Prenatal Drug Exposure and Drug-Abusing Environments

Research Findings from February, 2004 Director's Report

This section lists selected summaries from NIDA funded research projects that investigate the consequences of prenatal drug exposure. The summaries provided were selected from recent issues of the Director's Report to the National Advisory Council on Drug Abuse. For a more comprehensive listing of NIDA funded projects see the Director's Report.

Marijuana and Pregnancy

Earlier studies from Dr. S.K. Dey's laboratory has shown that in a mouse model, anandamide, an endogenous cannabinoid ligand, and its receptors play an important regulatory role in the establishment of normal pregnancy and these effects are dose and stage-specific as lower levels of endocannabinoids and CB receptors were found to be beneficial for implantation while higher concentrations were detrimental to this process. In a recent paper, they demonstrate that anandamide within a very narrow range regulates blastocyst function and implantation by differentially modulating mitogen-activated protein kinase (MAPK) signaling and Ca++ channel activity via CB1 receptors. Anandamide at a low concentration induces extracellular regulated kinase (ERK) phosphorylation and nuclear translocation in trophectoderm cells without influencing Ca++ channels, and renders the blastocyst competent for implantation in the receptive uterus. In contrast, anandamide at a higher concentration inhibits Ca++ channel activity and blastocyst competency for implantation without influencing MAPK signaling. These studies utilized genetic, pharmacological and physiological approaches to uncovering a potentially important regulatory mechanism for synchronizing blastocyst and uterine competency to implantation. This observation in addition to advancing our basic knowledge has high clinical relevance as elevated levels of anandamide could induce spontaneous early pregnancy losses in women who smoke marijuana. Wang, H., Matsumoto, H., Guo, Y., Paria, B.C., Roberts, R.L. and Dey, S.K. Differential G-protein Coupled Cannabinoid Receptor Signaling by Anandamide Directs Blastocyst Activation for Implantation. Proc Natl Acad Sci., pp. 14914-14919, 2003.

Maternal Vaccination Against Nicotine Reduces Nicotine Distribution to Fetal Brain in Rats

Vaccination of adult male rats against nicotine has been shown to reduce nicotine distribution to the brain. The current study examined whether vaccination of female rats before pregnancy would reduce the distribution to fetal brain of a single nicotine dose administered during gestation. Female rats immunized with a nicotine conjugate vaccine received a single dose of nicotine 0.03 mg/kg i.v. on gestational day 16 to 22. Five minutes later, vaccinated rats had substantially higher bound and lower unbound serum nicotine concentration and lower brain nicotine concentration than controls. Fetal brain nicotine concentration was reduced by 43% in vaccinated rats, comparable to the reduction in the maternal brain nicotine concentration. The whole-fetus nicotine concentration was not altered by vaccination. A similar experiment was performed in which pregnant rats were passively immunized with rabbit nicotine-specific IgG 7 or 21 mg/kg just before nicotine dosing. The effects of passive immunization on nicotine distribution in the mother were IgG dose-related and the higher dose reduced nicotine distribution to fetal brain by 60%. These data suggest that vaccine effects on nicotine distribution to serum and brain are similar in pregnant female rats to those previously reported in adult males. Vaccination of female rats before pregnancy, or passive immunization during pregnancy, can reduce the exposure of fetal brain to a single dose of maternally administered nicotine. Keyler, D.E., Shoeman, D., LeSage, M.G., Calvin, A.D. and Pentel, P.R. J Pharmacol Exp Ther., 305(2) pp. 587-592, 2003.

Prenatal Drug Exposure and Auditory Brain Response in Infancy

Results from the multi-site Maternal Lifestyle Study (MLS) indicate that prenatal cocaine and/or opiate exposure affects neural transmission in one-month old infants. Auditory brain stem response (ABR) was measured as an indicator of the functional integrity of the central nervous system in 477 exposed and 554 comparison infants matched for race, sex, and gestational age. Study sites were located in Detroit, Memphis, Miami, and Providence. Analyses were conducted for exposed and comparison groups and for level of prenatal cocaine exposure, with adjustment for covariates (alcohol, marijuana, tobacco, gestational age at birth, social class, and site). Heavy prenatal cocaine exposure (3 days per week, first trimester) was associated with an increase in the I-III, I-V, and III-V interpeak latencies, indicating prolongation of neural transmission. The I-V interpeak latency represents central brain stem conduction time from acoustic nerve to inferior colliculus in the midbrain, and may reflect delayed brainstem maturation. Heavy cocaine exposure was also related to a shorter latency to peak I, possibly indicating hypersensitivity to auditory stimuli. Hypersensitivity, or excitability, has been reported previously for cocaine-exposed infants. Infants with prenatal opiate exposure showed a longer latency to Peak V and a longer III-V interpeak latency, supporting previous findings in small samples of opiate-exposed infants. Lester, B.M., LaGasse, L., Seifer, R., et al. The Maternal Lifestyle Study (MLS): Effects of Prenatal Cocaine and/or Opiate Exposure on Auditory Brain Response at One Month. J Pediatrics, 142, pp. 279-285, 2003.

Cumulative Risk and Parenting Stress for Mothers of Drug-Exposed Infants

This study examined the relationship between cumulative environmental risks, parenting attitudes (parenting stress and potential for child abuse and neglect), and child development in a subgroup of 161 mothers and their drug-exposed infants who were part of a randomized longitudinal study of a home-based early intervention. Mothers with five or more environmental risk factors reported higher parenting stress than women with four or fewer risks and greater potential for child abuse and neglect than women with two or fewer risks at 6 and 18-month visits. Risks included depression, domestic violence, non-domestic violence, family size, homelessness, incarceration, absence of significant other in home, negative life events, psychiatric symptoms, and severity of drug use. Amount of risk was not related to children's mental, motor, or language development at 6, 12, or 18 months of age. Nair, P., Schuler, M.E., Black, M.M., Kettinger, L., and Harrington, D. Cumulative Environmental Risk in Substance Abusing Women: Early Intervention, Parenting Stress, Child Abuse Potential and Child Development. Child Abuse and Neglect, 27, pp. 997-1017, 2003.

Drug-Exposed Infants, Early Home Intervention, and Developmental Outcomes

Researchers at the University of Maryland have reported on effects of a home intervention program for prenatally drug-exposed infants and their families. Biological mother-infant dyads were randomly assigned to a control (n=54) or intervention (n=54) group at 2 weeks postpartum. Control families received brief monthly tracking visits. Intervention families received a developmentally-oriented home intervention, weekly through 6 months, and bi-weekly from 6 to 18 months. Developmental assessments were carried out at 6, 12, and 18 months of age, as were assessments of ongoing maternal drug use. During the 18-month period under study, there were no significant group differences in entry into drug treatment, or in reported ongoing use of cocaine and/or heroin, alcohol, or marijuana. Ongoing cocaine and/or heroin use was associated with lower infant mental development scores, and infant mental scores declined over the first 18 months post partum in this inner-city, low socioeconomic status sample. Nonetheless, infants in the intervention group had higher mental and motor development scores than did control infants. The investigators note the importance of including a drug treatment component in future interventions. Schuler, M.E., Nair, P. and Kettinger, L. Drug-Exposed Infants and Developmental Outcome. Archives of Pediatric and Adolescent Medicine, 157, pp. 133-138, 2003.