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PEDIATRICS Vol. 106 No. 1 July 2000, pp. 79-85
,
From the Departments of * Pediatrics and Neurology, and the
§ Drug Dependence Research Center, Department of Psychiatry,
University of California, San Francisco, San Francisco, California;
Kinderspital, University of Zurich, Zurich, Switzerland; ¶ School of
Medicine, University of Michigan, Ann Arbor, Michigan; and
# Smith-Kettlewell Eye Research Institute, San Francisco, California.
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ABSTRACT |
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Top
Abstract
Methods
Results
Discussion
Conclusion
References
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Objective. Maternal cigarette smoking, alcohol use, and other factors confound studies of in utero cocaine exposure. Our goal was to determine whether in utero cocaine exposure is associated with an abnormal neurologic examination in infants, while controlling for concomitant cigarette smoke exposure and other confounding variables.
Design. Healthy newborns with birth weights 
2000 g were
prospectively enrolled into a race-matched study of cocaine-exposed and
cocaine-unexposed infants. Urine and meconium samples were analyzed for
illicit drugs, the cocaine metabolite, benzoylecgonine, and the
nicotine metabolite, cotinine. A detailed neurological examination was performed at ~6 weeks of age by an examiner blinded to history.
Results. At 6 weeks of age, 40 cocaine-exposed infants and 56 cocaine-unexposed infants were examined. Tone abnormalities were the only neurologic abnormalities discovered, predominantly generalized hypertonia. Logistic models found that maternal urine cotinine levels were predictive of an abnormal neurologic examination, whereas cocaine exposure or benzoylecgonine levels were not. No interaction was found between maternal cigarette smoking and cocaine exposure. Race, ethanol exposure, prenatal care, homelessness, and head circumference were not predictive of an abnormal tone examination. The odds ratio for an abnormal examination was 2.9 (95% confidence interval: 1.04-8.25), if the maternal urine cotinine level was >200 ng/mL.
Conclusion. Our findings suggest that maternal cigarette smoking may be the major predictor of tone abnormalities reported in cocaine-exposed infants. Key words: cigarette, cocaine, cotinine, neonate, neurologic.
Cocaine use by pregnant women continues to be a significant
public health problem especially among the urban poor. The majority of
fetuses exposed to cocaine are also exposed to other toxins, including
maternal cigarette smoke.1-6 Reported maternal and fetal
effects of maternal cigarette smoking and of maternal cocaine use are
very similar and include fetal growth retardation,1,2,4
spontaneous abortions,6 premature labor and
delivery,4 placenta previa,4,5 placental
abruption,2,3 sudden infant death syndrome,7
and cognitive and behavioral deficits in children.8-11
Compared with fetal cocaine exposure, the deleterious effects of
maternal cigarette smoking on the fetus are unequivocal, because the
associations have been found repeatedly in large epidemiologic studies.
Hypertonia has been cited as the most common reason for referral of
cocaine-exposed infants to a pediatric
neurologist.12 Previous reports also have found an
increased incidence of hypertonia among infants of
smokers.13,14 The goal of this study was to determine the
type and incidence of neurologic sequelae, especially hypertonia, among
in utero cocaine-exposed infants, while independently controlling for
maternal cigarette smoking.
The prevalence of cigarette smoking among adult substance abusers seems
to be 80% or higher,15 even among pregnant women,12,16,17 and cocaine use may be associated with more
intense cigarette smoking.18 Cotinine, a major nicotine
metabolite with a long half-life, is a widely used quantitative
biomarker of cigarette smoking, which has been found to give more
accurate prevalence rates than smoking histories, and more accurate
estimates of daily nicotine intake from cigarette smoke than the count
of the number of cigarettes smoked per day.19,20 It can be
determined in plasma, saliva, or urine19 with good
correlation of levels among those sources.19,20
Quantitative cotinine levels show a dose-dependent relationship between
smoking and outcome, including obstetrical outcomes.21
Maternal or newborn cotinine levels have not been reported in studies
of in utero cocaine exposure.
There are limited reports regarding a comparable biomarker for cocaine.
Cocaine use is not a daily habit like cigarette smoking. Meconium22,23 analyses for cocaine or metabolites provide
higher in utero exposure rates than do history or urine cocaine
metabolite analyses and seem to reflect exposure during the third and
possibly second trimester. There are no reports that correlate
quantitative meconium levels with maternal use patterns. Two studies
have correlated meconium levels with outcome.24,25 A
significant inverse correlation was found between meconium levels and
birth weight, length, and head size24; and a correlation was found between meconium levels and scores on the Brazelton Neonatal
Behavioral Assessment Scales.25
In this study, maternal and newborn biologic samples were collected and
quantitatively analyzed for cocaine and its metabolites and for
nicotine and cotinine. These quantitative levels were investigated as
independent predictor measures of neurologic outcome in this
prospective, blinded, controlled study of 6-week-old infants.
Subjects
This study, approved by the University of California, San
Francisco, Committee on Human Research, was a prospective, blinded study of healthy cocaine-exposed infants and healthy cocaine-unexposed infants, matched for race of mother. All infants were born at San
Francisco General Hospital (SFGH), a county hospital serving a lower
socioeconomic patient population. The birthing population during the
enrollment period (n = 2539) was ~50% Hispanic, 22% Asian or Pacific Islander, 17% black, 9% white, and 9% other
or unknown ethnicity. The Hispanics and Asians were predominantly non-English-speaking immigrants. Each year between 15% and 20% of
newborns are tested by the hospital for drugs of abuse because they or
their parents are positive for at least 1 of the following and deemed
at risk: no prenatal care, history of substance abuse, obstetrical
suspicion (eg, placental abruption), intrauterine growth retardation,
history of prostitution, history of incarceration, major psychiatric
diagnosis, and family violence. These criteria have been validated
previously by the hospital with universal toxicology testing of
newborns and validated by us before this study. Among births that have
documented exposure to illicit drugs, the racial demographics were
~70% black, 20% white, and 10% Hispanics or other. Many
non-English-speaking Hispanic women present for delivery without
prenatal care; their infants are tested but are rarely positive for
drugs of abuse.
Enrollment occurred from August 1, 1994 to July 31, 1996. The
enrollment consent process was performed by a single research associate
on weekday mornings. The English-speaking mothers of all infants who
were at risk for in utero cocaine exposure17 and who met
study criteria (below) were approached for study enrollment. Mothers
without risk factors for substance abuse and who were of a similar
ethnic background were also approached for study enrollment. Because
the population of infants not at risk for cocaine exposure was much
larger than for those at risk, the cocaine-unexposed cohort was
enrolled in blocks of 10 by ethnicity and enrollment into that block
would cease until 10 at-risk infants had also been enrolled. Among the
mothers at risk for cocaine use, 70% consented to the study. Among the
mothers not at risk for cocaine use, 44% consented. There was
variability in consent by ethnicity. Among those approached for
enrollment, 67% of blacks, 37% of whites, and 26% of Hispanics
agreed to participate. Potential mothers were approached within 24 hours of birth for study consent. Mothers received an article of infant
clothing, a $20 grocery store food voucher, and taxi vouchers for the
follow-up visit at 6 weeks of age.
The exclusion criteria were: birth weight <2000 g; illness requiring
admission to the intensive care nursery or the step-down unit; maternal
age <18 years; non-English-speaking mothers; and polydrug exposure
except marijuana and ethanol. Subjects were considered to be
cocaine-exposed if any sample was positive for cocaine metabolite or if
the mother gave a history of use during the current pregnancy. Subjects
were considered to be cocaine-unexposed if there was no history of
illicit drug use during pregnancy and all samples were negative for
drugs of abuse except marijuana.
Sample Collection
The hospital collected urine from all at-risk newborns and
tested the urine for alcohol, amphetamines, barbiturates,
benzodiazepines, benzoylecgonine, opiates, and phencyclidine. The
hospital screened for the cocaine metabolite, benzoylecgonine, using
the kinetic interaction of microparticles in solution assay
(Roche Diagnostic Systems, Nutley, NJ), with confirmation using the
enzyme multiplication immunoassay technique (Syva Co, San Jose,
CA). The threshold for detection of benzoylecgonine was 300 ng/mL.
Research personnel collected samples of meconium, neonatal urine, and
maternal urine. After consent was obtained, diapers were saved by the
nursing staff and/or mothers, and meconium and urine were removed from
the diapers by study personnel. Meconium was assayed by Abbott
fluorescence polarization immunoassay for cocaine, cocaine metabolites
(cocaethylene, benzoylecgonine, and M-hydroxybenzoylecgonine), amphetamines, cannabinoids,
morphine, codeine, benzodiazepines, and barbiturates (US Drug Testing
Laboratories, Chicago, IL). Quantitative drug levels in meconium were
determined by gas chromatography/mass spectrometry, and the
threshold for detection for cocaine and metabolites was 25 ng/g (US
patent numbers 5 532 131 [July 2, 1996] and 5 587 323 [December
24, 1996]). The quantitative levels of cocaine and all of its
metabolites were converted to moles and summed. The molar sum was
converted to nanograms of cocaine per gram of meconium, and this number
was used for statistical analyses. Research urine samples were
acidified with sodium bisulfate and frozen until gas
chromatography/mass spectrometry analysis by the methods of
Jacob et al26,27 for the following: cocaine,
benzoylecgonine, nicotine, and cotinine. The levels of quantitation
were cocaine (5 ng/mL), benzoylecgonine (10 ng/mL), nicotine (1 ng/mL),
and cotinine (10 ng/mL).
Chart Reviews
All maternal and neonatal charts of enrolled subjects were
reviewed. All histories were obtained by chart review. Mothers were not
interviewed about their drug use history by study personnel for the
following reasons. Approximately 30% of substance-abusing women who
deliver at SFGH lose custody of their infants. Enrollment into the
study occurred at the same time as the Child Protective Services
investigation. The Committee on Human Research of the University of
California, San Francisco would not allow us to interview the mothers
because of the risk that the history may be used to deprive them of
custody of their infant. We also wanted to encourage participation by
mothers who had not received prenatal care, and these were the women at
greatest risk of losing custody of their infants. It was our experience
that interviewing this population for drug use, at the same time as a
Child Protective Services investigation, discouraged participation, and
that the histories were inaccurate.
All woman receiving prenatal care at SFGH were interviewed by an
experienced hospital social worker in each trimester and an alcohol and
drug use history was included in each interview. Women who had not
received prenatal care had an in-depth postpartum interview by the
hospital social worker. The records of these interviews are in the
hospital charts and were included for analysis. Smoking and alcohol
intake histories were obtained by the prenatal care provider and by the
prenatal care nutritionist during an initial prenatal care visit. Data
were extracted from the maternal and neonatal charts, including the
smoking, alcohol, and drug use history.
Physical and Neurologic Examinations
At 6 weeks of age, infants were brought to the General Clinical
Research Center at SFGH. Infants were examined by 1 pediatric neurologist who was blinded to all aspects of the infant's history and
to any previous examinations. The parents or caregivers did not meet
the examiner at any time. The neurologic examination at 6 weeks of age
included: 1) growth indices; 2) adaptive capacity (response to sound,
light, and examiner); 3) mental status (alertness, vocalization,
curiosity, and consolability); 4) presence of dysmorphism, neurocutaneous signs; 5) cranial nerve assessment; 6) tone (active, passive, truncal, upper extremities, and lower extremities; 7) power
(truncal, upper extremity, and lower extremity); 8) deep tendon
reflexes (right, left, biceps, triceps, patellar, and Achilles); and 9)
primitive reflexes (palmar, Moro, automatic walking, plantar, placing,
cortical thumb, suck, glabellar, and Babinski). At the end of the
examination, an overall assignment of a normal or abnormal neurologic
examination was made.
Urine Concentrations of Cotinine
The urine concentrations of the nicotine metabolite, cotinine,
were used in statistical tests as an indirect measure of maternal cigarette smoking. Maternal urine levels of cotinine were used. When no
maternal urine was available, the neonatal urine level was
used.28 The mother was designated a nonsmoker,
including passive smoking, if the urine cotinine level was <30
ng/mL.19,20
Statistics
Using the statistical program SAS (SAS, Cary, NC), the following
statistical tests were applied: 2-group comparisons were performed
using Student's t tests for continuous,
symmetrically distributed variables. Mann-Whitney U tests
were used for ordinal and nonsymmetrically distributed continuous
variables. One hundred fifty-three newborns were enrolled after birth before
discharge from the nursery, and 96 infants returned for a neurologic
examination at 6 weeks of age (Table 1). There was no difference in the variables listed in Table
2 between the cocaine-unexposed infants
who did not return for follow-up and those who did return. There was a
significant difference in birth weight in cocaine-exposed infants
(P = .052); cocaine-exposed infants who returned at 6 weeks had a mean birth weight of 3000 g (standard deviation
[SD]: 503), while those who did not return had a mean of 2780 g
(SD: 436). There was no statistically significant difference between
the cocaine-exposed infants who returned and those who did not return
at 6 weeks of age in regard to race, sex, urine benzoylecgonine level,
urine cotinine level, prenatal care, maternal alcohol use, head
circumference, length, entry into foster care, or homelessness.
TABLE 1 TABLE 2
METHODS
Top
Abstract
Methods
Results
Discussion
Conclusion
References
2 tests were used for 3 or more
level nominal variables and Fisher's exact test for proportions.
Logistic regression was used for a multivariate predictor of
normal/abnormal neurological examination. The statistical test used is
indicated with the P value in the "Results" section.
RESULTS
Top
Abstract
Methods
Results
Discussion
Conclusion
References
Number of Infants Enrolled and Number Who Returned at Six Weeks of
Age
Demographics of Study Population
The differences commonly reported by other investigators were found
between the cocaine-exposed and cocaine-unexposed infants and are
listed in Table 2. There was a statistically significant difference
(P = .015) found for race between cocaine-exposed and
cocaine-unexposed infants seen at 6 weeks of age. The same number of
blacks was enrolled in both cohorts (33 each), but more non-blacks were
enrolled in the cocaine-unexposed group. The racial imbalance occurred
because of block enrollment of the control cohorts
a block of 10 for
each race was too large and resulted in overenrollment of
cocaine-unexposed Hispanics, Asians, and Native Americans.
The outcome of interest was the neurologic examination at 6 weeks of age. There were 54 infants who had a normal neurologic examination result, and 42 infants who had an abnormal neurologic examination result. Tone abnormalities were the only neurologic abnormality found. The predominant tone abnormality was generalized hypertonia, and there were only 2 asymmetric neurologic examinations (R>L or L>R). Specifically, generalized hypertonia was found in 50% of the abnormal examinations, appendicular (arms and legs) hypertonia in 33%, and hypotonia in 17%.
Table 3 shows the percentages or means for each predictor variable for infants with a normal neurologic examination and for infants with an abnormal neurologic examination. Cocaine exposure was not associated with an abnormal neurologic examination. Urine samples were available for 93% of the enrollees. Among cocaine-exposed infants, 82.5% had positive urine or meconium assay results for cocaine or metabolite. Among the remaining 17.5% of cocaine-exposed infants, their cocaine exposure status was based on history. Among the cocaine-exposed infants, there was no statistically significant difference in urine benzoylecgonine levels between those with normal examinations and those with abnormal examinations (P = .7). The mean urine benzoylecgonine levels for those with normal examinations was 9.6 µg/mL (±12.6) and 10.3 µg/mL (±19.4) for those with abnormal examinations. Meconium samples were collected on 60.4% of all enrollees. Segregating the enrollees by exposure cohort, 68% of unexposed infants and 50% of cocaine-exposed infants had meconium collected. Segregating the enrollees by outcome, 55% of those with a normal examination and 68% of those with an abnormal examination had a meconium sample. In meconium, the mean sum of cocaine and its metabolites for the normal group was 832 ng/g (SD ± 2317), whereas for the abnormal group it was 881 ng/g (SD ± 1511); there was no significant difference (P = .9). Three meconium samples of cocaine-exposed infants were negative: 2 had benzoylecqonine-positive maternal or newborn urine and the third mother was a regular user until 2 months before birth when she became abstinent. Seven percent of cocaine-exposed infants were also meconium-positive for cannabinoids. Cocaine exposure was treated as a binary exposure because no relationship was found between cocaine or metabolite concentrations and outcome, and a substantial number of infants would be misclassified as unexposed because urine samples were negative or omitted because of missing meconium data.
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The mothers of 33% of the infants with a normal examination were smokers, whereas 55% were smokers for the abnormal examination group. There was a statistically significant difference between the mean urine cotinine levels of infants with normal examinations and those with abnormal examinations (Table 3). Specifically, looking only at the active smokers (cotinine = 30 ng/mL), those with a normal examination had a mean cotinine level of 161 ng/mL (median: 149 ng/mL; maximum: 592 ng/mL), whereas those with an abnormal examination had a mean cotinine level of 355 ng/mL (median: 306 ng/mL; maximum: 1170 ng/mL). No statistically significant differences were found between those infants with abnormal examinations and those with normal examinations for race, sex, prenatal care, homelessness, maternal alcohol use, maternal age, gestational age, parity, and growth indices (Table 3).
Logistic Regression
A logistic model was developed to investigate the relationship between abnormal neurologic examination and the predictors, cocaine exposure and maternal cigarette smoking (urine cotinine concentration). The model was statistically significant (P = .01). No statistically significant relationship was found between cocaine exposure and neurologic examination outcome (P = .8). This nonsignificant relationship held if urine BE concentration or meconium BE concentration was used instead of cocaine exposure. A significant relationship was found between the urine cotinine concentration and an outcome of an abnormal neurologic examination (P = .03). The odds ratio for an abnormal neurologic examination was 1.46 per 100 ng/mL of cotinine in the urine (95% confidence interval [CI]: 1.04-2.02). No interaction (P = .7) was found between cocaine exposure and maternal urine cotinine level. If cotinine levels were treated as a categorical variable (<30 ng/mL, 30-200 ng/mL, and >200 ng/mL), then the odds ratio for an abnormal examination for levels between 30 and 200 ng/mL was .8 (95% CI: .3-2.0), and it was 2.9 (95% CI: 1.04-8.2) for levels >200 ng/mL. Confounders were not significantly associated with outcome after controlling for cotinine levels (Table 4).
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The lack of association between cocaine exposure and an abnormal examination when controlling for smoking exposure is also clear from simple tabulation. Among 10 infants with smoking exposure but no cocaine exposure, 6 (60%) had an abnormal examination, similar to the rate of 55% (17 of 31) seen in those with both smoking and cocaine exposure, whereas those with cocaine exposure and no smoking exposure had a rate of 33% (3 of 9), which is similar to the rate of 35% (16 of 46) seen in those with neither cocaine nor smoking exposure.
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DISCUSSION |
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Top
Abstract
Methods
Results
Discussion
Conclusion
References
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These data indicate that tone abnormalities, predominantly hypertonia, which is a commonly reported physical finding among cocaine-exposed neonates, correlated with maternal cigarette smoking during pregnancy but not with in utero cocaine exposure. The correlation between maternal cigarette smoking and an abnormal examination was concentration dependent. As the concentration of cotinine increased, the risk of hypertonia increased. At cotinine concentrations >200 ng/mL, the odds ratio for an abnormal examination was 2.9.
Hypertonia in infancy has been previously reported to be associated with maternal cigarette smoking.13,14 A prospective longitudinal study of middle-class children found prenatal tobacco smoke exposure was associated with an increased incidence of hypertonia in infancy,13,14 and, in subsequent follow-up evaluations, adverse behavioral and cognitive effects have been found even into late childhood.8,9 These studies have not evaluated infant hypertonia as a predictor of childhood abnormalities.8,9,13,14
Cocaine use is measured in times per week while cigarette use is measured in cigarettes per day and/or how soon after awakening from sleep one has a cigarette. Animal studies indicate that continuous low-dose nicotine exposure is more deleterious to the developing central nervous system than episodic cocaine.29 In addition, tobacco smoke contains carbon monoxide, cyanide, oxidative gases, and 3000 or more other chemicals besides nicotine. Carbon monoxide is a potent fetotoxin,30 especially for the central nervous system, and exposure increases directly with the number of cigarettes smoked.31 It tightly binds to both maternal and fetal hemoglobin causing a functional anemia, and it also affects the dissociation of oxygen from hemoglobin so that greater tissue hypoxia is required to dissociate oxygen from hemoglobin.30
Studies of the effects of maternal cocaine use that carefully control for smoking have found that some putative obstetrical effects of prenatal cocaine exposure could be explained by maternal cigarette smoking,1-5 or that the obstetrical risk associated with smoking was greater than or equal to that of cocaine use.6 Recent studies have reported that cigarette smoking was a more important predictor of low birth weight than in utero cocaine exposure,1,2,5 and that infants born to women who both smoke cigarettes and use cocaine weigh 300 g less than infants of women who only use cocaine.5 It is medically feasible that adverse fetal effects that have been associated with cocaine exposure may be predominantly attributable to maternal cigarette smoking.
Previous studies of cocaine-exposed neonates have relied on maternal
history for cigarette smoking, by either chart review or
interview.12,16 This study is the first to use cotinine, a
widely accepted dose-dependent biomarker of maternal cigarette smoking,
in a study of cocaine-exposed newborns. The association between
maternal smoking and hypertonia would not have been ascertained if
maternal smoking history by chart review was used as the measure.
Determination of cotinine levels gave different smoker assignments than
cigarette smoking status by chart history, and also allowed estimation
of use. Based on cotinine levels, 19 infants had a change in maternal
smoking status or were able to be assigned a smoking status; 7 of these
had no history in the chart regarding maternal smoking status, 7 had a
chart history of maternal smoking but had cotinine levels <10 ng/mL,
and 5 had a chart history of nonsmoking but cotinine levels were 30
ng/mL (30, 112, 268, 344, and 439 ng/mL).
Reported rates of cigarette smoking among pregnant substance abusers varies from 28%1 to 90%.12,16 This wide disparity in smoking rates may indicate that many studies of in utero exposure may have been poorly controlled for smoking. Accurate determination of cigarette smoking status is obviously important, and maternal urine cotinine levels offer a quantitative biomarker of cigarette smoking. They are easy to obtain even in a population of substance-abusing women who have not received prenatal care. A maternal urine sample is collected nearly universally on all patients at the time of admission to Labor and Delivery; and cotinine is a stable compound in urine, so routine hospital urine samples can be retrieved from the hospital laboratory and used in prospective studies.32
Tone abnormalities in infants have been associated with cocaine exposure, alcohol exposure, and with black race. In this study, the high upper limits of the CIs for the odds ratios for cocaine, excess alcohol use, and race may indicate that these predictors may be important. The cocaine-exposed infants who did not return for follow-up were smaller, and their inclusion may have altered the study findings. But among those that did return, there were the typical growth and demographic differences between the cocaine-exposed and -unexposed infants (Table 2), and yet no statistical trend was evident between cocaine exposure and an abnormal examination (Tables 3 and 4).
The tone abnormality associated with fetal alcohol syndrome is hypotonia, and hypotonia accounted for 17% of the tone abnormalities found.33 Cocaine exposure has been reported to have a more pronounced effect on motor development of black infants, compared with white infants34; but the number of cocaine-exposed non-blacks in this study was small, and the study may be underpowered to evaluate non-blacks. Recently, a study of newborns found a dose-dependent relationship between neurologic abnormalities, including hypertonia and maternal hair levels of cocaine35; maternal smoking patterns were obtained by history with prevalence of 53% among the cocaine users. Although we used quantitative levels of cocaine metabolite in urine and meconium, we did not find an association with cocaine exposure (P = .7). Hair may offer a more reliable marker for cocaine exposure,6,36 and it can be collected at any time during the nursery stay, whereas meconium may be passed before birth or within hours of birth and inadvertently discarded or discarded before enrollment. A study that could quantitatively determine the magnitude of maternal cocaine use, in addition to cotinine levels, may find cocaine has an association with infant hypertonia.
A high prevalence of hypertonia among cocaine-exposed infants has been found by others.12,16,35 Among 6-week-old infants, Chiriboga et al12 found that 41% of cocaine-exposed 6-month-old infants were hypertonic, compared with 25% of unexposed infants. The prevalence of maternal cigarette smoking was 91% among cocaine users and 80% among nonusers. In a subsequent study of newborns, they also found a high incidence of hypertonia associated with cocaine exposure, but a lower prevalence of maternal smoking (53%).35 Similarly, Napiorkowski et al16 found that 60% of cocaine-exposed newborns were hypertonic, compared with 20% of unexposed newborns. Among the cocaine-exposed newborns, 90% of the mothers smoked cigarettes, compared with 40% of the unexposed cohort, but no data were provided regarding hypertonia and tobacco exposure.
These studies may not have adequately controlled for smoking. All 3 studies relied on cigarette-smoking histories. The 2 studies by Chiriboga et al12,35 found very different prevalence rates of smoking, 90%12 versus 53%.35 In the larger, more recent study,35 cocaine exposure was estimated by quantitative levels of cocaine in maternal hair, yet no biomarker was used for smoking. Cotinine concentrations in urine, plasma, or saliva correlate better with actual cigarette smoking than smoking histories. Separate from accurate and honest recall, individuals who smoke the same number of cigarettes may have very different smoke intake. Some people inhale shallowly and infrequently, whereas others may inhale deeply and frequently. Cotinine concentrations correct for recall bias, dishonest reporting, and different styles of smoking.19,20
What is the clinical significance of nonfocal hypertonia during infancy? The nonfocal hypertonia found by us and others does not seem to be a marker of later serious motor impairment, such as cerebral palsy, and among in utero exposed infants the hypertonia seems to resolve by 2 years of age.12 Although both infant hypertonia and childhood cognitive and behavioral problems have been found among those prenatally exposed to tobacco smoke or cocaine, no study has investigated infant hypertonia as a marker for adverse childhood cognitive or behavioral outcomes.
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CONCLUSION |
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Top
Abstract
Methods
Results
Discussion
Conclusion
References
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Our study found an association between an abnormal tone, predominantly hypertonia, and maternal cigarette smoking that was dose-dependent. This study suggests that previous studies of cocaine-exposed infants may have inadequately controlled for maternal cigarette smoking and that some outcomes that have been attributed to in utero cocaine exposure may actually be attributable to maternal cigarette smoking. It should be remembered that the effects of in utero cocaine exposure and maternal smoking are overshadowed by the poverty and other environmental conditions in which many of the exposed children live.9,37 Additionally, this study demonstrates the utility of cotinine as a biomarker for maternal smoking among cocaine-exposed newborns. Cotinine levels correlate better with actual nicotine intake than with smoking history,20 and these findings have been validated in obstetrical studies.38,39 Finally, the clinical significance of hypertonia in infancy is unknown, but it may be a marker for later childhood cognitive or behavioral problems. Future studies need to be designed to investigate the relationship between infant hypertonia and childhood behavioral and cognitive outcomes.
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ACKNOWLEDGMENTS |
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This work was conducted in the General Clinical Research Center at San Francisco General Hospital (RR00083-35). It was supported in part by Grant P20 NS32553 from the National Center for Research Resources (to D.M.F.); Grants K05 DA00053 and P50 DA01696 (to R.T.J.) and R01 DA09761 (to D.A.D.) from the National Institute on Drug Abuse, National Institutes of Health; and by the University of California, San Francisco Research Evaluation and Allocation Committee and the Roche Research Foundation.
We thank the nursing staff of San Francisco General Hospital Labor and Delivery and the staff of the San Francisco General Hospital General Clinical Research Center for their cooperation and dedication to study completion. We also thank Drs Neal Benowitz and Peyton Jacob, III, for their contributions, and Kaye Welch for editorial assistance.
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FOOTNOTES |
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Received for publication Jun 21, 1999; accepted Jan 24, 2000.
Reprint requests to (D.A.D.) Clinical Pharmacology, Box 0898 CRM, University of California, San Francisco, San Francisco, CA 94143-0898. E-mail: deliad{at}itsa.ucsf.edu
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ABBREVIATIONS |
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SFGH, San Francisco General Hospital; SD, standard deviation; CI, confidence interval.
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REFERENCES |
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Abstract
Methods
Results
Discussion
Conclusion
References
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 H S Bada, C R Bauer, S Shankaran, B Lester, L L Wright, A Das, K Poole, V L Smeriglio, L P Finnegan, and P L Maza Central and autonomic system signs with in utero drug exposure Arch. Dis. Child. Fetal Neonatal Ed., September 1, 2002; 87(2): F106 - 112. [Abstract] [Full Text] [PDF]
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