):1-23, 1988.

DeGangi, G.A., and Greenspan, S.I. The development of sensory functions in

infants. Phys Occupat Ther Pediatr 8(4):21-33, 1988.

DeGangi, G., and Greenspan, S.I. Test of Sensory Functions in Infants. Los

Angeles: Western Psychology Services, 1989.

Greenspan, S.I. The Development of the Ego: Implications for Personality

Theory, Psychopathology, and the Psychotherapeutic Process. Madison,

CT: International Universities Press, 1989.

Greenspan, S.I. The Psychology of Infant and Early Childhood Disorders:

Clinical Assessment, Treatment, and Prevention. Madison, CT: International

Universities Press, 1991.

AUTHOR

Stanley I. Greenspan, M.D.

7201 Glenbrook Road

Bethesda, MD 20814

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Regulatory Disorders II:

Psychophysiologic Perspectives

Stephen W. Porges and Stanley I. Greenspan

INTRODUCTION

Many infants exposed to drugs in utero have characteristics similar to a subset

of non-drug-exposed infants who have difficulty regulating their behavior.

These infants exhibit significant impairments in their ability to regulate internal

homeostatic processes (e.g., sleep patterns, digestion, general arousal) and in

organizing behavioral and physiological systems in response to environmental

challenges. This chapter discusses the behavioral and physiological

characteristics of the regulatory-disordered infant and how the construct of

regulatory disorders might be useful in the study of infants exposed to drugs in

utero.

The impact of prenatal drug exposure on the developing fetus and infant is

difficult to evaluate. The inability to control variables, either through selection or

manipulation, makes human research very different from animal studies and

highlights the methodological problems. For example, with human research, it

is not possible to control drug exposure or to remove all the confounding

variables related to outcome.

Drugs that increase the frequency of spontaneous abortions or massive

morphological abnormalities have been most easily detected. Prenatal

exposure to lead, alcohol, and thalidomide are historical examples. Yet, even

with these potent causal agents, the link between prenatal exposure and

outcome was not readily made. If the outcome characteristics are more subtle

related to neurophysiological, neurobehavioral, or socioemotional systems), it is

extremely difficult to develop causal links via traditional clinical observations.

Animal preparations have generally focused on the direct toxic effects of drugs.

However, toxicity may not be the major problem in dealing with the complex

(system that characterizes the human fetus within the intrauterine environment,

the drug-abusing pregnant woman within society, or the compromised

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caregiving capabilities of a drug abuser. It is possible that indirect and

interactive effects may contribute more to neurobehavioral debilitation than do

direct toxic effects.

Drug exposure can indirectly influence the fetus. For example, various drugs,

such as cocaine, have direct cardiovascular effects and can reduce the uterine

blood flood and, thus, indirectly compromise the fetus (van de Bor et al. 1990).

These indirect effects and interactions create problems in developing research

strategies and paradigms that will enable us to dissect the factors that are

related to prenatal drug exposure from the myriad social and health conditions

that, in themselves, are risk factors for developmental outcome.

Drug abuse does not exist independent of many other sociobiological factors

influencing the lives of pregnant women. Risks associated with drug abuse are

confounded, especially if the embryo-lethal or neurotoxic effects of the drugs

are minimal. For example, low birth weight is a risk factor whether it is or is not

associated with prenatal drug exposure. Causal arguments may be difficult to

make because many infants born of substance-abusing mothers experience

a variety of risk factors, including poorly managed pregnancies, teenage

pregnancies, highly stressed environments, and poor nutrition. In contrast to

these varied and interactive risk factors of pregnancy associated with prenatal

drug exposure, it is known that the offspring of these women are at extremely

high risk for problems associated both with adaptation to the extrauterine

environment and with normal neurophysiological regulation.

Similar to many high-risk infant populations, including premature and hypoxic

infants, infants exposed to drugs in utero exhibit significant impairment in their

ability to regulate internal homeostatic processes (i.e., sleep patterns, digestion,

general arousal) and to organize behavioral and physiological response

systems. These infants have deficient interactive abilities, emotional regulation,

motor maturity, and attentional and organizational responses to environmental

demands (e.g., see Chasnoff et al. 1985).

Before becoming too pessimistic regarding human research, let us deal with a

few issues. First, methods are improving that will allow the duration of exposure

to various drugs to be evaluated. For example, such sophisticated techniques

as meconium evaluations and radioimmunoassay of the hair may provide more

accurate detection and a potential evaluation of a time line of prenatal drug

exposure (Graham et al. 1989). Second, many of the interactive effects can be

statistically controlled. Third, methods of assessing neurobehavioral outcome

of these infants have improved. Methods using sophisticated techniques have

been developed to assess newborns, including acoustic evaluation of the infant

cry (Lester and Dreher 1989), extraction of a vagal tone index from the heart

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rate pattern (Porges 1988) neurobehavioral assessment of brain insult

(Gardner et al. 1990), and detailed quantification of behavioral patterns

(Brazelton 1973). Thus, researchers are becoming more successful in

describing the drug-exposed infant, even if the infant does not exhibit gross

abnormalities at birth.

To study the developmental sequelae of prenatal drug exposure, it is necessary

to have an appropriate model. In developing this model, the focus is on the

infant for two reasons: First, we are interested in assessing risk for these

infants and in developing appropriate interventions; second, it is the infant and

not the complex sociobiological context of the pregnancy that is most frequently

observed in clinical and research programs.

Regardless of the interaction with and confounding by other variables, the

neurobehavioral organization of many prenatal drug-exposed infants may be

described by two clusters of behavioral characteristics: hyperreactivity and

hyporeactivity. Hyperreactivity is associated with irritability, tremors, jitteriness,

and hypertonicity during early infancy. Hyporeactivity is associated with low

activity levels and hypotonicity. Both groups may have poor attention control

systems, state regulation, and digestive problems. Drug withdrawal may

exacerbate these symptoms.

The adaptive competence of the hyperreactive or hyporeactive infant provides

the basis for discussing regulatory disorders as a construct related to the

developmental outcome of infants prenatally exposed to drugs. The defining

characteristics of the regulatory-disordered infant and the theoretical relevance

of regulatory processes to cognitive and affective development have been

elaborated by Greenspan (1989). From a clinical research perspective,

Greenspan (this volume) describes observations of the behavioral, affective,

and cognitive characteristics of these regulatory-disordered infants.

The early regulation of arousal and physiological state is essential for

successful adaptation to the complex extrauterine environment. Infants must

accommodate to varying sensory challenges and maintain homeostatic

processes. The infant must be able to regulate sleep states, to digest food

effectively, to self-soothe in response to changing sensory stimuli, and to be

capable of contingent and appropriate responses to social stimuli.

In research with term and high-risk neonates, Porges (1988) identified

a physiological response system that seems to parallel many of the

neurobehavioral systems responsible for regulatory disorders. This system is

modulated by the vagus, a major component of the parasympathetic nervous

system. The vagus is a cranial nerve that conveys information from the brain

stem to many of the peripheral autonomic organs.

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In general, the vagal system is continuously functioning to maintain

physiological homeostasis. However, central nervous system responses

associated with perception or emotion may elicit immediate autonomic reactivity

via selective inhibition or excitation of vagal activity. Unlike its antagonistic

partner, the sympathetic nervous system, the vagus can respond rapidly to

foster the expression and regulation of autonomic reactivity. Moreover,

excursions from autonomic homeostasis arising from excitation may be rapidly

ameliorated by reflexive vagal activation. Thus, a well- functioning vagal

system should be associated with greater autonomic reactivity and more rapid

return to homeostatic level.

Vagal tone can be assessed by evaluating the amplitude of heart rate

oscillations mediated by the respiratory system. Usually, heart rate increases

during inhalation and decreases during exhalation. This component of heart

rate variability is often called respiratory sinus arrhythmia. In our research, it is

labeled v to emphasize that it is an estimate of vagal tone and is quantified

with a specific patented time-series-analysis technique (Porges 1985).

In investigations of the heart rate patterns of risk populations, differences in the

amplitude of respiratory sinus arrhythmia can be easily observed. In the study

of high-risk infants, Porges (1988) found that high-risk neonates have, in

general, lower vagal tone than do full-term infants. Moreover, within the highrisk sample, the developmental sequelae of the low-vagal-tone infant is different

than that of the higher vagal-tone infant. High-risk infants with low vagal tone

are more likely to suffer from apnea and to have poor long-term outcome.

With full-term neonates, the vagal-tone measure was associated with greater

irritability at birth (DiPietro et al. 1987) and higher Bayley scores at 15 months

(Larson et al. 1990). With 5-month-old infants, higher vagal tone was

associated with greater facial expressivity (Stifter et al. 1989). Thus, it appears

that vagal tone modulates behavioral, affective, and autonomic reactivity and

that many risk factors are associated with low vagal tone.

The vagal system is responsive to the changing needs of the organism. Often,

the vagal system will respond by selectively increasing or decreasing its

influence on the periphery. This might be observed as a withdrawal of vagal

tone to increase heart rate to support metabolic demands or an increase in

vagal tone to regulate polypeptides and gastric motility.

The adaptive success of the infant is not based merely on the tonic level of the

autonomic nervous system but also on the ability of the autonomic nervous

system to appropriately respond to environmental and internal challenges. For

example, we have studied vagal reactivity in preterms in response to gavage

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feeding. Vagal responsivity to orogastric stimulation is necessary for the

regulation of gastrointestinal hormones and motility. Thus, the clinical status of

the preterm infant might be related to vagal responsivity during gavage feeding.

However, Infants whose vagal tone increased during feeding and decreased

following feeding had significantly shorter hospitalizations. This effect was

independent of the gestational age, birth weight, baseline vagal tone, and the

occurrence and magnitude of transient bradycardias elicited by tube insertion.

In summary, independent of tonic basal levels, vagal responsivity to gavage

feeding can provide a measurable index of risk status (DiPietro and Porges

1991).

In other contexts, such as attention to the external environment or stress

associated with pain, the vagal system immediately reduces its influence on

periphery. For example, during circumcision there is a systematic reduction of

vagal tone during the invasive procedures, the degree of reduction being

related to basal levels (Porter et al. 1988).

Thus, we may hypothesize based on a large number of studies conducted

in our laboratory and in others that neonatal vagal tone is related to reactivity

and that low vagal tone is associated with clinical risk. Our research has

identified a second risk dimension related to vagal reactivity. We propose that

inappropriate and unreliable vagal responsivity is a physiological substrate of

regulatory disorders. Based on our previous studies relating high basal vagal

tone to irritability, we have approached the clinical problem of studying infants

with regulatory disorders. Therefore, in the study of hyperreactive regulatory

disordered infants, we would expect to identify a subset of infants who would

exhibit problems of vagal regulation in response to stimulation.

In our first study, we selected normal and regulatory-disordered 8-month-old

infants. We recorded vagal tone during a baseline condition and during the

administration of the Bayley Scales of Mental Development. In the normal

sample, the higher the baseline vagal tone, the greater the vagal withdrawal

during the task. This pattern also has been observed in normal adults when

evaluating the relationship between baseline vagal tone and changes during

sustained attention. For the regulatory-disordered infants, there was no

systematic relationship between baseline and vagal reactivity, although the

infants tended to have higher vagal tone during the baseline (DeGangi et al.

1991).

These infants were retested at 4 years on the McCarthy Scales of Children’s

Abilities. When the Bates dimension of fussy-difficult at 9 months was plotted

against the child’s score on general cognition, a very interesting relationship

emerged. Within the normal sample, the higher the level of cognitive

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performance, the greater the infant fussiness. These data are consistent with

other studies that have identified early irritability as a positive attribute (e.g.,

DiPietro et al. 1987). However, if we selected subjects with extreme irritability

and other regulatory problems (note that fussiness is merely one of the

dimensions required for the regulatory diagnosis), the relationship changed.

With this select sample, the greater the fussiness, the poorer the cognitive

performance. Moreover, as a sample, the regulatory-disordered infants had a

significantly lower level of cognitive performance. In a replication with an

independent sample, the relationship between baseline vagal tone and changes

in vagal tone was evaluated during both the Bayley test and the Fagan Test

of Infant Intelligence (Doussard-Roosevelt et al. 1990). The findings were

convergent. The regulatory-disordered infants had higher vagal tone and did

not exhibit a relationship between baseline vagal tone and suppression of vagal

tone during the attention-demanding tasks.

At 20 months, 42 infants from the second study were retested with a variety of

infant and maternal assessments. There was a striking stability of the fussiness

dimension, with a correlation of .72 and stability of the vagal-tone measure

during the Bayley test, r=.76. Moreover, important causal paths related the

difficult dimension, and not mental or motor development, to parenting stress

and to parenting self-esteem and marital satisfaction. Maternal mood state,

which was influenced by social support, contributed directly to marital

satisfaction and to parenting stress (Portales et al. 1990).

The identified causal paths relating infant difficultness to the family presents

a model that might be useful in studying infants and young children in a

substance-abusing environment. Substance abuse can affect the child and

family on a number of levels. Prenatal exposure might directly compromise the

young infant’s capacity to self-regulate. Maternal addiction might contribute to

maternal mood-state problems that would lead to parenting and family

problems. Also, the weak social-support system of the substance abuser might

contribute to these observed problems.

It is the authors’ belief that the regulatory problems of prenatal drug-exposed

infants, like those of most infants who exhibit regulatory problems, are

manifested in dysfunctional vagal regulation of autonomic processes. This

dysfunction would be manifested in attentional, emotional, sleep, and digestive

processes—all of which are dependent on vagal regulation.

The vagal system has been linked to drug exposure. In Science, a report (April

13, 1990) from the Federation of American Societies for Experimental Biology

described a study by Stephen W. Hull in which vagal reactivity was inhibited

and disorganized by cocaine. Moreover, current research at the National

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insititute on Drug Abuse Addiction Research Center, under the direction of Dr.

David Newlin, is demonstrating that marijuana and cocaine have massive and

rapid influences on vagal tone. Moreover, Newlin and colleagues (1990) have

demonstrated that low doses of alcohol block the normal vagal reflexes

associated with digestive processes.

It is possible that, via direct neurotoxic effects, various drugs such as cocaine

can influence the central cholinergic regulation and the parallel regulation of the

vagus. This might produce the behavioral characteristics of irritability and

emotional lability and the autonomic characteristics of sleep, arousal, and eating

disorders observed in infants who have been prenatally exposed to drugs.

Alternatively, reduced intrauterine blood flow may result in hypoxia or growth

retardation. These factors also may be causal in influencing the central

cholinergic system, which also influences vagal regulation. Thus, the

regulatory-disordered infant might exhibit autonomic hyperirritability caused by

defective central neural programs and mediated via neurotransmitters through

the vagus (for elaboration of this theory, see Porges 1991).

Measures of spontaneous vagal tone and changes in vagal tone during a

variety of psychological processes might identify the regulatory-disordered

infant. The results of our research on two independent samples provide

preliminary support for the vagotonic hypothesis. Our research has

demonstrated that the regulatory-disordered infant exhibits (1) atypical

spontaneous levels of vagal tone and (2) atypical changes in vagal tone during

sensory and cognitive challenges. These differences may reflect the difficulty

that the regulatory-disordered infant has in modulating the autonomic nervous

system to support the behavioral state required for attention and information

processing during cognitive activities (for a model relating vagal-tone

suppression to sustained attention, see Porges 1984).

CONCLUSION

The regulatory-disorder model is an important starting point in the study of the

neurobehavioral outcome of infants prenatally exposed to drugs. Many of the

behaviors observed in drug-exposed infants appear to be consistent with those

observed in regulatory-disordered infants. At the core of the regulatory

disorder appears to be the inability to appropriately inhibit both behavioral and

physiological reactivity in response to environmental demands. We have

speculated that similar inhibitory processes are required for a child to attend to

relevant stimuli. We believe that the successful accomplishment of many

adaptive processes, including sustained attention, requires systematic

modulation of vagal tone. The observed inability of the regulatory-disordered

infants to systematically regulate vagal tone may evolve into subsequent

developmental problems associated with attention skills and emotional control.

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Deficits in these processes would lead to general learning and emotional

problems. Followup evaluations of regulatory-disordered infants confirm these

speculations. Thus, the possibility exists that prenatal exposure to drugs and

postnatal stress associated with substance abuse environments may

compromise the infant’s ability to develop the regulatory processes necessary to

deal with the complex environment.

REFERENCES

Brazelton, T.B. Neonatal Behavioral Assessment Scale. Philadelphia:

Lippincott, 1973.

Chasnoff, I.J.; Burns, W.J.; Schnool, S.H.; and Burns, K.A. Cocaine use in

pregnancy. N Engl J Med 313(11):666-669, 1985.

DeGangi, G.A.; DiPietro, J.A.; Greenspan, S.I.; and Porges, SW.

Psychophysiological characteristics of the regulatory disordered infant. Inf

Behav Dev 14:37-50, 1991.

DiPietro, J.A.; Larson, SK.; and Porges, SW. Behavioral and heart-rate pattern

differences between breast-fed and bottle-fed neonates. Dev Psychol

23:467-474, 1987.

DiPietro, J.A., and Porges, S.W. Vagal responsiveness to gavage feeding as an

index of preterm status. Pediatr Res 29:231-236, 1991.

Doussard-Roosevelt, J.A.; Walker, P.S.; Portales, A.L.; Greenspan, S.I.; and

Porges, S.W. Vagal tone and the fussy infant: Atypical vagal reactivity in the

difficult infant. (Abstract.) Inf Behav Dev 13:352, 1990.

Gardner, J.M.; Karmel, B.Z.; Magnano, C.; Norton, K.I.; and Brown, E.G.

Neurobehavioral indicators of early brain insult in high-risk neonates,

Dev Psychol 26(4):563-575, 1990.

Graham, K.; Koren, G.; Klein, J.; Schneiderman, J.; and Greenwald, M.

Determination of gestational cocaine exposure by hair analysis. JAMA

262:3328-3330, 1989.

Greenspan, S.I. The Development of the Ego: Implications for Personality

Theory, Psychopathology, and the Psychotherapeutic Process. Madison, CT:

International Universities Press, 1989.

Larson, SK.; Porges, S.W.; and DiPietro, J.A. “Neonatal Psychophysiological

Assessment and 15-Month Developmental Outcome of Healthy Full-term

Infants.” Unpublished manuscript, 1990.

Lester, B.M., and Dreher, M. Effects of marijuana use during pregnancy on

newborn cry. Child Dev 60(4):765-771, 1989.

Newlin, D.B.; Byrne, E.A.; and Porges, SW. Vagal mediation of the effect of

alcohol on heart rate. Alcohol Clin Exp Res 14:421-424, 1990.

Porges, S.W. Physiological correlates of attention: Core process underlying

learning disorders. Pediatr Clin N Am: Symp Learn Disord 31:371-385,

1984.

180
Porges, S.W. “Method and Apparatus for Evaluating Rhythmic Oscillations in

Aperiodic Physiological Response Systems.” U.S. Patent 4,510,944. 16 Apr.

1985.

Porges, S.W. Neonatal vagal tone: Diagnostic and prognostic implications. In:

Vietze, P.N., and Vaughn, H.G., eds. Early Identification of Infants with

Developmental Disabilities. Philadelphia, PA: Grune and Stratton, 1988.

pp. 147-159.

Porges, S.W. Vagal tone: An autonomic mediator of affect. In: Garber, J.A.,

and Dodge, K.A., eds. The Development of Affect Regulation and

Dysregulation. New York: Cambridge University Press, 1991.

Portales, A.L.; Porges, S.W.; and Greenspan, S.I. Parenthood and the difficult

child. (Abstract.) Inf Behav Dev 13:573, 1990.

Porter, F.L.; Porges, S.W.; and Marshall, R.E. Newborn pain cries and vagal

tone: Parallel changes in response to circumcision, Child Dev 59:495-505,

1988.

Stifter, C.A.; Fox, N.A.; and Porges, S.W. Facial expressivity and vagal tone in

five- and ten-month old infants. Inf Behav Dev 12:127-137, 1989.

van de Bor, M.; Walther, F.J.; and Ebrahimi, M. Decreased cardiac output in

infants of mothers who abused cocaine. Pediatrics 85(1):30-32, 1990.

ACKNOWLEDGMENT

The research described in this chapter was supported in part by National

Institutes of Health grant HD-22628.

AUTHOR

Stephen W. Porges, Ph.D.

Professor

Department of Human Development

University of Maryland

College Park, MD 20742

Stanley I. Greenspan, M.D.

7201 Glenbrook Road

Bethesda, MD 20814

181
Discussion: Measurement of DrugInduced Physical and Behavioral

Delays and Abnormalities—A General

Framework

Joseph L. Jacobson

This chapter discusses the chapters of Sparber, Greenspan, and Porges and

Greenspan (this volume), then comments briefly on an important topic raised by

several authors in this volume, namely, the assessment of confounding

influences in drug studies.

Sparber makes an important and very helpful distinction between laboratory

animal studies that focus on whether a drug causes functional abnormalities

and those that ask fundamental questions about how drugs modify

developmental processes. In the former type of study, there is an emphasis on

degree of toxicity at different doses, thresholds below which no deficits are

observed, and on pharmacological agents that might protect the fetus from

adverse effects of the drug. These studies are more analogous to human

drug studies, where the focus is usually on whether and at what doses

developmental exposure impairs function. In both human and animal toxicity

studies, a range of developmental outcomes must be tested to evaluate the

safety of an exposure. Sparber’s second class of studies, which focus on

mechanism of action, are appropriate only after detrimental effects have

been demonstrated in either humans or laboratory animals. As noted in

Jacobson and Jacobson (this volume), although it is difficult to investigate

neuroanatomical and neurochemical mechanisms in human subjects, human

studies can contribute to the understanding of such mechanisms by

incorporating assessment procedures that are domain specific. Evidence of

lowered IQ scores provides little indication regarding which aspects of central

nervous system (CNS) function may be impaired, but a test indicating a specific

deficit in, for example, spatial memory would suggest possible damage to

hippocampus and related structures.

Several authors in this volume emphasize the accumulating evidence that

effects of developmental exposures to drugs are often indirect. This contrasts

182
with the classical teratogenic model, based on studies of x-irradiation,

thalidomide, and other substances, in which exposure during a critical period of

organogenesis causes a structural deformity with long-term implications for

function. Sparber emphasizes that deleterious effects of developmental

exposures to drugs are often indirect consequences of hypoxia, reduced blood

flow, malnutrition, or stress associated with withdrawal. At a different level of

analysis, Porges and Greenspan also point to indirect effects mediated by

environmental stress and lack of social support. An important working

hypothesis from classical behavioral teratology, which has influenced the work

of many in the field today, is that agents that produce gross CNS damage at

high doses are likely to be associated with subtle behavioral changes when

exposure occurs at lower levels (Hutchings 1978; Vorhees 1986). Whereas this

hypothesis remains plausible for agents that disrupt cell differentiation during

critical periods, it may not hold for substances that affect function indirectly.

Where hypoxia or malnutrition is the mechanism of action, deficits may be more

transitory or may occur only at very high exposure levels where fetal deprivation

is severe.

Sparber points out that one important goal of drug studies is to determine at

what dose levels a pharmacological agent may be “safe.” Citing data from an

important recent Lancet study (Koren et al. 1989), also noted by Zuckerman

(this volume), he suggests that bias by journals and funding agencies against

negative results and pressure from society to demonstrate deleterious effects

from illegal drugs have led to an overrepresentation of positive research results

in the cocaine literature. Although the concerns articulated are serious, it is

important to note that the scientific bias against negative findings has a sound

basis in research methodology. Inadequate sample size, insensitive measures,

and lack of research skill and/or precision all can lead to Type II error, that is,

failure to detect real effects. Therefore, the fact that pediatric journals may

publish more articles with negative effects is not, in itself, necessarily cause for

concern. On the other hand, evidence that the studies not accepted for

publication were more valid in the sense that they verified cocaine use more

often or had larger sample sizes does suggest that journal editors need to give

more serious consideration to the publication of negative results. Sound

research design always should be required in peer review journals. However,

due to the increased risk of Type II error, it may be advisable to subject studies

reporting negative effects to somewhat more stringent criteria in terms of

sample size, verification of exposure levels, and validity and sensitivity of the

outcome measures used.

Greenspan and Porges outline an important hypothesis suggesting that longterm effects of prenatal drug exposures on attention and learning may be

mediated by regulatory disorders, including sleep disturbances, difficulties in

183
self-consoling, and hypersensitivity to stimulation. This hypothesis focuses

attention on a dimension of human function first emphasized in Brazelton’s

pioneering work on newborns, which has received relatively little attention from

psychometricians. In addition, Porges has developed psychophysiological

measures involving vagal tone, which could facilitate identification of regulatory

disorders in drug-exposed children.

Porges and Greenspan point to evidence that infants exposed prenatally to

cocaine, alcohol, and other drugs appear to be at risk for regulatory disorders,

which they suggest may interfere with the attentional skills and emotional

control needed for learning during childhood. However, to date most of the

evidence of regulatory disorders in drug-exposed children comes from early

infancy when such disorders may be transitory and have little impact on

subsequent function. In their research on 4- and 7-year-old children exposed

prenatally to alcohol, Streissguth and associates (1984, 1986) reported deficits

in one aspect of self-regulation, sustained attention, which could be responsible

in part for the cognitive deficits observed in these children. Although there is

evidence that prenatal alcohol exposure also can have a direct impact on

neuronal development, the role of regulatory disorders clearly warrants further

investigation.

It has been noted that the failure of prenatal narcotics exposure to have a

negative impact on the Bayley Scales may be due to the limited sensitivity of

that instrument and does not necessarily indicate that no true differences exist.

This criticism points to the need for investigators to consider a broader range of

endpoints, including physiological and neuroendocrine, and potentially more

sensitive measures of cognitive function. It also underscores the importance of

focusing more attention on the sensitivity and validity of the measures used.

Inadequate measurement can substantially increase the risk of Type II error,

which is especially serious in teratological studies where, despite all caveats to

the contrary, a null finding is likely to be interpreted as evidence that a drug is

safe. Indeed, the only indication that a chemical may be safe is the failure of a

competent, comprehensive investigation to detect harmful effects. Therefore, it

is especially important to use highly sensitive and valid measures in this type of

study and to include sufficient numbers of highly exposed individuals so that, if

an effect exists, it will be detected.

Several authors in this volume allude to the difficulties associated with

controlling for confounding influences in human studies. For some

confounders, elegant experimental animal studies, such as those described by

Sparber for controlling for nutrition and drug withdrawal, can be very helpful.

Other confounders can be controlled by sampling subjects selectively to reduce

collinearity. More attention also needs to be paid to the reliability and validity of

184
the control variables used. Confounding influences are typically controlled

statistically by removing any variance attributable to the control variables before

entering drug exposure in a multivariate analysis. if exposure or outcome is not

adequately measured, there is an increased risk of Type II error. But, if control

variables are not measured adequately, the underestimation of their impact can

artificially inflate the variance attributed to exposure, increasing the risk of

attributing to the drug an effect that really is due to a confounder. An example

of this problem would be a study in which alcohol consumption and/or smoking

during pregnancy were assessed in a single dichotomous measure: Did the

mother smoke or drink alcohol? Unless smoking and drinking have the same

impact on development, neither exposure can be adequately assessed in a

single composite measure. Moreover, most effects of pregnancy drinking are at

high levels of exposure, yet most pregnant women drink at low levels. A

dichotomous measure may not be sufficiently powerful to detect the effects of

high-level drinking since most of those coded as drinkers will have consumed

very little alcohol.

More effort also needs to be devoted to identifying control variables that not

only are reliable and valid but also can be administered relatively quickly and

efficiently. Efficiency is important because there are so many potential

confounding influences that must be considered even though the confounders

are not the focus of the investigation. In some domains, such as

socioeconomic status (SES) and quality of intellectual stimulation by the parent,

valid and efficient measures have been developed. Thus, the Hollingshead

Scale has been shown to be a reliable predictor of early childhood cognitive

function (Gottfried 1985), and the HOME Inventory (Caldwell and Bradley

1984), which assesses parental input more directly, has been found to explain

variance in child performance over and above that attributable to SES (Brumitt

and Jacobson 1989; Gottfried and Gottfried 1984; Siegel 1984). Jacobson and

Jacobson (in press) have found that the Peabody Picture Vocabulatory TestRevised provides a quick, yet valid assessment of maternal cognitive function.

For other domains, however, such as familial stress or quality of maternal

support, more work is needed to develop measures that are both valid and

efficient to administer.

REFERENCES

Brumitt, G.A., and Jacobson, J.L. The influence of home environment and

socio-economic status on cognitive performance at 4 years. Abst Soc Res

Child Dev 6:203, 1989.

Caldwell, B.M., and Bradley, R.H. Home Observation for Measurement of the

Environment. Little Rock, AR: University of Arkansas Press, 1984.

185
Gottfried, A.W. Measures of socioeconomic status in child development

research: Data and recommendations. Merrill-Palmer Q 31:85-92, 1985.

Gottfried, A.W., and Gottfried, A.E. Home environment and cognitive

development in young children of middle-socioeconomic-status families. In:

Gottfried, A.W., ed. Home Environment and Early Cognitive Development:

Longitudinal Research. Orlando, FL: Academic Press, 1984.

Hutchings, D.E. Behavioral teratology: Embryopathic and behavioral effects of

drugs during pregnancy. In: Gottlieb, G., ed. Studies on the Development

of Behavior and the Nervous System. Vol. 4. New York: Academic Press,

1978.

Jacobson, S.W., and Jacobson, J.L. Early exposure to PCBs and other

suspected teratogens: Assessment of confounding. In: Greenbaum, C.,

and Auerbach, J., eds. Longitudinal Studies of Infants Born at Psychological

Risk. Norwood, NJ: Ablex, in press.

Koren, G.; Shear, H.; Graham, K.; and Einarson, T. Bias against the null

hypothesis: The reproductive hazards of cocaine. Lancet 8677:1440-1442,

1989.

Siegel, L. Home environmental influences on cognitive development in preterm

and full-term children during the first 5 years. In: Gottfried, A.W., ed. Home

Environment and Early Cognitive Development: Longitudinal Research.

Orlando, FL: Academic Press, 1984.

Streissguth, A.P.; Barr, H.M.; Sampson, P.D.; Parrish-Johnson, J.C.; Kirchner,

G.L.; and Martin, D.C. Attention, distraction, and reaction time at age 7 years

and prenatal alcohol exposure. Neurobehav Toxicol Teratol 8:717-725,

1986.

Streissguth, A.P.; Martin, D.C.; Barr, H.M.; Sandman, B.M.; Kirchner, G.L.; and

Darby, B.L. intrauterine alcohol and nicotine exposure: Attention and

reaction time in 4-year-old children. Dev Psychol 20:533-541, 1984.

Vorhees, C.V. Origins of behavioral teratology. in: Riley, E.P., and Vorhees,

C.V., eds. Handbook of Behavioral Teratology. New York: Plenum, 1986.

AUTHOR

Joseph L. Jacobson, Ph.D.

Associate Professor

Psychology Department

Wayne State University

71 West Warren Avenue

Detroit, Ml 48202

186
Postnatal Development of Cardiac and

Respiratory Control Following Prenatal

Drug Exposure

Ronald M. Harper

INTRODUCTION

Evidence of the effects of prenatal drug exposure on subsequent postnatal

cardiac and respiratory control is sparse. However, prenatal exposure to

particular agents results in the disturbance of several physiologic characteristics

in the newborn, particularly altered motor and sensory control systems and the

ways in which these systems interact. The activation of these systems is

closely allied with mechanisms underlying cardiac and respiratory control.

The integration of these physiologic systems with cardiorespiratory control

mechanisms during development raises several theoretical and methodological

issues.

The disturbed physiologic and structural characteristics following prenatal drug

exposure include growth retardation (Ryan et al. 1987; Chasnoff et al. 1987;

Zuckerman et al. 1989); disturbed sleep states (Dinges et al. 1980); disturbed

motor behavior, including tremors and extensor rigidity (Oro and Dixon 1987);

disruptions of normal breathing patterns, particularly during sleep (Chasnoff et

al. 1989; Ward et al. 1989a); evidence of exposure to extreme vasoconstriction

or hypoxia during fetal life (Telsey et al. 1988); and disruptions in the integrity

of sensory pathways or central processing of afferent activity (Church 1987;

Church and Gerkin 1988). At least some of the symptomatology associated

with prenatal drug exposure also may be characteristic of premature infants

because, at least superficially, particular characteristics such as retarded

growth and altered breathing patterns are shared in these populations. It is

the objective of this chapter to demonstrate the interaction of physiologic

mechanisms contributing to some of these signs that may be manifested in

these groups.

187
GROWTH AND DEVELOPMENT

Prenatal exposure to agents such as cocaine or marijuana results in adverse

growth effects, with infants exposed prenatally to cocaine exhibiting reduced

head circumference and diminished body weight (Ryan et al. 1987; Chasnoff et

al. 1987; Zuckerman et al. 1989), characteristics similar to those observed in

premature infants. The growth retardation may result from poor nutrition

associated with maternal self-neglect, from repetitive exposure to hypoxic

events induced by extreme vasoconstriction In the fetus and reduced blood flow

through the uterine artery (see below), or from other as yet undescribed cocaine

effects. Although prenatal opiate exposure exerts state organization changes

remarkably different from those of nonopiate substance exposure (see below),

certain aspects of birth weight and gross dimensions appear to be a function of

the amount of drug exposure, rather than whether the drug is an opiate or a

nonopiate (Dinges et al. 1980).

Normal respiratory patterning is dependent on age-appropriate development of

respiratory muscle and upper airway structures. Disproportionate growth or

retardation of structures within the upper airway might alter greatly the normal

sequence of respiratory patterning, particularly in certain sleep states, and the

potential for alteration of such development by prenatal drug exposure is

substantial (Lauder, this volume). Disturbances in upper airway structural

components are known to cause respiratory patterning difficulties, especially in

sleep; hypertrophy of the tongue musculature or enlarged tissue of the soft

palate, particularly when combined with micrognathia, leads to obstructive sleep

apnea (Harper 1988) (figure 1). Some animal models with recessed facial

structures, such as the English bulldog, are particularly prone to obstructive

apnea and early death (Hendricks et al. 1987). Thus, specific drug effects on

the development of craniofacial structures are particularly important because of

the potential influence of these structures on later respiratory function.

CARDIOVASCULAR SIGNS

The clinical cardiovascular dysfunction exhibited by infants who have been

exposed prenatally to drugs includes signs of ischemia or hypoxia suggestive of

repetitive exposure to extreme vasoconstriction. There is evidence that vessels

supplying the bowel have been affected, causing ischemia to that area (Telsey

et al. 1988). In addition, the incidence of cerebral vasculature abnormalities,

including ventricular bleeding, is excessive (Dixon and Bejar 1989) and there is

evidence of cerebral infarction (Chasnoff et al. 1986). Extreme vasoconstriction

should be expected from maternal use of cocaine because cocaine acts directly

to produce that effect when administered in animal models in which both

the mother and the fetus show transient hypertension following cocaine

188
FIGURE 1. Developmental disturbances in mandibular morphology,

particularly micrognafhia, can profoundly alter respirafory

patterning during sleep. Normal integrity of airflow is dependent

on respiratory cycling action of upper airway muscles, such as the

genioglossal fibers that move the tongue forward and dilate the

airway with each breath (A). REM sleep causes a relative loss of

tone in the tongue musculature, which enhances the possibility for

narrowing the airway; any additional condition, such as

micrognafhia (B), would cause the mass of the tongue to

approach even further the posterior pharyngeal wall and heighfen

the possibility for airway occlusion following negative pressure

generated by a descending diaphragm.

KEY: AW=waking; QS=quiet sleep; REM=rapid eye movement

SOURCE: Harper and Sauerland 1978, copyright 1978, Wiley-Liss

administration (Woods et al. 1989). Somewhat paradoxically, cocaine-exposed

neonates exhibit vasodilatory signs of abnormally dilated and “tortuous” iris

vessels (Isenberg et al. 1987). lsenberg and colleagues suggest that the

vasodilation may be a rebound phenomenon or that cocaine’s vasoconstrictive

effect acts on vessels downstream from the eyes.

Additional cardiovascular signs of prenatal exposure to cocaine include

elevated heart rate during quiet sleep. Heart rates are elevated over those of

189
controls both in normoxia and in hypoxic conditions (Woo et al. 1990); the

elevated rates during sleep are reminiscent of findings with premature infants,

infants who are at risk for sudden infant death syndrome (SIDS) (Harper et al.

1982), and infants who later succumb to SIDS (Schechtman et al. 1988).

Strong evidence exists that cocaine administered to the pregnant ewe enters

the fetal circulation, directly raises fetal blood pressure, and increases fetal

heart rate in addition to any indirect effects from maternal vasoconstriction and

diminished uterine artery blood flow (Moore et al. 1986; Woods et al. 1989).

Thus, fetal blood pressure effects resulting from exposure to cocaine are

greater than could be expected by hypoxia from uterine artery vasoconstriction

alone. In rats, cocaine readily passes to fetal brain tissue, where it particularly

stimulates metabolism in the female (Dow-Edwards 1989).

The consequences of repetitive extreme vasoconstriction and hypoxemia in

the fetus such as that induced by habitual cocaine use can be manifested

postnatally as local ischemia, as in the case of local bowel lesions described

earlier (Telsey et al. 1988). Repetitive exposure to hypoxia from

vasoconstrlction also has the potential to alter overall growth and development

of particular regions and to modify development of neurotransmitter release or

receptor responsivity. Major questions exist for the relative importance of

effects exerted by vasoconstriction on neural and other structural systems.

The cardiovascular sequelae of acute cocaine administration in animals are well

known and include tachycardia, greatly reduced heart rate variability, and

elicitation of a variety of conductive arrhythmias. Some of the arrhythmias

observed following cocaine administration follow patterns of extreme order

intermixed with other patterns; the patterning of cardiac R-R intervals (the time

between R waves of successive cardiac cycles) also follows an organization

of extreme order. Nonlinear dynamic procedures are of particular use in

assessing both the R-R interval and these moment-to-moment arrhythmia

patterns (Harper et al. 1989; Raetz et al., in press).

SLEEP STATES

Of all the considerations in assessing drug action on physiologic activity during

postnatal development, sleep state is of primary importance. Sleep state can

affect heart and respiratory rate and variability by a factor of two or more in

normal infants (Harper et al. 1983a). Differences between risk groups for SIDS

on measures of cardiac and respiratory control can disappear unless state is

controlled (Schechtman et al. 1988). Significant sources of cardiac variability,

such as respiratory contributions, emerge primarily in particular states (Trelease

et al. 1986). Adding to the complications of state are developmental changes:

190
The effect of state on physiology markedly changes with development, exerting

massive effects at some ages and minimal effects at others (Harper et al. 1976,

1983a). The temporal organization of state is useful in assessing neurologic

development in the infant, because abnormal numbers of arousals, prolonged

state durations, erratic circadian appearances of state, or abnormal “clustering”

of physiologic variables during particular states all may be indicative of

abnormal development (Monod and Pajot 1965; Monod et al. 1967; Harper et

al. 1983b).

The normal development of sleep state in the infant consists of 50- to 60-minute

epochs alternating between quiet and active sleep, modulated early in life by a

3- to 4-hour feeding rhythm and later (about 3 months) by single sleep periods

of 7 to 8 hours usually at night (figure 2). Premature infant sleep states are

more difficult to differentiate. Active and quiet periods can be differentiated at a

gestational age of from 3 to 6 weeks using several parameters and by single

measures several weeks earlier (Parmelee 1974). The normal development

of sleep state is characterized by increasing amounts of quiet sleep and

decreasing amounts of REM sleep, with the amount of quiet sleep doubling at 3

months over the newborn period. Because the relative proportion of REM sleep

to quiet sleep states changes so markedly at a time of peak risk for SIDS,

considerable attention has focused on the relationship between arousability

from each of these states and SIDS. Infants at risk for SIDS (Harper et al.

1981a) and infants who later succumb to SIDS (Schechtman et al. 1991) exhibit

alterations in organization of state, particularly at certain times of the night

(figure 3). Further examination of state organization in the prenatally drugexposed infant might contribute substantially to knowledge of mechanisms for

switching to an aroused condition to overcome potentially fatal challenges in

these infants.

Prenatal drug exposure can markedly affect the organization of sleep states.

Newborn infants who have been exposed chronically in utero to low-dose

methadone with or without heroin exhibit less quiet sleep and more REM sleep

than controls; infants fetally exposed to both opiates and nonopiates show

disturbed organization of sleep states (Dinges et al. 1980). Other investigators

describe a diminution in low-voltage, irregular state patterns and an increase in

“mixed” state patterns independent of the withdrawal syndrome even after

phenobarbital treatment (Stefanini et al. 1984).

Sleep state, arousal, and respiratory patterning are closely interrelated.

Disturbances in sleep state organization can interact with respiratory patterning

and greatly disturb the normal sequencing of breathing, The disorganization of

sleep states observed in prenatally cocaine-exposed infants can interact with

other physiologic activity such as respiratory patterning. The disorganization

191
FIGURE 2. (A) These traces illustrate the temporal organization of observerscored sleep states in a 1-month-old infant, together with the

corresponding changes in median heart rate (HRMD) and heart

rate variability (HRI, interquartile range) that accompany state

changes. Note that the REM states occur at approximately hourly

intervals and that heart rate undergoes a 3- to 4-hour modulation

(e.g., between 3.5 and 7 hours). (B) Spectral estimates of the

hourly organization of quiet and REM sleep development over

the first few months of life. The figure illustrates that multiple

temporal “organizers” operate on state timing, that this

organization matures, and that substantial physiological variation

accompanies each state.

KEY: AW=waking; QS=quiet sleep; REM=rapid eye movement

SOURCES: Harper et al. 1981a, copyright 1981, Academic Press; Harper

1985, copyright 1985, Academic Press

192
FIGURE 3. Binary plots of occurrence of waking across a 12-hour nighttime

recording period in eight infants who were siblings of SIDS victims

(SSIDS) and eight controls at 3 months of age. Note that the

SSIDS infants exhibited long interwaking periods and an absence

of short waking epochs. These findings suggest that these infants

at risk for SIDS tend to remain asleep and that they may exhibit a

relative “failure to arouse” from sleep when confronted with

challenges.

SOURCE: Harper et al. 1981b, copyright 1981, American Association for the

Advancement of Science

often consists of frequent arousals from sleeping states. Arousal events often

are associated with apnea in animal models (Baker and McGinty 1979).

Apneic occurrences may be concomitant with the transient hypertension

associated with an arousal episode, because a momentary rise in pressure

accompanies arousal events and momentary increases in pressure cause

suppression of diaphragmatic and upper airway activity, particularly if the

pressure rise occurs within a sleep state (Trelease et al. 1985). The increased

193
number of apneas observed in cocaine-exposed infants thus may reflect the

increased numbers of arousal events observed in these infants.

TEMPERATURE CONTROL: MOTOR AND RESPIRATORY INTERACTIONS

Both respiratory and cardiovascular patterning in infants depend heavily on

core temperature, although no descriptive data are available on temperature

regulation during sleep following prenatal drug exposure. Assessment of

temperature during different states Is important because rostral brain

temperature control mechanisms dissociate during REM sleep; that is, normal

mechanisms for controlling temperature are not operative during that state

(Parmeggiani 1980). Acute intravenous or intraventricular cocaine exposure

in adult cats leads to marked rises in temperature and tachypnea (figure 4)

(Harper et al. 1991). In rats the thermal response is apparently dependent

on ambient temperature, with hyperthermia accompanying high ambient

temperature (Lomax and Daniel 1990). Prenatal cocaine exposure has the

potential to greatly modify temperature-regulating mechanisms by interfering

with development of rostral brain regions, modifying neurotransmitters of

descending neural pathways, or altering receptors at the peripheral level.

Integrated Diaphragmatic Activity

Control

Cocaine

FIGURE 4. Integrated diaphragmatic electromyographic activity from a cat

before and 5 minutes following 5 mg/kg intravenous cocaine

administration. lntraventricular and intravenous cocaine

administration will raise respiratory rates rapidly in a cat,

approaching a fourfold to fivefold increase from baseline levels.

Time bar=1 second.

Prenatal cocaine exposure alters neural systems regulating motor control in a

significant fashion, since affected infants exhibit tremors postnatally; this finding

has been almost universal in the published literature (e.g., Chasnoff et al. 1987)

194
and anecdotal reports (M. Regalado, personal communication, February 1991).

Detailed characteristics of these tremors (e.g., frequency, amplitude, and

muscle distribution) have not been described, but it should be noted that a

major mechanism of many mammalian species for raising core temperature is

to produce high-frequency tremors, that is, shivering (Gordon 1990). One could

speculate that tremors associated with prenatal exposure to cocaine thus might

incidentally raise core temperature in the infant or the tremors may become a

learned response, to raise core temperature, in an infant for whom temperature

regulation is disturbed. The possibility of deficits in temperature regulation

existing in infants prenatally subjected to drugs should be considered when

questions related to swaddling of infants arise.

Motor Control

The tremors observed in infants exposed prenatally to cocaine may result

from a disturbance of motor control structures, perhaps by neurotransmitter

excess or depletion or supersensitivity of receptors. Tremors frequently are

concomitant with motor system neurotransmitter disturbance as evidenced

by the oscillatory motor activity observed in tardive dyskinesia of adults, a

syndrome specifically resulting from chronic use of benzodiazepine agents and

other neuroleptics (See and Ellison 1990). Chronic prenatal cocaine exposure

modifies benzodiazepine receptor densities in the rat model (McAllister et al.

1988); similar receptor modifications may take place in the human fetal brain

after long-term maternal cocaine use.

An additional postnatal motor pattern associated with prenatal cocaine

exposure is extensor hypertonicity, characterized by excessive activation of the

extensor musculature, at least during the waking state. Acute administration of

cocaine to adult ewes (Woods et al. 1989) or cats (Harper et al. 1991) results in

extreme extensor rigidity reminiscent of decerebrate rigidity. The extensor

rigidity observed in human infants prenatally exposed to cocaine is milder and

frequently described with reference to reactivity to stimulation. The excessive

muscle tone occurring in this condition most likely would generate heat beyond

normal values and may have the incidental effect of raising overall core

temperature (although that possibility has not been directly examined). if core

temperature is raised in these infants, tachypnea and fixed respiratory patterns

most likely would result, because respiratory pattern timing is heavily dependent

on core temperature (figure 5).

The relationships between core temperature and respiratory patterning are of

interest because of the supranormal temperatures found at autopsy in SIDS

victims (Stanton 1984). It is also of interest that one respiratory characteristic of

infants who later succumb to SIDS is a diminution of pauses in breathing of

195
Tremors

Increased core temperature

Elevated respiratory rate

FIGURE 5. This figure illustrates the possibility that motor activity, core

temperature, and respiratory rate are inextricably related.

Increased muscle activity leads to increased core temperature;

respiratory rate is heavily dependent on temperature.

from 4 to 30 seconds (Schechtman et al. 1991), suggesting a more fixed

respiratory patterning and perhaps a more “brittle” breathing pattern (i.e., these

infants are less able to cope with influences that lead to pauses in respiratory

cycling than normal infants). Siblings of SIDS victims also exhibit higher

respiratory rates and fewer apneas than controls (Hoppenbrouwers et al. 1980).

The relationship between SIDS and core temperature is speculative. However,

the interdependence of physiologic systems illustrates the potential for failure if

these interactions are altered. Thus, overall muscle tone, core temperature,

and respiratory patterning are inextricably related, and the effect of prenatal

drug exposure on neurotransmitters that regulate motor control or temperature

control inevitably also affects respiratory patterning.

Respiratory Control

Data on alterations of respiratory patterning following prenatal exposure to

drugs are much more sparse than reports of cardiovascular sequelae. The data

196
from infants exposed to prenatal cocaine suggest a variety of respiratory

patterning consequences, including enhanced periods of periodic breathing and

apnea of more than 6 seconds (Chasnoff et al. 1989). Infants of cocaineabusing mothers have abnormal arousal responses to hypoxia (Ward et al.

1989a), a finding that stresses the importance of potential drug effects on

organization of state as well as direct effects on respiratory control. In this latter

study, infants exposed to cocaine prenatally failed to make the transition from

quiet sleep to waking when subjected to hypoxia; two infants displayed extreme

periodic breathing and O2 desaturation. The diminished hypoxic arousal

responses are similar to responses observed in infants who exhibit “apnea of

infancy.” Cocaine-exposed infants also exhibit elevated catecholamines; mean

plasma norepinephrine levels in these infants show more than a twofold

increase from normal levels (Ward et al. 1989b).

The relationships among tremors, extensor motor hypertonicity, temperature,

respiratory patterning, and state organization may have some bearing on the

relationship of cocaine to SIDS. As mentioned earlier, SlDS victims have a

higher-than-normal core temperature following death (Stanton 1984). High core

temperatures could lead to tachypnea and to particular problems of breathing

control during REM sleep, when temperature control by rostral brain regions

appears to be greatly diminished or abolished (Parameggiani 1980). If core

temperatures of infants exposed in utero to cocaine are excessively high,

resulting from late-developing tremors and hypertonicity, the respiratory

consequences could be severe.

Acute cocaine administration results in extreme extensor rigidity in sheep and

adult cats. Cocaine is not alone in this characteristic; however, high-dose

opiate administration also results in extreme muscle hypertonicity and

respiratory depression (Lowenstein 1969). The respiratory depression may

result from direct action of opiates on brain stem respiratory regions. However,

because opiates cause extreme hypertonicity, respiratory cycling may be

masked by hyperactivity of breathing musculature, resulting in loss of airflow.

The consequences of the opiate-induced extreme hypertonicity may be similar

to those observed with cocaine; however, such muscle activation is followed by

rises in core temperature, which in turn may further alter “drives” to respiratory

patterning.

The possibility exists that in utero drug exposure can dramatically raise core

temperature in the human fetus, which then could alter spontaneous fetal

“respiratory” movements or subsequently alter responsivity of neural systems

that mediate respiratory or other motor patterning. Peripheral vasoconstriction

in the mother from cocaine use would raise maternal core temperature and fetal

temperature as well. Animal studies that manipulate temperature in fetal life,

197
through a uterine-implanted cooling apparatus or by cold fluid perfusion of the

fetal lamb (Gluckman et al. 1984), demonstrate significant temperature-related

breathing movement effects, including initiation of continuous respiratory

movements from respiratory muscle silence that are maintained for 15 minutes

after cooling ceases (Gluckman et al. 1984). It would be especially valuable to

assess the hyperthermic effects of prenatal cocaine on fetal breathing

movements.

In examining the influence of temperature on respiration, temperature effects

may be exerted differentially on upper airway musculature over the diaphragm

and thoracoabdominal musculature; some of these effects may be particularly

exerted on expiratory rather than inspiratory aspects of the respiratory cycle.

For example, Johnson (1988) demonstrated the necessity for laryngeal

constrictors to maintain thoracic volume in young lambs, a mechanism familiar

to every neonatologist who has listened to newborn “grunting,” a mechanism

used frequently to “rest” the diaphragm under conditions of excessive load. The

laryngeal constrictors are under separate control from the phrenic motoneurons

controlling the diaphragm, and control of these output neurons to the larynx is

mediated by separate central neural pathways, including the periaqueductal

gray projections to laryngeal motoneurons (Holstege 1989). These descending

projections may use very different neurotransmitters than neural mechanisms

mediating cyclic diaphragmatic action. Such neural transmitters may be

affected differentially by drugs of exposure during fetal development.

SENSORY INTEGRATION

A major concern in examining the function of any complex integrative system

such as that involved in respiratory patterning or cardiovascular control is the

integrity of afferent systems. These systems determine the sensory properties

of chemical, chest wall expansion, irritant, and airflow stimulation (in the case of

respiration) and baroreceptor, temperature, and chemical stimulation, among

other sensory sources, for the cardiovascular system. Thus, if prenatal drug

exposure alters thresholds in afferent systems that sense CO2

 or hypoxia,

respiratory pattern control systems dependent on such chemical senses

obviously would be affected. Similarly, respiratory timing is heavily determined

by afferent activity from lung and chest wall stretch receptors to switch

respiratory phases; similarly, alterations in this sensory system would greatly

affect respiratory patterning.

Although prenatal drug exposure may alter these sensory systems, little

information is available on prenatal drug exposure effects on these sensory

processing systems; however, the available clinical data suggest that prenatal

drug exposure can cause substantial damage to primary visual and auditory

198
sensory systems. Prenatal cocaine exposure alters visual evoked potentials

(Dixon et al. 1987) is associated with dilated vessels in the iris (as described

earlier), and has been implicated in subsequent microphthaimia, persistent

hyperplastic primary vitreous, and retinopathy of prematurity (Teske and Trese

1987). Infants with a diagnosis of fetal alcohol syndrome have a greater

probability of exhibiting a variety of visual system abnormalities (Stromland

1985). Similarly, the auditory sensory system can be damaged severely with

early alcohol or cocaine exposure, with altered auditory evoked potentials in

infants and animals, and a variety of structural signs in animals, including

cochiear damage (Church 1987; Church and Overbeck 1989). These

alterations in specific sensory systems of vision and audition suggest that other

sensory systems directly related to cardiac and respiratory patterning might be

affected as well. Dopamine receptors in the carotid body likely would be

affected by prenatal cocaine exposure, for example, and the excessive levels of

catechoiamines found in drug-exposed infants might well interact with these

sensors, Although the information on drug effects on such sensory systems is

meager, a chemical sensory process closely allied to the afferent system used

to assess CO2

, namely the olfactory system, appears to be altered in behavioral

tasks in rat pups exposed to cocaine (Spear et al. 1989). This may be

an integrative task deficit rather than a specific sensory deficit: cocaine

preferentially concentrates in olfactory mucosa of fetal mice (Brittebo 1988).

The olfactory system shares many neuroanatomical projections with the

respiratory chemosensory system and may provide an important source of

“drive” to respiration by sensing nasal airflow; disturbance to the olfactory

system not only might directly alter respiratory patterning but also suggests that

the chemosensory system may be similarly damaged by prenatal drug

exposure.

EEG

The first few months of life in normal full-term infants are accompanied by

characteristic electroencephalogram (EEG) changes as measured by spectral

procedures or by raw traces (Schulte and Bell 1973; Parmelee 1974; Sterman

et al. 1977). Preterm infants exhibit EEG traces markedly different from those

of full-term infants; in particular, the traces of preterm infants exhibit significantly

lower amplitude spectral values at different bands and lower amplitude photicevoked responses than those of full-term infants (Duffy et al. 1990). The

premature infant quiet sleep EEG pattern (until 40 weeks conceptional age)

typically consists of a “burst and flat” pattern (trace alternant); at 3 to 8 months,

the most prominent pattern is slow waves with 11-14 Hz spindles (Parmelee

1974). In REM sleep, the premature infant EEG consists of occasional slow

waves occurring in conjunction with low-amplitude faster activity; after 40 weeks

conceptional age, 4-6 Hz activity appears. The characteristics of any one state

merge with those of other states in the very young infant.

199
There are limited data available on modification of infant EEG characteristics by

early drug exposure. Any assessment of such data must be interpreted in the

context of sleep states and must recognize the frequent arousals or transitions

from different states observed in these infants. Acceleration in development

of particular EEG spectral bands has been noted in infants at risk for SIDS

(Sterman et al. 1982). Development of “coupling” or interpendencies between

bilaterally recorded EEG signals may be of assistance in quantifying EEG

development postnatally.

Assessment of EEG should be constrained by a realization of what the

underlying signals represent, the differential distribution of EEG signals on the

skull, the multiplicity of influences on cortical EEG, and the relatively scant

knowledge of effects of neurotransmitter depletion/excess on such activities.

Multiple “arousal” systems may activate the EEG, operating through the classic

thaiamic systems (Steriade et al. 1982) and through ascending ventral systems

rising through the basal forebrain, which can elicit arousal even in the absence

of the thalamus (Vanderwolf and Stewart 1988). “Arousal” here is defined as a

desynchronization of the EEG, or a reduction in slow waves. Considerable

evidence exists that EEG “arousal” can be dissociated from behavioral arousal;

high-amplitude slow waves can occur in an atropinized animal, for example,

although the animal can be extremely alert (Wikler 1952). It also now appears

that at least two major neurotransmitters, a cholinergic system and a

serotonergic system, may underlie these EEG arousal systems (Vanderwolf

and Baker 1986). The serotonergic system may be of particular interest in

this context because of the role this neurotransmitter plays in modulating

temperature and motor activity as well as the possibility for interaction with other

agents to cause structural deficits in prenatal life (Lauder, this volume).

Prenatal drug effects on the serotonergic system thus may have profound

indirect effects on respiratory control, particularly within the context of state.

SUMMARY

Of primary importance in the consideration of animal models of prenatal drug

exposure is the recognition of interdependence among physiologic systems, the

pervading influence of sleep and waking states, and the potential Interaction

between drug-induced structural changes and physiologic function. It is difficult

for a drug effect on the cardiovascular system not to modify respiratory pattern:

any change in blood pressure, systemic perfusion, or heart rate is immediately

reflected in breathing; respiratory pattern, in turn, through negative thoracic

pressure and other sensory activity, can alter cardiac patterning. The

respiratory system itself is one component of a somatic motor system, and

neural motor control structures undergo substantial modification by drug action.

200
Enhancing or diminishing any aspect of interaction is the influence of sleep

states, which nonlinearly can alter relationships between physiologic systems,

occasionally dissociating systems, as in the case of temperature effects on

breathing during REM sleep. Finally, drug-induced structural changes that alter

morphology of the upper airway can result In obstructive respiratory events,

leading to pronounced cardiovascular sequelae.

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ACKNOWLEDGMENT

This research was supported by National Institute on Drug Abuse grant DA04913.

AUTHOR

Ronald M. Harper, Ph.D.

Professor

Department of Anatomy and Cell Biology

University of California at Los Angeles

Los Angeles, CA 90024-1763

205
Endocrine Function as a Target of

Perinatal Drug Effects: Methodologic

Issues

Cynthia Kuhn, Diane Ignar, and Rolf Windh

INTRODUCTION

Gestational exposure to many drugs of abuse, including ethanol, marijuana,

cocaine, and heroin, causes a general impairment of somatic growth and

physical development in addition to many agent-specific effects on particular

developmental events (Hollister 1986; Zagon and McLaughlin 1984; Rosett and

Weiner 1984). The physiologic mechanisms mediating this growth suppression

are not well understood and probably involve many factors, including placental

insufficiency, inadequate nutrition, and direct impairment of protein or nucleic

acid synthesis. Because both maternal and fetal endocrine function are known

to contribute substantially to regulation of growth, there is a growing

appreciation of the possible role that drug-induced changes in endocrine

function might play in somatic growth and development. Endocrine factors play

an additional and perhaps more important role after birth, when growth

regulation becomes independent of maternal factors and is governed entirely by

metabolic and endocrine functions within the offspring. Therefore, evaluation of

drug effects on maternal, fetal, and neonatal endocrine function may prove

important in understanding the physiologic consequences of drug exposure

during development. Furthermore, endocrine function provides a model system

for studying the impact of drugs on specific central nervous system (CNS)

systems.

Unfortunately, the few studies of endocrine function in human infants exposed

to drugs in utero have used diverse and often inappropriate methodologies for

evaluating endocrine function. However, several laboratories working in animal

models have demonstrated convincingly that, when function is evaluated

appropriately, marked perturbations of development can be detected. The

purposes of this chapter are to (1) briefly describe endocrine functions in the

parent or offspring that play a role in regulation of growth and development, (2)

summarize current information available about drug effects on these systems,

206
(3) discuss the use of animal models of endocrine function to elucidate drug

effects, and (4) discuss methodologic issues in appropriate evaluation of drug

effects on endocrine function.

ENDOCRINE FACTORS IN DEVELOPMENT

In the developing fetus, endocrine function is both a modulator of growth and a

rapidly developing organ system that represents a target of drug action,

Endocrine regulation of fetal and postnatal growth and development differ

dramatically from each other. In the developing fetus, fetal, placental, and

maternal factors all integrate to modulate growth and development. Most fetal

endocrine systems are functional in many mammals by midgestation, and fetal

hormone secretion is critical to normal growth and development. The fetal

thyroid is vital for growth (Fisher et al. 1977), and the fetal gonad plays a welldescribed, vital role in sexual differentiation of both the gonad and the brain

(Gorski 1984; Winter et al. 1981). Finally, the activity of the fetal adrenal cortex

is vital for physiologic homeostasis, normal differentiation of metabolic

enzymes, and pulmonary surfactant production. In addition, fetal secretion of

insulin is thought to regulate growth (Casey et al. 1985). Therefore, fetal

endocrine function plays an important role in specific developmental events.

Although placental transfer of physiologically active glucocorticoid, thyroid

hormone, or growth hormone is minimal (Nathienelsz 1976), fetal endocrine

function can be affected indirectly through perturbations of maternal metabolic

state (e.g., hyperglycemia evoking insulin secretion in the fetus). Placental

factors also play a role in growth regulation. Placental lactogen assumes the

role of growth hormone in the fetus during gestation, when pituitary growth

hormone plays little role in growth regulation.

Postnatally, neonate hormone secretion becomes almost completely

autonomous, although maternal hormones in milk may play a modulatory role

in endocrine function in the offspring. Thyroid and adrenocortical function

continue to be critical to normal growth and development. In addition, pituitary

secretion of growth hormone becomes a major regulator of somatic growth.

Finally, sexual differentiation continues postnatally and remains critically

dependent upon appropriate hypothalamic regulation of luteinizing hormone

(LH) and follicle-stimulating hormone (FSH) secretion (McEwen 1987).

MECHANISM OF DRUG ACTION IN THE FETUS

The endocrine functions described above are potential targets of drug action.

The mechanisms through which drugs might act are shown in figure 1. Most

drugs of abuse act primarily within the CNS on the afferent input to the

releasing factor neurons in the hypothalamus. However, additional direct

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FIGURE 1. Schematic indicating potential sites of psychoactive drug action

on endocrine function

actions on peripheral neurons and/or the target glands themselves have been

described. In the developing animal, the various elements of this axis are being

assembled, and there are additional potential sites of drug action, as shown in

figure 2. Drugs can inhibit protein synthesis, specific gene expression, or some

aspect of initial embryogenesis. For example, oral contraceptives can influence

the developing gonad, and alcohol influences protein synthesis in general.

Drugs also can act through inhibition of fetal endocrine functions. For example,

some antithyroid drugs cross the placenta, inhibit thyroid hormone production in

the fetus, and produce fetal hypothyroidism (Cooper 1984). Similarly, opioids

and ethanol can directly inhibit testosterone production from the developing

testes in some situations (Singh et al. 1980; Anderson et al. 1987, 1989). Also,

agents that act through specific neurotransmitter systems can influence

hormone production through actions on the hypothalamus. This probably

represents a major site of opiate, cocaine, tetrahydrocannabinol (THC), and

208
FIGURE 2. Schematic indicating potential sites of psychoactive drug action on

endocrine function during development

ethanol action. Finally, the potential interruption of hormone action at the

receptor or postreceptor level represents an unexplored area.

ENDOCRINE CONSEQUENCES OF DRUGS OF ABUSE IN ADULTS

The major rationale for concern about potential drug effects on endocrine

function is the broad literature demonstrating effects of almost all drugs of

abuse on endocrine systems in adults. These are summarized briefly below.

Opiates stimulate receptors for endogenous opioids, which play a role in

regulation of every major endocrine system. Acute opiate administration affects

LH, FSH, prolactin (PRL), growth hormone (GH), adrenocorticotrophic hormone

(ACTH), vasopressin, oxytocin, and insulin. These effects are robust enough

209
that chronic opiate exposure suppresses thyroid and gonadal function and

alters glucose homeostasis in adults (Kuhn and Windh 1991). Marijuana,

through actions on hypothalamic neurotransmitter systems, decreases LH

secretion, and suppresses ovulation during chronic administration in the female

and in males decreases testosterone synthesis and sperm production (Tyrey

1984; Smith and Asch 1987). Ethanol has direct effects on the testes in

humans and animals that impair testosterone production and cause abnormal

sperm production (Smith and Asch 1987; Gavaler and Van Thiel 1987). In

addition, ethanol inhibits vasopressin secretion and has been reported to elicit

changes in GH, PRL, and possibly adrenocortical function (Anderson 1981;

Anderson et al. 1989). While there is little information available yet about

neuroendocrine effects of cocaine in humans, preliminary studies in rodents and

nonhuman primates suggest that cocaine, through actions on central

monoamine systems, influences LH, PRL, and ACTH secretion (Borowsky and

Kuhn 1991a; Mendelson et al. 1989; Moldow and Fischman 1987). These

effects in rodents are robust enough to disrupt estrous cyclicity during chronic

administration.

Most of these endocrine effects occur through actions on specific receptor

mechanisms at anatomically defined sites within the hypothalamus. Opioid

inhibition of LH secretion in females provides a well-described example (Kalra

and Kalra 1984). Opiates inhibit LH secretion through actions on opiate

receptors that impair transmission in the afferent noradrenergic control that is

stimulatory to luteinizing hormone releasing hormone (LH-RH) secretion.

DRUG EFFECTS ON OFFSPRING ENDOCRINE FUNCTION IN HUMANS

Despite the overwhelming evidence that many drugs of abuse have marked

effects on endocrine function, the literature on endocrine function in offspring of

drug-using women is sparse. A series of studies in offspring of opiate-addicted

women revealed only a transient elevation of thyroxine, renin, and sympathetic

nervous system activity, with normal levels of other major hormones (Jhaveri et

al. 1980; Rosenfeld et al. 1981; Dube et al. 1981; Glass 1982). There are no

extant studies published on endocrine function in offspring of THC- or cocaineexposed infants. However, pubertal arrest has been reported in older children

chronically exposed to THC (Copeland et al. 1980).

Studies in humans are highly compromised by methodologic problems,

including poor maternal nutrition that could directly influence hormone secretion,

polydrug use; maternal illness, including human immunodeficiency virus (HIV)

infection in intravenous drug users; and the difficulty of long-term followup in the

patient population. However, there are three issues of experimental design that

are more important reasons that endocrine effects have not been detected in

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offspring of drug-using women: (1) the timing of the assessment relative to

cessation of drug exposure (usually at birth) or the ontogeny of the endocrine

system under investigation, (2) the index used for evaluation, and (3) the failure

of most studies to focus on the most likely targets (e.g., opiate receptors after

perinatal opiates, catecholamine mechanisms after cocaine).

Most of the few extant studies of drug effects on offspring endocrine function

employed single assessments of hormone concentration in the circulation at an

arbitrary time point, usually during the first postnatal weeks. There are many

serious limitations to the use of single assessments. First, infants during this

period of time are experiencing drug abstinence, which is often accompanied by

a marked endocrine response that can bear little resemblance to the initial

action of the drug (Eisenberg and Sparber 1978; Kuhn and Bartolome 1985).

The second and major issue relates to the timing of such assessments relative

to the endocrine function under consideration. One example of the importance

of sampling time is shown in figure 3, which summarizes work on the ontogeny

of growth hormone secretion in the rat. Obviously, a single sample taken near

birth might not detect significant changes in the ontogenetic pattern of

secretion, particularly if changes were mediated by effects on systems that

matured later. Therefore, a single sampling minimizes the chance of detecting

physiologically significant changes. Third, because most evaluations must be

conducted postnatally, changes that occurred in the fetus before drug was

withdrawn can be drastically underestimated. For example, chronic exposure to

opiates in utero could produce a prolonged suppression of thyroxine or

testosterone production, which would never be detected. Finally, many studies

neglect the most likely target of drug action: the neural mechanisms that

mediate the actions of the drugs to which the fetus was exposed. Assessing

the effects of some drugs, such as ethanol and THC, is difficult, because

specific mechanisms are not well understood. However, many physiologic and

pharmacologic tools are available to assess the effects of other drugs. For

example, figure 4 contrasts the corticosterone response of morphine-tolerant

rats to a test dose of morphine and to the classic “stressor,” ether. While

opiate-dependent mechanisms are markedly unresponsive, other aspects of

adrenocortical regulation are quite normal. Therefore, single arbitrary measures

might not detect substantial physiologic changes.

USE OF ANIMAL MODELS TO ASSESS ENDOCRINE FUNCTION

Given the difficulties cited above, it is likely that effects of drugs of abuse on

endocrine maturation are markedly underestimated by the typical assessments

conducted in humans. Animal models offer the obvious benefits of

experimental control of drug dose, duration and timing of exposure, as well as

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FIGURE 3. Schematic showing the ontogeny of growth hormone secretion in

the rat

SOURCES: Blazquez et al. 1974; Khorram et al. 1983; Kuhn and Schanberg

1981; Rieutort and Jost 1976; Rieutort 1981; Walker et al. 1977

the option to conduct more invasive studies than in humans. Therefore,

endocrine development can be studied across ontogeny and sampled at

appropriate times, and more thorough methodologies can be used to evaluate

function. In addition, most animal models mature more quickly than humans, so

that ontogeny can be studied through puberty within a short period. However,

an animal model also must fulfill two other criteria. First, the mechanism of

drug action must be similar in the animal model and in the human. For most of

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FIGURE 4. Serum corticosterone levels in neonatal rats treated chronically

with saline or morphine (increasing doses from 20 mg/kg,

increasing 5 mg/kg/day starting on day 2 for 5 days to 40 mg/kg

bid) and treated acutely with morphine (10 mg/kg) or exposed to

ether for 30 seconds 45 minutes before blood collection (n=8- 10/

group)

*Indicates p<.05 or better relative to saline-treated control

the drugs under consideration (stimulants, THC, opiates, and ethanol), the

fundamental mechanisms of drug action are similar across most mammalian

species. Second, the drug action on the specific endocrine system under study

must be similar.

Fortunately, an appropriate experimental animal model exists for each of the

major endocrine systems that are important in growth and differentiation. Rats,

primates, and sheep all show major similarities to humans in the general

maturation of gonads and hypothalamic control of gonadal function (Gluckman

1982; Nathienelsz 1976). Similarly, prolactin secretion, particularly the

important dopaminergic control, is similar in humans, primates, rodents, and

sheep (Gluckman et al. 1980; Gluckman 1982; McMillian and Deayton 1989).

213
The basic hypothalamo-pituitary-adrenal (HPA) axis controlling thyroid hormone

secretion again is fairly similar across these species, although specific neural

controls have not been so well delineated (Fisher et al. 1977). Therefore, in

terms of the pharmacology of drug action, the general neurobiologic sites of

action, and the general scheme of endocrine development, several mammalian

animal models can adequately model drug effects on endocrine function in the

human.

The rodent provides the advantages of rapid development, low cost, and

similarity in many endocrine systems. The only disadvantage of the rat is that a

major amount of neuroendocrine development that occurs prenatally in the

human occurs postnatally in the rat. This characteristic can be either a benefit

or a disadvantage. The advantage is that the specific developmental events

(e.g., sexual differentiation of LH secretion) that occur postnatally in the rat can

be studied directly in the offspring. While this provides a significant advantage

in studies of the mechanism of drug action, developmental events that are

influenced by drug effects on maternal physiology (e.g., cocaine-induced

impairment of placental blood flow) will not be detected using this model.

It is possible to investigate separately the impact on maternal and offspring

endocrine function using the fetal sheep, as many events that occur postnatally

in the rat occur prenatally in the sheep. The additional strength of this model is

that both maternal and fetal circulations can be sampled, and in vivo physiologic

studies can be conducted. The elegant work of Grumbach and colleagues has

demonstrated the value of this model (Gluckman et al. 1980; Clark et al. 1989;

Cuttler et al. 1985).

Finally, the primate obviously provides the closest model in terms of

development. Many endocrine functions can be assessed carefully in the

developing primate, which has proved particularly useful in studies of puberty

(Ojeda et al. 1980; Resko and Ellinwood 1984). The disadvantages are clear:

expense, slow development, and ethical issues involved in experimentation.

In summary, there are several excellent animal models for studying drug effects

on endocrine development. Overall, the rodent has been used most widely and

represents a valuable model with the one limitation discussed above. Other

small mammals (mice, dogs, cats, rabbits, hamsters) have been studied much

less extensively because assay techniques for pituitary hormones are more

limited, and they have not been so widely exploited in the pharmacology

literature.

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METHODOLOGIC ISSUES IN EVALUATING ENDOCRINE FUNCTION IN

DEVELOPING ANIMALS

Dose, Duration, and Timing

The first group of methodologic considerations are not unique to endocrine

systems: the issues of dose, duration, and timing of drug exposure. Regarding

dose, two approaches are generally used in animal studies. The first is to

attempt to approximate human dose regimens. The disadvantage of this

strategy is that such treatment paradigms will not detect deficits that occur at

low frequency. This has been a particularly sensitive issue in the area of

ethanol-induced deficits, in which deficits seem to be clearly dose-related. An

alternative approach has been to give doses exceeding those commonly used

in humans. The benefit of this strategy is that no potential adverse effects go

undetected. The disadvantage is that physiologic compromise of the mother is

maximal using such a strategy, and deficits might be described that never occur

at typical dose levels. Nutritional compromise of the mother or offspring can be

a major Issue with high-dose regimens, which is particularly problematic for

studying endocrine functions such as thyroid function that are sensitive to

nutrition. Obviously, the optimal strategy is to conduct dose-response studies,

modeling different levels of drug exposure. Unfortunately, this approach is

expensive, time-consuming, and animal-intensive. A compromise strategy that

has proved productive is to bracket high- and low-dose regimens with a

restricted dose-response approach in combination with careful utilization of

nutritional controls,

The second issue in evaluating endocrine effects of perinatal drug exposure is

the timing of exposure. The expected effect of a drug obviously is determined

by the physiologic process that it disrupts. Therefore, the timing must take into

account the ontogeny of the system under study. For most endocrine systems,

the first trimester is the time of rapid organogenesis and differentiation. During

the end of the first and the beginning of the second trimester, many of the

neurotransmitter systems through which these drugs act are developing, while

during the end of gestation and the first postnatal weeks, the major events are

active synaptogenesis, sexual differentiation, and overall growth. Therefore,

drugs that inhibit testosterone production, for example, would be particularly

effective during later phases of development, when testosterone production is

critical. Similarly, cocaine should be most effective within the fetal brain after

catecholamine synapses have formed. However, effects on placental blood

flow would affect development throughout.

Sexual differentiation provides the best example of the impact of timing on

endocrine consequences. For example, opioid control of LH secretion provides

215
a useful example. Opioid inhibition of LH secretion can be demonstrated in

female rats immediately after birth, while in males opioid inhibition cannot be

demonstrated until near puberty (Cicero et al. 1986; Blank et al. 1979). Early

studies of vaginal opening in females treated chronically with opiates did not

report uniform, dramatic inhibition of sexual development (Blank et al. 1979;

Litto et al. 1983; Sonderegger et al. 1979; Vathy et al. 1983; Zimmerman et al.

1974), an effect that seemed inconsistent with the early opioid inhibition that

had been demonstrated. However, more careful examination demonstrated

that opioid inhibition of LH secretion diminished markedly near puberty, an

effect that is thought to contribute to the onset of cyclic LH secretion in many

mammalian species, including humans (Bhanot and Wilkinson 1983). Early

studies involved gestational and postnatal studies, during periods of time when

endogenous opioid inhibition of LH secretion was already maximal. When

opiate effects on reproductive function were studied in males, preceding the

time of puberty, when endogenous opioid influences are minimal, a much more

dramatic effect was observed. However, a marked inhibition of LH secretion,

decreased secretion of testosterone, and impaired morphologic development of

the gonads occurred when animals were treated during the sensitive period

(Cicero et al. 1989).

The other major timing issue pertains to the development of tolerance. If drug

treatments are conducted throughout development, without regard to possible

critical periods, it is possible that tolerance to the primary endocrine action of

the drug develops before the critical period is reached. The effects of THC on

pubertal development provide a good example of this problem. In the adult,

THC inhibits LH production (Tyrey 1984). Acute THC administration to the

developing rat also has this action (Field and Tyrey 1986). Therefore,

suppression of LH secretion should delay pubertal development in females,

which is dependent on pulsatile secretion of LH. However, chronic THC

administration through development does not achieve this goal, while limited

chronic treatment during the peripubertal period does so (Field and Tyrey 1984,

1986; Wenger et al. 1988) because tolerance develops to the ability of THC to

inhibit LH production in neonates (Field and Tyrey 1986).

Phasic Nature of Hormone Secretion

The second major methodoiogic issue specific to evaluating endocrine function

in development is the phasic nature of hormone secretion, This basic

characteristic determines the nature of assessments that must be conducted.

For example, in the human, basal growth hormone secretion is very low and a

poor indicator of pituitary secretory capacity. Most endocrinologists instead

measure the growth hormone response to a pharmacologic challenge.

Furthermore, diurnal rhythms in hormone secretion (cortisoi, for example) are

important considerations in timing.

216
Similarly, effects of drugs of abuse on neuroendocrine function can best be

detected by evaluating evoked changes in hormone secretion. As described

above, the HPA axis provides a representative example of this issue. First,

HPA activation can be triggered by several stimuli that act through distinct

neural mechanisms. Therefore, multiple mechanisms can be evaluated by

comparing the response of various evocative stimuli. As shown in figure 5,

stresses as well as neurotransmitters evoke marked secretion of corticosterone

even in neonatal rats. Furthermore, using this strategy, the particular neural

mechanism that is the target of drug action (opiate receptors, etc.), can be

tested in comparison with independent mechanisms that might not be affected.

Furthermore, drug-induced changes can be characterized even more

thoroughly by evaluating the time course of the response.

The adaptations involved in tolerance and abstinence superimpose additional

phasic endocrine responses. For example, following chronic administration of

morphine, animals or humans show daily cycles of corticosterone secretion that

are entrained to the daily dose. As seen in figure 6, rats show abstinenceinduced elevations between doses, When drug is administered, a marked fall

occurs, followed by a surge of drug-induced secretion. After the drug-induced

FIGURE 5. Serum corticosterone levels in 10-day-old neonatal rats after

administration of morphine (5 mg/kg), physostigmine (0.25 mg/

kg), quipazine (5 mg/kg), or exposure to ether (30 seconds) or

immobilization (30 min) (n=8-10/group)

217
surge diminishes, levels begin to rise again with abstinence. When drug is

withdrawn for several days, basal levels are completely normal. If animals were

sampled at a specific, single time point, widely different conclusions would be

reached about the state of adrenocortical stimulation caused by morphine.

Furthermore, impose upon this cyclic change in hormone secretion during

repeated injections the typical ontogenetic pattern of HPA axis function. As

shown in figure 7, the capacity of the axis to respond to morphine is markedly

suppressed during the first 2 weeks of life. However, morphine is still capable

of eliciting changes in secretion, which if anything are more prolonged.

In summary, when developing animals are treated chronically with morphine, a

single arbitrary blood sample could give very different pictures of HPA function,

depending on when blood is sampled. As shown in figure 8, if animals are

sampled at the end of a chronic regimen, corticosterone levels are enhanced

during abstinence. If animals are sampled several days later, basal levels are

normal. However, if animals are sampled after a challenge injection of

FIGURE 6. Serum corticosterone in opiate-tolerant adult rats at various times

after the last injection on day 5 of an increasing dose morphine

treatment regimen (see figure 4 legend)

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FIGURE 7. Ontogeny of endocrine response to morphine (5 mg/kg). Rat

pups were treated with saline or morphine (10 mg/kg) and killed

30 minutes later, and serum hormone levels determined by

radioimmunoassay (n=8-10/group).

morphine, markedly suppressed responses are observed, reflecting tolerance.

Therefore, one could conclude levels were either (1) enhanced, (2) normal, or

(3) suppressed. These findings demonstrate the importance of sampling basal

levels, changes evoked by normal stimuli for this pathway, as well as changes

evoked by the drug itself.

The vulnerability of endocrine function, like other CNS functions, is determined

by the combination of the ontogeny of the system, the dose and timing of drug

exposure, and the methods used to evaluate endocrine function. The extensive

work of Cicero’s laboratory on opiate actions on reproductive development

provides a good demonstration of the interaction of all these factors (Cicero et

al. 1975, 1976, 1977). A single injection of morphine suppresses LH and

testosterone production, which become more exaggerated with chronic

treatment until tolerance develops. However, there are marked developmental

changes in the function of the axis in general and in its response to morphine.

Analogous treatment regimens have no effect in the male immediately after

birth but markedly inhibit testosterone later, after opioid regulation of LH

secretion has been established. Furthermore, Cicero and colleagues (1989)

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FIGURE 8. Serum corticosterone levels in 10-day-old rats following a 5-day

morphine treatment regimen (5 mg/kg bid increasing 5 mg/kg/day

to 25 mg/kg bid). Abstinent pups were killed 12 hours after the

last injection. Basal pups were killed 48 hours after the last

injection following a sing/e saline injection, and morphine pups

were killed 48 hours after the last injection following a single

treatment with morphine (20 mg/kg) (n=8-10/group).

have shown that prepubertal male rats show a diminished ability to become

tolerant to morphine effects on gonadal function. Therefore, the magnitude of

evoked changes in hormone secretion is even greater in the developing animal

than in the adult. These findings demonstrate that exposure to opiates in

development might cause more severe outcome than in adult animals, because

the developing receptor systems lack the capacity to downregulate their

function as efficiently as the adult. Therefore, the opiate-addicted female can

self-administer doses of opiates to which she is highly tolerant but to which her

fetus will respond dramatically. Finally, like many developing systems, the

impact of drug exposure during development on endocrine function can appear

long after exposure has ended. Pubertal development is a prime example of

the “delayed” effects of perinatal drug exposure. It is well known that exposure

of the developing rat to steroid during the “critical period” around the time of

birth can prevent the eventual development of cyclic LH secretion (McEwen

1987). Therefore, many drugs that influence gonadal steroid production during

220
early development could have consequences not detected until much later. It

has been reported that gestational exposure to THC has such effects (Kumar et

al. 1986).

STRESS AND ENDOCRINE CHANGES IN DEVELOPMENT

The contribution of stress on either the dam or the offspring to endocrine

function in development has probably been underestimated. Stress elicits

marked changes in almost every endocrine function. Therefore, drug

administration to either dam or offspring could cause endocrine changes that

were secondary to the primary site of drug action and more related to the

“stress” imposed by the drug. For example, it has been demonstrated clearly in

several animal models that intense stress to pregnant dams alters adrenal

gland function in the offspring (Cadet et al. 1986). Therefore, it is possible that

the physiologic and/or psychologic stresses of the drug-using lifestyle, including

malnutrition, periodic abstinence, and disturbed sleep, contribute significantly to

the endocrine state of the pregnant woman. Such changes cannot be detected

in endocrine studies conducted postnatally and must be considered in

experimental design of animal models.

The “stress” of periodic drug abstinence is experienced by the offspring as well

as the pregnant woman. It has been suggested that opiate abstinence at birth

plays an important role in the neurobehavioral sequelae of perinatal opiate

addiction (Lichtblau and Sparber 1984). Furthermore, even neonatal rats show

abstinence-related endocrine responses (figure 8). The endocrine impact of

THC, alcohol, or stimulant abstinence is unknown even in adults and is totally

unexplored in developing animals.

The development of normal reproductive function is another endocrine function

in which maternal stress has been reported to influence normal development

(Herrenkohl 1986; Ward 1984). This function provides an example of how a

drug might elicit a response indirectly. It has been shown in animal models that

gestational stress influences neonate sexual differentiation and that this

response appears mediated by activation of opioid systems in the dam or

offspring.

Finally, drug effects on maternal behavior can have a major impact on hormone

secretion in the offspring. Many aspects of neonate physiology are affected by

maternal behavior. In rats inappropriate maternal behavior is capable of

eliciting dramatic changes in growth hormone and corticosterone secretion

(Pauk et al. 1986). Similar findings have been reported in monkeys denied

appropriate maternal care (Coe et al. 1978). Therefore, maternal impairment

associated with the drug-taking lifestyle can have an impact on offspring

endocrine function through behavioral mechanisms.

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MATERNAL ENDOCRINE FUNCTION AS A TARGET OF DRUG ACTION

The previous paragraph raises another important issue: the relative contribution

of drug-induced changes in maternal vs. neonate physiology. Drug-induced

changes in maternal endocrine function represent one possible mediator of such

effects. There are several mechanisms by which this can happen.

This first is mediated by changes in the physiology of the pregnant animal. It

has been shown recently that ethanol administration to pregnant rats elicits

changes in the dam’s adrenocortical function (Weinberg and Bezio 1987).

These effects do not necessarily cease at birth, nor are they simplistically

mediated by maternal hormones influencing offspring endocrine organs directly.

For example, maternal hyperglycemia is transmitted to the developing fetus,

which responds by hypersecreting insulin, as described previously. Both the

elevated glucose and the insulin have been implicated in disrupted growth in the

fetus. As most drugs that influence autonomic function have measurable effects

on blood glucose (including cocaine, amphetamine, alcohol, and opiates), this is

another maternal physiologic response that can mediate physiologic change in

the offspring.

Finally, a growing literature has demonstrated that most maternal hormones are

present in milk and cross into the offspring circulation intact. These hormones

include PRL, thyroid-stimulating hormone (TSH), LH-RH, and gonadotropinreleasing hormone (Gn-RH) (Grosvenor and Whitworth 1983; Kacsoh et al.

1989; Koldovsky et al. 1989; Mosinger and Placer 1959; Werner et al. 1986).

These maternally derived hormones play an important role in offspring endocrine

regulation during the immediate postnatal period when many endocrine functions

in the neonate are immature. For example, maternal PRL crosses into the

offspring through the milk in amounts sufficient to produce direct PRL effects on

developing dopamine neurons (Grosvenor and Whitworth 1983; Shyr et al.

1986). This finding is potentially important in consideration of drug effects on

development, given the recent demonstration by Mendelsohn and collegues

(1989) and Borowsky and Kuhn (1991b) that cocaine inhibits PRL secretion in

rodents and primates.

In summary, there are at least three described mechanisms by which changes in

maternal endocrine status can influence fetal development: direct transfer of

maternal hormone, indirect offspring responses to altered maternal physiology,

and altered transfer of milk-borne hormones. As outlined in the beginning of this

chapter, most drugs of abuse influence adult endocrine function. Therefore,

these indirect offspring adaptations represent a likely target of drug action on

maternal physiology.

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ANIMAL STUDIES OF DRUG EFFECTS ON OFFSPRING ENDOCRINE

FUNCTION

No one study can address all potential drug effects. Furthermore, many of the

endocrine responses described above represent fairly subtle abnormalities that

are dwarfed by the major neurologic and physiologic damage experienced by

the offspring. Nevertheless, a growing animal literature has shown that

exposure to psychoactive drugs during ontogeny affects endocrine

development. These are summarized below as a demonstration of the multiple

abnormalities that can be detected if appropriate evaluation of endocrine

function is conducted. These studies employ a variety of treatment paradigms

and endocrine indices, but each demonstrates a substantial consequence on

fetal development.

The important role that endogenous opioids play in normal endocrine regulation

is translated into multiple potential actions of opiates in the developing fetus.

The major impact of opiates during development is on reproductive function.

Cicero and colleagues (1989) have demonstrated that exposure of male rats to

opiates tonically inhibits LH production, decreases testosterone production by

the developing testes, and retards morphologic maturation of the testes. Two

studies (Bakke et al. 1973; Litto et al. 1983) reported that gestational opiate

exposure delayed pubertal development in both males and females and

diminished feedback sensitivity of the hypothalamus to gonadal steroids. Other

studies (Sonderegger et al, 1979; Zimmerman et al. 1974) reported little or no

alteration in pubertal development but did report impaired glucocorticoid

responses to stress in adults exposed to morphine during development. These

conflicting results reflect in part the variable vulnerability of different opiate

receptor systems and different endocrine responses to perinatal opiate

treatment. Kuhn and Bartolome (1984) have shown that marked attenuation of

hypothalamo-pituitary adrenal can result from perinatal opiate treatment, while

other endocrine functions, including PRL and GH secretion, are fairly resistant

to perturbation,

Disruption of reproductive development results from THC exposure either

during gestation or during puberty (Chakravarty et al. 1979; Field and Tyrey

1984, 1986; Gupta and Elbracht 1983; Kumar et al. 1986). However, the

endocrine effects of THC are not well understood even in adults, and conflicting

results of THC effects on maternal endocrine function during pregnancy have

been reported (Blaunstein et al. 1983; Asch and Smith 1986).

In contrast to studies on THC, there are numerous reports of gestational alcohol

effects on endocrine functions. Furthermore, some of the effects reported

possibly play a role in the developmental effects of ethanol. The most important

223
of these are several reports of decreased circulating thyroid hormone levels in

developing rats or sheep exposed to ethanol during gestation (Castro et al.

1986; Kornguth et al. 1979; Portoles et al. 1988). In addition, significant effects

on maternal endocrine function, including decreases in GH, PRL, estriol, and

thyroid hormones, have been reported (Lee and Wakabayashi 1986; Guerri et

al. 1984). A single report in humans that decreased estriol production is

correlated with the severity of fetal alcohol syndrome is a particularly intriguing

suggestion that maternal endocrine factors might play a role in the

developmental effects of opiate exposure (Halmesmaki et al. 1987).

Furthermore, placental as well as maternal endocrine function may be affected

by ethanol: Altered somatomedin binding in placenta has also been reported

(Kennedy 1984). Finally, several long-lasting effects of perinatal ethanol

exposure have been reported in rats exposed to ethanol during gestation,

including altered glucoregulatory responses and marked perturbation of

adrenocortical function (Angelogianni and Gianoulakis 1989; McGivern et al.

1986; Lopez-Tejero et al. 1989; Singh et al. 1984; Taylor et al. 1981, 1984,

1986; Weinberg 1988, 1989).

ENDOCRINE FUNCTION AS A MODEL SYSTEM FOR STUDYING

DEVELOPMENTAL EFFECTS OF DRUGS

This last section addresses a different approach to the investigation of

endocrine function: its utility as a model system for studying drug effects on

specific neural systems rather than as a mediator of growth disruption. As well

as being an important factor for growth, hormone secretion provides an easily

measured function of the nervous system that can be quantitated across

development. Unlike many physiologic and behavioral responses to drugs,

hormone secretion changes only quantitatively across development; most

responses remain qualitatively similar. Furthermore, endocrine responses can

be quantitated with some accuracy, in contrast to other drug effects such as

euphoria and sedation. For these reasons, endocrine function can provide an

extremely useful model system for evaluating the impact of drugs on specific

neural systems.

This fact has been used to develop endocrine responses to agonist challenge

as markers of opiate receptor function through development. Studies of opiate

effects on the HPA axis provide an example of the power of this approach.

Acute opiate administration to rats elicits a marked rise in ACTH and

corticosterone secretion (Kokka et al. 1973). This response reflects actions on

at least two opiate receptors (Pfeiffer et al. 1985; Eisenberg 1985; lyengar et al.

1986). When adult rats are treated chronically with receptor-specific agonists,

specific tolerance develops at the appropriate receptor. Therefore, this

endocrine response can be used as an indicator of the sensitivity of the two

224
receptors. Furthermore, as shown in figure 4, HPA responses to opiate

agonists can be contrasted with responses to agents acting through different

neural mechanisms to identify the extent of the adaptations in HPA function.

This strategy of using evoked changes in hormone secretion can reveal

adaptations in function that are highly specific for both the receptor type and the

timeframe of exposure. This strategy has provided an extremely powerful tool

in evaluating the neural consequences of perinatal drug exposure.

SUMMARY

The goal of this chapter is to indicate potential endocrine targets of perinatal

drug exposure, to describe the methodologic issues involved in detecting

changes in hormone secretion, and to provide examples of several endocrine

systems in which exposure to drugs during development significantly impaired

normal endocrine development. Finally, we attempted to show that endocrine

function is both a target and useful marker for detecting effects of drug of abuse

on development that provides the advantages of accurate quantitation and

relative response stability across ontogeny.

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AUTHORS

Cynthia Kuhn, Ph.D.

Associate Professor of Pharmacology

Rolf Windh, B.A.

Department of Pharmacology

Duke University Medical Center, Box 3813

Durham, NC 27710

Diane Ignar, Ph.D.

Fellow

National Institute of Environtmental Health Sciences

P.C. Box 12233

Research Triangle Park, NC 27709

232
Discussion: Neuroteratology of

Cocaine—Relationship to Developing

Monoamine Systems

Jean M. Lauder

DEVELOPMENTAL EFFECTS OF COCAINE

The epidemic of cocaine abuse across all sectors of the human population,

including women in various stages of pregnancy, has led to concern about

effects on embryonic, fetal, and postnatal development of their offspring.

Clinical studies suggest that this now popular drug of abuse may indeed be the

cause of a number of developmental defects as well as an important factor in

the outcome of pregnancy.

Human Studies

Increases in spontaneous abortions, abruptio placentae, preterm labor, fetal

deaths, still births, low birth weights, decreased head circumference, skull

defects, microcephaly, intracerebral hemorrhage, cardiovascular abnormalities,

and hypertension in fetuses and newborns have been reported in clinical

studies of cocaine-abusing mothers (Bingol et al. 1987; Chasnoff et al. 1987;

Chasnoff, this volume; Hadeed and Siegel 1989; lsenberg et al. 1987; Little et

al. 1989; Ryan et al. 1987; Zuckerman et al. 1989).

A number of behavioral disturbances have been noted in children of cocaineabusing women that suggest abnormal functional development of the nervous

system. These include disturbed interactive behavior and motor function

(including tremors and hyperactivity), increased irritability, depressed

organizational response to environmental stimuli, visual disturbances, altered

visual evoked potentials, disturbed sleep states, abnormal arousal responses to

hypoxia, disruption of normal breathing patterns during sleep, and increased

sudden infant death syndrome (SIDS) (Chasnoff et al. 1987, 1989; Davidson

Ward et al. 1989a, 1989b; Dixon et al. 1987; Oro and Dixon 1987).

233
Animal Studies

In the human population of substance abusers, who often use multiple drugs, it

is difficult to ascertain the exact drug-related etiology of developmental defects.

Animal studies have the advantage of providing an opportunity to observe

effects of one suspected agent at a time on a variety of parameters of structural

and functional development. Data obtained from such studies are useful in

understanding the effects of drugs on the developing human, provided possible

species-related differences are kept in mind.

Animal studies have provided information on the effects of cocaine administered

during different periods of prenatal and postnatal development. In general, the

findings of these studies are similar to those in humans in terms of behavioral

defects, growth retardation and disturbances of pregnancy, including abruptio

placentae, spontaneous abortions, and fetal deaths (Church et al. 1988; Dow

Edwards 1988, 1989; Fantel and MacPhail 1982; Henderson and McMillan

1990).

Many of these studies have provided valuable information regarding specific

changes in behavior and the function of neurotransmitter systems, which clearly

implicate the developing nervous system in the teratology of cocaine. Recent

studies by Dow Edwards (1988, 1989; Dow Edwards et al. 1988) in rats using

the 2-deoxyglucose method indicate specific brain regions affected by neonatal

exposure to cocaine. Interestingly, neonatal treatment only produced significant

effects in females, with the greatest changes occurring in structures related to

the limbic system where metabolic activity was increased. These changes were

accompanied by hyperactive behavior following pharmacologic challenge with

amphetamine. In prenatal studies, however, males also were affected (D.L.

Dow Edwards, personal communication, April 1990). Together with the

observed effects on the limbic system, a known projection area of dopamine

neurons (Kalivas and Nemeroff 1988), the effects of amphetamine suggest

alterations in the developing dopaminergic system (Buelke-Sam 1986;

Woolverton 1986).

Other studies have reported delayed development of the righting reflex,

decreased learning and memory and shock-elicited wall climbing, as well as

increased locomotor activity, following subcutaneous cocaine injection

throughout pregnancy (Henderson and McMillan 1990) or gestational days 8 to

20 (Spear et al. 1989a, 1989b). Spear and colleagues (1989b) have related

changes in wall-climbing behavior to developing catecholamine systems, based

on previous studies with 6-hydroxydopamine (Emerich et al. 1985). Suckling, a

serotonin (5-HT)-related behavior, was not affected by cocaine in the same

study (Spear et al. 1989b). Accelerated development of the righting reflex, cliff

234
avoidance, startle response, and decreased activity in response to

amphetamine, have been reported following injection of cocaine during the last

trimester of pregnancy (Sobrian et al. 1990). All these studies suggest the

importance of critical developmental periods in the functional changes observed

following cocaine use in pregnancy, as well as the involvement of developing

catecholamine systems.

Microcephaly and small head circumference have been reported in clinical

studies of cocaine abuse during pregnancy. Of interest in this regard is a recent

report of changes in ornithine decarboxylase levels in developing rat cortex

following prenatal exposure to cocaine (Bondy et al. 1990), since this enzyme

is known to be active in proliferating cells. Of particular importance is the

finding that levels of this enzyme first decreased and then increased during

the postnatal period in treated animals, suggesting first an inhibition of cell

proliferation, followed by a rebound. Such an effect could have severe

consequences for cortical development where correct timing of separate

developmental events is critical (Rakic 1988) and might explain some of the

features of microcephaly found in humans following prenatal cocaine abuse

(Hadeed and Siegel 1989).

EFFECTS OF COCAINE ON ADULT MONOAMINERGIC NEURONS

Evidence for cocaine effects on monoaminergic neurons is unequivocal.

Cocaine is a potent inhibitor of the reuptake of dopamine (DA), norepinephrine

(NE), and 5-HT into presynaptic nerve terminals in the rat (Koe 1976; Lakoski

and Cunningham 1988; Taylor and Ho 1978; Randrup and Braestrup 1977),

and cocaine binding sites have been associated with DA and 5-HT nerve

terminals in the striatum (Kennedy and Hanbauer 1983) and cerebral cortex

(Reith et al. 1983; Reith 1988). Cocaine receptors are thought to be directly

linked to the uptake transporters for DA and 5-HT (Reith et al. 1983, 1986), and

those on the striatal DA transporter mediate the reinforcing (addictive) qualities

of cocaine (Ritz et al. 1987). DA receptors of the D2 subtype are thought to

mediate the self-adminstration of cocaine in monkeys (Woolverton et al. 1984;

Woolverton 1986), and D1 receptors also have been reported to do so in the

rat (Koob et al. 1987). Both D1 and NE receptors appear to be involved in

the discriminative stimulus properties of cocaine, based on the effects of

d-amphetamine in monkeys (Woolverton and Kleven 1988). D2 receptors are

also involved in the locomotor stmulatory properties of cocaine, with D1

receptors apparently playing an ancillary role (Bhattacharyya et al. 1979;

Heikkila et al. 1979; Scheel-Kruger et al. 1977).

Cocaine alters the functioning of brain monoamines by blocking their reuptake

into presynaptic terminals as well as by affecting their turnover, synthesis, and

235
the firing of the neurons that contain them. For example, cocaine increases

striatal DA levels and turnover (Church et al. 1987; Patrick and Barchas 1977)

but decreases the levels of NE and 5-HT in the diencephalon, midbrain, and

brain stem (Bhattacharyya et al. 1979; Pradhan et al. 1978), probably by

inhibiting the enzymes responsible for their synthesis (Trulson et al. 1986). In

addition, systemic cocaine administration inhibits the firing of brain stem NE

neurons (Pitts and Marwah 1986a, 1986b, 1987a) and DA neurons in the

midbrain (Einhorn et al. 1988; Pitts and Marwah 1987b). Cocaine clearly

inhibits the functioning of 5-HT neuronal systems in the central nervous system

(CNS) (Blackburn et al. 1967; Friedman et al. 1975; Ross and Renyi 1967,

1969; Taylor and Ho 1978), both by inhibiting reuptake into nerve terminals and

by inhibiting 5-HT synthesis (Knapp and Mandell 1972). Systemic cocaine

administration also inhibits the spontaneous activity of brain stem 5-HT neurons

(Cunningham and Lakoski 1986; Pitts and Marwah 1986a). In addition,

inhibition of 5-HT synthesis and receptor blockade potentiate the ability of

cocaine to increase locomotor activity (Scheel-Kruger et al. 1977).

COCAINE AND DEVELOPING MONOAMINERGIC SYSTEMS

The effects of cocaine on monoamine uptake, synthesis, and receptors in the

adult brain as well as developmental effects on such behaviors as shock-elicited

wall climbing and amphetamine-induced locomotor activity (discussed above)

make it reasonable to speculate that developing monoaminergic systems may

be important substrates for the neuroteratologic effects of cocaine, especially

given the precocious development and trophic influences they exert on the

ontogeny of other brain cells, including their synaptic partners.

Monoamines may have evolved to their roles in chemical neurotransmission

from more general humoral functions in primitive organisms (Buznikov 1984;

McMahon 1974; Roth et al. 1982; Tompkins 1975). These phylogenetically old

functions appear to be reiterated in the embryo (Harris 1981) where these same

substances influence a variety of developmental events including cell

proliferation, neurite outgrowth, and synaptogenesis (lauder 1988; Mattson

1988). Cocaine, by affecting the ontogeny of monoaminergic systems, also

may exert influences on other components of developing brain circuitry due to

the trophic actions of these neurotransmitters on other cells.

CNS monoamine neurons are early developing neurotransmitter systems,

beginning their differentiation prior to most of their target cells. In the rat, the

NE neurons of the locus coeruelus, DA neurons of the substantia nigra, and

5-HT neurons of the raphe nuclei are formed during the second week of

gestation and begin to synthesize transmitter immediately after their last cell

division (Lauder and Bloom 1974). In the human brain, both 5-HT and

236
catecholamine neurons can be detected by the end of the second month of

gestation (Olsen et al. 1973; Pickel et al. 1980). In both animals and humans,

monoamine neurons rapidly elaborate axons that innervate forebrain regions

within a short time (Lidov and Molliver 1982a, 1982b; Olsen et al. 1973; Pickel

et al. 1980; Olsen and Seiger 1972; Specht et al. 1981; Wallace and Lauder

1983). The neurotransmitters contained in these neurons appear to influence

the ontogeny of cells with which they interact during their growth and

differentiation, making the developing brain particularly vulnerable to insult by

psychoactive drugs (Lauder 1983; Lauder and Krebs 1984).

Studies with the catecholamine neurotoxin 6-hydroxydopamine (6-HODA) in the

rat suggest that depletion of brain catecholamines during the early postnatal

period produces a variety of changes in developing brain regions innervated by

NE or DA nerve terminals. These effects include alterations in cerebellar

development (Lovell 1982), reduced cortical thickness (Kalsbeek et al. 1987),

decreased cortical cell density (Onteniente et al. 1980), increased synaptic

density in the subcortical plate region (Blue and Parnevalis 1982), sprouting of

cortical and striatal 5-HT axons (Berger et al. 1985; Blue and Molliver 1987;

Luthman et al. 1987; Towle et al. 1987), changes in the dendritic arrangement

In somatosensory barrel fields (Loeb et al. 1987), and altered plasticity of

the visual cortex (Kasamatsu and Pettigrew 1979; Shlrokawa et al. 1989).

Depletion of DA in the developing rat or rabbit by reserpine or a-methyl-ptyrosine reduces the amount of neuropil in the striatum and alters motor activity

(Tennyson et al. 1982, 1983). These effects are relevant to in vitro studies

where DA has been shown to inhibit neurite outgrowth in specific target cells

(Lankford et al. 1987; McCobb et al. 1988), an effect that appears to be

mediated by DA receptors (Lankford et al. 1988). It might be expected that

exposure to cocaine during different critical periods could exert a variety of

region-specific changes in brain development by increasing or decreasing the

levels of catecholamines due to blockade of their reuptake into developing

nerve terminals and/or inhibiting their synthesis in cell bodies.

5-HT also exerts trophic influences on neural development. Since cocaine

inhibits 5-HT reuptake and biosynthesis in the adult brain, it also may affect

these processes in developing 5-HT neurons. Inhibition of 5-HT synthesis in

embryonic rat brain and raphe neurons (Lauder et al. 1981, 1985) leads to

delayed differentiation of cells spatio-temporally associated with developing

5-HT axons (Lauder and Krebs 1978; Lauder et al. 1982). Such effects may

lead to mistimed neurogenesis between affected and unaffected brain regions,

thereby altering the development of their synaptic connections.

In culture, 5-HT neurons and their target cells respond to direct application of

this transmitter by an inhibition of growth cone activity and a retraction of

237
affected neurites, as well as by alterations in synapse formation (Haydon et al.

1984; McCobb et al. 1988). Snail embryos treated with the 5-HT neurotoxln

5,7-dihydroxytryptamine, and raised to adulthood, exhibit alterations in the

dendritic morphology of specific 5-HT target cells (Goldberg and Kater 1989).

In complex (organotypic) cultures of rat brain regions such as cerebral cortex

and hippocampus, stimulation of neurite outgrowth, glial proliferation, and

synaptogenesis occurs when 5-HT is added to the culture medium (Chubakov

et al. 1986; Gromova et al. 1983).

In dissociated cell cultures from embryonic rat brain, 5-HT or 5-HT1

 agonists

influence the morphological and biochemical differentiation of 5-HT neurons

(Azmitia and Whitaker-Azmitia 1987; Jonakait et al. 1988; Whitaker-Azmitia and

Azmitia 1986) but not catecholamine neurons (Liu and Lauder 1991; Liu et al.

1990). These effects appear to involve activation of receptors on 5-HT neurons

(autoreceptors) (Whitaker-Azmitia and Azmitia 1986), target neurons (Azmitia

and Whitaker-Azmitia 1987), and glia (Whitaker-Azmitia and Azmitia 1989).

With regard to glial 5-HT receptors, treatment of neonatal astrocytes (WhitakerAzmitia and Azmitia 1989) or embryonic radial glia and astrocytes (Liu et al.

1990) with 5-HT, or 5-HT1A agonists, stimulates the release of factors that affect

the survival and growth of 5-HT neurons. The factor(s) released from

embryonic glia following stimulation by 5-HT (and nialamide) (Liu et al. 1990)

does not significantly affect catecholamine neurons, suggesting possible

specificity for the serotonergic phenotype. A 5-HT growth factor released from

neonatal astrocytes following activation of 5-HT1A receptors has been reported

to be the protein S100 (Whitaker-Azmitia et al. 1990).

Recently, cocaine has been reported to inhibit survival, development of 5-HT

uptake, and neurite outgrowth in cultured embryonic 5-HT neurons (Azmitia et

al. 1989; DeGeorge et al. 1989). This inhibition represents the first evidence

that cocaine can alter the morphological and biochemical differentiation of

embryonic 5-HT neurons and suggests that investigation of the effects of

cocaine on the developing serotonergic system may be fruitful.

The vulnerability of neurotransmitter receptors to developmental insult has been

demonstrated repeatedly in studies of postnatal receptor expression following

prenatal exposure to psychoactive drugs (Kellogg 1988; Miller and Friedhoff

1988; Schwaab et al. 1988). For example, prenatal exposure to the

monoamine uptake inhibitor and tricyclic antidepressant imipramine leads to

alterations in the numbers of B-adrenergic receptors expressed postnatally in

the rat brain (Ali et al. 1986; Jason et al. 1981). Likewise, treatment of pregnant

rats with neuroleptics such as haloperidol, butaclamol, or a-methyl-p-tyrosine

(an inhibitor of catecholamine biosynthesis) reduces the number of D2

238
receptors present in offspring and the ability of such receptors to be

upregulated in the adult (Miller and Friedhoff 1986, 1988; Rosengarten and

Friedhoff 1979). Moreover, days 15 to 18 of gestation in the rat appear to be a

critical period for such effects, since later treatment with the same agents

produces opposite effects, similar to the adult pattern of response. This period

may represent the time when DA receptors are developing into their mature

state (Miller and Friedhoff 1988). Since cocaine exerts some of its behavioral

effects via D2 receptors, these components of the DA system may be prime

candidates for studying developmental effects of cocaine.

As with catecholamine receptors, treatment of pregnant rats with pharmacologic

agents affecting 5-HT synthesis (p-chlorophenylalanine) or receptors

(5-methoxytryptamine) leads to changes in the number of 5-HT receptors

expressed in offspring (Whitaker-Azmitia et al. 1987), suggesting that the

expression or maturation of these receptors may be modulated by 5-HT during

embryogenesis. Since cocaine inhibits the development of 5-HT uptake as well

as the survival and growth of cultured 5-HT neurons, as discussed above, it is

possible that this drug could indirectly alter embryonic 5-HT receptors during the

critical period of expression and/or maturation.

SUMMARY

The effects of cocaine on monoaminergic systems in the adult brain and in

tissue culture, coupled with the behavioral profiles of animals and humans

exposed in utero, suggest that catecholamine and 5-HT neurons and their

receptors may be especially vulnerable to this drug during critical periods of

their development. Future studies designed to examine the effects of cocaine

on specific features of developing monoaminergic systems, such as the

expression of reuptake mechanisms and receptors, neurite outgrowth,

and synaptogenesis, will be important in further elucidating potential

neuroteratologic effects of cocaine abuse in pregnancy.

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AUTHOR

Jean M. Lauder, Ph.D.

Professor

Department of Ceil Biology and Anatomy

University of North Carolina School of Medicine

CB 37090

Chapel Hill, NC 27599-7090

247
Assessment of Teratogenic Effects on

Cognitive and Behavioral Development

in Infancy and Childhood

Joseph L. Jacobson end Sandra W. Jacobson

INTRODUCTION

This chapter focuses on the assessment of developmental delays and

abnormalities in cognitive functioning associated with in utero exposure to

drugs and other toxic substances. First, procedures for assessing cognitive

performance in infancy are reviewed, particularly two: the Bayley Scales of

Infant Development, the most widely used standardized infant test, and the

Fagan Visual Recognition Memory paradigm, the most popular of a newer

generation of tests using an information-processing approach to infant

assessment. Next is a discussion of which ages may be optimal for

developmental assessment. Infant assessment procedures are differentially

sensitive at different ages, and performance at certain ages may be more

predictive of long-term developmental outcome. Children also differ in their

willingness or ability to cooperate with particular testing paradigms at different

ages. Finally, the chapter presents three approaches for assessing cognitive

functioning in childhood: standardized IQ tests, newer reaction-time tests

designed to evaluate cognitive-processing efficiency, and procedures for

assessing sustained attention and activity levels.

INFANT ASSESSMENT

The Bayley Scales of Infant Development, which has been standardized for

use with infants between the ages of 1 and 30 months (Bayley 1969), provides

two standardized scores: the Mental Development Index and the Psychomotor

Development Index. The Bayley has been the most extensively used

instrument for assessing the effects of prenatal exposure to suspected

teratogens. Bayley performance has been found to be affected by in utero

exposure to alcohol (Streissguth et al. 1980; O’Connor et al. 1986), lead

(Bellinger et al. 1987; Dietrich et al. 1987), methodone (Hans, in press), and

polychlorinated biphenyl, an environmental toxin (Gladen et al. 1988).

248
Despite these findings, the Bayley has been extensively criticized in recent

years. Inspired by the Gesell (1928) Development Schedule, it grew out of a

maturationist tradition that regarded infant development as a series of

milestones programmed to emerge over time. The primary purpose of the

assessment was to determine where In the normal sequence of development a

particular infant fell at the time of testing. Figure 1 shows an excerpt from the

scoring sheet for the Mental Development Index. Behaviors are arranged in

order of the median age at which they were passed in the standardization

sample and reflect a broad range of skills. Items 74 and 75 are primarily

attentional; items 78, 80, and 82 require fine motor coordination: and item 79 is

a precursor of language.

Figure 1 illustrates one of the principal weaknesses of the Bayley for the study

of developmental neurotoxicity: It was not designed to evaluate functioning

within specific domains. Items assessing cognitive processing typically require

fine motor manipulation, as in item 80, where the infant must pull a string to

show his or her understanding of the means-ends relationship between it and

the ring. A failure on this item may be due to either a cognitive or fine motor

impairment or to a lack of motivation to perform the manipulation. Because

the test was not designed to evaluate specific domains of functioning, many

important domains are represented by very few items. This raises at least two

problems for the assessment drug-related developmental abnormalities. First,

there is a risk of Type II error, that is, failure to detect deficits in specific aspects

of cognitive functioning not adequately represented among the items tested.

Second, where a perinatal exposure is found to be associated with a poorer

overall Bayley score, the test provides little information regarding which specific

aspects of functioning are impaired. Data on specific deficits can provide

important clues for investigating the neurochemical and/or neuroanatomical

mechanisms responsible for drug-related central nervous system (CNS) effects.

When administered during the first year of life, the Bayley has very poor

predictive validity for later cognitive functioning, except for those infants who are

grossly mentally impaired (McCall et al. 1972). Because the drug researcher is

interested primarily in effects on longer term functioning, this limited predictive

validity may be problematic, It should be noted, however, that most teratogenic

exposures found to be associated with poorer Bayley scores also are

associated with poorer cognitive performance in the school-age child. Thus,

the Bayley appears to be sufficiently sensitive to detect group differences

associated with teratogenic exposure, even if it is not sufficiently reliable to

predict childhood test scores for individual infants.

Two explanations have been advanced for the Bayley’s poor predictive validity.

McCall has argued from the perspective of developmental stage theory that

249
To score: Check P (Pass) or F (Fail). If “Other,” mark O (Omit), R (Refused), or RPT (Reported by mother).

Age

Placement Score

Item and Range Situ- Item Title Notes

No. (Months) ation P F Other

74

(4-10)

M Attends to scribbling

75

(5-10)

I Looks for fallen spoon

76

(4-12)

K Playful response to mirror

77

(4-10)

H Retains 2 of 3 cubes offered

78

(5-10)

A

1 Manipulates bell: interest in detail

79

(5-12)

G

1 Vocalizes 4 different syllables

80 7.1 D

2 Pulls string adaptively: secures ring

(5-10)

81 7.6 E

1 Cooperotes in games Note skill at pat-o-coke for

(5-12) Motor Scale item 44

82 7.6 H Attempts to secure 3 cubes

(5-14)

FIGURE 1. Excerpt from scoring sheet for the Baylay Mental Development Index

SOURCE: Bayley 1969, copyright 1969, The Psychological Corporation, reproduced by permission, all rights reserved
predictive validity from infancy to childhood is not to be expected, because

intelligent behavior undergoes significant qualitative transformations as the

child matures (McCall et al. 1977). The infant who advances rapidly during an

early stage of development will not necessarily be more advanced at later

stages when different aspects of functioning may become more focal. On the

other hand, Bornstein and others have argued that the Bayley’s emphasis on

reaching, grasping, and orienting bears little conceptual relation to the encoding

and information-processing skills that provide the basis of cognitive functioning

in childhood and adutthood (Bornstein and Sigman 1986; Zelazo 1979). They

suggest that direct tests of infant information-processing skill should be more

valid and, therefore, more predictive.

The Fagan Visual Recognition Memory Test (Fagan and Singer 1983) is

designed to assess infant information processing more directly. The infant is

seated on the mother’s lap in front of an observation chamber containing two

stimulus plaques. An observer watches through a peephole in the back of the

stage and records the infant’s gaze direction on an electronic event recorder.

The infant initially is shown two identical target photos, which appear

simultaneously in the right and left positions until he or she has looked at them

for a total of 20 seconds. The familiar target then is paired with a novel target

for two 5-second recognition periods, reversing left-right positions from one

period to the next. Because the normative response at this age is to spend

more time looking at the novel stimulus, infants who recognize the original

target will spend more time looking at the new one. Looking longer at the

unfamiliar stimulus, therefore, indicates the ability to recall the original target

and to discriminate it from the new one. Although this task requires relatively

complex information processing involving stimulus discrimination and memory

storage and retrieval, the motoric response—a shift in gaze direction—is

minimal.

The Fagan has been found to be sensitive to prenatal exposure to

poiychlorinated biphenyis in human infants (Jacobson et al. 1985) and to

methylmercury in laboratory monkeys (Gunderson et al. 1986). Moderate

predictive validity has been reported from performance at 6 to 7 months of age

to cognitive functioning at 4 to 7 years (Fagan and McGrath 1981; Rose et al.

1989). in addition to novelty preference, several attentional measures can be

derived from this paradigm, including average duration of visual fixation and

time off task (Coiombo et al. 1988; Rose and Feldman 1987; Jacobson et al.

1989).

OPTIMAL AGES FOR DEVELOPMENTAL ASSESSMENT

McCall and colleagues (1977) investigated discontinuities in mental

performance in a principal-components analysis of data from the Berkeley

251
Growth Study, in which a cohort of infants was assessed monthly on the Bayley

Scales. This analysis yielded five empirically derived stages of cognitive

development (summarized in table 1), which are remarkably similar to the

stages described by Piaget on the basis of clinical observation of his three

children and by researchers who have investigated attentional and play

development during infancy (e.g., Kagan 1970; Fenson et al. 1976). If McCall

and colleagues are correct that mental functioning undergoes fundamental

reorganization as the infant progresses through these stages, then assessment

procedures that are sensitive or predictive at one age may be less so at others.

Thus, the Fagan test may provide a “window” into the infant’s informationprocessing capacity at 6 or 7 months but by 12 months may be cognitively less

challenging and, therefore, less indicative of mental competence. Similarly, the

Bayley may be less sensitive to teratogenic effects at 18 to 20 months when

some, but not all, normally developing children are making an important

transition to spoken language. During the preschool period, 4 to 5 years

appears to be the best age for cognitive assessment. It is often difficult for

younger preschool children to lend themselves to structured tasks, a difficulty

that is likely to be compounded for the teratogenically exposed child. For

example, we found that polychiorinated biphenyl-exposed preschoolers were

less likely to complete the McCarthy Scale testing procedure (Jacobson and

Jacobson, in press). The period between 5 and 7 years is one of relatively

rapid developmental change in cognitive functioning. Sometimes referred to as

the “5 to 7 shift,” this period is marked by an improved understanding of the

TABLE 1. Stages of infant cognitive development

Age

Stage (months) Name Characterization Plagetian Stage

I 0-2 Newborn Exercise of endogenous

behavioral dispositions

II 2-7

III 7-13

Complete

subjectivity

Means-ends

World known only through

infant’s own actions

Separate cause and effect

IV 13-21 Objectification Objects have an

of environmental Independent existence

entitles

V 21+ Symbolic Relations can exist

relations independent of actions

and specific entitles

Reflex

Primary and secondary

circular reactions

Coordlnation of

secondary schemes

Tertiary circular

reactions

Beginning of thought

252
nature of reality, as indicated by mastery of the Piagetian conservation tasks, as

well as an increased ability by the child to monitor his or her behavior, which

makes it possible to begin formal schooling. During this period of rapid growth,

much of the variance in cognitive performance may be due to individual

differences in rate of cognitive maturation and/or exposure to formal educational

settings. Given these competing sources of variance, it may be especially

difficult to detect effects associated with teratogenic exposure during this period.

At this point, given the assessment paradigms currently available, 6 to 12

months, 4 to 5 years, and 7 to 10 years appear to be the best ages for

developmental neurotoxicity testing, Most effects of teratogenic exposure

found on the Bayley are from the 6- to 12-month period, and evidence for the

predictive validity of the Fagan is strongest at 6 to 7 months. Preschool

assessments can be administered most effectively at 4 to 5 years, and by age 7

the child has made the transition to formal schooling and is ready for more

structured testing paradigms.

CHILDHOOD ASSESSMENTS

The most popular cognitive assessments for the preschool-age child are the

McCarthy Scales of Children’s Abilities and the Stanford-Binet IQ Test. Each

comprises a series of subtests focusing on specific domains, such as block

building, pictorial memory, draw-a-design, and counting and sorting. Most

children find these assessments enjoyable and, if the examiner develops

the appropriate rapport, they can be administered in a game-like manner.

The McCarthy provides standardized test scores in five domains: verbal,

perceptual-performance, quantitative, memory, and motor. The General

Cognitive Index, computed by summing raw scores from three of these

domains, is standardized to a mean of 100 and standard deviation of 15 (like an

IQ score) and is highly correlated with IQ as assessed on the Stanford-Binet.

The newest version of the Stanford-Binet also provides standardized scores in

specific domains: verbal, abstract/visual, quantitative, and short-term memory.

As noted earlier, domain-specific data are important for the drug researcher,

because a teratogenic exposure may affect only certain aspects of cognitive

function and because evidence of a deficit in a particular domain may provide

important clues regarding underlying neurochemical or neuroanatomical

mechanisms.

in addition to IQ testing, some behavioral teratologists have begun to use

newer, more experimental paradigms that are designed to assess specific

aspects of cognitive function more directly and could be more sensitive to subtle

effects. In our research on polychlorinated biphenyls, we have begun to use

reaction-time paradigms from the field of information-processing psychology to

assess cognitive-processing efficiency within specific domains. This approach

253
FIGURE 2. Sternberg recognition memory paradigm: Reaction time by

memory load

is exemplified by the Sternberg (1969) visual search and recognition memory

task. The child is shown a stimulus array of one, two, or four objects, which he

or she is asked to remember. A series of test stimuli then appear individually on

the screen. The child is instructed to press a red button when shown an object

that appeared in the original array and a black button if the object was not in the

original array. Performance is analyzed by computing the slope and intercept of

a line connecting the child’s mean reaction times for the different memory loads.

Figure 2, based on data we collected in a pilot study in Israel, shows mean

reaction times for the children’s responses to the red button. As expected, it

took the children somewhat longer to process the information when the memory

load was larger. Figure 3 compares the reaction times of children with higher or

lower performance IQ scores on the Wechsler Intelligence Scales for ChildrenRevised. The flatter slope for the higher IQ children indicates more efficient

short-term memory, because it did not take these children appreciably longer to

process the larger memory load than the smaller load. Other aspects of shortterm memory processing, including encoding, decision, and response time, are

assessed in terms of the intercept, which measures reaction time irrespective of

254
FIGURE 3. Sternberg recognition memory paradigm performance by

performance IQ score

memory load Looking at the intercept, the higher IQ children’s response times

are again faster, indicating more efficient processing.

This type of paradigm also can be used to assess cognitive-processing

efficiency in contexts not involving short-term memory. In Kail’s (1986) mentalrotation task, the child is shown one of eight alphanumeric characters presented

upright, together with the same character or its mirror image, rotated at an angle

clockwise from the vertical (figure 4). The child must decide whether the pairs

of stimuli are identical or mirror images and respond as quickly as possible

without making errors. Performance is analyzed by computing the slope and

255
FIGURE 4. Sample problems from the Kail mental-rotation paradigm

SOURCE: Kail et al. 1980, copyright 1980, Academic Press

intercept of a line connecting the child’s mean reaction times at the different

degrees of rotation (figure 5). A flatter slope is assumed to indicate more

efficient spatial reasoning because processing time for objects rotated at more

extreme angles is not appreciably longer than for those closer to upright.

Reaction times on both the short-term memory and mental-rotation tasks

become markedly faster as children grow older. Comparisons of performance

across several of these tasks can indicate the degree to which observed deficits

are domain specific or reflect impairment in aspects of cognitive processing that

affect multiple domains.

Two outcomes that have been of considerable interest to investigators of

teratogenic exposures are sustained attention and activity level. Sustained

attention can be assessed in a vigilance or continuous performance paradigm.

In the task we have used, the child sits in front of a video monitor that displays a

picture of a house. Any of three stimuli—an apple, a butterfly, or a cat—can

appear in any of the three windows of the house, but the child is told to press

the red button only when the cat comes to the window. The cat appears 42

times over a 12-minute period at random intervals ranging from 4.5 to 52.0

seconds. Three measures are tabulated: reaction time to the criterion stimulus,

256
FIGURE 5. Kail mental-rotation paradigm: Reaction time by degree of

rotation (male eighth graders)

SOURCE: Keating et al. 1985

errors of omission (failing to press the button in response to the criterion

stimulus), and errors of commission (pressing in the absence of the criterion,

which is a measure of impulsivity). Streissguth and associates (1984, 1986)

have found relationships between prenatal alcohol exposure and poorer

sustained attention on this type of paradigm at both 4 and 7 years.

Needleman and associates (1979) found sustained attention deficits in low-level

lead-exposed children using rating scales completed by classroom teachers.

Exposed children were more likely to be rated as easily distracted during school

work, were less able to persist with a task for a reasonable amount of time,

were overexcitable and impulsive, and were unable to follow a sequence of

directions. Both the continuous-performance and rating-scale approaches for

assessing sustained attention have their limitations. Whereas the child’s score

on a 12-minute laboratory paradigm may be affected by his or her mood or level

of fatigue on the day of testing, rating scales are less objective and less subject

to halo effects. For this reason, multiple measures are recommended,

particularly for outcomes considered focal to the study.

257
Activity level can be assessed in infants and children using an actometer—

a mechanical device strapped to the arm or waist that records number of

movements per unit of time. Eaton (1983) found that actometer readings from

a single 20-minute nursery school free-play session were not very reliable,

however, presumably due to day-to-day variability in the child’s mood and in the

activities he or she chose to engage in. Data from 20-minute sessions spread

over 4 or 5 days, on the other hand, were considerably more reliable; coefficient

alphas were in the .70s, compared with only .33 for a single-day assessment.

Perhaps even more impressive was the finding that parental ratings of a child’s

activity level were highly correlated with actometer readings totaled over 14

sessions (r=.78). Contrary to conventional wisdom regarding parental bias,

parents apparently were able to provide highly accurate assessments of their

children’s activity levels. Another approach that has been recommended for

assessing activity level and sustained attention is direct behavioral observation

in which certain target behaviors, such as fidgeting or off-task behavior, are

coded as present or absent within discrete time intervals (Barkley 1988). This

approach, which has been validated with hyperactive children, has not been

used extensively in teratological studies to date.

CONCLUSION

It should be emphasized that, despite a plethora of available alternatives, the

Bayley and childhood IQ tests remain the most widely used procedures for

assessing the developmental effects of in utero toxic exposure. Although

the Bayley has been criticized for confounding assessment of cognitive

competence with sensorimotor dexterity, the breadth of domains it taps may

enhance its sensitivity to teratogenic insult. Due to dissatisfaction with the

Bayley’s poor predictive validity, many ongoing studies have added the Fagan

recognition memory paradigm; whether the Fagan will prove as sensitive to

teratogenic exposure has yet to be determined. IQ tests have been used

extensively with young children because they are valid predictors of school

performance. Despite controversy regarding their interpretation, there is a

broad consensus that IQ scores reflect at least some important aspects of

intelligence. Problems arise in teratological studies when low-level exposures

are found to be associated with small decrements in IQ, because the functional

significance of a 4- to 8-point deficit is not understood. In principle, a small

deficit in an IQ test, which reflects diverse cognitive competences, could

indicate significant impairment in one or two specific domains of cognitive

function. Detailed assessments of specific domains would be needed to

address this issue.

258
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1979.

AUTHORS

Joseph L. Jacobson, Ph.D.

Associate Professor

Sandra W. Jacobson, Ph.D.

Research Scientist

Psychology Department

Wayne State University

71 West Warren Avenue

Detroit, Ml 48202

261
New Methodologies for Evaluating

Residual Brain Damage in Infants

Exposed to Drugs of Abuse: Objective

Methods for Describing Movements,

Facial Expressions, and

Communicative Behaviors

Edward Z. Tronick, Marjorie Beeghly, Linda Fetters, and

M. Katherine Welnberg

This chapter describes three methods for characterizing the functional

organization of movements, facial expressions, and communicative gestures:

(1) kinematic analysis of movement, (2) muscle and template systems for

coding facial expressions, and (3) video-based coding systems to examine

communicative configurations. These methods promise to assess possible

residual brain damage affecting the organization of neuromotor functioning of

infants and children under 2 who were exposed in utero to cocaine and other

illicit drugs.

The chapter focuses on the control of movement because this is a primary brain

function in the infant and presents a number of approaches that may be

particularly relevant to the study of movement in infants exposed in utero to illicit

drugs.

Organization of spontaneous movements (e.g., general patterns of infant

“nondirected” activity)

Organization of instrumental movements (e.g., reaching)

Organization of facial expressions (e.g., patterns of muscle movements

controlling facial expressions)

Organization of communicative configurations of the limbs, hands, and head

(e.g., withdrawal and defensive patterns associated with stressful social

interactions)

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In the past, the assessment of abnormalities in movement control such as

jitteriness, jerkiness, cogwheel-like movements, “funny looking” facial

configurations, or asymmetries were based on clinical judgment and considered

“soft” signs of neurological dysfunction. However, new technology based on

infrared sensors, video recordings, and computers makes it possible to describe

normal and abnormal infant movements in a more precise and objective

manner. Although this technology is in a fledgling stage and, therefore, must be

used cautiously, it holds great potential for detecting underlying dysfunction.

EFFECTS OF PRENATAL COCAINE EXPOSURE ON INFANT GROWTH

AND DEVELOPMENT

lntrauterine Growth Retardation

Much evidence suggests that a disruption of intrauterine growth occurs in the

cocaine-exposed infant. Exposed infants have higher rates of prematurity and

show depressed weight, length, and head circumference (Zuckerman et al.

1989; Chasnoff and Griffith 1989). These effects remain even when use of

other potentially growth-retarding substances are controlled statistically

(Zuckerman et al. 1989; Ryan et al. 1987; Hadeed and Siegel 1989). Increased

incidence of microcephaly also has been reported (Hadeed and Siegel 1989).

Reports of intrauterine growth retardation (IUGR) in cocaine-exposed infants

raise concerns about postnatal behavior and development, because it is well

documented that IUGR is associated with compromised neuromotor and

socioemotional sequelae. For example, several researchers have documented

that IUGR results in poor state organization, hypotonla, decreased motor

maturity, and an increased number of abnormal reflexes durlng the newborn

period (Als et al. 1976; Beeghly et al. 1988; Lester et al. 1986; Lester and

Zeskind 1978). IUGR also is associated with long-term sequelae, including

neurobehaviorai deficits (Beeghly et al. 1988, 1990; Vohr et al. 1979), social

dysfunction in infancy (Beeghly et al. 1989, 1990), preschool cognitive deficits

(Walther and Ramaekers 1982), language delays (Walther and Ramaekers

1982), and poor academic performance (Henricksen et al. 1986).

Brain Damage

A number of preliminary findings are suggestive of residual brain damage to

infants exposed to cocaine in utero. Among such effects are clinically obvious

cerebral infarctions (Chasnoff et al. 1986) and clinically silent major ultrasound

abnormalities in the deep brain (Dixon and Bejar 1988). Cases of perinatai

cerebral infarction, seizures, intraventricular hemorrhage, and periventricular

ieukomalacia also have been reported (Oro and Dixon 1987; Cohen et al. 1989;

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Chasnoff et al. 1986). These effects often are ascribed to the vasoconstrictive

and hypertensive effects of cocaine, although direct effects associated with

the drug’s action on the catecholamine system should not be discounted, as

Mirochnick and coworkers (in press) are beginning to demonstrate.

Neurobehavioral Deficits

Neurobehavioral functional deficits from in utero exposure to cocaine have

been reported in neonates, including abnormal electroencephalogram (EEG)

findings and abnormal visual and auditory-evoked responses (Shih et al. 1989).

Disruption of brain stem function is possible because of cardiorespiratoty

abnormalities that occur at a higher incidence in cocaine-exposed infants

compared with opiate-exposed controls (Chasnoff et al. 1989). Increased

jitteriness among infants with cocaine metabolites in their urine at birth have

been noted (Parker et al. 1989). In a series of important studies, Chasnoff and

colleagues (1989) compared cocaine-exposed infants, opiate-exposed infants,

and nonexposed infants on the Brazelton Neonatal Behavioral Assessment

Scale (NBAS) (Brazelton 1984) and found increased tremulousness, poor

social interactive behavior, and poor organization of behavioral states. Other

neurobehavioral signs that have been found include increased irritability, highpitched and excessive crying, jitteriness, hyperactivity, rigidtty, hypertonicity,

hypotonia, coarse and choreiform movements, vigorous sucking, and abnormal

neuromuscular signs (Fulroth et al. 1989; Doberczak et al. 1988).

Motor Deficits

The long-term compromise of motor function is unknown. Schneider (1988)

has described deficits in muscle tone, reflexes, and volitional movements in

cocaine-exposed infants at 4 months of age. Furthermore, clinicians often

report persistent distal hypertonia in exposed infants.

Cognitive Deficits

Unfortunately, reports related to cognitive, motoric, and neurobehaviorai

deficits (Chasnoff and Griffith 1989; Rodning et al. 1989; Howard 1989) are

compromised by a number of serious methodological problems. The

techniques used are imprecise, based on clinical judgment, often insensitive

to the parameters and dimensions of concern, and only poorly quantifiable

(Tronick and Beeghly, in press). Many of these problems can be resolved

by new measurement systems to be reported here: kinematic analysis of

movement, muscle and template systems for coding facial expressions, and

video-based coding systems to examine communicative configurations. These

techniques permit objective descriptions of the behaviors that are most likely to

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be sensitive to brain dysfunction resulting from cocaine exposure. Moreover,

these measures can be readily coordinated with one another through the use of

similar experimental paradlgms and settings. This results in a rather complete

characterization of the infant’s neurobehavioral organization and the quality of

the infant’s interactions with the mother or other social partners.

KlNEMATlC ANALYSIS

Kinematic analysis specifies components of movement in an objective,

quantifiable, and precise fashion (Fetters and Todd 1987; Kluzik et al. 1990). A

typical kinematic analysis system weds high-speed computer technology with

high-resolution infrared sensors to track the movement of tiny infrared-emitting

diodes attached to the limbs of individuals whose movements are the subject of

study. Kinematic analysis has been used to develop detailed descriptions and

theoretical accounts of movement and motor control for normal adults (Harris et

al. 1984), normal infants (Jeannerod 1988), infants born prematurely (Claman

and Zeffiro 1986), and infants with central nervous system dysfunction (Fisk and

Goodale 1988).

Kinematic data describe movement, irrespective of its causation (Winter 1987),

in terms of position and the derivations of position. Thus, if reaching is the

movement under study, the exact positions of the wrist, elbow, and shoulder in

three-dimensional space are specified. The angles of the joints as the

movement occurs and the rate at which these points change also are

considered. Parameters such as angular velocities and accelerations,

movement unit size, pause times between movements, and others are

computed. Because kinematic parameters are objective and precise, one might

cautiously argue that motor dysfunction uncovered by kinematic analysis, as

opposed to other forms of motor assessment, is less likely to reflect the

caretaking experienced by the infant. Thus, this technology may be extremely

useful for uncovering residual brain damage.

A fundamental unit of kinematic analysis is the movement unit. Brooks (1974)

described continuous vs. discontinuous arm movement in monkeys with brain

lesions. A single acceleration followed by a single deceleration was a

characteristic of reaches for the intact monkeys, whereas the cerebellarlesioned animals displayed multiple acceleration/deceleration units.

Fetters and Todd (1987) and Von Hofsten (1979) defined the fundamental unit

of kinematic analysis in human adults and infants as the portion of movement

(e.g., a reach) between one acceleration and one deceleration, or the portion of

the movement between subsequent points in a curvature-speed relationship

(figure 1).

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FIGURE 1. The curvature-speed relationship is the fundamental movement

unit of motor organization.

This speed-curvature coupling also has been demonstrated in studies of adult

reaching movements (Abend et al. 1982). When subjects were asked to

produce curved reaches to a stationary target, they chunked their reaches into

untts, as defined by a decrease in speed coupled with an increase in curvature.

Similar results have been found in studies of adult handwriting (Viviani and

Terzuolo 1980).

Disturbances of kinematic parameters have been found to be associated with

central nervous system (CNS) damage. For instance, patients suffering from

cerebral vascular accidents (Lough et al. 1984) or posterior parietal lesions

(Jeannerod 1988) evidence aberrant movement during reaching tasks.

Kinematic parameters of patients with parietal lesions are distinguishable from

those of patients with frontal lobe lesions, cerebellar lesions, and premotor

cortex lesions (Claman and Zeffiro 1986; Fisk and Goodale 1988) or those of

normals.

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Movement organization has been studied in the developing infant. Thelen

(1982) studied kicking and Fetters and Todd (1987) studied reaching. From

7 to 12 months of age in normal full-term Infants, the number of movement units

decreases from 2.87 to 2.33, the straightness ratio (i.e., the distance the hand

travels compared with the shortest distance to the target) decreases from 2.05

to 1.71; the percentage of the total reach that Is made up by the first movement

unit increases from .48 to .63; and the total duration remains constant at

approximately 1.209 sec. These findings (Fetters and Todd 1987) demonstrate

that early reaches in the young infant include multiple units, with the number of

units decreasing with maturii. Thus, jerky stop-start actions give way to one

smooth, continuous acceleration, followed by a single deceleration. A mature

reach, which is achieved early in the second year of life, is characterized by a

single movement unit with only one stop-start action. This suggests that a lower

number of movement units reflects greater control of the reaching movement.

Thus, counting and timing movement units offers an important quantitative

measure of changes of control or coordination. Clearly, this advance in

understanding allows for a precise description of clinically useful patterns such

as jerkiness, tremulousness, and cogwheel forms of movement that heretofore

have been described only subjectively.

In a recent study of healthy preterm infants at 7, 9, and 12 months of age

(corrected), Fetters and Todd (1987) demonstrated subtle differences in the

movement strategies of healthy preterm infants compared with normal fullterms. As a group, healthy preterms are considered to be at low risk for

developmental problems compared with less healthy preterm infants. Using

kinematic analysis, these investigators found that preterms had a greater

number of movement units in their reaches compared with full-term controls,

even though, as in controls, the number of movement units in their reaches

decreased from 3.15 to 2.54. In addition, as in controls, the straightness ratio

of these preterm reaches increased from 2.13 to 1.56, and the duration was

relatively constant at approximately 1.215 seconds. Unlike the full-term infants,

however, the proportion of the reach made up by the first movement unit was

unchanged from 7 to 13 months and made up only 48 percent of their reaches

at 12 months. Thus, although the number of movement units within reaches

decreased as the preterm infants got older, they did not elongate the first unit;

that is, preterm reaching, even at 1 year of age, was characterized by multiple

units of similar duration. These differences in neuromotor organization indicate

a significant compromise of the healthy preterm infant’s neuromotor functioning.

Yet these subtle abnormalities are typically undetected by conventional

methods of developmental assessment.

Long-term effects of brain dysfunction were demonstrated using kinematic

analysis in a study of five children, ages 7 to 12, with cerebral palsy (Kluzik et

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al. 1990). In this study, an infant reaching for a target was compared before

and immediately after physical therapy treatment. Kluzik and colleagues found

that the reaches of these moderately to severely involved spastic children could

be described as slow, jerky in quality, and curvilinear in path. Before treatment,

the children averaged 3.7 movement units; the average duration of reach was

1,692 ms; and the straightness ratio was 1.2. By comparison, age-matched

controls typically perform this movement with a single movement in 300 to 600

ms (Kluzik et al. 1990). Following treatment, the number of movement

units decreased to 2.7, and average duration decreased to 1,267 ms (both

statistically significant). Furthermore, the duration of the first movement unit in

relation to the entire duration of the reach was significantly greater following

treatment. This indicates that the reach was becoming characterized by a

single movement unit (a single stop-start action), which is typical of mature,

well-controlled reaching movements. The length the hand traveled

(straightness) and the extent to which associated reactions occurred did not

differ significantly after treatment.

Kinematic analysis is clearly a major advance over more clinical assessments of

neuromotor functioning that rely on observer judgment and experience. While

behavioral measures are effective in describing major forms of dysfunction,

kinematic analysis detects subtle forms of dysfunction that are indicative of

brain damage. Kinematic analysis has the additional advantage of being able

to provide these data in both structured contexts (i.e., the examiner assisting

the infant in organizing the task) and unstructured settings (i.e., tasks requiring

self-organization by the infant). This advantage is critical because cocaineexposed babies appear to have most difficulty when testing requires selforganization, self-initiation, and followthrough (Rodning et al. 1989).

Furthermore, kinematic methods yield operational definitions of measures and

data that are sensitive to even minor levels of dysfunction and therapeutic

change. These qualities make kinematic analysis an extremely likely candidate

for detecting any existing neuromotor dysfunction associated with brain damage

in cocaine-exposed infants.

Paradigms for Eliciting Movements

A typical kinematic analysis is the WATSMART Version 2.7 (Northern Digital

Company). The WATSMART is a noncontact, nonintrusive optoelectric system

capable of recording high-speed kinematic motion as well as high-resolution

static displacements (figure 2). It is also capable of rendering three-dimensional

graphic displays of infrared light-emitting diodes (IREDs) in space. The IREDs

are tracked simultaneously by two highly accurate infrared sensors (cameras)

placed on a track approximately 6 feet above the seated subject and at

approximately a 90-degree angle to each other and a 45-degree angle to the

plane of movement. The accuracy is valid over the full 33-degree vertical and

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horizontal fields of view (45 degrees diagonal). The WATSMART cameras are

initially calibrated in relation to the test area using a 1m cube fixed grid with 24

IREDs embedded at known locations. As long as neither the cameras nor the

work station are disturbed, the system is reliable and accurate. The

WATSMART is used in conjunction with a PC Limited System 200 computer

(Dell Computer Corporation), an IBM AT clone.

The IREDs are fired sequentially by the central controller unit via a lightweight

strobe attached to the chair back (Scholz 1989). As the subject moves, the

FIGURE 2. Diagrammatic sketch of the WATSMART laboratory setup for

assessing adult movement

KEY: C1 and C2= infrared sensors; VC=video camera; T=target; W=wrist IRED

marker

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instantaneous position of each marker is digitized at a rate of 200 Hz, with a

resolution of approximately 1.0 mm. Any occluded points are flagged, and the

data are interpolated, if necessary, for the occluded points. Raw data are

converted to three-dimensional coordinates for graphic display of movement by

use of a direct linear transformation algorithm (Scholz 1989). When care is

taken to reduce reflected light in the measurement area and to prevent rotation

of the IREDs away from the cameras, highly reliable recordings of position

(r>.99; error<0.5 degree) can be obtained using WATSMART (Scholz 1989).

Reliability of movement trajectory is particularly sensitive to movement of the

IREDs away from the plane of the cameras, especially at endpoints of

movements (Scholz 1989). The reliability values for reproducing a fixed target

length rotated in three-dimensional space are below 2 mm. This means that the

WATSMART system reproduces the absolute length of the moving ruler with

errors of 2 mm or less.

Additional videotaping of reaching movements enhances interpretation of

WATSMART recordings The video data are coupled with a time-code

generator to record the precise time of movements. Systems based solely on

video technology are now available.

Procedures for eliciting storable movements can begin in the newborn period

and continue longitudinally. During the newborn period, spontaneous

movements can be elicited with inanimate visual and auditory stimuli, such as a

rattle, and/or with animate stimuli, such as the examiner’s face and voice. Of

course, special attention must be paid to the newborn’s behavioral state

because it is likely to modify the quality of the movements observed.

Importantly, these same procedures can be used over the course of

development because they will continue to be effective in eliciting spontaneous

and instrumental movements, as well as facial expressions and communicative

configurations. in older infants, reaches can be elicited easily with an object

placed in front of the child seated in a high chair. Spontaneous movements can

be elicited when the infant is sitting or lying without the use of an object or when

interacting with an adult in face-to-face play.

We expect that normal infant movements will contain fewer movement units and

decreased peak velocity in comparison with the movements of drug-exposed

infants. In particular, we expect that the movements of cocaine-exposed infants

will (1) be made up of a greater number of movement units (i.e., less smooth);

(2) be less oriented toward the midline/target (i.e., less accurate/less directed);

(3) have more minor accelerations and decelerations not large enough to be

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considered movement units (i.e, fine tremor); (4) evidence higher velocity

movements: and (5) show a greater number of associated head movements. In

other words, it is expected that normal infant movements will be quantified as

smooth, well-oriented, and controlled compared with the movements of cocaineexposed infants, which will contain many stop-start actions.

FACIAL EXPRESSIONS ANALYSIS

Methodologies are now available for objectively coding facial expressions

(Ekman and Friesen 1978; lzard 1979; lzard et al. 1980). Facial expressions

are a crucial component of the infants communicative capacities. They provide

caretakers with information necessary for the successful meeting of the infant’s

homeostatic and developmental requirements (Tronick 1989). Survival and

development depend significantly, therefore, on the integrity of this signaling

system. Reflecting this adaptive function, large areas of the brain are devoted

to the control of facial expressions. Indeed, one might argue that no other

system shows the variety and subtlety of movement patterns as early in

development as does the facial musculature and that it may be the most

developed of the infant’s motor systems (Izard 1971). Thus, although not

traditionally viewed as an assessment domain, analyses of the integrity and

organization of facial expressions may prove to be especially fruitful.

Most facial measurement systems can be loosely grouped into two categories:

template-based systems and anatomically comprehensive systems. Templatebased systems, such as Izard’s Maximally Discriminative Facial Movement

Coding System (MAX) (Izard 1979) and System for Identifying Affect

Expressions by Holistic Judgements (AFFEX) (Izard et al. 1980), identify

patterns of facial muscle movements that have been empirically or theoretically

linked to discrete emotions.

Anatomically comprehensive systems, such as Ekman and Friesen’s Facial

Action Coding System (FACS) (Ekman and Friesen 1978), code emotionally

significant facial movements as well as any other facial behavior, regardless of

its relation to affect. Both types of scoring systems are designed to eliminate

subjective bias in identifying emotional expressions by focusing on distinct facial

muscle configurations in specific areas of the face.

Izard’s MAX and AFFEX systems are designed specifically for use with young

children. The basic assumption is that infant emotions are expressed in

organized patterns of facial movements. The emotions identified by MAX and

AFFEX include interest-excitement, enjoyment-joy, surprise-astonishment,

sadness-dejection, anger-rage, disgust-contempt, fear-terror, shame-shyness,

discomfort-pain, or distress-anguish. To score these emotions, coders look for

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anatomical changes in the musculature of three regions of the face: the

forehead/eyebrows/nasal root region, the eyes/nose/cheeks region, and the

mouth/lips/chin region. Coders using the AFFEX system make judgments

about the presence of emotions from the pattern of the entire face at once,

whereas coders using MAX need to complete three runs of each video segment

to score each facial region separately.

The objectivity of the two systems stems from the fact that coders make

judgments regarding the presence or absence of clearly defined facial

movements. They do not make judgments based on their perception of the

emotional content of the expression or on the context in which the expression

occurs. Furthermore, because each of the fundamental emotions is defined in

terms of a specific set of facial movements, they can be differentiated from each

other, as well as from blends of emotions or from facial patterns not specified by

MAX or AFFEX.

Ekman and Friesen’s FACS is designed to score the facial expressions of

adults. FACS is more comprehensive than MAX and AFFEX, recording all

observable facial muscle movements, regardless of their importance in

determining emotional expressions. The system distinguishes 24 discrete

action units, 20 miscellaneous facial actions, and 14 action units designating

head and eye positions. The system identifies six emotions—joy, surprise,

sadness, anger, disgust, and fear—by analyzing the muscle movements in the

forehead/eyebrows/nasal root region, the eyes/nose/cheeks region, and the

mouth/lips/chin region. Recently, FACS has been adapted for use with infants.

Oster’s (1990) BABY FACS is designed to precisely describe facial expressions

at each stage of development and to determine the affective meaning of these

expressions by taking into account their antecedents and behavioral correlates.

The major disadvantage of FACS is that its comprehensiveness makes it more

time-consuming than the MAX or AFFEX systems. Nevertheless, because

FACS codes all facial movements and does not specify a priori which facial

patterns are significant, the system can be used to evaluate the role of facial

movements that are not obviously or necessarily emotional. Moreover, it is

precise enough to evaluate variations in timing, intensity, and sequencing of the

components that make up facial expressions (Campos et al. 1983).

Methodological advances in facial-expression scoring have been instrumental in

investigating the importance and function of emotlons and their development

from infancy to adulthood. Research during infancy has relied heavily on the

use of MAX and AFFEX and has emphasized the developmental emergence

and function of emotions. This work indicates that certain facial expressions are

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present at birth, whereas others become functional later In development.

Furthermore, these facial expressions tend to occur in response to particular

events and are remarkably similar to the facial expressions of adults. Research

also has established that mothers and other adults are sensitive to these

emotional displays, even when the Infant is very young and in the absence of

contextual cues (Campos et al. 1983).

To date, these coding systems have not often been employed with clinical

populations such as drug-exposed infants, even though they could readily be

used to address issues of concern. For example, are exposed infants able to

control their facial musculature in a manner that results in fully formed and

well-organized expressions, or do they show dysfunctional patterns (e.g.,

asymmetries)? Do they lack particular expressions? Is the timing of the

different components that make up an expression well organized, or do these

infants evidence problems in controlling movements in a simultaneous and

sequential fashion? Do they evidence normal relations between facial

expressions and environmental events, or do they respond with expressions

that are inappropriate and dysfunctional (e.g., distress faces in response to

normal interactive play)? It is critical to note that dysfunction in the ability to

modulate facial expressions is likely to reflect underlying damage to the

systems controlling these expressions. Such dysfunction also would distort the

infant’s communicative abilities and, consequently, the ability of others to

interact with the infant.

Paradigms for Eliciting Facial Expressions

Criteria for paradigms useful in studying the organization of facial expressions in

cocaine-exposed infants include (1) availability of normative data, (2) likelihood

that the paradigm will elicit a wide range of normal facial expressions, and (3)

ability to stress the infant’s current developmental capacities to bring out

underlying differences. Only the latter criterion requires some elaboration.

In general, dysfunction is more evident in a stressed than in an unstressed

system. A dysfunctional child in a standard paradigm may perform within

normal limits when the task is easy or well structured. When a task becomes

difficult or places more demands on the child for self-regulation and selfinitiation, however, previously unnoticed problems may become evident. For

instance, facial expressions may become asymmetrical only when an infant is

highly aroused. In support of this hypothesis, recall that cocaine-exposed

infants appear to perform within normal limits on well-structured cognitive tasks,

yet perform significantly below agemates on more unstructured tasks, which

require more self-regulation and self-initiation (Rodning et al. 1989).

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Three assessment paradigms satisfy these criteria:

1. Normal and stressful face-to-face interactions between adults and infants 1

year of age or younger

2. Ainsworth and colleagues’ (1978) Strange Situation paradigm for children 1

year and older

3. Unstructured, structured, and distorted interactive play involving children 2

years of age and older

Face-to-Face Paradigm

The face-to-face paradigm is a sequence of three episodes in which a normal

social interaction is followed by a perturbated interaction and then another

normal social interaction. In the normal conditions, mothers are simply

instructed to play with the infant. Although the nature of the perturbated

interactions varies from study to study, the two most common distortions include

having the mother (1) remain still-faced and unresponsive (Tronick et al. 1978)

or (2) assume a withdrawn, depressed countenance (Cohn and Tronick 1983),

In the still-face condition, mothers are told to look at the infant with a neutral

face and not to touch or talk to the infant. In the depressed condition, mothers

are told to speak in a monotone, to minimize movement and touch, and to act

tired and depressed. The still-face has an advantage over the simulated

depression condition because it is more easily standardized. The length of

each episode varies across studies, with an average duration of 2 to 3 minutes.

The typical face-to-face laboratory consists of a video studio and an adjoining

equipment room. The studio is equipped with an infant seat mounted on a

table, an adjustable stool for the mother, two cameras, a microphone, and an

intercom (figure 3). The infant is seated in the infant seat placed on a table

surrounded by an alcove of curtains. The mother sits on the adjustable stool in

front of the infant. One camera is focused on the infant and one on the mother.

Both video pictures are transmitted through a digital timer and split-screen

generator into a single videorecorder to produce simultaneous frontal views of

the mother and the infant. The digital timer, split-screen generator, and

videorecorder are located in the adjoining equipment room in which the

experimenter times the episodes and gives the mother instructions via the

intercom (Tronick et al. 1980). The setup and camera angles produce

extremely clear recordings of the infants’ and the adults’ facial expressions

and gestural behaviors.

Normative behavioral data for infant-mother interaction and the still-face are

available (Tronick 1989). Weinberg and Tronick (1991a), Malatesta and

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FIGURE 3. Diagrammatic sketch of the face-to-face laboratory setup

colleagues (1989), Oster and Ekman (1978), Cohn and Tronick (1983), lzard

and colleagues (1980), and Tronick and Weinberg (1990a) present data on

facial expression coding for children from birth to ages 2 years and older. In

these reports, normal infants display a wide range of facial expressions

representing well-organized, dynamically changing configurations of

movements that are specific to environmental events. For example, normal

infants predominantly display Joy and Interest faces in normal interactions but

Anger, Sad, and Interest faces to the still-face (Weinberg and Tronick 1991a)

(table 1). Whether cocaine-exposed infants show well-organized facial

expressions in response to specific events is unknown. Evaluation of the

integrity of these functions in different environmental situations would be

extremely important.

Ainsworth’s Strange Situation

The Ainsworth Strange Situation (Ainsworth et al. 1978) is a standardized

laboratory procedure designed for 12- to 18-month-old infants and their

mothers. Its purpose is to assess the quality of the infant’s attachment to the

mother and to evaluate the infant’s ability to use the mother as a resource

275
TABLE 1. Proportion of time infants displayed each AFFEX-coded facial

expression during play 1, the still-face, and play 2

Proportions of each facial expression

Facial expression* Play 1 Still-Face Play 2

Joy .26a

† .06b.32c

Interest .60a

.72b.51C

Sadness .00a.04b.03c

Anger .04a.07b.06b

*AFFEX codes are mutually exclusive.

†Different superscripts are significantly different from each other at p<.001.

SOURCE: Weinberg and Tronick (1991a)

(“secure base”) for coping with stress. Attachment theory posits that forming a

secure attachment relationship with the mother is a major, age-appropriate task

of late infancy. Moreover, it contends that the quality of the infant’s attachment

to his or her mother predicts to the quality of the child’s developmental outcome

(Ainsworth et al. 1978).

The Strange Situation consists of eight increasingly stressful episodes arranged

in a standard sequence (table 2). The procedure assesses how the infant uses

his or her mother as a secure base for exploration in an unfamiliar environment

and how he or she responds to the appearance of a stranger, to separations

from and subsequent reunions with the mother, and to attempts by the mother

and the stranger to soothe him or her (figure 4). The entire procedure is

videotaped and takes approximately 25 minutes.

Although a large body of research attests to the validity and reliability of Strange

Situation behavior, coded according to attachment constructs (Ainsworth et al.

1978), investigators have not typically assessed the organization of facial

expressions per se using this paradigm. However, the Strange Situation elicits

a rich array of infant facial expressions and behaviors. For best results, input

from two cameras should be used to obtain clear views of the mobile infant’s

face. For example, Weinberg and Tronick (1991b) have demonstrated that 1-

year-olds display a wide range of facial expressions in the Strange Situation

that occur reliably in response to specific episodes and contexts. Analyzing the

276
TABLE 2. Summary of episodes of the strange situation

Number of

Episodes

Persons

Present Duration Brief Description of Action

1 Mother, baby,

and observer

2 Mother and

baby

3 Stranger,

mother, and

baby

4 Stranger

and baby

5 Mother and

baby

6 Baby

7 Stranger

and baby

8 Mother and

baby

30 sec

3 min

3 min

3 min First separation episode. Stranger’s

or lessa

behavior is geared to that of baby.

3 min

or moreb

First reunion episode. Mother greets and/

or comforts baby, then tries to settle baby

again in play. Mother then leaves,

saying “bye-bye.”

3 mln

or lessa

3 min

or lessa

3 min

Observer introduces mother and baby to

experimental room, then leaves.

Mother is nonparticipant while baby

explores; If necessary, play is stimulated

after 2 minutes.

Stranger enters. First minute: Stranger

silent. Second minute: Stranger

converses with mother. Third minute:

Stranger approaches baby. After 3

minutes mother leaves unobtrusively.

Second separation episode.

Continuation of second separation.

Stranger enters and gears behavior to

that of baby.

Second reunion episode. Mother enters,

then greets and picks baby up.

Meanwhile stranger leaves

unobtrusively.

aEpisode is curtailed if the baby is unduly distressed.

bEpisode is prolonged if more time is required for the baby to become reinvolved in play.

SOURCE: Ainsworth et al. 1978, copyright 1978, Erlbaum

facial expressions of infants exposed to cocaine in this standard context would

allow comparison of the development and organization of facial configurations

of this sample with those of nonexposed children.

277
FIGURE 4. Diagrammatic sketch of Ainsworth’s Strange Situation

KEY: S=stranger; M=mother

Play Paradigms

Play paradigms are quite numerous (Rubin et al. 1983). Children’s play has

long been regarded as a powerful index of toddlers’ cognitive-motivational

competence and affective expressiveness (Piaget 1962; Vygotsky 1978). Play

is a salient and meaningful activity for most toddlers—an important means by

which they explore the environment and form concepts about objects, events,

causality, and interpersonal relationships (Bruner 1964, 1972).

In many play paradigms, the examiner typically seats the child and mother/adult

on the floor of a laboratory playroom with a box of standard, age-appropriate

toys. The dyad then is invited to play with the toys. In general, mothers are

instructed to play with the child “as you normally would at home.” In some

studies, maternal behavior is constrained with the instructions not to direct the

276
child’s play but to participate in play and be responsive to any requests for help

or social interaction. The dyad’s play behavior is videotaped (15 to 30 minutes)

from behind one-way mirrors. Facial expressions (and other behaviors) may be

coded from these video recordings.

Contextual issues need to be considered in the design of play-assessment

paradigms, because they have been demonstrated to affect children’s play

performance and affective involvement in systematic ways. For instance,

children tend to exhibit more enthusiasm and higher object play maturity

when interacting with an involved (as opposed to a passive) adult partner.

Similarly, modeling paradigms elicit higher levels of play maturity and affective

involvement for many children than do free-play procedures (McCune-Nicolich

and Fenson 1984). However, not all children respond to structure with

improved performance: Children with socioemotional delays and behavior

problems appear to perform better in unstructured conditions (Kennedy et al.

1991).

Among the available play paradigms described in the extant literature (Rubin et

al. 1983), three play procedures have proven useful for eliciting a wide range of

infant facial expressions, especially when used in combination with each other.

These paradigms, taken together, include structured as well as unstructured

phases and vary in the level of stress they introduce.

Free Play. During unstructured play with an older partner, children’s ageappropriate social, emotional, and cognitive functioning can be observed

(Beeghly et al. 1989). Moreover, children initiate, organize, and sustain play

activities during free play, allowing a glimpse of their self-regulatory capacities.

Facial expressions and overall assessments of child competence and wellbeing also are measured in this context. As children show greater enthusiasm

and produce developmentally more mature forms of play behavior when playing

with an actively involved adult, including an interested, nondirective adult

partner is recommended.

Structured Social Play. Structured play paradigms involving social turntaking

games are useful for measuring developmental changes in children’s social

interactive skills. Ross and Lollis (1987) demonstrated significant age-related

increases in toddlers’ (9 to 18 months) ability to participate actively in social

games with adults during late infancy and toddlerhood. They used a structured

turntaking procedure with two phases: (1) establishment of reciprocal

turntaking games with standard objects and (2) an interruption period involving

a pause in adult behavior analogous to the still-face condition of the face-toface paradigm (described above). Children’s ability to initiate and sustain

turntaking as well as their verbal and behavioral attempts to regulate and

279
reestablish turntaking were measured. Furthermore, affective expressions can

be expected to vary widely in this paradigm.

Self-Regulatory Play Paradigm. The Self-Regulatory Play Paradigm is a

structured, five-phase social play procedure (Beeghly et al., in preparation)

designed to assess toddlers’ ability to initiate, maintain, and regulate/reestablish

social interaction with an adult. In the first phase, the mother plays naturally

with her child for 5 minutes. In the second phase, an unfamiliar adult then

establishes reciprocal turntaking games with the child for 5 minutes. After a 30-

second pause, a 2-minute interruption phase follows, during which the adult’s

behavior, affect, and vocalizations become completely noncontingent with the

child. The adult scrambles toys in a somewhat disorganized manner while

vocalizing and producing positive affect. Following this phase, the adult pauses

for 30 seconds and then attempts to reestablish turntaking games with the child

for an additional 5 minutes. In the final phase, the mother again plays with her

child for 5 minutes, as in phase 1. The content and organization of children’s

affective, social-communicative, and behavioral responses during each

segment are coded.

We recommend that these three play paradigms be used in conjunction with

each other, because together they (1) include structured as well as unstructured

components, (2) vary in the level of stress they introduce, and (3) are powerful

elicitors of a wide variation in the affective expressions of the child, making

children’s self-regulatory and social-communicative abilities readily apparent. In

addition, qualitative aspects of children’s play performance can be measured

(e.g., quality of responsiveness, cost of attention) that are not directly tapped in

standardized psychometric tests. Thus, play assessments may discriminate

high- and low-risk groups of children better than psychometric tests. Rodning

and colleagues (1989) reported that children exposed to multiple drugs of

abuse in utero exhibited representational play less frequently and less

coherently during unstructured free play than controls. In contrast, these drugexposed children performed within the normal range on standardized

psychometric tests of sensorimotor development.

COMMUNICATIVE CONFIGURATIONS

In addition to facial expressions, communicative behaviors are well organized

and available to exacting description. Investigators hypothesize that a “natural”

relation between communicative behaviors and facial expressions exists (Cohn

and Tronick 1983; Gaensbauer et al. 1979; Tronick et al. 1980). Recently,

Weinberg and Tronick (1991a) demonstrated that facial expressions and

communicative behaviors co-occur in a reliable, highly organized fashion.

280
Communicative configurations may be used to evaluate the effects of cocaine

exposure on infant socioemotional development.

Because communicative configurations are most easily elicited in the same

paradigms that are used for eliciting facial expressions alone, no additional

data collection is required to evaluate their organization. Thus, the organization

and timing of facial expressions, communicative behaviors, and combinations

of both can be evaluated. Similarly, the relations of facial expressions,

communicative behaviors, and combinations of both to external events can be

examined.

Several researchers have developed scoring systems that cluster behaviors

and facial expressions into communicative configurations (Cohn and Tronick

1983; Gaensbauer et al. 1979; Tronick et al. 1980). These scoring systems

combine information about facial and vocal expressions, posture, gaze, and

type of activity on an a priori basis. Matias and colleagues (1989), however,

have reported strong correlations between detailed codes of behavior, including

facial expressions, and Beebe and Gerstman (1980) have found that behaviors

and facial expressions change as “packages” as a function of changes of

rhythm in mother-infant interactions. Furthermore, Brazelton and colleagues

(1974) found that the newborn’s alert face is accompanied by smooth

movements, eyes oriented toward mother, and fleeting smiles, grimaces, and

vocalizations. Periods of withdrawal, on the other hand, are characterized by

glazed or dull expressions, little movement, and face and eyes oriented away

from the mother. In addition, Fogel and Hannan (1985) have speculated that

some discrete hand movements may be associated with particular arousal

states. These authors found that pointing tends to occur before or after

mouthing and vocalizations, curling of fingers during vocalizations, and

spreading of fingers when the infant is looking away from the mother.

Weinberg and Tronick (1991) examined the relations among the modalities of

face, voice, gesture, gaze, and self-regulatory and withdrawal behaviors that

typically occur in normal and perturbated interactions of mothers and infants.

As noted, normal interactions typically elicit positive expressions, elicit whereas

perturbated interactions (e.g., the mother holding a still-face) often elicit

negative affective states. Coding of these interactions used systems designed

to separately characterize facial expressions, gestures, self-comforting

behaviors, vocalizations, and gaze (Tronick and Weinberg 1990b). These

codes are presented in abbreviated form in table 3. They can be used with any

high-quality videorecording of infant behavior. Coding is best carried out by

coders trained on only one or a few of the codes. This results in highly reliable

and objective coding.

281
TABLE 3. The lnfant Regulatory Scoring System (IRSS)

Social engagement The infant looks at or glances at the mother’s face.

Object engagement The infant looks at or manipulates an object for 2

seconds or more.

Scans The infant briefly glances at objects or around the

laboratory without focusing on anything for longer

than 2 seconds.

Signals/solicitations Vocalizations: The infant signals the mother by

vocalizing with neutral/positive, fussy, or crying

vocalizations.

Gestures: The infant signals the mother by gesturing

to be picked up or by moving his or her arms in an

organized manner in the direction of the mother

(e.g., banging his or her arms or kicking his or her

legs).

Oral behavior/

self-comforting

The infant self-comforts by sucking on his or her

body (e.g., thumb sucking) or sucking on an object

(e.g., the chair strap).

Escape/get away The infant attempts to distance himself or herself

from the mother by turning, twisting, or arching his

or her body.

Distress indicators The infant exhibits behaviors that indicate distress

such as spitting up, hiccupping, or heavy breathing.

Inhibition/ freezing The infant inhibits his or her perceptual, motor, and/

or attentional processes to minimize engagement

with the mother and the surroundings.

SOURCE: Weinberg and Tronick (1991a)

Weinberg and Tronick (1991a) found that in both normal and perturbated

interactions (i.e., still-face), 6-month-old infants’ behaviors were strongly related

to one another and to facial expressions (coded by Izard’s AFFEX system; table

4). Specifically, facial expressions of joy were most likely to occur when the

infant was looking at the mother, positively vocalizing, and mouthing a body

282
part. Together these behaviors formed a coherent configuration of positive

person-oriented behaviors. This characterization was supported further by the

finding that AFFEX joy was unlikely to co-occur with behaviors that exclude

positive social engagement such as fussy vocalizations, crying, and escape/get

away. Facial expressions of interest tended to co-occur with sustained and

brief exploration of objects and with mouthing objects. AFFEX interest was

unlikely to co-occur with behaviors indicative of a positive, socially oriented

engagement (e.g., positive vocalizations) and with behaviors indicative of social

disengagement (e.g., crying or attempts to escape/get away). These data

suggest that the affective configuration of interest is characterized by an active

engagement with the inanimate environment.

TABLE 4. Likely and unlikely affective action configurations

Type Likely Configurations Unlikely Configurations

1 Facial expression of joy

Look at mother

Positive vocalizations

Mouthing body part

2 Facial expression of interest Facial expression of interest

Look at objects Look at mother

Scans Mouthing body part

Mouthing objects Escape/get away

3 Facial expression of sadness

Fussy vocalizations

Facial expression of sadness

Positive vocalizations

4 Facial expression of anger

Scans

Fussy vocalizations

Crying

Pick-me-up gestures

Escape/get away

Facial expression of anger

Look at objects

Positive vocalizations

Gestural signals

Distress indicators

Facial expression of joy

Look at objects

Scans

Fussy vocalizations

Crying

Mouthing objects

Pick-me-up gestures

Escape/get away

SOURCE: Weinberg and Tronick (1991a)

283
Facial expressions of sadness were primarily associated with fussy

vocalizations. Furthermore, infants displaylng sadness were unlikely to look at

either the mother or objects and to vocalize in a fussy manner or cry. Thus, this

configuration reflected a passive withdrawn state characterized by reduced

involvement with both people and objects and by low levels of activity. Facial

expressions of anger, on the other hand, were associated with several active

behaviors such as scans, fussy vocalizations, fullblown crying, pick-me-up

gestures, and attempts to escape/get away. Together these behaviors reflect a

negative affective state characterized by behaviors that function to actively

disengage the infant from both the mother and the inanimate environment. This

characterization was further confirmed by the finding that AFFEX anger is

unlikely to co-occur with looking at objects, indicative of engagement with the

inanimate environment, or with gestural signals and positive vocalizations,

behaviors indicative of a positive social engagement. This study supports the

assumption that highly organized communicative configurations exist during

infancy. Based on this research, one can hypothesize that cocaine-exposed

infants will evidence disorganized communicative configurations and relations to

stimulus events.

CONCLUSION

Until recently, investigators have regarded the control of movement as closed

to objective scrutiny, although they have long recognized it as a central

dimension of infant functioning. In this chapter, three objective, reliable

methods of assessing movement control are described that open up new ways

of uncovering possible forms of brain dysfunction in infants: (1) kinematic

analysis of movement, which taps the organization of both spontaneous and

instrumental movements; (2) muscle and template-based systems for coding

facial expressions, which objectively measure patterns of movements

controlling facial expressions; and (3) video-based coding systems to examine

configurations of communicative behavior and affect. All these methods tap

movement patterns that provide critical indices of the functional organization of

the CNS. Moreover, these techniques provide objective descriptions of

movement patterns that are most likely to be sensitive to brain dysfunction

resulting from cocaine exposure.

In addition, specific paradigms for eliciting movement patterns are described for

use with these three assessment methods. With the exception of kinematic

analysis, none of these paradigms was originally designed to assess movement

control in infants and young children. Yet, each of these well-known,

standardized paradigms allows a full and rich characterization of the child’s

movement in a few settings and in a limited timeframe.

284
Moreover, to the extent that one observes infants in interaction with their

mothers in these paradigms, one also can use these procedures to evaluate

with precision the quality of the mother-child interaction. This is crucial,

because the mother-infant relationship is a major determinant of the child’s

functioning and developmental outcome when considered in conjunction with

the integrity of the child’s CNS (Tronick 1989).

By offering increased precision and objectivity to the assessment of movement

control, the three methods described in this chapter may revolutionize our ability

to detect and quantify brain dysfunction in early childhood. It is our belief that

these methods hold great promise for the assessment of infants and young

child exposed in utero to cocaine or other illicit substances.

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infants. Under review, 1991a.

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N Engl J Med 320:762-768, 1989.

AUTHORS

Edward Z. Tronick, Ph.D.

Associate Professor of Pediatrics

Harvard Medical School

Chief

Child Development Unit

289
Marjorie Beeghly, Ph.D.

Assistant Professor

Harvard Medical School

Research Director

Child Development Unit

M. Katherine Weinberg, M.S.

Research Director

Child Development Unit

The Children’s Hospital

300 Longwood Avenue

Boston, MA 02115

Linda Fetters, Ph.D.

Associate Professor of Physical Therapy

Sargent College

Boston University

One University Road

Boston MA 02215

290
Rationale and Methodologies for

Developing Nonhuman Primate Models

of Prenatal Drug Exposure

Stephen J. Suomi and J. Dee Higley

BACKGROUND AND RATIONALE

The recent escalation of cocaine abuse and addiction has increased awareness

of a difficult and growing problem. Because many cocaine users are females of

childbearing age, the number of infants exposed prenatally to cocaine has

reached epidemic proportions. General estimates of the percentage of all

infants exposed prenatally to cocaine in the United States range from about 15

to 20 percent of the total infant population (Chasnoff et al. 1990; Frank et al.

1988), with some childbearing populations at much greater risk to abuse drugs

during pregnancy than others (Amaro et al. 1989; Zuckerman et al. 1989). In

some areas of the Nation, nearly 50 percent of the females who give birth report

or test positive for recent cocaine use at time of delivery (Osterloh and Lee

1989; Amaro et al. 1990). Closely paralleling this epidemic is the recent

increase in female polydrug use and the continued problem of female addiction

to other drugs such as opiates and alcohol (Osterloh and Lee 1989; Edelin et al.

1988; Krug 1989), further increasing the risk to developing fetuses of exposure

to harmful substances. Given the sheer number of infants and children that

have been or will be affected by prenatal exposure, the diverse number of

medical and psychological problems that these infants tend to show, and the

relative ignorance of long-term outcomes of prenatal drug exposure, it seems

imperative that these children be studied extensively to develop effective

treatment and prevention programs.

Although to date there are few if any long-term studies of children exposed

prenatally to cocaine, recent studies have examined neonates or performed

short-term followup investigations of infants exposed in utero to cocaine and

other abused drugs. Postnatal clinical reports of these infants indicate that they

present a diverse range of medical and psychological problems, depending in

part on whether additional illicit drugs were used, on the type of illicit drug and

frequency of abuse by the pregnant mother, and the timing and duration of

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prenatal exposure. These postnatal problems include a variety of behavioral

and temperamental deficits, with wide interindividual differences in severity

(Chasnoff and Griffith 1989; Cherukuri et al. 1988; Kaye et al. 1989; Kopp

1983).

Predicting outcomes and establishing cause-effect relationships between

human prenatal drug exposure and neonatal deficits can be highly problematic,

given the numerous uncontrolled and confounding variables that can potentially

affect vulnerability and specific outcomes. Cocaine users, for example, may

differ from nonusers in terms of their nutritional state, weight gain during

pregnancy, and the amount of prenatal care they receive. Each of these

variables also produces its own effects on the growing fetus, thereby posing an

ethical dilemma when constructing suitable control groups. More importantly,

however, failure to obtain accurate information about the time course and

dosage of drug use by pregnant women adds substantial error variance to the

data, as well as making it difficult to pinpoint those exposure periods in which

the fetus is most sensitive to insult. Finally, interactions between drugs also

must be taken into account. Cocaine users frequently use other licit (e.g.,

nicotine, alcohol) and illicit drugs in combination. Extensive use of illicit and licit

drugs already is known to increase fetal risk.

Because many of these variables cannot be readily controlled in human settings

for both ethical and practical reasons, some investigators have turned to animal

models to address these issues. These researchers have been able to show

that when animal subjects are exposed during pregnancy to abused drugs

under highly controlled experimental conditions, physical and behavioral

anomalies result in the exposed offspring that resemble many of the symptoms

seen in drug-exposed human infants (e.g., Henderson and McMillen 1990;

lnouye et al. 1985; Spear et al. 1989; Bowden et al. 1983). Thus, animal

models can be developed that provide the needed control over extraneous

variables, allowing researchers to establish cause-effect relationships and

assess both short- and long-term outcomes after prenatal exposure to illicit

drugs. Of course, the validity and utility of any animal model depend ultimately

on the degree to which the findings from the animal model generalize to the

human phenomenon in question (Harlow et al. 1972; Suomi and lmmelmann

1983). Some of the most compelling animal models have used nonhuman

primates, humankind’s closest biological relatives.

To date, few if any investigators have begun to establish any nonhuman

primate models explicitly designed to examine the short- or long-term

physiological, cognitive, or social-emotional consequences of prenatal exposure

to cocaine. However, this is not to say that such models could not be readily

developed. On the contrary, the current database regarding nonhuman primate

biobehavioral development and the state-of-the-art experimental designs and

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methodologies now available to primate researchers strongly suggest that such

models are quite feasible and are apt to be of considerable significance in

advancing basic knowledge at the human level.

There are several areas in which carefully developed nonhuman primate

models of prenatal drug exposure could make significant contributions to

knowledge regarding the human phenomena. First, nonhuman primate models

could provide information regarding effects of prenatal drug exposure on the

fetus prior to birth and on neonatal reflex and response patterns of prenatally

exposed infants shortly after birth. Second, appropriate nonhuman primate

models could be used to assess possible cognitive, social, and emotional

deficits as well as to evaluate the efficacy of various postnatal intervention

efforts during late infancy and juvenile periods, for which well-established

normative developmental milestones already exist for several nonhuman

primate species. Finally, because most nonhuman primate species mature

several times faster than Homo sapiens, it is feasible to carry out long-term

longitudinal studies of prenatally exposed individuals through puberty and into

the next generation. These studies could be conducted prospectively within a

4- or 5-year period, modeling a developmental transition that would be very

difficult and extraordinarily time-consuming to study systematically in human

adolescents and young adults who have been prenatally exposed to cocaine

and/or other abused substances. In the sections that follow, each of these

areas is addressed in detail.

PRIMATE MODELS INVESTIGATING PRENATAL AND PERINATAL

EFFECTS OF DRUG EXPOSURE

As mentioned previously, one of the strongest arguments favoring the

development of animal models of prenatal drug exposure involves the

opportunity to manipulate systematically the frequency, dose level, and period

of prenatal exposure under highly controlled conditions and to compare the

consequences of such manipulations with nonexposed fetuses whose mothers

are otherwise maintained under identical conditions of diet, housing, etc.

Prospective studies of this type should enable investigators to establish causal

dose/timing-outcome relationships, especially if they were to use nonhuman

primate species for which there exists a large normative database regarding the

timing and sequence of prenatal development (Kemnitz et al. 1984). Several

different techniques for exposing fetuses of different gestational ages to precise

quantities of specific toxins have been developed in recent years. Although a

detailed discussion of such techniques is beyond the scope of this chapter, it is

clear that appropriate methodologies for simulating prenatal exposure to

cocaine at predetermined gestational ages, frequencies, and dosages now exist

and could be used in nonhuman primate models.

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A range of prenatal and perinatal outcome measures also exists that would be

relevant for a primate model of prenatal cocaine exposure. Most of these

measures have been developed either to document species-normative patterns

of fetal growth and maturation or to characterize the effects of different maternal

diets (e.g., those low in protein or high in cholesterol) or maternal exposure to

environmental toxins (e.g., PCBs or dioxin) during pregnancy. Standardized

sets of teratological measures of organ and tissue growth, differentiation, and/

or degeneration typically are obtained in fetuses at specified gestational ages

in many of these studies (e.g,, Uno et al. 1990). Other studies have used

ultrasonic techniques to characterize fetal development throughout the entire

pregnancy; many of these investigations have included evaluations of postnatal

viability as well. For a few nonhuman primate species, such as rhesus

monkeys (Macaca mulatta), the extant literature is sufficiently detailed to

provide a solid basis for characterizing and evaluating any adverse

consequences of various schedules and levels of prenatal exposure to cocaine.

In addition to these physical growth measures, there is an expanding database

concerning normative patterns of neonatal reflex and behavioral development in

several nonhuman primate species. Some of these data come from extensive

longitudinal studies of newborns under carefully controlled and standardized

nursery rearing and test conditions, for example, the infant test battery

developed at the University of Washington Primate Center (Ruppenthal 1986),

which is standardized for pigtail macaques, crab-eating macaques, and

baboons. Other neonatal assessment instruments have been taken directly

from the human neonate and infant literature and adapted for other primate

species. For example, Schneider (1984, 1987) has modified the Brazelton

Neonatal Behavioral Assessment Scale (Brazelton 1973), perhaps the most

widely used behavioral and reflex assessment device in the human infant

clinical literature, for use with rhesus monkeys, whereas Bard and colleagues

(1990) have standardized the same assessment scales for use with nurseryreared chimpanzee neonates. These standardized test batteries have been

used to detect behavioral abnormalities in rhesus monkey neonates prenatally

exposed to very low levels of environmental toxins (Levin et al. 1988) and

prenatally exposed to a noise stressor (e.g., Schneider et al. 1991), as well as

differentiating premature from full-term infants in terms of reflex capabilities and

predominant state patterns (Bard et al. 1990). Such abnormalities in neonatal

response patterns, typically below the threshold of detection using more

traditional neurological tests, also have been shown to be predictive of various

cognitive and behavioral deficits emerging later in life (Levin et al. 1988;

Schneider et al. 1991).

It seems likely that these neonatal test batteries could be readily used to

characterize and quantify neonatal reflex and behavioral deficits resulting from

294
various degrees of prenatal drug exposure in nonhuman primate subjects.

Moreover, at least some of these neonatal assessment batteries have been

directly derived from assessment instruments developed and standardized for

use with human infant clinical populations should greatly facilitate possible

cross-species comparisons. On the one hand, such comparisons already

have been useful in establishing the validity of nonhuman primate models in

detecting the consequences of prenatal insults (e.g., exposure to environmental

toxins) that yield similar adverse consequences in the human case. On the

other hand, the use of similar or identical dependent measures in the primate

model could be employed to identify those specific outcomes in the human case

that can be linked directly to prenatal cocaine exposure rather than to other

potentially confounding factors.

Finally, many of the above-described sets of prenatal measures and neonatal

assessments already have been demonstrated to be sensitive to several of the

factors that are likely to be relevant for cocaine-abusing pregnant women. This

fact can be exploited in generating interactive models that go beyond “direct”

evaluation of “pure” prenatal cocaine exposure effects. In other words, it should

be possible to model not only specific schedules and levels of prenatal cocaine

exposure but also other factors such as diet, maternal age and size, stress

during pregnancy, or prenatal exposure to other drugs (alcohol, nicotine, etc.) in

prospective nonhuman primate studies. Carefully constructed multifactor

experimental designs could be used to evaluate the relative contributions of

these other factors to prenatal and neonatal outcomes among cocaine-exposed

subjects as well as to identify possible interactive or synergistic effects of

various combinations of these different risk factors. Such multiple-risk studies

could readily complement the findings from “direct effect” models in which the

only independent variable involved differential prenatal exposure to cocaine.

Thus, carefully designed studies using nonhuman primate models have the

potential to isolate fetal and perinatal effects of prenatal cocaine exposure and

to specify various interaction/synergistic patterns involving other specific risk

factors likely to be relevant in a large proportion of the cases contributing to the

human drug abuse epidemic.

PRIMATE MODELS OF INFANT AND CHILDHOOD EFFECTS

Perhaps the most valuable contributions that nonhuman primate models of

prenatal drug abuse could provide involve studies focusing on developmental

processes in infancy and childhood. It is here where primate models are most

likely to make unique contributions to knowledge regarding the human

condition, in large part because the ethical and practical limitations on both

evaluative and intervention research with human infants and children are

enormous, often reflecting social policy issues and restrictions more than

295
matters of rigorous experimental design. For example, there can be numerous

hurdles to overcome in obtaining blood samples or other physiological

measures from human neonates or infants. Various legal complications may

arise when identifying mothers as cocaine users and/or their infants as cocaine

addicted.

Moreover, one of the most significant problems in the research on human

infants exposed to cocaine in utero concerns followup assessments to monitor

developmental trends. Not only is postnatal drug exposure a potential

confounding variable, but also tracking of these infants can be extremely difficult

because mothers are unwilling subjects or are no longer In the same area. In

contrast, the strongest impact of primate models at this level (i.e., infant and

childhood effects) is on the generation of a detailed and stable database

of developmental effects. An enormous body of knowledge has been

accumulated regarding species-normative patterns of physical, physiological,

cognitive, social, and emotional development from infancy to puberty in several

nonhuman primate species. Moreover, much is known about how such

normative developmental patterns can be influenced by a variety of postnatal

environmental circumstances, stresses, and insults as well as how faithfully

such patterns generalize to Homo sapiens.

Over the past 30 years, major progress has been made in documenting the

developmental changes, understanding the underlying processes, and

specifying the parallels with human cognitive development in several primate

species, including rhesus monkeys and pigtail macaques and chimpanzees.

Although some of the earlier test instruments were designed specifically for

each nonhuman primate species being investigated, most of the current efforts

to study cognitive development in nonhuman primates use measures either

taken directly from the human literature or demonstrated to produce findings

that parallel those from human studies.

For example, Schneider and colleagues (e.g., Schneider 1987; Schneider et al.

1991) have developed a rhesus monkey version of the Bayley Scales of Infant

Development (Bayley 1969), one of the most widely used instruments for

assessing cognitive, motor, and social-emotional capabilities in human toddlers,

and Bard (in preparation) has developed a comparable version of the Bayley

Scales for young chimpanzees. Gunderson and colleagues (Gunderson and

Sackett 1984; Gunderson et al. 1989) have modified for young pigtail macaques

the procedure developed by Fantz (1964) for testing the visual perception

capabilities and emergence of novelty preferences of human infants. A variety

of investigators (e.g., Parker 1977; Wise et al. 1974) have demonstrated that

Old World monkeys and great apes go through the same early stages of

296
cognitive development in the same Invariant order as Piaget (1951) has

described for human Infants and young children.

These and other well-established procedures for assessing cognitive

development in a variety of nonhuman primate species could be used in

developmental studies of prenatally exposed infants, with the twin advantages

of (1) well-established developmental norms, facilitating the detection of

exposure effects and/or interactions, and (2) clear-cut generality to specific

aspects of human cognitive development, facilitating cross-species

comparisons and extrapolation of patterns of results. In fact, virtually all the

new human infant measures described by Jacobson and Jacobson (this

volume) and by Tronick and colleagues (this volume) could be used in such

primate models.

In a similar vein, the well-established literature on social and emotional

development in different species of nonhuman primates, particularly with

respect to mother-infant attachment bonds and emerging relationships with

peers, lends itself well to use in potential primate models of prenatal drug

exposure. Not only is there a solid base of knowledge regarding speciesnormative patterns of social-emotional development, but also a huge body of

data exists regarding the consequences of rearing under varying conditions of

social deprivation as well as the efficacy of various experimental interventions

or “therapies” designed to reverse the effects of early social deprivation

(e.g., Mitchell 1970; Suomi 1982), and the efficacy of various experimental

interventions or “therapies” designed to reverse the effects of early social

deprlvation (e.g., Suomi and Harlow 1972; Novak and Harlow 1975). Some of

the conditions of early social deprivation in primates bear striking resemblance

to many of the socially impoverished environments faced by all too many

offspring of human substance-abusing mothers, again facilitating the

development of primate models that can model potentially relevant aspects of

the human condition. Moreover, as was the case for measures of cognitive

development, most of the dependent measures commonly employed in studies

of primate social-emotional development—observational scoring systems using

predetermined behavioral categories, rating scales, Q-sort procedures, and

physiological indices of emotional state (e.g., heart rate patterns and cortisol

levels)—also are being used in studies of social-emotional development in

human infants, toddlers, and preschool children, enhancing the opportunities for

cross-species comparisons.

LONGITUDINAL EFFECTS OF PRENATAL DRUG EXPOSURE

Nonhuman primate models using monkeys can provide yet another unique

opportunity to understand the long-term consequences of prenatal drug

297
exposure. Given the relative rate at which monkeys and humans develop, it

seems likely that substantial information can be obtained on the long-term

effects of prenatal cocaine exposure in monkeys prior to actually observing the

patterns that might develop in the human population. In this regard, nonhuman

primate work may be predictive of these later human problems and may enable

researchers to plan appropriate interventions or treatments in advance of the

developing disorders.

Several questions are of critical importance in regard to these long-term

developmental considerations. The first concerns the patterns of deficit seen

in adolescence and early adulthood. Is there a gradual decline, a continuation,

or an increase in the social and cognitive problems that appear in early

development? A longitudinal focus may reveal the extent to which the

developing system can accommodate prenatal insults either naturally or through

specifically designed interventions.

Of particular concern is the extent to which new deficits may appear, perhaps

associated with some of the major biological and social markers of adolescence

(e.g., puberty and sexual activity). The early-experience literature concerning

nonhuman primates is replete with examples in which very early experiences

continue to inflict damage on animals into adulthood. Monkeys reared in

isolation during the first 6 months of life, for example, typically exhibit new

deficits that are related to reproduction and parental care as they pass through

adolescence and into adulthood (Harlow et al. 1966; Suomi 1982).

Longitudinal studies of abuse (both substance and physical abuse) often reveal

cascading multigenerational patterns in which offspring carry on the abuse of

their parents and in turn pass it along to their offspring. These findings have

broad implications not only in the social and political spheres but also in terms

of the cost as measured both economically and in lost lives. It is therefore

critical to determine the precise link, if any, between prenatal cocaine exposure

and subsequent cocaine abuse. Are cocaine-exposed offspring more

vulnerable to developing a pattern of abuse in adolescence and adulthood and,

if so, is this a reflection of greater sensitivity to the drug? At present, these

questions may best be answered with research on nonhuman primates.

EFFECTS OF ENVIRONMENTAL CHALLENGES

Recent studies of primate social-emotional development have highlighted two

basic principles that seem likely to be highly relevant for evaluation of the

consequences of prenatal drug exposure in humans and in primate models.

First, it is clear that many at-risk subjects whose behavior and emotional

expressions appear completely normal under stable and familiar environmental

298
circumstances display major deficits under conditions of stress. For example,

rhesus monkey infants reared during the first 6 months of life without mothers

but with access to peers, and then placed into normal monkey groups, generally

develop relatively normal social behavioral repertoires and emotional

expressions in terms of patterns of peer play, relative position in the groupdominance hierarchy, reproductive and subsequent parental behavior, and

socialization of emotions. However, if peer-reared monkeys are briefly

separated from their social group, they exhibit far more severe biobehavioral

reactions—higher levels of disturbance behavior, higher and more stable heart

rates, higher levels of plasma cortisol and adrenocorticotropic hormone (ACTH),

and greater monoamine turnover—than their mother-reared counterparts (e.g.,

Higley and Suomi 1989). Other primate studies focusing on other at-risk

subgroups of subjects (e.g., Novak and Harlow 1979) suggest that this pattern

may represent a widespread general principle: that aberrant behavioral and

physiological responses to challenging and/or stressful situations may be

largely masked under stable, familiar conditions. Anecdotal reports of young

children prenatally exposed to cocaine suggest a similar pattern of extreme

emotional response to novel or stressful environments (e.g., entry into

preschool) in some children who appear to be perfectly normal in home

settings. Those investigators contemplating development of primate models of

prenatal drug exposure thus might consider testing their subjects in a variety of

different settings as they are growing up.

CONCLUSIONS

To date, there has been relatively little effort devoted to the creation of animal

models of prenatal cocaine exposure that use nonhuman primates as subjects.

However, the development of such primate models would appear to be

important and timely, because of their potential for major contribution to

understanding the human condition and developing effective intervention

strategies and therapies. Carefully controlled studies with nonhuman primates

could enable investigators to pinpoint the effects of prenatal cocaine exposure

on physical growth, physiological processes, and cognitive and social-emotional

development from birth to maturity as well as to explore the consequences of

interactions with other drugs or postnatal challenges. Although longitudinal

studies using nonhuman primates tend to be more expensive and timeconsuming than studies using rodents or other nonprimate animals, the degree

to which the physical, physiological, cognitive, and social-emotional processes

in nonhuman primates generalize to Homo sapiens is unique. Thus, the time

appears ripe for the development of viable primate models of prenatal cocaine

exposure.

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and Farrell, P.M. Brain damage induced by prenatal exposure to

dexamethasone in fetal rhesus macaques. I. Hippocampus. Dev Brain Res

53:157-167, 1990.

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AUTHORS

Stephen J. Suomi, Ph.D.

Chief

Laboratory of Comparative Ethology

National Institute of Child Health and Human Development

Building 31, Room B2B15

Bethesda, MD 20892

J. Dee Higley, Ph.D.

Staff Fellow

Laboratory of Clinical Studies—Primate Unit

National Institute on Alcohol Abuse and Alcoholism

National Institutes of Health Animal Center

P.O. Box 289

Poolesville, MD 20837

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Discussion: Measurement of DrugInduced Delays in Learning and

Cognition and Social and Emotional

Development

Sheldon B. Sparber

INTRODUCTION

This monograph critically evaluates methodological aspects of research into the

potential deleterious consequences of prenatal exposure to drugs of abuse,

including clinical research and research with animal models. The problems

associated with this research, which uses evaluative and analytical techniques

drawn from traditional clinical and basic sciences, are complex. Superimposed

upon specialized, often divergent, disciplinary approaches to developmental

issues is the special need to incorporate principles of pharmacological sciences,

including drug disposition and pharmacodynamics, whether studies are

retrospective or prospective, animal or clinical. The three preceding chapters

(Jacobson and Jacobson, Tronick and colleagues, Suomi and Higley) offer

insight into how future research strategies might improve the clinical

assessment of drug-exposed children and primates. This chapter discusses the

potential special problems one may expect to encounter in interdisciplinary

research, which seems to be the hallmark of developmental pharmacology/

toxicology studies. For example:

1. How should one separate causal from correlational relationships in such

studies? Is the agent directly responsible for outcomes; is undernutrition

secondary to withdrawal; or is infection caused by dirty needles responsible

for developmental dysfunction?

2. Are databases from previous studies on normal and severely affected

subjects reliable enough to use in place of contemporaneous controls,

especially for assessing seemingly subtle impairment?

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3. When and how should one account for the magnitude and duration, as well

as time during development, when drug exposure occurs?

4. How can one separate the direct effects of drug exposure on the

developing subject from the indirect effects of early experience with the

lifestyles of drug-abusing parents and/or maternal behaviors that may be

altered by drugs? Direct drug effects on the child prenatally as well as

indirectly through modification of caretakers’ behavior must be considered

in the design, execution, and interpretation of studies of the effect of

prenatal exposure to illicit drugs.

These are a few additional factors that should be considered by the interested

reader contemplating future utility of the methods being suggested by the

researchers in this section. These issues are by no means unique to the

chapters under discussion, but they are necessary considerations if one wishes

to derive meaningful and interpretable data from developmental drug studies in

general.

ASSESSMENT OF TERATOGENIC EFFECTS

Jacobson and Jacobson’s chapter focuses, in part, on the strengths and

weaknesses of the Bayley Scales of Infant Development for assessing

developmental milestones in normal infants and those exposed to various

insults in utero, including alcohol, lead, and PCBs, among others. While they

acknowledge the Bayley’s sensitivity for assessing milestones, they argue that

its principal drawback is that it does not tap into “specific domains” designed to

assess attention, fine motor coordination, precursors to language, etc., to

determine the reason(s) why an infant may not make a motoric response (e.g.,

pull a string to obtain a plastic ring). Is it because the subject cannot form the

proper “means-end” relationship, because of a sensory or attention impairment,

or because the stimulus may not be sufficiently reinforcing? This inability to

accurately predict cognitive performance in early childhood may occur in

part because the Bayley provides a more global analysis of subcomponents

of behavior such as information processing, which may be assessed

independently only later in development. One possible way to evaluate

information processing is by using the Fagan Visual Recognition Memory Test.

A specific behavior, such as eye gaze toward a visual target, is the dependent

variable assessed. Jacobson and Jacobson reported its effectiveness

in detecting consequences of exposure to PCBs in human infants and to

methylmercury in laboratory monkeys. The Fagan appears to have better

predictive validity than the Bayley for performance during the early school years

of 4 to 7 years of age. Poor performance on the Fagan could reflect deficits or

dysfunction within one or more so-called domains on which visual recognition

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performance depends. For example, methylmercury is known to affect the

visual cortex as a primary site for inducing lesions, tunnel vision and blindness

being one of the earliest signs of poisoning in older children and adults.

Although fetal methylmercury poisoning is associated with central nervous

system (CNS) lesions of a more diffuse nature, poor performance on the Fagan

by children exposed to this neurotoxin could reflect such a sensory (i.e., visual)

impairment. Alternatively, poor performance on the Fagan could reflect a

difference in reinforcement efficacy of the target photos presented to exposed

and control subjects. Lastly, poor performance could be due to an actual deficit

in information processing, which is necessary for the ability to discriminate a

novel from a familiar target. It is posssible that a combination of the above

impairments could result from a developmental insult. As described, the Fagan

will not discriminate these and other possibilities. However, the procedure

could easily be modified to incorporate tests for such possibilities, and therein

lies one of its strengths.

The Fagan also “taps” into a domain that may be associated with the level of

cognitive function, namely, novelty preference or attention. The age when a

child is tested may be a critical variable when considering either the Bayley,

the Fagan, or any other assessment instrument. A significant delay or

enhancement of functional maturation caused by exposure to a drug

during development theoretically can affect a child’s level of interest (i.e.,

attentiveness) or motor capacity (i.e., responsiveness, thereby affecting

performance, relative to age-matched control subjects. While the Bayley may

be sensitive to teratogenic insult when used at 6 to 12 months of age, Jacobson

and Jacobson suggest that the Fagan has greater predictive validity when used

at 6 to 7 months of age. They also suggest the use of the McCarthy scales and

Stanford-Binet IQ tests for assessing preschool-age children because they

comprise a series of subtests focusing on specific domains, such as block

building, pictorial memory, draw-a-design, counting, and sorting. Such a

multidimensional assessment, they argue, is important for detecting specific

aspects of cognitive function/dysfunction in exposed infants and may offer clues

as to “underlying neurochemicai or neuroanatomicai mechanisms.”

By the time the child reaches school age, a more focused type of cognitive

testing protocol may be useful. This might include evaluating short-term

memory through a visual search and recognition task, spatial reasoning ability,

and sustained attention and activity level. While most of these abilities are

assessed through interactive computer-based systems of analysis that use a

visual modality, other sensory systems (e.g., auditory or somatosensory) could

be developed to evaluate more specific sensory domains. Protocols of this type

provide greater objectivity than conventional clinical judgments, and

interinstitutional reliability should be good to excellent.

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There are limitations to focused cognitive testing, however. If deficits are seen

prior to the ages of 4 to 5, they will be difficult to interpret because even children

not exposed to drugs may have difficulty performing focused tasks. Secondly,

for successful completion of these tasks, “numerous abilities are required.”

Thus, it becomes difficult to sort out the factors that determine whether the test

item was passed or failed.

The most sensitive and reliable measure may be straightforward measures of

motor activity, social-play analysis, and attention prior to age 2 and very

elementary speech and language tests measuring processes such as onset

time and articulation through the ages of 3 to 4. Beyond this age more

cognitive tests involving reaction time and information processing efficiency may

be used.

OBJECTIVE METHODS FOR DESCRIBING MOVEMENT, FACIAL

EXPRESSIONS, AND COMMUNICATIVE BEHAVIORS

In their chapter, Tronick and colleagues present arguments favoring the notion

that four different classes of movement by infants, when objectively measured,

will be of potential utility for assessing altered organization of neuromotor

function representing residual brain damage. They classify such behaviors as

(1) spontaneous or “nondirected activity”; (2) instrumental movements, implying

they are goal-directed and altered by their consequences; (3) facial expression

as the external analog of anger (and perhaps other “emotions”); and (4)

combinations of movements of limbs, head, etc., that are interpreted as the

infant’s expression or communication defensive patterns and/or stress.

Tronick and colleagues describe new technologies for objectively, rather than

subjectively, measuring these movements to replace past reliance on clinical

judgments. Such judgments were not easily quantifiable and thus must vary

greatly from institution to institution, or from person to person within the same

institution. They also make the point that numerous reports of intrauterine

growth retardation (IUGR) and prematurity in cocaine-exposed infants, for

example, imply that there should also be evidence of disrupted motor function

during the period of infancy. Since IUGR (degree not specified) has been

shown to be associated with sundry cognitive and other behavioral dysfunctions

during preschool and school years, the implication is that any other variable that

causes IUGR (e.g., illicit drug use by pregnant women) should also cause or be

associated with later dysfunction.

When overt signs of acute brain trauma, such as cocaine-associated

cerebrovascular accidents and seizures, are considered, it should not be

surprising if one or more of the four categories of motor behaviors described by

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Tronick and coworkers is also deemed to be different from “normal.” Indeed,

such neurobehavioral assessments, carried out longitudinally, may be

invaluable in diagnosing and judging the prognosis, as well as the

effectiveness, of any treatment interventions chosen for such infants. They

argue, perhaps rightly so, that the reports of altered neurobehavioral function in

children exposed to various drugs of abuse, mainly cocaine, are “compromised

by serious methodological issues,” mainly reliance upon subjective, clinical

judgments. The new methods they propose, including kinematic movement

analyses, templates for coding facial expressions, and coding systems for

‘communicative configurations” based on video recordings, may offer more

objective alternatives. Tronick and colleagues describe the results of such

kinematic analyses of otherwise healthy preterm infants, which revealed that the

number of “movement units” decreased when they reached for objects, as is

seen during development of healthy full-term infants. However, movement

units, straightness ratios, and other measures, such as movement duration,

showed subtle differences compared with full-term infants of the same age.

Because kinematic analyses allowed such a demonstration of small differences

in neuromotor organization up to 1 year of age, which otherwise would go

undetected by more conventional clinical judgments, Tronick and colleagues

believe the method detected “a significant compromise of the healthy preterm

infant’s neuromotor functioning.” Whether these observations indicate

biologically nonsignificant, transient delays or are predictive of impending, longterm or permanent dysfunction that will translate into one or more

developmental or adult disabilities remains an important research issue that

deserves further attention.

Other techniques, such as the use of templates for coding facial expressions

and coding systems for communicative configurations, are more subjectively

scored and/or interpreted, regardless of whether videotapes or computer

spreadsheets are used for analyses. Sufficient numbers of well-trained

individuals and appropriate interrater reliabilities will need to be established as

these techniques continue to be used.

The concept of using an “unmasking” manipulation, such as stressing or

“increasing task demands” by stretching the limitations of a system to determine

if a dysfunction first exists and then tracking the return to baseline, should

provide useful information about possible drug-induced behavioral deficits.

This approach has been used successfully in animal behavioral teratology

laboratories. Tronick and coworkers make an important point that “a

dysfunctional child in a standard paradigm may perform quite ‘normally’ when a

task is easy. However, when a task becomes difficult, previously unnoticed

problems may become evident.”

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In conclusion, this author was impressed with the potential utility of kinematic

analyses of motor behavior for tapping brain function of specific regions and

objectively determining the “mechanism” of altered motor behavior. Many of the

dependent variables used to assess motor behavior may be influenced by

nonmotoric factors that can be manipulated and controlled systematically in this

procedure. For example, a drug-exposed infant may be unable to perceive or

be attracted to an object placed within its reach because of motivational factors

or sensory, cerebellar, extrapyramidal, or neuromuscular dysfunction.

Kinematic analysis has great potential to aid in the diagnosis of these deficits,

test the effectiveness of treatment interventions, and/or give insight into the

prognosis of infants at risk for subtle behavioral or cognitive dysfunctions

because of passive exposure to drugs or other insults in utero or during early

postnatal development.

DEVELOPING NONHUMAN PRIMATE MODELS

In their chapter, Suomi and Higley argue for the utilization of infrahuman

primates for research into the possible later effects of exposure during

development to illicit, abused drugs (e.g., cocaine) on physiological, cognitive,

or social-emotional variables. Primates are chosen because these species are

“our closest biological relatives” and because infrahuman primates can be

assessed before birth and shortly after birth, as well as during adolescence, in

adulthood, and perhaps across generations. The use of primates instead of

human subjects for developmental drug studies cannot be criticized. Welldesigned studies with limited numbers of primate subjects can be used to

confirm the reliability and validity of results obtained with greater numbers of

nonprimate experimental subjects, such as those that have been carried out

successfully with rodents and sheep.

Suomi and Higley describe the potential use of infrahuman primates for prenatal

drug studies based on work done in their laboratory. This work utilizes

ethological behavior analyses to study behaviors under naturalistic (field)

conditions. Since monkeys are generally social creatures, living and foraging in

troupes where dominant and subordinate adults, adolescents, and infants form

social hierarchies, such an analysis offers the experimenter an opportunity to

study influences on behavior and behavioral development in a more complex

context than the average laboratory setting. Careful framing of specific

research questions is important, however, because the behavior of subjects

within a complex social group is very different than the behavior of subjects who

are raised and live relatively individually. For example, when a drug

manipulation is done prenatally and then primates are evaluated postnatally

within a social group, a sideward glance or display of subordination could be

misinterpreted as a sign of excessive aggression by one or more members of

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the troupe. Many behaviors analyzed may be due only in part to the action of

the drug per se, which then is superimposed onto a variety of other social

responses occurring in the group.

SUMMARY

Methods of the type described in these three chapters promise to be useful in

isolating and characterizing the type and degree of CNS deficit, if any, caused

by drugs alone or in combination with many of the so-called confounding factors

that are ordinarily covaried out in retrospective studies or controlled for in

prospective studies. Important factors to be considered include the importance

of undernutrition, infection, polydrug abuse, hypoxia, and early postnatal

experience, acting alone or in concert, to affect the abilities and disabilities of atrisk infants.

AUTHOR

Sheldon B. Sparber, Ph.D.

Professor

Departments of Pharmacology, Psychiatry, and Psychology

University of Minnesota

435 Delaware Street, S.E.

Minneapolis, MN 55455

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Following Drug-Exposed Infants Into

Middle Childhood: Challenges to

Researchers

Sydney L. Hans

INTRODUCTION

Clinical research examining the effects that drugs of abuse taken during

pregnancy may have on child development has focused primarily on the

neonatal period and the first 2 years of life. Because widespread interest in the

effects of drug use during pregnancy is relatively new, few investigators have

had the opportunity to follow samples of drug-exposed infants to school age.

The purpose of this chapter is to discuss the rationale for conducting long-term

followup research of drug-exposed infants and some of the challenges in

executing such research.

RATIONALE FOR FOLLOWUP STUDIES

Studies that follow infants exposed in utero to drugs of abuse to middle

childhood are essential to understand the behavioral teratological effects of

such drugs. While useful information on drug-exposed children can be derived

from cross-sectional research, only longitudinal investigations beginning before

birth can ensure the most accurate information possible about mothers’ actual

drug use during pregnancy. Similarly, only longitudinal investigations can

provide accurate information about other relevant variables that might be

confounded with maternal drug use such as perinatal problems and early

history of care.

Studies of school-age children are important to the field of human behavioral

teratology regardless of the observed effects of a particular drug during infancy.

The organization and meaning of behavior are different at different age periods,

as are the demands placed on children by the environment at different ages. In

particular, there are major shifts in behavior around the time children enter

school (White 1970). Thus, the manifestations of prenatal drug exposure might

take different forms at different developmental stages or be more clearly

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observable at different ages. While it is possible that one might observe a

consistent developmental effect across age periods—such as consistently poor

fine motor coordination—it is also possible that one might observe different

types of effects at different ages or different degrees of effects at different ages.

For example, in studying the effects of a particular drug, it is important to

assess the extent to which the child recovers from the insults of perinatal drug

exposure. The central nervous system retains a great degree of plasticity until

fairly late in development that may allow for substantial recovery from some

types of early insults (Rutter 1987a). It is also important to assess the extent

to which there may be sleeper effects (Mednick 1981) that are not clearly

observable until school age. Sleeper effects are plausible because many of the

types of behavior typically observed during infancy—in particular the acquisition

of motor and sensorimotor milestones—are highly resistant to perturbations in

development (Horowitz 1989). The higher cognitive functioning processes

required of the older child may be much more vulnerable to the negative effects

of prenatal events or pathology in the early environment.

BACKGROUND TO RESEARCH

The observations presented in this chapter are based in large part on

experience in one particular longitudinal study. For over a decade, the

University of Chicago Parent Health and Child Development Project has studied

longitudinally children whose mothers used methadone during pregnancy and a

drug-free comparison group (Marcus et al. 1984). Participant families were

recruited during the mothers’ pregnancies through the obstetrical clinics at

Chicago Lying-In Hospital between 1978 and 1982. Special weekly obstetrical

clinics were held for drug-addicted women.

At that time the patient population in the clinics consisted primarily of lowermiddle- and low-income African-American women living on the city’s south side.

The typical mother enrolled in the study was in her late 20s, was unmarried but

living with a male partner, and had given birth to two or three previous children.

The typical methadone-using mother was receiving less than 20 mg of

methadone a day and occasionally used other substances.

Prior to delivery, information was gathered not only about the women’s

substance use but also their socioeconomic status, intellectual functioning,

and mental health. The final sample of neonates available for assessment

consisted of 45 methadone-exposed children and 47 comparison children. At

the end of the second year of life, the sample consisted of 38 methadoneexposed children and 46 comparison children. Most of the attrition was from

the methadone group, and most was due to the death or disablement of the

children (Hans 1989).

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The behavior of the children born into the sample was similar to that of other

infants exposed to methadone who have been described in the literature (Hans

et al. 1984). During the first week of life, methadone-exposed neonates differed

from comparison infants in motoric and state behavior (Jeremy and Hans 1985;

Hans et al., in press). Relative to comparison-group infants, they were more

jerky, tremulous, tense, active, and better able to put hand in mouth. They were

also more irritable and more highly aroused. By the end of the first month these

differences diminished, although there was still a tendency for the methadoneexposed infants to have elevated general body tonus. Throughout the first 2

years of life, the methadone infants lagged slightly behind comparison infants in

their acquisition of motor and sensorimotor milestones (Hans 1989; Hans et al.

1984). These differences were consistent but did not reach statistical

significance at most ages. Methadone-exposed infants also were observed to

be more active than comparison infants (primarily at 4 months of age), to have a

shorter attention span (particularly at 12 months of age), and to have poorer

motor coordination (Hans and Marcus 1983).

CHALLENGES TO CONDUCTING FOLLOWUP RESEARCH

In 1987 the project researchers began planning and conducting a school-age

followup study of the children in the methadone study. This work presents

several scientific, logistical, and ethical challenges, including (1) designing a

study with a strong theoretical basis, (2) using research strategies that might

illuminate causal antecedents of children’s behavioral problems, (3) maintaining

contact with the participants over time, (4) maintaining positive, mutually

beneficial relationships with participant families, (5) protecting the rights of the

participants, and (6) generating “useful” information. A discussion of these

challenges follows.

Theoretical Framework

Human behavioral teratology is a scientific discipline in its infancy. Most

research in the field to date has been atheoretical in its design. Typically,

studies have assessed children exposed to drugs using standardized

instruments that, while appropriate to a particular age of interest, were not

chosen to test specific hypotheses. For example, in the projects research on

methadone-exposed infants, there are now several sets of data using the

Neonatal Behavioral Assessment Scale and the Bayley Scales of Infant

Development; there are also several data sets using standardized intelligence

tests in preschool followup studies. The scientific strength of relying on

standard measures is the production of a set of replicated findings from

multiple samples (Hans et al. 1984). Yet, as the discipline begins to develop,

investigators increasingly should be choosing measures that allow them to test

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specific hypotheses. In designing followup studies, there are several sources

from which hypotheses can come:

Studies of the behavior of drug-exposed infants

Clinical case reports of drug-exposed children

Cross-sectional reports of children with drug-using parents

Studies of animal behavior

Studies of animal neurochemistry and neuroanatomy

Followup studies of children exposed to other substances

Followup studies of children from other high-risk groups

In designing the study of school-age methadone-exposed children, there were

several of these sources of information from which to draw ideas. First were the

project’s infancy findings indicating motor dyscoordination and attentional

problems in drug-exposed infants. Second, while there were no previous

longitudinal data on school-age methadone-exposed children, several

investigators (Kaltenbach et al. 1978; Strauss et al. 1979; Lifshitz et al. 1985;

Wilson et al. 1979) had reported followup data on the development of opioidexposed children in the preschool years. In these studies opioid-exposed

children were reported to be more active, to have poorer fine motor

coordination, and to have less well-focused attention than comparison children.

These findings of poor attention, high activity, and soft neurological signs,

including motor dyscoordination, were intriguing because they suggested that in

utero exposure to opioid drugs might result in symptoms of attention deficit

hyperactivity disorder (ADHD) (American Psychiatric Association 1987).

Hypothesizing that methadone-exposed children develop disorders of attention

is not inconsistent with data on followup of children exposed to other

substances. In particular, Streissguth and colleagues (1986) found a pattern of

neurobehavioral deficits related to prenatal alcohol exposure that includes

memory and attention deficits similar to those observed in children with

attention deficit disorders.

Thus, this followup study focused on the hypothesis that children exposed

prenatally to methadone might display symptoms of attention deficit disorder at

school age. The project researchers decided to develop an assessment

battery that would focus on the assessment of ADHD from a multifaceted,

multiobserver approach.

In the research on methadone, the following types of assessments were

planned:

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A psychiatric interview was chosen to establish clinical criteria for ADHD as

reported by the mother and the child.

Teacher rating scales were chosen that focused on aspects of attention and

hyperactivity.

An intelligence scale was included to be able to make differential diagnoses

of various learning and attentional problems.

A continuous performance test was chosen to be able to finely quantify

aspects of sustained attention and to separate aspects of attentional

dysfunctioning related to impulsivity from those related to processing errors.

A neurological assessment was selected to look clinically at a variety of

large and fine motor skills.

A battery of electronically scored fine motor and tremor assessments was

chosen to provide quantified measures of fine motor dysfunctioning.

The attention deficit hypothesis thus guided the choice of instruments. It also

could have guided the experimental design. For example, one might have

wished to build in a comparison group of hyperactive children or children with

other types of learning disabilities. Such a strategy has been useful in other

high-risk research focusing on attention deficit; Nuechterlein (1983) was able to

clarify the nature of attention deficits in children at risk for schizophrenia by

comparing them with clinically hyperactive children.

Strategies for llluminating Causal Antecedents of Behavior Problems

Perhaps the single most difficult methodological issue confronting those in the

field of human behavioral teratology is trying to understand causal factors

without being able to implement experimental research designs. Because

clinical researchers have no control over mothers’ use of substances during

pregnancy and no control of children’s rearing environment after birth, no

human study will ever provide definitive evidence about the behavioral

teratological effects of a drug. While it would be inappropriate to hold human

studies up to the standards of animal research, it is nevertheless desirable for

clinical investigators to try to identify the most plausible sources of behavioral

problems in children from drug-using families. Much of the research on drugexposed infants has made the mistake of assuming that, because mothers in

their drug and comparison groups have been matched on a limited number of

demographic variables, any differences between drug-exposed infants and

comparison groups are due to teratological factors. Yet there are many

alternative causal factors that might explain such differences, including

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increased incidence of perinatal complications in drug-exposed children, a poor

child-rearing environment provided by drug-using families, and the genetic

transmission of behavior problems found in drug-using parents (Aylward 1982;

Marcus and Hans 1982). The numbers of nonteratological causal explanations

for behavioral problems in children of drug-using parents only become greater

as children reach school age.

Several techniques are available for illuminating the plausibility of alternative

causal factors in human behavioral teratology studies. One such technique is

the inclusion of multiple control groups in a study. Possible comparison groups

in addition to unexposed infants might be drug-exposed children in adoptive

homes or children of drug-using mothers who were drug-free during pregnancy.

The most important technique for looking at nonteratological causal factors is

inclusion of measures that assess such possible factors. In followup work, the

project researchers have chosen to look extensively at sources of variation in

the child’s rearing experience, specifically exploring:

Family stressors

Maternal mental health

Family interpersonal relationships

Childrearing values held by the mother

Children’s perception of their parents

Mother’s style of interaction with the child

Child outcome measures need to be carefully analyzed not only in relation to

maternal drug use but also to measures of nonteratological factors. It is

particularly important to look at the interaction between drug exposure and

other factors. For example, one needs to explore questions of whether drug

effects occur only in the presence of other risk factors such as impoverished

environment or in children of only one sex. Interactions between drug exposure

and environmental factors might lead to theories that drug exposure sensitizes

children to the effects of poor environments (Hans 1989) and that particular

environmental conditions can protect children from the effects of prenatal

biological insult environments (Rutter 1987b).

Maintaining Contact With Participants Over Time

The relatively unstable lifestyle of many drug-using families often makes

tracking their whereabouts over time a difficult task. Telephone service is

intermittent in drug-using households. Families change residences frequently.

Women may live in the homes of different friends and relatives at different

times. Mail may not be reliably received in dangerous neighborhoods.

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To maintain contact with participants over time, it is important for researchers to

have information on how to locate the mother’s entire social network. In this

methadone study, files are maintained of participant names and addresses and

of the names and addresses of other family members and friends. For drugusing mothers, it is also important to keep information on the drug abuse

treatment facilities at which they have previously received treatment.

Between assessment sessions, project researchers try to make periodic

contacts with families, either through a friendly telephone call or a card in the

mail. If mail is returned undelivered, other family members and friends are

contacted to locate the participant before the “trail grows cold.”

When there are difficulties contacting other family members, staff members

have often relied on locating information available in computer data banks.

While access to different types of information will vary in different localities,

there are many types of data banks that are open to the public and others to

which researchers may be able to achieve access by going through appropriate

institutional channels or by obtaining appropriate consent in advance from

families. Examples of data banks that might prove useful in locating families

include telephone listings, voter registration records, birth and death records,

public aid records, public housing records, postal records, child welfare records,

driver’s license records, and school enrollment information.

Maintaining Positive, Mutually Beneficial Relationships With Participants

Another major challenge to working with drug-using families is helping them feel

positive about their experience in the research project. If families do not feel

positively toward the research project, sample attrition will be high. In work with

drug-using families, project researchers have used many techniques for

creating a positive experience for families. In scheduling appointments the

families’ schedules are accommodated. If families desire, they are picked up at

their homes by a driver and transported to the project site. The staff will

routinely wait 2 hours after the scheduled appointment time for late families to

arrive. Children and parents are always given generous positive feedback

during the interview and testing sessions. Mothers and children are offered

snacks during research sessions. Photographs of the children are taken at

each session to give to the parents, and during the school-age assessments

families are given copies of videotapes made when their children were infants.

At the end of each session, the children select a present for themselves, and

mothers receive monetary compensation for their time. Greeting cards are

sent to parents on birthdays (their own and the children’s) and on holidays

(particularly Mother’s Day).

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Most of the feelings family members have toward the research project come

from the characteristics of the research staff members with whom they interact

in the research sessions. In working with African-American families, AfricanAmerican staff members are hired so that the families will feel comfortable.

But more important than staff members’ racial or ethnic identity is their capacity

to be sensitive to the types of difficulties experienced by parents, by individuals

living in poverty, and by those addicted to drugs. For most parents and children

in this research, having the opportunity to talk about themselves to an

interested person is a unique and positive experience. Yet for such an

experience to be a positive one, staff members must be warm and have a

genuine interest in and respect for the families. Their attitudes are ultimately

what families sense. Consistently communicating respect to families can be

difficult when a mother repeatedly makes staff members wait, arrives for

sessions while “under the influence,” is evasive in her communication, or

manipulates the staff member to meet her own needs. School-age children can

similarly try the patience of the staff through their oppositional behavior. Staff

members need to be patient and flexible.

While staff characteristics are at the core of the relationship that develops

between families and the research project, the underlying model of the research

and the selection of instruments also play a role in how the family experiences

the research project. Human behavioral teratology research is based on a

developmental psychopathology model. Many of the research questions and

hypotheses in the field focus on problem behavior in problem families. Yet to

barrage parents with questions about their own and their children’s problems

may alienate and insult them. Questioning children about problems in their

own behavior and problems in their families is similarly intimidating to them.

In this pilot work using psychiatric interviews, researchers became concerned

that such a negative approach damaged rapport between researcher and

participant. It is normal for adults and children, particularly those who have not

sought help for a problem, to respond in a defensive and evasive manner to the

kinds of questions Included in such interviews. There also was concern that

results of research relying primarily on a pathological model, as has much

research on poor children and children from minority populations (McLoyd

1990), would produce overly simplistic conclusions that ignore the complexity

and dignity of the participants’ lives. Therefore, staff members made an effort to

alter some of the research protocols to include more positive material on the

achievements of children and their families and to make the theoretical

perspective somewhat more positive by considering children’s adaptive skills

and the factors that protect children and foster their resilience (Garmezy and

Masten 1986).

317
Ultimately, the most important part of showing respect to families lies in seeing

that the research benefits not only the researcher but also the families. Benefits

may come to some mothers and children from the positive stimulation of

participating in the research project or in the form of financial compensation.

Alternatively, benefits may need to come from direct efforts of the research staff

to help families with their individual needs. Researchers working with drugusing families—even researchers not working In a clinic setting—must be

prepared to see that families receive help with their problems. Helping families

receive help is not only an ethical responsibility but also a key to maintaining

positive relationships with families and ultimately to minimizing sample attrition.

It is important that the research team includes a member who is able to

consider the needs of these families and to make appropriate referrals when it

is apparent that the family is not being adequately helped by existing services.

It is also a good practice to review each case periodically to determine whether

any action needs to be undertaken. In this project’s experience with the

methadone study, the types of problems experienced by families become

increasingly complex as the children become older and the availability of

appropriate referrals becomes more difficult. Investigators need to have

available appropriate and affordable referrals for child and adult medical

problems, domestic violence and other family problems, legal problems, child

behavior problems, acquired immunodeficiency syndrome (AIDS) counseling

and testing, and educational problems.

Protecting the Rights of Participants

While all clinical researchers must deal with the ethical issues of informed

consent and confidentiality, these issues are particularly challenging when

working with drug-using families and become increasingly complex as the

children under study become older.

In research with school-age children it is important to explain the research not

only to the parents but also to the child. Before beginning assessment, one

must explain clearly to children what procedures they will be experiencing. The

children should have the opportunity to explore the assessment room and any

apparatus with which they will be working and to meet the examiners. In clinical

research, it is also important that both parents and children understand that

what they say will be treated with confidentiality and to understand the limits of

such confidentiality. In general terms, the limits of confidentiality are when it

appears that the child or someone else may be hurt (Taylor and Adelman

1989).

In working with school-age children, protecting confidentiality is not always easy

or natural. Seemingly trivial breaches of confidentiality are potentially harmful to

318
the child. For example, it might be tempting casually to report to the parent a

“cute” comment the child made about some aspect of family life. Yet such an

offhand comment might embarrass the child if he or she discovers it was

reported and might cause the child to lose trust in the researcher. Parents

who discover from the researcher that children reported freely on aspects of

family life might also feel that the child violated aspects of family privacy and

reprimand or punish the child for his or her discussions with the researcher.

There are two basic ways in which the researcher may need to break

confidentiality: (1) breaking confidentiality with the family and reporting

information to outside authorities and (2) breaking confidentiality with the child

and reporting information to the parent.

Researchers may be mandated by law to report information on child abuse and

neglect to the State. Such obligations to report supersede the confidentiality

of the researcher-participant relationship and probably supersede Federal

certificates of researcher confidentiality such as those granted by the National

Institute on Drug Abuse (NIDA). In this project, in cases where child abuse or

neglect appear clear, researchers always first discuss with the parent the need

to make a report. Then the staff members plan with the parent how such a

report will be made and offer to accompany the family through the process.

Project experience teaches that parents recognize their need for help and

ultimately are grateful for the intervention. The project has never lost a family to

followup because of intervening in such a manner.

The researcher is also morally obligated to break confidentiality in situations in

which the child or someone else is likely to get hurt, for example, when the child

reports suicidal thoughts. It is often very difficult to decide when a problem is

serious enough to warrant breaking the important promise of confidentiality. In

this work staff have discovered that there is rarely a clear-cut situation in which

confidentiality should be broken. For example, is the danger to the child who

is experimenting with alcohol at age 10 great enough to warrant breaking

confidentiality and telling the parent? Sometimes the staff has concerns about

whether reporting a problem behavior to a particular parent will truly help the

child or only place him or her at increased danger of abuse from an erratic

parent. In any situation where a staff member breaks confidentiality by

reporting to the parent, the staff member first discusses the problem with the

child, who usually will indicate a willingness to report himself or herself to the

parent or to discuss the matter jointly with the parent. The staff always tries to

minimize the negative consequences of the disclosure by considering in

advance possible plans of action that might be recommended to the parent.

319
Generating Useful lnformation

Finally, scientists working with clinical populations need to be cognizant of

their obligation to provide not only scientifically interesting information but also

information that will be useful to those providing services to the population

under study—in this case, drug-using families with children. While most

clinical studies of drug-exposed infants and children were initiated to provide

enlightenment about teratological effects of particular substances, their greatest

value may ultimately lie in suggesting ways of helping children affected by drug

abuse.

It is a challenge to most scientists to conduct and report research in a manner

that will be truly useful to those working directly with families. Yet those in

the fields of public policy, medicine, social work, and education are making

decisions every day about how to intervene with drug-using families, how and

when to treat disabilities experienced by drug-exposed children, whether drugusing parents are capable of caring for their children, and which families should

receive limited prevention and intervention resources. To make such decisions,

those professionals need better information about the nature of problematic

outcomes to be expected in children exposed to various drugs and about the

antecedents and correlates of such problems. The types of questions raised by

those conducting human behavioral teratology work and those in the helping

professions are related but may be different in subtle ways. For example,

while the scientist may typically ask whether drug-exposed children have

poorer mean scores on a particular intelligence scale than comparison

children, the helping professional needs to know what proportion of drugexposed children have scores on that intelligence scale that are problematic

and need intervention. While the scientist may report that drug exposure has a

teratological effect on the child, causing biological damage that is manifested in

problematic behavior, the helping professional needs to know what aspects of

the child’s environment help to ameliorate such teratological effects or to

exacerbate them. In designing studies and reporting results it is a challenge,

but a worthwhile one, for scientists to consider the potential use of their data to

those in the helping professions.

CONCLUSION

Long-term followup studies of drug-exposed children are essential for truly

understanding the behavioral teratological effects of drugs on human

populations. Yet conducting these studies presents many challenges to the

researcher. Some of these challenges are the scientific and logistical ones of

designing and conducting good research in a difficult and “messy” field with a

sometimes difficult population. Others are the more human and ethical

challenges of working with families in a manner that benefits them directly

320
through their participation In the research and that will ultimately be of use to

others trying to help the population under study.

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Garmezy, N., and Masten, A.S. Stress, competence, and resilience: Common

frontiers for therapist and psychopathologist. Behav Ther 17:500-521, 1986.

Hans, S.L. Developmental consequences of prenatal exposure to methadone.

Ann N Y Acad Sci 562:195-207,1989.

Hans, S.L.; Jeremy, R.J.; and Henson, L.G. The development of children

exposed in utero to opioid drugs. In: Greenbaum, C.W., and Auerbach,

J.G., eds. Longitudinal Studies of Children at Risk: Cross-National

Perspectives. Norwood, NJ: Ablex Press, in press.

Hans, S.L., and Marcus, J. Motor and attentional behavior in infants of

methadone maintained women. In: Harris, L.S., ed. Problems of Drug

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Drug Abuse Research Monograph 43. DHHS Pub. No. (ADM)83-1264.

Washington, DC: U.S. Govt. Print. Off., 1983. pp. 287-293.

Hans, S.L.; Marcus, J.; Jeremy, R.J.; and Auerbach, J.G. Neurobehavioral

development of children exposed in utero to opioid drugs. In: Yanai, J., ed.

Neurobehavioral Teratology. Amsterdam: Elsevier, 1984. pp. 249-273.

Horowitz, F.D. “The Concept of Risk: A Re-Evaluation.” Paper presented at

the meeting of the Society for Research in Child Development, Kansas City,

MO, April 1989.

Jeremy, R.J., and Hans, S.L. Behavior of neonates exposed in utero to

methadone as assessed on the Brazelton scale. Infant Behav Dev 8:323-

336, 1985.

Kaltenbach, K.; Graziani, L.J.; and Finnegan, L.P. Development of children

born to women who received methadone during pregnancy. Pediatr Res

12:372, 1978.

Lifshitz, M.H.; Wilson, G.S.; Smith, E.O’B.; and Desmond, M.M. Factors

affecting head growth and intellectual function in children of drug addicts.

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Marcus, J., and Hans, S.L. A methodological model to study the effects of

toxins on child development. Neurobehav Toxicol Teratol 4:483-487, 1982.

Marcus, J.; Hans, S.L.; Patterson, C.B.; and Morris, A.J. A longitudinal study of

offspring born to methadone-maintained women. I. Design, methodology,

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and description of women’s resources for functioning. Am J Drug Alcohol

Abuse 10:135-160, 1984.

McLoyd, V.C. Minority children: Introduction to the special issue. Child Dev

61:263-267, 1990.

Mednick, S.A. Methods of prospective, longitudinal research. In: Mednick,

S.A., and Baert, A.E., eds. Prospective Longitudinal Research: An Empirical

Basis for the Primary Prevention of Psychosocial Disorders. Oxford: Oxford

University Press, 1981. pp. 11-15.

Nuechterlein, K.H. Signal detection in vigilance tasks and behavioral attributes

among offspring of schizophrenic mothers and among hyperactive children.

J Abnorm Psychol 92:4-28, 1983.

Rutter, M. Continuities and discontinuities from infancy. In: Osofsky, J.D., ed.

Handbook of Infant Development. 2d ed. New York: Wiley, 1987a. pp.

1256-1296.

Rutter, M. Psychosocial resilience and protective mechanisms. Am J

Orthopsychiarty 57:316-331, 1987b.

Strauss, M.E.; Lessen-Firestone, J.K.; Chavez, C.J.; and Stryker, J.C. Children

of methadone-treated women at five years of age. Pharmacol Biochem

Behav 11:3-6, 1979.

Streissguth, A.P.; Barr, H.M.; Sampson, P.D.; Parrish-Johnson, J.C.; Kirchner,

G.L.; and Martin, D.C. Attention, distraction and reaction time at age 7 years

and prenatal alcohol exposure. Neurobehav Toxicol Teratol 8:717-725, 1986.

Taylor, L., and Adelman, H.S. Reframing the confidentiality dilemma to work in

children’s best interests. Professional Psychol Res Practice 20:79-83, 1989.

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between five and seven years. Bull Orton Soc 20:41-57, 1970.

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63:135-141, 1979.

ACKNOWLEDGMENT

The followup study described in this chapter is supported by National Institute on

Drug Abuse grant DA-05396.

AUTHOR

Sydney L. Hans, Ph.D.

Research Associate (Associate Professor)

Department of Psychiatry

University of Chicago

Box 411

5841 South Maryland Avenue

Chicago, IL 60637

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Patterns of Growth and Development

in Narcotic-Exposed Children

Marta H. Lifschitz and Geraldine S. Wilson

INTRODUCTION

Low birth weight is the most frequent and clearly documented adverse outcome

associated with gestational exposure to narcotics and other toxic addictive

substances, including nicotine, alcohol, marijuana, and cocaine. While

decreased birth weight can be attributed primarily to impaired fetal growth, an

increased occurrence of premature birth, as reported with maternal use of

heroin and cocaine, may also play a role (Zelson et al. 1971; Wilson et al. 1973;

Oro and Dixon 1987). The persistence of effects of maternal narcotic use

on growth beyond the perinatal period has been suggested by several

investigators (Wilson et al. 1973, 1979; Chasnoff et al. 1980; Bauman and

Levine 1986; Hans 1989), while others have reported normal postnatal growth

(Strauss et al. 1979; Rosen and Johnson 1982, 1985). To date, clinical studies

have failed to establish a direct relationship between narcotic use during

pregnancy and growth. The investigation of drug-abusing women and their

offspring has been compromised by a variety of both practical and theoretical

issues. Longitudinal studies of children exposed to illicit drugs during

pregnancy are few in number, and many have serious methodological

limitations. The initial cohort is often small and the rate of attrition is high. In

addition, the history of drug exposure is poorly documented, and the issue of

polydrug use is often ignored. Comparison groups are absent from early

studies and, when included, are often poorly defined. Unfortunately, the

techniques of data analysis are often inadequate for the interpretation of

multifactorial outcome effects.

One purpose of this chapter is to review longitudinal studies of postnatal growth

and its relationship to cognitive development in children prenatally exposed to

narcotics. The second aim is to discuss methodologic issues regarding stability

of outcome measures across time and the relative impact of direct drug effects

within the context of other measures known to influence somatic growth.

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WEIGHT AND LENGTH AT BIRTH

A well-established finding in infants of heroin-addicted mothers is a high

incidence of low birth weight. Early studies of drug-exposed pregnancies failed

to differentiate the small-for-gestational-age (SGA) or growth-retarded infant

from the preterm infant of less than 37 weeks of gestation. Differentiation

between premature birth and growth retardation is important because the

conditions differ in terms of causative mechanisms, perinatal complications, and

postnatal growth patterns.

The question of causal relationship between specific drug exposure and

impaired fetal growth must be analyzed within the context of a multitude of

variables that are known to affect fetal size. Impaired intrauterine growth has

been associated with poor maternal weight gain, maternal undernutrition,

absence of prenatal care, preeclampsia, chronic maternal illness, unmarried

status, intrauterine infections (Miller and Hassanein 1973), smoking (Longo

1982), and heavy alcohol consumption (Streissguth et al. 1989). Many of

these factors are common during the pregnancy of the drug-abusing woman

(Finnegan et al. 1972; Naeye et al. 1973). Fetal and postnatal growth are also

influenced by race (Wilcox 1981), maternal age (Goldstein 1971), and sex of the

infant (Wingerd and Schoen 1974).

In one of the largest perinatal studies, reviewing 384 births to heroin addicts

over a 10-year period, Zelson and colleagues (1971) found a 50-percent

incidence of low birth weight (<2,500 g). The hospital incidence for the same

period was 15 percent. Forty percent of the low birth weight infants born to

addicted women were SGA. No prospective studies of comparable size have

been conducted to enable an examination of nutritional, hormonal, biochemical,

and biologic variables as they interact with maternal drug use.

The introduction of methadone treatment added a new dimension to the study

of fetal exposure to narcotics. Early experience indicated that involvement in

treatment programs resulted in modification of risk factors associated with illicit

drug use (Finnegan et al. 1972). However, subsequent studies failed to show

consistent improvement in pregnancy outcome or birth size.

Similar rates of low birth weight in infants of 45 heroin addicts and 46

methadone-treated women (44.4 percent and 47.8 percent, respectively) were

interpreted by Zelson and coworkers (1973) as indicating that narcotics, either

methadone or heroin, adversely affected fetal growth. These researchers

observed a tendency for birth weight to increase relative to the duration of

methadone treatment but did not analyze the contribution of associated social,

biologic, or health variables.

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Kandall and colleagues (1976) concluded that methadone administration during

pregnancy appeared to correct heroin-associated fetal growth retardation in a

dose-dependent manner. While they studied a large sample (337 neonates) by

group comparisons of variables that might influence birth weight, the study had

two weaknesses: Data were largely retrospective, and the contribution of each

potentially confounding factor (maternal age, prenatal care, and race) was

analyzed separately rather than in a multivariate model.

The prospective study by Wilson and colleagues (1981) of 39 methadonetreated women and 29 untreated heroin addicts enrolled during pregnancy

showed no improvement In birth size with methadone treatment despite

improved nutrition and compliance with prenatal care. They postulated that

continued polydrug use by the methadone-treated mothers may have affected

birth size, although birth weight and length were unaffected in Chasnoff and

colleagues’ study (1982) of polydrug users who were not exposed to opiates.

Analysis of covariance was applied to Wilson’s prospective cohort to investigate

the effect of drug addiction on length at birth (Lifschitz et al. 1983). Although

infants in both treated and untreated drug groups were shorter than the

comparison group, when group means were adjusted for sex, race, prenatal

care, weight gain during pregnancy, maternal nutrition, prenatal risk, and

smoking, they no longer differed significantly. This suggests that the growth

impairment observed in infants born to narcotic-dependent women is unrelated

to action of the narcotic but secondary to the adverse social and health factors

commonly associated with addiction. These findings are confirmed by a larger

study of 220 infants born to methadone-maintained mothers that utilized

regression analysis to demonstrate that three variables (number of prenatal

visits, gestational stage at first prenatal care visit, and the interval of the

pregnancy during which the woman received prenatal care) contribute

significant increments to the proportion of variance with respect to birth weight

(Suffet and Brotman 1984). Methadone dose at the time of delivery was not a

significant factor.

HEAD SIZE AT BIRTH

Small head size was reported in a descriptive study of 67 heroin-exposed

neonates (Vargas et al. 1975). The head circumference of 25 (39 percent) of

the infants was below the 10th percentile for gestational age; 15 of these infants

were also SGA. Although these observations were retrospective and

uncontrolled, they suggested the need for further research because of the

serious implications of impaired brain growth for future cognitive development.

There is evidence that the period of most rapid brain growth occurs prenatally in

the human; peak growth occurs about the time of birth, and cell division ends

325
about 5 to 6 months after birth (Winick 1969). Severe malnutrition of the mother

during famine conditions results in reductions of weight, length, and head

circumference at birth (Stein and Susser 1975). Data from the Dutch famine

indicated that fetal weight gain is particularly related to maternal diet during the

last trimester of pregnancy, the critical period for myelination in the human brain

(Winick 1969). Reduced head size (microencephaly) at birth also may be

related to intrauterine infections, a relatively common complication of pregnancy

in narcotic-dependent women (Volpe 1987; Naeye et al. 1973).

Literature on narcotic-exposed infants yields almost no information about their

head growth before the era of methadone treatment. Chasnoff and colleagues

(1980) first reported that mean head circumference at birth was low (at the 5th

percentile) in 15 methadone-exposed infants, while birth weight and length were

at the 10th percentile. Controls were not included. Rosen and Johnson (1982)

then reported a differential effect of methadone on head growth in a prospective

study of 62 infants. Although their mean birth weight did not differ significantly

from that of the 32 comparison infants, the incidence of microencephaly (head

size below the 3rd percentile) was increased in methadone-exposed infants

(p<0.001). Multiple-regression analyses were performed to determine the

contribution of other factors to developmental outcome; head size at birth,

however, was not included (Rosen and Johnson 1982). In a controlled study of

39 infants whose mothers were maintained on low-dose methadone without

evidence of other drug use, mean head circumference was significantly less

than that of controls after adjustment for confounding variables (Chasnoff et al.

1982). A study by Lifschitz and colleagues (1985), which included heroinexposed infants and infants born to a heterogeneous group of polydrug-abusing

methadone-maintained mothers, also demonstrated significant differences in

mean head size at birth between drug groups and controls. The preliminary

correlation analysis showed a strong inverse relationship between a quantitative

estimate of narcotic exposure and head size at birth that appeared to

substantiate Chasnoff’s impression that opiate exposure directly affected fetal

head growth. However, narcotic exposure lost its significance after adjustment

for confounding variables. Unlike Rosen, Lifschitz and coworkers were unable

to demonstrate an increased incidence of microencephaly at birth.

The studies reviewed suggest, but fail to demonstrate conclusively, a causal

relationship between prenatal exposure to narcotics (or associated factors) and

impaired fetal head growth. In part, the inability to confirm the adverse effects

of maternal narcotic use may be related to small sample size. A recent study

that prospectively ascertained cocaine and marijuana use in a general prenatal

care sample of 1,226 mother-infant dyads, indicated that each of the drugs was

independently associated with impaired fetal growth when other potentially

confounding variables were analytically controlled (Zuckerman et al. 1989).

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POSTNATAL LINEAR GROWTH

Early descriptive studies of infants of heroin addicts suggested the existence of

long-term effects of linear growth (Wilson et al. 1973). Wilson (1975) observed

that infants born to narcotic-addicted mothers not only demonstrated a high rate

of intrauterine growth retardation but also showed postnatal growth disturbance;

some children with appropriate measurements at birth subsequently fell

below normative levels. Although birth measurements were appropriate for

gestational age in 28 of 29 neonates delivered to methadone-maintained

mothers, 25 percent of them showed growth disturbance postnatally. The

decline in growth rate was usually evident by 6 months.

Both intrauterine and postnatal growth are known to be affected by a variety of

factors, the most important of which is genetic potential. Parental stature is the

predominant influence on children’s growth (Wingerd and Schoen 1974). The

consideration of other factors is not likely to be meaningful unless parental

height is taken into account. In Wingerd and Schoen’s sample, parental height

alone accounted for 88.6 percent of the variation in height at 5 years of age.

Maternal parity has been shown to exert a marked influence on growth. Firstborn babies are smaller at birth but grow faster during the first 3 months of

postnatal life. By 1 year of age, they have usually shifted growth curves; and,

by 5 and 7 years, they are taller than subsequent offspring (Prentice et al. 1987;

Wingerd and Schoen 1974; Goldstein 1971). Although an American study did

not document the importance of socioeconomic factors as determinants of

growth (Wingerd and Schoen 1974), a British report showed that by 7 years of

age, children born to mothers of low socioeconomic status were shorter than

those of higher socioeconomic class. Emotional deprivation and physical

neglect or abuse are commonly associated with failure to thrive and may result

in permanent linear growth impairment (Altemeier et al. 1985). The age of the

mother at the time of birth also plays a role. By 7 years of age, children of

mothers under 25 years at delivery were smaller than children born to mothers

who were 25 years or over (Goldstein 1971).

The rate of growth is a very important factor to consider in growth studies.

During early infancy, the infant shifts from a growth rate that is predominantly

determined by intrauterine conditions to one that reflects genetic background.

Infants achieve their genetically determined channel of growth by 4 to 18

months (Smith et al. 1976; Sorva et al. 1989). Low-birth-weight infants tend to

remain shorter than average (Goldstein 1971). When Kimble and colleagues

(1982) studied the growth of infants who weighed below 1,500 g at birth and

were appropriate for gestational age, they found that between the ages of 1 and

3 years the growth curve paralleled, but fell below, that of normal children.

Because a substantial percentage of those infants can be expected to fall below

327
the 5th percentile on the National Center for Health Statistics growth charts

(National Center for Health Statistics 1976), special growth curves for infants

born prematurely have been designed (Keen and Pearse 1988). These findings

reaffirm the need to consider the length of gestation in any study that

investigates growth.

Growth among SGA infants is markedly diverse during the first 6 months of

postnatal life. Some infants catch up rapidly, while others continue to grow at a

slow rate into childhood and remain small (Ounsted et al. 1988; Fithardinge

and Steven 1972). Animal experiments have suggested that the capacity for

catchup growth after a period of induced growth deficiency seems to be limited

to early life. There may be a critical period during which the number of cells

sets the stage for future growth (Winick 1969). Naeye and coworkers (1973)

suggested that heroin directly attenuated growth. They demonstrated that the

small size of organs in infants exposed to heroin in the third trimester of

pregnancy resulted mainly from a subnormal number of cells, whereas

undernutrition during pregnancy in nonaddicted women restricted the size of

individual cells as well as their number. If cell numbers are indeed decreased,

infants of heroin-addicted mothers would not be expected to show catchup

growth. An early, cross-sectional study supported this assumption (Wilson

et al. 1979). Although this study controlled for several environmental and

demographic factors, it was limited by a retrospective collection of perinatal and

early childhood data: and it was not possible to trace many factors that may

potentially affect growth. Information on parental height, growth trajectory, and

health history is lacking; therefore, the results are inconclusive.

A preliminary uncontrolled study of 15 methadone-exposed infants reported

that early growth was depressed (mean birth weight and length at the 10th

percentile), after which the growth rate accelerated by 4 to 6 months (Chasnoff

et al. 1980). The researchers postulated that the early growth impairment could

have resulted from the direct effect of methadone on the hypothalamic

hypophyseal axis of the newborn, as suggested by animal studies (Friedler

1978). However, no hormonal or neurochemical studies were performed to

substantiate this suggestion, nor were factors such as maternal nutritional

status or genetic background considered. The accelerated growth pattern in

these infants could reflect catchup growth after a period of in utero nutritional

deprivation or a shift in percentiles as determined genetically. In a crosssectional study of 70 preschool children exposed prenatally to methadone and

70 controls matched for sociodemographic variables, there was a tendency for

drug-exposed children who had shown signs of withdrawal at birth to have lower

preschool weight and height (Bauman and Levine 1986). Growth was not

reported for the controls. Worthy of consideration is a longitudinal study of 30

methadone-exposed children and 44 comparison subjects, in which the

328
researchers found that, by 2 years of age, the exposed infants were two

centimeters shorter than the comparison subjects after adjustment for sex

(Hans 1989). The analysis considered socioeconomic status, maternal

intellectual performance, pregnancy and birth complications, and birth weight,

but it failed to include the most important predictive factor, midparental height,

as an independent variable.

The Houston longitudinal study found that after 3 months of age the length of

heroin-exposed and methadone-exposed subjects did not differ significantly

from that of drug-free controls (Wilson et al. 1981). At 3 years, mean height

was similar for all three groups (figures 1 and 2). The incidence of short stature

(height below the 10th percentile) was doubled in the drug-exposed groups (23

percent for the heroin, 26 percent for the methadone, and 11 percent for the

comparison) but was not statistically significant (Lifschitz et al. 1983). Of the

13 children with short stature at 3 years, only 3 had been SGA at birth. The

remaining SGA infants achieved catchup in length by 6 months, a pattern

usually seen in infants who suffer intrauterine growth retardation (Fitzhardinge

and Steven 1972).

FIGURE 1. Deviance of unadjusted length from comparison group mean,

drug-exposed males (0 line=comparison group mean)

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FIGURE 2. Deviance of unadjusted length from comparison group mean,

drug-exposed females

Analysis of variance was used to investigate the interaction of narcotic exposure

during pregnancy with factors widely accepted as affecting linear growth

(Lifschitz et al. 1983). Three-year height was significantly associated with birth

length, midparental height, and maternal cigarette smoking. When adjusted for

these three factors and race, the mean height of the methadone group was

significantly lower than that of the heroin group. The adjusted height of the

comparison group did not differ significantly from that of either drug group.

These data do not substantiate the hypothesis that narcotic use during

pregnancy has direct long-term detrimental effects on postnatal growth.

POSTNATAL HEAD GROWTH AND INTELLECTUAL FUNCTION

The major concern about chronic exposure to narcotics during gestation is the

potential toxicity to the vulnerable brain of the developing fetus. It has been

postulated that neurotransmitter function may be altered and that brain growth

may be impaired (Wilson 1975; Wilson et al. 1979; Rosen and Johnson 1985;

Hans 1989). Winick (1970) has reported that brain size in severe malnutrition

is reduced proportionally to head circumference, raising the possibility that

narcotic-exposed children with impaired postnatal head growth are at risk for

permanent neurologic and intellectual sequelae.

330
Studies of SGA babies who were not exposed to drugs suggest ongoing

neurodevelopmental problems related to poor head growth. A report on a

small sample of full-term SGA female children found that those whose head

circumference was below the 10th percentile at 1 year had lower intelligence

quotient (IQ) at school age than those whose head size had reached the 25th

percentile or above (Babson and Henderson 1974). Ounsted and coworkers

(1988) studied prospectively a large sample of SGA infants and a group of

controls who were adequate for gestational age (AGA). From the age of 2

months onward, the SGA group showed evidence of neurological delay.

Positive associations were found between changes in somatic measures and

neurological scores from birth through 6 months; infants who grew faster also

matured faster during this period and vice versa. In addition, significantly

positive correlations existed for both head circumference and height with

developmental scores at 7 years. These were due mainly to an association

between small size and low scores rather than larger children and higher

scores. The extrapolation of these data to the drug-exposed children might

imply that lack of catchup head growth during the first 6 months of life in

children who were SGA at birth would predict poor neurodevelopmental

outcome. In the authors’ experience, however, most of the narcotic-exposed

infants followed to the preschool age demonstrated an accelerated rate of head

growth during the first 3 months of postnatal life (figures 3 and 4). By 3 years of

age, the mean head measurements were similar and fell below the 50th

percentile for all three groups. Although head circumferences below the 10th

percentile occurred more commonly among children of narcotic-dependent

women (six heroin, 24 percent; six methadone, 23 percent; and five

comparison, 12 percent), the difference was not statistically significant (Lifschitz

et al. 1985).

Tracking individual growth curves provides insight into the inconsistent growth

patterns of this population and the inability to predict outcome from a single

data point. In one study, only 2 of the 17 preschool children with small head

size had shown small heads at birth (one heroin, one comparison) (Lifschitz et

al. 1985). These data indicate that, in narcotic-exposed children, deceleration

of head growth may occur postnatally. In fact, in five of the six heroin-exposed

children with small heads at 3 years, the decline in the rate of head growth

began after the first year of life. The trend toward postnatal deceleration of

head growth observed in narcotic-exposed children may have important clinical

implications; the small size of the sample, however, hinders its statistical

strength and precludes firm conclusions. Regression analysis determined that

perinatal and genetic variables were more predictive of preschool head size

than postnatal environmental factors. Birth weight, intrapartum risk score, and

race (head size adjusted for age and sex was largest for blacks and smallest for

Hispanics) were significantly associated with outcome.

331
FIGURE 3. Deviance of unadjusted head circumference from comparison

group mean, drug-exposed males

Contrary to expectations, in the Houston study, preschool head size was not

significantly related to intellectual performance. Regression analysis indicated

that cognitive abilities were best predicted by environmental factors, as

measured by the Home Observation for Measurement of Environment score

(Bradley and Caldwell 1977), along with two prenatal variables—the amount of

prenatal care, and the prenatal risk score. Intellectual performance did not

correlate with the amount of prenatal exposure to narcotics; however, low

cognitive scores were significantly more frequent in the heroin group. Five (20

percent) of the 25 heroin-exposed children were functioning in the retarded

range, a sevenfold increase over the expected rate in the general population.

A consistently higher incidence of head circumference below the third percentile

was seen in a group of methadone-exposed children studied longitudinally by

Rosen and Johnson (1985). At 3 years, there were no differences in mental

development between children in the methadone-exposed and the comparison

group; lower scores were more prevalent, however, among the methadone

group. In contrast with the Houston study, measurement of head circumference

did correlate with mental performance. Furthermore, cluster analysis

documented that children exposed to methadone overwhelmingly (85 percent)

332
FIGURE 4. Deviance of unadjusted head circumference from comparison

group mean, drug-exposed females

constituted the group with the weakest outcome. This cluster consisted of

children who had the lowest developmental scores, mean head circumferences

in the sixth percentile, and higher number of referrals for educational or

developmental problems.

Another prospective study of infants exposed to methadone indicated that,

when compared to unexposed controls at 2 years of age, the study subjects

were shorter and had smaller head circumference and less favorable

developmental scores (Hans 1989). Hans used an interesting analytical model;

the sample was dichotomized into high- and low-risk groups, and drug effects

were examined within risk groups using analysis of variance. Methadoneexposed infants lagged behind the comparison infants in all three categories

of risk: socioeconomic status, maternal IQ, and pregnancy and birth

complications. Head circumference at 2 years was strongly correlated with

complications of pregnancy and birth. In contrast with the Houston study, Hans

found an independent drug effect. Although cognitive development did not

differ significantly between groups, examination of infants raised in families at

the lowest socioeconomic levels indicated clear differences in mental scores

between methadone-exposed and unexposed infants. The researcher

333
suggested that methadone exposure may increase the vulnerability of children

to the effects of an impoverished environment.

Although there is no consensus that narcotic exposure during gestation affects

head growth and intellectual development directly, there is general agreement

that the combination of maternal narcotic and polydrug use, poor maternal

health, and obstetrical and birth complications do affect the developing fetus.

Furthermore, a vulnerable infant, who often must undergo narcotic withdrawal

during the first few months of life and “catch up” physically and developmentally

in a suboptimal environment, is undoubtedly at risk for impaired postnatal

growth and development.

COMMENTS

Despite increasingly numerous reports on the consequences of chronic narcotic

use during pregnancy, little is known of the long-lasting effects of these

substances on the exposed child.

As in any other area of research, the studies on fetal exposure to drugs have

undergone the following evolution. The report of an isolated clinical finding

is immediately followed by small, cross-sectional studies, then by larger

retrospective reports in an attempt to sort out prevalence rates of specific

adverse effects. Occurrences of new findings are compared to the prevalence

rate of the same condition in the general population. Then, carefully designed

and controlled cohort studies are reported, most of which are retrospective.

Several animal models are developed. Investigators in the basic sciences

follow the clinical literature, attempting to elucidate mechanisms by which drug

exposure may adversely affect the fetus. Although animal experiments have

proven useful, particularly because of their ability to randomize the sample

and obtain longitudinal data without struggling with issues of attrition, their

importance is ultimately limited by the insoluble problems of extrapolation of

results to humans. At this time, clinical investigators have collected enough

pilot data to warrant prospective, controlled, long-term studies. The design of

such clinical studies will be “flawed” from inception by a variety of methodologic

issues. Ethically, drug-dependent pregnant women cannot be randomized

into treatment and nontreatment groups. Once in contact with health care

professionals, every effort is made to improve the milieu of the drug user and

her fetus. This is accomplished by improving her access to and utilization of

medical care and other support systems, thereby promoting a healthier lifestyle

with alterations of drug use through counseling or chemical detoxification.

These interventions involve changes in the most important independent variable

to be examined: drug use.

334
A second major design problem relates to the vast number of confounding

variables that must be considered in the analyses of long-term effects of drug

use during pregnancy. The more carefully researchers plan analyses to control

for confounding variable, the larger the requirements for sample size.

In attempts to improve the ability to distinguish the effects of pregnancy drug

use on outcome, some recent studies made use of new statistical approaches

(e.g., cluster analyses and dichotomy of the sample). These and other creative

models should be used to define direct and indirect fetal and child risks of

chronic maternal drug abuse. Longitudinal studies are costly and difficult to

perform because of the high attrition rate of the sample. Changing patterns of

drug abuse complicate study design and outcome. Knowledge of long-term

outcome in children exposed to specific substances during gestation may be

substantially enhanced by monographs such as this, which seek to develop a

consensus on such issues as criteria for patient inclusion; methods of

documenting drug exposure: methods for identifying and reporting critical

sociodemographic data, both prenatally and longitudinally; and outcome

measures sensitive to suspected problems.

A strong argument could be made for collaborative investigation of long-term

effects of maternal drug use. A multicentered project that provides a statistically

powerful sample, standard protocol, and support services needed to prevent

attrition would be the ideal means by which to answer today’s questions. It is

clear that a very large population must be studied over an extended period of

time to definitively address the expected outcome of drug-exposed children and

determine which factors (social or biologic) are most predictive of outcome.

Thus far, data have been derived primarily from large inner-city hospitals, since

smaller centers caring for a limited number of drug-dependent subjects have

been unable to effectively compete for funding. Inclusion of small centers would

broaden the database and make the population more representative of society.

The authors’ experience with drug-dependent women in Houston suggests that

compliance may be more readily achieved in a “small community” setting.

While New York and Detroit nurseries were caring for hundreds of drugexposed babies annually, in Houston, only 70 drug-addicted women delivered

over a 2-year period. The county hospital serving the entire Houston

metropolitan area became the center for the obstetrical care of pregnant

addicts. While the research team networked closely with drug treatment

programs, the center focused on the addicts pregnancy rather than on her

addiction. Drug treatment or direct drug counseling were not provided, but

every effort was made to refer each subject to the most appropriate treatment

program. It became apparent that these mothers wore their “white hat” in the

clinic, leaving their “black hat” for the treatment program.

335
A prime factor in achieving long-term compliance appeared to be the continuity

of supportive services by project staff, beginning with first contact during

pregnancy. A staff member (nurse, social worker, and/or physician) saw the

mother at each appointed visit, responded to all phone calls and drop-in visits,

and vigorously pursued missed appointments. A close working relationship

developed with those subjects who availed themselves of prenatal care. The

relationship with women first presenting in labor was more tenuous; in most

instances, efforts were directed toward engaging family members, who

frequently became primary caretakers. For the majority of participants, the

“bonding” with project staff appeared to motivate them to cooperate. For the

recalcitrant few, frequent contact by phone or home vislt and “pick up and

delivery” for all protocol sessions were effective.

The authors believe that the type of participation needed from families involved

in such comprehensive studies necessitates more than token cooperation,

which is most effectively accomplished by giving the participants something in

return. Experience suggests that the staffs concern and availability were

essential to the project’s success and more effective than monetary rewards.

SUMMARY

The results of the studies reviewed indicate that intrauterine growth is adversely

affected by drug use during pregnancy. Whether the impairment is a direct

effect of narcotic exposure or is the result of the interaction of deleterious

health, environmental, and socioeconomic factors closely associated with the

lifestyle of the woman who abuses drugs cannot be determined at present.

Reports on the long-term effects of drug use on growth and intellectual

functioning in the offspring of women who abuse drugs are not consistent.

While some studies indicate that most of the exposed infants exhibit catchup

growth by 6 months of age (Lifschitz et al. 1983, 1985), one methodologically

strong study suggests that methadone may have a small direct teratogenic

effect reflected in reduced head size at 2 years of age (Hans 1989).

Unexplained is the pattern of growth deceleration observed in some narcoticexposed children (Lifschitz et al. 1983, 1985).

The few available reports on long-term outcome concur that narcotic-exposed

children have a high incidence of behavioral and learning problems (Strauss et

al. 1979; Rosen and Johnson 1985; Wilson 1989), but population studies have

been too small to demonstrate that they differ significantly from controls. There

is a suggestion that narcotic use during pregnancy promotes a biological

vulnerability to adverse environments, manifested in the neurobehavioral and

intellectual areas.

336
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ACKNOWLEDGMENTS

The work described in this chapter was supported by National Institute on Drug

Abuse grant DA-00915, by the American Legion, and by the USDA/ARS,

Children’s Nutrition Research Center, Baylor College of Medicine, Houston, TX.

AUTHORS

Marta H. Lifschitz, M.D.

Assistant Professor of Pediatrics

Geraldine S. Wilson, M.D.

Associate Professor of Pediatrics

Baylor College of Medicine

Meyer Center for Developmental Pediatrics

8080 North Stadium Drive, Suite 2300

Houston, TX 77054

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Integrity of Psychopathology

Diagnoses Across the Lifespan

Patricia Cohen and Judith S. Brook

INTRODUCTION

This chapter addresses two aspects of diagnoses of psychopathology: (1)

measurement issues, including the age at which they can first be assessed with

some reliability, and (2) the persistence of serious problems from one period of

life to the next, covering the span from early childhood to early adulthood. The

three diagnostic groups covered in some detail are attention deficit/hyperactivity

disorder (ADHD), conduct disorder, and anxiety disorders; however, the

evidence will often need to be taken from studies of symptoms rather than

studies of the whole syndrome. Because clear criteria for diagnoses of

psychopathology in childhood are a very recent phenomena, little information is

as yet available on persistence over more than a very short span of time.

Therefore, in addition to a brief synopsis of the literature on each syndrome,

this chapter presents data on persistence of disorders from early childhood

through young adulthood from the Children in the Community (CIC) study as

representative of the state of current knowledge on these topics. In light of the

fact that investigations of the risk of psychopathology associated with prenatal

drug exposure are likely to examine children selected for risk status rather than

those who are service-seeking, this chapter focuses on epidemiological studies

of children rather than on clinical populations; although, in some cases, the

latter may represent the only current evidence. Neither the reliability of the

diagnosis nor the level of stability over time is independent of the source of the

diagnostic information; it usually will be necessary to identify ages at which

parent, child, teacher, or observer may produce sound assessment of each

syndrome.

MEASUREMENT OF PSYCHOPATHOLOGY IN CHILDREN

Symptom Checklists and Screening Measures of Children’s Problems

A major issue in the assessment of children is deciding who will provide the

information regarding children’s symptoms, impairment, and functional level. As

340
shown in a comprehensive review by Achenbach and colleagues (1987) the

various sources of this information—parents, children, teachers, or mental

health professionals—usually agree rather little on either symptoms or

diagnoses, especially in populations not actively seeking treatment. Direct

observations of children likewise are frequently discrepant from information

from other sources. The most widely recommended solution to this problem of

disagreement is to seek information from as many sources as possible. Which

sources are available are a function partly of the age of the child and partly of

the particular population being studied. Parents are the primary source of such

information about infancy and early childhood, and it is well established that

mothers are more likely to note and report problems than are fathers. At these

ages, observational data also may be feasible for at least some problems.

For children in middle childhood, it is widely agreed that data from teachers

should be used to supplement reports from parents. By late childhood and

adolescence, reliable and useful information can and should be obtained from

the children themselves, as well as from their parents. As children enter junior

and senior high school, it is less likely that detailed description of symptoms and

problems will be obtainable from schools.

One important consideration in the selection of assessment measures is the

availability of some kind of normative data based on the instruments. Table 1

presents scaled or screening measures of psychopathology in children as

reported by parents, teachers, or self-report. These may be described as

established instruments in the sense that at least some normative information is

available. The Richman scales (Richman et al. 1982) have been used in

epidemiological studies in the United States and in the United Kingdom. As can

be seen by the relatively few items in the Behaviour Checklist, they cover a

broad spectrum with little room for discrimination of specific types of problems.

The other measures in table 1 include more specific measures of types of

problems, as well as an overall score. The Child Behavior Checklist (CBCL)

(Achenbach and Edelbrock 1983) has been developed with special forms for

the preschool age groups and is the single most thoroughly normed instrument.

In administering self-report measures to younger children, it is generally

necessary to have an interviewer or teacher read the items aloud. Only two

setf-report measures attempt to cover more than a single domain of problems:

the CBCL and the Children’s Self-Report Psychiatric Rating Scale (CSPR)

(Beitchman et al. 1985). The CBCL self-report version covers material

approximately parallel to that covered in the parent and teacher report versions.

The CSPR Scale is more global, having been developed to discriminate broadly

between community and mental health treatment samples. A recent book on

the assessment of children (Rutter et al. 1988) provides more detail on most of

these instruments, as well as a discussion of issues to be considered in their

selection.

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TABLE 1. Checklists and questionnaires for assessing symptoms of

psychopathology in children

Title, Author

Ages Covered

Number

of Items Parent Report Teacher Report Self-Report

Behaviour Checklist

(Richman et al. 1982)

12 3-6

Preschool Behavior Questionnaire

(Behar 1977)

36 3-6

Behavior Problems Checklist

(Quay 1983)

89 5-17 5-17

Conners Parent (Teacher)

Rating Scale (Conners 1969)*

93 (39) 6-14 4-12

Child Behavior Checklist 126-138 2-18 6-16 11-18

(Achenbach and Edelbrock 1983)

Revised Children’s Manifest

Anxiety Scale (Reynolds and

Paget 1981)

Children’s Depression Inventory

(Kovaks 1981)

Short Children’s Depression

Inventory (Carlson and Cantwell

1980)

Children’s Self-Report Psychiatric

Rating Scale (Beitchman et al.

1985)

Self-Reported Antisocial Behavior

(Loeber et al., in press)

62 6-19

27 8-17

13 7-17

33 7-12

33 6-14

*See also Goyette et al. 1978.

Interviews for Diagnosing Psychopathology in Children

Over the past decade there has been an effort to develop psychiatric diagnostic

instruments for children that utilize interviews of parents and children. These

interviews have several properties that commend their use:

1. They emphasize problems at the severe end of the distribution.

342
2. They include probes for functional significance, severity of distress,

frequency and duration, and associated impairment that should improve the

quality of the responses.

3. They permit the counting of children with problems and thus can be more

immediately translated into service needs.

4. They encourage identification of risk factors in an epidemiological

framework, thus allowing for relevant indices, such as attributable risk.

5. They allow fairly fine differentiation of the nature of the problem.

6. They permit flexible analytic models because they can yield scaled

measures as well as diagnoses.

Perhaps their greatest drawback is that they are relatively time-consuming.

Interviews in different populations, given in their entirety to cover all potential

diagnoses, range between 45 minutes and over 2 hours. Furthermore, the

current evidence casts doubt on the validity of the information obtained by

interviews of children under the age of 9 or 10 that is not corroborated through

interviews of parents or teachers.

Current diagnostic instruments attempt to cover all diagnostic criteria explicitly,

and most are available in versions matching the DSM-III-R criteria, and perhaps

even anticipating some DSM-IV changes. The most popular semistructured

interview designed for administration by clinicians is the Kiddie-Schedule for

Affective Disorders and Schizophrenia (K-SADS) (Chambers et al. 1985), which

exists in at least one relatively recent version. However, the evidence that such

semistructured clinical interviews are superior to fully structured interviews is

entirely lacking; and, for most research purposes, the use of one of the

structured interviews designed for administration by clinicians or trained lay

interviewers may be advisable.

The two most popular such instruments are the Diagnostic Interview for

Children and Adolescents (DICA) (Reich et al. 1982) and the Diagnostic

Interview Schedule for Children (DISC) (Costello et al. 1984). Another

instrument that requires more clinical inference by the interviewer is the Child

Assessment Schedule (CAS) (Hodges et al. 1982). Each of these interview

schedules obtains parallel information from parent and child interviews, and

each has been subject to several revisions and field trials. The DISC has a

revised and expanded version covering DSM-III-R and most likely DSM-IV

diagnostic criteria (DISC-2.1) (Shaffer et al. 1991). This interview is being used

343
in the four-site national study of large random samples of children sponsored by

the National Institute of Mental Health.

Age Considerations In the Assessment of Three Fairly Prevalent

Diagnoses

ADHD. It is probable that children showing very extreme levels of hyperactivity

and distractibility can be identified in the preschool years and even in infancy

with some reliability. Nevertheless, ADHD ordinarily is detected unambiguously

only when children enter the more structured demands of school, and most

children with ADHD have such a problem from at least the first grade.

Problems often intensify as the demands of school increase, and children

are most often brought to treatment centers between the ages of 8 and 12.

Identification of the problem in a single site—the school only or the home only—

is not unusual; therefore, reliable assessment of the problem often may involve

discrepant information from parent and teacher. Furthermore, confirmation of

the diagnosis by observation in a clinic setting is usually not possible, as the

novel setting and one-to-one interaction often minimizes these problems, even

in children with severe problems. Children usually are not considered to be

very good at self-reporting these problems before the late childhood years,

when they develop the perspective for comparison with other children and

awareness of difficulties with teachers or other adults.

By middle to late adolescence, ADHD is rarely diagnosed, although the general

problems of hyperactivity, impulsivity, and poor concentration are far from

absent in the adult population. It is probable that as opportunities to “niche

pick” increase in these years, those with this disorder find settings in which the

problems are not so distressing, handicapping, or liable to produce failure.

Anxiety Disorders. Clear extremes of anxious withdrawal, especially from

novel stimuli, are present in some children by age 2. Extreme levels of anxiety

usually are identified in the nursery years by parent report and may be

confirmed by structured observation. Fears and anxieties are very common

in prepubertal children, and it is probable that the necessary perspective

for assessing whether one’s problems are atypically severe develops only

gradually in the late childhood years. Mothers are the principal source of

diagnostic information in the early elementary school years; in general, it cannot

be assumed that teachers are particularly attentive to these problems. It is the

belief of some researchers that self-report is the primary relevant source of

information by age 10 or 11; however, empirical evidence on the relative validity

of information from different sources for anxiety disorders at these ages is still

lacking. In the postpubertal years, self-report should be considered essential to

the diagnosis.

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During the elementary school years, the most debilitating manifestations of

anxiety are probably (1) avoidant disorder, in which the child avoids everyone

unfamiliar; (2) separation anxiety, in which the child clings to a parent both

inside and outside the house; and (3) school phobia. By midadolescence, the

forms of anxiety appear to be more similar to adult problems, with social phobia,

a mix of anxious and depressive symptoms, and physiological manifestations of

anxiety becoming more prominent.

Conduct Disorder. Diagnosable conduct disorder, which requires clearly

antisocial and often illegal behavior, requires a development level and access

to independent action that rarely appears before middle childhood. However,

precursors of this syndrome, including aggression toward people or objects

and defiance, are measurable by parent report even at nursery school ages.

Information on these problems may be obtained from teachers, parents, or from

self-report during the elementary school years. By adolescence, it appears that

the youth is likely to be the best source of information regarding illegal and

antisocial activities. In adulthood, the kinds of activities generally change to fit

the adult environment, and the problem is called antisocial personality disorder,

presumably because it is by that time a fairly stable trait-like behavior pattern.

PERSISTENCE OF SYNDROMES FROM BIRTH TO ADULTHOOD

As noted, the diagnostic criteria for childhood psychopathology have been

spelled out clearly only in the last decade; as yet, little information is available

on clearly defined syndromes. Because the major large-sample source of such

information is the DISC-based longitudinal CIC study of randomly sampled

children in two upstate New York counties (Cohen and Brook 1987; Velez et al.

1989), these age-specific diagnostic stabilities will be reported as representative

of current estimates. For diagnostic measures, the odds ratio contrasts

diagnosis at followup for those initially diagnosed compared with those children

not initially diagnosed. In addition, major reviews of the stability of symptoms or

problems that are relevant to the diagnostic groups are cited, as well as findings

from relevant individual longitudinal studies of symptom or problem measures.

The fact of statistically significant and sometimes impressive levels of problem

persistence should not be taken to imply the absence of change or the

presence of stable underlying qualities in the child that may be expressed

differently at different ages (Clarke and Clarke 1984). Rather, as in all physical

and behavioral patterns, large amounts of change in relative position of

individual children are to be expected; and the presence of excess risk for future

problems of a similar kind cannot be taken to be equivalent to a negative

prognosis for most children exhibiting these problems. In general, as in the

case of measured Intelligence, stability from very early childhood to late

345
childhood, adolescence, or adulthood is likely to be modest. Stability can be

expected to decline as a function of the magnitude of the interval over which it

is measured, as a function of changes in the source or kind of information, and

as a function of major changes in the setting of the assessed individuals.

Persistence From Early to Middle Childhood

ADHD. Relatively little information on the outcome of preschool attention/

hyperactivity problems is available. Recent data from the CIC showed that the

odds of having diagnosable ADHD at ages 10 to 13 were about 4 1/2 times as

great (odds ratio=4.62) if the children were identified by mothers as having such

problems at ages 2 to 4. Table 2 provides a summary of CIC stability data.

Anxiety. Trait anxiety (i.e., anxiety measured as a continuous variable) is

among the most stable of behavioral patterns in early childhood. However,

observational and laboratory data gathered by Kagan and colleagues (1989)

over the span from 14 months to age 4 found no stability in anxious/withdrawn

behavior from the earliest assessments to the 4-year assessments, although

children who showed extreme levels of anxious behavior both at 14 months and

at 20 months were more likely to show anxious patterns at age 4. In the CIC

data, anxiety as reported by mothers of 2- to 4-year-olds was quite stable, with

a correlation over 8 years of .4. Nevertheless, the relationship between early

anxiety and diagnosable anxiety disorder in late childhood based on combined

mother and child interviews was not significant.

TABLE 2. Odds ratios for subsequent diagnosis for children with and without

earlier diagnosis

Age Span Covered

Early to Middle Middle Childhood Adolescence

Childhood to Adolescence to Young Adulthood

(2-4 to 10-12) (5-10 to 13-18) (16-18 to 19-21)

(n=385) (n=444) (n=208)

ADHD 4.6 11.2 16.9

Overanxious disorder — 7.8 11.8

Conduct disorder 3.7 19.3 18.2

NOTE: All data are taken from the CIC Project. All table odds ratios are

statistically significant using the .01 criterion.

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Conduct Disorder. A review of the stability of aggressive behavior by Olweus

(1979) concluded that the aggressive component of conduct disorder is as

stable as is intelligence. More recent research by Richman and coworkers

(1982) reported that children presenting aggressive or management problems

at age 4 were much more likely to show conduct disorder symptoms at age 8.

In the CIC data, children who presented aggressive or management problems

at ages 1 through 4 had an odds of diagnosable conduct disorder 8 years later,

nearly 4 times that of those who did not show such early problems (3.7 odds

ratio).

Persistence From Middle Childhood to Adolescence

ADHD. Because the diagnostic criteria for ADHD require onset of symptoms in

the earliest school years, children obtaining the diagnosis in late childhood or

adolescence must necessarily have had the diagnosis at earlier assessment.

Therefore, if diagnostic criteria are strictly followed, the odds for persistent

diagnosis compared to the odds for new diagnosis must be infinite. If this

restriction is ignored, some data are available on diagnostic stability. Huessy

and colleagues (1973) found that 37 of 64 children identified as in the top 20

percent in these symptoms in the second grade were still in the top 20 percent 3

years later, yielding an odds ratio of about 7. In the CIC study, the odds of

ADHD in adolescence was 11 times as large for children with this diagnosis in

middle to late childhood (odds=11.2).

Anxiety. In the CIC project data, the odds of overanxious disorder in

adolescence was about eight times as great for children receiving such a

diagnosis in middle to late childhood (odds=7.8).

Conduct Disorder. It has long been known that early onset of antisocial

behavior is a risk factor for higher stability of such behavior. Among the many

studies investigating aggression and delinquent behaviors, Roff and Wirt (1984)

showed the correlation of late grade school predelinquency or aggression with

adolescent delinquency to be in the range of .25 to .30. Eron and Huesmann

(1984) found the stability of aggression from age 8 to age 19 to be .42. In fact,

aggression at age 8 predicted aggression at age 30 (r=.25).

In the CIC data, the odds of a diagnosable conduct disorder in adolescence

was 19 times as great if the child had such a diagnosis in middle to late

childhood (odds=19.3).

Persistence From Adolescence to Adulthood

Since some of the early followup studies of children showing delinquent

behaviors in childhood and adolescence, it has been known that most adult

347
antisocial behavior is preceded by these earlier behaviors (Robins 1966).

Sampling a more representative population, Roff and Wirt (1984) showed both

adolescent aggression and adolescent delinquency to be correlated with adult

criminality (r=.24 and .41, respectively).

In the CIC data, the odds ratios for young adult diagnosis (ages 19 to 21)

for those with an earlier adolescent diagnosis (ages 16 to 18) compared to

those without an earlier adolescent diagnosis were 16.9 for ADHD, 11.8 for

overanxious disorder, and 18.2 for conduct disorder. Taken as a whole, as

shown in table 2, the stability of diagnosis tends to increase over the span from

early childhood to adulthood.

Heterotypic Integrity: Progressions From One Diagnosable Disorder to

Another

In many cases it is suspected or known that the presence of a certain diagnosis

at one age predisposes the individual to develop another diagnosis at a

subsequent age. Some of these hypothetical or empirical connections were

mentioned earlier, such as the possible connections between the anxiety

disorders and especially those between child separation anxiety or school

refusal and adult agoraphobia. Although this review does not attempt to cover

the current evidence on heterotypic progressions, the topic is an important one

and also raises some methodological and substantive issues that are only

currently being addressed. It has long been known that children diagnosed with

ADHD are likely to appear in subsequent years with frank conduct disorder or

delinquent behaviors. As Quay and colleagues (1987) point out, the difficulty is

that there is a very high comorbidity between these two diagnoses throughout

childhood, and what appears to be a progression may only be the changing

face of comorbidity. To sort out heterotypic continuities, it is necessary to

differentiate between children with and without signs of comorbidity.

Another common area for comorbidity in childhood psychopathology is major

depression. Several recent epidemiological studies covering middle to late

childhood through adolescence have found that all cases of major depression at

these ages had at least one comorbid condition, among which conduct disorder

and opposition/defiant disorder are probably the most likely (for a review of

these cohorts, see Costello 1989).

Perhaps particularly relevant for this monograph, conduct disorder has

long been known to be an antecedent risk factor for substance abuse in

adolescence. CIC data also show that aggressive and behavioral management

problems at ages 5 to 10 are risks for adolescent drug use (Brook et al. 1989).

348
Perinatal or Early Risks for Later Manifestation of Psychopathology

Finally, modest stability of a given syndrome from early childhood should not be

taken to imply that the effects of early risks, including prenatal or perinatal

problems, may not emerge newly after early childhood. For the most part,

evidence of “sleeper effects” of traumatic events (i.e., problems appearing at a

later period without evidence of immediate problem) is sparse. However, there

are reasons to think that certain kinds of biological insults, whether genetic,

congenital, or occurring early in life, may first be manifest when the relevant

brain structures are called into use. For example, it is hypothesized that

schizophrenia may manifest almost entirely postpubertally because that is the

first time the prefrontal cortex is an active influence on behavior. Similarly, in

the CIC study, perinatal problems predicted newly manifest syndromes in late

childhood and adolescence, presumably for similar reasons (Cohen et al. 1989).

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and Revised Child Behavior Profile. Burlington, VT: University of Vermont,

Department of Psychiatry, 1983.

Achenbach, T.M.; McConaughy, S.H.; and Howell, C.T. Child/adolescent

behavioral and emotional problems: Implications of cross-informant

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Behar, L.B. The Preschool Behavior Questionnaire. J Abnorm Child Psychol

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Brook, J.S.; Nomura, C.; and Cohen, P. Prenatal, perinatal, and early childhood

risk factors and drug involvement in adolescence. Genet Soc Gen Psychol

Monogr 115:221-241, 1989.

Carlson, G., and Cantwell, D.P. A survey of depressive symptoms, syndrome

and disorder in a child psychiatric population. J Child Psychol Psychiatry

21:19-25, 1980.

Chambers, W.; Puig-Antich, J.; Hirsch, M.; Paez, P.; Ambrosini, P.J.; Tabrizi,

M.A.; and Davies, M. The assessment of affective disorders in children and

adolescents by semi-structured interview: Test-retest reliability of the KSADS-P. Arch Gen Psychiatry 42:696-702, 1985.

Clarke, A.D.B., and Clarke, A.M. Constancy and change in the growth of

human characteristics. J Child Psychol Psychiatry 25:191-210, 1984.

Cohen, P., and Brook, J.S. Family factors related to the persistence of

psychopathology in childhood and adolescence. Psychiatry 50:631-638,

1987.

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Cohen, P.; Velez, C.N.; Brook, J.S.; and Smith, J. Mechanisms of the

relationship between perinatal problems, early childhood illness, and

psychopathology in late childhood and adolescence. Child Dev 60:701-709,

1989.

Conners, C.K. A teacher rating scale for use in drug studies with children.

Am J Psychiatry 126:884-888, 1969.

Costello, A.J.; Edelbrock, C.; Dulcan, M.K.; Kalas, R.; and Klaric, S.H.

“Development and Testing of the NIMH Diagnostic Interview Schedule for

Children in a Clinic Population.” Final report (Contract No. RFP-DB-81-0027)

Rockville, MD. Center for Epidemiologic Studies, National Institute of Mental

Health, 1984.

Costello, E.J. Developments in child psychiatric epidemiology. J Am Acad

Child Adolesc Psychiatry 28:848-852, 1989.

Eron, L.D., and Huesman, L.R. The relation of prosocial behavior to the

development of aggression and psychopathology. Aggressive Behav

10(3):201-211, 1984.

Goyette, C.H.; Conners, C.K.; and Ulrich, R.F. Normative data on Revised

Conners Parent and Teacher Rating Scales. J Abnorm Child Psychol 6:221-

236, 1978.

Hodges, K.; McKnew, D.; Cytryn, L.; Stern, L.; and Kline, J. The Child

Assessment Schedule (CAS) diagnostic interview: A report on reliability and

validity. J Am Acad Child Psychiatry 21:468-473, 1982.

Huessy, H.R.; Marshall, C.D; and Gendron, R.A. Five hundred children

followed from grade 2 through grade 5 for the prevalence of behavior

disorder. Paedo Psychiatry 39:301-309, 1973.

Kagan, J.; Reznick, J.S.; and Gibbons, J. Inhibited and uninhibited types of

children. Child Dev 60:838-845, 1989.

Kovaks, M. Rating scales to assess depression in school-aged children.

Acta Paedopsychiatry 46:305-315, 1981,

Loeber, R.; Stouthamer-Loeber, M.; and Van Kammen, W.B. Development of a

new measure of self-reported antisocial behavior for young children:

Prevalence and reliability. In: Klein, M.W., ed. Self-Report Methodology in

Criminological Research. Boston: Kluwer-Nijhoff, in press.

Olweus, D. Stability of aggressive reaction patterns in males: A review.

Psychol Bull 88:852-875, 1979.

Quay, H.C. A dimensional approach to behavior disorder: The Revised

Behavior Problem Checklist. Sch Psychol Rev 12:244-249, 1983.

Quay, H.C.; Routh, D.K.; and Shapiro, S.K. Psychopathology of childhood:

From description to validation. Annu Rev Psychol 38:491-532, 1987.

Reich, W.; Herjanic, B.; Welner, Z.; and Gandhy, P.R. Development of a

structured psychiatric interview for children: Agreement of diagnosis

comparing parent and child. J Abnorm Child Psychol 10:325-336, 1982.

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Reynolds, C.R., and Paget, K.D. Factor analysis of the Revised Children’s

Manifest Anxiety Scale for blacks, whites, males and females with a national

normative sample. J Consult Clin Psychol 44:352-359, 1981.

Richman, N.; Stevenson, J.; and Graham, P. Preschool to School: A

Behavioural Study, London: Academic Press, 1982.

Robins, L.N. Deviant Children Grown Up. Baltimore, MD: Williams and

Wilkins, 1966.

Roff, J.D., and Wirt, R.D. Childhood social adjustment, adolescent status, and

young adult mental health. Am J Orthopsychiatry 54:595-602, 1984.

Rutter, M.; Tuma, A.H.; and Lann, I.S., eds. Assessment and Diagnosis in

Child Psychopathology. New York: Guilford Press, 1988. 477 pp.

Shaffer, D.; Fisher, P.; Piacintini, J.; Schwab-Stone, M.; and Wicks, J.

Diagnostic Interview Schedule for Children: DISC 2.1. New York: Division

of Child and Adolescent Psychiatry, Columbia University College of

Physicians and Surgeons, 1991.

Velez, C.N.; Johnson, J.; and Cohen, P. The Children in the Community

Project: Longitudinal analyses of selected risk factors for childhood

psychopathology. J Am Acad Child Adolesc Psychiatry 28:861-864, 1989.

ACKNOWLEDGMENT

The CIC Project was supported by National Institute of Mental Health Grant

MH-36971 to Patricia Cohen, Principal Investigator, and by National Institute on

Drug Abuse grant DA-03188 to Judith Brook, Principal Investigator.

AUTHORS

Patricia Cohen, Ph.D.

Professor of Clinical Epidemiology and Psychiatry

Columbia University School of Public Health and

College of Physicians and Surgeons

Research Scientist

New York State Psychiatric Institute

Box 47

722 West 168 Street

New York, NY 10032

Judith S. Brook, Ed.D.

Professor of Psychiatry

Mount Sinai School of Medicine

Department of Psychiatry

New York Medical College

Valhalla, NY 10595

351
Discussion: Drug Effects—A Search

for Mechanisms

Barry Zuckerman

INTRODUCTION

Three of the chapters in this monograph (Lifschitz and Wilson; Hans; Cohen

and Brook) highlight the relationship between social and biologic factors, issues

regarding the measurement of psychopathology, and strategies to maintain

contact with and protect the rights of subjects. The ability to determine the

validity of a relationship between prenatal drug exposure and long-term

outcomes will be increased if a mechanism is identified that helps to explain the

association. This chapter focuses on possible mechanisms by which maternal

drug use during pregnancy may alter the subsequent growth and development

of the exposed child and reemphasizes the vital importance of considering the

social environment as a covariable in any study concerning long-term

outcomes.

MODELS OF DEVELOPMENT

How does maternal drug use affect the exposed fetus? It is particularly difficult

to attribute a long-term outcome to any prenatal event, including attributing later

psychopathology to prenatal drug exposure. The closer the exposure to the

measurement of outcome, the greater the ability to make causal inference.

A nosology of psychopathology or a predictive assessment of behavioral

functioning during infancy would help increase understanding of the impact of

prenatal drug exposure. It is unlikely that psychopathology during later

childhood or adolescence can be caused solely by in utero drug exposure.

The information presented by Cohen and Brook (this volume) regarding the

measurement of psychopathology and behavior disorders in school-age

children and adolescents is helpful because measures in infancy are not

available.

Early theories of child development implied that poor developmental outcome

was the result of a single risk factor (e.g. hypoxia, prematurity, or In the present

case, in utero exposure to psychoactive drugs) thought to affect the central

352
nervous system (CNS). This approach is called the main-effect model of

development and implies a linear cause-and-effect relationship between risk

and outcome. Information to support this model was based on retrospective

studies of children with significant neurologic problems who had high rates of

perinatal problems. Prospective studies, however, showed developmental

outcomes to be largely unpredictable solely by the presence or degree of a

biologic insult. Rather, children’s development could best be understood by a

transactional model of development that describes a dynamic interplay between

the environment and the child, so that the child is shaped by the environment

and the environment is actively modified by the child (Sameroff and Chandler

1975).

Available information, much of it in a preliminary stage, provides clues to

aspects of the dynamic interplay that may contribute to the later functioning of

drug-exposed infants. These clues to possible mechanisms include biologic

vulnerabilities within the CNS from the direct and indirect effects of prenatal

drug(s) and social factors in the child’s environment. This chapter focuses

primarily on prenatal cocaine exposure because its use among pregnant

women is increasing and because, although much information is available about

cocaine, little is known about its effects on the fetus.

POSSIBLE MECHANISMS

Cocaine can affect the fetus by both direct and indirect mechanisms. Cocaine’s

primary action is to prevent the reuptake of norepinephrine, epinephrine, and

dopamine at presynaptic sites. This leads to increases in CNS and peripheral

catecholamine concentrations. Alterations in these neurotransmitters could

directly affect the developing CNS. Peripherally, these changes result

in increased temperature, increased heart rate, and vasoconstriction.

Vasoconstriction of the placental vessels and subsequent fetal hypoxia is an

indirect mechanism of cocaine’s effect on the fetus. Because most mothers

who use cocaine also smoke cigarettes and marijuana, cocaine may exacerbate

the known hypoxia associated with marijuana and cigarette smoking, thereby

inducing a cumulative hypoxic effect.

BIOLOGIC VULNERABILITIES ATTRIBUTABLE TO INDIRECT EFFECTS

Growth

Examining growth parameters of newborns exposed to cocaine in utero

provides information regarding indirect mechanisms. Anthropometric

assessments of body composition and proportionality provide important

information regarding the mechanisms of growth impairment, as well as

prognosis for future growth (Frisancho et al. 1977; Harrison et al. 1983;

353
Georgieff et al. 1988; Miller and Merrit 1979; Villar and Belizan 1982) and may

shed light on some unanswered questions identified by Lifschitz and Wilson

(this volume).

Frank and colleagues (1990) assessed fat and lean body mass by measuring

fat folds and mean upper arm muscle circumference in the nonfat area of

the upper arm, respectively. The study found that marijuana, like cigarettes,

depresses indicators of lean body mass while sparing fat deposition, consistent

with a hypoxic or other nonnutritional mechanism (Frisancho et al. 1977). This

finding remained after controlling for maternal cigarette use and nutritional

status and is consistent with studies showing that marijuana smoking produces

hypoxia at the pulmonary level (Clapp et al. 1986; Abrams et al. 1985;

Niederreither et al. 1985). In addition, marijuana elevates carbon monoxide to

levels higher than those attained by smoking cigarettes (Wu et al. 1988).

Cocaine, on the other hand, is associated with indicators of both depressed

neonatal fat stores and lean body mass (Frank et al. 1990), a pattern commonly

associated with maternal malnutrition (Frisancho et al. 1977; Harrison et al.

1983). This finding remained even after nutritional markers such as maternal

weight for height at conception and pregnancy weight gain were analytically

controlled. It is possible that transfer of nutrients to the fetus is impaired due to

vasoconstriction caused by cocaine, regardless of maternal nutritional status.

In addition, cocaine also may diminish birth weight by increasing fetal

metabolism through its effect on the sympathetic nervous system.

Among neonates, body proportionality is measured by the ponderal index

(weight in grams/length in cm3 x 100), which is thought to indicate timing of

prenatal insults and also may be related to postnatal growth (Miller and Merritt

1979; Villar and Belizan 1982). A low ponderal index (a long, thin newborn)

indicates reduced soft tissue mass with relative sparing of linear growth,

reflecting fetal malnutrition in the third trimester. In contrast, infants whose birth

weights are depressed and ponderal indices are normal (symmetrically growthretarded newborns) suffer impairment of linear growth that suggests an early

and/or chronic process starting early in gestation,

Frank and colleagues (1990) have shown that positive urine assays for

marijuana and cocaine during pregnancy are both associated with a

symmetrical pattern of intrauterine growth retardation, suggesting a

chronic prenatal insult. Cocaine-exposed infants also had smaller head

circumferences. Newborns from other study populations with symmetrical

growth retardation have poorer postneonatal growth and development than

infants with either asymmetrical intrauterine growth retardation or normal

intrauterine growth, particularly if head circumference is also depressed (Holms

354
et al. 1977; Davies et al. 1979; Viliar et al. 1984). Whether this will also be true

for marijuana- and cocaine-exposed newborns is unknown.

Central Nervous System

Another indirect mechanism that may contribute to long-term outcome are

the lesions that are seen as echolucencies and echodensities in the CNS

associated with prenatal cocaine/amphetamine exposure (Dixon and Bejar

1989). It is known that extensive intraventricular (Grade Ill and/or IV

hemorrhage), but not echodensities (including small cysts among premature

infants), is associated with poor neurodevelopmental outcome (Bennett et al.

1990). However, in cocaine-exposed infants, the locations of these lesions are

different than those found among asphyxiated infants; whether these lesions

are clinically important is unknown. Among cocaine-exposed infants, the

lesions tend to be located in the frontal lobe and basal ganglia. It is postulated

that this distribution is attributable to early development of musculature in the

blood vessels leading to these regions. Thus, subsequent impairments among

cocaine-exposed newborns may involve frontal-lobe dysfunction (such as

higher level cognitive functions, perceptual motor tasks, and/or affective states)

and may be different from those shown for premature or asphyxiated infants.

New or different assessments may need to be developed and/or considered to

detect the functional consequences of these lesions.

BIOLOGIC VULNERABILITIES ATTRIBUTABLE TO DIRECT EFFECTS

Cocaine’s direct effect on the fetal brain may be influenced by many factors,

including maternal metabolism of cocaine and changing lipid concentration

of the developing fetal brain. Cholinesterase is the primary enzyme that

metabolizes cocaine. Cholinesterase levels are usually low in pregnant women

and fetuses, thereby decreasing the metabolism of cocaine and increasing

duration of exposure during pregnancy. However, in an investigation

determining cholinesterase levels during pregnancy starting at preconception

until 3 months postpartum, cholinesterase levels did not decrease for all

women, and for some women it actually increased (Evans et al. 1988). Women

with high cholinesterase levels metabolize cocaine more quickly, thereby

decreasing duration of exposure to the fetus and decreasing potential CNS

impairment. Thus, some maternal-fetal units may be relatively less vulnerable

to the detrimental effects of cocaine than others.

In animals, administration of cocaine results in higher concentrations in the

adult brain than in the fetal brain (Wiggins et al. 1989). Because cocaine is

lipophilic, this may be due to the increased lipid content of the adult brain.

Thus, it is possible that cocaine’s concentration in the fetal brain may increase

during gestation as the lipid concentration of the brain increases.

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A direct effect of cocaine on the brain may be due to its ability to alter

neurotransmitters. This possibility is supported by changes in neurobehavioral

(Chasnoff et al. 1985) and cardiac functioning (van der Bor et al. 1990) in

cocaine-exposed newborns. To assess the effects of prenatal cocaine

exposure on catecholamine physiology, Mirochnick and coworkers (in press)

conducted a preliminary investigation to determine circulating levels of

catecholamines in neonates and their relationship to neurobehavioral

functioning. Among full-term, appropriate-for-gestational-age infants, the

catecholamine precursor dihydroxyphenylalanine (DOPA) was increased

in cocaine-exposed (n=12) compared with unexposed newborns (n=8).

Circulating DOPA is believed to be derived substantially from sympathetic

neurons, so that measurement of circulating DOPA may reflect neuronal

catecholamine biosynthesis (Eisenhofer et al. 1986).

There were no statistically significant differences in norepinephrine (NE) and

dopamine concentrations among the cocaine-exposed comparison subjects in

the Microchnick study. However, inspection of the norepinephrine results

suggests a trend to increased NE concentrations in the cocaine-exposed group.

One member of the control group had an NE concentration several times higher

than any other infant in the control group. Had this outlier been removed, NE

concentrations in the cocaine-exposed newborns would have been almost twice

that in the control infants and would have approached statistical significance in

the small study population. Among the cocaine-exposed infants, those with

high NE concentrations were least responsive to auditory and visual stimuli

(orientation subscale) as measured by the Neonatal Behavioral Assessment

Scale. This finding raises the possibility that this behavioral disturbance, which

has been shown in other studies of cocaine-exposed newborns (e.g., Chasnoff

et al. 1985), may be mediated in part by elevated levels of NE. However,

measurements were made on blood and do not necessarily indicate changes in

the CNS. Although it is possible that catecholamine changes shown in this

preliminary study are attributable entirely to chronic stress associated with

cocaine-induced vasoconstriction and hypoxia in utero, a study of 2-monthold infants showed increased levels of circulating NE, suggesting ongoing

disturbance in the catecholamine systems (Ward et al. 1989). Further

investigations are needed to determine whether the catecholamines and their

metabolites are elevated in the CNS.

The impact of increased levels of neurotransmitters on the developing CNS

raises important questions regarding long-term CNS effects, including

diagnoses associated with alterations of these neurotransmitters such as

attention deficit/hyperactivity disorder (ADHD) (Raskin et al. 1984) and

depression (Gold et al. 1988). Because females suffer higher rates of

depression compared to males, females may be more vulnerable to the direct

356
effects of cocaine on the CNS. A study of rats exposed to cocaine showed

increased rates of brain functional activity among females (but not males)

especially in the cingulate cortex and the ventral tegmental area, which have

high concentrations of dopaminergic synapses (Weiss et al. 1981). With this

possibility in mind, Frank and Zuckerman (unpublished data) reanalyzed

neonatal neurodevelopmental assessment data among newborns exposed

prenatally to cocaine. Prior analysis combining both male and female neonates

had not shown any difference between cocaine-exposed and nonexposed

infants. This preliminary reanalysis showed poorer neurodevelopmental scores,

as measured by the Neurologic and Adaptive Capacity Scale developed

by Amiel Tison, among cocaine-exposed female infants compared with

nonexposed female infants. The differences remained when confounding

variables were controlled. No difference was seen between exposed and

nonexposed males.

These preliminary data suggest that catecholamine activity may be increased

in cocaine-exposed newborns and may be associated with concurrent

neurobehavioral abnormalities. Longitudinal studies are needed to delineate

the nature, magnitude, and duration of the relationship among prenatal cocaine

exposure, catecholamine physiology, and long-term child functioning, including

psychopathology. Analysis of cocaine-exposed infants should be stratified by

gender to avoid missing significant association due to potential differential

vulnerabilities to cocaine in the CNS. Global outcome measures such as

cognitive performance, developmental quotients, or psychiatric diagnoses may

not identify prenatal effects of cocaine. The potential impact on the CNS of

neurotransmitter alterations or small localized hemorrhages suggests specific

outcome measures such as regulation of attentional states, problems with

information processing, or the ability to regulate affect or anxiety.

SOCIAL ENVIRONMENT

Prospective studies of biologically at-risk newborns during the past 20

years highlight the importance of a good social environment in optimizing

development in the face of biologic vulnerabilities. This protective effect of the

social environment is consistent with the transactional model of development in

predicting children’s development (Sameroff and Chandler 1975). For example,

among an extensively studied group of premature infants, intelligence quotient

(IQ) scores at 7 years of age were lower among infants who at 1 month of age

were neurologically immature as indicated by a decreased amount of an

electroencephalogram (EEG) pattern called trace alternans. However, among

infants with low trace alternans, responsive caretaking (measured by direct

observation) resulted in an IQ similar to infants who were not neurologically

immature (Beckwith and Parmalee 1986). Thus, responsive caretaking

357
appeared to be a protective factor for premature children with biologic

vulnerability. In another study, children with equivalent levels of perinatal stress

had better outcomes if their families had a high level of stability. It was only the

combination of high perinatal stress and low family stability that impaired

children’s developmental functioning Werner 1989). The importance of the

environment in modifying perinatal risk factors also has been shown in studies

of drug-exposed infants. Hans (this volume) found that only when prenatal

methadone exposure was combined with low social class could impaired

development be demonstrated compared with a control group. Lifschitz and

colleagues (1985) also showed that the quality of the postnatal environment,

and not the amount of maternal opiate use, appeared to be the more important

determinant of outcome among opiate-exposed infants. The transactional

model of development predicts that the biologic vulnerability created by in utero

cocaine exposure can be highly modified or exacerbated by social factors.

Unfortunately, drug- and alcohol-abusing mothers are at high risk for

dysfunctional caretaking. Because of the highly addictive nature of cocaine, it is

likely that cocaine addiction causes significant disturbances in mothering

behavior. At this time, little information on caregiving characteristics of cocaineusing women is available.

As part of an ongoing study of health behaviors and psychosocial

characteristics of young mothers, Greer and Zuckerman (unpublished data)

evaluated caregiving behaviors in the homes of 35 young mothers when their

children were approximately 1 year of age. The Home Observation for

Measurement of the Environment was used to assess the social and physical

environment of the home, and the Nursing Child Assessment Teaching Scale

was used to evaluate the responsiveness and sensitivity of the mother-child

relationship. These assessments were done by an observer who was blind to

the mother’s drug use and other psychosocial characteristics. Inspection of the

data showed the scores of two mothers to be more deviant than were the

scores of the remainder of the group. Further exploration revealed that these

two mothers were the only cocaine users in the sample. The two cocaine-using

mothers provided less nurturing and attentive home environments and were

less responsive and supportive in interactions with their infants compared

with the other mothers. For example, one of the mothers’ involvement and

interaction with her 1-year-old son was minimal, except for shouting at him. In

response to the examiner’s request to ask her son to build a tower of three

blocks, she said: “Do this,” building the tower herself and then returning to her

breakfast and cigarette. The child, however, did receive stimulation and support

from a 3-year-old brother, an 8-year-old cousin, and his father. These case

reports are consistent with clinical observation and need to be replicated with

studies of larger sample sizes.

358
Mothers usually do not use drugs in isolation. The father of the baby, friends,

and even grandparents are likely to be drug users. This drug-using

environment is likely to involve violence, including women being victims of

violence during their pregnancy (Amaro et al. 1990). Children born into this

type of environment are most likely at an increased risk of physical abuse.

Even if the child is not directly abused, being reared in a violent, dangerous

environment that involves witnessing violence may have important physiologic,

behavioral, and emotional consequences (van der Kilk 1988).

Although Hans (this volume) points out that children of drug-using parents may

be at high risk for ADHD because of a direct effect of cocaine on the CNS, the

social environment also may contribute to this outcome. For example, maternal

depression may contribute to the development of short attention span in

children. The depressed mother’s tendency to initiate and terminate more

frequently their children’s interaction with objects was associated with a shorter

attention span in her child. Because depression is a common comorbidity of

cocaine abuse, this social interactive mechanism may contribute to symptoms

associated with ADHD.

NEED FOR MATERNAL-CHILD CENTERS

It is important to determine the long-term effects and associated mechanisms

of prenatal cocaine use. In the process, understanding of brain behavior

relationships also may be improved. An important but unanswered question is

whether good caretaking will help compensate for cocaine-induced direct or

indirect biological vulnerability. However, the likelihood of good caretaking

without comprehensive intervention for drug-using mothers and their children is

unlikely because of cocaine’s significant adverse effect on behavior and

functioning.

The last National Institute on Drug Abuse technical review conference on

perinatal drug use was held approximately 5 years ago. Unfortunately, the

scientific community is only slightly more knowledgeable now than it was then.

The Nation is experiencing an epidemic of perinatal drug use without reliable

knowledge of the prevalence of such use, the short-term and long-term impact

of these drugs, and the most effective treatment strategies. There are also an

inadequate number of researchers trained in investigating perinatal drug effects.

To effectively move the field ahead, one to four mother-child centers devoted to

research, training of investigators and clinicians, and clinical care need to be

developed. A service component is an important part of such centers because

the ability to conduct longitudinal studies of the long-term effects of drugs

depends on maintaining a study population. For drug-using mothers and their

infants, this is best accomplished in the context of a comprehensive service

359
program. Without such a focused and extensive commitment, the ability to

understand and help drug-exposed infants and their parents will remain limited.

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ACKNOWLEDGMENT

Support for the work described in this chapter was provided by the Harris

Foundation.

AUTHOR

Barry Zuckerman, M.D.

Professor of Pediatrics

Department of Pediatrics and Public Health

Boston University School of Medicine

Director

Division of Developmental and Behavioral Pediatrics

Boston City Hospital

Talbot 214

818 Harrison Avenue

Boston, MA 02118

362
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25 BEHAVIORAL ANALYSIS AND TREATMENT OF SUBSTANCE ABUSE.

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38 DRUG ABUSE AND THE AMERICAN ADOLESCENT. Dan J. Lettieri,

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40 ADOLESCENT MARIJUANA ABUSERS AND THEIR FAMILIES. Herbert

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47 PREVENTING ADOLESCENT DRUG ABUSE: INTERVENTION

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Jacqueline P. Ludford, M.S., eds. A RAUS Review Report.

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48 MEASUREMENT IN THE ANALYSIS AND TREATMENT OF SMOKING

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50 COCAINE: PHARMACOLOGY, EFFECTS, AND TREATMENT OF

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51 DRUG ABUSE TREATMENT EVALUATION: STRATEGIES, PROGRESS,

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52 TESTING DRUGS FOR PHYSICAL DEPENDENCE POTENTIAL AND

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53 PHARMACOLOGICAL ADJUNCTS IN SMOKING CESSATION. John

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54 MECHANISMS OF TOLERANCE AND DEPENDENCE. Charles Wm.

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55 PROBLEMS OF DRUG DEPENDENCE, 1984: PROCEEDINGS OF THE

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56 ETIOLOGY OF DRUG ABUSE: IMPLICATIONS FOR PREVENTION.

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57 SELF-REPORT METHODS OF ESTIMATING DRUG USE: MEETING

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J. Kozel, M.S.; and Louise G. Richards, Ph.D., eds.

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60 PRENATAL DRUG EXPOSURE: KINETICS AND DYNAMICS. C. Nora

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64 PHENCYCLIDINE: AN UPDATE. Doris H. Clouet, Ph.D., ed.

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65 WOMEN AND DRUGS: A NEW ERA FOR RESEARCH. Barbara A. Ray,

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50TH ANNUAL SCIENTIFIC MEETING, THE COMMITTEE ON PROBLEMS

OF DRUG DEPENDENCE, INC. Louis S. Harris, Ph.D., ed.

GPO Stock #017-024-01362-5 $17

91 DRUGS IN THE WORKPLACE: RESEARCH AND EVALUATION DATA.

Steven W. Gust, Ph.D., and J. Michael Walsh, Ph.D., eds.

GPO Stock #017-024-01384-6 $10 NTIS PB #90-147257/AS $39

92 TESTING FOR ABUSE LIABILITY OF DRUGS IN HUMANS. Marian W.

Fischman, Ph.D., and Nancy K. Meilo, Ph.D., eds.

GPO Stock #017-024-01379-0 $12 NTIS PB #90-148933/AS $45

93 AIDS AND INTRAVENOUS DRUG USE: FUTURE DIRECTIONS FOR

COMMUNITY-BASED PREVENTION RESEARCH. C.G. Leukefeld, D.S.W.;

R.J. Battjes, D.S.W.; and Z. Amsel, D.Sc., eds.

GPO Stock #017-024-01388-9 $10 NTIS PB #90-148941/AS $39

94 PHARMACOLOGY AND TOXICOLOGY OF AMPHETAMINE AND

RELATED DESIGNER DRUGS. Khursheed Asghar, Ph.D., and Errol De

Souza, Ph.D., eds.

GPO Stock #017-024-01386-2 $11 NTIS PB #90-148958/AS $39

95 PROBLEMS OF DRUG DEPENDENCE, 1989: PROCEEDINGS OF THE

51ST ANNUAL SCIENTIFIC MEETING, THE COMMITTEE ON PROBLEMS

OF DRUG DEPENDENCE, INC. Louis S. Harris, Ph.D., ed.

GPO Stock #017-024-01399-4 $21 NTIS PB #90-237660/AS $67

96 DRUGS OF ABUSE: CHEMISTRY, PHARMACOLOGY, IMMUNOLOGY,

AND AIDS. Phuong Thi Kim Pham, Ph.D., and Kenner Rice, Ph.D., eds.

GPO Stock #017-024-01403-6 $8 NTIS PB #90-237678/AS $31

97 NEUROBIOLOGY OF DRUG ABUSE: LEARNING AND MEMORY. Lynda

Erinoff, Ph.D., ed.

GPO Stock #017-024-01404-4 $8 NTIS PB #90-237686/AS $31

98 THE COLLECTION AND INTERPRETATION OF DATA FROM HIDDEN

POPULATIONS. Elizabeth Y. Lambert, M.S., ed.

GPO Stock #017-024-01407-9 $4.75 NTIS PB #90-237694/AS $23

99 RESEARCH FINDINGS ON SMOKING OF ABUSED SUBSTANCES.

C. Nora Chiang, Ph.D., and Richard L. Hawks, Ph.D., eds.

GPO Stock #017-024-01412-5 $5 NTIS PB #91-141119 $23

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100 DRUGS IN THE WORKPLACE: RESEARCH AND EVALUATION DATA.

VOL. II. Steven W. Gust, Ph.D., and J. Michael Walsh, Ph.D., eds.

101 RESIDUAL EFFECTS OF ABUSED DRUGS ON BEHAVIOR. John W.

Spencer, Ph.D., and John J. Boren, Ph.D., eds.

GPO Stock #017-024-01426-7 $6 NTIS PB #91-172858/AS $31

102 ANABOLIC STEROID ABUSE. Geraline C. Lin, Ph.D., and Lynda Erinoff,

Ph.D., eds.

GPO Stock #017-024-01425-7 $8 NTIS PB #91-172866/AS $31

103 DRUGS AND VIOLENCE: CAUSES, CORRELATES, AND

CONSEQUENCES. Mario De La Rosa, Ph.D.; Elizabeth Y. Lambert, M.S.;

and Bernard Gropper, Ph.D., eds.

GPO Stock #017-024-01427-3 $9 NTIS PB #91-172841/AS $31

104 PSYCHOTHERAPY AND COUNSELING IN THE TREATMENT OF

DRUG ABUSE. Lisa Simon Onken, Ph.D., and Jack D. Blaine, M.D., eds.

GPO Stock #017-024-01429-0 $4 NTIS PB #91-172874/AS $23

105 PROBLEMS OF DRUG DEPENDENCE, 1990: PROCEEDINGS OF THE

52ND ANNUAL SCIENTIFIC MEETING, THE COMMITTEE ON PROBLEMS

OF DRUG DEPENDENCE, INC. Louis S. Harris, Ph.D., ed.

GPO Stock #017-024-01435-4 $22

106 IMPROVING DRUG ABUSE TREATMENT. Roy W. Pickens, Ph.D.; Carl

G. Leukefeld, D.S.W.; and Charles R. Schuster, Ph.D., eds.

GPO Stock #017-024-01439-7 $12

107 DRUG ABUSE PREVENTION INTERVENTION RESEARCH:

METHODOLOGICAL ISSUES. Carl G. Leukefeld, D.S.W., and William J.

Bukoski, Ph.D., eds.

GPO Stock #017-024-01441-9 $9

108 CARDIOVASCULAR TOXICITY OF COCAINE: UNDERLYING

MECHANISMS. Pushpa V. Thadani, Ph.D., ed.

GPO Stock #017-024-01446-0

109 LONGITUDINAL STUDIES OF HIV INFECTION IN INTRAVENOUS

DRUG USERS: METHODOLOGICAL ISSUES IN NATURAL HISTORY

RESEARCH. Peter Hartsock, Dr.P.H., and Sander G. Genser, M.D., M.P.H.,

GPO Stock #017-024-01445-1

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110 THE EPIDEMIOLOGY OF COCAINE USE AND ABUSE. Susan Schober,

Ph.D., and Charles Schade, M.D., M.P.H., eds.

111 MOLECULAR APPROACHES TO DRUG ABUSE RESEARCH:

VOLUME I. Theresa N.H. Lee, Ph.D., ed.

112 EMERGING TECHNOLOGIES AND NEW DIRECTIONS IN DRUG

ABUSE RESEARCH. Rao S. Rapaka, Ph.D.; Alexandros Makriyannis, Ph.D.;

and Michael J. Kuhar, Ph.D., eds.

113 ECONOMIC COSTS, COST-EFFECTIVENESS, FINANCING, AND

COMMUNITY-BASED DRUG TREATMENT. William S. Cartwright, Ph.D.,

and James M. Kaple, Ph.D., eds.

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DHHS Publication No (ADM) 91-1837

Alcohol, Drug Abuse, and Mental Health Administration

Printed 1991