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A
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POSTNEONATAL MENTAL AND MOTOR
DEVELOPMENT OF INFANTS EXPOSED IN UTERO
TO OPIOID DRUGS
SYDNEY L. HANS
Department of Psychiatry, The University of Chicago
RITA J. JEREMY
Department of Pediatrics, The University of California, San Francisco
ABSTRACT: We compared the mental and motor development of 33 infants from innercity, African American families whose mothers used opioid drugs during pregnancy with that of 45 infants from demographically comparable families where the mothers were not users of opioids. We found that during the
first 2 years of life, the children exposed to opioid drugs showed poorer functioning on Bayley Scales
mental and psychomotor development indices as well as on Infant Behavior Record ratings of mental
and motor functioning. Although both groups of children performed in the normal range during infancy,
both groups showed sharp declines in their developmental scores during the second year of life relative
to norms. The poorer performance of the opioid-exposed group in mental development was related to
social-environmental risk factors; in psychomotor development, to reduced birth weight.
RESUMEN: En este estudio se comparó el desarrollo mental y motor de 33 infantes que provenı́an de
familias afro-norteamericanas de barrios pobres del centro de la ciudad y cuyas madres habı́an usado
drogas similares al opio durante el embarazo, con 45 infantes de familias demográficamente comparables
donde las madres no usaron tales drogas. Encontramos que durante los dos primeros años de vida, los
niños expuestos a dichas drogas mostraron un funcionamiento más débil en los ı́ndices de desarrollo
mental y sicomotor de las Escalas Bailey, ası́ como en las clasificaciones de funcionamiento mental y
motor de la Trayectoria de Comportamiento Infantil (Infant Behavior Record). Aunque ambos grupos de
niños actuaron dentro de lo normal durante la infancia, los dos mostraron una declinación fuerte en cuanto
a los puntajes de desarrollo durante el segundo año de vida, en lo relativo a las normas. La más débil
actuación del grupo de niños expuestos a estas drogas en lo que respecta al desarrollo mental fue relacionada con factores de riesgo socio-ambientales; y en cuanto el desarrollo sicomotor, al bajo peso al
momento del nacimiento.
Data for this article were collected with the support of grant PHS 5 R01 8 DA-01884 from the National Institute on
Drug Abuse. While preparing this article, the first author was supported by grant R01 DA05396-01A1 from the
National Institute on Drug Abuse. We thank Wendy Rabinowitz, Susan Lutgendorf, Karen Freel, and Ora Aviezer for
their assistance in collecting the data; and Joseph Marcus, Carrie Patterson, Victor Bernstein, and Linda Henson for
their support throughout the conduct of this study and preparation of this article. Direct correspondence to: Sydney
L. Hans, Department of Psychiatry, MC3077, 5841 S. Maryland Avenue, Chicago, IL 60637; phone: (773) 702-6313;
fax: (773) 702-5352.
INFANT MENTAL HEALTH JOURNAL, Vol. 22(3), 300– 315 (2001)
䊚 2001 Michigan Association for Infant Mental Health
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RÉSUMÉ: Nous avons comparé le développement mental et moteur de 33 enfants en très bas âge issus de
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quartiers très défavorisés, de familles noires américaines dont les mères utilisèrent des drogues dérivées
de l’opium durant leur grossesse avec 45 enfants en très bas âge issus de familles à la démographie
comparable, et dont les mères n’utilisèrent pas de drogues dérivées de l’opium durant leur grossesse.
Nous avons trouvé que durant les deux premières années de la vie, les enfants exposés à des drogues
dérivées de l’opium réussissaient bien moins bien aux indices de développement mental et psychomoteur
de l’Echelle de Bayley et réussissaient également bien moins bien pour ce qui concerne les scores de
fonctionnement mental et moteur du Niveau de Comportement du Nourrisson (Infant Behavior Record
en anglais). Bien que les deux groupes d’enfants se comportèrent normalement durant la toute petite
enfance, les deux groupes firent preuve de très fortes baisses dans leur scores comportemental durant leur
deuxième année, comparé aux normes. La plus mauvaise performance (en développement mental) du
groupe exposés aux drogues dérivées de l’opium était liée à des facteurs de risques du milieu social, et,
pour ce qui concerne le développement psychomoteur, à un poids à la naissance très bas.
ZUSAMMENFASSUNG: Wir verglichen die geistige und motorische Entwicklung von 33 Kleinkindern aus
innenstädtischen, afroamerikanischen Familien in denen die Mütter Opiate während der Schwangerschaft
eingenommen hatten, mit demographisch vergleichbaren Familien von 45 Kindern, deren Mütter keine
Opiate einnahmen. Wir fanden, dass in den ersten zwei Lebensjahren die Kinder, die Opiaten ausgesetzt
waren, schlechtere Werte der geistigen und psychomotorischen Entwicklungsparametern auf der Bayley
Skala hatten, sowohl als auch in der geistigen und motorischen Funktionen, gemessen mit dem KleinkindVerhaltens-Bogen. Obwohl beide Gruppen von Babys im ersten Lebensjahr dieselbe Leistung zeigten,
hatten beide Gruppen starke Abfälle in ihren Entwicklungsparametern im zweiten Lebensjahr im Vergleich zu den Normen. Die schlechteren Ergebnisse der opiat-ausgestzten Gruppe im Bezug auf die
geistige Entwicklung kann in Beziehung gesetzt werden zu sozial— umweltbedingten Risikofaktoren; bei
der psychomotorischen Entwicklung zu dem geringeren Geburtsgewicht.
*
*
*
Abuse of alcohol and drugs during pregnancy is an issue of great public concern in the
United States (e.g., Kantrowitz, 1990; Toufexis, 1991). Yet, most research on this topic has
focused on the use of alcohol and cocaine during pregnancy.
The present article addresses the impact of maternal opioid abuse on early child development. Abuse of opioid drugs — the drugs that pharmacologically are related to morphine —
is a longstanding social problem in the United States (cf. Zagon & McLaughlin, 1984). While
opioid addiction decreased during the recent cocaine epidemic, there has been a resurgence of
opioid use as part of the historically cyclical nature of drug abuse in this country (Frank &
Galea, 1996; Musto, 1987). For most of the 20th century, American opioid abuse primarily
involved illicit heroin, intravenously injected (Kinlock, Hanlon & Nurco, 1998). Recently, as
purer, inhalable forms of heroin have been introduced, a new generation of heroin users has
emerged (Martin, Hecker & Clark, 1991). A large proportion of heroin addicts are from lower
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socio-economic strata, and their drug abuse further depletes their limited physical, medical,
and social-emotional resources. As users of illicit drugs, heroin users must structure their
lifestyles around drug procurement, and usually resort to illegal activities to support their habits.
Since the mid-1970s, chronic heroin addicts who seek treatment in the United States have
often been admitted to government-funded methadone maintenance programs where they receive free daily oral doses of methadone, a synthetic opioid (cf. Hutchings, 1985; Parrino,
1993; Payte, 1997). Methadone has effects similar to, but longer lasting than those of heroin,
thus making methadone better suited for treatment programs in which medication is administered on a once daily basis. Methadone is generally dispensed in a clinic setting that may also
provide a variety of social services and medical supervision to its clients. In general, people
maintained on methadone lead more stable lives than they did as heroin addicts, and are assured
of better pharmacological control of their addiction.
Opioid drugs easily cross the placenta (Blinick, Inturrisi, Jerez, & Wallach, 1975) and
have effects on the fetus that can be clearly observed during the neonatal period. Numerous
studies of opioid exposure on human fetal growth have found that maternal use of opioid
drugs — even medically supervised use of methadone — is related to lower weight at birth and
to reduced head circumference (reviewed by Hans, 1992). Although maternal opioid use has
generally been confounded with exposure to other drugs (including tobacco and alcohol), poor
quality prenatal care, poor maternal nutrition, and maternal infection, the number of replications
of the basic findings and the similar lowered birth weight in opioid-exposed rat pups (cf. Zagon
& McLaughlin, 1984) suggest that the opioids themselves are at least one contributor to lowered
birth weight in exposed children. Currently, the reduced birth weight and head circumference
are believed to be the result of intrauterine growth retardation rather than premature birth
(Doberczak, Thorton, Berstein, & Kandall, 1987; Kandall, Albin, Gartner, Lee, Eidelman, &
Lowinson, 1977).
Within 1 to 3 days of birth, most infants born to opioid-addicted women show clear clinical
signs of narcotics abstinence — or withdrawal (Desmond & Wilson, 1975; Kandall, 1998;
Pierog, 1977; Zelson, Rubio, & Wasserman, 1971). These signs include a large number of
symptoms of both nonspecific central and autonomic nervous system dysfunction. Among the
more frequently observed medical signs of neonatal abstinence are: poor sleeping, hyperactive
reflexes, convulsions, poor feeding, regurgitation, diarrhea, dehydration, yawning, sneezing,
nasal stuffiness, sweating, skin mottling, fever, rapid respiration, and excoriation of skin. Carefully controlled observational studies of these children using the Neonatal Behavioral Assessment Scale (Brazelton, 1973) have also shown a clear pattern of abnormal neonatal behavior
during the period of withdrawal (Chasnoff, Hatcher & Burns, 1982; Jeremy & Hans, 1985;
Strauss, Lessen-Firestone, Starr & Ostrea, 1975). The replicated evidence from these studies
(reviewed by Hans, 1992) leads to the conclusion that opioid-exposed neonates are much more
easily aroused and aroused to higher levels than other newborns. This pattern of behavior is
similar to the increased irritability reported by adults withdrawing from opioid drugs. In addition, opioid-exposed newborns show poorer motor control (tremulousness and jerkiness) and
higher muscle tonus — both signs of increased CNS irritability and similar to motoric symptoms
reported in adults experiencing narcotics withdrawal. Opioid-exposed neonates are also less
likely to be in alert states during testing, although when alert, the quality of their responsiveness
is normal. Some evidence suggests that neonates who were prenatally exposed to opioids orient
and habituate relatively better to auditory than to visual stimuli, possibly because visual stimuli
require more highly organized states of attentiveness to process effectively.
The dramatic symptoms of neonatal abstinence diminish quickly over the first month of
life until they are clinically nonsignificant (e.g., Jeremy & Hans, 1985). It remains an open
question whether subtle behavioral problems linger past the neonatal period or emerge as
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development progresses. A small number of studies, all using relatively limited sample sizes
with limited statistical power have presented different findings on this issue (reviewed in Hans,
1998). Some studies have concluded that there are no developmental deficits after the neonatal
period due to maternal opioid use (Kaltenbach & Finnegan, 1987; Kaltenbach, Graziani, &
Finnegan, 1979). Most others have reported small differences between exposed and unexposed
children, particularly on aspects of behavior measured through rating scales or other qualitative
techniques (Hans, 1989; Johnson, Diano & Rosen 1984; Rosen & Johnson, 1982; Strauss,
Starr, Ostrea, Chavez, & Stryker, 1976; Wilson, 1989; Wilson, Desmond, & Wait, 1981). There
have been no reports of serious developmental problems attributable to prenatal opioid exposure.
Because most studies of opioid-exposed children, in fact, most studies of children of drugusing parents, have been conducted out of concern for the drug’s potential teratological or toxic
effects, other mechanisms that might explain associations between maternal drug abuse and
child development have generally not been given adequate attention in research on children
exposed to opioids in utero (Aylward, 1982; Hans, 1992; Marcus & Hans, 1982). Other factors
associated with maternal opioid use during pregnancy that could affect child development
include: (a) use of alcohol or nonopioid drugs that could have teratological or toxic effects, (b)
familial behavioral and learning disorders that could be transmitted genetically, (c) pregnancy
and delivery complications, including reduced fetal growth, that may be related to maternal
drug use, and (d) postnatal psychosocial factors, including the effects of poverty, stress, maternal psychopathology, maternal life style, disruptions in maternal care, and direct interaction
with the primary caregiver.
Yet, relatively little attention has been given in empirical studies of prenatal opioid exposure to whether differences between exposed and unexposed children can be attributed to
the direct teratological effects of the drug or whether they might be explained by other factors.
An exception is the work of Johnson, Glassman, Fiks, and Rosen (1987), who found evidence
that drug effects on cognitive and neurological behavior in 3-year-old children were not direct
but related to labor and delivery complications and disorganized family environments.
The present article reports on a longitudinal study of the mental and motor development
during the first 2 years of life of infants exposed prenatally to opioid drugs. The goals of the
article are to discuss as to whether the behavior of infants born to drug-addicted women differs
from that of demographically comparable unexposed children, but, more importantly, to explore
the relation of drug exposure to mental and motor development in conjunction with other risk
factors. In particular, we ask whether any drug effects might be attributable to other variables
that are associated with maternal opioid use, specifically use of other potentially teratogenic
substances, pregnancy and birth complications, and social-environmental factors.
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METHOD
Subjects
This article will report on the development during the first 2 years of life of 33 children who
were exposed prenatally to opioid drugs and a comparison group of 45 infants whose mothers
were not using any opioid drugs during pregnancy.
Between the years of 1978 and 1982, 36 women who used opioid drugs throughout pregnancy were recruited during pregnancy at the prenatal clinics of Chicago Lying-In Hospital.
Drug-using mothers were excluded from the sample who had chronic medical problems such
as diabetes, obvious mental illness, or who were not between the ages of 18 and 35. All women
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at the time of recruitment were participating in methadone-maintenance programs for the treatment of intravenous heroin abuse. Most women had been involved in methadone-maintenance
throughout pregnancy, some had sought treatment during pregnancy. Methadone dosages during pregnancy ranged from 3 to 40 mg per 24-hour period with a mean of less than 20 mg.
These dosing levels are lower than reported in most other studies of prenatal opioid exposure.
During the 4-year recruitment period, the women from the methadone group delivered 42
infants, including one pair of twins. Infants were excluded from this paper who had identifiable
medical conditions impacting their test performance. Data from nine of these infants were not
collected or are not presented in this article for the following reasons: infant death (n ⫽ 4,
including one of the twins), infant who suffered a stroke and could not be administered Bayley
Scales (n ⫽ 1), child with extremely poor Bayley scores who was later diagnosed as autistic
(n ⫽ 1), infants with data missing from more than one of the five assessment ages (n ⫽ 3).
A comparison group of 43 pregnant women who used no opioid drugs was recruited from
the same prenatal clinics. In addition to the age and illness exclusion criteria used for the opioid
group, women were excluded from the comparison group who had any reported history of
opioid or cocaine use, who had a positive urine screen for opioid or cocaine use, or who
consumed more than one drink a day of alcohol. The comparison-group mothers delivered 47
infants during the duration of the recruitment, including one pair of twins. Data from two of
the comparison-group infants were not collected or are not presented in this paper for the
following reasons: infant with cerebral palsy who scored extremely poorly on Bayley Scale
items involving motoric responses (n ⫽ 1) and infants with data missing from more than one
of the five assessment ages (n ⫽ 1).
All women from opioid and comparison groups were African Americans residing in lowincome innercity neighborhoods. All women received regular prenatal care at a university
medical center beginning no later than the second trimester. The drug-using women received
transportation from their homes to prenatal appointments provided by their methadone clinics.
As research participants, women received prenatal ultrasound screening and fetal monitoring
during labor that were not provided as part of routine obstetric practice at the time of the study.
All infants remained with their families after birth. The two groups were similar on age (methadone mean ⫽ 27.1 years, comparison mean ⫽ 25.8), socio-economic status (methadone 58%
Hollingshead level 5; comparison 51% level 5), number of previous children (methadone mean
3.2, comparison mean 2.8), and intelligence (methadone mean ⫽ 89.9, SD ⫽ 12.0; comparison
mean ⫽ 89.7, SD ⫽ 9.8).
Sibling pairs were included in all statistical analyses. No families provided more than two
children for the study. Although inclusion of sibling pairs violates rules of independent sampling, it should be noted that sibling pairs often had quite different mental and motor performance as well as quite different risk profiles because of differences in birth weight, prenatal
exposure patterns, and patterns of parent – child interaction.
The neonatal behavior of these infants was assessed at 3 days and 1 month, and has been
described by Jeremy and Hans (1985). The postneonatal behavior of the infants was followed
longitudinally at 4, 8, 12, 18, and 24 months of age, and will be reported in this article.
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Mental and Motor Outcome Variables
At each of the follow-up ages, infants and their mothers were transported to a laboratory at the
University of Chicago for assessment on the Bayley Scales of Infant Development (Bayley,
1969). Carefully trained and supervised female examiners who were blind to any information
about the mothers’ drug use or infants’ medical history administered the examination. At the
end of each session, examiners were asked to guess whether the child was from the opioid or
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comparison group. It is noteworthy that the examiners’ guesses were not correlated with infants’
actual group membership at any age after the neonatal period.
The Bayley Scales of Infant Development (Bayley, 1969) consist of three parts: mental
and motor sections that evaluate level of performance, and a behavior section that evaluates
the quality of performance. The mental and motor sections are scored on age-normed scales
called the Mental Development Index (MDI) and the Psychomotor Development Index (PDI),
each with a mean of 100 and a standard deviation of 16. The third section, the Infant Behavior
Record (IBR), rates qualitative aspects of the infant’s behavior on a series of nine- and fivepoint items completed by the examiner at the end of the testing session and based on the clinical
impressions made throughout the session. Matheny (1980) has identified factors for consolidating the 27 IBR items; the item composition of these factors was slightly different at different
ages. Following Matheny’s analyses, we identified three subsets of IBR items that we judged
reflected aspects of neurobehavioral functioning, and that had validity across ages and made
sums of those items. The sums were: Attention Sum (object orientation, #8, goal directedness,
#11, and attention span, #12); Activity Level Sum (activity, #14, energy level, #25), and Motor
Coordination Problems Sum (coordination of gross muscle movements, #26, coordination of
fine muscles #27). It should be noted that the IBR gross and fine coordination items are scaled
so that higher scores indicate greater problems.
Three of the subjects followed longitudinally were not administered the Bayley Scales at
the 24-month assessment only. So as not to drop these subjects from statistical analyses involving repeated measures, their MDI, PDI, and IBR sums were estimated by taking a median
of their personal scores at the 18-month assessment and the average scores for the entire sample
at 24 months.
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Measurement of Opioid Exposure
After their recruitment, usually during the third trimester, mothers were interviewed about their
drug-use history with a modified version of the University of Washington Pregnancy and Health
Questionnaire (1974). Urine toxicology screens were conducted at the time the interview was
administered and repeated later during pregnancy. Because mothers’ methadone doses were all
relatively low, and because some mothers occasionally supplemented with illegal opioids
whose use could not be reliably assessed, opioid exposure was coded for this study as a dichotomous grouping variable rather than as a continuous measure of dose level.
Other Relevant Variables
We examined three types of variables that could mediate an association with maternal opioid
use: use of substances other than opioids, environmental factors, and birth weight.
Use of substances other than opioids. While many of the opioid-group women occasionally
used other opioid drugs (primarily heroin and pentazocine), the use of illicit nonopioid drugs
was considerably lower at the time the families were recruited than it is today, and in particular,
the expense of cocaine prevented its frequent use by low-income women. Women’s use of
drugs and alcohol in the past and during the present pregnancy was determined through an
intake interview and a modified version of the University of Washington Pregnancy and Health
Questionnaire (1974). Urine toxicology screening was conducted twice during pregnancy to
verify the self-reports. Based on the mothers’ self-reports, alcohol use was coded into three
categories: abstinence, light to moderate (less than two drinks per day on average), and heavy
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drinking (greater than or equal to two drinks a day). Cigarette use was coded into three categories: abstinence, less than a pack a day, and at least a pack a day. Marijuana use was coded
into four categories: abstinence, irregular use (once a week or less), regular light use (two to
five joints per week), and regular heavy use (five joints or more per week). Cocaine use was
coded into two categories: abstinence and use at least once during pregnancy. Reports were
made separately for prepregnancy and each trimester of pregnancy and were highly intercorrelated across time epoch (e.g., between first and third trimesters, r ⫽ .92 for cigarettes, .83
for marijuana, and .69 for alcohol). Because reports were actually being made during the third
trimester of pregnancy and biochemical verification was available for third trimester reports,
only the third trimester variables were entered into the analyses described below. Exploratory
analyses were conducted examining relations of child behavior to first trimester and prepregnancy substance use patterns and patterns of binge drinking, but are not reported because
patterns of significant findings were not substantially different than those generated from the
third trimester variables.
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Social-environmental risk factors. Because our own previous work and that of others has
indicated that a measure of cumulative social-environmental risk is a more powerful predictor
of child functioning than individual measures of such risk, we computed a social-environmental
risk score. Following from the work of Sameroff and colleagues (Sameroff, Seifer, Barocas,
Zax, & Greenspan, 1987), we did this by dichotomizing and tallying eight social-environmental
risk variables: maternal education, maternal IQ, family socioeconomic status, maternal adaptive
functioning, psychosocial stressors, and maternal behavior in interaction with the infants at 4,
12, and 24 months (see Bernstein & Hans, 1994, for further details of risk score calculation).
A number of the variables that went into this risk score were assessed during prenatal interviews
as follows: maternal education (measured in terms of years of school completed, less than 11
years counted as a risk), family socioeconomic status (measured on the Hollingshead TwoFactor Index of Social Position; Hollingshead & Redlich, 1958; Level 5 counted as a risk),
maternal adaptive functioning (following psychiatric interviewing rated on DSM-III Axis 5,
American Psychiatric Association, 1987, with poor or worse counted as a risk), maternal
stressors (following psychiatric interviewing scaled on DSM-III Axis 4; more than moderate
psychosocial stressors counted as a risk), and maternal intelligence (measured by the full-scale
score from the Wechsler Adult Intelligence Scale; Wechsler, 1955; with IQ less than 85 counted
as a risk). Maternal behavior in interaction with the infant was scored from videotapes at three
ages. When the children were 4, 12, and 24 months old, they were videotaped in interaction
with their caregivers in a laboratory setting in a variety of structured and unstructured situations
that lasted between 15 and 40 minutes. The video sessions were rated on the Parent – Child
Observations Guides for Program Planning (PCOGs) (Bernstein, Percansky, & Hans, 1987) by
raters who resolved their disagreements on each item by consensus. Data on the reliability and
validity for the PCOGS have been reported elsewhere (Bernstein, Hans & Percansky, 1991),
as have findings from the present sample (Bernstein & Hans, 1994). For the present report risk
was determined based on maternal PCOG scores summed across categories at each of the three
ages and dichotomized at a mean split.
Birth weight. Because prenatal opioid exposure has often been related to reduced birth weight,
in particular intrauterine growth retardation, birth weight measured at the hospital was included
as a covariate.
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RESULTS
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Simple Drug Effects
To keep the total number of statistical tests to a minimum and maintain the integrity of the
statistical protection levels, we employed repeated measures analyses. Huynh-Feldt epsilon
statistics and associated p values were examined in each repeated measures analysis to insure
that the assumptions for compound symmetry in repeated measures analyses were not being
violated.
Separate repeated-measures analyses of variance were computed on each of the five types
of outcome variables (MDI, PDI, Attention Sum, Activity Level Sum, and Motor Coordination
Sum) with age (five levels) as the repeated-measure and opioid exposure as the dichotomous
independent variable. There were significant or marginally significant main effects for drug
exposure for MDI, PDI, IBR Attention Sum, and IBR Motor Coordination Sum, but not the
IBR Activity Level Sum. Opioid-exposed children had lower developmental scores, poorer
motor coordination, and were less attentive. There were significant age effects on each of the
five types of Bayley scores. Single degree of freedom polynomial tests of linear order were
significant for each of the age effects. The two age-normed scores, MDI and PDI, dropped
with age relative to norms. For the IBR scores, which are not formally age normed, attention
and activity level increased, and motor problems decreased. There were no significant age by
drug exposure interactions on any of the five analyses. Table 1 presents the Bayley child
behavior means and standard deviations by drug group, and Table 2 presents the results of the
repeated-measures ANOVAS.
Cofactor Analyses
We also analyzed effects on developmental outcomes of potentially confounding variables: use
of four substances other than opioids, cumulative social-environmental risks, and birth weight.
We first examined whether these five variables were related to maternal opioid usage. Table 3
presents the opioid group differences on these variables. Opioid-using mothers were, in fact,
heavier users of tobacco, marijuana, and cocaine. The groups did not differ in terms of alcohol
use; both groups were low consumers of alcohol. Moderate and heavy drinkers had been
excluded from the comparison group and the opioid users tended not to drink heavily. Children
exposed in utero had lower birth weights (although only two were born at less than 37 weeks
gestational age). Opioid-using mothers had higher social-environmental risk scores (although
they differed on only three of the nine individual items that made up the cumulative scores —
adaptive functioning, stressors, and 24-month parenting).
We next computed repeated-measures analyses of covariance (ANCOVAs) on each of the
four neurobehavioral outcome measures that had been related to maternal opioid usage (MDI,
PDI, Attention Sum, Motor Coordination Sum) using opioid exposure as the primary grouping
variable and tobacco, marijuana, alcohol, cocaine, social-environmental risk, and birth weight
as covariates. In each of these analyses, preliminary analyses were conducted to determine
whether the homogeneity of slopes assumption was violated by interaction effects between
opioid exposure and any of the other cofactors. There were no such interaction effects. The
results of these ANCOVAs for each outcome measure follow.
MDI. With the inclusion of the covariates in the model, opioid exposure no longer had a
significant effect on the repeated measures of the MDI. Only one of the covariates — socialenvironmental risk — showed a significant independent relation with MDI; more risk factors
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TABLE 1. Child Behavior Means and Standard Deviations by Age and Drug Group
Age in Months
Mental development
index
Opioid
Comparison
Psychomotor development index
Opioid
Comparison
IBR attention sum
Opioid
Comparison
IBR coordination
problems
Opioid
Comparison
IBR activity level
sum
Opioid
Comparison
12
18
24
Mean
Across Age
4
8
111
(12.3)
114
(15.1)
116
(19.5)
120
(20.2)
107
(14.3)
109
(13.7)
95**
(16.3)
103
(13.1)
92
(12.7)
96
(12.3)
104*
(7.8)
108
(8.3)
116
(12.5)
121
(12.3)
111
(12.4)
111
(12.4)
106
(18.0)
110
(17.7)
105
(17.6)
109
(17.8)
100*
(14.2)
108
(14.9)
108
(9.2)
112
(10.4)
12.8
(3.9)
13.1
(4.2)
17.7
(2.1)
18.0
(2.6)
16.3**
(2.8)
18.2
(2.7)
16.8
(2.5)
17.4
(2.5)
16.5
(3.1)
17.4
(2.5)
16.0*
(1.4)
16.8
(1.6)
6.0
(1.1)
5.8
(1.1)
6.1
(1.2)
5.6
(1.2)
5.8
(1.2)
5.5
(0.9)
5.7
(1.0)
5.4
(1.1)
5.5**
(1.2)
4.7
(1.3)
5.8**
(0.7)
5.4
(0.7)
7.9*
(1.8)
7.0
(1.4)
8.4
(1.8)
8.1
(1.5)
8.6
(1.3)
8.6
(1.7)
8.9
(1.5)
8.9
(1.8)
9.2
(1.5)
8.7
(1.7)
8.6
(1.0)
8.3
(1.0)
* Univariate opioid effect p ⬍ .05.
** Univariate opioid effect p ⬍ .01.
were associated with poorer MDI scores. Figure 1 plots cumulative social-environmental risk
(uncorrected for other variables) by average MDI across the five ages. Using the regression
line as an estimate, the difference between the fewest (0) and greatest (7) number of risk factors
out of a possible nine amounted to approximately 10 points of the Mental Development Index,
about two-thirds of a standard deviation. To explore whether particular components of the
social-environmental risk index were more strongly related to MDI than others, similar repeated
measures analyses were computed substituting each of the eight individual risk components
for the cumulative score. In none of these analyses was an individual social-environmental risk
factor a statistically significant predictor of MDI scores.
PDI. With inclusion of the covariates, there was also no significant effect of opioid exposure
on the PDI. Only one of the covariates — birth weight — showed a significant unique relation
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TABLE 2. Repeated Measures Analyses of Variance without and with Covariates
MDI
F(1,76)
Opioid exposure
Marijuana exposure
Tobacco exposure
Cocaine exposure
Alcohol exposure
Birth weight
Social-environmental
risk
Repeated measure
(age)
4.84*
F(1,70)
0.05
0.86
0.24
0.07
1.87
0.04
4.29*
PDI
F(1,76)
3.25⫹
F(1,70)
0.37
0.41
2.16
0.52
1.92
3.77*
1.51
IBR
Coordination
IBR Attention
Problems
F(1,76) F(1,70) F(1,76) F(1,70)
5.21*
0.00
2.66
3.62⫹
0.22
0.03
0.47
1.89
7.07*
1.57
0.49
0.04
0.29
0.38
2.83⫹
0.94
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IBR Activity
F(1,76) F(1,70)
2.20
1.73
0.51
0.67
0.79
0.05
0.00
2.47
F(4,304) F(4,280) F(4,304) F(4,280) F(4,304) F(4,280) F(4,304) F(4,280) F(4,304) F(4,280)
36.99*** 0.33
14.80*** 2.51*
37.27*** 0.68
7.40*** 1.57
13.72*** 1.71
⫹ p ⬍ .10.
* p ⬍ .05.
*** p ⬍ .001.
TABLE 3. Differences between Opioid and Comparison Groups on Potential Confounding Variables
Group
Opioid
Comparison
n ⫽ 33
15
6
4
8
n ⫽ 45
36
5
4
0
Statistics
␹2(3) ⫽ 15.25**
Marijuana exposure
None
Irregular
Regular
Heavy
Tobacco exposure
None
⬍ Pack per day
ⱖ Pack per day
4
21
8
17
28
0
␹2(2) ⫽ 15.57***
Cocaine exposure
None
At least one time
20
13
45
0
␹2(2) ⫽ 21.3***
Alcohol exposure
None
Light/moderate
Heavy
22
9
2
35
10
0
␹2(2) ⫽ 2.00
2922
3236
(592)
(393)
3.49
1.87
(2.0)
(1.2)
Birth weight in
grams (M and SD)
Social-environmental
risk (M and SD)
** p ⬍ .01.
*** p ⬍ .001.
t ⫽ 2.82**
t ⫽ 4.21***
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FIGURE 1. Scatterplot of social-environmental risk scores by mean Bayley MDI scores averaged
across five ages. Circles signify infants exposed to opioid; squares signify comparison infants. Linear
regression line plotted.
with the repeated measures of PDI; lower birth weight was related to poorer PDI scores. Out
of concern that these results might be unduly affected by the one child whose birth weight
placed him in the the very low birth weight range, the MANCOVA was recomputed excluding
that child, and results were similar. Figure 2 plots birth weight by mean PDI (uncorrected for
other variables) across the five ages. Using the regression line as an estimate, each thousand
grams of birth weight was associated with five PDI points.
FIGURE 2. Scatterplot of birth weight by mean Bayley PDI scores averaged across five ages. Circles
signify infants exposed to opioid; squares signify comparison infants. Linear regression line plotted.
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IBR sums. With inclusion of the covariates, there was also no significant effect of opioid
exposure on the IBR Attention Sum, Motor Coordination Problems Sum, or Activity Level
Sum. Prenatal tobacco exposure showed a trend to be related to poorer attention over age.
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DISCUSSION
In the data presented, children whose mothers used opioid drugs during pregnancy showed
significantly poorer mental and motor development during the first 2 years of life than did a
group of demographically comparable children whose mothers had not used opioid drugs;
opioid-exposed children performed more poorly on both mental and motor development and
on both developmental scores and qualitative ratings scales. However, differences between the
two groups were not large. Average developmental scores for children of drug-using women
were within the normal range and only four points lower than for the comparison group,
although these small lags were detected consistently across ages. Although IBR scores are not
age-normed, the scores for infants in this sample are similar to those reported in the normative
sample (Bayley, 1969). Even though small effects such as these can have major public health
implications, they do not suggest cause for clinical concern in assessing the developmental
potential of any individual infant (Lester, LaGasse, & Seifer, 1998).
Although the data suggest that children with opioid-using mothers are at somewhat greater
risk for poor mental and motor development during the first years of life than their peers whose
mothers were not using drugs, they suggest that such lags are more strongly related to other
factors associated with maternal drug use and that different risk factors may be influencing
different domains of behavior.
It appears that much of the effect of maternal opioid drug use on mental development of
infant offspring is attributable to the experience of more social-environmental risk factors by
children in substance-abusing families. Many of the social risk factors experienced by the
opioid-exposed infants in the present sample were ones shared with the comparison group, but
they also included a particularly high incidence of maternal psychopathology and insensitive
parenting (Hans, 1999; Hans, Bernstein & Henson, 1999). Other studies have suggested that
home environment may be the source of the relation between maternal drug use and child
mental development (Azuma & Chasnoff, 1993; Johnson et al., 1987). The children in the
present sample whose mothers used opioid drugs were more likely to experience multiple
social-environmental risk than other low-income children, and this cumulation of risk factors
was related to mental development as assessed on the Bayley Scales. In this sample, a composite
of risk factors is a better predictor of functioning than any particular risk factor. Other studies
of high-risk children have also found cumulative social-environmental risks to be more powerful predictors of early mental development than specific risk factors (Liaw & Brooks-Gunn,
1994; Sameroff et al., 1987).
The impact of high-risk environments on children in this study was also reflected in the
steady drop in mental performance during the second year of life by both groups of children
relative to age adjusted norms. It is important to note that the decline over age in both groups
of children from urban, low-income families was far greater than the differential performance
related to opioid exposure. Numerous other studies exploring issues of poverty, low maternal
education, and low birth weight have also reported similar patterns of slowed acquisition of
mental developmental milestones beginning in the second year of life (cf. Aylward, 1992). A
decline in Bayley MDI scores during the second year of life has been found in methadoneexposed and nonexposed groups in other samples (Johnson et al., 1984; Kaltenbach & Fin-
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negan, 1979; Wilson, 1989). It should be noted that the present study did not use the more
recently normed Bayley Scales of Infant Development II (Bayley, 1993) for assessment.
Whereas opioid exposure effects on MDI were attributable to social-environmental factors,
we found opioid exposure effects on PDI and IBR ratings of motor coordination problems
were mediated by birth weight. Other studies of drug-exposed children have suggested that
some effects of prenatal exposure may be mediated by low birth weight (Brown, Bakeman,
Coles, Sexson, & Demi, 1998; Lester et al., 1991;). It has been repeatedly documented in
human and animal research that maternal opioid use is associated with decreased birth weight
(Hans, 1992), and more so with intrauterine growth retardation than with prematurity. The
mechanism by which opioids lead to reduced growth in some infants remains unclear, although
evidence from preclinical studies suggests that it is probably not undernutrition (cf. Zagon &
McLaughlin, 1992). Others have suggested that prenatal opioid exposure is associated with a
reduction in organ cell number, rather than cell size, suggesting a mechanism early in pregnancy
(Doberczak et al., 1987; Naeye, Blanc, Leblanc, & Khatamee, 1973). The present study offers
little toward an understanding of causal factors involved in growth retardation associated with
prenatal opioid exposure. However, that growth retardation in utero would be related specifically to neuromotor findings is consistent with others studies of infants affected by intrauterine
growth retardation (Tomchek, Lane, & Ottenbacher, 1997).
The data presented here suggest that maternal opioid use during pregnancy is associated
with a variety of types of infant outcomes, and that in the absence of other social-environmental
risk factors or low birth weight, maternal opioid use does not have a major impact on aspects
of development assessed on standardized infant tests. The mental and motor development of
opioid-exposed children — although slightly poorer than that of nonexposed and declining a
little during the second year of life — still remains within the normal range of functioning
during infancy. Altogether, our findings suggest that prenatal exposure to opioids under medically controlled conditions should not be a source of public alarm. On the other hand, our data
do not address the risks of continued unsupervised opioid use throughout pregnancy, particularly when injected intravenously. In addition, mothers; methadone dose levels in the present
study were considerably lower than those typically dispensed at methadone clinics currently
(cf. D’Aunno, Folz-Murphy & Lin, 1999). Research has clearly documented that higher doses
of methadone are more effective deterrents against relapse (Ball & Ross, 1991), and no research
has documented whether higher levels of exposure are related to greater infant problems, as is
typically the case for teratogenic substances (Vorhees, 1986). The present study, because it
found little relation between cocaine and alcohol use with infant outcomes, should also not be
used to conclude that use of these substances is safe during pregnancy, because usage levels
in the present sample were very low, and quantification of them was relatively crude.
Another limitation of the present study is its reliance on a standard developmental assessment tool. Because the Bayley Scales assess development from a variety of domains, it may
not be as sensitive as other measures to teratological effects that are focused on particular
functional abilities. Narrow-band tests are more likely to detect specific functional deficits,
which in turn, will provide better information about the brain mechanisms underlying toxic
exposures as well as potential interventions for helping children with such exposures (Jacobson
& Jacobson, 1996).
These data provide further evidence of the importance of the environment on child development. From a policy point of view, they suggest that focus should be placed both on
increasing access to and quality of prenatal care for women who use drugs, and — critically
important — complementing it by improving the rearing environments of their drug-exposed
children.
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