6 5 2 Potter et al. The Journal o f Pediatrics October 1994

Maternal coca ine use without ev idence of fetal exposure

Susan Potter , BSc, Julia Klein, MSc, G r a c e V a l i a n t e , Dale M. Stack, PhD, Apos to los P a p a g e o r g i o u , MD, Wi l l iam Stot t , PhD, Doug las Lewis, PhD, G i d e o n Koren, MD, and Philip R. Zelazo, 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 Hospi- tal, 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 high- light the need to address interpatient variability. (J PEDIATR 4994;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 pre-

mature 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 ben-

zoylecgonine 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 differ-

ent placentae. 8 This hypothesis is supported by in vitro per-

Supported 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 Psychol- ogy, Montreal Children's Hospital, McGill University, 2300 Tup- per, 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 vari-

abilities 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 R E P O R T

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 admit- ted 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 dur- ing the first 3 months of pregnancy. She also reported drinking 12 beers per month during the first 3 months of pregnancy and smok- ing 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.

M E T H O D S

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, co-

tinine. Meconium samples were also analyzed for cannab-

inoids 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

The Journal of Pediatrics Volume 125, Number 4

analysis. Mec0nium samples were analyzed for cocaine, benzoylecgonine, cotinine, cannabinoids, and amphet- amine 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 (pe- riod 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 sam- ples 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 mg 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).

R E S U L T S

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-re- sponse curve in women. 13 Each segment also had high con- centrations O f nicotine and cotinine, consistent with cont- inuous 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 sam- ples. However, the meconiurn sample showed the presence of cotinine and also contained trace amounts of amphet- amines. Similarly, benzoylecgonine was not detected in the infant's hair sample, but nicotine and cotinine were detected with both radioimmunoassay and thermal desorption anal- ysis (Table).

D I S C U S S I O N

This mother voluntarily admitted to intravenous cocaine use throughout her pregnancy, and her report was con- firmed by analysis of her hair samples. Nonetheless, it ap- pears 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 nic- otine and cotinine and the trace amounts of amphetamine

Potter et al. 65 3

Table. Benzoylecgonine, nicotine, and cotinine

concentrations in maternal and infant hair samples

Period of Benzoylecgonine Nicotine Cotinine exposure (ng/mg) (ng/mg) (ng/rng)

Mother At 2 mo after 0.8 6.5 0.4

delivery In 3rd trimester 0.9 11.8 0.2 In 2rid trimester 3.1 14.5 0.3 In 1st trimester 2.3 23.4 0.3

Infant Undetectable 3.0 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 fe- tuses while sparing others. 4

Cocaine has a mean distribution volume of 2 L/kg 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 pla- centa to decreasing levels over time, with many hours with- out 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 partic- ular placenta to bind large amounts of the xenobiotic arriv- ing 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.

R E F E R E N C E S

1. Lutiger B, Graham K, Einarson T, Koren G. Relationship be- tween gestational cocaine use and pregnancy outcome: a me- ta-analysis. Tetralogy 1991;44:404-14.

2. Chasnoff IJ, Lewis DE. Cocaine metabolism during pregnancy [Abstract]. Pediatr Res 1988;23257A.

3. Browne SP, Tebbett IR, Moore CM, Dusick A, Covert R, Yee

GT. Analysis of meconium for cocaine in neonates. J Chro- matogr 1992;575:158-61.

4. Koren G. Maternal-fetal toxicology. New York: Marcel Dek- ker, 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.

6 5 4 Potter et al. The Journal of Pediatrics October 1994

Determination of gestational cocaine exposure by hair analy- sis. JAMA 1989;262:3328-30.

7. Kligman AM. Pathological dynamics of human hair loss: 1. telogen effluvium. Arch Dermatol 1961;83:175-98.

8. Bingol N, Fuchs M, Diaz V, et al. Teratogenicity of cocaine in humans. J PEDIATR 1986;110:93-6.

9. 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.

10. Simone C, Derewlany L, Oskamp M, Koren G. Placental me- tabolism and transplacental pharmacokinetics of cocaine: per- fusion 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 ex- ternal 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 gesta- tion are drugs detectable in meconium [Abstract ] ? Pediatr Res 1993;33:67A.

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