This study is the first to document human dose-response effects of in utero cocaine exposure on the neurobehavioral performance of the infant.7,8,35
In this sample, after controlling for covariates, heavier maternal use of cocaine was associated with poorer regulation of arousal (ie, state regulation and excitability) late in the newborn period but not in the immediate postpartum period. Significant dose effects were found in this sample of infants for habituation and motor performance in the immediate postpartum period and later in the newborn period for reflexes and autonomic stability, as well as on the supplementary qualifier items, but these effects disappeared when potentially confounding variables were controlled for analytically.
The study’s prospective, longitudinal design overcomes, at least in part, many of the methodological problems of earlier research. Examiners were masked to exposure status. Importantly, the sample represents the spectrum of the cocaine-using population of medically indigent, English-speaking women in Boston. The sample was drawn from a general obstetric population of mothers, and the newborns were clinically healthy, full-term, and free of heroin, methadone, barbiturates, phencyclidine, and amphetamines. The sample is not biased against heavier cocaine users, who may not enroll in prenatal care7,36,37
or who do not give birth in hospitals. In Boston virtually all women receive prenatal care and give birth in hospitals. Of course, some of the heaviest using mothers may still have been missed. Missing the heaviest users might have occurred if one were to assume that they are more likely to refuse to participate, even though refusers and compilers did not differ with respect to demographic or clinical characteristics. However, were such a bias to occur, it would work against finding dose-related effects.
Thus, heterogeneity of the amount of use, as indicated by the newly developed composite index based on self-reports and meconium assays,22
was large enough to detect dose-related neurobehavioral effects, even though meconium measurement has been generally thought to be only an all-or-none measurement. Although unmeasured confounders may have affected neurobehavioral performance, the finding of significant dose-response effects after controlling for many covariates suggests a specific effect of cocaine on newborn neurobehavioral performance. Indeed, the dose-response relationships found are likely to underestimate the effects of prenatal exposure because of the exclusion of preterm, IUGR, and other at-risk infants from the sample and the possibility that some of the heaviest-using mothers were still missed.
The emergent independent effects of cocaine at 3 weeks postpartum on state regulation and excitability reflect an impairment in the infant’s ability to modulate arousal. These effects are not likely to be attributable to the direct acute exposure of the infant after delivery. First, cocaine-using women are routinely discouraged from breastfeeding at Boston City Hospital, so that direct mother-to-infant transfer of cocaine is likely to end at delivery, with the exception of passive postnatal exposure. Second, after in utero exposure, cocaine metabolites clear the newborn’s body in 7 days, as assessed by RIA methods.3
Third, if the effect seen were attributable to acute infant intoxication, one would expect to see other neurobehavioral effects. These effects were not observed. Fourth, similar to other studies,5,17
effects are seen late rather than early in the newborn period.
These late-emerging neurobehavioral effects might be expected if in utero cocaine exposure is associated with evolving neuroanatomic damage38
or disruption of the neurotransmitter systems (eg, the mono-aminergic system, which is thought to control the modulation of arousal and attention).37,39
Dysfunction of this or other systems might result in the observed effects and even an infant withdrawal syndrome. Little in these findings supports the hypothesis that the exposed newborn’s neurobehavior is compromised because of IUGR, for two reasons: (1) the effects of cocaine persist after controlling for birth weight adjusted for gender and gestational age4,6
; and (2) IUGR was not associated with the depression cluster among the cocaine-exposed infants, as Lester and Tronick4
have hypothesized and found in previous research,9,28
The habituation effect found in this study replicates and extends previous findings.10,11
This effect was no longer significant after controlling for confounders, as was the case in other studies.7,10,11
Similarly, as in other studies,17,40
the significant associations of in utero cocaine exposure with 3-week motor, reflex, and autonomic stability clusters were no longer significant after controlling for covariates. Thus, these effects could not be specifically attributed to cocaine but, rather, are related to other risk factors, such as maternal anesthesia, alcohol, birth weight, and prenatal risk.4,5,17
The effects of a combination of factors are evident in the findings for the NBAS supplementary qualifier items. These clinical judgments demonstrate that exposed newborns at both the early and late examinations were judged to have less regulatory capacity, poorer state regulation, poorer motor tone, and less responsivity than the nonexposed infants. Moreover, the exposed infants were more difficult to examine and less rewarding to the examiner. However, unlike the findings for the specific neurobehavioral items, the clinically recognizable differences for the supplementary qualifier items were not statistically significant after adjusting for covariates. Clinicians correctly judge cocaine-exposed infants to have poorer functional status than unexposed infants, but it is incorrect simply to attribute their dysfunction to maternal cocaine use. Rather, these findings indicate that cocaine exposure is a marker for a number of other adverse lifestyle factors that contribute to the infant’s poorer functioning. Thus, the clinician needs to consider not only cocaine, but these other factors when managing the care of the exposed mother and her infant.
Caution must be exercised in generalizing these results to other populations in which the mix of risk factors and other exposures may be different from those reported here. Moreover, it is important to note that although neurobehavioral effects were found that were consistent with previous reports, several domains of newborn functioning, (eg, orientation), were unaffected. With the exception of the dose-response relationships for excitability and state regulation at 2 to 3 weeks, which indicate specific neonatal neurobehavioral effects of maternal cocaine use, other domains of neurobehavioral functioning of even the heavily exposed infants were indistinguishable from the those of the unexposed infants.14
For the pediatric provider, prenatal cocaine exposure should serve as a flag that the infant is likely to show clinically detectable compromised neurobehavioral status throughout the newborn period. These characteristics make the infants both more sensitive to disruptive care giving and more difficult to care for, leading to a self-reinforcing process that may exacerbate initial neurobehavioral impairments. Thus, in utero cocaine exposure needs to be prevented. However, when prevention fails, intervention with the care giver-child dyad can be beneficial in limiting further neurobehavioral dysfunction caused by the disruption of mutual regulatory processes that determine extrauterine development.9
In summary, this research documents a dose-related association between the level of in utero cocaine exposure and neurobehavioral performance during the late newborn period. In addition, our findings indicate that a combination of other factors, including cocaine, compromises newborn neurobehavioral performance. In utero cocaine exposure thus has a measurable effect on the exposed newborn’s emerging neurobehavioral capacity to regulate arousal. It is not known whether this problem progresses developmentally, but it would be critical to know its course, because regulation of arousal and attention is critical to learning. Longitudinal studies focusing on the development of infants’ capacity to regulate arousal and attention are warranted, especially in the context of social interaction.9