Table of Contents

To go to chapter, click on name or page number

Introduction

Theodore M. Pinkert...................................................1

Prenatal Opioid Exposure and the Problem of Causal Inference

Donald E. Hutchings...................................................... 6

Effects of Prenatal Exposure to Cannabinoids

Ernest L. Abel........................................................ 20

Measurement of Substance Use During Pregnancy:

Methodologic Issues

Nancy L. Day, Diane K. Wagener, and Paul M. Taylor......... 36

Marijuana: Prenatal and Postnatal Exposure In the Human

Katherine Tennes, Nanci Avitable, Carol Blackard, Cecilia

Boyles, Bernice Hassoun, Larry Holmes, and Marie Kreye......48

Postnatal Consequences of Maternal Marijuana Use

P.A. Fried.............................................................. 61

Long—Term Effects of Prenatal Methadone Maintenance

Tove S. Rosen and Helen L. Johnson.............................. 73

Effects of Maternal Narcotic vs. Nonnarcotic Addiction on Neonatal Neurobehavior and

Infant Development

Ira J. Chasnoff...................................................... 84

Developmental Consequences of Maternal Drug Use During Pregnancy

Barry Zuckerman......................................................96

List of NIDA Research Monographs.................................... 107
Current Research on the

Consequences of Maternal

Drug Abuse

Editor:

Theodore M. Pinkert, M.D., J.D.

Division of Preclinical Research

National Institute on Drug Abuse

NIDA Research Monograph 59

1985

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iii

ACKNOWLEDGMENT

This monograph is based upon papers presented at a technical review on prenatal drug

exposure and consequences of maternal drug use which took place on September 24—25,

1984, at Bethesda, Maryland. The meeting was sponsored by the Division of Preclinical

Research and the Division of Clinical Research, National Institute on Drug Abuse.

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Printed 1985

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1

Introduction

Theodore M. Pinkert, M.D., J.D.

The study of the consequences of maternal drug abuse represents one of the most

compelling areas of research in the drug abuse field. The potential victims of this

problem have no say in the maternal behaviors, which may place them at risk. Therefore,

it is incumbent upon the research community to attempt to delineate the potential hazards

to the fetus, the newborn, the infant, and the child, so that deficits may be identified in

sufficient time to compensate, where possible, with specific treatment interventions.

The purpose of this volume is to focus attention on recent studies of the effects of

maternal substance abuse on offspring. The material presented includes reviews of animal

data, as well as the results of large interdisciplinary clinical studies, which were

originally presented on September 24th and 25th, 1984, at a National Institute on Drug

Abuse Technical Review sponsored by the Divisions of Preclinical and Clinical

Research. (The papers presented in the preclinical portion of this meeting will be

published in a separate volume, entitled Prenatal Drug Exposure:

Kinetics and Dynamics.)

In the opening chapter of this monograph, Dr. Donald Hutchings defines the field of

study known as behavioral teratology and provides a conceptual and historical framework

that facilitates an understanding of what inferences may reasonably be drawn from both

the animal and clinical literature. His studies in behavioral teratology integrate

developmental toxicology and teratology with developmental psychology and focus on a

variety of neurobehavioral changes that are crucial to the development and maturation of

the individual.

The next chapter, by Dr. Ernest Abel, elaborates on the difficulties inherent in attempting

to understand the interactive nature of the maternal and fetoplacental units. Through a

careful review of his own work, and that of others, he provides important insights into the

limitations and strengths of both
2

epidemiological and clinical studies. He also points out the value of animal studies in

providing the methodological rigor necessary (in combination with the human studies) to

establish the most convincing demonstration of causality when adverse pregnancy

outcomes are suspected from one or more chemical agents. Then he reviews the effects of

marijuana (A5—THC) on pregnant animals and their offspring and discusses both the

results and the methodological pitfalls to be avoided in these studies.

In the following chapter, Dr. Nancy Day and her colleagues analyze the problems faced

by clinical researchers in obtaining reliable and valid results using the instruments and

techniques currently employed in prenatal research. The two major challenges identified

are: (1) When questionnaire formats are used, do subjects understand the questions and

report accurately? and (2) How does one obtain accurate measures of complex and

changing events (substance abuse patterns) for specific time periods which coincide with

different stages of fetal vulnerability, so that the prediction of biological effects can be

made with a high degree of probability?

In the same chapter, the authors suggest techniques for eliciting accurate patterns of

maternal drug intake and describe how these techniques are implemented in their current

research on the effects of maternal marijuana and alcohol use during pregnancy. The

value of the assessment instruments they have developed is that they measure both the

quantity and frequency of drug intake in a manner that more closely resembles the way

subjects naturally organize their own memory of substance use——in terms of both

language and sequence.

The authors also elaborate other techniques which are designed to overcome accuracy

problems created either by the patient’s deliberate misrepresentation of past drug intake

or by their flawed recall of remote events. These techniques include the bogus pipeline,

which attempts to overcome misrepresentation of drug use, and the breakdown of

prepregnancy and first trimester events into specific time intervals to aid in more accurate

recall of the quantity and frequency of drug use.

The next chapter, by Katherine Tennes and colleagues, describes the results of a large

clinical study on the effects of prenatal marijuana exposure. Participating women

responded to structured questionnaires about themselves, their habits (substance abuse,

nutritional, etc.), and the habits of the father, if known. After delivery, infants were

examined for birth measurements, physical anomalies, and muscle tone, and the

Brazelton Neonatal Behavioral Assessment Scale was administered. At 1 year of age, the

infant's physical parameters were reexamined and they were evaluated on the Bayley

Infant Scale of Mental and Motor Development and Behavior Checklist.

One finding of this study is that maternal marijuana use
3

decreased from previous levels of consumption as the pregnancy advanced. At delivery,

no significant differences in 12 indices of obstetrical complications were detected that

could not be attributed to parity, or to the amount of pain—relieving medication

administered (although users of marijuana required more pain—relieving medication than

nonusers). Heavy marijuana use was found to be associated with an increase in male over

female offspring, but with a decrease in infant length at birth. No increase in

teratogenicity, or decrease in APGAR or Brazelton scores, was associated with prenatal

marijuana use. No significant differences were detected in physical measurements or

Bayley scores at 1 year.

The authors point out that some of their outcome data are in disagreement with previous

clinical studies, and they explore possible reasons for the difference in results. In

addition, the authors caution that studies examining the effects of maternal marijuana use

on more complex cognitive functioning in offspring have yet to be performed.

In the next chapter, Dr. Peter Fried reports on another major clinical study of maternal

marijuana use, but in a population with significantly different demographics than the

previous study. Among his findings were that gestation was shortened by maternal

marijuana use and that there were neurobehavioral effects, as measured by altered visual

responses and changes in state regulation (heightened tremors and startles), in the

newborn. Although not yet completed, studies employing neuro- opthalmological and

electrophysiological testing suggested that prenatal exposure to marijuana might delay

maturation of the visual system.

In agreement with the Tennes study, there were no differences in rates of miscarriage,

obstetrical complications. APGAR scores, or teratological effects between the

marijuana—using population and the comparison group. (Studies of both animal and

human populations which suggest different results are presented and discussed.) In

addition, data collected from developmental tests administered to the infants at 6—month

intervals after birth failed to discriminate infants of marijuana—using mothers from

either matched controls or the general population. Dr. Fried cautions that it is not at all

clear whether neurological findings present at birth are transient, or compensated for by

maturation. He suggests the possibility that the tests currently used to measure

developmental neurological disturbances in the newborn and neonate may not have

sufficient discriminatory sensitivity to detect subtle differences that may remain in the

older, marijuana—exposed infant or child.

In the next chapter, Drs. Rosen and Johnson review their findings on the prenatal effects

and postnatal consequences to the offspring of methadone—maintained mothers. Their

results include analyses of methadone’s effects upon the neonatal and infant periods of

development, and they present recent data from their
4

oldest cohorts of children, who are now in the 4— to 7—year—old age range.

Among the effects on offspring of methadone—maintained mothers was a higher

incidence of small—for—gestational—age infants, and infants below the third percentile

in head circumference. In addition, the maternal methadone dose and the length of time

on methadone had a positive correlation with a higher incidence of obstetrical

complications, decreased birth weight, and decreased infant performance on certain

Brazelton measures. Neurological and developmental testing continued to reveal

significant differences between methadone—exposed children and a comparison group

through the 36—month evaluations. These differences included an increased incidence of

abnormal reflexes, nystagmus, infections, abnormal muscle tone, and delayed

developmental milestones among the methadone—exposed infants.

As the children reached school age, those who did poorly neuro— developmentally at

earlier evaluations continued to do poorly. A trend toward lower scores in receptive

language evaluations was evident among the methadone—exposed children. Their

neurological evaluations demonstrated a higher prevalence of abnormalities of fine and

gross motor coordination, poor balance, decreased attention span, hyperactivity, and

speech and language delays. There was also a higher incidence of referrals for behavioral

and academic problems. However, as the comparison group of children (a population

selected from women in a low socioeconomic status similar to that of the

methadone—maintained mothers) approached school age, they too began to show poor

performance in testing. This raises important questions about the interaction between

prenatal environments and the socioeconomic status of the child in the postnatal

environment.

In the following chapter, Dr. Ira Chasnoff compares the effects on offspring of the

maternal use of narcotic versus nonnarcotic substances. Unique in this group of reports,

his study is an attempt to distinguish the in utero effects of narcotic use (methadone and

pentazocine/tripelennamine groups), from non— narcotic drug use (including a small

group of women whose primary drug of abuse was phencyclidine EPCPJ, and another

group with mixed sedative/hypnotic exposure, including marijuana).

Although the number of subjects in each group was small, infants exposed in utero to

narcotic substances showed fairly consistent decreases in birth weight, length, and head

circumference from both the sedative/hypnotic group and the comparison group. The

methadone—exposed group of neonates also demonstrated deficits in auditory orientation

and motor maturity. Infants exposed to both narcotic and nonnarcotic drugs showed

decrements in state regulation, and infants exposed to PCP showed increased state

liability and poor consolability when compared to all other drug—exposed groups. As

was manifested in the preceding Rosen and Johnson material, the scores of the

comparison group of
5

infants began to fall away from the normal range toward that of the drug—exposed

infants by 24 months of age.

In the last chapter, Dr. Barry Zuckerman reviews the developmental consequences of

maternal drug use. He describes the features compatible with the fetal alcohol syndrome

and discusses research which suggests that these features may reflect a final common

pathway of numerous agents (Including drugs of abuse), rather than a specific teratogenic

effect of alcohol.

In addition, the author stresses the importance to developmental outcome studies of

repeated assessments over time, and he suggests the application of newer physiologic

techniques such as evoked responses, Brain Electrical Activity Mapping (BEAM),

Positron Emission Tomography (PET Scan), and Nuclear Magnetic Resonance (NMR),

to enhance our understanding of the effects of prenatal drug exposure.

In summary, much remains to be learned about the specific developmental effects of a

variety of commonly used and abused drugs. The research community has not yet

exhausted the potential for the development and application of new testing techniques

and Instruments that will help us to identify the scope of subtle cognitive and motor

effects caused by prenatal drug exposure. Beyond these refinements lies the possibility of

understanding the particular mechanisms through which these drugs exert their effects. It

is the hope of those who participated in the conference that what lies herein will stimulate

research into the many unanswered questions In this area.

AUTHOR

Theodore N. Pinkert, M.D., J.D.

Deputy Director

Division of Preclinical Research

National Institute on Drug Abuse

Rockville, Maryland 20857
6

Prenatal Opioid Exposure and the Problem of Causal

Inference

Donald E. Hutchings, Ph.D.

Descriptions in the medical literature of human neonates undergoing withdrawal

following maternal opioid drug abuse during pregnancy date to the latter part of the 19th

century. Because of an extremely high mortality rate among infants showing severe

symptoms, the major concern through the 1960s was with diagnosis, treatment, and

management of the passively addicted newborn. In the United States, the opioid most

commonly abused then, as now, was heroin.

Methadone was first synthesized by the Germans during World War II, and, following

favorable preliminary findings of Dole and Nyswander in 1965 of its effectiveness in the

treatment of the heroin addict, it was made available for wide-scale use In drug treatment

programs. By 1975, there were some 70,000 to 80,000 heroin addicts in methadone

maintenance programs throughout the country and a significant proportion were women

of childbearing age. At the time, it was estimated that in New York City metropolitan

area alone, 10,000 to 12,000 such women were enrolled in methadone programs, yet little

was known of possible risk to the fetus and newborn. With the advent of methadone

maintenance as an experimental treatment for heroin addiction in the early 1970s,

attention turned to the question of reproductive hazard and developmental toxicity. The

problem shifted from one of managing an infant whose mother abused heroin during

pregnancy to concern over both the possible short- and long—term neurobehavioral

effects in infants whose mothers were administered methadone as a medical treatment.

The clinical literature of the early 1970s consisted largely of the description of

methadone effects in the neonate. Controversy subsequently emerged over reported

differences between heroin and methadone. Some workers reported that methadone

appeared to be less toxic to the newborn than heroin, whereas others found that it

produced a neonatal withdrawal syndrome that was more severe, prolonged, and difficult

to control chemotherapeutically. Methadone also appeared to be associated with a higher

frequency of seizures and incidence of jaundice. (For review, see Householder et al.

1982.) A major obstacle to drawing meaningful conclusions from these observations has

been the nature of the population under
7

study. Reviews of the literature have emphasized the difficulty of attributing, with any

degree of confidence, later sequelae among the exposed offspring solely to prenatal

opioid exposure (Householder et al. 1984). A large proportion of the women are from low

socioeconomic levels and have had a long history of drug abuse with associated medical

complications. Many have poor diets, are heavy smokers, and currently use marijuana,

cocaine, barbiturates, tranquilizers, or alcohol—often in a pattern of polydrug abuse.

Adding to the list of confounding variables, neonates undergoing withdrawal, depending

on the severity, type, and duration of symptoms, may be administered paregoric,

diazepam, chlorpromazine, or phenobarbital for several days to weeks after birth.

One consequence of these interpretive problems was that the mid— 1970s also saw

several laboratories attempt to develop animal models of prenatal methadone exposure,

The hope was that animal experiments would yield less ambiguous data on the

developmental toxicity of methadone, independent of the myriad uncontrolled variables

that muddied the clinical observations. (For a recent review of the animal and clinical

literature, see Hutchings and Fifer, in press.)

Before turning to some of the methodologic and interpretive problems of animal tests of

methadone, it may be useful to examine some terms and theoretical considerations that

are important for understanding the effects of chemicals on developing organisms.

TERMINOLOGY AND THEORETICAL CONSIDERATIONS

The appendix appearing at the end of this chapter contains definitions of several common

terms as well as a synopsis of pharmaceutical compounds known or suspected of being

developmentally toxic in humans. These are divided into two categories: 1) agents that

produce gross structural malformations such as thalidomide and alcohol; and 2) agents

that produce toxic effects but not gross structural malformations. All of the opioids fall

into this latter category. Although problems of nomenclature persist, the term

“developmental toxicology” is sometimes used to refer to the general scientific discipline

that is concerned with chemically induced perturbations in development, with

teratogenesis or altered morphogenesis being a special case of toxic effects on the

embryo. However, as a scientific discipline, teratology is concerned not only with

malformations induced by exogenous agents but also with those that arise spontaneously

or are of genetic origin. Therefore, the field of teratology cannot simply fall under the

general umbrella of toxicology.

There are a few important points that need to be emphasized here, especially for those not

well acquainted with the principles of teratology and developmental toxicology. Essential

to an understanding of a developmental toxic effect is to appreciate that for a given class

of compounds, such as ethanol or thalidomide, adverse effects are produced in the

embryo by a mechanism that is qualitatively different from its pharmacological activity in

the adult.
8

For example, the well-documented effects of ethanol in the adult— central nervous

system (CNS) depression, tolerance, and physical dependence—are produced by ethanol

per Se. Ethanol readily crosses the placenta and may indeed be the embryotoxic culprit.

Alternatively, a host of other biochemical events are likely involved. For example,

acetaldehyde—the major metabolite of ethanol—may be embryotoxic; or transport

mechanisms of the placenta might be affected by acetaldehyde, alcohol, or both. The

nutritional status of the mother, folic acid levels, blood pressure, and oxygen transfer may

also be altered. Together, these would make up a complex sequence of pathogenic events

that converge on a final common pathway of adverse outcome. Such a scheme of

hypothetical mechanisms is shown in table 1.

Implicit in this scheme is the assumption that exogenous compounds that produce

embryotoxicity do so by affecting some cells and not others—in other words the effects

are selective. The vulnerable cells are considered to be endowed with a special sensitivity

so that they are targeted by a particular compound, whereas other cells are resistant and

remain unaffected (Skalko 1981). One of the major features of this differential

endowment of resistance and sensitivity in the embryo is that these characteristics

change, moment by moment, as the process of development continues.

However, if it is shown that a compound crosses the placenta and enters embryonic

circulation—and nearly every compound does—that fact tells us only that, and nothing

more; its mere presence in the embryo does not mean that it is producing a toxic effect.

Generally, there must be a special vulnerability before that substance can have an

embryotoxic effect. Therefore, it is misleading to portray the embryo as having a kind of

gossamer fragility that will be silently ravaged by all alien invaders. Rather, the evidence

supports the view that the embryo has multiple lines of defense, is a feisty combatant,

and, even if knocked down and out, has enormous powers of recuperation and repair.

Without belaboring this point, let me simply point out that despite a colossal increase in

industrial chemicals, environmental pollutants, and pharmaceuticals since World War II,

the frequency of birth defects appears to have remained relatively stable.

DOSE-RESPONSE RELATIONSHIPS

Though dose—response relationships are one of the most critical issues in developmental

toxicology, they are too often misunderstood, oversimplified, or simply neglected.

Because studies of developmental toxicology involve two mutually interacting biological

systems—the mother and fetoplacental unit—dose—response relationships are

exquisitely complex and involve interactive, pharmacological, and toxic effects in the

mother and offspring. An appreciation of the problem may be developed with a few

examples. For this purpose, the term “toxicity” will be used here in the generic sense; a

more detailed description would require a far more precise specification of response

selectivity, target tissues, target organ systems, functional impairment, etc.
9
10

Before discussing dose-response interactions in the maternal/ fetoplacental unit, two

points should be made about variations in response in the dam and offspring. First, a

phenomenon frequently overlooked in developmental toxicology studies is that in the

rodent, the physiological state of pregnancy itself can cause a significant shift in the dose

response of the mother. For example, with methadone, the acute LD—50 dose is

dramatically lowered during pregnancy as compared with the nonpregnant animal—an

effect that appears to be related to reduced metabolism in maternal liver. The result is that

doses easily handled by the nonpregnant animal may be lethal in the pregnant animal.

Clearly, when one is first establishing a dose range for study in a developmental

toxicology experiment, the values must be selected on the basis of the response of the

pregnant animal.

The second point to make is that below a dose level that is lethal to the embryo, there

may be two embryotoxic responses, each with their respective thresholds. This is

depicted in figure 1, showing that as dose increases above the “no observable effect

level” (NOEL), the first embryotoxic response is an impairment in function, followed by

a second threshold after which gross structural malformations are produced. Both vitamin

A and salicylate in the rat are good examples of teratogens that produce functional effects

at a lower dose range and dysmorphogenesis at a higher dose range (For review, see

Hutchings 1983.)

To illustrate dose-response effects in the maternal/fetoplacental unit, let us examine a few

hypothetical dose-response profiles. These attempt to illustrate different types of

relationships and interactions between the dose response of the mother and embryo. The

general scheme, as shown in figure 2, depicts a maternal dose—response function in the

lower bar; as dose is increased from subpharmaco-logical levels through the

pharmacological range of the compound, there is a corresponding increase in toxicity

culminating in death.
11

The top bar depicts the embryonic dose—response, ranging from the NOEL to

embryolethality, as a function of maternal dose response.

The hypothetical profile shown in figure 2 depicts a compound similar to thalidomide in

humans. This shows that subpharmacologic maternal levels correspond to the NOEL in

the embryo. However, at subtoxic, pharmacological levels in the mother, the compound is

highly embryotoxic. In the case of thalidomide, the embryotoxic response is the

occurrence of altered morphogenesis. Another compound with the same sort of profile

and embryotoxic response in humans is the vitamin A derivative, isotretinoin. However,

such compounds are far more the exception than the rule in animal studies of

developmental toxicity. And to add to the complexity, thalidomide is not teratogenic in

the rat, but vitamin A is. With both compounds, however, humans appear to be the most

sensitive species.

A common type of profile encountered in animal studies is shown in figure 3. This shows

that within the pharmacological range of the compound, and at levels that are not toxic to

the mother, there is no embryotoxic response. Embryotoxicity is only seen at levels that

produce maternal toxicity. One example in the rat is phencyclidine (PCP), which has

been shown to be teratogenic, but only at doses that are highly toxic to the dam. In the

case of PCP, we administered two doses that were pharmacologically potent as measured

by behavioral effects in the dam (5 or 10 mg/kg) but of relatively low maternal toxicity

based on maternal weight gain. Yet, we observed normal birth weights and not postnatal

behavioral effects on two independent measures (Hutchings et al. 1984).
12

PRIMARY VERSUS SECONDARY EFFECTS

What should be eminently clear from these profiles is that dose-response relationships,

though complex, are critical for a meaningful description and understanding of effects.

Moreover, it is essential that every study include some measure of maternal dose

response. This is of particular importance when embryotoxicity is found only at doses

that produce maternal toxicity. Under these circumstances, it is important to determine

whether the effects produced in the offspring are primary effects of the compound or

secondary to maternal toxicity. For example, CNS depressants can suppress maternal

breathing and in turn produce fetal anoxia and brain damage; other compounds produce

reduced food intake and/or decrease fluid intake with subsequent undernutrition or

dehydration and electrolyte imbalance. In short, if we are to make any sense of the

embryotoxic effects of a particular compound, it is important to know if these effects are

produced only at doses that make the mother sick or also at doses that show no maternal

toxicity. This is the first step in trying to make some judgment about the reproductive

hazard of the compound.

PRENATAL METHADONE—PROBLEMS OF PHARMACOKINETICS

The problem of maternal and offspring dose response applies equally to the opioid

compounds, but these are further complicated with the phenomena both in the mother and

in the offspring of tolerance, physical dependence, and abstinence. These properties

present serious problems of management for the clinician working with opioid-dependent

mothers, but pose for the scientist studying animal models intractable problems of

methodology and interpretation. One result has been a rather heated debate among

researchers as to
13

what constitutes an adequate perinatal animal model (see Sparber 1983 and

accompanying critiques).

When we first started our work in 1972, we were unable to find any reliable data on

animals and, instead, utilized the available human observations. It was clear from the

Dole and Nyswander studies of the late 1960s that the 80 to 120 mg/day dose of

methadone easily “held” their patients until the next day’s dose and the current estimate

of the half—life of methadone in humans is about 24 hours. In the literature of the early

1970s, and before levo-alpha-acetylmethadol (LAAM) came on the scene with any

prominence, methadone was always compared with morphine and characterized as

having a much longer duration of action. When we began administering methadone to

pregnant rats, we were impressed not only with its relative potency as compared to

morphine but also with our finding that it took twice as long for the animal to develop

tolerance to it. To give some idea of the difference, Davis and Ling (1972) administered

an initial dose of 15 mg/kg of morphine subcutaneous early in gestation, followed by 5

mg/kg increments every 2 days, achieving a final dose of 45 mg/kg by late pregnancy.

This regimen produced tolerance and no maternal deaths. With methadone, we found that

an initial oral dose of 10 to 15 mg/kg exceeded the LD 50 and it was necessary not only

to lower the Initial dose but also to allow more time for the pregnant dam to develop

tolerance. To achieve the same result with methadone that Davis and Ling did with

morphine, we had to start with an initial dose of only 5 mg/kg and increase the dose by

only 2.5 mg/kg every 4 days. With this regimen, we achieved a final maintenance dose of

10 mg/kg without death or significant maternal toxicity.

In collaboration with Dr. Tove Rosen, we had determined a dose-response methadone

blood level in the mothers and offspring 60 minutes after their last dose, just prior to

parturition (Hutchings et al. 1976). At the time, we assumed that the compound was

persisting at tissue levels that produced physical dependence in the mothers. We based

this on the report of Misra et al. (1973) who found that the half-life was about 1.4 hours

for tolerant animals. However, they also found that measurable quantities of methadone

persisted in brain and other tissues up to 3 weeks or longer, even though no measurable

amounts of drug were present in plasma after 24 hours.

We would come to appreciate, particularly after the discovery of opiate receptors, that

these findings of persistent quantities of methadone derived from whole brain must be

interpreted with great caution; that It is important to distinguish concentrations that are

nonspecifically tissue bound and not necessarily producing any pharmacological effects

from concentrations that are, in fact, acting on receptors.

Thus, it appears that our dosing regimen, while clearly producing tolerance in the dam,

probably did not maintain a state of physical dependence over 24 hours. Given the longer

duration of action of methadone in the pregnant animal, it is reasonable to assume a half-
14

life of 3 to 5 hours. Sparber (1983) makes an important point in stressing that if future

animal models of perinatal opioid exposure are to include the feature of physical

dependence, they will have to employ a method of drug administration that maintains

sufficient blood levels. One caveat, however, is that if such blood levels are maintained,

the tradeoff may be a high neonatal mortality. And if the researcher has to administer an

opioid or other drugs to reduce fetal infant withdrawal symptoms in rats, as clinicians

must treat passively addicted babies with life-threatening symptoms, there may not be

much gained by studying an animal model.

On the other hand, perhaps physical dependence is not necessary to produce some sort of

embryotoxic response. For example, except for the tolerance and physical dependence

that might be produced by a single dose of ethanol, these conditions do not appear

necessary to produce teratogenic effects in the mouse. Randall and Anton (1984)

produced both limb and kidney defects with only one acute dose of ethanol during

embryogenesis. Again, the questions of mechanism and what is necessary and sufficient

to produce a particular offspring effect remain. Are sustained tissue levels necessary or

will a single or a few daily pulses of the compound during a sensitive period be sufficient

to cross some threshold or perturbate a developmental pathway?

For example, a feature of methadone—exposed human infants of interest to us is the

prolonged abstinence found to persist in some infants until around 4 months of age.

Characterized by CNS arousal and sleep disturbance, it had been suggested that this may

have resulted from the slow clearance of the compound by the neonate. We developed a

behavioral sleep paradigm for the preweanling rat and showed that prenatal methadone

exposure—using the dosing regimen described above—severely disrupted the rats’ sleep

pattern during the second and third postnatal week of life. As in humans, the effects were

transitory and disappeared by 30 days of age (Hutchings et al. 1979). Given our rat

mothers were probably not physically dependent, we tentatively concluded that this sort

of exposure is sufficient to produce an opioid—induced rebound hyperexcitability in the

offspring. Moreover, a radioactive tag study indicated that the compound did not persist

in any significant amounts in offspring brain beyond the first several days after birth

(Levitt et al. 1982). Further, the administration of naloxone failed to elicit any detectable

withdrawal symptoms. So, we produced under experimental conditions a rat model of

what may be occurring in human infants and concluded that this sort of effect persists

long after the compound is cleared from tissue.

CONCLUSION

The combined human and animal data lead to the unequivocal conclusion that a variety of

compounds can produce extremely subtle to severe damage in the developing CNS, with

functional effects ranging from minor impairments of attention, impulse control, and

activity to frank mental retardation. As with birth defects, these deficits may also be of

genetic origin or arise spontaneously.
15

Therefore, in the clinical situation, one must take care to distinguish the primary toxic

effects of a compound from secondary environmental—interactive effects and, in

addition, consider that a genetic disorder might also contribute to long—term clinical

outcome.

For example, there is no question that the opioids produce neonatal abstinence

characterized by increased CNS arousal. Clinical observations suggest that this altered

state results in a newborn that is less alert and less attentive with the result that the

mother— infant interaction is compromised. This, in turn, may lead to secondary

impairments of both cognitive and emotional development that emerge during the first

year of life. (For a detailed discussion of possible effects on mother-infant interaction, see

Hutchings and Fifer, in press.) Additionally, if a genetically transmitted behavior disorder

of minimal brain dysfunction is associated with or contributed to a mother becoming a

drug abuser in the first place, the clinical picture in her offspring may be even more

complex. This could include a mixture of neonatal abstinence effects and the postnatal

sequelae described above, and a genetically transmitted behavior disorder of attention

deficit and impulse disorder giving rise to school failure in middle childhood, and drug

abuse emerging in adolescence. And on it goes to the next generation.

It is these sorts of complex multifactorial effects that we must appreciate and that animal

studies might help sort out. What must first occur, however, is the development of more

precise animal research techniques and, with respect to drugs of abuse, several

laboratories will have to study the same compounds from a basic research perspective in

order to generate a reliable database and consensus of effects. Most important, the animal

findings must be compared with the clinical observations. This mutual tradeoff crossvalidates both the human and animal findings in a way that is impossible when the same

observations are made independently and in isolation. The result could be a powerful and

meaningful set of comparative observations that relate prenatal drug effects to a general

set of embryotoxic and behavioral principles.

REFERENCES

Davis, W., and Ling, C. Prenatal morphine effects on survival and behavior of rat

offspring. Commun Chem Pathol Pharmacol 3:205— 214, 1972.

Hutchings, D.E., and Fifer, W.P. Neurobehavioral effects in human and animal offspring

following prenatal exposure to methadone. In:

Riley, E., and Vorhees, C., eds. Handbook of Behavioral Teratolog),. New York:

Plenum Press, in press.

Hutchings, D.E.; Bodnarenko, S.F.; and Diaz—DeLeon, R. Phencyclidine during

pregnancy in the rat: Effects on locomotor activity in the offspring. Pharmacol

Biochem Behav 20:251—254, 1984.

Hutchings, D.E.; Feraru, E.; Gorinson, H.S.; and Golden, R. The effects of prenatal

exposure to methadone on the rest—activity cycle of the pre-weanling rat. Neurobehav

Toxicol 1:33-40, 1979.
16

Hutchings, D.E.; Hunt, H.; Towey, J.P.; Rosen, T.S.; and Gorinson,

H.S. Methadone during pregnancy in the rat: Dose level effects

on maternal and perinatal and growth in the offspring. J

Pharmacol Exp Ther 197:171—179, 1976.

Levitt, M.; Hutchings, D.E.; and Bodnarenko, S.R. The fate of tritium derived from

prenatally administered 3H methadone in neonatal rats. Pharmacol Behav

19:1051—1053, 1983.

Levitt, M.; Hutchings, D.E.; Bodnarenko, S.R.; and Leicach, L. The postnatal persistence

of methadone following prenatal exposure. Neurobehav Toxicol Teratol 4:383—385,

1982.

Misra, A.L.; Mule, S.J.; Block, R.; and Vadlamini, N.L. Physiological disposition and

metabolism of levo-methadone-1H3 in nontolerant and tolerant rats. J Pharmacol Exp

Ther 185:287—299, 1973.

Randall, C.L., and Anton, R.F. Aspirin reduces alcohol-induced prenatal mortality and

malformations in mice. Alcoholism: Clin Exp Res 8:513—515, 1984.

Skalko, R.G. Biochemical Mechanisms in developmental toxicology.

In: Kimmel, C.A., and Buelke-Sam, J., eds. Developmental

Toxicology. New York: Raven Press, 1981.

Sparber, S. Preclinical perinatal and developmental effects of methadone: Behavioral and

biochemical aspects. In: Cooper, J.R.; Altman, F.; Brown, B.; and Czechowicz, D., eds.

Research on the Treatment of Narcotic Addiction: State of the Art. NatiThal Institute

on Drug Abuse Treatment. Research Monograph Series. DHHS Pub. No. (ADM)

83—1281. Washington, D.C.: Supt. of Docs., U.S. Govt. Print. Off., 1983. pp.

368—374.

Wilson, J.G. Environment and Birth Defects. New York: Academic Press, 1973.

APPENDIX

ADVERSE EFFECTS OF DRUGS DURING PREGNANCY: OUTLINE OF

COMPOUNDS THAT ARE DEVELOPMENTALLY TOXIC IN MAN

Developmental Toxicology—the study of chemically induced alterations in the normal

sequence of developmental processes.

Teratology—the study of the causes, mechanisms, and sequelae of perturbed

developmental events in organisms that undergo ontogenesis. Traditionally, the study of

abnormal morphogenesis.

Congenital Malformations—structural abnormalities of prenatal origin that are present at

birth and that seriously interfere with viability or physical well—being.

Behavioral Teratology—an integration of developmental toxicology and teratology with

experimental psychology—is primarily concerned with the study of neurobehavioral

changes that result from exposure of germ cells, embryos, fetuses, and immature

postnatal individuals to a variety of environmental disturbances and events.
17

Approximately 50% of human conceptuses fail to reach term and perhaps as many as half

of those lost are structurally abnormal. Approximately 3% of newborns have one or more

significant congenital malformations at birth and, by the end of the first postnatal year, an

additional 3% are found to have developmental abnormalities. An additional group,

whose size cannot be estimated, is born with functional abnormalities of the nervous,

respiratory, gastrointestinal, and immunologic systems. Some unknown proportion of all

these effects may be due to environmental insult during prenatal life.

Causes

Little is known of specific causes. Estimated that 10% to 15% of all human congenital

malformations are due to environmental agents and another 10% to 15% to hereditary

factors, such as gene mutations and chromosomal aberrations. The remainder are

considered to result from unknown causes and complex interactions between multifactorially determined hereditary susceptibilities and environmental factors that

precipitate abnormal developmental sequences within the conceptus and its associated

membranes.

Drugs/Chemicals Producing Malformations In Man

Thalidomide—one of the most potent teratogens known to man. Produces array of birth

defects; most dramatic and debilitating is severe limb reduction or phocomelia.

Ethanol—in amounts consumed alcoholically (approximately 6 ounces pure ethanol/day).

Produces fetal alcohol syndrome (FAS) characterized by pre— and post-natal growth

retardation, developmental delay, craniofacial anomalies, joint defects, and mild to severe

mental retardation. Of mothers consuming these large amounts of ethanol, only about

10% to 15% give birth to infants with frank symptoms of the FAS.

Aminopterin—folic acid antagonist used illegally as an abortifacient. Produces

embryonic and fetal death and varied malformations in survivors.

Diethylstilbestrol—a synthetic nonsteroidal estrogen. Produces vaginal cancer in female

offspring during teen years. Possible effects on gender—related behavior.

Vitamin A—compounds in the vitamin A family, including palmitate and retinoic acid,

are potent teratogens in high doses. One form— isotretinoin—marketed as “Accutane,” a

prescription drug for the treatment of cystic acne, has been documented as a human

teratogen. Exposure causes CNS malformations and defects of the external ear. It was

marketed with clear and explicit warning to physicians and consumers of its

teratogenicity.
18

Hydantoin—anticonvulsant; strongly suspected of causing a fetal hydantoin syndrome

characterized by mild to moderate growth deficiency, reduced brain size, short nose with

anteverted nostrils, long philtrum and bowed upper lip, and small distal digits with

unusually small nails. Data from relatively small numbers suggest mild to moderate

mental retardation.

Trimethadione—anticonvulsant; suspected of causing a fetal trimethadione syndrome

characterized by developmental delay, speech difficulty, V-shaped eyebrows, low-set

ears with anteriorly folded helix, palatal anomaly, and irregular teeth. Of few cases

reported, mild mental retardation suggested as component of syndrome.

Lithium—some evidence of increased risk of cardiovascular malformations. Data still

being collected in the Register of Lithium Babies.

Drugs/Chemicals Producing Neurobehavioral Effects In The Absence Of Gross

Structural Malformations

Several classes of compounds—tranquilizers, stimulants, hypnotics, analgesics—are

generally not teratogenic in animals or man, but may produce long-term neurobehavioral

effects. The mechanism of their embryotoxicity remains unknown, but early pathogenesis

and the final common pathway probably involve biochemical, rather than gross

morphological, effects. Few of these are well documented in man.

Barbiturates—used as an anticonvulsant or may be abused. Produce a neonatal

withdrawal syndrome characterized by hyperactivity, restlessness, disturbed sleep,

tremors, sneezing, hiccuping, vasomotor instability, hyperphagia, vomiting, and diarrhea.

Some infants symptomatic for up to 6 months—no long—term follow-up.

Opioids—Heroin, Methadone—high frequency of abuse. Methadone used to treat heroin

addiction. Neonatal withdrawal syndrome similar to that described for barbiturates.

Symptoms characterized by CNS excitability may persist until 4 to 6 months of age.

Follow-up to 5 years suggests risk of Attention Deficit Disorder.

Amphetamine—diet control, abuse. Suspected of producing neurobehavioral effects

based on animal studies. No human data available.

Phencyclidine—drug of abuse (angel dust). Suspected of producing adverse effects based

only on case study reports. Animal data inconclusive.

Marijuana—drug of abuse. No evidence of teratogenicity in man. In heavy users, some

neonatal irritability around the time of birth; symptoms disappear by 30 days of age.

Long-term follow-up did not find any persistent effects detectable during preschool years.
19

GENERAL REVIEWS

Hutchings, D.E. Behavioral teratology: A new frontier in neurobehavioral research. In:

Johnson, E.M., and Kochhar, D.M., eds. Handbook of Experimental Pharmacology:

Teratogenesis and Reproductive Toxicologl,. New York: Springer-Verlag, 1983.

Kalter, H., and Warkany, J. Congenital malformations: Etiologic factors and their role in

prevention. N Engl J Med 308:424-431/491—497, 1983.

Abel, E.L. Prenatal exposure to cannabis: A critical review of effects of growth,

development and behavior. Behav Neurol Biol

29:137—156, 1980.

Abel, E.L. Consumption of alcohol during pregnancy: A review of effects on growth and

development of offspring. Hum Biol 54:421-

453, 1982.

Ehrhardt, A.A., and Meyer—Bahlburg, H.F.L. Effects of prenatal sex hormones on

gender related behavior. Science 211:1312-1318, 1981.

Householder, J.; Hatcher, R.; Burns, W.; and Chasnoff, I. Infants born to

narcotic—addicted mothers. Psychol Bull 92:453-468, 1982.

Hutchings, D.E. Falling angels: The hazards of phencyclidine abuse. Neurobehav Toxicol

Teratol 4:429-434, 1982.

Hutchings, D.E., and Fifer, W.P, Neurobehavioral effects in human and animal offspring

following prenatal exposure to methadone. In:

Riley, E., and Vorhees, C., eds. Handbook of Behavioral

Teratology,. New York: Plenum Press, in press.

Vorhees, C.V. Fetal anticonvulsant syndrome in rats: Dose and period-response

relationships of prenatal diphenylhydantoin, trimethadione and phenobarbital exposure

on the structural and functional development of the offspring. JPET 227:274-287,

1983.

AUTHOR

Donald E. Hutchings, Ph.D.

New York State Psychiatric Institute

722 West 168th Street

New York, New York 10032
20

Effects of Prenatal Exposure to Cannabinoids

Ernest L. Abel, Ph.D.

Marijuana is among the most widely used psychoactive substances in the Western world.

In the United States, about 255 of Americans 18 to 25 years of age use it to some degree

(U.S. Department of Health, Education, and Welfare 1980). Considerable marijuana use

also appears to be occurring among pregnant women (Sokol et al. 1980; Hingson et al.

1982; Linn et al. 1983; Fried et al. 1984; Gibson et al. 1983). It is only in the last few

years, however, that critical attention has been focused on the possibility that these

substances can cause birth defects and postnatal behavioral aberrations, although

delta—9—tetrahydrocannabinol (69—THC), the principal psychoactive ingredient in

marijuana, is known to cross the placenta (Abel 1983). Before examining the data

relevant to this issue, the first part of this review will examine some of the general

methodological considerations which should be kept in mind in evaluating research in

this area.

CLINICAL AND EPIDEMIOLOGICAL STUDIES

Since experimental administration of drugs to pregnant women is unethical, evaluation of

potential teratogens is limited to clinical observations or epidemiological investigations.

Although clinical reports can be of considerable importance in alerting physicians and

health care providers to possible agents causing abnormal development, they are often

difficult to evaluate. For example, two early clinical reports of malformations in children

born to marijuana users (Hecht et al. 1968; Carakushansky et al. 1969) were inconclusive

since the mothers of these children were users of other drugs as well.

When clinical reports are followed by epidemiological studies involving larger numbers

of patients, a better appreciation of incidence and causation is possible. Such

epidemiological studies can be divided into two types, retrospective and prospective,

each of which has its own strengths and shortcomings.
21

In most retrospective studies, information from large numbers of’ cases is obtained from

hospital records. However, such records are often inadequate or incomplete,

thoroughness of reporting varies widely, and criteria for assessment of anomalies may

also vary. In contrast to retrospective studies, prospective studies carefully establish

criteria and protocols for maternal histories and examination of infants in prenatal health

clinics. However, women who are usually most seriously at risk for giving birth to infants

with drug—related anomalies may not attend prenatal health care facilities and, therefore,

do not participate in prospective studies, resulting in underestimation of whatever

problem is being investigated. Because prospective studies are so rigid in their design,

they also are less flexible in allowing for changes to be incorporated as new information

is obtained. Also, prospective studies cannot anticipate knowledge. For example, in the

U.S. Collaborative Perinatal Project (Heinonen et al. 1977) which prospectively

evaluated 55,000 consecutive births, no information was obtained with respect to

maternal marijuana consumption because, at the time of the original protocol, marijuana

was not a suspected teratogen.

In addition to these general problems, epidemiological studies are limited to the

observations evident at the time of examination.

Even when diagnostic criteria have been standardized so that statistical evaluation is

possible, the number of cases may be too few to derive any “significant” results.

Diagnoses also may not be “blind” to the history of drug use, resulting in a higher than

normal likelihood of some association simply because it is being actively searched for. A

third possibility in epidemiological investigations is confounding.” Any specific drug

ingested by a pregnant women is but one of a multitude of possible pregnancy risks

(cofactors) along with the use of other drugs, general health, age, and exposure to

environmental pollutants. While complex statistical procedures may be used to “control”

or “adjust” for various known factors to support suspected links between agent and

outcome, there are limitations to such procedures and many risks are still unknown.

Consequently, confounding is always a possibility.

Epidemiological studies may document associations between suspected teratogens and

adverse pregnancy outcomes, but they cannot demonstrate causality convincingly. To

demonstrate causality, there is a need for better control and isolation of potential factors

resulting in anomalies. At present, the best means of achieving such methodological rigor

is through studies in animals, although such studies carry with them their own intrinsic

problems.
22

STUDIES IN ANIMALS

Considerable attention has been devoted to “animal models” for duplicating various

defects allegedly resulting from prenatal exposure to particular drugs. Such studies can be

of special interest because they allow manipulation of variables that would otherwise be

impossible to control in humans.

A major advantage of animal studies is the ability to perform dose—response

evaluations. A given dose of a drug may or may not be teratogenic. If the dose does not

produce observable defects, one cannot conclude that it is not teratogenic, since the tests

may have been too insensitive or the dose may simply have been too low to produce an

effect.

It is also advantageous to determine drug levels actually in the blood. In some cases,

drugs such as alcohol are readily absorbed from the intestine or areas of injection. Other

drugs such as marijuana are water—insoluble and except for inhalation are poorly

absorbed from sites of administration. Thus, some doses may produce little or no effect

because they do not achieve levels in the blood required for an effect to occur. If levels of

drug in the blood are known, there is also the advantage of being able to extrapolate to

humans somewhat more heuristically than is the case when extrapolating on the basis of

dose per body weight. At present, blood alcohol levels are relatively easy to determine,

whereas blood levels of 69—THC, the principal psychoactive ingredient in marijuana,

cannot be determined in most laboratories because of lack of equipment and

sophistication.

ROUTE AND METHOD OF ADMINISTRATION

A basic issue involving administration of cannabinoids into the body is route of

administration. In humans, the principal route by which marijuana is taken into the body

is via the lungs in the form of smoke. In such cases, only about 50%to 75% of the

A

9—THC present in the smoke is absorbed (Manno et al. 1970; Mikes and Waser 1971)

and various transformations of cannabinoids occur due to heat—induced carboxylation

(Kuppers et al. 1975). The other route by which marijuana is taken into the body by

humans is by mouth. About 3 times as much of the drug has to be consumed in this way

to have an effect comparable to that obtained via smoking (Isbell et al. 1967).

In animals, cannabinoid compounds can also be administered by inhalation (Charlebois

and Fried 1980). However, very little 9—THC is absorbed by animals in this way.

Exposure to “smoking machines” also means that only a few animals can be treated at

any time.

Intraperitoneal administration is sometimes used to administer cannabinoids to animals,

but is inadvisable because of the possibility of piercing the amniotic sac, injecting fetuses
23

directly, and because of the possibility of peritonitis if injections are repeated (Manning

et al. 1971). Abdominal discomfort can also be observed in animals injected in this way

(Carlini et al. 1970). Subcutaneous injection is another route but can result in abscesses at

the site of injection. The more preferable route for administration of cannabinoids to

pregnant animals is the oral route. However, this requires frequent handling of animals

and, therefore, introduces the possibility of additional stress. Furthermore, after oral

administration the rate of absorption is relatively slow and levels of drug in the blood

remain considerably below those encountered with other routes of administration. These

differences are apparent from studies of 9—THC—induced toxicity in animals. In

rodents, —THC is 2.5 times more toxic when inhaled compared to when given

intravenously (Rosenkrantz and Braude 1971), 10 times more toxic when given

intravenously compared to intraperitoneally and twice as toxic when given intravenously

compared to orally (Phillips et al. 1971).

Although animals are typically given considerably greater amounts of —THC than

would ever be taken by humans, comparison of drug effects on the basis of administered

dose is misleading. Many factors contribute to quantitative differences in the amount of a

drug that is necessary to produce various effects in each species, e.g., higher metabolic

rate of animals, distribution, excretion, route of administration, etc.

PLACENTAL TRANSPORT

Although cannabinoids are able to cross the placenta, the placenta in some species of

rodents provides a barrier for complete transmission to the fetus (Abel 1983) and may

also provide such a barrier in humans.

NUTRITIONAL FACTORS

An important methodological problem encountered with respect to administration of

cannabinoids in animals is that these compounds depress food and water consumption

(Abel l975a). As a result, there is the possibility of “confounding” between drug exposure

and drug—related undernutrition.

One approach to this problem is to use a “pair—feeding” technique by which one group

of animals is alloted only the food and water consumed the previous day by

cannabinoid—treated animals. In this way, animals can be equated for food and for water

intake, and the only difference is drug exposure. A second control consists of a group

given ad lib food and water, to assess the role of decreased food and water intake per se.

Comparisons can then be made between drug—treated animals and both pair—fed and ad

lib fed animals. If drug—treated animals differ from ad lib fed animals but not pair—fed

animals, the result could likely be due to drug—related undernutrition rather than direct

pharmacological
24

factors. However, if drug—related animals also differ from pair—fed animals, the result

could be attributed to the drug’s pharmacological effects.

Table 1 illustrates the importance of inclusion of the pair—feeding procedure when

cannabinoids are administered to animals. In this study, pregnant rats were treated with

10 or 150 9 mg/kg —THC and their food and water intake and weight gain during

pregnancy were compared to ad lib fed animals. As indicated by the table, drug—treated

animals ate less food, drank less water, and gained less weight during pregnancy,

underscoring the need to control for these factors.

TABLE 1

Effects of Oral Administration of Marijuana Extract on Food and

Water Consumption and Weight Gain During Pregnancy in Rats

Dosage

10 mg/kg day 150 mg/kg Ad lib

Total food 323 255 480

consumption(g)

Total water 5514 442 824

consumption(ml)

Weight gain(g) 101 72 149

Pair—feeding is a deceptive process however. There is no point in pair—feeding animals

that weigh 1400 g with those weighing 200 g, for instance. Even if animals weigh the

same, there is still the possibility of differences in metabolic rate. Furthermore, drugs

such as the cannabinoids may affect utilization of nutrients through reducing nutrient

transmission across the gut or placenta.

For example, Abel (1983) intubated pregnant rats which were treated with marijuana

(100 mg/kg), alcohol (2 g/kg), or vehicle. Another group was not treated. The untreated

animals were fed ad lib. The marijuana—, alcohol—, and vehicle—treated animals all

received the same amount of food and water. Despite receiving the same food and water

allotment, alcohol—treated animals gained less weight than vehicle—treated animals,

and marijuana—treated animals gained less weight than alcohol—treated animals.
25

POSTNATAL FACTORS

Another important methodological issue concerns how offspring are cared for after birth.

Since considerable development occurs postnatally in rats and mice, postnatal factors

have the potential for affecting development independent of prenatal insult. In the case of

marijuana, there may be residual effects of drug exposure during pregnancy on postnatal

maternal behavior or lactational performance (Singh et al. 1981). Such residual effects

could arise because cannabinoids are stored in body fat (Kreuz and Axelrod 1973) and

cam be secreted back into the blood after drug treatment has stopped. Since cannabinoids

are also secreted into milk (Jakubovic et al. 1973), they could be ingested postnatally by

nursing pups, thus confounding pre— and post—natal exposure. Marijuana has also been

shown to affect maternal behavior adversely (Abel 1972, 1975b; Frischknecht at al. 1980;

Kaplan 1979).

To study the possibility of residual maternal effects, rat pups born to nontreated dams

were placed with marijuana—treated dams that had just given birth and had had their

own offspring removed (Abel et al. 1979). These latter dams had been treated with

marijuana only during pregnancy. Another group had been treated with vehicle and had

been pair—fed. A third group had been nontreated and was fed ad lib. There was no

postnatal drug exposure, yet offspring raised by animals exposed to marijuana during

pregnancy did not grow at the same rate as control offspring. When these offspring were

tested in the open field, offspring raised by drug—exposed dams also reared significantly

less often than control offspring.

To deal with this problem of residual effects, we remove offspring as soon as possible

from their biological mothers and place them with nondrug—treated surrogate mothers

that have also just given birth. While removal of their own litters and discovery of a new

litter may introduce some stress to the surrogate mothers which could affect their

maternal behavior, such stress is more than compensated for by removal of the potential

for residual effects noted above.

RESORPTION RATE

Both marijuana extract and 9—THC increase resorption rate in pregnant mice,

regardless of route of administration. Studies relating to this point are summarized in

table 2.
26

TABLE 2

Effects of Cannabinoids on Resorption Rate in Mice

Compound Route Effect Reference

cannabis smoke + Rosenkrantz et al.

extract inhalation 1978

cannabis i.p. + Persaud & Ellington

extract 1967

cannabis p.o. + Kostellow et al.

extract 1978

9—THC i.p. + Harbison & Mantilla—Plata

1972

9—THC i.v. + Joneja

1976

9—THC p.o. + Fleischman et al.

1980

In rats, this increased resorption rate produced by both marijuana extract and A9—THC is

less robust (Persaud and Ellington 1968; Rosenkrantz et al. 1978; Banerjee et al., 1975;

Wright et al., 1976). Furthermore, the absence of controls for cannabinoid—related

undernutrition leaves open the possibility that this effect is due to maternal

undernutrition, rather than to the direct effects of the cannabinoids on pregnancy.

Studies of “sensitive periods” for this effect have identified gestation day 8 as the most

critical time for cannabinoid—related resorptions (Joneja 1976; Mantilla—Plata et al.

1975; Fleischman et al. 1980).

MALFORMATIONS

Except for two previously mentioned reports in which mothers used marijuana in addition

to other drugs, there are no reports of malformations in children born to women who

smoked marijuana during pregnancy (Fried 1982; Gibson et al. 1983). Reports of

teratogenic effects of cannabinoids in animals are inconsistent and have rarely controlled

for drug—induced maternal undernutrition. The mouse appears to be the most sensitive

species for these effects (Abel 1980), but within this species there are important

differences in susceptibilities of strains of mice (Joneja 1976).
27

INTRAUTERINE GROWTH RETARDATION

Epidemiological Studies

Fried (1980, 1982) reported that marijuana use prior to or during pregnancy did not affect

birth weight, birth length, or head circumference in children born to marijuana takers

when corrected for gestation length. In these studies, pregnant women were divided into

irregular users (less than one marijuana cigarette per week), moderate users (two to five

marijuana cigarettes per week), and heavy users (more than five marijuana cigarettes per

week). There were only 21 “moderate” and “heavy” users in this study (Fried 1982), so

their results should be considered tentative. Gibson et al. (1983) found a significant

decrease in birth weight in children born to women who smoked marijuana, but this

decrease was no longer significant when corrected for gestation length. Greenland and

co—workers (1982), on the other hand, did not observe a significant effect of maternal

marijuana use on birth weight or gestation length.

Intrauterine growth retardation is one of the most reliable effects of prenatal exposure to

cannabinoids in animals (Abel et al. 1980; Abel et al. 1981; Fried and Charlebois 1979;

Persaud and Ellington 1967; Wright et al. 1976; Pace et al. 1971; Geber and Schramm

1969; Cozens et al. 1980).

Our studies on intrauterine growth retardation in rats resulting from in utero exposure to

cannabinoids (Abel 1979, 1982; Abel et al. 1980; Greizerstein and Abel 1981; Abel et al.

1981) were designed to evaluate drug—related effects under controlled conditions to

permit distinctions to be made between the combined effects of cannabinoid exposure

and undernutrition, and the effects of undernutrition alone. This was accomplished using

the previously described “pair—feeding” control procedure whereby one group of

pregnant animals was drug treated and allowed ad libitum access to food and water,

whereas other drug— and vehicle—treated groups were only given food and water equal

to that consumed by the first group.

Using this control procedure, our studies have shown that crude marijuana extract and 

9—THC produce dose—related decreases in the weight of rat offspring at birth and also

increase postnatal mortality. We have also shown that this effect is probably not due to

the secondary effects of drug—related maternal undernutrition. Even though the food and

water consumption of drug—treated and control dams was equalized, drug—exposed

offspring still weighed less at birth.

Although we employed pair—feeding control measures, rats treated with marijuana still

gained less weight than pair—fed controls. This suggests that maternal undernutrition

cannot be dismissed as a possible factor contributing to the effects of prenatal

cannabinoid exposure. In this regard, Charlebois and Fried (1980)
28

reported that supplementation of regular laboratory diet with protein attenuated the

efforts of marijuana—induced intrauterine growth retardation. A comparable effect of

increased dietary protein has also been reported in conjunction with the effects of

prenatal alcohol exposure in rats (Weiner et al. 1981).

Other studies from our laboratory have examined “critical periods” during development

for the growth—retarding effects of cannabinoids (Abel et al. 1981). These studies have

shown that the most sensitive period for marijuana’s effects on intrauterine growth

retardation is during the third trimester of pregnancy. This is also the most sensitive

period for the increase in postnatal mortality produced by marijuana in the rat.

Related studies from our laboratory examined the effects of prenatal exposure to

cannabinoids on newborn rat body composition (Greizerstein and Abel 1981). Such

exposure resulted in decreased lipid body content and higher sodium and lower calcium

body levels compared to pair—fed offspring. These aberrations suggest

cannabinoid—induced delay of in utero maturational processes.

LONG LASTING EFFECTS ON GROWTH RETARDATION

Few studies have examined whether the reduction in birth weight associated with prenatal

marijuana exposure persists after birth. As noted above, such studies must control for

residual drug effects on maternal behavior to minimize confounding of pre— and

post—natal factors.

Our studies examining this issue have been inconsistent. In our first study (Abel et al.

1980), rats born to mothers receiving 150 mg/kg/day weighed less than pair—fed

controls at 21 days of age but, at 11 weeks of age, only female offspring weighed less

than controls. In a subsequent study (Abel et al. 1981), in which mothers received 200

mg/kg/day cannabis extract, offspring did not weigh less than pair—fed controls at 2 days

of age. In a third study (Abel 19814) offspring whose mothers received 50 mg/kg/day of

9—THC weighed less at 7, but not at 21, days of age, compared to pair—fed controls.

BEHAVIORAL EFFECTS

Epidemiological Studies

Fried (1980) reported that children born to women who were “moderate” or “heavy”

marijuana smokers (see above for criteria) responded less to light stimuli, habituated less

to such stimuli, and “self quieted” themselves less than other infants. In a subsequent

report (Fried 1982), such children also had heightened tremor and startle responses. Also

of interest was the occurrence
29

of high pitched cries (cri du chat) among one—third of the children born to marijuana

users.

When these children were tested at 30 days of age using the Prechtl neurological exam,

previously observed differences in response to visual stimuli were no longer evident, nor

did children differ in tremor incidence at this age. At 12 months of age, children born to

marijuana users also did not differ from controls on the mental, motor, or behavioral

scales of the Hayley Scale of Infant Development, or on any physical measurements of

growth.

Studies in Animals

There have been relatively few studies of the long—term behavioral consequences of

prenatal alcohol exposure in animals. Most of the studies that have been conducted in this

area have not controlled for drug—related maternal undernutrition or postnatal

maternally mediated residual effects (see above). When such controls have been

included, there have been very few instances of significant long—term sequelae which

can be attributed to prenatal cannabinoid exposure.

ACTIVITY

Prenatal exposure to cannabinoids has been reported to increase activity in offspring

(Borgen et al. 1973), but there are also reports of decreased activity (Charlebois and Fried

1980; Kawash et al. 1980; Uyeno 1973) as well as no changes in activity (Abel 1979;

Vardaris et al. 1976). With the exception of the study by Abel et al. (1979), drug—related

maternal undernutrition was not taken into account, and only Abel et al. C 1979) and

Borgen et al. (1973) took residual effects of cannabinoids on maternal behavior into

account.

MOTOR ACTIVITY

In our first study (Abel 1979), we reported that rats prenatally exposed to cannabis

extract were unable to remain on a Rotarod as long as pair—fed controls. However, we

have not been able to replicate this observation using cannabis extract (Abel et al. 1980)

or A9—THC (Abel 19814).

LEARNING/MEMORY

Effects of prenatal exposure to cannabinoids on learning/memory function in animals are

as inconsistent as effects on activity and motor function.

Using a water—maze to assess behavior, Abel (1979) and Charlebois and Fried C 1980)

did not observe any effects on learning, whereas Kawash et al. (1980) reported that rats

prenatally exposed to cannabinoids were unable to learn this problem as well as controls

(not pair-fed).
30

Uyeno (1973) did not observe any effect of prenatal cannabinoid exposure in learning a

two—channel maze. Likewise, Abel (1981, 19814) could not detect differences between

rats prenatally exposed to cannabis extract or 9—THC and pair—fed controls in active

shock avoidance learning or brightness discrimination learning. Gianutsos and Abbatiello

(1972), on the other hand, did find that female offspring prenatally exposed to cannabis

did not perform as well as controls (not pair—fed) on Lashley maze learning.

PERSEVERATION BEHAVIOR

Abel (1979, 19814) tested animals for their perseverative behavior in a T—maze.

Typically, rats placed in such mazes alternate their entry into different areas of the maze

on each trial. Failure to alternate indicates perseverative behavior. In this test,

cannabinoid—exposed rats did not differ from pair—fed controls.

VISUAL ATTENTION

Golub et al. (1981) administered —THC (2.14 mg/kg) to monkeys during pregnancy

and lactation. At 12 and 214 months of age, offspring of these animals were presented

with pairs of stimuli—— a blank slide or a picture of toys. Cannabinoid—exposed

offspring spent more time looking at both slides than controls, a result interpreted as “a

failure to inhibit the response to stimuli.” In a subsequent study (Golub et al. 1982),

stimuli of varying complexity and novelty were presented to determine which properties

of the stimuli affected attention. Complexity did not affect duration of attention in

drug—treated offspring, but novelty did prolong attention. This effect of visual stimuli in

monkeys prenatally exposed to marijuana is especially interesting, since Fried (1982)

likewise reported changes in response to visual stimuli in children born to marijuana

smokers.

SEXUAL BEHAVIOR

The only aspect of behavior in which there appears to be a consistent effect of perinatal

marijuana exposure involves sexual activity. Dalterio and Bartke (1979) reported that

perinatal exposure to 9—THC resulted in decreased sexual responsiveness (increased

latency to mount and number of mounts) in male mice. Testosterone levels in these mice

were not decreased. In a subsequent study (Dalterio 1980), copulating behavior in male

mice was again suppressed relative to controls. Testes weights were also reduced, but

testosterone levels did not differ significantly from controls. Likewise, Hatoum et al.

(1981) observed decreased sexual responsiveness in male mice when mothers received 

9—THC prior to parturition and for the first 5 days after parturition. Fried and Charlebois

C 1979) reported that the F1 generation of rats prenatally exposed to marijuana took

longer to mate than controls. (In this latter study, offspring were cross—fostered after

birth.)
31

Summary and Conclusions

Prenatal exposure to cannabinoids does not produce gross malformations in humans and

only does so with any consistency in mice following exposure to relatively high doses

and following the intraperitoneal route of administration. Resorption rates are reliably

increased in mice but not rats following in utero cannabinoid exposure. There is also a

reliable decrease in maternal food and water consumption and weight gain during

pregnancy associated with maternal cannabinoid administration. This effect may account

for many of the effects associated with prenatal exposure to cannabinoids, e.g., increased

resorption rate.

Prenatal exposure to cannabinoids produces a reliable decrease in birth weight in animals,

but this is the only postnatal effect on offspring that has been reliably documented.

Studies examining long—term postnatal effects are generally inconsistent. This

inconsistency may be due to methodological flaws in experimental design, such as

absence of controls for drug—related undernutrition and residual effects of maternal

cannabinoid exposure during postnatal nursing. When such controls have been

implemented, postnatal effects of prenatal cannabinoid exposure have not been reliably

observed.

REFERENCES

Abel, E.L. Suppression of pup—retrieving behavior in rats following administration of

1—A 9—tetrahydrocannabinol.

Experientia 29:1527—1528, 1972.

Abel, E.L. Cannabis: Effects on hunger and thirst. flal1aL..~±QI 15:235—281, 1975a.

Abel E.L. Suppression of maternal behavior in the mouse by Li —tetrahydrocannabinol.

Fed Proc 314: 1532, 1975b.

Abel, E.L. Behavioral teratology of marihuana extract in rats. Neurobehav Toxlcol

1:285—287, 1979.

Abel, E.L. Prenatal exposure to cannabis: A critical review of effects on growth,

development and behavior. Behav Neural Biol

29:137—156, 1980.

Abel, E.L. Behavioral teratology of alcohol. Psychol Bull 90:5614—581, 1981.

Abel, E.L. Marihuana. Tobacco. Alcohol and Reproduction. Boca Raton, Florida: CRC

Press, 1983.

Abel, E.L. Effects of A 9—THC on pregnancy and offspring in rats. Neurobehav Toxicol

Teratol 6:29—32, 19814.

Abel, E.L. Alcohol—enhancement of marihuana—induced feto toxicity. IiratQ1~gy~, in

press.

Abel, E.L.; Bush, R.; Dintcheff, B.A.; and Ernst, C.A.S. Critical periods for

marihuana—induced intrauterine growth retardation in the rat. Neurobehav Toxicol

Teratol 3:351—3514, 1981.
32

Abel, E.L.; Day, N.; Dintcheff, B.A.; and Ernst, C.A.S. Inhibition of postnatal maternal

performance in rats treated with marihuana extract during pregnancy. Bull Psychol Soc

114:353, 1979.

Abel, E.L.; Dintcheff, B.A.; and Day, N. Effects of marihuana on pregnant rats and their

offspring. Psychopharmacology 71:71—714, 1980.

Banerjee, B.N.; Galbreath, C.; and Sofia, R.D. Teratologic evaluation of synthetic

9—tetrahydrocannabinol in rats. Teratology 11:99—102, 1975.

Borgen, L.A.; Davis, W.M.; and Pace, H.B. Effects of prenatal

—tetrahydrocannabinol on the development of rat offspring.

Pharmacol Biochem Behav 1:203—206, 1973.

Carakushansky, G.; Neu, R.L.; and Gardner, L.I. Lysergide and cannabis as possible

teratogens in man. ~ 1:150—151, 1969.

Carlini, E.A.; Hamaoui, A.; Bieniek, D.; and Korte, F. Effects of

(—)—69—transtetrahydrocannabinol and synthetic derivative on maze performance of

rats. arm ~ 14:359—368, 1970.

Charlebois, A.T., and Fried, P.A. Interactive effects of nutrition and cannabis upon rat

perinatal development. Develop Psychobiol 13(6):591-605, 1980.

Cozens, D.D.; Clark, H.; Palmer, A.K.; Hardy, N.; Nahas, 0.0.; and Harvey, D.J. The

effect of a crude marihuana extract on embryonic and fetal development of the rabbit.

In: Nahas, 0.0., and Paton, W.D.M., eds. Marihuana Biological Effects. New York:

Pergamon Press, 1980. p. 1469.

Dalterio, S. Perinatal or adult exposure to cannabinoids alters male reproductive

functions in mice. Pharmacol Biochem Behav

12:1143—153, 1980.

Dalterio, S., and Bartke, A. Perinatal exposure to cannabinoids alters male reproductive

function in mice. Science

205:11420—11422, 1979.

Fleischman, R.W.; Naqui, R.H.; and Rosenkrantz, H. The embryotoxic effects of

cannabinoids in rats and mice. J Environ Pathol Toxicol 14:1471—1482, 1980.

Fried, P.A. Marihuana use by pregnant women: Neurobehavioral effects in neonates.

Drug Alcohol Depend 6:1415—14214, 1980.

Fried, P.A. Marihuana use by pregnant women and effects of offspring: An update.

Neurobehav Toxicol Teratol 14:1451—14514, 1982.

Fried, P.A., and Charlebois, A.T. Cannabis administered during pregnancy: First— and

second—generation effects in rats. Physiol Psychol 7:307—310, 1979.

Fried, P.A.; Innes, K.S.; and Barnes, M.V. Soft drug use prior to and during pregnancy: A

comparison of samples over a four—year period. Drug Alcohol Depend 13:161—176,

19814.

Frischknecht, Hans—R.; Seizer, B.; and Waser, P.O. Behavioral effects of hashish in

mice. II. Nursing behavior and development of the sucklings. Psychopharmacology

70:155—161, 1980.

Geber, W.F., and Schramm, L.C. Effect of marihuana extract on fetal hamster and

rabbits. Toxicol Appl Pharmacol 114:276—282, 1969.
33

Gianutsos, G., and Abbatiello, E.R. The effect of prenatal cannabis sativa on maze

learning ability in the rat. Psychopharmacology 27:117—122, 1972.

Gibson, G.T.; Baghurst, P.A.; and Colley, D.P. Maternal alcohol, tobacco and cannabis

consumption and the outcome of pregnancy. Aust NZ J Obstet Gvnaec 23:15—19,

1983.

Golub, M.S.; Sassenrath, E.N.; and Champman, L.F. Regulation of visual attention in

offspring of female monkeys treated chronically with 9—tetrahydrocannabinol.

Devel Psychol

114:507—512, 1981.

Golub, M.S.; Sassenrath, N.; and Chapman, L.F. An analysis of altered attention in

monkeys exposed to delta—9— tetrahydrocannabinol during development.

Neurobehav Toxicol Teratol 14:1469—1472, 1982.

Greenland, S.; Staisch, K.J.; Brown, N.; and Gross, S.J. Effects of marijuana on human

pregnancy, labor, and delivery. Neurobehav Toxicol Teratol 14:14147—1450, 1982.

Greizerstein, H.B., and Abel, E.L In Utero. exposure to marihuana extract: Changes in

neonate rat body composition. Neurobehav Toxicol Teratol 3:53—56, 1981.

Harbison, R.D., and Mantilla—Plata, B. Prenatal toxicity, maternal distribution and

placental transfer of tetrahydrocannabinol. J Pharmacol Exp Ther 180:14146—1453,

1972.

Hatoum, N.S.; Davis, W.M.; Elsobly, M.A.; and Turner, C.E. Perinatal exposure to

cannabichromene and A9—tetra— hydrocannabinol: Separate and combined effects on

viability of pups and on male reproductive system at maturity. Toxicol Lett

8:1141—1146, 1981.

Hecht, F.; Beals, R.; Lees, N.; Jolly, H.; and Roberts, P. Lysergic—acid diethylamide and

cannabis as possible teratogens in man. Lancet. 2:1087, 1968.

Heinonen, O.P.; Slone, D.; and Shapiro, S. Birth Defects and Drugs in Pregnancy.

Littleton, MA: Publishing Sciences Group, 1977.

Hingson, H.; Gold, J.B.; Morelo6k, S.; Wayne, H.; Herein, T.; Alpert, J.J.; Zuckerman,

B.; and Day, N. Maternal cigarette smoking, psychoactive substance use, and infant

Apgar scores. Obstet Gynecol 11414:259—266, 1982.

Isbell, H.; Gorodetzsky, C.E.; Jasinski, D,; Claussen, V.; Von Spulak, F.; and Korte, F.

Effects of C—) delta—9— transtetrahydrocannabinol in man. Psychopharmacology

11:1814—188, 1967.

Jakubovic, A.; Hattori, T.; and McGeer, P.L. Radioactivity in suckled rats after giving

9

c—tetrahydrocannabinol to the mother. Eur Pharmacol 22:221—223, 1973.

Joneja, M.G. A study of teratological effects of intravenous, subcutaneous, and

intragastric administration of A9—tetra— hydrocannabinol in mice. Teratology 36:15

1—162, 1976.

Kaplan, J.N. Maternal responsiveness in the squirrel monkey following chronic

administration of 9—THC. Pharmacol Biochem Behav. 11:539—5143, 1979.
34

Kawash, G.F.; Yeung, D.L.; and Berg, S.D. Effects of administration of cannabis resin

during pregnancy on emotionality and learning in rats offspring. Percent Motor ~ki11.a

50:359—365, 1980.

Kostellow, A.B.; Bloch, E.; Morrill, G.A.; and Fujimoto, G.I. Effects of cannabinoids on

estrus cycle, reproductive capacity, and fetal development in A/J mice. ~ 31:858, 1978.

Kreuz, D.S., and Axelrod, J. Delta—9—tetrahydrocannabinol:

Localization in body fat. ~ 179:391—392, 1973. Kuppers, F.J.E.M.; Bercht, C.A.L.;

Salemink, C.A.; Lousberg,

R.J.J.C.; Terlouw, J.K.; and Heerma, W. Cannabis, XIV. Pyrolysis of cannabidiol ——

analysis of the volatile constituents. J Chromatogr 108:375—379, 1975.

Linn, S.; Schoenbaum, S.C.; Monson, R.R.; Rosner, R.; Stubblefield, P.C.; and Rayn,

K.J. The association of marijuana with outcome of pregnancy. Am Public Health

73:1161—11614, 1983.

Manning, F.J.; McDonough, J.H.; Elsmore, T.F.; Saleer, C.; and Sodetz, F.J. Inhibition of

normal growth by chronic administration of A9—tetrahydrocannabinol. ~

1714:14214—1427, 1971.

Manna, J.E.; Kiplinger, G.F.; Haine, S.E.; Bennett, I.F.; and Forney, R.B. Comparative

effects of smoking marihuana or placebo on human motor and mental performance.

Clin Pharmacol Ther 11:808—815, 1970.

Mantilla—Plata, B.; Clewe, C.L.; and Harbison, R.D. 9—tetrahydrocannabinol-induced

changes in prenatal growth and development of mice. Toxicol Appl Pharmacol

33:333—3140, 1975.

Mikes, F.,and Waster, P.O. Marihuana components: Effects of smoking on

delta—9—tetrahydrocannabinol and cannabidiol.

~ 172:1158—1159, 1971.

Pace, H.B.; Davis, W.M.; and Borgen, L.A. Teratogenesis and marihuana. Ann NY Acad

Sci 191:123—132, 1971.

Persaud, T.V.N., and Ellington, A.C. Cannabis in early pregnancy. Lancet 2:1306, 1967.

Persaud, T.V.N., and Ellington, A.C. Teratogenic activity of cannabis resin. ~

2:1406—1407, 1968..

Phillips, R.N.; Turk, R.F.; and Forney, R.B. Acute toxicity of

delta—9—tetrahydrocannabinol in rats and mice. ~

~ 136:260—263, 1971.

Rosenkrantz, H., and Braude, M.C. Acute, subacute and 23—day chronic marihuana

inhalation toxicities in the rats. Toxicol Appl Pharmacol 28:1428—14141, 19714.

Rosenkrantz, H.; Fleischman, R.W.; and Barker, J.R. Embryotoxicity of marihuana by

inhalation. E~ 37:737, 1978.

Singh, N.; Gupta, M.L.; and Bhargava, K.P. Teratogenic potential of cannabis sativa in

albino rats. Med Plant Res 143:56—58, 1981.

Sokol, R.J.; Miller, S.1.; and Reed, 0. Alcohol abuse during pregnancy: An epidemiologic

study. Alcohol: Clin Excer Res

14:137—1145, 1980.
35

U.S. Department of Health, Education, and Welfare, Public Health

Service, Marijuana and Health. Eighth Annual Report to the

Congress from the Secretary of Health, Education, and Welfare,

1980, DHEW Pub. No. (ADM) 80—9145. Washington, D.C.: U.S. Govt.

Print. Off., 1980.

Uyeno, E.T. Delta—9—tetrahydrocannabinol administered during pregnancy of the rat.

Proceed West Pharmacol Soc 16:614—67, 1973.

Vardaris, R.M.; Weisz, D.J.; Faze, A.; and Rawitch, A.B. Chronic administration of

delta—9—tetrahydrocannabinol to pregnant rats:

Studies of pup behavior and placental transfer. Pharmacol

Biochem Behav 14:2149—2514, 1976.

Weiner, 5.0.; Shoemaker, W.J.; Koda, L.Y.; and Bloom, F.E.

Interaction of ethanol and nutrition during gestation:

Influence on maternal and offspring development in the rat.

J Pharmacol Exo Ther 216:572—579, 1981.

Wright, P.L.; Smith, S.H.; Keplinger, M.L.; Calandra, L.C.; and Braude, M.C.

Reproductive and teratologic studies with ~9—tetrahydrocannabinol and crude

marihuana extract. Toxicol Appl Pharmacol 38:223—235, 1976.

Author

Ernest L. Abel, Ph.D.

Research Institute on Alcoholism

1021 Main Street

Buffalo, New York 114203
36

Measurement of Substance Use

During Pregnancy: Methodologic

Issues

Nancy L. Day, Ph.D., Diane K. Wagener, Ph.D., and Paul M. Taylor, M.D.

This paper discusses some methodologic issues in the measurement of substance use,

particularly the more complex issue of measuring substance use during pregnancy. Two

specific questions are addressed in this presentation:

(1) Whether the questions on use result in accurate assessment of use, and (2) Whether

respondents report use accurately. Some of these methodological issues are illustrated

with data from our ongoing research on substance use during pregnancy and its effect on

outcome.

The assessment of substance use is complicated because there are as many patterns of use

as there are users. These patterns, however, can be described by the frequency, quantity,

and type of substance. The combination of these three variables defines the pattern of use.

Measurement of these parameters will be discussed specifically with reference to

marijuana use.

The first descriptor, frequency, is generally considered to be a measure of how much the

substance is part of one’s life (Room 1977). Clearly, marijuana is a more important part

of the life of women who smoke daily compared to women who use marijuana monthly

or even less often. This more frequent use has biological implications in terms of

exposure, and also has social implications, in that the frequency of substance use

correlates very highly with other behaviors, including the use of other substances prior to

and during pregnancy (Alpert et al. 1981).

The standard method of collecting data on frequency has been to present the subject with

an ordinal ranking of frequencies. There are several problematic issues that need to be

considered, however, with this type of assessment. First, from a simple mechanistic

viewpoint, the fineness or crudeness of the groupings is an important element in accuracy

of assessment. Global categorizations such as daily, often, rarely, or never are so broad as

to be meaningless. In addition, qualitative terms such as often and rarely may mean quite

different things to different respondents.
37

At the opposite end of the spectrum, some researchers simply ask how many times the

subject has smoked marijuana in a given time period (Greenland et al. 1983). While the

specificity of this latter query seems more satisfactory, it too has serious drawbacks. This

measure is a rather curious mixture of frequency and quantity and misses the pattern of

use.

This kind of metric can be adapted as a time—line follow— back (Sobell et al. 1980;

Tennes and Blackard 1980). In this assessment, subjects are asked to recall specific

incidents of use for each day over a given time period. Using this technique, it is possible

to obtain patterns of use as well as amounts of use because the quantity is measured for

each incident of use. However, because this technique asks for recall over a specific

period of time, care must be taken to ascertain whether it reflects a usual or aberrant

pattern for that subject, as well as whether the subject’s recall is accurate. Another variant

of this method of data collection is the diary method where respondents are requested to

write down all use as it occurs. While this theoretically corrects for some of the memory

problems of the time—line technique, it requires a high level of motivation from the

subject.

More commonly, researchers have asked subjects to report frequency of use in terms of

incidents per day, week, or month. While these data are easy to organize, there are some

problems inherent in this method. The issue of grouping is again germane, as the

broadness or fineness of the categories can seriously bias estimates. This becomes a

problem not so much with the ordinal ranking of subjects, assuming the groupings are not

too broad, but with attempts to accurately assess the biological effects of certain doses.

The inaccuracies of grouping are also propagated by the need to code data for analysis

and to create scales. In most cases, for example, a woman who reports a use level of 1 to

2 times a day will be coded as 1.5 times a day even though she may use only once a day,

or she may use twice a day, double the former amount. Due to the need for data

reduction, however, these women would be scored as equivalent,

The value of simple frequency assessments is further limited in that the reported

frequency will be the usual frequency for that time period. Researchers tend to regard

frequency as a constant and seldom allow for variability. This conflicts with reality, since

we can document seasonal and situational changes in frequency of substance use. Again,

in the assessment of biological, or in the case of pregnancy, teratogenic effects, the

“ripples” in the system may have major effects and yet may be missed because of the

form of questioning. Practically, even if a respondent volunteers that she used marijuana

at a much more frequent rate for a period of time within the time frame considered,
38

it is very difficult to incorporate this information into the data analysis because of the

analytic need for a single, preferably continuous, measure of use.

Quantity, the other major descriptor of patterns of use, is similarly difficult to assess. We

ask about the number of joints smoked per incident, for example, and this serves in some

respects as a measure of dose, and also as a reflection of whether a subject uses the

substance to the point of intoxication, or in more moderate amounts (Room 1977). Thus,

it represents a style of use as well as an estimate of the dose received.

Quantity, like frequency, varies. In the measurement of drug use, however, most

assessments have been of the usual quantity used, e.g., “How much (how many joints) do

you usually smoke?” (National Institute on Drug Abuse 1981). The answers then

represent ~ usual pattern, often one that the respondent considers to be more socially

appropriate. All use that differs from the usual quantity will be missed in the assessment.

Thus, any use greater than the usual, or less than the usual, is not considered.

Another major problem with quantity lies in the estimation of the actual amount

consumed. One joint can be of varying sizes and/or varying strengths. In marijuana,

unlike alcohol, there is no standardized “proof” of content, and again, unlike alcohol,

different methods of consumption yield different degrees of exposure (Nahas 1979; Abel

1980). Additionally, the availability of other substances, such as hashish and sinsemilla,

makes the measurement of quantity, or dose, problematic. We also found in our pilot

testing that women would report smoking, for example, six or seven joints on an

occasion; but, on further questioning, it would turn out that these joints were shared

among several friends. Therefore, since marijuana use, unlike the use of many other

substances, is a social behavior, it is essential to determine whether the reported

quantities were shared or used alone.

Biological assessments are useful measures of the recency of use, and have been used

successfully in studies during pregnancy (Greenland et al. 1982) . These tests, however,

have some of the same drawbacks as the interview data. It is not possible to determine

pattern of use from a laboratory test because it only measures exposure at the time the

user is tested. Furthermore, there is only a short period of time following marijuana

consumption in which laboratory tests can detect or measure levels of cannabinoids in

biological fluids of users. This creates a problem for research when we want to cover, for

example, the span of a trimester. The researcher must choose between the option of

monitoring the women very frequently, i.e., at about 2—week intervals, or less

frequently, and having blank spots in the time spanned by
39

the biological assessment. The first method of frequent assessment could interfere

directly with the behavior of the study population. The second method could result in

misleading or incomplete data. In addition, laboratory testing of illicit substances will

increase both refusal and noncompliance rates, especially in the user groups.

There is a major analytic need for scales that represent the use patterns reported by the

subjects. This process is, of course, a necessary step in data reduction. It is highly

problematic, however, to take two measures, frequency and quantity, that in themselves

are not particularly accurate, and combine them in an algorithm that may just compound

the inaccuracy. The most commonly used scale is the usual—quantity/usual—frequency

measure.

In our own data, we can illustrate the inaccuracy resulting from asking only about usual

quantity and frequency of use. Among the first 290 women in our study who used

marijuana, average daily use was calculated to be .7 joints per day, or approximately 5

joints per week. Eliciting maximum quantity increased our estimates of use by 30%, and

the addition of questions about use of quantities less than the usual quantity contributed

an additional 5.5% to the total reported use. Thus, the usual quantity that our subjects

reported represented only 64% of the amount of use reported when we added questions

about quantities greater than and less than the usual reported amount. For the first

trimester, usual quantity and frequency represented only 57% of the total use.

Among those women who reported using quantities greater than their usual prepregnancy

quantity, the mean quantity reported was 3.6 joints. Clearly this represents fairly heavy

use and thus greater single dose exposure. On the average, marijuana users who increased

their quantity did so about once a week. Quantities less than usual are consumed even

more frequently (0.2 per day or about 1.4 times per week). Though occurring more

frequently, the relatively small quantities consumed (mean quantity = .9 joints per

occasion) do not contribute as much to the overall average daily use.

When measuring the teratogenic effect of drug use during pregnancy, this level of

inaccuracy becomes unacceptable because we are misestimating the dose as well as the

pattern of delivery of the dose. That is, it is quite possible that a larger exposure at a

critical point in the fetal development could have a greater impact than the same dosage

spread out over a longer time period. For this reason, it is critical to select measures of

quantity and frequency that will allow the data to reflect the variance from the mean as

well as the mean experience.
40

One type of measure that has been used in various forms in fetal alcohol research is the

volume variability scale, developed originally by Cahalan et al. (1969). This series of

questions ascertains frequency and then asks the subject to indicate for each drinking

time whether she drank various numbers of drinks (5 or more, 3—4, 1—2) “nearly every

time, more than half of the time, less than half the time, once in a while, or never.” The

proportion of drinking incidents spent at each volume level is then calculated to yield a

volume—variability score that reflects the variability in quantity.

The Khavari Alcohol Test or KAT scale (Khavari and Farber

1978) is a variant of this technique, though simplified.

It asks overall frequency of use and usual quantity.

Maximum quantity and frequency of maximum quantity are then

ascertained.

These measures also allow one to create different scales that can reflect differing

concerns. Calculation of average daily use gives an overall average estimate of use during

the time period. With data on variable quantities, it is also possible to look at the

frequency with which a woman uses, for example, five or more joints to assess the

frequency of use of higher amounts.

There are, of course, a number of other ways to combine the data once they are gathered.

But the important point to be made is that each scale highlights one aspect of drug use

while suppressing others. A measure of frequent heavy use will reflect those who, for

example, use five or more joints when they smoke, but not those who smoke an

equivalent amount in more frequent, smaller doses. These different attributes can be

compared analytically to explore the relative contributions of the individual scales, as

they reflect patterns of use, to the explanation of the variance in the outcome.

Because of the importance of obtaining accurate measures of both marijuana and alcohol

use, we conducted an extensive pilot test in our study to develop these assessments.

Several variants of traditional questions were pretested using usual quantity and

frequency and several scales from alcohol research including the volume variability (VV)

scale and the KAT scale discussed above.

Our population is a lower class population of women 18 to 30 years of age who attend the

outpatient prenatal clinic at Magee—Womens Hospital in Pittsburgh. sixty percent have

graduated from high school, 50% are married, 40% are minorities, predominantly black.
41

We found that our population initially had problems with the format of the questions.

First, they had difficulty because the standard method of assessment asks women to give

an overall, total frequency of use, and then to partition that use into the proportion of time

she might spend using various quantities. This requires fairly complex mathematical

thinking that may not result in accurate measurement under the time and social pressures

of the interview. Second, particularly with respect to the marijuana use, it is not clear that

women think in terms of frequency first. There has been very little research on how

subjects cognitively organize their own assessments of use, but it seemed to be easier for

our subjects to think first of quantity and then to describe frequency.

In recognition of this fact, we designed our use assessments to respond to the way our

subjects seemed to be organizing their patterns of use. In our study, we first ask questions

about quantity, e.g., “When you smoke marijuana, how many joints do you usually

smoke?” and then questions about frequency, such as “How often do you smoke this

amount?” After this, the respondent is asked “Do you smoke more than this amount?” . . .

“How many joints?”

“How often?” . . . and further, “Do you smoke less?” and again, “How many

joints?” and “How often?” With

few exceptions, our pilot test subjects felt that these questions were easy to answer and

described their use accurately. From these questions, it is possible to develop scales that

reflect variability in both quantity and frequency, measures of the frequency of heavy

use, and measures of average daily use.

We conducted validity tests on these measures comparing our instruments to the VV

scale, the KAT scale, and the usual quantity—frequency. There were no significant

differences in the rank order of subjects on our measures compared to the other scales.

However, the overall average daily use obtained was significantly higher.

Complementary to concern about the validity of the method of assessment is an equally

important issue of whether the subjects’ answers are accurate. Two major reasons for

inaccuracy are deliberate misrepresentation and errors in r e cal 1.

Deliberate misreporting is an important issue when measuring an illicit substance or a

substance whose use might be licit but is negatively labeled at particular times, such as

alcohol use during pregnancy. We have tried several techniques to increase reporting

accuracy. The first was simply to lead into the marijuana questions in a nonthreatening

manner. They are imbedded in a section on social supports and drug use by friends.
42

We have also employed the bogus pipeline technique (Jones and Sigall 1971). This is a

method of convincing the subject that you have a laboratory assessment of use when in

fact you do not. Interestingly, while the use of the bogus pipeline did significantly

increase reporting of other illicit drugs, it did not significantly increase marijuana

reporting, leading us to the conclusion that our marijuana assessments were relatively

accurate. Further, we discovered during our pilot phase that most women were reluctant

to report using any substance currently. However, when asked about use last month or

some time in the past, they would respond. As a result, we changed our study design to

interview in the fourth month about use during the first trimester, in the seventh month

about use during the second trimester, and at delivery we assess the third trimester.

Errors in recall are also important. In the pilot study, we interviewed all clinic women

about their use, regardless of month of pregnancy. Women in late pregnancy reported

approximately half of the first trimester use that women early in their pregnancy reported.

Since there is no reason to believe that these women differed in any way, this represents

the problem of accurately recalling actual use during the first trimester, some 6 months

earlier. In our study 82% of the women who used marijuana prior to their pregnancy

reported a decrease in use during the first trimester. Remembering and accurately

reporting a behavior that is changing is difficult, especially many months later.

An accurate assessment of first trimester use is crucial, however, when we are looking for

teratogenic effects. The first trimester of pregnancy is the most vulnerable time for the

developing fetus. It is the time of major organ and systems development, and the time

that major birth defects occur. Also, because of the sequential timing of developmental

events during this time period, the same dose of a substance at different time points

during organogenesis will have different effects. Thus, it is questionable whether data

that average use estimates over the first trimester are sufficiently specific to reflect the

relationship between exposure and effect.

A further difficulty with assessment of first trimester use is that though researchers may

count conception as the beginning of the pregnancy, it is not clear whether pregnant

women really think back to that point when asked to report events during the first

trimester.

We have developed a technique to assess the use of marijuana during the first trimester

that allows us to circumvent this problem. Early in the interview, women are asked to

indicate on a calendar the month and part of the month (beginning, middle, or end) when

they: (a) got
43

pregnant; (b) recognized their pregnancy; and (c) had their pregnancy confirmed by a

pregnancy test. Later in the interview, we ascertain marijuana use prior to pregnancy and

in the first trimester of pregnancy. Immediately after these questions, the interviewer

returns to the calendar and asks the subject whether for the time period between

conception and recognition of pregnancy, her marijuana use was more like that which she

reported prior to pregnancy or more like the rate she reported for her first trimester. After

this, we ask the same set of questions about the time period from recognition to

diagnosis. The dates of conception, recognition, and diagnosis and the rates of marijuana

use prior to and during pregnancy are used to calculate a month—by—month rate of

marijuana use and a weighted estimate of the average daily use for the first trimester.

Sixty—six percent of all marijuana users reported that from conception to recognition of

pregnancy, their use was similar to their prepregnancy pattern and 33% reported that

from recognition to diagnosis, they were still using marijuana at their prepregnancy rate.

When we looked only at women who had an average daily use of two or more joints prior

to pregnancy, 83% said that from conception to recognition their use was similar to their

prepregnancy pattern, and 52% reported that from recognition to diagnosis their use was

similar to their prepregnancy pattern.

On the average, there were 30.5 days from conception to recognition for the total

population, 31.2 days for all marijuana users and 33.2 days for women who smoked two

or more joints per day prior to pregnancy. The time span from recognition to diagnosis

was also lengthened for these heavier smokers, who had a mean of 22.1 days compared to

20.1 days for all marijuana users and 19.3 days for the total population. Therefore, the

heavier users were more likely to continue to use marijuana at their prepregnancy rate,

and they used marijuana at this higher rate for a greater part of the first trimester.

The reported and calculated estimates of the average daily use of marijuana are given in

table 1. A total of 11.6% of our subjects reported smoking two or more joints per day

before their pregnancy, although only 3.4% of the women reported using two or more

joints per day during the first trimester of pregnancy, an apparent decrease of two—

thirds. However, when we calculated the average daily use as described above, 5.5% of

the subjects actually used an average of two or more joints per day during the first

trimester. In other words, only about two—thirds of the women who were calculated as

using at least two joints per day reported doing so; a sensitivity rate of 63%. The

sensitivity rate for those calculated as using one joint
44

per day was 60% and for those calculated to have a rate of one to six per week, 51%. This

reflects the pattern of misreporting downward. Overall, we found that 56% of the subjects

underreported their use when we compared the calculated rate to the actual reported rate.

This means that studies that use the more global assessment of first trimester use

underestimate the actual amount of exposure in more than half of the cases.

Since the teratogenic effect of any drug can be specific to certain time periods, we

calculated rates separately for each month of the first trimester. This allowed us to

determine whether the effect is a direct function of extended use over a period of time as

long as 3 months, or whether it is the result of exposure over a shorter more specific time

period. In table 1 the calculated average daily use is shown for each month of the first

trimester. During the first month of pregnancy, 8.1% of the subjects had a calculated use

of two or more joints per day. That is, 70% of the women who used marijuana at this rate

prior to pregnancy continued at that rate through the first month of pregnancy. However,

only 42% of these women reported using that amount for the first trimester, Of those

women who we calculated as having used marijuana at the rate of two or more joints per

day during the first month but who did not report this rate, 58% actually reported no first

trimester use at all.

Thus, the rate that women report for first trimester use is particularly inaccurate during

the early part of the
45

first trimester. In fact, in the absence of estimates of first month use, it is quite clear that

the prior—to— pregnancy rate is a better estimator of use during this time period than is

the reported first trimester use. This is especially true for estimates of use among heavy

users.

The other end of the scale is also problematic in terms of misclassification of subjects.

Eighty percent of our subjects reported using no marijuana during the first trimester.

However, on closer questioning, only 67% used none during the first trimester. That is,

about one out of every five women who reported no marijuana use during the first

trimester was actually a user.

We began this paper by pointing out that the measurement of substance use is a

complicated issue. We have attempted to highlight some of the areas of difficulty. In

particular, it is essential that we work to develop valid instruments to measure substance

use and that, particularly for studies of use during pregnancy, these questions be designed

to give us information about pattern of use in addition to average use.

An additional serious problem lies in the accuracy of subject’s reports about their use,

particularly during the first trimester. Our data clearly demonstrate that reports of first

trimester use really only represent late first trimester use, the most recent memory. This is

not surprising since drug use decreases during the first trimester for most women, and

accurate recall is difficult. This means, however, that previous studies using reports of

first trimester use underestimated the exposure and seriously underestimated the exposure

during the first month of pregnancy.

Abel, E. Prenatal exposure to cannabis: A critical review of effects on growth,

development and behavior. Behav Neural Biol 29:137—156, 1980.

Alpert, A.; Day, N.; Dooling, E.; Hingson, R.; Oppenheimer, E.; Rosett, H.; Weiner, L.;

and Zuckerman,

B. Maternal alcohol consumption and newborn assessment:

Methodology of the Boston City Hospital prospective study. Neurobehav Toxicol

Teratol 3:195—201, 1981.

Cahalan, D.; Cisin, I.; and Crossley, H. American Drinking Practices New Brunswick,

NJ: Rutgers Center of Alcohol Studies, Monograph No. 6, 1969.

Greenland, S.; Richwald, G.; and Honda, G. The effects of marijuana use during

pregnancy. II. A study in a low— risk home—delivery population. Drug Alcohol

Depend 11:359—366, 1983.
46

Greenland, S.; Staisch, K.; Brown, N.; and Gross, S. The

effects of marijuana use during pregnancy. I. A

preliminary study. Am J Obstet Gynecol 143:488—413,

1982.

Jones, B., and Sigall, H. The bogus pipeline: A new

paradigm for measuring affect and attitude. Psychol Bull 76:349—364, 1971.

Khavari, K., and Farber, P. A profile instrument for the quantification and assessment of

alcohol consumption. J Stud Alcohol 39:1525—1539, 1978.

Nahas, G. Current status of marijuana research. JMIA 242(25) :2775—2778, 1979.

National Institute on Drug Abuse. Drug Abuse Instrument Handbook. By Nehemkis, A.;

Macan, M.; and Lettieri, D.J., eds. DHHS Pub. No. (ADM) 78—394. Washington,

D.C.: Supt. of Docs., U.S. Govt. Print, Off. 1978.

Room, R. The measurement and distribution of drinking patterns and problems in general

populations. In:

Edwards, G.; Gross, M.M.; Keller, M.; Moser, J.; and Room, R. eds. Alcohol-Related

Disabilities Geneva:

World Health Organization, Offset Pub. No. 32, 1977. pp. 2-38.

Sobell, M.B.; Maisto, S.A.; Sobell, L.C.; Cooper, A.M.; Cooper, T.C.; and Sanders, B.

Developing a prototype for evaluating alcohol treatment effectiveness. In:

Sobell, L.; Sobell, M.; and Ward, B., eds. Ey~1jj.a.ting

Alcohol and Drug Abuse Treatment Effectiveness: Recent Advances.

~ New York: Pergamon Press, 1980.

Tennes, K., and Blackard, C. Maternal alcohol

consumption, birthweight, and minor physical anomalies. Am J Obstet Gynecol.

138:774—788, 1988.

This research is supported by two grants from the

National Institute on Drug Abuse: “Marijuana,

Psychological Factors and Pregnancy Outcome” (DA83209)

and “The Effect of Marijuana Use During Pregnancy”

(DA88898) and a grant from the National Institute on

Alcohol Abuse and Alcoholism: “The Effect of Alcohol Use

During Pregnancy” (AA86398).
47

Authors

Nancy L. Day, Ph.D.

Assistant Professor of Psychiatry and Epidemiology

University of Pittsburgh

Western Psychiatric Institute and Clinic

Pittsburgh, PA

Diane K. Wagener, Ph.D.

Associate Professor of Psychiatry, Biostatistics and

Epidemiology

University of Pittsburgh

Western Psychiatric Institute and Clinic

Pittsburgh, PA

Paul M. Taylor, M.D.

Professor of Pediatrics and Obstetrics and Gynecology

University of Pittsburgh

Magee—Womens Hospital

Pittsburgh, PA
48

Marijuana: Prenatal and Postnatal Exposure in the

Human

Katherine Tennes, M.A., Nanci Avitable, M.A., Carol

Blackard, M.D., Cecilia Boyles, M.A., Bernice Hassoun, B.S., Larry

Holmes, M.S., and Marie Kreye, Ph.D.

Recent studies of prenatal exposure to marijuana have produced presumptive evidence

that marijuana has an adverse effect on growth and development of the fetus. Two

investigators (Linn et al. 1983; Gibson et al. 1983) reported a decrease in birth weight

and an increase in malformations in marijuana— exposed infants, but differences

between marijuana users and nonusers were not statistically significant when

confounding factors were taken into account. Hingson et al. (1982) reported that woman

who used marijuana during pregnancy delivered infants with a mean birth weight 105

grams lighter than infants of nonusers, and the infants were five times mere likely than

infants of nonusers to have features compatible with Fetal Alcohol Syndrome. Although

confounding factors were controlled statistically, the investigators cautioned that

marijuana use might identify a group of women at higher pregnancy risk due to

unexplored maternal factors, rather than identifying a specific agent causing abnormal

fetal development. In a preliminary report from an ongoing prospective study in Canada,

Fried (1980, 1982) found no difference in birth weight between marijuana users and

nonusers, but infants of heavy users had shorter gestations and signs of neurobehavioral

immaturity as compared with matched controls.

Some protection from potentially harmful effects of cannabis on fetal development may

be due to the partial restriction of cannabis compounds by the placenta. In a recent study

of placental transfer of —9—’IHC and the principal metalxilite, 9—carboxy—THC

(Blackard and Tennes 1984), levels of the cannabinoids were found to be

two—and—a—half to seven times higher in maternal plasma than in fetal cord plasma at

delivery in 10 women who used marijuana daily. Although these results may not apply to

placental transfer at periods of gestation other than delivery, or to peak plasma

concentrations immediately after smoking, the findings are in agreement with animal

studies that have indicated that the fetus is exposed to appreciably less cannabis than is

ingested by the mother (Reviews: Bloch et al. 1978; Abel 1980).
49

Because of the limited number of studies and the complexity of factors that need to be

controlled in human clinical research of illicit drug use, it has been difficult to estimate

the seriousness of risks associated with marijuana use during pregnancy.

This paper reports our study of the effects of marijuana in a population of pregnant

women known to include a relatively high proportion of marijuana users (Tennes and

Blackard 1980). The purpose of the study was to investigate effects of exposure to

marijuana on fetal growth and development at birth and at 1 year of age.

Method

Population and Data Collection

During a 12—month period beginning in November 1981, 1,032 pregnant women were

approached at the prenatal—care clinics of Denver General and University Hospitals

during the women’s regular clinic visits. The population served by these clinics is

predominantly of lower-middle to lower—class socioeconomic status. The subjects

selected were at least 24 weeks pregnant. Vietnamese and Hispanic women who did not

speak English were excluded.

Of those approached, 865 women gave informed consent and were interviewed by one of

three experienced interviewers. A structured questionnaire developed in a previous study

(Tennes and Blackard 1980) was used to obtain information on demographics, illnesses,

and medications, as well as use of caffeine, nicotine, alcohol, marijuana, and other illicit

drugs. Specific details about kind, potency, aid physiologic effects of marijuana, as well

as use by the child's father, were obtained. After delivery, the women were interviewed a

second time to cover drug use in the interval between the initial interview and delivery.

An attrition rate of 16% between the initial approach and delivery was due to 8% who

refused to participate and 8% who moved away or delivered at a different hospital.

Infants of the 756 participating women were scheduled between 24 and 72 hours of age

for an examination by one of four examiners who were blind to all information about the

mother. we developed a systematic examination procedure which included measurement

of length, head circumference, and palpebral fissures; the Brazelton Neonatal Behavioral

Assessment Scale (Brazelton 1973), a scale of muscle tone derived from Parmalee

(Howard 1976); and a checklist of 34 minor physical anomalies prepared by Blackard

and Tennes (1981). All examiners had been certified for administration of the Brazelton

prior to this research.
50

Birth weight, the Dubowitz score for gestational age (Dubowitz et al. 1970), Apgar scores

and neonatal clinical data were obtained from the infants’ hospital charts. Antepartum

and intrapartum clinical data on the women were obtained from their medical records.

Women with diabetes, renal, or collagen disease were excluded.

At 1 year of age, infants of a selected sample of marijuana users and controls were seen

for measurements and examination with the Bayley Infant Scale of Mental and Motor

Development and Behavior Checklist (1969). After the examination, the mothers were

interviewed regarding the child’s health, routine care, behavioral traits, and special

problem during the first year. Women who had breastfed completed a questionnaire

regarding drug use during breastfeeding. Two investigators were present at all

examinations, one acting as examiner aid the other as observer, and all scales were scored

independently by each. Correlation coefficients between examiners’ aid observers’ scores

of mental and motor development were .95 and .97.

RESULTS

Thirty—four percent of the 756 women in the sample reported using marijuana during

pregnancy. Marijuana users were significantly different from nonusers (p ( .001) in age,

marital status, number of prior live births, and frequency of induced abortions (table 1).

No significant differences were found between users and nonusers in race, socioeconomic

status, spontaneous abortions, or previous stillbirths. Alcohol, nicotine, and other illicit

drugs (hash, cocaine, amphetamines, LSD, barbiturates, PCP, or psilocybin) were sore

frequently used by marijuana smokers than by nonsmokers.

TABLE 1

Significant Differences (p < .001) in Demographics

Between Marijuana Users and Nonusers.

Demographics Nonusers Users

N=498 N=258

Mean age (mean years) 23.0 years 21.8 years

Marital status: Married 58% 42%

Single or

Cohabiting 32% 51%

Prior live births 57% 37%

Elective abortions 20% 32%

Nicotine use 30% 40%

Alcohol use 30% 70%

Other illicit drugs 4% 31%
51

Levels of Exposure

To estimate the dose—response relationships between drugs and outcome variables, the

number of times the women used the drug was totaled for each week of the pregnancy,

and the weekly amounts were summed to estimate the exposure for the entire pregnancy

or for each trimester separately. The unit of measure for alcohol was number of drinks of

beer, wine, or liquor; for nicotine, packs per day; for marijuana, the number of joints; for

the other illicit drugs, the number of occasions the drug was used.

There was a significant linear dose—relationship between the women’s use of marijuana

aid alcohol (r=.45, p<.Ol), but not between marijuana and nicotine (r=.07, n.s.).

There was a high correlation between amounts of marijuana smoked by trimesters (r =

.71 and .73), but the amounts smoked decreased during pregnancy. To examine change in

marijuana use during pregnancy, estimates of marijuana were converted to an

approximate weekly average and the women were categorized as nonusers, light (one

time only to once a week), moderate (more than one a week but less than daily), and

heavy (once or more daily). The categories were established for each trimester.

The proportion of women in each category shifted during the course of pregnancy (table

2). Nonusers increased from 68% in the first trimester to 84% in the third, aid the number

of daily users declined from 10% in the first trimester to 2% in the third. The women who

continued to smoke daily throughout pregnancy decreased from a mean of 4.5 (S.D.=4.5)

per day in the first trimester to a mean of one a day (S.D.=1.1) in the third.

TABLE 2

Changes in Reported Marijuana Use During Pregnancy

First Second Third

Trimester Trimester Trimester

Level of Use

Nonuser 519 (68%)601 (79%)633 (84%)

Light 87 (12%) 73 (10%) 67 (9%)

Moderate 89 (10%) 49 (6%) 42 (5%)

Heavy 72 (10%) 33 (4%) 14 (2%)
52

Pregnancy and Delivery Complications

We compared the frequency of medical complications among nonusers and marijuana

groups. No dose—response relationship was found for a specific complication nor for the

total number of complications incurred by each woman. The only differences found in

medical histories was that marijuana users gained significantly more weight during

pregnancy than nonusers (mean gain by users 36.25 lbs., nonusers 32.0 lbs.).

We compared marijuana users and nonusers on 12 indices of complications at delivery,

namely: precipitous labor, prolonged labor, need for oxytocin, chorioamnionitis,

abnormal presentation, fetal distress, meconiun staining, placental abruption, assisted

vaginal delivery, cesarean section, pain relief requirements, and narcotics used in labor.

The only significant difference between users and nonusers was an increased requirement

for pain—relieving medication during labor (users 67%, nonusers 57%, p ( .01). In

multiple—variant analysis of factors contributing to narcotic dose and to administration

of analgesics, only parity and delivery complications were significant determinants. Since

more marijuana users than nonusers were primiparous, the difference in pain—relieving

medication may be attributed to parity rather than marijuana.

Infant Outcomes

Heavy marijuana use was found to be associated with an increase in male over female

offspring, a finding previously reported by Fried (1982). Women who reported smoking

marijuana three times a week or more throughout pregnancy (N = 31) gave birth to 61%

males and 38% females as compared with 50% males and 49% females among nonusers

(N = 498). Among fathers who were reported to be chronic smokers of more than one

‘joint” a day, the ratio was 67% males to 33% females (table 3).

Table 3

Ratio of Male to Female Births for Fathers Using Marijuana

Frequency of Marijuana Use

 One A Day More Than

 No Data Nonuser Or Less One A Day

Females 96 (52%) 158 (47%) 71 (55%) 35 (33%)

Males 87 (48%) 181 (53%) 58 (45%) 70 (67%)

Chi square = 13.29, p=.004
53

Intrauterine Growth

Multivariate analyses of the impact of marijuana on three measures of fetal growth—birth

weight, length aid head circumference—did not yield uniform results.

Infant length was the only measure influenced by marijuana when confounding variables

were taken into account. Of eight variables, accounting for 22% of the variance in length,

marijuana (total amount used during the first trimester) entered the regression on the

fourth step (table 4). Other confounding variables considered in the regression that did

not reach significance were: mother’s age, parity, Hispanic race, socioeconomic status,

caffeine, alcohol, hash, amphetamines, aid cocaine. As calculated from the

unstandardized p—coefficients, the reduction of .55 centimeters in length, attributable to

smoking an average of three joints a day during the first trimester, was roughly

comparable to the reduction of .48 centimeters attributable to smoking

one—and—a—half packs per day of cigarettes.

When the analysis was repeated for second and third trimester use of drugs, or for the

total amount smoked during pregnancy, marijuana did not have a significant impact on

infant length.

TABLE 4

Step—wise Multiple Regressions on Infant Length at Birth

Dependent Variable: Length Mean = 49.8 cm., S.D. = 2.23

Variables Significance r2 change Beta

Gestational age (weeks) .000 .100 .29

Infant Sex .000 .035 .19

Nicotine (packs per day) .000 .019 —.13

Marijuana, first trimester .001 .015 —.07

Weight gain during pregnancy .001 .014 .13

Ponderal Index .001 .015 .12

Mother’s Height .007 .009 .11

Black Race .009 .008 —.09

N=659 R=.47 R

2=.22

In contrast to the findings on length, no independent effect of marijuana on birth weight

or head circumference was found when marijuana was considered either by trimesters or

by the total amount smoked.

We also analyzed multiple drug Lee, not as an assessment of the synergistic effect of

several drugs, but rather as a surrogate variable representing lifestyle attributes of women

who used one or more illicit drugs other than marijuana. This measure of the
54

number of different kinds of other illicit drugs, regardless of frequency, was found to

have a significant but marginal impact on the regression on birth weight (p < .01, r2

change = .006, p= —.07). The calculated reduction in birth weight associated with

exposure to four different illicit drugs other than marijuana was 199 grass. Thus, infants

of women who use multiple illicit drugs, regardless of kind or amount, appear to be at an

increased risk for a significant reduction in birth weight.

Gestational Age

The total amount of marijuana used during pregnancy was positively correlated with the

infant’s gestational age at birth (r = .10). Three indices of gestational age that had been

recorded were the woman’ s reported last menstrual period, the Dobowitz examination of

the infant, and the obstetrician’s estimate given in the medical record. The mean or mode

of the three was used as the estimate. In a multiple regression analysis, five variables

accounted for 4 percent of the variance in gestational age (table 5). Two of the significant

variables, pregnancy complications and black race, are known to be associated with

preterm deliveries (Berkowitz et al. 1982). The three other significant variables, weight

gain, ponderal index, and marijuana, were associated with prolongation of gestation.

Additional noncontributing variables entered in the regression were Hispanic race,

mother’s age aid height, infant sex, socioeconomic status, parity, and abortions (yes and

no). None of 31 women who smoked an average of three times or more a week

throughout pregnancy gave birth preterm (before 37 weeks), as compared with 7% of

nonusers.

I'd like

TABLE 5

Step-wise Multiple Regression of Gestational Age Dependent Variable:

Gestational Age Mean=39.88 weeks,

S.D.1 .65

Variables Significance r2 change ß-coefficient

Ponderal Index .01 .01 .14

Pregnancy

 complications .01 .009 —.09

Weight gain .01 .009 .11

Marijuana .03 .006 .09

Black race .04 .005 —.08

N=719 MultipleR= .23 R

2 .04
55

Postnatal Outcomes

No associations were observed between exposure to marijuana and assessments of the

infants’ postnatal course in the nursery period. Apgar scores of less than seven were not

more frequent among nonusers (23%) than users (light 13%, moderate 13%, heavy 22%).

Nursery complications as measured by time in high—risk nursery, time in isolette,

jaundice, peripheral hematocrit, Dextrostex, weight change, presence of hypothermia, or

feeding problems were no different in exposed than in nonexposed infants.

We found no evidence of a teratogenic effect associated with marijuana nor with the

other illicit drugs. Of 39 infants with major malformations recorded in the infants’

medical records, 12 (31%) were children of marijuana users, which is the expected

percentage for the population. Likewise, no disproportionate increase in any of 34 minor

anomalies observed by the investigators, or pattern of these anomalies, was evident in

either dose—response relationships to the drugs or time during gestation of the exposure.

Furthermore, there was no increase in the total number of anomalies per infant in the

exposed subjects.

None of the variance in infants’ responses to individual items on the Brazelton scale, nor

to scores on clusters of the Brazelton items (adopted from factor analysis of the scale by

Lester’ et al. 1982) was accounted for by exposure to marijuana, alcohol, nicotine, or

other illicit drugs.

Three variables—black race, nicotine, and gestational age—made significant

contributions to the prediction of variance in muscle tone (Multiple R = .16, p<.O1).

However, exposure to marijuana was not associated with either hyper— or hypotonicity.

Fried (1980) reported that infants of heavy marijuana users, as compared with matched

controls, had heightened tremulousness and startles. To examine this relationship, in

addition to the assessment of these behaviors on the Brazelton, 46 infants whose mothers

reported using marijuana within 48 hours of delivery were compared with nonexposed

infants. No increase in startles, tremors, or other neurobehavioral measures was apparent

in these infants.

Evaluation of One—Year-Old Infants

Seventy—nine women who had reported smoking marijuana an average of seven times a

week or more for one or more trimesters of pregnancy were selected for the follow-up

study when the children were 1 year of age. Eighty women who had reported smoking

less
56

than an average of seven times a week, and 80 women who were nonusers were selected

randomly from each of these groups as controls.

Sixty percent of those selected were located and agreed to participate in the examination.

Although 10% fewer users than nonusers were located, the difference in attrition was not

statistically different among groups (X2 = 2.42, p<.10). Additional cases were lost from

the analysis by delays beyond 2 weeks from the child’s birthday in arranging the appointments. The final data base consisted of infants of 38 heavy users, 44 light or moderate

users, and 47 nonusers. There were significantly more first—born infants among the

marijuana users (73%) than nonusers (32%), (X2 = 19.2, p<.001) and also a higher

percentage of males (table 6).

TABLE 6

Growth and Development of One—Year-Old Infants Selected for

Level of Prenatal Exposure to Marijuana

Means

Marijuana Weight Height Mental Motor

Category N Males% (kgs) (cms) Score Score

Nonusers 47 55 8.9 72.3 104.6 98.3

Light and

Moderate 44 50 9.3 73.0 101.8 103.3

Heavy 38 63 9.1 72.8 104.8 98.2

No significant differences in infant outcome measures were observed among the groups

(table 6). Multiple regression analysis on total amount of marijuana use reported during

pregnancy, controlling for sex and parity, revealed no independent association of prenatal

exposure to marijuana on growth or development scores. No significant differences

attributable to marijuana were found in infant temperament, as assessed by the Bayley

Behavior Checklist, or by the mothers’ reports of illnesses, eating or sleeping problems,

or personality characteristics during the first year.

Exposure to Marijuana During Breastfeeding

Sixty—two of the infants seen at 1 year of age had been breast— fed. Of these, 27 of the

mothers reported using marijuana during breastfeeding; 12 of them smoked once a month

or less, 9 weekly, and 6 daily.

No significant difference was found between users and nonusers in the age infants were

weaned, suggesting that marijuana did not interfere with lactation.
57

Comparison of infant outcomes on growth, or on mental and motor development,

revealed no apparent effects of postnatal marijuana exposure. Since statistical analyses

were limited due to the small numbers and lack of comparability among cases for

duration or dose, raw data for growth and development of the infants of six women who

reported using marijuana daily during breast— feeding are given in table 7.

TABLE 7

Individual Data for Six One—Year-Old Infants Exposed

Daily to Marijuana Prenatally and Through Breastfeeding

Subjects

Infant Characteristics 1 2 3 4 5 6

Number of weeks breastfed 52 52 28 12 12 12

Prenatal exposure (av. per day) 1 2 1 3.6 2 2

Infamtsex M M F N F M

Height (cns) 76 72 69 74 73 75

Weight (kgs) 9.0 10.9 7.7 9.0 9.0 

12.1

Mental Score 109 122 84 89 93 

112

Motor Score 105 98 63 98 98 111

DISCUSSION

The findings in this investigation are consistent with other studies that have reported a

trend toward or a significant reduction in fetal growth associated with exposure to

marijuana during gestation (Hingson et al. 1982: Linn et al. 1983; Gibson et al. 1983).

The previous studies found an impact on birth weight, whereas in the present study the

impact was on length. This discrepancy may be related to different smoking habits in the

populations sampled. In the present study an effect on birth weight may have been

prevented by the marked reduction in number of women smoking and in amounts of

marijuana consumed in the third trimester, which is the crucial period for fetal weight

gain, and by the better—than—average weight gain during pregnancy by the marijuana

users. Similarly, the effect on length may have been detected because of the high

proportion of women ingesting relatively large doses of marijuana in the first trimester,

when growth of cells may be affected (Miller and Merritt 1979; Redmond 1979). Further

research comparing different populations and habit patterns is needed to clarify these

discrepancies.

The finding of a positive correlation between length of gestation aid marijuana exposure

is in conflict with reports of an inverse relationship between gestation and marijuana by

two investigators (Fried 1982; Gibson et al. 1983). In one animal study, gestation was

found to be prolonged by 1 to 2 days in
58

rats exposed to A—9—TSC throughout pregnancy (Borgen et al. 1971). The evidence of

prolonged gestation in the human from the present study is weak in terms of the

magnitude of the effect calculated from the equation, which was an average of two days

delay associated with daily marijuana exposure throughout pregnancy. Research using

animal models to investigate marijuana effects on maintenance of pregnancy or initiation

of delivery may be required to resolve this controversy.

To our knowledge, no other study of humans has reported a significant increase in male

births associated with father’s marijuana use. In two animal studies, an increase in male

offspring was observed in rats and in chimpanzees sired by males exposed to marijuana

prior to mating (Fried and Charlebois 1979; Grilley et al. 1974). - In the present study,

the assumption that marijuana is the sole determinant of the altered ratio is subject to

question, since no information about the father’s use of other drugs was obtained. If the

finding is confirmed in other human studies, it would be of interest to determine the

mechanisms involved in the reduction of female births.

Although there was no apparent increase in malformations among marijuana—exposed

infants, the results of this study cannot be considered as providing firm evidence that

marijuana or the other illicit drugs used by the women are not teratogens. Since the

subjects in the study were selected after 6 months gestation, we could not investigate the

possibility that exposure to marijuana early in gestation is associated with lethality for

severely malformed fetuses. Our examination included inspection for minor physical

anomalies compatible with Fetal Alcohol Syndrome which Hingson et al. (1982) had

reported to be increased among marijuana users. Failure to replicate Hingson’5 findings

may have been due to differences in criteria used to make the subtle clinical judgments

required to discriminate a unique pattern of anomalies. Nonetheless, the findings from

this study are compatible with experimental animal studies that report an absence of

malformations associated with —9—THC administered orally in doses equivalent to

heavy human use (Wright et al. 1976).

The results of examinations of development and behavior in the neonate and at 1 year of

age do not suggest that fetal or postnatal exposure to marijuana is associated with marked

deficits in central nervous system functioning. Discrepancies between the present study

and Fried’s observation of poor habituation to a visual stimulus, increased tremors, and a

peculiar cry as characteristics of marijuana—exposed neonates (1980) may be due to

unknown differences in the two samples or differences in methodology.

Fried (1982), in agreement with the present study, reported no negative effects associated

with prenatal marijuana use in a small number of infants examined at one year of age. In

the present study, the evaluation of effects at 1 year of age may
59

have been biased ~y the self—selection of women who participated in the 1—year

follow-up. However, there were no differences in refusal rates between marijuana users

and controls to suggest that more marijuana users than controls failed to participate if the

infant was developing poorly.

Although evidence of effects on central nervous system functioning in the neonate are

inconclusive and no convincing evidence of effects lasting until 1 year of age have been

produced, the possibility of effects on more complex cognitive functioning which

develops after infancy, particularly the acquisition of verbal learning, have not been

addressed to date.

In conclusion, several additional areas of research are needed to estimate the health risk

associated with prenatal exposure to marijuana. Investigations of pregnant women are

appropriate to establish the dose level of cannabis that may be related to adverse effects

on fetal growth. Comparative studies with different species might clarify the effects of

cannabis on duration of pregnancy. Additional longitudinal studies of children are needed

to determine if there are long—term health risks associated with prenatal exposure.

REFERENCES

Abel, B. Prenatal exposure to cannabis: a critical review of effects on growth,

development, and behavior. Behav Neural Biol 29:137—156, 1980.

Bayley, N. Manual for the Bayley Scales of Infant Development. New York: The

Psychological Corporation, 1969.

Berkowitz, C.; Holford, T.; and Berkowitz, R. Effects of cigarette smoking, alcohol,

coffee and tea consumption on preterm delivery. Early Hum Dev 7:239—250, 1982.

Blackard, C, and Tennes, K.Mi physical anomalies in the neonate. Paper presented at

Biennial Meeting of the Society for Research in Child Development, Boston, April,

1981.

Blackard, C, and Tennes, K. Placental Transfer of Cannabinoids in the Human. N Engl J

Med 331:797, 1984.

Bloch, B.; Thysen, B.; Morrill, G.A.; Gardner, E.; and Fujimoto, C. Effects of

cannabinoids on reproduction and development. Vitan Horm 36:203—258, 1978.

Borgen, L.A.; Davis, W.M.; and Pace, H.B. Effects of synthetic

A—9—tetrahydrocannabinol on pregnancy and offspring in the rat. Toxicol

Pharmacol 20:480—486, 1971.

Brazelton, T. Neonatal behavioral assessment scale. Clinics in Developmental Medicine

No. 50. London: Willian Heinenann, 1973.

Dubowitz, L; Dubowitz, A.; and Goldberg, C. Clinical assessment of gestational age in

the newborn infant. J Pediatr 77:1—10, 1970.

Fried, P. Marijuana use by pregnant women: neurobehavioral effects in neonates. p~

Alcohol Depend 6:415—424, 1980.

Fried, P. Marijuana use by pregnant women aid effects on offspring: an update.

Neurobehav Toxicol Teratol 4:451—454, 1982.
60

Fried, P.,and Charlebois, A. Effects upon rat offspring following cannabis inhalation

before and/or after mating. Can J Psychol 33:125—132, 1979.

Gibson, G.; Baghurst, P.; and Colley, D. Maternal alcohol, tobacco, and cannabis

consumption and the outcome of pregnancy. Aust NZ J Obstet Gynaecol 23:15—19,

1983.

Grilley, D.M.; Ferraro, D.P.; and Braude, M.C. Observations on the reproductive activity

of chimpanzees following long—term exposure to marijuana. Pharmacology

11:304—307, 1974.

Hingson, R.; Alpert, J.; Day, N.; Dooling, B.; Kayne, H.; Morelock, S.; Oppenheimer, B.;

Rosett, H.; Weiner, L.; and Zuckerman, B. Effects of maternal drinking aid marijuana

use on fetal growth and development. Pediatrics 70:539—546, 1982.

Howard, J.; Parmalee, A.H.; Kopp, C.B.; and Littman, B. A neurological comparison of

pre—term and full—term infants at term conception age. J Pediatr 88:995—1002,

1976.

Lester, B.M.; Als, H.; and Brazelton, B. Regional obstetric anesthesia aid newborn

behavior: a reanalysis toward synergistic effects. Child Dev 53:687—692, 1982.

Linn, S.; Schoenbaum, R.; Monson, R.; Stubblefield P.; and Ryan, K. The association of

marijuana use with outcome of pregnancy. Am J Public Health 72:1161—1164, 1983.

Miller, H., and Merritt, T. Fetal Growth in Humans. Chicago: Year Book Medical

Publishers, 1979.

Redmond, G. Effect of drugs on intrauterine growth. Clin in Prenatal 6:5—19, 1979.

Tennes, K., and Blackard, C. Maternal alcohol consumption, birthweight aid minor

physical anomalies. Am J Obstet Gynecol 138:774—780, 1980.

Wright, P.L.; Smith, S.H.; Keplinger, M.L.; Calandra, J.C.; and Braude, M.C.

Reproductive and teratologic studies with delta—9—tetrahydrocannabinol aid crude

marijuana extract. Toxicol ~ Pharmacol 38:223—235, 1976.

Acknowledgments

Supported by NIDA Grant ROI nP~02569 and NIMA Medical Student Research Stipend

*MA 14517. Gary Zerbe assisted with statistical analyses; Michael McMartin and

Douglas Carter aided in data gathering.

Authors

Katherine Tennes, M.A.

Nanci Avitable, M.A.

Carol Blackard, M.D.

Cecelia Boyles, M.A.

Bernice Hassoun, B.S.

Larry Holmes, M.S.

Marie Kreye, Ph.D.

University of Colorado Health Sciences Center

4200 East Ninth Avenue, Box C—264

Denver, Colorado 80262
61

Postnatal Consequences of Maternal Marijuana Use

P. A. Fried, Ph.D.

Interest in marijuana’s effects on various aspects of reproduction has a surprisingly long

history. In his absorbing account of cannabis, Abel (1980) describes how Eastern

European folk medicine has proclaimed for several centuries that marijuana could be

used to hasten delivery. Reports from India that circulated widely in Europe discussed

marijuana as both a sexual stimulant and a sexual inhibitor and, in the mid 1800s, the

U.S. Dispensory (the widely read pharmacopea of the time) reiterated what the Arabs had

been saying in the 16th century--that marijuana possessed aphrodisiac properties.

More contemporary reports that link marijuana with increased sexual pleasure have been

plagued by the difficulty of separating the drug’s effect from the drug user’s overall

lifestyle and the value placed on sexual activity (Abel 1981).

Moving from the realm of anecdotal reports to more objective reproductive

measurements, one comes across a number of studies that have explored the relationship

between maternal marijuana ingestion and fetal outcome in a variety of nonhuman

species. A review of the data and an interpretation of these works is described by Abel

(this volume). With respect to the human fetus, however, we are still very much at the

frontier of knowledge.

Cannabis constituents can cross the placenta and be stored in the amniotic fluid (Harbison

and Mantilla-Plata 1972; ldanpaun-Heikkila et al. 1969). Transfer of marijuana

constituents from mother to infant can also occur via the milk as animal studies have

shown (Jakubovic et al. 1974). This method of potential exposure of the neonate takes on

considerable importance in the human as central nervous system (particularly glial and

myelin growth) develops extensively postnatally.

The combination of the absence of information with respect to humans, the animal work

from our own laboratory as well as others, the prevalence of marijuana use by women of

reproductive age, and the cooperation of a number of hospitals in the Ottawa area led to

what
62

we have called the Ottawa Prenatal Prospective Study. Since 1978, data has been

collected from approximately 700 pregnant women in the Ottawa area for this study.

Mothers-to-be are informed of the study by their obstetricians or by notices in waiting

rooms of prenatal clinics in the four largest area hospitals. Upon volunteering to

participate, each subject is interviewed once during each of the trimesters remaining in

her pregnancy. The volunteer method of subject recruitment, dictated mainly by ethical

considerations, serves to increase the reliability of self-report (discussed below) and to

increase the likelihood of a long-term commitment to the study by the participants. Aside

from the subjects who have moved from the Ottawa region (29%), we have maintained a

retention rate of over 98% during the past 4 years.

During each of the interviews, typically conducted in the home of the mother-to-be,

information is collected concerning socio-demographic status, mother’s health (both

currently and prior to the pregnancy), father’s health history, obstetrical history of

previous pregnancies, a 24-hour dietary recall, and past and present drug use, with

particular emphasis on marijuana, alcohol, and cigarette use. For the drug histories,

information is gathered pertaining to the year before pregnancy and each trimester of

pregnancy.

The details of the interview and the categorization of the various drugs have been

described earlier (Fried et al. 1980). Because the range of marijuana use in the sample

was quite broad and bimodal in distribution, the drug data were usually not treated as a

continuous variable, but rather as an interval variable. Four levels of use have been

developed (Fried et al. 1980; Fried 1982): nonuser; irregular user (one joint or less per

week or exposure to the exhaled smoke of others); moderate user (two to five joints per

week); and heavy user (more than five joints per week). If hashish use was reported, the

number of joints was multiplied by five to take into account the estimated greater

concentration of tetrahydrocannabinol (THC) in hashish (the major psychoactive

ingredient in cannabis) (Lerner and Zeffert 1968).

The method of using interviews to assess such variables as nutrition and drug habits

raises critical issues of both validity and reliability. Several factors are relevant. Despite

the potential shortcomings of self-reporting questionnaires, there is no practical

alternative method of establishing the information needed for this type of investigation. A

number of procedures to enhance the probability of an accurate self-report have been

utilized in the present research. First, in order to develop a relaxed rapport, the same

female interviewer “followed” the mother-to-be during her entire pregnancy. Second, the

questionnaire was administered once during each trimester and, during each of these

interviews, the questions pertaining to drug use for each trimester were repeated,

permitting a test-retest reliability measure. With marijuana, the consistency of self-report

was very high, with fewer than 7% of the women inconsistently reporting their marijuana

usage. When an inconsistency was reported, the higher figure was utilized.
63

The demographic details and the extent of drug use during pregnancy among the first 407

subjects in the study have recently been published (Fried et al. 1984), as has a

comparison of drug use before, during, and after pregnancy (Fried et al., in press). In the

present sample, 80% stated that they did not use any marijuana in the year before

pregnancy, 12% used it irregularly, 3% smoked 2 to 5 joints per week, and 5% smoked 6

or more joints per week. Upon becoming pregnant, usage declined significantly, but

during each of the trimesters the percentages remained relatively constant with 90%

reporting no use, 6% reporting irregular use, 1% smoking 2 to 5 joints, and 3% reporting

6 or more joints per week.

Many, but not all, of the women who smoked marijuana regularly during pregnancy

differed from the remainder of the sample on a number of factors that could be associated

with adverse effects on the course of pregnancy and on the development of the offspring.

These potential confounding factors included lower socioeconomic level, less formal

education, and increased cigarette smoking. Increased alcohol consumption was also

associated with heavy marijuana use, although not as strongly as was cigarette smoking.

With respect to age, the heavy marijuana users were a significant 3.2 years younger than

the remainder of the sample. However, no differences in parity were noted. Further,

nutritional adequacy did not differ among the four categories of marijuana use.

A variety of variables have been examined during the course of the ongoing Ottawa

Prenatal Prospective Study. The work that has been carried out and the work that is

presently underway are described in table I.

One aspect that we have considered is the course of pregnancy (Fried et al. 1983). In our

work, no differences have been found between the marijuana users and their matched

controls (matched in terms of alcohol use, cigarette use, and family income) in terms of

rate of miscarriage, type of presentation at birth, Apgar status, and the frequency of

complications or major anomalies at birth.

In a recent report, Greenland et al. (1982) described the results of the effects of marijuana

use in 35 pregnancies. The women included in the investigation reported not using other

illicit drugs and were recruited from two California prenatal clinics. Compared to control

subjects, significant differences in duration of labor (both protracted and prolonged) were

observed, as well as an increased incidence of meconium staining among the infants born

to marijuana users. A subsequent study (Greenland et al. 1983), which was designed to

replicate the first, did not find that these adverse outcomes reached statistical

significance. One of the principal differences in the two studies was a general higher

level of health and living conditions among the women who participated in the second

study. The sample in the latter report was more similar in terms of ethnicity, education,

and general health to the Ottawa subjects than were the women in Greenland’s first

report.
64
65

In one animal study (Charlebois and Fried 1980), the interaction of marijuana with other

pregnancy risk factors has been demonstrated and is consistent with Greenland’s

observations. In Charlebois and Fried’s study, rats were exposed to either cannabis

smoke, placebo smoke, or no smoke while concurrently consuming one of three diets

differing in protein concentration. Both the diet and drug treatments were administered

20 days prior to and throughout gestation. A number of dependent variables, including

stillbirths, litter destruction, and postnatal deaths, were potentiated by a combination of a

low protein diet and cannabis smoke. Interestingly, some physiological and

developmental milestones that were delayed in the normal-protein-diet/cannabis-smoke

condition were attenuated in the high-protein-diet/cannabis-smoke condition.

An additional pregnancy variable that was noted in the Ottawa study was an inverse doseresponse relationship between marijuana use and the length of gestation (Fried et al.

1984). An average use of marijuana six or more times per week during pregnancy was

associated with a significant reduction in length of gestation of 1.1 weeks after

statistically adjusting for nicotine, alcohol, parity, mother’s prepregnancy weight, and the

child’s sex. With similar adjustments, no reduction in birth weight was noted once

gestational age was taken into account. The association between marijuana use and

shortened gestation is consistent with historical anecdotes that have, over the past

centuries, described how cannabis has been used as a method to increase the vigor of

contractions and shorten labor (Abel 1980).

Animal work has indicated that cannabis constituents can alter a wide range of pituitaryovarian and adrenal hormones (Dalterio and Bartke 1979; Harclerode 1980; Smith 1980).

Harclerode’s study provides indirect evidence that THC can affect steroid production by

the placenta. Although the underlying physiological nature of the shortened gestation

length associated with heavy marijuana use can only be speculated upon at this stage of

research, a likely candidate for the mechanism of action is marijuana’s influence upon the

reproductive hormonal system.

As part of the Ottawa Prenatal Prospective Study, we have examined the relationship

between marijuana and minor physical anomalies (MPA) (O’Connell and Fried, in press).

The offspring of 25 cannabis using women and the offspring of 25 matched controls were

examined for the presence of a large number of anomalies. None of the anomalies noted

occurred more frequently among the offspring of cannabis users, nor were the number of

anomalies present in an individual correlated with maternal cannabis use. Although a

pattern of anomalies was not detected among the offspring of cannabis users, two

anomalies--true ocular hypertelorism and severe epicanthus--were found only among

children of heavy users of cannabis.

The lack of a definite relationship between minor physical anomalies and prenatal

cannabis exposure is compatible with several other reports in the recent literature (Linn et

al. 1983; Rosett et al. 1983). Apparent exceptions are one large generally prospective

study (Hingson
66

et al. 1982) and two reports based on five Individual cases (Qazi et al. 1982; Qazi et al.

1983). All of these studies examined neonatal outcome in relation to maternal alcohol or

marijuana consumption in large, racially mixed, inner-city samples.

Rosett et al. (1983) found that the risk of congenital anomaly was greater among

offspring of women who drank heavily throughout pregnancy as compared to those of

women who stopped drinking, but the risk was not increased by the use of cigarettes or

marijuana.

Linn et al. (1983) found crude associations between marijuana use and lowered birth

weight, prematurity, and major malformations, which disappeared when demographic

characteristics, other drug use, and medical history were controlled for.

The reports of congenital anomalies related to maternal cannabis use have dealt with

those anomalies which are part of the diagnostic criteria of the fetal alcohol syndrome

(FAS). Flingson et al. (1982) found that women who smoked marijuana during pregnancy

were five times more likely than nonusers to deliver a child with features considered

compatible with the fetal alcohol syndrome (CFAS).

In the case reports, Qazi et al. (1982; 1983) suggested a link between prenatal cannabis

exposure and FAS-type features because, in four of the five cases reported, the mothers

were regular users of cannabis, but denied use of alcohol or any other psychoactive drugs

during pregnancy. However, little demographic information or medical history was given

in the reports, and no matching to control potentially confounding variables was

undertaken.

The lack of statistically significant CFAS features in the Ottawa sample may be due to at

least three factors: sample size, age of the subjects, and the relative “risk status” of the

women in the Study.

First, the sample size in the Ottawa Prenatal Prospective Study hindered the finding of

significant relations among the variables studied. This difficulty has been encountered by

other researchers in similar studies (Greenland et al. 1982). If the 2% rate of occurrence

of CFAS found in Hingson’s study could be considered accurate and was applied to the

present sample, only one child would be expected to meet the diagnosis.

The subject of the Hingson et al. (1982) study were all examined during the first week of

extra-uterine life. The mean age of the subjects in the present study was 28.8 months.

This difference is an important one considering that some MPA’s are transient, being

seen only in the neonatal period, or gradually changing as development proceeds through

infancy, e.g., epicanthal folds (Smith 1974). Evidence suggests that features indicative of

fetal alcohol effects may normalize with age, thus suggesting a delay, rather than a

deficit, in development (Majewski 1981).
67

As maternal nutrition interacts with cannabis consumption during pregnancy to influence

fetal outcome (Charlebois and Fried 1980), it is not surprising that definite physical

effects have been reported only in a sample where poor nutrition (as evidenced by low

weight gain) and poor prenatal care are common. The influence of cannabis may be one

of potentiation of the maternal factors which have a direct effect on fetal outcome. This

interaction was not evident in the sample, which appeared, overall, to be better nourished

than those of Hingson et al. (1982). The mean weight gain of the present sample was

16.02 kilograms compared to 13.64 kilograms in the Hingson sample. Several maternal

factors combined to place the children of the Ottawa Prenatal Prospective Study at a low

risk for environmentally induced congenital anomalies. The mothers lacked any chronic

or debilitating diseases; received prenatal care; had an improved nutritional status; and

had a higher socioeconomic status (i.e., 18% of the Hingson sample had a yearly income

of less than $6,000, but only 2% of the present sample did).

Published data pertaining to the issue of the potential behavioral teratological effects of in

utero marijuana exposure are limited to the work arising from the Ottawa Prenatal

Prospective Study. The widely used Brazelton Neonatal Behavioral Assessment Scale

(NBAS) (Brazelton 1973) is utilized in an effort to quantify the newborn’s response to

external stimuli, motor organization, and ability to regulate alertness (table 1). In the

Ottawa Prenatal Prospective Study, the examination is conducted at 60 to 80 hours

postpartum, midway between feedings in a warm quiet room free from sudden extraneous

noises, and located close to the hospital nursery. Observed behaviors include

consolability, self—quieting, irritability, tremulousness, startles, alertness, orientation to

animate and inanimate visual and auditory stimuli, habituation to stimuli in various

modalities, hand-to-mouth movements, pull-to-sit muscle tone, Moro reflex, and liability

of states. Assessment is carried out by two trained raters who are not aware of the

mother’s drug history.

A number of group differences have emerged using the Brazelton Scale (Fried 1980;

Fried 1982). Smoking marijuana regularly during pregnancy was correlated with a

marked decrease in the likelihood of the offspring responding to a light repeatedly

directed at their eyes. Among infants born to women categorized as heavy users, 46% did

not respond to the light in contrast to 16% of the babies born to matched nonusers (X2 =

4.282, p < .04). Among the babies of the heavy users that did respond to the light, 33%

failed to habituate compared to 7% of the matched controls. In the auditory modality,

there were no differences between the marijuana offspring and the matched controls.

The apparent association between in utero marijuana exposure and visual functioning has

been reported in previously published nonhuman primate work. Golub et al. (1981)

examined the behavior of offspring of monkeys who had received daily treatment of

tetrahydrocannabinol prior to and during pregnancy and throughout lactation. The types

of behavior that were examined at I and 2 years of age included regulation of activity

level, environmental responsiveness, problem solving, and social interaction. The

category of behavior that
68

distinguished cannabis offspring from control offspring was visual attentiveness. In

comparison to the offspring of untreated animals, the experimental babies failed to

habituate visually to novel visual stimuli. It may also be noteworthy that Lodge (1977)

and Finnegan (1981) observed that babies born to methadone-using mothers also

responded poorly to visual stimuli, but were not abnormal in their responsiveness to

auditory stimulation.

The most consistent and visible consequences of regular heavy marijuana consumption

were significantly heightened tremors and startles. Among those offspring born to heavy

marijuana users, 73% displayed marked tremors (a score of 7 or higher on the Brazelton

Scale) contrasted to 30% of matched controls (X2 = 6.744, p < .009). Startles

(spontaneous and elicited) were also more pronounced among the offspring of heavy

marijuana users (X2 = 5.287, p < .03). These, together with the altered visual

responsiveness, may reflect neurological dysfunction, possibly in the form of nervous

system immaturity or a manifestation of drug withdrawal. However, unlike infants going

through narcotic withdrawal, the marijuana babies were not more irritable than controls

and were readily consolable. Finally, at this age, in our study, no association was

observed between the degree of activity or of alertness and maternal marijuana use.

The Prechtl and Beintema neurological examination (1969) is given at 9 and 30 days of

age (table 1). By using standardized techniques to elicit a comprehensive selection of

reflexes and responses, this neurological inventory is designed to measure subtle

qualitative and quantitative differences in behavior. Results from this test indicate that the

altered responsiveness of the visual system noted above persisted in those infants whose

mothers smoked marijuana six or more times per week during their pregnancy. The

consistency was rather striking. Of the offspring of the heavy marijuana users who failed

to respond to the visual stimuli at 3 days of age, 71% were not responsive at 9 days and

50% continued to be unresponsive at 30 days. In contrast, all of the babies of heavy users

that did respond to the visual stimulus during the Brazelton test continued to respond on

the Prechtl test at 9 days of age. Among the matched controls who did not respond on the

Brazelton, all did respond at 9 days, and all but one at 30 days when tested on the Prechtl.

As part of the Prechtl test, various extraocular movements were also examined, and some

abnormalities among the marijuana infants were noted. In order to pursue these “soft”

visual signs of the potential effect of intrauterine exposure to marijuana, a series of

neuro-ophthalmological and electrophysiological tests are presently being conducted

jointly with Drs. B. W. Tansley (sensory psychologist) and H.

T. J. Mount (neuro-ophthalmologist). Included in this neuro-ophthalmological battery are

pupillary responses, gaze preponderance, tracking capability, optokinetic reflexes, and

visual-evoked potentials to a patterned stimuli.

The preliminary results are quite striking. The dimension of interest in the pattern-evoked

cortical response are the latencies of various
69

components of the waveform, with particular emphasis on the major positive component,

P100, which occurs at approximately 100 milliseconds after the stimulus onset in adults.

This component tends to be later in children and begins to approximate the adult

waveform by 10 years of age.

Twenty children born to mothers who used marijuana prenatally were matched with 15

control children on the basis of child’s age (3 to 6 years) and mothers’ prenatal use of

alcohol and nicotine. Findings showed that the P100 latency is consistently delayed in

both left and right eye monocular condition. This is consistent with the notion that

prenatal exposure to marijuana may delay the maturation of the visual system.

The ophthalmological examination has also demonstrated differences among the

marijuana subjects and their controls in terms of myopia, strabismus, abnormal

oculomotor functioning, and unusual discs. The neuro-ophthalmologist, examining the

children without knowledge of their prenatal history, noted that 35% of the marijuana

subjects had more than one of the above problems, as compared to only 6% of the

controls (z = 2.43, p < .008).

The Prechtl examinations also revealed some motor differences among the babies born to

the heavy marijuana users. Most prominent were the marked tremors which at 9 days

were observed in 43% of the babies contrasted with 12% of the matched controls (X2 =

9.362, p ( .003), and at 30 days were still present in 25% of the heavy marijuana offspring

and only 8% of the controls (X2 = 3.806, p < .06). The tremors among the babies born to

the heavy marijuana users were significantly more likely to be low frequency, high

amplitude in nature compared to the controls. Other motor differences observed among

the infants of heavy marijuana users included an exaggerated Moro reflex, increased

occurrence of athetoid movements and disinhibition in a number of motor tests. Like

some of the observations made soon after birth, many of these behaviors are similar to

those observed in infants undergoing narcotic withdrawal (Finnegan 1981).

In the Ottawa study, children are administered the Bayley Scale of Infant Development

(Bayley 1969) at 6, 12, 18, and 24 months of age (table 1). The mental portion of this test

assesses sensory perceptual abilities, early acquisition of object constancy, problem

solving, and the onset of vocalization. The motor portion is directed at assessing both

gross and fine motor abilities. A temperament portion measures more clinical aspects of

behavior, evaluating various general aspects of the child’s functioning rather than

assessing particular skills. At 18, 24, 36, and 48 months of age, the Reynell Expressive

Language and Verbal Comprehension Scale (Reynell 1969) is administered and, at 36

and 48 months, the McCarthy Scales of Children’s Abilities (McCarthy 1972) is given.

Table I outlines the tests administered to the infants and children at the various ages.

Group data collected from the tests administered at 6 and 12 months of age failed to

discriminate between those babies born to heavy
70

marijuana users and either those born to matched controls or normative scores based on

the general population. However, among the offspring of the heavy marijuana users, two

subgroups were identified. Although the number of subjects that fulfill the criteria for

inclusion within the subgroups is small, the results are quite pronounced. Among those

babies who demonstrated a consistent decrease in visual responsiveness on all three

neonatal tests and for whom the two Bayley scores are available (N = 6), the mean

Mental Developmental Index (MDI) was 82 (range 60 - 92) at 6 months, and 96 (range

75 - ill) at 12 months. Among the few children who did not show the neonatal decreased

visual responsivity, but who were born to mothers with similar heavy marijuana habits (N

= 7), the mean MDI at 6 months was 118 (range 106 - 129), and at 12 months was 106

(range 98 - 120). Among the matched controls, the mean MDI at 6 months was 102 and

at 12 months, 101. At 18 and 24 months, no differences were noted on the MDI between

the offspring of the heavy marijuana users who were consistently visually less responsive

as neonates and those who had normal visual responses.

An examination of both the overall motor portion of the Bayley Psychomotor

Developmental Index (PDI) and the fine and gross motor clusters at 6, 12, 18, and 24

months failed to reveal any differences between the offspring of marijuana users and

matched controls. Further, subdividing the babies born to mothers who used marijuana

heavily into those who showed marked tremors on the neonatal tests and those who did

not failed to distinguish the babies on the Bayley motor tests.

The picture that has emerged to date is that there are a number of neonatal

neurobehavioral variables that are correlated with in utero marijuana exposure that persist

after controlling for nonmarijuana drug habits, the history of previous pregnancies,

socioeconomic status, and nutritional (including caffeine) intake.

Finally, the general observation that the neonatal nervous system alterations seen in the

offspring of regular maternal marijuana users seemingly does not express itself in poorer

performance on cognitive and motor tests at U and 2 years of age must be interpreted

cautiously. It is not at all clear whether this is the true state of affairs arising because

neurological disturbances present at birth are truly transient and are overcome, or

compensated for with maturity, or whether the tests used at the Ii and 2 year ages might

have a decreased discriminatory sensitivity to subtle cognitive differences that actually

may exist.

REFERENCES

Abel, E.L. Marihuana: The First Twelve Thousand Years. New York:

Plenum Press, 1980.

Abel, E.L. Marihuana and sex: A critical survey. Drug Alcohol Depend 8:1-22, 1981.

Bayley, N. Manual for the Bayley Scales of Infant Development. New

York: Psychological Corporation, 1969.
71

Brazelton, T.B. Neonatal Behavioral Assessment Scale. London: Heinemann, 1973.

Charlebois, A.T., and Fried, P.A. The interactive effects of nutrition and cannabis upon

rat perinatal development. Dev Psychobiol 13:591-605, 1980.

Dalterio, S., and Bartke, A. Perinatal exposure to cannabinoids alters male reproductive

function in mice. Science 205:1420-1422, 1979.

Finnegan, L.P. The effects of narcotics and alcohol on pregnancy and the newborn. Ann

NY Acad Sci 362:136-157, 1981.

Fried, P.A. Marihuana use by pregnant women: Neurobehavioral effects in neonates.

Drug Alcohol Depend 6:415-424, 1980.

Fried, P.A. Marihuana use by pregnant women and effects on offspring: An update.

Neurobehav Toxicol Teratol 4:451-454, 1982.

Fried, P.A.; Barnes, M.V.; and Drake, E.R. Soft drug use after pregnancy compared to

use before and during pregnancy. Am 11 Obstet Gynecol, in press.

Fried, P.A.; Buckingham, M.; and Von Kulmiz, P. Marihuana use during pregnancy and

perinatal risk factors. Am J Obstet Gynecol 146:992-994, 1983.

Fried, P.A.; Innes, K.S.; and Barnes, M.V. Soft drug use prior to and during pregnancy: A

comparison of samples over a four year period. Drug Alcohol Depend 13:161-176,

1984.

Fried, P.A.; Watkinson, B.; Grant, A.; and Knights, R.M. Changing patterns of soft drug

use prior to and during pregnancy: A prospective study. Drug Alcohol Depend 6:323-

343, 1980.

Fried, P.A.; Watkinson, B.; and Willan, A. Marihuana use during pregnancy and

decreased length of gestation. Am J Obstet Gynecol 150:23—27, 1984.

Golub, M.S.; Sassenrath, E.N.; and Chapman, C.F. Regulation of visual attention in

offspring of female monkeys treated chronically with L~. 9-tetrahydrocannabinol. Dev

Psychobiol 14:507-512, 1981.

Greenland, S.; Staisch, K.; Brown, N.; and Gross, S. The effects of marihuana use during

pregnancy. I. A preliminary epidemiologic study. Am J Obstet Gynecol 143:408-413,

1982.

Greenland, S.; Staisch, K.; Brown, N.; and Gross, S. Effects of marijuana on human

pregnancy, labor, and delivery. Neurobehav Toxicol Teratol 4:447-450, 1983.

Harbison, R., and Mantilla-Plata, B. Prenatal toxicity. Maternal distribution and placenta

transfer of tetrahydrocannabinol. J Pharmac Exp Ther 180:446-453, 1972.

Harclerode, J. The effect of marijuana on reproduction and

development. In: Petersen, R.C., ed. Marihuana Research Findings:

1980. National Institute on Drug Abuse Research Monograph 31.

Washington, D.C.: Supt. of Docs., U.S. Govt. Print. Off., 1980. pp. 137-166.

Hingson, R.; Alpert, J.; Day, N.; Dooling, E.; Kayne, H.; Morelock, S.; Oppenheimer, E.;

and Zuckerman, B. Effects of maternal drinking and marijuana use on fetal growth and

development. Pediatrics 70:539-546, 1982.

Idanpaun-Heikkila, J.; Fritchie, G.E.; Englert, L.F.; Ho, B.T.; and Mclsaac, W.M.

Placental transfer of tritiated- l-delta-9-T HC. N EngI J Med 281:330, 1969.

Jakubovic, A.; Tait, R.M.; and McGeer, P.L. Excretion of THC and its metabolites in

ewe’s milk. Toxicol Appl Pharmacol 28:38-43, 1974.

Lerner, M., and Zeffert, J.T. Determination of tetrahydrocannabinol isomers in marijuana
72

and hashish. Bull Narc 20:53, 1968.

Linn, S.; Schoenbaum, S.C.; Monson, R.R.; Rosner, R.; Stubblefield, P.C.; and Ryan,

K.J. The association of marijuana use with outcome of pregnancy. Am J Public Health

73:1161-1164, 1983.

Lodge, A. Developmental findings with infants born to mothers on methadone

maintenance: A preliminary report. In: Beschner, G., and Brotman, R., eds. National

Institute on Drug Abuse Symposium on Comprehensive Health Care for Addicted

Families and Their Children. Washington, D.C.: Supt. of Docs., U.S. Govt. Print. Off.,

1977. pp. 79-85.

Majewski, F. Alcohol embryopathy: Some facts and speculations about pathogenesis.

Neurobehav Toxicol Teratol 3:129-144, 1981.

McCarthy, D. Manual for the McCarthy Scales of Children’s Abilities. New York:

Psychological Association, 1972.

O’Connell, C.M., and Fried, P.A. An investigation of prenatal cannabis exposure and

minor physical anomalies in a low risk population. Neurobehav Toxicol Teratol, in

press.

Prechtl, H.F.R., and Beintema, D. Neurological examination of the full term infant. Clin

Devel Med 12:1101, 1969.

Qazi, Q.H.; Mariano, E.; BelIer, E.; Milman, D.; and Crumbleholme, W. Is marihuana

smoking fetotoxic? Pediatr Res 16:272A, 1982.

Qazi, Q.H.; Mariano, E.; BelIer, E.; Milman, D.; Crumbleholme, W.; and Buendia, M.

Abnormalities in offspring associated with prenatal marihuana exposure. Pediatr Res

17:1534, 1983.

Reynell, J. Reynell Developmental Language Scale. Slough, Bucks,

England: N.F.E.R. Nelson Publishing Co., 1969.

Rosett, H.L.; Weiner, L.; Lee, A.; Zuckerman, B.; Dooling, E.; and Oppenheimer, E.

Patterns of alcohol consumption and fetal development. Obstet Gynecol 61:539-546,

1983.

Smith, C.G. Effects of marihuana on neuroendocrine function. In:

Petersen, R.C., ed. Marihuana Research Findings:1980. National

Institute on Drug Abuse Research Monograph 31. DHHS Pub. No.

(ADM) 80-1001. Washington, D.C.: Supt. of Docs., U.S. Govt. Print.

Off., 1980. pp. 120-136.

Smith, D.W. Recognizable Patterns of Human Malformation.

Philadelphia:W.B. Saunders, 1974.

ACKNOWLEDGMENTS

This research is supported by a grant to the author from National

Health and Welfare, Canada.

AUTHOR

P.A. Fried, Ph.D.

Department of Psychology

Carleton University

Ottawa, Ontario

KIS 5B6
73

Long-Term Effects of Prenatal Methadone

Maintenance

Tove S. Rosen, M.D., and Helen L. Johnson, Ph.D.

Methadone maintenance has been the treatment of choice for heroin addiction for several

years. The prenatal and early neonatal effects have been described in several reports

(Kandall et al. 1979; Finnegan 1983). However, there have been few reports on the longterm effects of methadone maintenance during pregnancy on the child’s somatic and

neurobehavioral development. Some investigators have described mild neurobehavioral

abnormalities, while others have found none (Finnegan 1983: Wilson et al. 1981;

Lifschitz et al. 1983; Strauss et al. 1979).

Since 1977, we have followed a group of children born to mothers on methadone

maintenance during pregnancy and a matched group of children born to drug-free

mothers. The children are now between 3j and 7 years old. This report covers in some

detail our findings from the neonatal period through 36 months. The trends in the data

that have been collected thus far on the children who have reached ages 4, 5, 6, and 7

years will then be discussed.

METHODS

Fifty-seven mothers on methadone maintenance were enrolled in the study during

pregnancy. After delivery, their children were enrolled in the follow-up study. The 31

comparison mothers and their neonates were enrolled within 24 hours after birth and

were matched to the methadone subjects for maternal race, socioeconomic status (SES),

sex, birth weight, and gestational age. A total of 61 infants (30 females and 31 males) of

methadone maintained mothers and 32 infants (15 females and 17 males) of comparison

mothers were enrolled in the follow-up study. There were 4 sibling pairs in the

methadone group and 1 sibling pair in the comparison group. By the time the child

reached

36 months of age, the attrition rate was 36% in the methadone group and 28% in the

comparison group. At the present time, in the 7th year of the study, the attrition rate is

43% for both groups. Comparisons were made between the lost and continuing subjects,

and no significant differences were found in the prenatal and neonatal characteristics.

Table 1 is a summary of the maternal and neonatal data at intake. Although the

comparison mothers are significantly younger than the methadone mothers, both groups

are well within optimal childbearing age. Another significant finding is that
74

methadone mothers smoke more than one pack of cigarettes/day with higher frequency

than the comparison mothers. In the methadone group, maternal urines were analyzed

during pregnancy for drugs of abuse, using the homogeneous enzyme immunoassay

procedure (EMIT) (SYVA Palo Alto, Calif) and thin-layer chromatography. Multidrug

abuse of such drugs as diazepines, opiates, cocaine, barbiturates, and tricyclics was

evident in 56% of the methadone mothers. Fifteen percent were also moderate to severe

alcohol abusers, as evaluated by frequent history taking. By 36 months, 10% of the

mothers on methadone maintenance had discontinued their methadone use. Also,

significantly more comparison mothers than methadone mothers were working and off

welfare by 36 months (p<.O2).

TABLE 1

Maternal and Neonatal Data at Intake

Maternal Data Methadone Comparison

Age 26.8+5* 22+.9*

Race (%)

 White 7.3 3.6

 Black 78.2 78.6

 Hispanic 14.5 17.9

Obstetrical

 complications (%) 22.2 14.3

Methadone dose 42+3

 (mg/day)

Months on methadone 43+3 —-

Multidrug abuse (%) 56 0

Tobacco (1 pack/day) 90* 28.6*

Neonatal Data

Birth weight (gin) 3129+192 3037+101

Premature rate (%) 15.4 11

SGA (%) 13 3

Apgar score 1 7.4+.3 8.1+.l

Apgar score 5 8.5+.2 9.0+.1

Sex (n)

 Males 31 17

 Females 30 15

Withdrawal syndrome (%) 75.1 —-

 Severe (%) 23.3

 Moderate (%) 51.8 ——

 Mild (%) 24.9 ——

* p<.05
75

NEONATAL PERIOD

Procedures

All neonates had a physical and neurological evaluation within 48 hours of birth.

Gestational age was determined by the estimated date of conception (EDC) when known

and/or using Dubowitz criteria (1970). Severity of narcotic abstinence syndrome was

evaluated using a withdrawal scoring system modified from one used by Finnegan et al.

(1975) daily until discharge. In addition, Brazelton’s Neonatal Behavioral Assessment

Scale was administered to each infant between 48 and 96 hours after birth (Brazelton

1973).

Results

As illustrated in table 1, there was a higher incidence of small for gestational age infants

and head circumferences below the third percentile in the methadone group (p<.05).

These findings were not associated with alcohol intake or tobacco smoking. The

incidence of narcotic withdrawal was 75%, with 75% of these cases exhibiting moderate

to severe symptoms. In early infancy, at approximately 2 weeks of age, 20 infants of

mothers on methadone maintenance developed elevated systolic blood pressure as

measured using the Doppler. The mean systolic blood pressure was 95, with a range of 59

to 132 mm/Hg. This occurred irrespective of the severity of narcotic abstinence

syndrome, and lasted for about 12 weeks. This systolic hypertension may be secondary to

autonomic nervous system dysfunction as a result of in utero narcotic drug exposure

(Rosen and Johnson

1982).

Correlations were run between prenatal and neonatal variables. Methadone dose and

length of methadone maintenance correlated positively with the presence of obstetrical

complications and the severity of narcotic abstinence syndrome (p<.01). Maternal

methadone dose also correlated positively with birth weight (p<.05). The Brazelton

Behavioral Assessments, done at 48 to 72 hours of life, revealed several differences

between the methadone group and comparison group infants. The methadone neonates

were less responsive to rattle decrement, less responsive to inanimate visual orientation,

less alert, less cuddly, and less consolable. They also demonstrated increased tone, less

motor maturity, increased pull-to-sit, and more tremulousness. Many of these findings

were most likely related to the infants’ experiencing narcotic abstinence syndrome.

FOLLOWUP: 2 TO 36 MONTHS

Procedures

After birth, the infants were seen at the follow-up clinic at 2, 4, 6, 8, 10, and 12 months of

age and then every 6 months. Each follow-up visit included physical, neurological, and

behavioral evaluations, as well as routine well baby care. Emergency medical care and

social service assistance also were provided when necessary.
76

In general, the physical and neurological examination covered growth parameters, cranial

nerves, tone, gross and fine motor coordination, normal and abnormal reflexes, and

developmental milestones. In addition, hospital and clinical charts were reviewed for

emergency room/clinic visits and number and type of infections and referrals. The

behavioral evaluation included the Bayley Scales of Infant Development, which was

given at 6, 12, 18, and 24 months of age, and the Merrill-Palmer Scale of mental tests at

36 months. At 30 and 36 months, a 30-minute mother—infant interaction session,

including both free play and structured task situation, was videotaped. Spontaneous

language production in these tapes was analyzed, using Brown’s (1973) procedures for

computing length of utterance.

Results

During the first 36 months follow-up there were no significant differences in somatic

growth among the two groups. There was a consistently higher incidence of head

circumferences below the third percentile in the methadone group of children. Many of

these children demonstrated eye disorders, such as strabismus and/or nystagmus. With

respect to the rate of infections during the first 24 months of life, the methadone children

had significantly more episodes of acute and chronic otitis media (p<.OOl). These

episodes may have been due either to therapeutic noncompliance or to an early immune

deficit. The neurological evaluations, summarized in table 2, showed a significantly

higher incidence of abnormalities in the methadone children. These abnormalities

included hypotonia or hypertonia, poor fine motor coordination, delays in attaining

developmental milestones, and poor language development. The Bayley Scales scores are

summarized in table 3. All mean scores were within the range for normal performance.

However, the methadone group scored significantly lower on both the Mental

Development Index (MDI) and Psychomotor Development Index (PDI) at 12 and 18

months, and on the PDI at 24 months (p<.05). To determine if there were differences in

score distribution, the frequency of Bayley scores below 85 was examined in each group

at both 12 and 24 months. Methadone children had disproportionately more low scores at

12 months in both MDI and PDI scales (p<.O5). Further analysis of the components of

the Bayley Scales revealed that responsiveness to verbal requests from others by 12

months of age was only present in 18% of the methadone children as compared to 50% of

the comparison children. The ability to express wants, usually present by 18 months, was

evident in only 28% of methadone versus 47% of comparison children at this age (Rosen

and Johnson 1982).

To evaluate consistency of neurobehavioral performance across measures and across

time, correlations between Bayley MDI and PDI scores and neurological assessments

were run for each subject group. In the methadone group, there were strong correlations

between Bayley scores at different time points, as well as between the neurological

evaluations and Bayley scores at both 12 and 24 months (p<.05 for all correlations).
77

TABLE 2 Neurological Evaluations (6-36 months)

Suspect to Abnormal (%)

Age (mo.) Methadone Comparison

6 (n~45) (n=25)

44.3 36

12 (n~46) (n=22)

22* 4.5

18 (n=38) (n~23)

18.3* 4.3

24 (n=39) (n=21)

20.6* 43*

36 (n=39) (n=23)

32 13

TABLE 3

Developmental Evaluations

I. Bayley Scales of Infant Development

Methadone Comparison

6 months (n=41) (n=23)

 MDI 95+2.5 100.7+4.2

 PDI lOT.0+2.8 105.1+2.9

12 months (n=41) (n=22)

 MDI 98.4+2.7 107.0+2.8*

 PDI 94.9+2.5 102.8+2.3*

 85 (MDI) 20%

(PDI) 20%

18 months (n=38) (n=23)

 MDI 96+2.3 .106.4+3.6*

 PDI 92.6+2.4 105.3+2.2*

24 months (n=34) (n=22)

 MDI 90.4+2.6 96.9+3.1

 PDI 99.1+2.7 108.is2.7*

 85 (MDI) 39 15*

(PDI) 17 5

II. Merrill-Palmer Scale

36 months (n=39) (n=21)

NIPS 44.6+2.1 46.3+2.3

SPP 55.7+4.4 63.1+5.1

25% 18% 4%

* p ~•.05
78

The relationship between various prenatal and neonatal characteristics and developmental

outcome was further examined at 18 and 24 months. Perinatal variables included

maternal age, length of methadone maintenance, methadone dose, multidrug abuse,

obstetrical complications, Apgar score at 5 minutes, and severity of narcotic abstinence

syndrome. There were no significant correlations between these perinatal variables and

developmental outcome (Rosen and Johnson 1982; Johnson et al. 1984). An analysis of

covariance in a regression mode indicated that treatment group (methadone vs.

comparison) and sex (male vs. female) were the only factors related to poor

developmental outcome (Rosen and Johnson 1982; Johnson et al. 1984). The scores of

the Brazelton Neonatal Assessment Scale did not correlate with the 18 months

neurodevelopmental outcome.

At 36 months there were no differences in the mean Merrill—Palmer scores and

percentiles, although lower scores were more prevalent in the methadone group.

Measurement of head circumference and the neurological evaluation correlated with the

Merrill—Palmer scores.

Using the videotapes, an analysis of spontaneous language production with mean lengths

of utterances (MLU) was performed at 36 months. The MLU was based on 50, rather

than 100, utterances due to only 30 minutes of videotaping. However, even with this

lower utterance requirement it was necessary to drop 5 methadone and 6 comparison

children from the analysis. The mean MLU for the methadone children was 2.71 + .66

and 3.14 + .66 (p<.O7) for the comparison children. These MLU samples are lower than

those reported for middle-class samples (Brown 1973).

Cluster analysis was used to determine whether the study population was comprised of

homogeneous groups having distinct patterns of developmental outcome (Hartigan 1975).

In this analysis, developmental outcome was defined by four variables: percentile head

circumference, neurological examination, Merrill—Palmer Scales scores, and number of

referrals for educational and/or developmental problems. The mean scores are illustrated

in table 4. Cluster III, the group showing the weakest developmental status, consisted

overwhelmingly of methadone children (85%) 5:1 ratio. This suggests that some children

born to mothers on methadone maintenance demonstrate no long-term effects, while for

others, their outcome is guarded. The factors that distinguish one group from the other are

not yet known. We found no differences in Clusters I and Ill as far as prenatal and

neonatal factors were concerned. At present, we are further examining the environmental

and early experiences of these infants.

FOLLOWUP: 37 TO 84 MONTHS

Procedures

Children are seen for routine follow-up evaluations every 6 months, although the project

continues to provide emergency medical care and social service assistance when needed.

The focus of the physical and neurological evaluations remains on growth parameters,

tone, motor coordination, and developmental milestones.
79

TABLE 4

Summary of Variable Means for 3-Cluster Analysis of

Continuing Subjects at 36 Months

Cluster I II III

Head circumference (%) 61.5+13.7 32.5+7.1 6.0+5.2

Neurological

evaluation @ l.4+.6 l.2+.5 1.4+.?

Merrill-Palmer

score ~ 52.1+14.7 45.1±9.4 41.0+9.7

Referral for

Special Services @ 0

Number of methadone

subjects (n=36) 9 10 17

Number of comparison

subjects (n=18) 4 11 3

@ M±SD

The behavioral evaluations have concentrated on language and perceptual development.

Between 42 and 60 months, children receive verbal and comprehension tests and the

Perceptual Integration Test. At 66 and 78 months, the children receive three standardized

measures of emerging skills. The first, the Boehm Test of basic concepts. measures

mastering of basic relational concepts. The Boehm Test is widely used and has been

standardized for inner-city children. The second measure is the Motor—Free Visual

Perception Test (MVPT), which yields a perceptual quotient relating the child’s

perceptual development to his age. The third measure is the Northwestern Syntax

Screening Test, which yields separate scores for receptive and expressive language skills.

In addition, children receive the McCarthy Scales of Children’s Abilities at 72 months,

and the Wechsler Intelligence Scale for Children-Revised at 84 months.

Results

Because not all of the children have reached 84 months, results are preliminary. Again,

there are no differences in height and weight between the methadone and comparison

children. These children are generally healthy. There are three children with generalized

lymphadenopathy of unknown etiology which, thus far, have yielded negative workups.

Neurological evaluations, summarized in table 5, show a higher prevalence of

abnormalities of fine and gross motor coordination, poor balance, hyperactivity,

decreased attention span, and speech and language delays in the methadone children.

Significance
80

was not determined as the numbers are still incomplete in each group. Table 6 is a

summary of the behavioral evaluations. As the children approach school age, it appears

that the differences between the two groups are diminishing. There is a trend toward

lower scores in the Northwestern receptive language evaluations among the methadone

children. There is also a higher incidence of referrals among the methadone children for

behavioral and academic problems. Those children who showed poor neurological

development at 18 to 36 months continue to do poorly at 37 to 84 months. As the

comparison group children approach school age they have begun to show poor

performance in testing. This has been reported by others in children from low

socioeconomic class. There is no significant difference in the McCarthy Scales between

the two groups. Further preliminary analysis of the McCarthy scores, in relation to the

three clusters created, reveal the following: Cluster I means the GCI score was 100.7+4;

Cluster II score was 83.6+3; and Cluster III score was 85.4+3. Those children in Cluster

III continued to perform poorly. The children in Cluster II showed poor performance on

the McCarthy Scales. This most likely reflects the deteriorating performance of the

comparison children..

TABLE 5

Neurological Evaluations (48-72 months)

Suspect to Abnormal (%)

Age (mo.) Methadone Comparison

48 (n=36) (n=19)

44 32

60 (n=31) (n=15)

42 33

72 (n=20) (n=9)

50 11.1

DISCUSSION

The data from our study reveal no uniform long-term effects of prenatal methadone

maintenance. In the first 36 months of life, however, children in the methadone group do

exhibit a higher incidence of minor neurological abnormalities and lower scores on

developmental evaluations. While the comparison children seem to do better during the

first 36 months of age, their performance deteriorates as they approach school age. The

methadone children show very little flexibility in developmental course. Children in the

methadone group seem to continue early patterns of performance and developmental

status without a change. Thus, despite exposure to similar prenatal as well as postnatal

environmental stresses, some methadone children do well initially and throughout early

childhood, while others do poorly
81

initially, and then continue to show poorer development. At the same time, however,

various prenatal variables (e.g., use of other drugs, obstetrical history, and neonatal

course) did not correlate with neurodevelopmental outcome. The methadone-exposed

babies, born at high risk, have special needs which place extra demands on their mothers.

However, many of these mothers themselves have many special needs and problems

which make it very difficult for them to adjust to their infants’ needs. Consequently,

inconsistent mothering and unstable environments may further accentuate the effects of

early infant characteristics (Thomas and Chess 1977). In examining further the

characteristics of the children who did well on the Merrill-Palmer at 36 months, two

factors emerged: maternal education and family stability. Other researchers have also

reported on children who were born at risk, but who were able to overcome their

handicaps because they were reared in stable environments with parents responsive to

their needs (Sameroff 1975; Werner et al. 1968).

TABLE 6

Developmental Evaluations (66-78 months)

Methadone Comparison

MVPT PQ 66 mo. (n=13) 85.08+3.72 (n=6) 96.8+ 3.9

78 mo. (n=12) 95.8+ 3.7 (n=7) 98.4+ 7.3

Boehm % 66 mo. (n=12) 62.9+ 8.3 (n=6) 82.5+10.6

78 mo. (n=12) 31.5+ 6.9 (n=7) 39.3+10.4

NW Rec % 66 mo.(n=l0) 40.2+10.9 (n=5) 58.0+14.8

78 mo. (n=12) 41.9+ 7.2 (n=7) 28.4+ 7.9

NW exp % 66 mo. (n=10) 25.9+ 7.9 (n=5) 31.6+15.2

78 mo.

MGCI 72 mo. (n=18) 89.22+3.4 (n=l0) 88.9+ 3.2

(M± SE)

In our study, as the children got older, the differences in mean scores between the groups

have become smaller. This phenomenon has already been noted at 36 months on the

Merrill-Palmer Scales and at 72 months on the McCarthy scores. This type of decline in

scores has been shown in low SES children by others after 24 months (Bradley and

Caldwell 1976). In analyzing individual tasks, however, the methadone children seem to

have particular difficulty with tasks which are highly structured or involve verbal

instruction. In summary, a child born to a mother on methadone maintenance is not only

exposed to a drug or drugs in utero, but is also exposed to the continued emotional,

familial, and environmental instability associated with the drug culture. This places the

child at even greater risk for long—term developmental difficulties.
82

An examination of the interaction between prenatal factors, early experience, and environment

should be used to plan intervention and treatment programs to enhance the subsequent

development of these children.

REFERENCES

Bradley, R.H. and Caldwell, B.M. Early home environment and changes in mental test

performance in children from 6 to 36 months. Devel Psychol 12:93, 1976.

Brazelton, T. B. Neonatal Behavioral Assessment Scale. London:

Spastics International Medical Publications, 1973.

Brown, R., ed. A First Language. Cambridge, MA: Harvard University Press, 1973.

Dubowitz, L.M.S.; Dubowitz, V.; and Goldberg, C. Clinical assessment of gestational age in the

newborn infant. J Pediatr 77:1, 1970.

Finnegan, L.P. Pathophysiological and behavioral effects of the transplacental transfer of

narcotic drugs to the fetuses and neonates of narcotic dependent mothers. Bull Narc 31:1—58,

1979.

Finnegan, L.P. Clinical, perinatal and developmental effects of

methadone. In: Cooper, J.R.; Altman, F.; Brown, B.S.; and

Czechowicz, D., eds. Research on the Treatment of Narcotic

Addiction: State of the Art. National Institute on Drug Abuse

Monograph. DHHS Pub. No. (ADM) 83-1281. Washington, D.C.:

Supt. of Does., U.S. Govt. Print. Off., 1983. pp. 392-443. Finnegan, L.P.; Kron, R.E.;

Connaughton, J.F., Jr.; and Emich, J.P.

Neonatal abstinence syndromes: Assessment and management. Addict Dis Intl J 2:141,

1975.

Hartigan, J.A. Clustering Algorithms. New York: John Wiley & Sons, 1975.

Johnson, H.L.; Diano, A.; and Rosen, T.S. 24—month neurobehavioral follow-up of children of

methadone-maintained mothers. Infant Behav Dev 7:115—123, 1984.

Kandall, S.R.; Albin, S.; Gartner, L.M.; Leek, S.; Eldelman, A.; and Lowinan, J. The narcotic

dependent mother: Fetal and neonatal consequences. Early Hum Dev 1/2:159, 1979.

Lifschitz, M.H.; Wilson, G.S.; O’Brian, J.; Faneth, E.; and Desmond, M.M. Fetal and postnatal

growth of children born to narcotic-dependent women. J Pediatr 102:646, 1983.

Rosen, T.S., and Johnson, H.L. Children of methadone-maintained mothers: Follow—up to 18

months of age. J Pediatr 101:192, 1982.

Sameroff, A.J. Early influences on development: Fact or fancy? Merrill—Palmer 21:267—294,

1975.

Strauss, M.E.; Lessen-Firestone, J.K.; Chavez, C.J.; and Stryker, J.C. Children of methadonetreated women at five years of age. Pharmacol Biochem Behav 11:3, 1979.

Thomas, A., and Chess, S. Temperament and Development. New York:

Brunner/Mazel, 1977.

Werner, E.; Honzik, M.; and Smith, R. Predictors of intelligence and achievement at 10 years

from 20-month pediatric/psychological exams. Child Dev 39:1063—1075, 1968.

Wilson, G.S.; Desmond, M.M.; arid Wast, R.B. Follow-up of methadone-treated and untreated

narcotic-dependent women and their infants:

Health, developmental and social implications. J Pediatr 98:716, 1981.
83

AUTHORS

Tove S. Rosen, M.D.

Department of Pediatrics

College of Physicians and Surgeons of Columbia University

630 West 168th Street

New York, New York 10032

Helen L. Johnson, Ph.D.

Department of Pediatrics

College of Physicians and Surgeons of Columbia University

630 West 168th Street

New York, New York 10032
84

Effects of Maternal Narcotic vs.

Nonnarcotic Addiction on Neonatal

Neurobehavior and Infant

Development

Ira J. Chasnoff, M.D.

There is no question that the number of women using and abusing nonnarcotic drugs far

exceeds the number who are addicted to narcotics (Chambers and Hart 1977). Current

data show that 63% to 93.5% of women use analgesics during pregnancy and that

sedative drug use ranges from 22% to 28% (Doering and Stewart 1978; Forfar and

Nelson 1973; Hill 1973). However, until recently, little attention has been given to

pregnancies complicated by the maternal use of drugs other than heroin and methadone.

At the Perinatal Addiction Project of Northwestern Memorial Hospital, the last 5 years

have seen a rapid increase in the proportion of women enrolling in our program who are

using and abusing non-narcotic substances during pregnancy. Screening of all women

presenting to Prentice Women’s Hospital and Maternity Center for prenatal care during a

6-month period in 1982 revealed that 3% of these women had evidence of sedativehypnotics in their urine at the time of admission to the general maternity clinic (Chasnoff

et al., in press). Reflecting the increasing popularity of phencyclidine hydrochloride

(PCP) in the United States (Showalter and Thorton 1977), a number of pregnant women

who abuse PCP have entered the Perinatal Addiction Project. The present report will

review the intrauterine growth, neonatal behavior, and growth and development of infants

whose mothers used nonnarcotic substances during pregnancy. These infants will be

compared to infants born to mothers who used narcotics during pregnancy and to infants

delivered to women with no history or evidence of substance abuse.

SUBJECTS AND METHODS

Data are available on 95 infants born to mothers enrolled in the Perinatal Addiction

Project between December 1976 and December 1982. All of the women were enrolled in

the first or early second trimester of pregnancy and completed a course of intensive

prenatal care. Maternal urine samples were obtained regularly to screen for illicit drug

use. For neonatal assessment, the 95 infants were divided according to the type of

primary maternal addiction:

heroin/methadone (N=5l), Group I; mixed sedative/stimulant (N=22),
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Group II; pentazocine/tripelennamine (N=13), Group III; and PCP (N=9), Group IV.

Mothers in Group I conceived while on heroin. Forty-seven of these women were abusing

heroin only. Four women abused an additional one or two nonnarcotic drugs. Upon

admission to the program, each woman was placed on a variable initial daily dose of

methadone. This dosage was steadily decreased to the lowest level which would prevent

craving or withdrawal in the mother. By the beginning of the third trimester, each woman

was on a maintenance dose of methadone, ranging from 5 to 40 mg daily (mean=15.9,

S.D.=1O.4). This dose was held at the same level for the rest of the pregnancy, and no

woman was completely withdrawn during pregnancy. Daily urine screens indicated that

all but three of the women remained clean of narcotic and non narcotic drugs, other than

the prescribed methadone.

Mothers in Group II were addicted to multiple licit and/or illicit nonnarcotic drugs. Each

woman used two to five of the following drugs in various combinations before and during

pregnancy: phenobarbital, diazepam, marijuana, alcohol, and cocaine. These women

received the same regimen of prenatal care as Group I except that they did not receive

methadone. Although abstinence was the objective for this group, only five of the women

remained clean of drug use throughout the third trimester of pregnancy.

Thirteen infants were delivered to women who abused a combination of pentazocine and

tripelennamine (T’s and blues, respectively) during pregnancy (Group III). All of the

women in this group sporadically used other, nonnarcotic drugs, but T’s and blues were

the only drugs consistently used throughout pregnancy. Although abstinence was the

objective of the program, none remained clean of T’s and blues during the third trimester

of pregnancy.

Group IV infants were delivered to nine women whose primary drug of abuse throughout

pregnancy was PCP. All of the women had positive urine screens which demonstrated

sporadic use of other nonnarcotic drugs in addition to the PCP, which was the only

substance used heavily (at least 5 days per week) throughout the third trimester.

Three of the Group II women sporadically used T’s and blues or PCP during pregnancy,

but this use was very limited and did not occur in the third trimester. Hence, these three

women were included in Group II based on their primary abuse of various sedatives and

stimulants throughout pregnancy.

For comparison, infants of a group of drug-free mothers (Group V, N27) were selected

for neonatal assessment in the order the women presented for prenatal care to the clinic of

Prentice Women’s Hospital and Maternity Center. These women had no history or

evidence of drug or alcohol abuse, and management of prenatal care and nutrition was

similar to the four drug-abusing groups of women.
86

All groups were evaluated for maternal factors which might affect neonatal outcome:

race, maternal age, education, gravidity, prenatal care, nutrition, cigarette smoking, and

drug use. Analysis of variance and chi—square analysis were utilized for statistical

analysis of these parameters. All neonates were examined at birth, and weight, crown-toheel length, and fronto—occipital head circumference were recorded. The Brazelton

Neonatal Behavioral Assessment Scale (BNBAS) (Brazelton 1976) was administered at 2

days of age by trained examiners who were blind to the infants’ prenatal history. Results

of neonatal data were analyzed utilizing analysis of variance. For those items which

reached statistical significance ((.05), the Fischer’s LSD (Kirk 1968) was utilized to

identify homogenous subsets.

For long-term follow-up, the opiate-exposed infants (Groups I and III) were combined

into Group A, and nonopiate-exposed infants (Groups II and IV) were combined into

Group B. The previous group of control infants (Group V) was expanded to include a

total of 35 infants to serve as controls for long-term assessment (Group

C). The Bayley Scales of Infant Development (Bayley 1969) were administered to all

infants at 3, 6, 12, and 24 months of age. The infants were examined at these same time

intervals, and weight, fronto-occipital head circumference, and crown—to—heel length

were recorded. Differences between control and each drug—exposed group of infants at

each interval for all parameters of growth and development were analyzed through use of

the two—tailed t test.

RESULTS

Neonatal Assessment

Demographic data (age, gravidity, education) for the women in Groups I through V were

similar, as was the frequency of cigarette smoking in each of the groups. However, racial

distribution varied between the groups (table 1). Thus, for analysis of neonatal data, race

was controlled through covariate analysis when each drug-using group was compared to

the Group V mothers and infants.

All infants were delivered at term gestation as determined by the criteria of Ballard et al.

(1977). There was an even distribution of infants by sex in each group. Apgar scores in

the five groups were similar, and no significant perinatal complications occurred in any

group. Twelve infants in Group I required therapy for significant withdrawal, based on

clinical criteria of marked irritability, poor feeding, and/or excessive weight loss. No

infants in the other drug groups required therapy for withdrawal.

Somatic Measures

Infants delivered to mothers in Group I and in Group III had a significantly lower weight

and length than control (Group V) infants (table 2). In addition, these Group I and Group

III infants had significantly smaller head circumference than both the control infants and

those in Groups II and IV. These differences remained when
87
88
89

race was statistically controlled. The birth weights, lengths, and head circumferences of

the sedative/stimulant- and PCP-exposed infants were not significantly different from

those of the control infants.

Neonatal Behavior

Means and standard deviations for those BNBAS items for which statistically significant

differences were obtained are listed in table

3. Significant differences were obtained in items related to interactive ability, motor

maturity, and state control. Items related to visual and auditory orientation and motor

maturity differentiated the methadone-dependent group from both the control and all

other drug groups (Fischer’s LSD). All four groups of drug-exposed neonates showed

deficits in state control with an abnormal predominant state, an increased lability of state,

and poor consolability. In addition, PCP-exposed infants (Group IV) showed significantly

increased lability of states and poor consolability when compared to all other drug groups

(Fischer’s LSD).

Infant Assessment: Two-Year Follow-up

In this portion of the study, demographic data for the two drug-exposed groups of infants

and the control group of infants were again similar. In addition, upon combining Groups I

and III (opiate-exposed infants) into Group A and Groups II and IV (nonopiate—exposed

infants) into Group B, racial distribution was similar for the two study groups and the

control group (C): 53% white, 43% black, 4% Hispanic in Group A; 58% white, 39%

black, 3% Hispanic in Group B; 52% white, 40% black, 6% Hispanic, 2% Oriental in

Group C.

Somatic Growth

Infants in Group A had significantly lower weight and length than the Group C drug-free

infants at both 3 and 6 months (t test) (table 4). By 12 months of age, Group A infants

had caught up in weight and length to the control infants. [lead circumference

measurements for the opiate-exposed Group A infants did not exhibit such catch—up

growth, however, and head circumference for these infants remained significantly smaller

than that of the control infants throughout the 2-year follow-up. Polydrug-exposed infants

in Group B exhibited normal growth patterns throughout the 2-year period for all

parameters, except that head growth had slowed by 18 months, and mean head

circumferences at 18 and 24 months were significantly smaller than those of the control

infants. Growth parameters for PCP-exposed infants were almost identical to those of the

polydrug-exposed infants, so that separate analysis was not performed.

Infant Development

Mean scores of the three groups of infants on the Bayley Scales of Infant Development

are shown in table 5. Group A infants had significantly lower Mental Developmental

Index (MDI) scores from
90
91
92
93

Controls at 6 and 12 months (t test). Group B infants had a significantly lower MDI at 6

months and Psychomotor Developmental Index (PDI) at 3 months. If PCP infants were

considered separately, their scores were almost identical to the polydrug-exposed infants.

In general, scores for both Groups A and B and for the control group of infants were in

the normal range, but exhibited a downward trend by 24 months of age.

DISCUSSION

The extensive literature devoted to the effects of intrauterine exposure to heroin and

methadone on the fetus and neonate has recently been reviewed (Householder et al.

1982). However, information regarding the outcome of nonnarcotic-exposed neonates is

sparse. In the present study, newborns delivered to women whose primary substance of

abuse was sedative/stimulants or PCP were found to demonstrate marked deficits in

neonatal behavior. These two groups of infants showed significantly poorer state

organization and consolability than the drug-free controls. In addition, when internal

comparisons were made, the PCP-exposed neonates were found to demonstrate more

lability of state and poorer consolability than all other groups of drug-exposed neonates.

The unique neurobehavioral changes of the PCP-exposed infants during the neonatal

period clearly differentiated them from the other drug-exposed newborns (Chasnoff et al.

1983). The low threshold of stimulation and rapid changes in state are similar to behavior

reported in children and adults intoxicated with PCP (Showalter and Thorton 1977;

Welch and Correa 1980).

Sedative/stimulant- and PCP-exposed neonates did not manifest significant differences

from normals in somatic growth measures at birth, orientation, or motor maturity

responses. Deficits in intrauterine growth appeared mainly in narcotic-exposed infants,

especially in relation to head growth. Similar to methadone-exposed neonates, neonates

exposed to T’s and blues showed significantly lower somatic growth rates and poorer

state control than the drug-free controls, although the methadone-addicted neonates could

be further differentiated by poorer visual and auditory orientation responses and poorer

motor control. The similarities between the methadone-exposed and the T’s and bluesexposed neonates may be related to the mixed opiate agonist-antagonist properties of

pentazocine (Chasnoff et al. 1983).

There are no previous studies evaluating long-term patterns of growth and development

in nonnarcotic-exposed infants, although preliminary developmental data have been

examined (Chasnoff et al. • in press). The nonnarcotic-exposed infants in the present

study demonstrated normal growth patterns in weight and length throughout the 2-year

follow-up period. The narcotic-exposed infants, on the other hand, demonstrated early

deficits in growth at 3 and 6 months and subsequently caught up to normals by 12 months

of age. This same early stunting of growth during the period of subacute withdrawal for

the narcotic-exposed infants is similar to the early growth patterns of

methadone—addicted infants reported by our group in 1982 (Chasnoff et al.).
94

The early depression of growth could be due to the direct effect of methadone on the

hypothalamic-hypophyseal axis of the newborn (Friedler and Cochin 1972). With the

slow excretion of the methadone by the newborn, plasma and tissue drug levels fall, the

endocrinological effect of the drug subsides, and growth recovers.

The mean head circumference of the narcotic-addicted newborns was significantly

smaller than controls at birth and remained so throughout the 2-year follow-up period.

The inhibitory effects of heroin on fetal growth include effects on brain growth (Chasnoff

et al. 1982; Naeye et al. 1973). The mean head circumference of the nonnarcotic-exposed

infants was normal at birth and continued so until 12 months. By 18 months of age,

however, head growth had slowed and the mean head circumference for these infants had

fallen to a significantly lower level. Small head size in young infants has been reported to

be predictive of poor developmental outcome (Gross et al. 1983) and may be another

indicator of the high-risk status of all drug-exposed infants.

Two-year developmental follow-up showed that the drug-exposed infants’ development,

as measured on the Bayley Scales of Infant Development, was comparable to that of the

drug-free infants. The isolated instances in which mean MDI or mean PDI fell to a low

level are probably not clinically significant in that all scores were within the normal

range, as defined for the Bayley Scales (100±S.D. 10). Of greater concern is the fact that

all three groups of infants, including controls, demonstrated a downward trend in mean

developmental scores by 2 years of age. From the present data, it appears that the infants’

environment and subsequent lack of stimulation had a more direct influence on 2-year

development than maternal drug use during pregnancy.

The problems involved in evaluating the effects of maternal substance abuse on the

developing fetus and infant are multiple, not the least of which are the difficulties

involved in following these infants over a long period of time. The chaotic and transient

nature of the drug-seeking environment impairs the early intervention and intensive

follow-up necessary to insure each infant’s maximum development. In addition, most

women from substance-abusing backgrounds lack a proper model for parenting. These

factors, compounded by the early neurobehavioral deficits of the drug-exposed newborns,

earmark these infants to be at high risk for developmental and school problems. Maternal

and perinatal addiction programs should be aimed at not only helping the mothers to deal

with their addiction but teaching them the parenting skills necessary for proper infant

stimulation and subsequent development. Future programs must develop methods to

ensure adequate follow-up of all infants born to substance-abusing women.

REFERENCES

Ballard, J.L.; Dazmaier, K; and Driver, M. A simplified assessment of gestational age.

Pediatr Res 11:372, 1977.

Bayley, N. Bayley Scales of Infant Development. New York:

Psychological Corp., 1969.
95

Brazelton, T . B. Neonatal Behavioral Assessment Scale. Philadelphia: Spastics

International Medical Publications, 1976.

Chambers, C.D., and Hart, L.G. Drug use patterns in pregnant women. In: Rementeria,

ed. Drug Abuse In Pregnancy and Neonatal Effects. St. Louis: Mosby, 1977.

Chasnoff, I.J.; Hatcher, R.; and Burns, W.J. Early growth patterns of methadone-addicted

infants. Am J Dis Child

134:1049—1051, 1980. — _____

Chasnoff, I.J.; Hatcher, R.; and Burns, W.J. Polydrug and methadone-addicted newborns:

a continuum of impairment? Pediatrics 70:210—213, 1982.

Chasnoff, I.J.; Burns, W.J.; Hatcher, R.; and Burns, K. Phencyclidine: effects on the fetus

and neonate. Dev Pharmacol Ther 6:404—408, 1983.

Chasnoff, I.J.; Burns, W.J.; Hatcher, R.; and Schnoll, S.H. Pentazocine and

tripelennamine (T’s and blues): effects on the fetus and neonate. Dev Pharmacol Ther

6:162—165, 1983.

Chasnoff, I.J.; Schnoll, S.H.; Burns, W.H.; and Burns, K. Maternal nonnarcotic substance

abuse during pregnancy:

effects on infant development. Neurobehav Toxicol Teratol, in press.

Doering, P.L., and Stewart, R’$B. The extent and character of drug consumption during

pregnancy. JAMA 239:843-846, 1978.

Forfar, J.O., and Nelson, M.N. Epidemiology of drugs taken by pregnant women: drugs

that may affect the fetus adversely. Clin Pharmacol Ther 14:632-642, 1973.

Friedler, G., and Cochin, J. Growth retardation in offspring of female rats treated with

morphine prior to conception. Science 175:654—656, 1972.

Gross, S.J.; Ochler, J.M.; and Eckerman, C.O. Head growth and developmental outcome

in very low-birth-weight infants. Pediatrics 71:70—75 1983.

Hill, R.M. Drugs ingested by pregnant women. Clin Pharmacol Ther 14:654—659, 1973.

Householder, J.; Hatcher, R.; Burns, W.J.; and Chasnoff, I.J. Infants born to narcoticaddicted mothers. Psychol Bull

92:453—468, 1982.

Kirk, R. Experimental Design: Procedures for the Behavioral Sciences. Belmont,

California: Brooks/Cole, 1968, p. 87.

Naeye, R.L.; Blanc, W.A.; and LeBlanc, W. Heroin and the fetus. Pediatr Res 7:321,

1973.

Showalter, C.V., and Thorton, W.E. Clinical pharmacology of phencyclidine toxicity.

Am J Psychiatry 134:1234—1238, 1977.

Welch, M.J., and Correa, G.A. PCP intoxication in young children and infants. Clin

Pediatr 19:510-514, 1980.

AUTHOR

Ira J. Chasnoff, M.D.

Departments of Pediatrics and Psychiatry

Northwestern University Medical School

Northwestern Memorial Hospital

Chicago, Illinois
96

Developmental Consequences of

Maternal Drug Use During

Pregnancy

Barry Zuckerman, M.D.

The consumption of psychoactive substances during pregnancy has a negative impact on

fetal growth. Heroin, methadone, and heavy alcohol consumption during pregnancy are

associated with lower birth weight and central nervous system (C NS) dysfunction.

Recent evidence suggests that marijuana use also may be associated with lower birth

weight No information documents the impact of cocaine use on fetal outcome.

This paper will primarily present information pertaining to the identification of the major

independent variables associated with developmental outcome for infants exposed

prenatally to a variety of drugs Information regarding developmental assessment will also

be presented.

STRUCTURAL TERATOGENICITY-FEATURES COMPATIBLE WITH FETAL

ALCOHOL SYNDROME

In addition to lower birth weight, infants of mothers who consume large amounts of

alcohol during pregnancy may exhibit a pattern of physical anomalies referred to as the

Fetal Alcohol Syndrome (FAS). Because the reported incidence of the syndrome is rare

(between 1 and 2 per 1000 live births), criteria developed by Hansen et al (1978) are used

to classify infants as having features compatible with the fetal alcohol syndrome (CFAS).

This classification is an attempt to identify an association between lower levels of

drinking and less extensive fetal involvement. Each infant is rated according to the

following criteria: 1) small size for gestational age (weight, length, or both, less than the

third percentile); 2) microcephaly (head circumferences less than the third percentile); 3)

short palpebral fissures Class than 1.8 cm wide in infants >36 weeks’ gestational age);

and 4) multiple dysmorphic features, judged by clinical observation, including: broad low

nasal bridge, epicanthic folds, thin upper lip, hypoplastic philtrum, small nails, limitation

of joint movement, large hemangiomas, altered palmar crease patterns, cardiac murmurs,

and ear anomalies. Infants are classified as having features compatible with the fetal

alcohol syndrome if rated abnormal on at least two of the four criteria. One of the two

criteria must be either short palpebral fissures or multiple dysmorphic features.
97

CFAS features may not be specific to alcohol. Of 1,384 infants examined in a study

(Hingson et al. 1982) of the effect of alcohol on fetal development, conducted at Boston

City Hospita1 (BCH), 31 (2.3%) had features compatible with the fetal alcohol

syndrome. Women who smoked marijuana during pregnancy were five times more likely

than nonusers to deliver a child with CFAS features (p<.00l). Women who gained less

than 5 pounds during pregnancy were 2.6 tines more likely to deliver a CFAS child than

women who exhibited the mean weight gain in the sample (p<.00l). The relative risk for

women who were expc8ed to roentgenograms was 2.8 compared with women who were

not exposed (p<.02). In contrast, the relative risk for women who averaged two or more

drinks daily compared with nondrinkers was 0.6 and not significant. This is the only

study that the author is aware of that attempts to identify a possible association between

factors other than alcohol and CFAS.

Features compatible with FAS may reflect a final common pathway of numerous agents

or combination of agents rather than a specific teratogenic effect of alcohol. This may be

more true with fetal alcohol effects, which are identified when two of three areas (growth,

dysmorphology, and C NS related development) demonstrate abnormality. while some

investigators consider the facial dysmorphology the most unique aspect of FAS, a recent

report demonstrates the similarity between the facial appearance in FAS and the face of

children born to mothers with phenylketonuria (Lipson et a]. 1981). In reviewing her

work and other studies regarding craniofacial dysmorphogenosis, Sulik (1984) also

concludes that the creation of the FAS phenotype may not be unique to alcohol. Animal

studies suggest that teratogen exposure, such as might be seen with high levels of alcohol

during the gastrulation (primitive streak) stage of development, results in the interference

with the formation of the prechordal mesoderm. At this stage of development, teratogens

must get to the embryo by diffusion, since the placenta is not yet formed. A teratogenic

process at this stage of development will result in the craniofacial, brain, and eye defects

noted in severe forms of FAS which is on the mild end of the spectrum of malformations

which extends to holoprosencephaly (failure of cleavage of the prosencephalon, a

primary brain vesicle in the embryo, with a deficit in midline facial development). Other

agents, such as other drugs or radiation, or a combination of agents, may also interfere

with embryogenosis at this stage. The commonly accepted association between alcohol

and this constellation of dysmorphic features known as FAS may be because alcohol is

the teratogen to which humans expose themselves most frequently. In summary, there is

epidemiologic and animal data to suggest that alcohol may not be specific to either end of

the spectrum of malformations associated with FAS.

VALIDITY OF SELF-REPORTED DRUG USE

The unreliability of self-reported drug use may explain the inconsistent association of the

use of some drugs and fetal growth in the research literature to date. The association

between low birth weight and certain substances, such as cigarettes, heroin, and

methadone, is fairly consistent across studies. The association of low birth weight and

other substances, however, such as the moderate use of alcohol and marijuana, differs

from investigation to investigation.
98

A pilot study conducted at Boston City Hospita1 (Zuckerman et al, in press) raises questions

about the validity of self-reported drug use. Seventy-five pregnant women were interviewed

about their consumption of marijuana and other drugs. In addition, a urine sample was

analyzed for the presence of marijuana metabolites. The urine assay technique used detects

marijuana metabolites 5 to 7 days after smoking one marijuana cigarette. Eighteen women

(24%) had urine samples positive for the presence of marijuana metabolites. Eight of these

women (12.5%) reported not having smoked marijuana in the previous week. While all

eight women reported having used marijuana at some point, four of them reported using

marijuana prior to, but not during, their pregnancy. The other four acknowledged using

marijuana during their pregnancy, but not during the week before the interview. Had we

relied on self-reporting alone, we would have missed 15% (4 of 27) of the women who used

marijuana during pregnancy. The misclassification of 15% of women who did consume

marijuana during pregnancy might result in an underestimation of an association between

marijuana use and neonatal growth.

This B C H study also found a greater percentage of pregnant women reporting marijuana

use, smoking cigarettes, and drinking alcohol during pregnancy than did a 1977-79 study

(Hingson et al. 1982) at BCH (table

1). There are four possible, not necessarily mutually exclusive, explanations for the

discrepancy between these findings 1) Awareness that their self-report might be confirmed

by urine assay may have prompted more women to report their substance use accurately in

the 1983 sample, compared to the earlier study: 2) Demographic differences between the

two study populations may account for the different patterns of substance use identified; 3)

Health habits during pregnancy may be determined more accurately by prenatal rather than

postpartum interview, because there is less risk of recall bias; and 4) True changes in drug

use during pregnancy from the late 1970s to the early 1980s may be reflected in this data.

The first explanation is consistent with the bogus pipeline paradigm (Jones and Sigall 1971)

that involves connecting subjects to a fictitious lie detector type device. Subjects are then

asked to report their feelings and attitudes toward topics likely to alicit highly socially

desirable responses. Various studies demonstrate that participants in the bogus pipeline

condition give more truthful responses to questions subject to high social desirability bias

than those asked to answer without a lie detection type device (Quigley-Fernandez and

Tedeschi 1978). The higher rate of reported drug use in our recent study may be due to

women’s knowledge that their urine was to be assayed. Correspondingly, the lower rate of

drug use in our previous study may be due to underreporting because of social stigma

attached to the illegal status of some of the drugs. Pregnant women, particularly, may feel

pressure to underreport certain health habits if they believe thc6e habits will damage their

unborn infant.

One could speculate that in the absence of urine samples, people might systematically

underreport drug use. The effects of underreported factors may be underestimated or

incorrectly attributed to other habits. Specifically, if Illicit substances such as marijuana or

cocaine are more
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TABLE 1

Self-Reported Substance Use Any Time During Pregnancy

Boston City Hospital Pilot Project

Study June 1983+

Substance Use During Pregnancy Feb. 1977-Oct. 1979*

N=1690 N=75

Marijuana 14% 31%

Cigarettes 48% 60%

Psychoactive Drugs 1% 11%

Alcohol 38% 64%

* Hingson et aLl982

+ Zuckerman ~ al, in press

often underreported than legal substances, such as alcohol or cigarettes, researchers may

misattribute the effects of illicit psychoactive substances to alcohol and cigarettes. This

may help explain the reported consistency in the association between cigarette smoking

and lower birth weight. and the lack of consistency in findings concerning the effects of

other either illicit or socially undesirable substances upon birth weight The accurate

determination of such substance use is critical to the interpretation of our ongoing study

and all previous work in the field. We are conducting a methodological trial to assess the

impact of urine testing upon the reporting of cigarette, marijuana, alcohol, cocaine, and

other psychoactive drug use during pregnancy. Our hypotheses are 1) More pregnant

women will report drug use when they know their urine will be tented; and 2) the impact

of the urine assay will be greater for drugs that are illegal or considered l~ socially

desirable. Use of illicit drugs, such as marijuana and cocaine, will be underreported more

often than alcohol consumption or cigarette smoking when urine tests are not obtained.

BEHAVIORAL TERATOGENICITY-NEUROBEHAVIORAL ASSESSMENT OF

THE NEONATE

The Neonatal Behavioral Assessment Scale (NBAS) developed by Brazelton (1973) is

the most commonly used assessment of neonatal neurobehavioral functioning. The scale

assess 20 reflexes and 26 behavioral items, such as the ability of the neonate to habituate

to stimuli; to orient to social and nonsocial stimuli to regulate states of arousal,

vasomotor functioning, and activity level4 and to exhibit social behaviors, such as

smiling or cuddling. A newborn’s neurobehavioral
100

functioning is a reflection of genetic endowment coupled with intrauterine exposures and

experiences. The scale has been extensively used in the fo1lo wing types of studies: 1) to

evaluate the effect of prenatal and intrapartum effects on newborn behavior; 2) to relate

newborn behavior to maternal responsivity; 3) to compare different clinical populations

of infants; and 4) to determine the predictive validity of the scale to later developmental

outcome. An important consideration in the use of the scale is the magnitude of

decrements in performance. Behaviors are assessed on a nine-point scale. Differences in

performance of l~ than one point may not be clinically significant. This is a special

problem when large numbers of subjects are assessed, and statistically significant

differences in behavioral functioning may not be clinically significant.

The behavioral teratogenicity of prenatal opiate ingestion is described in terms of a

withdrawal syndrome. Specific behavioral characteristics of opiate addicted newborns

identified by the NBAS include numerous state changes, tremors, motor in maturity,

decreased alertness, decreased ability to habituate to stimuli, and decreased auditory and

visual orientation. (Soule et al. 1974; Strauss et al 1976; Chasnoff et al. 1982).

Alcohol consumption during pregnancy is associated with infants who have poorer ability

to habituate and have a lowered level of arousal (Streissguth et al 1983). Using a special

pressurized mattress, neonates of mothers who were heavy alcohol users during

pregnancy demonstrate poorer state regulation as manifested by a decrease in total

amount of sleep and an increase in the fragmentation of sleep periods (Rosette et al

1979). Fried (1980) demonstrated that infants of mothers who used marijuana during

pregnancy were less likely to respond to and habituate to repeated visual stimuli than

infants of mothers who did not use marijuana during pregnancy. The infants exposed to

marijuana in utero also demonstrated more tremors and startles. Finally, in a study of the

effects of prenatal exposure to smoking, caffeine, and small amounts of alcohol, Jacoteen

(in press) demonstrated independent effects on behavior by alcohol and caffeine, but not

cigarette smoking. The obvious withdrawal symptoms of opiate-exposed newborns and

these studies which control for confounding variables suggest a behavioral teratogenetic

effect of prenatal drug exposure of the specified agents. The independent effect of

marijuana remains to be conclusively demonstrated.

It cannot be ascertained from these findings whether the observed behavioral differences

reflect permanent CNS damage, or a transient drug or withdrawal effect on CNS

functioning. Even if the behavioral dysfunction is transient. it may have an indirect effect

on later childhood functioning via mother-infant interaction. For example, a decreased

ability for an infant to habituate may result in a more irritable infant. Excessive crying is

reported as the reason for battering by 80% of the abusing parents whose infants are less

than 1 year old (Weston 1968). Infants with poor arousal may not elicit sufficient caretaking (stimulation and nutrition) from their mothers, which may contribute to a cycle of

failure to thrive. This cycle may be compounded when a mother is less sensitive to her

infant’s signals because of her own drug use.
101

CONSEDERATIONS REGARDING DEVELOPMENTAL ASSESSMENTS

Developmental outcome studies should include repeated assessments over time. An

assessment at any one point in time can only demonstrate a dysfunction at that time; one

cannot assume that a particular symptom, delay, or dysfunction will endure over time. For

example, the Bayley Test of Infant Development only becomes modestly predictive of early

school age LQ. at 18 months. The study of children asphyxiated at birth demonstrates this

point (Corah et al 1965). Compared to nonasphyxiated children, children suffering from

asphyxia had more neurobehavioral signs at birth, and, at 3 years of age, scored lower on all

tests of cognitive function and had more positive neurologic findings. However, when

reassessed at age 7, significant LQ. differences had disappeared between the anoxic group

and control population. Similar findings are reported between children with neonatal

hyperbilirubinemia compared to controls. Children with hyperbilirubinemia had decreased

motor development at 8 months and increased evidence of neurologic abnormalities at 1 year.

However, there was no difference in LQ. scores and neurologic examination between groups

at age 4 and 7 years (Ruben et al. 1979). These findings emphasize the value of repeated

assessments and suggest plasticity of the central nervous system.

In addition to repeated assessments, numerous skills should be assessed to best understand a

child’s central nervous system functioning. A false conclusion about an adverse effect of an

in utero exposure might be made if only I. Q. scores are used. I. Q. scores reflect a

summation of numerous skills. Children with learning disabilities may have significant

deficits in their perceptual or language functioning, but have an average LQ.. In utero

exposure to a drug may result in a significant CNS deficit in one area of functioning, which is

balanced by a strength in another area. Multiple areas of functioning should be assessed.

Developmental assessment should include age appropriate assessment of perceptual1

cognitive, and motor skills; speech and language abilities; and behavior (especially

attentional abilities). Laboratory assessments of attention in young children may be a more

sensitive indicator of future cognitive or memory functioning than developmental testing.

In addition to these clinical assessments, newer physiologic techniques such as evoked

responses (somatosensory, visual, and train stem auditory), Electroencephalogram (EEG),

Brain Electrical Activity Mapping (BEAM), Positron Emission Tomography (PET Scanner),

and Nuclear Magnetic Resonance (NM R), may prove to be important adjuncts in assessing

central nervous system functioning more objectively and with greater sensitivity in both

neonates and older children. Neonatal assessments are especially important because

postnatal. factors are less likely to confound the results. These electrophysiologic techniques

have an added advantage of being able to be used in the neonatal period.

MULTIFACTORIAL MODEL FOR DEVELOPMENTAL OUTCOME

Outcomes measured in the neonatal period can be ascribed best to intrauterine events. Low

birth weight is the major adverse outcome described for numerous substances, such as

cigarettes, alcohol, heroin,
102

and marijuana, used during pregnancy. The significance of low birth weight is its

association with increased infant mortality and morbidity. The Select Panel for the

Promotion of Child Health (1981) reported that very low birth weight is among the most

significant predictors of later developmental deficits. However, correlations between

birth weight and developmental outcome demonstrate conflicting findings due in part to

methodologic differences among studies (Kiely and Paneth 1981).

Few studies have assessed the relationship between substance use during pregnancy and

developmental outcome. At 18 months of age, children born to methadone-maintained

mothers had more neuralgic signs and significantly lower scores on the Bayley Test of

Infant Development (Rosen and Johnson 1982). Retrospective studies have associated

alcohol consumption during pregnancy with lower LQ. scores (Streissguth et al 1978) and

learning disorders or hyperactivity (Shaywitz et al 1980). A prospective study of children

exposed to alcohol in utero demonstrates a small but statistically significant decrease in their

scores at 8 months on the Bayley Scales of Infant Development (Streissguth et al 1980).

Research in the past 20 years on the outcome of newborns with perinatal complications and

low birth weight provides an important source of information to understand better the

developmental consequences of drug exposure during pregnancy. Pasamanick and Knobloch

(1966) coined the term “continuum of reproductive causality’ to describe the relationship

between perinatal factors, such as anoxia, low birth weight. and delivery complications, to

deviant development, such as cerebral palsy, epilepsy, mental retardation, and learning

disorder. They demonstrated in a retrospective study that children having more serious

conditions, such as cerebral palsy, had more obstetrical complications than children who had

mild disorders, such as a learning problem. They proposed that the greater the perinatal

insult1 the greater the brain damage, and the worse the clinical condition. Subsequent

prospective studies on anoxia and low birth weight do not completely support this entirely

biologic explanation of outcome. For instance, infants with low Apgars (<5) at 5 minutes,

demonstrate a four-fold increase in neurologic abnormalities at 1 year compared to infants

with higher Apgar scores. However, 96% of the infants with low Apgars did not

demonstrate any gross neurologic abnormality (Drage et al 1968). While hypoxic insult

contributes to poor outcome for some children, the vast majority of children appear to do

well1 and individual prediction is limited. Other studies of low birth weight (Drillien 1964)

and perinatal complications (Werner et al 1971) suggest that poor outcome is most likely to

occur when the adverse condition is associated with low socioeconomic status of the family.

Perinatal complications can be considered somewhat analogous to prenatal drug exposure

because both of these events can result in C NS damage. Perinatal asphyxia is associated

with hypoxic-ischemic injury of the brain. Animal research has clearly documented an

adverse impact of methadone (Zagon and McLaughlin 1978) and alcohol (Abel et al. 1983)

on the developing brain. Animal research has also directly assessed the plasticity of the

developing brain. When experimental lesions are induced in selected areas of adult

monkey’s brain, the associated function is permanently lost. However, when these same

lesions are
103

experimentally induced prenatally, the monkeys perform as well as normal animals

(Goldman-Rakic and Galkin 1978). By injecting tritiated amino acids, Goldman-Rakic

(1978) demonstrated the reorganization of CNS connections following a specific

experimentally induced brain lesion. The process of C NS reorganization and four other

possible pathways for recovery of function in infants with known CNS insult are reviewed

by Saint James-Roberts (1979).

Sameroff and Chandler (1975) propose a transactional model of development to explain the

perinatal risk research findings. This model states that developmental and behavioral

outcome are due to ongoing reciprocal interactions between the organism and the

environment. This model goes beyond a unitary model, which explains outcome either

entirely by biologic or environmental factors. Research in the past 10 years has furthered

the understanding of the developmental process by defining characteristics of the child,

such as temperament and behavior, and the child’s environment. including maternal

depression, social supports, surrogate child care, and quality of the home environment. A

recent study demonstrates that responsive caregiving is the most important factor

associated with developmental competence at 5 years of age for low birth weight infants

(Cohen et al 1982). Neonatal problems per se did not contribute to the developmental

vulnerability of these infants.

One study directly controlled for the caretaking environment of drug using mothers by

comparing four groups of children: a heroin-exposed group, a drug environment

comparison group (children who lived with addicts or whose parents used heroin after the

birth of the child), and two groups matched for perinatal complications and socioeconomic

status. There were few differences between the in utero exposed children compared to the

children exposed to the social environment of drug using caretakers (Wilson et a]. 1979).

To best understand the developmental consequences of prenatal drug exposure, one must

understand both the in utero environmental effect (teratogenic effect on the brain) and the

postnatal environmental effect (drug using caretakers). The effect of the social environment

in research models must go beyond the measurement of socioeconomic status. More

specific aspects of the caretaking environment. such as mother-infant interaction, social

supports, etc., need to be included. Characteristics such as depression may be very

important because there is a known association between depression and heroin-methadone,

and marijuana use. Children of drug users may be subject to a double jeopardy. They may

suffer in utero effects on their central nervous system associated with drug abuse and then

suffer from poor environmental circumstances due to non-optimal parenting associated

with a drug user’s lifestyle. From a public health perspective, injuries are the leading cause

of childhood morbidity and mortality. It has never been adequately studied whether

children of drug-using mothers sustain more injuries. Do drug—using mothers provide the

same level of supervision and compliance with safety guidelines as nondrug using

mothers?

In summary, developmental outcome is the result of a complex interaction of a variety of

factors. In utero exposure to certain
104

substances, best documented by studies using excessive amounts of heroin, methadone,

and alcohol, represents a significant source of biological vulnerability. The valid

identification of specific drugs associated with a behavioral or structural teratogenic

effect on the fetus remain a source of methodologic concern. These drugs may interact

synergistically, as well as with poor nutrition or health, to further impair optimal in utero

growth. Many conditions associated with poor developmental outcome are more

prevalent among people living in poverty, which further confounds the effect of prenatal

drug exposure. These conditions include drug exposure, increased perinatal

complications, congenital infections, and postnatal health factors such as lead exposure

and malnutrition; social factors like maternal depression; lower maternal education; and

less optimal caretaking environments. Studies that assess the developmental

consequences of in utero drug exposure need to assess the variables that are associated

with childhood outcomes, especially those variables that are more likely to be found

among mothers whose lifestyles involve excessive drug use.

REFERENCES

Abel, E.L.; Jacobson, S.; and Sherwin, B.T. In utero alcohol exposure:

Functional and structural brain damage. Neurobehav Toxicol Teratol 5:363—366, 1983.

Brazelton, T.B. Neonatal Behavioral Assessment Scale. Philadelphia:

Spastics International Medical Publications, 1973.

Chasnoff, LF.; Hatcher, R.; and Burno, W.J. Polydrug and methadone addicted newborns: A

continuum of impairment? Pediatrics 70:210, 1982.

Cohen, S.E.; Sigman, M.; Parmelee, A.H.; and Beckwith, L. Perinatal risk and developmental

outcome in pre-term infants. Semin Perinatol 6:334—339, 1982.

Comb, N.L.; Anthony, E.J.; Painter, P.; Stern, J.A.; and Thurston, D.L. Effects of perinatal

anoxia after seven years. No. 596, 79(3), 1965.

Dorus, W., and Senay, E.C. Depression, demographic dimensions, and drug abuse. Am J

Psychiatry 137:699—703, 1980.

Drage, j.S.; Kennedy, C.; Berendes, H.; Schwab, K.; and WeiSS,W. The five-minute apgar score.

Dev Med Child Neurol 8:141, 1968.

Drillien, C.M. The Growth And Development Of The Prematurely Born Infant. Edinburgh:

Livingstone, 1964.

Fried, P.A. Marijuana use by pregnant women: neurobehavioral effects on neonates. ~ Alcohol

Depend 1980.

Goldman- Rakic, P.S. Neuronal plasticity in primate telencephalon:

Anomalous crossed corticocaudate projections induced by prenatal removal of frontal

association cortex. Science 202:768, 1978.

Goldman-Rakic, P.S., and Galkin, ~F. W. Prenatal removal of frontal association cortex in the

rhesus monkey: anatomical and functional consequences in postnatal life. Brain Res

52:451—485, 1978.

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, 1978.

Hingson, R.; Alpert, J.; Day, N.; Dooling, E.; Kayne, H.; Morelock, S.; Oppenheimer, E.; and

Zuckerman, B.S. Effects of maternal drinking and marijuana use on fetal growth and

development Pediatrics 70:539-546, 1982.
105

Jacobson, S.W.; Fein, G.G.; Jacobson, J.L.; Schwartz, P.M.; and Dowler, J. K. Neonatal

correlates of prenatal exposure to smoking, caffeine, and alcohol. Infant Behavior and

Development. 7:253—265, 1984.

Jones, E.E., and Sigall, H. The Bogus pipeline: a new paradigm for measuring affect and attitude.

Psychol Bull 76:349—364, 1971.

Kiely, J., and Paneth, N. Follow-up studi f low birth weight infants suggestions for design,

analysis, and reporting. Dev Med Child Neurol

23:96—100, 1981.

I4son, A.H.; Yu, J.S.; O’Hafloran, M.T.; and Williams, R. Alcohol and phenylketonuria. Lancet

1:717—718, 1981.

Pasamanick, B., and Knobloch, H. Retrospective studies on the Epidemiology of reproductive

causality: Old and new. Merrill-Palmer 12:7—26, 1966.

Paton, S.; Keseler, R.; and Kandel, D. Depressive mood and adolescent illicit drug use.’ a

longitudinal analysis. J Genet Psychol 131:267-289, 1977.

Quigley—Fernandez, B., and Tedeschi, J.T. The bogus pipeline as lie detector: two validity

studies. J Pers Soc Psychol 36:247-256, 1978.

Rosen, T.S., and Johnson, H.L. Children of methadone maintained mothers. Follow-up to 18

months of age. J Pediatr 101:192-196, 1982.

Rosett, H.L.; Snyder, P.A.; Sander, L.W.; and Gould, J.B. Effects of maternal drinking on

neonatal state regulation. Dev Med Child Neurol 21:464, 1979.

Ruben, R.A.; Balow, B.; and Fisch, R.O. Neonatal serum bilirubin levels related to cognitive

development at ages 4-7 years. J Pediatr 94:602—604, 1979.

Saint James-Roberts, I. Neurological plasticity, recovery from brain insult and child

development. In: Advances in Child Development. New York Academic Press, 1981.

Sameroff, A.J. and Chandler, M .J. Reproductive risk and the continuum

of care-taking causality. In: Horowitz, F.D.; Heatherington, M.;

Scarr-Salapatek, S.; and Siegel, G., eds. Review of Child

Development Research Volume 4. Chicago: University of Chicago

Press, 1975.

Select Panel for the Promotion of Child Health, 1981 Report to the

United States Congress and the Secretary of Health and Human

Services on Better Health for Our Children: A National Strategy.

DHHS Pub. No. 79-55071. Washington, D.C.: Supt. of Docs., U.S. Govt. Print. Off., 1981.

Shaywitz, S.E.; Cohen, D.J.; and Shaywitz, B.A. Behavior and learning difficulties in children of

normal intelligence born to alcoholic mothers. J Pediatr 96:978, 1980.

Soule, A.B.; Standley, K.; Cepan, S.; and Davis, M. Clinical uses of the Brazelton Neonatal

Scale. Pediatrics 54:583, 1974.

Strauss, M.; Starr, R.H.; Oshea, E.M.; Chavez, C.J.; and Styker, J.C. Behavioral concomitant of

prenatal addiction to narcotics. J Pediatr 89:842, 1976.

Streissguth, A.P.; Barr, H.M.; and Martin, D.C. Maternal alcohol use and neonatal habituation

assessed with the Brazelton scale. Child Develop 54:1109-1118, 1983.

Streisaguth, A.P.~ Herman, C.S.; and Smith, D.W. Intelligence, behavior, and dysmorphogenesis

in the fetal alcohol syndrome: a report on 20 clinical cases. J Pediatr 92:363, 1978.
106

Streissguth, A.P.; Barr, H.M.; Martin, D.C.; and Herman, C.S. Effects of maternal alcohol,

nicotine, and caffeine use during pregnancy on infant development at 8 months. Alcoholism:

Clin ~ Res

4:152—164, 1980.

Sulik, K.K. Critical periods for alcohol Teratogenesis in mice with special reference to the

gastrulation stage of emixyogenesis. Mechanisms of Alcohol Damage In Utero, Ciba

Foundation Symposium 105, London: Pitman Press, 1984. pp. 124—141.

Werner, E.E.; Bierman, J.M.; and French, F.E. The Children of Kausi.

Honolulu: University of Hawaii Press, 1971.

Weston, J. The pathology of child abuse. In: HeIfer, R. and Kempe, C., eds. The Battered Child.

Chicago: The University of Chicago Press, 1968.

Wilson, G.W.; McCreary, R.; Kean, J.; and Baxter, J.D. The development of preschool children

of heroin-addicted mothers: A controlled study. Pediatrics 63:135, 1979.

Zagon, 1.5., and McI~ii~i~Iii7P.J. Perinatal methadone exposure and brain development a

biochemical study. J Neurochem 31:49-54, 1978.

Zuckerman, B.S.; Hingson, R.; Marelock, S.; Amaro, H.; Frank, D.; Sorenson, J.R.; Kayne, H.;

and Tiinperi, R. A pilot study assessing maternal marijuana use by urine assay during

pregnancy. National Institute on Drug Abuse Research Monograph, in press.

ACKNOWLEDGEMENT

This research is supported by a grant from the National Institute on

Drug Abuse: "Maternal Marijuana Use and Pregnancy Outcome" (lR 01

DA03508—0l).

AUTHOR

Barry Zuckerman, M.D.

Associate Professor of Pediatrics

Director - Child Development Unit

Boston University School of Medicine

Boston City Hospital

818 Harrison Avenue

Boston, MA 02118
107

National Institute on Drug Abuse

Research Monograph Series

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1 FINDINGS OF DRUG ABUSE RESEARCH. Not available from NCDAI.

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4 NARCOTIC ANTAGONISTS: THE SEARCH FOR LONG—ACTING PREPARATIONS.

Robert Millette, Ph.D., ed.

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17 RESEARCH ON SMOKING BEHAVIOR. Murray E. Jarvik, M.D., Ph.D.,

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27 PROBLEMS OF DRUG DEPENDENCE, 1979: PROCEEDINGS OF THE 41ST

ANNUAL SCIENTIFIC MEETING, THE COMMITTEE ON PROBLEMS OF DRUG DE

PENDENCE, INC. L.S. Harris, Ph.D., ed. Not available from NCDAI.

GPO Stock #017—024—00981—4 $9.00 NTIS PB #80—175482 $37

28 NARCOTIC ANTAGONISTS: NALTREXONE PHARMACOCHEMISTRY AND

SUSTAINED—RELEASE PREPARATIONS. Robert Willette, Ph.D., and Gene Barnett, Ph.D.,

eds. Papers report research on sustained— release and long—acting devices for use with the

narcotic antagonist naltrexone. Not available from NCDAI.

GPO Stock #017—024—01081—2 $7.00 NTIS PB #81—238875 $23.50

29 DRUG ABUSE DEATHS IN NINE CITIES: A SURVEY REPORT. Louis A.

Gottschalk, M.D., et al. Not available from NCDAI.

GPO Stock #017—024—00982—2 $6.50 NTIS PB #80—178882 $17.50

30 THEORIES ON DRUG ABUSE: SELECTED CONTEMPORARY PERSPECTIVES.

Dan J. Lettieri, Ph.D.; Mollie Sayers; and Helen Wallenstein

Pearson, eds. Volume presents summaries of major contemporary

theories of drug abuse by each of 43 leading theorists.

GPO Stock #017—024—00997—1 $10.00 Not available from NTIS

31 MARIJUANA RESEARCH FINDINGS: 1980. Robert C. Petersen, Ph.D., ed. The text of the

8th Marijuana and Health report to Congress and the background scientific papers on which it

was based. GPO out of stock NTIS PB #80—215171 $20.50

32 GC/MS ASSAYS FOR ABUSED DRUGS IN BODY FLUIDS. Rodger L. Foltz, Ph.D.;

Allison F. Fentiman, Jr., Ph.D.; and Ruth B. Foltz. A collection of methods for quantitative

analysis of several important drugs of abuse by gas chromatography— mass spectrometry.

GPO Stock #017—024—01015—4 $6.00 NTIS PB #81—133746 $19

33 BENZODIAZEPINES: A REVIEW OF RESEARCH RESULTS, 1980. Stephen

I. Szara, M.D., D.Sc. , and Jacqueline P. Ludford, M.S., eds.

A RAUS (Research Analysis and Utilization System) Review Report

on the abuse liability of the benzodiazepine “tranquilizers.”

GPO Stock #017—024—01108—8 $5.00 NTIS PB #82—139106 $13

34 PROBLEMS OF DRUG DEPENDENCE, 1980: PROCEEDINGS OF THE 42ND

ANNUAL SCIENTIFIC MEETING, THE COMMITTEE ON PROBLEMS OF DRUG

DEPENDENCE, INC. Louis S. Harris, Ph.D.. ed. Not available from

NCDAI.

GPO Stock #017—024—01061—8 $8.00 NTIS PB #81—194847 $34

35 DEMOGRAPHIC TRENDS AND DRUG ABUSE, 1980—1995. Louise G. Richards, Ph.D.,

ed. Estimates of probable extent and nature of nonmedical drug use, 1980—1995, based on age

structure and other characteristics of U.S. population.

GPO Stock #017—024—01087—1 $4.50.NTIS PB #82—103417 $13
112

36 NEW APPROACHES TO TREATMENT OF CHRONIC PAIN: A REVIEW OF MULTI

DISCIPLINARY PAIN CLINICS AND PAIN CENTERS. Lorenz K.Y. Ng, M.D.

ed. Discussions by active practitioners in the treatment of pain.

GPO Stock #017—024—01082—1 $5.50.NTIS PB #81—240913 $19

37 BEHAVIORAL PHARMACOLOGY OF HUMAN DRUG DEPENDENCE. Travis

Thompson, Ph.D., and Chris E. Johanson, Ph.D., eds. Presents a growing body of data,

systematically derived, on the behavioral mechanisms involved in use and abuse of drugs.

GPO Stock #017—024—01109—6 $6.50 NTIS PB #82—136961 $25

38 DRUG ABUSE AND THE AMERICAN ADOLESCENT. Dan J. Lettieri, Ph.D., and

Jacqueline P. Ludford, M.S. , eds. A RAUS Review Report, emphasizing use of marijuana:

epidemiology, soclo— demographic and personality factors, family and peer influence,

delinquency, and biomedical consequences.

GPO Stock #017—024—01107—0 $4.50 NTIS PB #82—148198 $14.50

39 YOUNG MEN AND DRUGS IN MANHATTAN: A CAUSAL ANALYSIS. Richard R.

Clayton, Ph.D., and Harwin L. Voss, Ph.D. Examines the etiology and natural history of drug use,

with special focus on heroin. Includes a Lifetime Drug Use Index.

GPO Stock #017—024—01097—9 $5.50 NTIS PB #82—147372 $19

40 ADOLESCENT MARIJUANA ABUSERS AND THEIR FAMILIES. Herbert Hendin, M.D.,

Ann Pollinger, Ph.D., Richard Ulman, Ph.D., and Arthur Carr, Ph.D. A psychodynamic study of

adolescents involved In heavy marijuana use, to determine what interaction between family and

adolescent gives rise to drug abuse.

GPO Stock #017—024—01098—7 $4.50 NTIS PB #82—133117 $13

41 PROBLEMS OF DRUG DEPENDENCE, 1981: PROCEEDINGS OF THE 43RD

ANNUAL SCIENTIFIC MEETING, THE COMMITTEE ON PROBLEMS OF DRUG

DEPENDENCE, INC. Louis S. Harris, Ph.D., ed. Not available from

NCDAI.

Not available from GPO NTIS PB #82—190760 $41.50

42 THE ANALYSIS OF CANNABINOIDS IN BIOLOGICAL FLUIDS. Richard L. Hawks,

Ph.D., ed. Varied approaches to sensitive, reliable, and accessible quantitative assays for the

chemical constituents of marijuana, for researchers. Not available from NCDAI.

GPO Stock #017—024—01151—7 $5 NTIS PB #83—136044 $1643

43 PROBLEMS OF DRUG DEPENDENCE, 1982: PROCEEDINGS OF THE 44TH

ANNUAL SCIENTIFIC MEETING, THE COMMITTEE ON PROBLEMS OF DRUG

DEPENDENCE, INC. Louis S. Harris, Ph.D., ed. Not available from

NCDAI.

GPO Stock #017—024—01162—2 $8.50 NTIS PB #83—252—692/AS $40
113

51 DRUG ABUSE TREATMENT EVALUATION: STRATEGIES, PROGRESS, AND

PROSPECTS. Frank N. Tins, Ph.D., ed. A state—of—the—art review of drug abuse treatment

evaluation, identifying research needs, promising approaches, and emerging issues.

GPO Stock #017—020—01218—1 $4.50 NTIS PB 85—150365/AS $17.50

52 TESTING DRUGS FOR PHYSICAL DEPENDENCE POTENTIAL AND ABUSE

LIABILITY. Joseph V. Brady, Ph.D., and Scott E. Lukas, Ph.D., eds. Describes animal and

human test procedures for assessing dependence potential and abuse liability of Opioids,

stimulants, depressants, hallucinogens, cannabinoids. and dissociative anesthetics.

GPO Stock #017—024—0204—1 $4.25 NTIS PB 85—150373/AS $16

54 MECHANISMS OF TOLERANCE AND DEPENDENCE. Charles Win. Sharp, Ph.D.. ed.

Review of basic knowledge concerning the mechanism of action of opiates and other drugs in

producing tolerance and/or dependence.

GPO Stock #017—024—01213—1 $8.50 NTIS PB No. to be assigned.

55 PROBLEMS OF DRUG DEPENDENCE, 1984. PROCEEDINGS OF THE 46TH

ANNUAL SCIENTIFIC MEETING, THE COMMITTEE ON PROBLEMS OF DRUG

DEPENDENCE, INC. Louis S. Harris, Ph.D., ed.

IN PRESS OR PREPARATION

53 PHARMACOLOGICAL ADJUNCTS IN SMOKING CESSATION. John Grabowski, Ph.D.,

ed.

56 ETIOLOGY OF DRUG ABUSE: IMPLICATIONS FOR PREVENTION. Coryl LaRue Jones,

Ph.D., and Robert J. Battjes, D.S.W., eds.

57 SELF—REPORT METHODS OF ESTIMATING DRUG USE: MEETING CURRENT

CHALLENGES TO VALIDITY. Beatrice A. Rouse, Ph.D., Nicholas J.

Kozel, M.S. , and Louise G. Richards, Ph.D., eds.

58 PROGRESS IN THE DEVELOPMENT OF COST—EFFECTIVE TREATMENT FOR

DRUG ABUSERS. Rebecca S. Ashery. D.S.W. , ed.

60 PRENATAL DRUG EXPOSURE: KINETICS AND DYNAMICS. C. Nora Chiang, Ph.D.,

and Charles C. Lee, Ph.D., eds.