Gideon Koren, MD, and Philip R. Zelazo, PhD. From the Department of Psychology and Research Institute, McGill University and Montreal. Children's Hospital ...
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The Journal o f Pediatrics October 1994
Maternal c o c a i n e use without e v i d e n c e of fetal exposure Susan Potter, BSc, Julia Klein, MSc, G r a c e V a l i a n t e , D a l e M. S t a c k , PhD, A p o s t o l o s P a p a g e o r g i o u , MD, William Stott, PhD, D o u g l a s Lewis, PhD, G i d e o n Koren, MD, a n d Philip R. Z e l a z o , PhD From the Department of Psychology and Research Institute, McGill University and Montreal Children's Hospital, Montreal, Canada; the Division of Clinical Pharmacology, Department of Pediatrics and Research Institute, Hospital for Sick Children, University of Toronto, Canada; the Departments of Psychology, Concordia University and Montreal Children's Hospital, Montreal; the Departments of Neonatology and Pediatrics, Sir Mortimer B. Davis-Jewish General Hospital, Montreal; SCIEX, Division of MDS Health Group, Toronto; and United States Drug Testing Laboratory, Chicago, Illinois
We report a case of lack of fetal exposure to cocaine and benzoylecgonine as evidenced by meconium and hair analysis, but exposure to nicotine and its metabolite cotinine, after extensive maternal use of cocaine and nicotine. These data suggest that the mode of maternal use of cocaine and individual differences in placental hand ling of the drug may protect some fetuses, and highlight the need to address interpatient variability. (J PEDIATR4994;125:652-4)
The potential effects of maternal cocaine use on the fetus are controversial; despite numerous studies comparing infants exposed to cocaine with control infants, the role of cocaine in causing abnormalities has not been clearly established. 1 The altered pharmacokinetics of cocaine in the very premature neonate were first reported by Chasnoff and Lewis. 2 Recently Browne et al. 3 reported that very low birth weight neonates exposed to cocaine do not have benzoylecgonine in their meconium. Generally, however, cocaine and its metabolite benzoylecgonine can be found in neonatal urine, 4 meconium, s and hair samples. 6 Cocaine appears to accumulate in meconium from the sixteenth week of gestation and is available during the first day of life. Neonatal hair grows during the last 3 to 4 months of pregnancy and accumulates cocaine in a dose-dependent manner. Unlike meconium, neonatal hair is available for 3 to 6 months after birth. 7 It has been hypothesized that cocaine adversely affects some fetuses while not damaging many others as a result of the large variability in the handling of this agent by different placentae. 8 This hypothesis is supported by in vitro perSupported by the Stairs Fund, Department of Psychology, McGill University, and the Medical Research Council of Canada. Submitted for publication Oct. 8, 1993; accepted May 10, 1994. Reprint requests: Philip R. Zelazo, PhD, Department of Psychology, Montreal Children's Hospital, McGill University, 2300 Tupper, Montreal, Quebec H3H 1P3, Canada. Copyright © 1994 by Mosby-Year Book, Inc. 0022-3476/94/$3.00 + 0 9/26/57496
fusion studies with human placentae showing large variabilities in the ability to bind and transfer cocaine. 9, 10 We report a case of confirmed maternal use of cocaine that supports this hypothesis. CASE REPORT In February 1993, a 26-year-old white woman gave birth to a girl; the gestational age was 32 weeks, and the birth weight was 1750 gm. As part of a larger study examining the effects of in utero cocaine exposure on the information processing abilities of the newborn infant (Potter S, Zelazo PR, Stack DM, Valiante G, Papageorgiou A: unpublished data), the mother voluntarily admitted once-daily use of 2 to 5 gm cocaine throughout pregnancy by the intravenous route, and use of 0.5 to 1 grn hashish weekly during the first 3 months of pregnancy. She also reported drinking 12 beers per month during the first 3 months of pregnancy and smoking between 20 and 40 cigarettes per day throughout the pregnancy. Results of physical and neurologic examinations of the infant were normal. The infant has been placed in a foster home, and the mother, who wishes to raise her child, has been enrolled in a drug rehabilitation program. METHODS Urine, meconium, and hair samples from the neonate were collected and analyzed for detection of cocaine and benzoylecgonine, as well as nicotine and its metabolite, cotinine. Meconium samples were also analyzed for cannabinoids and amphetamines. A hair sample from the mother was obtained for benzoylecgonine, nicotine, and cotinine analysis 2 months after delivery. A commercial radioimmunoassay was used for urine
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analysis. Mec0nium samples were analyzed for cocaine, benzoylecgonine, cotinine, cannabinoids, and amphetamine s by gas chromatography-mass spectometry using a modification of the procedure of Clarke et al. 5 The limit of quantitation was 5 ng/gm; the limit of detection was 2 ng/ gm. Assuming hair growth at a rate of 1 cm per month, 5 the maternal hair sample was sectioned to reflect cocaine and cigarette use in thefirst, second, and third trimesters (period of low cocaine use because the mother was hospitalized for 3 weeks without access to cocaine) of the pregnancy, as well as after pregnancy (drug-free period). The maternal hair segments and the neonatal hair samples were analyzed for cocaine, benzoylecgonine, nicotine, and cotinine by previously described methods bY means of radiojmmunoassay.ll, 12 The limit of quantitation is 0.025 ng/mg hair for cocaine and 0.25 ng/mg for cotinine when 2 m g of hair is used: The results were confirmed by thermal desorption mass spectrometric analysis using a SCIEX Aromic 9100 tandem mass spectrometer (SCIEX Ltd., Thornhill, Ontario, Canada). RESULTS Analysis of maternal hair sections confirmed the mother's self-report of cocaine and cigarette use. Hair concentrations of benzoylecgonine (Table) and the verbal report of cocaine use were consistent with our previously published dose-response curve in women. 13 Each segment also had high concentrations Of nicotine and cotinine, consistent with continuous smoking throughout pregnancy. The detection of cocaine in the maternal hair analysis by radioimmun0assay was further confirmed by the thermal desorption method. Converselyl cocaine, benzoylecgonine, and eannabinoids were not detected in the infant's urine and meconium samples. However, the meconiurn sample showed the presence of cotinine and also contained trace amounts of amphetamines. Similarly, benzoylecgonine was not detected in the infant's hair sample, but nicotine and cotinine were detected with both radioimmunoassay and thermal desorption analysis (Table). DISCUSSION This mother voluntarily admitted to intravenous cocaine use throughout her pregnancy, and her report was confirmed by analysis of her hair samples. Nonetheless, it appears that her offspring was not exposed in utero to cocaine, at least not after 16 weeks of gestation, when meconium accumulation of the drug begins. 14 The agreement between the infant's meconium and hair test s lends credibility to this observation, indicating that negative test results are not merely caused by their limited sensitivities. The positive results on hair and meconium tests for nicotine and cotinine and the trace amounts of amphetamine
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Table. Benzoylecgonine, nicotine, a n d cotinine concentrations in maternal and infant hair samples Period of exposure Mother At 2 mo after delivery In 3rd trimester In 2rid trimester In 1st trimester Infant
Benzoylecgonine Nicotine Cotinine (ng/mg) (ng/mg) (ng/rng) 0.8
6.5
0.4
0.9 3.1 2.3 Undetectable
11.8 14.5 23.4 3.0
0.2 0.3 0.3 0.1
present in the meconium further suggest that, although these xenobiotics crossed the placenta, cocaine did not. For decades the placenta was perceived as a barrier that protects the fetus from exposure to xen0bi0tics circulating in the maternal system. As analytic methods have improved, it has been shown that the placenta has metabolizing capacity. 4 Even the known teratogens affect only a percentage of fetuses while sparing others. 4 Cocaine has a mean distribution volume of 2 L / k g and an elimination half-life between 40 and 80 minutes. If the pregnant woman had injected the drug intravenously once daily, the rapid elimination would have exposed the placenta to decreasing levels over time, with many hours without circulating levels. We have recently shown that the in vitro perfused human placenta may bind and retain up to one third of continuously circulated doses. 9 Data from our current case suggest that rapid elimination of cocaine from the mother, potentially coupled wit h ability of this particular placenta to bind large amounts of the xenobiotic arriving at the placental vessels, could have protected the fetus from exposure to this drug. This case highlights the need to address interpatient variability in maternal and placental handling of cocaine as a possible explanation for the large variability seen in pregnancy outcome. REFERENCES
1. Lutiger B, Graham K, Einarson T, Koren G. Relationship between gestational cocaine use and pregnancy outcome: a meta-analysis. Tetralogy 1991;44:404-14. 2. Chasnoff IJ, Lewis DE. Cocaine metabolism during pregnancy [Abstract]. Pediatr Res 1988;23257A. 3. BrowneSP, Tebbett IR, Moore CM, Dusick A, Covert R, Y e e GT. Analysis of meconium for cocaine in neonates. J Chromatogr 1992;575:158-61. 4. Koren G. Maternal-fetal toxicology. New York: Marcel Dekker, 1990. 5. Clarke GD, Rosenzweig B, Raisys VA. Analysis of cocaine and benzoylecgonine in meconium of infants born to cocaine dependent mothers [Abstract ~0327]. Clin Chem 1990;36: 1022. 6. Graham K, Koren G, Klein J, Schneiderman J, Greenwald M.
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Determination of gestational cocaine exposure by hair analysis. JAMA 1989;262:3328-30. Kligman AM. Pathological dynamics of human hair loss: 1. telogen effluvium. Arch Dermatol 1961;83:175-98. Bingol N, Fuchs M, Diaz V, et al. Teratogenicity of cocaine in humans. J PEDIATR 1986;110:93-6. Simone CU, Derewlany LO; Oskamp M, Knie B, Koren G. Transfer of cocaine and benzoylecgonine across the perfused human placental cotyledon. Am J Obstet Gynecol 1994; 170:1404-10. Simone C, Derewlany L, Oskamp M, Koren G. Placental metabolism and transplacental pharmacokinetics of cocaine: perfusion studies with the human placental cotyledon [Abstract]. Pediatr Res 1993;33:69A.
11. Koren G, Klein J, Forman R, Graham K. Hair analysis of cocaine differentiation between systemic exposure and external contamination found. J Clin Pharmacol 1992;32: 671-5. 12. Klein J, Chitayat D, Koren G. Hair analysis as a marker for fetal exposure to maternal smoking. N Engl J Med 1993;328: 66-7. 13. Forman R, Schneiderman J, Klein J, et al. Accumulation of cocaine in maternal and fetal hair; the dose response curve. Life Sci 1992;50:1333-41. 14. Ostrea EM, Knapp KD, Romero A, et al. How early in gestation are drugs detectable in meconium [Abstract ] ? Pediatr Res 1993;33:67A.
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