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Diffusion Tensor Imaging Studies of Prenatal Drug Exposure: Challenges of Poly-Drug Use in Pregnant Women
EDITORIALS
November 2011
Diffusion Tensor Imaging Studies of Prenatal Drug Exposure: Challenges of Poly-Drug Use in Pregnant Women
S
tudying prenatal drug exposures in human subjects is tended to be older than the mothers who did not use tobacco challenging for several reasons. Unreliable self(P = .07). Although not statistically significant (P = .17), the reports, the stigma associated with maternal drug and prevalence of alcohol use in smoking mothers was consideralcohol consumption, and children who are no longer living ably higher (74% of the sample reported alcohol use during with biological parents all make it difficult to obtain accurate pregnancy) than in children whose mothers did not smoke exposure histories. The frequency of multi(53% of the sample reported alcohol use See related article, p 771 ple drug exposures creates difficulties anaduring pregnancy). lyzing and interpreting data. However, we know from Although most retrospective studies likely suffer from the animal studies that many drugs have individual effects on same bias toward smoking and alcohol poly-drug exposure, the developing brain during fetal development. Alcohol the study described here had the advantage of actually knowblocks N-methyl-D-aspartic acid receptors, increases g-amiing smoking history because of the prospective nature of data nobutyric acidergic activity, and disrupts growth factor collection by which mothers self-reported substance use durreceptors1; cocaine and methamphetamine each affect ing pregnancy.6 Although several studies demonstrate white 2,3 dopamine-signaling pathways, although in different ways ; matter abnormalities related to heavy prenatal alcohol expoand nicotine binds to nicotinic acetylcholine receptors, sure (reviewed by Wozniak and Muetzel7), earlier work has 4 not focused on the separate impact of concomitant tobacco altering cell proliferation. Human studies of the effects of exposure. Thus, it is not clear whether the effects observed prenatal drug exposure on brain development tend to focus in the present report are more about maternal smoking, maon one drug, but typically many subjects have additional ternal drinking, or the combination. It is possible that the drug exposures that may confound interpretation. Therefore, sample studied here had quantities of alcohol exposures human studies that are able to isolate effects of a particular that would have been below the threshold for most prospecdrug are very rare, but very valuable for accurately attributing tive studies focusing on fetal alcohol spectrum disorders, but brain changes to specific prenatal exposures. that is difficult to determine because quantities of exposure In this issue of The Journal, Liu et al report the effects of prewere not reported in this cohort of the Maternal Lifestyle natal cocaine and tobacco exposure on brain structure in adoStudy sample.6 The lack of significant differences related to lescents and partly address the issue of poly-drug exposure.5 From a prospective, multi-site longitudinal study of prenatal cocaine exposure is intriguing, although earlier studies8 and drug exposure, they selected 40 adolescents, 20 of whom had the trend toward significantly altered FA observed by Liu prenatal cocaine exposure and 23 who were prenatally exposed et al suggest subtle effects of prenatal cocaine exposure on to tobacco (15 exposed to both). Diffusion tensor imaging and brain white matter. region-of-interest analysis were used to measure two common In sum, the problem of poly-drug exposure is difficult to diffusion tensor imaging parameters: fractional anisotropy overcome. Liu et al address some of the issues that have con(FA) and mean diffusivity in 5 subregions of the corpus calfounded earlier studies, but even with a very large sample to losum. Cocaine-exposed adolescents showed no significant difdraw from, this study was not able to eliminate the confound ferences from non-exposed subjects; however, adolescents with of alcohol exposure. Although it remains unclear which exprenatal tobacco exposure had significantly lower FA, an indiposures may have the strongest or most widespread effects, cator of white matter integrity, in the anterior midbody of the this study and others provide a clear message that prenatal corpus callosum compared with subjects without prenatal exposure to drugs of abuse, whether cocaine, tobacco, tobacco exposure. Futhermore, lower FA values in this region alcohol, or a combination of substances, does affect brain dewere significantly associated with increased sensation-seeking velopment in behaviorally significant ways. Liu et al highlight behavior in the adolescents with prenatal tobacco exposure, the importance of addressing poly-drug exposure, including demonstrating a link between the structural brain effects of pretobacco, for future research studies and also underscore the natal tobacco exposure and behavior. need to prevent prenatal drug, tobacco, and alcohol expoThe authors provide a relatively detailed table of maternal sures before they occur. n characteristics. Although the cocaine-exposure contrast Catherine Lebel, PhD groups were well matched for maternal age and alcohol use Developmental Cognitive Neuroimaging Laboratory during pregnancy, the tobacco exposure contrast groups Children’s Hospital Los Angeles were not. The mothers who used tobacco during pregnancy
FA
Fractional anisotropy
0022-3476/$ - see front matter. Copyright ª 2011 Mosby Inc. All rights reserved. 10.1016/j.jpeds.2011.06.023
709
THE JOURNAL OF PEDIATRICS
www.jpeds.com
Elizabeth Sowell, PhD Developmental Cognitive Neuroimaging Laboratory Children’s Hospital Los Angeles Department of Pediatrics Keck School of Medicine University of Southern California Los Angeles, California Reprint requests: Elizabeth Sowell, PhD, USC Keck School of Medicine, Developmental Cognitive Neuroimaging Laboratory, Childrens Hospital Los Angeles, 4650 Sunset Blvd, Mailstop #130, Los Angeles, CA 90027. E-mail: [email protected]
References 1. Miller MW. Effect of prenatal exposure to ethanol on glutamate and GABA immunoreactivity in macaque somatosensory and motor cortices: critical timing of exposure. Neuroscience 2006;138:97-107.
Vol. 159, No. 5 2. Harvey JA. Cocaine effects on the developing brain: current status. Neurosci Biobehav Rev 2004;27:751-64. 3. Slamberova R, Pometlova M, Charousova P. Postnatal development of rat pups is altered by prenatal methamphetamine exposure. Prog Neuropsychopharmacol Biol Psychiatry 2006;30:82-8. 4. Roy TS, Seidler FJ, Slotkin TA. Prenatal nicotine exposure evokes alterations of cell structure in hippocampus and somatosensory cortex. J Pharmacol Exp Ther 2002;300:124-33. 5. Liu J, Cohen RA, Gongvatana A, Sheinkopf SJ, Lester BM. Impact of prenatal exposure to cocaine and tobacco on diffusion tensor imaging and sensation seeking in adolescents. J Pediatr 2011;159:771-5. 6. Lester BM, ElSohly M, Wright LL, Smeriglio VL, Verter J, Bauer CR, et al. The Maternal Lifestyle Study: drug use by meconium toxicology and maternal self-report. Pediatrics 2001;107:309-17. 7. Wozniak JR, Muetzel RL. What does diffusion tensor imaging reveal about the brain and cognition in fetal alcohol spectrum disorders? Neuropsychol Rev 2011;21:133-47. 8. Warner TD, Behnke M, Eyler FD, Padgett K, Leonard C, Hou W, et al. Diffusion tensor imaging of frontal white matter and executive functioning in cocaine-exposed children. Pediatrics 2006;118:2014-24.
Safe at Home?
M
ost research on drug-exposed children focuses on Clandestine methamphetamine laboratories are full of toxic prenatal exposures and outcomes. The report by chemicals used in the manufacturing process, including solMoller et al in this issue of The Journal1 adds to vents (eg, methanol, toluene, acetone, camping stove fuel, the scant but important literature on drug exposure in chilFreon, tricholoroethane), acids (eg, phosphoric acid, hydrodren removed from drug-producing homes. Law enforcechloric acid), and bases (eg, sodium hydroxide).2 Many of these chemicals are recognized carcinogens ment statistics document a substantial See related article, p 766 or respiratory irritants, and can cause chemincrease in domestic illicit drug production, ical injuries from inhalation, ingestion, or dermal contact. primarily marijuana and methamphetamine, in the United Electrical hazards (eg, the large number of fans and intense States and Canada since 2000. Moller et al cite data estimatlighting in marijuana growing houses) and the frequent exing that as many as 10 000 children in the province of Ontario plosions and fires in methamphetamine labs make these danlived in drug-producing homes during 2000-2003. gerous homes. Methamphetamine laboratories are frequently Using hair samples, which can be positive for a drug expofound in substandard housing in terms of insect and rodent sure occurring 6 months or longer before testing, Moller et al infestation, hygiene and sanitary needs, safety for children, found that 32% of children tested positive for an illicit suband cleanliness for food preparation. All of these issues manstance. The vast majority of these children were in good physdate the need for timely home inspections by someone ical health compared with Canadian prevalence rates for trained in identifying environmental hazards before decicomparable health problems in their age group, although besions can be made about returning children to their homes. havioral problems were not assessed in depth. Pointing to the Children from drug-producing homes also may be exrelative good medical health of these children, including the posed to a toxic family environment regardless of whether one-third who tested positive for one or more illicit subor not their home is physically clean and safe. Domestic viostances, Moller et al argue against the policy of automatically lence; physical, sexual, and emotional abuse; parental subremoving these children from their families. stance abuse, mental illness, and criminal behavior; and In the best of all possible worlds, we could make an physical, emotional, medical, educational, and informed risk assessment of the safety of children in drugdental neglect are not uncommon in drug-producing homes. producing homes, which would factor into a case-by-case We have data on the long-term negative effects on children exdecision about whether to return a child to parental care or posed to these toxic family environments. The seminal Adto remove the child from the home. If the idea is to replace verse Childhood Experiences Study, which followed an an automatic removal policy with a policy that requires adult cohort that was retrospectively identified as having a case-by-case assessment of children living in drugbeen exposed to the adverse experiences in childhood, found producing homes, it is worth considering what we should a graded effect, such that individuals with more adverse be assessing and how good our assessments are at predicting risks and outcomes. Moller et al make clear that there are other hazards in 0022-3476/$ - see front matter. Copyright ª 2011 Mosby Inc. drug-producing homes beyond exposure to illicit drugs. All rights reserved. 10.1016/j.jpeds.2011.07.031
710
November 2011
Diffusion Tensor Imaging Studies of Prenatal Drug Exposure: Challenges of Poly-Drug Use in Pregnant Women
S
tudying prenatal drug exposures in human subjects is tended to be older than the mothers who did not use tobacco challenging for several reasons. Unreliable self(P = .07). Although not statistically significant (P = .17), the reports, the stigma associated with maternal drug and prevalence of alcohol use in smoking mothers was consideralcohol consumption, and children who are no longer living ably higher (74% of the sample reported alcohol use during with biological parents all make it difficult to obtain accurate pregnancy) than in children whose mothers did not smoke exposure histories. The frequency of multi(53% of the sample reported alcohol use See related article, p 771 ple drug exposures creates difficulties anaduring pregnancy). lyzing and interpreting data. However, we know from Although most retrospective studies likely suffer from the animal studies that many drugs have individual effects on same bias toward smoking and alcohol poly-drug exposure, the developing brain during fetal development. Alcohol the study described here had the advantage of actually knowblocks N-methyl-D-aspartic acid receptors, increases g-amiing smoking history because of the prospective nature of data nobutyric acidergic activity, and disrupts growth factor collection by which mothers self-reported substance use durreceptors1; cocaine and methamphetamine each affect ing pregnancy.6 Although several studies demonstrate white 2,3 dopamine-signaling pathways, although in different ways ; matter abnormalities related to heavy prenatal alcohol expoand nicotine binds to nicotinic acetylcholine receptors, sure (reviewed by Wozniak and Muetzel7), earlier work has 4 not focused on the separate impact of concomitant tobacco altering cell proliferation. Human studies of the effects of exposure. Thus, it is not clear whether the effects observed prenatal drug exposure on brain development tend to focus in the present report are more about maternal smoking, maon one drug, but typically many subjects have additional ternal drinking, or the combination. It is possible that the drug exposures that may confound interpretation. Therefore, sample studied here had quantities of alcohol exposures human studies that are able to isolate effects of a particular that would have been below the threshold for most prospecdrug are very rare, but very valuable for accurately attributing tive studies focusing on fetal alcohol spectrum disorders, but brain changes to specific prenatal exposures. that is difficult to determine because quantities of exposure In this issue of The Journal, Liu et al report the effects of prewere not reported in this cohort of the Maternal Lifestyle natal cocaine and tobacco exposure on brain structure in adoStudy sample.6 The lack of significant differences related to lescents and partly address the issue of poly-drug exposure.5 From a prospective, multi-site longitudinal study of prenatal cocaine exposure is intriguing, although earlier studies8 and drug exposure, they selected 40 adolescents, 20 of whom had the trend toward significantly altered FA observed by Liu prenatal cocaine exposure and 23 who were prenatally exposed et al suggest subtle effects of prenatal cocaine exposure on to tobacco (15 exposed to both). Diffusion tensor imaging and brain white matter. region-of-interest analysis were used to measure two common In sum, the problem of poly-drug exposure is difficult to diffusion tensor imaging parameters: fractional anisotropy overcome. Liu et al address some of the issues that have con(FA) and mean diffusivity in 5 subregions of the corpus calfounded earlier studies, but even with a very large sample to losum. Cocaine-exposed adolescents showed no significant difdraw from, this study was not able to eliminate the confound ferences from non-exposed subjects; however, adolescents with of alcohol exposure. Although it remains unclear which exprenatal tobacco exposure had significantly lower FA, an indiposures may have the strongest or most widespread effects, cator of white matter integrity, in the anterior midbody of the this study and others provide a clear message that prenatal corpus callosum compared with subjects without prenatal exposure to drugs of abuse, whether cocaine, tobacco, tobacco exposure. Futhermore, lower FA values in this region alcohol, or a combination of substances, does affect brain dewere significantly associated with increased sensation-seeking velopment in behaviorally significant ways. Liu et al highlight behavior in the adolescents with prenatal tobacco exposure, the importance of addressing poly-drug exposure, including demonstrating a link between the structural brain effects of pretobacco, for future research studies and also underscore the natal tobacco exposure and behavior. need to prevent prenatal drug, tobacco, and alcohol expoThe authors provide a relatively detailed table of maternal sures before they occur. n characteristics. Although the cocaine-exposure contrast Catherine Lebel, PhD groups were well matched for maternal age and alcohol use Developmental Cognitive Neuroimaging Laboratory during pregnancy, the tobacco exposure contrast groups Children’s Hospital Los Angeles were not. The mothers who used tobacco during pregnancy
FA
Fractional anisotropy
0022-3476/$ - see front matter. Copyright ª 2011 Mosby Inc. All rights reserved. 10.1016/j.jpeds.2011.06.023
709
THE JOURNAL OF PEDIATRICS
www.jpeds.com
Elizabeth Sowell, PhD Developmental Cognitive Neuroimaging Laboratory Children’s Hospital Los Angeles Department of Pediatrics Keck School of Medicine University of Southern California Los Angeles, California Reprint requests: Elizabeth Sowell, PhD, USC Keck School of Medicine, Developmental Cognitive Neuroimaging Laboratory, Childrens Hospital Los Angeles, 4650 Sunset Blvd, Mailstop #130, Los Angeles, CA 90027. E-mail: [email protected]
References 1. Miller MW. Effect of prenatal exposure to ethanol on glutamate and GABA immunoreactivity in macaque somatosensory and motor cortices: critical timing of exposure. Neuroscience 2006;138:97-107.
Vol. 159, No. 5 2. Harvey JA. Cocaine effects on the developing brain: current status. Neurosci Biobehav Rev 2004;27:751-64. 3. Slamberova R, Pometlova M, Charousova P. Postnatal development of rat pups is altered by prenatal methamphetamine exposure. Prog Neuropsychopharmacol Biol Psychiatry 2006;30:82-8. 4. Roy TS, Seidler FJ, Slotkin TA. Prenatal nicotine exposure evokes alterations of cell structure in hippocampus and somatosensory cortex. J Pharmacol Exp Ther 2002;300:124-33. 5. Liu J, Cohen RA, Gongvatana A, Sheinkopf SJ, Lester BM. Impact of prenatal exposure to cocaine and tobacco on diffusion tensor imaging and sensation seeking in adolescents. J Pediatr 2011;159:771-5. 6. Lester BM, ElSohly M, Wright LL, Smeriglio VL, Verter J, Bauer CR, et al. The Maternal Lifestyle Study: drug use by meconium toxicology and maternal self-report. Pediatrics 2001;107:309-17. 7. Wozniak JR, Muetzel RL. What does diffusion tensor imaging reveal about the brain and cognition in fetal alcohol spectrum disorders? Neuropsychol Rev 2011;21:133-47. 8. Warner TD, Behnke M, Eyler FD, Padgett K, Leonard C, Hou W, et al. Diffusion tensor imaging of frontal white matter and executive functioning in cocaine-exposed children. Pediatrics 2006;118:2014-24.
Safe at Home?
M
ost research on drug-exposed children focuses on Clandestine methamphetamine laboratories are full of toxic prenatal exposures and outcomes. The report by chemicals used in the manufacturing process, including solMoller et al in this issue of The Journal1 adds to vents (eg, methanol, toluene, acetone, camping stove fuel, the scant but important literature on drug exposure in chilFreon, tricholoroethane), acids (eg, phosphoric acid, hydrodren removed from drug-producing homes. Law enforcechloric acid), and bases (eg, sodium hydroxide).2 Many of these chemicals are recognized carcinogens ment statistics document a substantial See related article, p 766 or respiratory irritants, and can cause chemincrease in domestic illicit drug production, ical injuries from inhalation, ingestion, or dermal contact. primarily marijuana and methamphetamine, in the United Electrical hazards (eg, the large number of fans and intense States and Canada since 2000. Moller et al cite data estimatlighting in marijuana growing houses) and the frequent exing that as many as 10 000 children in the province of Ontario plosions and fires in methamphetamine labs make these danlived in drug-producing homes during 2000-2003. gerous homes. Methamphetamine laboratories are frequently Using hair samples, which can be positive for a drug expofound in substandard housing in terms of insect and rodent sure occurring 6 months or longer before testing, Moller et al infestation, hygiene and sanitary needs, safety for children, found that 32% of children tested positive for an illicit suband cleanliness for food preparation. All of these issues manstance. The vast majority of these children were in good physdate the need for timely home inspections by someone ical health compared with Canadian prevalence rates for trained in identifying environmental hazards before decicomparable health problems in their age group, although besions can be made about returning children to their homes. havioral problems were not assessed in depth. Pointing to the Children from drug-producing homes also may be exrelative good medical health of these children, including the posed to a toxic family environment regardless of whether one-third who tested positive for one or more illicit subor not their home is physically clean and safe. Domestic viostances, Moller et al argue against the policy of automatically lence; physical, sexual, and emotional abuse; parental subremoving these children from their families. stance abuse, mental illness, and criminal behavior; and In the best of all possible worlds, we could make an physical, emotional, medical, educational, and informed risk assessment of the safety of children in drugdental neglect are not uncommon in drug-producing homes. producing homes, which would factor into a case-by-case We have data on the long-term negative effects on children exdecision about whether to return a child to parental care or posed to these toxic family environments. The seminal Adto remove the child from the home. If the idea is to replace verse Childhood Experiences Study, which followed an an automatic removal policy with a policy that requires adult cohort that was retrospectively identified as having a case-by-case assessment of children living in drugbeen exposed to the adverse experiences in childhood, found producing homes, it is worth considering what we should a graded effect, such that individuals with more adverse be assessing and how good our assessments are at predicting risks and outcomes. Moller et al make clear that there are other hazards in 0022-3476/$ - see front matter. Copyright ª 2011 Mosby Inc. drug-producing homes beyond exposure to illicit drugs. All rights reserved. 10.1016/j.jpeds.2011.07.031
710