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The puzzle of cocaine's effects following maternal use during pregnancy: Still unsolved
Neurotoxicoiogy and Teratology, Vol. 15, pp. 295-296, 1993
0892-0362/93 $6.00 + .00 Copyright © 1993 Pergamon Press Ltd.
Printed in the U.S.A. All fights reserved.
COMMENTARY
The Puzzle of Cocaine's Effects Following Maternal Use During Pregnancy: Still Unsolved DIANA DOW-EDWARDS
Department of Pharmacology, Box 29, State University of New York Health Science Center, 450. Clarkson Avenue, Brooklyn, N Y 11203
DR. DON HUTCHINGS' paper is a refreshing departure from the majority of clinical studies regarding cocaine effects on pregnancy and the fetus. Such studies are usually quick to cast cocaine as a structural and functional teratogen worse than alcohol and sweeping across the country without regard to race or socioeconomic class. In all likelihood, neither is true. I would agree with Dr. Hutchings that the bulk of published evidence does not support the notion that cocaine is a potent structural teratogen. Genitourinary tract malformations do appear to be the only malformation produced by cocaine with any degree of reliability. Undoubtedly, cocaine's effects on the vascular system are responsible for these effects, as well as other malformations. Disruption of fragile capillary walls at a critical time during embryo- or fetogenesis could lead to transient ischemia in the tissue surrounding the break and result in local tissue damage. In fact, Webster et al. (10) have reported that maternal cocaine administration in the rat produced cerebral infarcts in the fetus that resemble those produced by transient hypoxia. It is virtually impossible to establish "cause and effect" relationships between cocaine and even major vascular accidents in clinical studies because of the lack of knowledge about precisely when in embryo- or fetogenesis the cocaine exposure might have occurred. Therefore, it is only through animal studies that a firm association between cocaine and a given pathologic event can be estabfished. My single reservation with Dr. Hutchings paper is that it does not address a significant void in the clinical literature: that there are no thorough neurologic assessments of children born to women who use cocaine. To date, the Bayley Scale of Infant Development and the NBAS have been used to assess the stage of mental and motor development and to determine the ability of the infant to regulate his/her own state and to interact with his/her environment. Neither are reliably altered in cocaine-exposed children perhaps because of the problems
of small sample sizes, etc. In animal studies, the attainment of developmental milestones such as day of crawling, walking etc., indices that are roughly equivalent to those items measured in the Bayley, are also not affected by prenatal cocaine exposure (1,8). However, some preliminary work has shown that prenatal cocaine changes the ability of the pups to respond to environmental cues; a level of responding roughly equivalent to the NBAS. In addition, there is a large body of literature showing that cocaine alters the responses to pharmacologic or environmental stress. Drugs affecting critical dopamine (DA), serotonin (5-HT), and/or norepinephrine (NE) systems produce behaviors that are measurably different in cocaine-exposed rats (5,6,7). Use of brain imaging techniques that can detect very small differences in function, has shown that cocaine exposed rats have altered basal function in many neuronal circuits (2,3,4). Dr. Spear's laboratory (8) has demonstrated that cocaine-exposed rats also show altered integration of behavior in tasks of learning and memory. Before such changes can be demonstrated in human studies, more sophisticated types of neurological testing will be needed. In summary, it is my belief that cocaine in sufficiently high doses has the potential to produce a host of functional alterations-but, that these are not likely to be demonstrated clinically. The reason why cocaine's effects on fetal development will remain a mystery is because women who use the highest amounts of the drug do not seek prenatal care. For example, 60% of the women with urines testing positive for cocaine in a large study at KCHC/SUNY received no prenatal care (9). These women would not be participants in controlled prospective studies since they would not be enrolled through a prenatal care clinic. I agree that there is no room for hysterics in the media and in the minds of the health care community. However, cocaine is clearly not a sheep in wolf's clothing.
295
296
DOW-EDWARDS REFERENCES
1. Donohue, L. M.; Freed, L. A.; Hughes, H. E.; Dow-Edwards, D. L. Maternal toxicity and offspring development following geso tational exposure to cocaine in the rat. Society for Neuroscience 16:456.13; 1990 (abstr). 2. Dow-Edwards, D. L.; Freed, L. A.; Milhorat, T. H. Stimulation of brain metabofism by perinatal cocaine exposure. Dev. Brain Res. 42:137-141; 1988. 3. Dow-Edwards, D. L.; Freed, L. A.; Fico, T. A. Structural and functional effects of prenatal cocaine exposure in adult rat brain. Dev. Brain Res. 57:263-268; 1990. 4. Dow-Edwards, D. L.; Freed-Malen, L. A.; Hughes, H. E. Longterm alterations in brain function following exposure to cocaine during the preweauling period. Dev. Brain Res. 72:309--313; 1993. 5. Hughes, H. E.; Pringle, G. F.; Scribani, L. A.; Dow-Edwards, D. L. Cocaine treatment in neonatal rats affects the adult behavioral response to amphetamine. Nenrotoxicol. Teratol. 13:335-339; 1991. 6. Hughes, H. E.; Grose, E. A.; Dow-Edwards, D. L. Perinatal
7. 8.
9.
10.
exposure to cocaine or fluoxetine interacts with gender in predicting the acoustic startle response following 8OH DPAT and MCPP injection in adult rats, Soc. Neurosci. Abstr. 18:155.3; 1992. Hughes, H. E.; Donohue, L. M.; Dow-Edwards, D. L. Prenatal cocaine exposure affects the acoustic startle response in adult rats. Behav. Brain Res. (in press). Spear, L. P.; Heyser, C. J. Cocaine and the developing nervous system: Laboratory f'mdings. In: Zagon, I. S.; Slotkin, T. A., eds. Maternal substance abuse and the developing nervous system. San Diego, CA: Academic Press; 1992:155-175. Valencia, G.; McCalla, S.; da Silva, M.; Minkoff, H.; Delke, I.; Salwen, M.; Flores, R.; Glass, L. Epidemiology of cocaine use during pregnancy at Kings County Hospital Center (KCHC). Pediatr. Res. 25:265A; 1989 (abstr). Webster, W. S.; Brown-Woodman, P. D. C.; Lipson, A. H.; Ritchie, H. E. Fetal brain damage in the rat following prenatal exposure to cocaine. Neurotoxicol. Teratol. 13:621-626; 1991.
0892-0362/93 $6.00 + .00 Copyright © 1993 Pergamon Press Ltd.
Printed in the U.S.A. All fights reserved.
COMMENTARY
The Puzzle of Cocaine's Effects Following Maternal Use During Pregnancy: Still Unsolved DIANA DOW-EDWARDS
Department of Pharmacology, Box 29, State University of New York Health Science Center, 450. Clarkson Avenue, Brooklyn, N Y 11203
DR. DON HUTCHINGS' paper is a refreshing departure from the majority of clinical studies regarding cocaine effects on pregnancy and the fetus. Such studies are usually quick to cast cocaine as a structural and functional teratogen worse than alcohol and sweeping across the country without regard to race or socioeconomic class. In all likelihood, neither is true. I would agree with Dr. Hutchings that the bulk of published evidence does not support the notion that cocaine is a potent structural teratogen. Genitourinary tract malformations do appear to be the only malformation produced by cocaine with any degree of reliability. Undoubtedly, cocaine's effects on the vascular system are responsible for these effects, as well as other malformations. Disruption of fragile capillary walls at a critical time during embryo- or fetogenesis could lead to transient ischemia in the tissue surrounding the break and result in local tissue damage. In fact, Webster et al. (10) have reported that maternal cocaine administration in the rat produced cerebral infarcts in the fetus that resemble those produced by transient hypoxia. It is virtually impossible to establish "cause and effect" relationships between cocaine and even major vascular accidents in clinical studies because of the lack of knowledge about precisely when in embryo- or fetogenesis the cocaine exposure might have occurred. Therefore, it is only through animal studies that a firm association between cocaine and a given pathologic event can be estabfished. My single reservation with Dr. Hutchings paper is that it does not address a significant void in the clinical literature: that there are no thorough neurologic assessments of children born to women who use cocaine. To date, the Bayley Scale of Infant Development and the NBAS have been used to assess the stage of mental and motor development and to determine the ability of the infant to regulate his/her own state and to interact with his/her environment. Neither are reliably altered in cocaine-exposed children perhaps because of the problems
of small sample sizes, etc. In animal studies, the attainment of developmental milestones such as day of crawling, walking etc., indices that are roughly equivalent to those items measured in the Bayley, are also not affected by prenatal cocaine exposure (1,8). However, some preliminary work has shown that prenatal cocaine changes the ability of the pups to respond to environmental cues; a level of responding roughly equivalent to the NBAS. In addition, there is a large body of literature showing that cocaine alters the responses to pharmacologic or environmental stress. Drugs affecting critical dopamine (DA), serotonin (5-HT), and/or norepinephrine (NE) systems produce behaviors that are measurably different in cocaine-exposed rats (5,6,7). Use of brain imaging techniques that can detect very small differences in function, has shown that cocaine exposed rats have altered basal function in many neuronal circuits (2,3,4). Dr. Spear's laboratory (8) has demonstrated that cocaine-exposed rats also show altered integration of behavior in tasks of learning and memory. Before such changes can be demonstrated in human studies, more sophisticated types of neurological testing will be needed. In summary, it is my belief that cocaine in sufficiently high doses has the potential to produce a host of functional alterations-but, that these are not likely to be demonstrated clinically. The reason why cocaine's effects on fetal development will remain a mystery is because women who use the highest amounts of the drug do not seek prenatal care. For example, 60% of the women with urines testing positive for cocaine in a large study at KCHC/SUNY received no prenatal care (9). These women would not be participants in controlled prospective studies since they would not be enrolled through a prenatal care clinic. I agree that there is no room for hysterics in the media and in the minds of the health care community. However, cocaine is clearly not a sheep in wolf's clothing.
295
296
DOW-EDWARDS REFERENCES
1. Donohue, L. M.; Freed, L. A.; Hughes, H. E.; Dow-Edwards, D. L. Maternal toxicity and offspring development following geso tational exposure to cocaine in the rat. Society for Neuroscience 16:456.13; 1990 (abstr). 2. Dow-Edwards, D. L.; Freed, L. A.; Milhorat, T. H. Stimulation of brain metabofism by perinatal cocaine exposure. Dev. Brain Res. 42:137-141; 1988. 3. Dow-Edwards, D. L.; Freed, L. A.; Fico, T. A. Structural and functional effects of prenatal cocaine exposure in adult rat brain. Dev. Brain Res. 57:263-268; 1990. 4. Dow-Edwards, D. L.; Freed-Malen, L. A.; Hughes, H. E. Longterm alterations in brain function following exposure to cocaine during the preweauling period. Dev. Brain Res. 72:309--313; 1993. 5. Hughes, H. E.; Pringle, G. F.; Scribani, L. A.; Dow-Edwards, D. L. Cocaine treatment in neonatal rats affects the adult behavioral response to amphetamine. Nenrotoxicol. Teratol. 13:335-339; 1991. 6. Hughes, H. E.; Grose, E. A.; Dow-Edwards, D. L. Perinatal
7. 8.
9.
10.
exposure to cocaine or fluoxetine interacts with gender in predicting the acoustic startle response following 8OH DPAT and MCPP injection in adult rats, Soc. Neurosci. Abstr. 18:155.3; 1992. Hughes, H. E.; Donohue, L. M.; Dow-Edwards, D. L. Prenatal cocaine exposure affects the acoustic startle response in adult rats. Behav. Brain Res. (in press). Spear, L. P.; Heyser, C. J. Cocaine and the developing nervous system: Laboratory f'mdings. In: Zagon, I. S.; Slotkin, T. A., eds. Maternal substance abuse and the developing nervous system. San Diego, CA: Academic Press; 1992:155-175. Valencia, G.; McCalla, S.; da Silva, M.; Minkoff, H.; Delke, I.; Salwen, M.; Flores, R.; Glass, L. Epidemiology of cocaine use during pregnancy at Kings County Hospital Center (KCHC). Pediatr. Res. 25:265A; 1989 (abstr). Webster, W. S.; Brown-Woodman, P. D. C.; Lipson, A. H.; Ritchie, H. E. Fetal brain damage in the rat following prenatal exposure to cocaine. Neurotoxicol. Teratol. 13:621-626; 1991.