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Scientists are just beginning to understand the subtle way in which fetal cocaine exposure affects subsequent neurobehavioral development, according to panelists at a conference held by the New York Academy of Sciences last month in Washington, D.C.
Cocaine exposure at levels normally experienced by humans does not create dramatic deformities or drastic decrements in brain development, despite the sensational stories that blanketed the popular press several years ago, panelists observed. But there is growing evidence that prenatal exposure may lead to subtle but significant decrements in neurobehavioral development.
Steven Hyman, M.D., director of the National Institute of Mental Health (NIMH), summed up the challenges faced by researchers trying to unravel the interwoven matrix of variables affecting the human fetus in the real world as opposed to laboratory rats undergoing drug testing. Drugs, observed Hyman, "are much easier to experiment with than things like context."
Although there is growing evidence of cocaine’s harmful impact on the fetus, Hyman added, "I don’t want to be nightmarishly deterministic" or to suggest that "once you’ve derailed this [developmental] train, that’s it."
Herbert Kleber, M.D., is a member of APA’s Council on Addiction Psychiatry. He spoke with Psychiatric News about the implications of the conference.
"In the 1980’s there was major concern - exaggerated - that fetal cocaine exposure during pregnancy led to irreparable damage," remarked Kleber. As more research was done indicating the complexity of the interaction between cocaine, poverty, malnutrition, poor prenatal care, and use of other substances including alcohol and tobacco, "the pendulum swung too far in the other direction and people were saying ‘there’s no evidence these crack babies are for real; it’s another hype of the drug war.’ Hopefully, what we’re seeing now is the pendulum swinging back to the middle."
That middle is defined by several concepts, according to Kleber. One is that "cocaine use during pregnancy is harmful to the fetus, although at times it’s hard to separate that harm from other factors in the mother’s life."
Another equally important concept is that "some of the effects can be compensated for by appropriate postnatal care." There are "real effects," Kleber added, but this does not imply that cocaine-exposed infants are hopeless.
What is most convincing to Kleber is that the changes seen in humans after prenatal cocaine exposure are "consistent with what one would predict with knowledge of cocaine’s effects on the brain" and "similar to those changes found in laboratory animals experimentally subjected to cocaine in utero."
Obstetrician James Woods Jr., M.D., who runs a perinatal clinic, has observed birth complications that he believes are at least partially a result of cocaine use. At this juncture, said Woods, it is impossible to induce from particular observed incidents the general impact cocaine may have over the long run.
He believes that scientists may find answers by focusing on the first trimester, during which the human fetus has highly permeable skin. This permeability implies that the fetus may be bathed internally in an amniotic cocaine solution following maternal cocaine use. Amniotic processes clear cocaine very slowly. This prolongs fetal exposure during this period, which is known to be critical to fetal neurotransmitter formation, Woods explained.
Janina Galler, M.D., is a professor of psychiatry and public health and director of the Center for Behavioral Development and Mental Retardation at Boston University School of Medicine. Galler’s research in rats has focused on distinguishing the developmental effects of prenatal cocaine exposure from those of prenatal malnutrition.
Her research team gave female rats cocaine at a dosage of 30 milligrams per kilogram twice weekly for five weeks prior to pregnancy. From day 3 to day 18 of pregnancy the rats received a daily injection of 30 milligrams per kilogram. "We picked a dose that minimized mortality and gross fetal deformity," she explained.
"One of the problems with the animal literature is that the doses given are very, very high. It is extremely unlikely that humans would be chronically exposed to such doses," she noted.
The cocaine-exposed rat pups were compared with a group subjected to malnutrition in utero and a group subjected to both malnutrition and cocaine in utero.
To Galler’s surprise, the research team found that the adverse effects of malnutrition and cocaine were largely independent, not synergistic. "We were surprised about that," she remarked.
Cocaine independently impacted activity levels. "The cocaine-exposed animals were significantly less active than the non-cocaine exposed," said Galler. Malnutrition did not affect overall activity levels, but it had a clear adverse effect on pups’ homing ability, that is, their ability to find their way back to a nest scented with the smell of their mother and litter mates. Malnutrition also harmed performance in various maze tests.
The only area where there was negative synergy between cocaine and malnutrition was in the appearance of developmental milestones, including the righting reflex, cliff avoidance, and auditory startle, said Galler.
"The bottom line is that there clearly are effects. There’s not a lot of evidence of synergistic effects other than early development of reflexes. And both cocaine and malnutrition, in animal models in very controlled circumstances, have adverse effects."
How should these complex and subtle findings be reflected in policy? Rather than condemning mothers and demonizing children, "policy, particularly if a child has been exposed [to cocaine], needs to emphasize comprehensive care for these kids, including a supportive rearing environment. These kids are growing up in environments where they are not getting what they need emotionally and nutritionally. There’s a lot of deprivation; there’s a high percentage of infectious diseases," said Galler.
While "we all agree that it’s important to try to discourage cocaine use by pregnant women, it is equally important to focus on enriching the prenatal and postnatal environments in other respects."
That includes ensuring that children get good nutrition and aren’t "just left in front of the TV," Galler added.
Pediatrician Deborah Frank, M.D., of the Boston University School of Medicine admonished the gathering of distinguished scientists not to jump to conclusions about what is attributable to prenatal cocaine exposure versus a variety of potentially negative environmental variables to which cocaine-exposed infants are often also exposed. Frank and colleagues conducted a meta-analysis of nine studies on cocaine-exposed infants using several widely accepted measures including the Brazelton Neonatal Behavioral Assessment Scale (BNBAS). There was little agreement in the findings, she noted.
Based on her analysis, said Frank, she concluded that the effects of cocaine exposure are dose related, inconsistent, and not drastic.
Flashing magazine covers from several years ago when the mass media were depicting cocaine-exposed children as "a demonic biological underclass," she cautioned that it is far easier to sensationalize the effects of illicit drugs than to explain subtlety, nuance, and the complexity of variables that influence neurobehavioral development.
Gale Richardson, Ph.D., of the Western Psychiatric Institute and Clinic at the University of Pittsburgh is conducting a longitudinal study of cocaine-exposed children and has accumulated data on her cohort through age 3. She began following 325 pregnant women beginning in their fourth or fifth month and has reevaluated their children at intervals at birth, one year, and three years. She has had an extremely high follow-up rate of 95 percent.
A possible confounder is that infants prenatally exposed to cocaine were also likely exposed to alcohol and nicotine in utero, Richardson cautioned. Another confounder is that the home environment of cocaine-exposed infants continued to be less stimulating through the first three years of follow-up compared with that of the mothers who did not use cocaine. Hence decrements may be increased by lack of environmental stimulation and maternal use of other substances.
At one year, Richardson found the cocaine-exposed children were rated more fussy and difficult and less adaptable than nonexposed children by both their mothers and independent, blinded raters. Children showed a shorter attention span, more restlessness, and other behavioral difficulties. Similar findings continued through age 3.
"We believe the image of the crack baby as depicted in the media is not accurate," said Richardson. "However, there are subtle effects" from prenatal cocaine exposure. "The cocaine effects that we see are small - you wouldn’t notice them in any one child in the clinic."
Panel moderator Theodore Slotkin, Ph.D., a pharmacologist from Duke University Medical Center in Durham, N.C., commented that "because this is such a politically visible issue," it is likely that bad studies may be picked up and amplified by the news media, obscuring the facts.
NIMH’s Hyman remarked that "what we’ve heard today reminds us that there is a panoply of potentially relevant mechanisms. What we are calling ‘confounders’ are all part of the mix" affecting neuro-behavioral development.