Prenatal Drug Exposure and Drug-Abusing Environments

Research Findings from February, 2005 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.

Prenatal Cocaine: Quantity of Exposure and Gender Influences on School-Age Behavior

Investigators at Wayne State University have reported that both level of prenatal cocaine exposure and gender were significantly associated with school-age behavioral outcomes. Prenatal cocaine exposure was defined in two ways: dichotomous and ordinal. The dichotomous measure consisted of no exposure or any pregnancy exposure. The ordinal measure had three levels (none, some, persistent), with persistent prenatal exposure defined as continued cocaine use up until delivery as evidenced by positive maternal and/or infant urine testing at delivery. Data analyses were based on a total of 473 children, 204 of whom were prenatally exposed to cocaine; 24 of the cocaine-exposed children were classified as having persistent exposure. Behavior at 6 years of age was assessed using a teacher-report scale involving fourteen problem behavior areas. Boys with any prenatal cocaine exposure scored significantly higher (more problem behaviors) than non-exposed boys on the hyperactivity item. No similar cocaine effect was observed for girls. Boys, but not girls, with persistent exposure had more problems in central processing, motor skills, handling abstract concepts, and passivity to the environment. Covariates controlled for include prenatal exposure to alcohol and other illicit drugs, and postnatal drug use in the home. Delaney-Black, V., Covington, C., Nordstrom, B., et al. Prenatal Cocaine: Quantity of Exposure and Gender Moderation. Developmental and Behavioral Pediatrics, 25(4), pp. 254-263, 2004.

Prenatal Cocaine Exposure and Language Development

Recently-published results from two separate projects provide new information regarding associations between prenatal cocaine exposure and aspects of language development. From the University of Miami, Vogel and colleagues report that when the children in their study were 3 years old (424 children, 226 cocaine-exposed, 198 non-cocaine-exposed), there was a decrease in expressive language score with increasing level of prenatal cocaine exposure. Receptive language was more modestly, and not significantly, related to prenatal cocaine exposure. Using the same language assessment scale, the Clinical Evaluation of Language Fundamentals - Preschool (CELF-P), Lewis and co-investigators at Case Western Reserve University report that for their sample of 4-year-olds (189 cocaine-exposed and 185 non-cocaine-exposed), children exposed to cocaine in utero had poorer expressive and total language scores, and had more mild receptive language delays than nonexposed children. In both studies, the analyses took into account several key variables (e.g., prenatal exposures to alcohol, tobacco, and marijuana). Morrow, C.E., Vogel, A.L., Anthony, J.C., et al. Expressive and Receptive Language Functioning in Preschool Children with Prenatal Cocaine Exposure. Journal of Pediatric Psychology, 29(7), pp. 543-554, 2004; Lewis, B.A., Singer, L.T., Short, E.J., et al. Four-Year Language Outcomes of Children Exposed to Cocaine in Utero. Neurotoxicology and Teratology, 26(5), pp. 617-627, 2004.

In Utero Marijuana Exposure Associated with Abnormal Amygdala Dopamine D2 Gene Expression in the Human Fetus

Dr. Yasmin Hurd and her colleagues, using in situ hybridization histochemistry, have published the first description of neurobiological effects of in utero exposure to cannabis in the human fetus. Their results demonstrate that cannabis exposure during prenatal development causes a decrease in dopamine D2 mRNA expression in the amygdala and that the magnitude of this decrease was positively correlated with the level of exposure. Importantly, this decrease in D2 mRNA was gender-specific, occurring in males but not in females. This alteration in the mesocorticolimbic dopaminergic brain circuitry during development may contribute to the emotional and cognitive deficits that have been reported in children prenatally exposed to cannabis. Wang, X., Dow-Edwards, D., Anderson, V., Minkoff, H., Hurd, Y.L. Biological Psychiatry 56, pp. 909-915, 2004.

Neonatal Abstinence Syndrome in Methadone-exposed Infants is Altered by Level of Prenatal Tobacco Exposure

Maternal tobacco consumption during pregnancy has been associated with lower birth weight infants, preterm births, intrauterine growth retardation, smaller head circumference and increase in morbidity, yet few studies have examined the role tobacco has on the opiate neonatal abstinence syndrome (NAS). This study examined the effect of prenatal tobacco exposure on NAS for infants born to mothers maintained on methadone during gestation. Twenty-nine pregnant women and their newborn infants participated in this study. Tobacco exposure was based on maternal self-report with 16 women reporting cigarette consumption of 10 or less per day and 13 reporting smoking 20 cigarettes or more a day. The onset, peak, and duration of NAS were examined. Results showed that infants born to mothers who reported smoking 20 or more cigarettes per day had significantly higher NAS peak scores of 9.8 versus 4.8, and took longer to peak (113.0 h versus 37.8 h), than light smokers of 10 or fewer cigarettes per day. Investigators concluded that tobacco use in conjunction with methadone plays an important role in the timing and severity of NAS in prenatally exposed infants. Choo, R.E., Huestis, M.A., Schroeder, J.R., Shin, A.S. and Jones, H.E. Drug and Alcohol Dependence, 75, pp. 253-260, 2004.

Methamphetamine and Amphetamine Concentrations in Meconium of Neonates of Women Enrolled in the IDEAL Study of In Utero Methamphetamine Exposure

The Infant Development, Environment, and Lifestyle (IDEAL) study is a multi-center, longitudinal investigation of the effects of prenatal methamphetamine exposure. Meconium, a useful matrix for identifying in utero drug exposure, was employed to identify gestational drug use. Of the 13,808 mothers screened, 1631 were consented and 176 enrolled. MA exposed mothers (n=84) were identified by self-report of gestational MA use and/or GC/MS confirmation of MA, AMP, and/or MDMA in infant meconium. Comparison participants (n=92) were matched by race, birth weight, maternal education and type of insurance, denied amphetamines use and had negative meconium results. Among the 1631 mothers, self-reported use rates were 5.2% (amphetamines), 25% (tobacco) and 5.9% (cannabis). Positive meconium screening rates were 3.6% for any amphetamine, 20% cotinine and 11.2% cannabis. For specimens that screened positive, 40.7% of amphetamines and 20.2% of cannabis specimens were confirmed. On average, 68% of the meconium from neonates whose mothers reported 3rd trimester use had detectable MA, while detection rates were ²10% for self-reported use during the 1st and/or 2nd trimesters. Mean +/- SD, median and range of MA concentrations were 3674 +/- 3406, 2623, 479 to 13,431 ng/g meconium and AMP 569 +/- 543, 403, 30 to 2000 ng/g meconium in infants whose mothers reported 3rd trimester use. However, the highest MA (19,376 and 16,976 ng/g) and AMP (2765 ng/g) concentrations were found in offspring born to women who reported MA use only in the 1st or 1st and 2nd trimesters, raising questions about the self-report. The log transformed meconium MA concentrations significantly correlated with the frequency of MA use in the 3rd trimester (r=0.645, P=0.004), although variability prevents prediction of frequency of use for an individual mother. AMP was always detected in MA positive meconium. In 55% of the GCMS positive samples, the ratios of amphetamine to MA were 0.1 to 0.2; 14% were less than 0.1 and 18% were 0.2 to 0.3. Meconium analysis for MA is a useful adjunct to self-report for identification of MA exposure; however, the greatest sensitivity was achieved with specimens collected from offspring of women who reported use in the 3rd trimester. Further research is needed to determine if there are additional MA metabolites in meconium that could improve the identification of MA-exposed infants. Zhao, Z., Liu, J., LaGasse, L.L., Derauf, C., Grant, P., Shah, R., Arria, A., Haning, W., Smith, L.M., Lester, B. and Huestis, M.A., Poster, 2004. Joint Meeting of the Society of Forensic Toxicologists and The International Association of Forensic Toxicologists, Washington, DC, August 28-September 3, 2004.