August
2006 VOLUME
3, NUMBER 12
In
this issue...
Methamphetamine, a highly-addictive stimulant, was first synthesized
in 1893 by a Japanese pharmacologist and its addictive potential became
evident after World War II. While it has been abused in pockets of the
United States for decades, currently its growing use throughout the
country is attracting the attention of the medical and law enforcement
communities as well as the media. Physiologically, methamphetamine appears
similar to cocaine, but it is less expensive and far longer acting,
suggesting great potential to supplant cocaine as the drug of choice
in many areas.
For the neonatologist, knowledge regarding the effects of methamphetamine
is important because women of childbearing age appear to have high rates
of abuse and adverse neonatal effects have been described. Methamphetamine-exposed
infants are frequently premature and born to mothers with little prenatal
care. Other comorbid medical and social conditions exist that mandate
a team approach involving obstetrics, neonatology/pediatrics, social
work, and state social services.
In this
issue, we review existing animal and human studies that describe fetal
methamphetamine physiology and the effects of antenatal exposure on
neonatal growth, brain structure and neurodevelopment, and discuss research
reporting the child abuse and neglect potential among methamphetamine
users.
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Guest
Editor of the Month |
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Commentary
& Reviews:
Declan P. O’Riordan, M.D.
Attending Neonatologist
St. Luke's Regional Medical Center
Boise, ID
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Guest Faculty Disclosure:
Declan P. O’Riordan, M.D
Faculty Disclosure: No relationship with commercial supporters.
Unlabelled/Unapproved Uses:
No faculty member has indicated that their presentation will include information on off label products.
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Learning
Objectives
The
Johns Hopkins University School of Medicine and The Institute for Johns
Hopkins Nursing take responsibility for the content, quality, and scientific
integrity of this CME/CE activity.
At
the conclusion of this activity, participants should be able to:
- Describe the association between prenatal methamphetamine exposure
and decreased fetal growth;
- Discuss the central nervous system damage, including intraventricular
hemorrhage, white matter lesions, and decreased growth of subcortical
gray structures, associated with fetal methamphetamine exposure;
- Identify the neurobehavioral alterations in the newborn produced
by antenatal methamphetamine exposure.
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Course Directors
Edward E, Lawson, M.D.
Professor
Department of Pediatrics Neonatology
The Johns Hopkins University
School of Medicine
Lawrence M. Nogee, M.D.
Associate Professor
Department of Pediatrics Neonatology
The Johns Hopkins University
School of Medicine
Christoph U. Lehmann, M.D.
Assistant Professor
Department of Pediatrics,
Health Information
Science and Dermatology
The Johns Hopkins University
School of Medicine
Mary Terhaar, RN
Assistant Professor
Undergraduate Instruction,
The Johns Hopkins University
School of Nursing
Robert J. Kopotic, MSN, RRT, FAARC
Director of Clinical Programs
ConMed Corporation
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Commentary |
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The use
of methamphetamine (also known as “meth”, “blue acid”,
“biker dope”, “hillbilly crack” and many other
slang terms) is growing in the United States and other Western countries.
It is a highly addictive synthetic stimulant that is easily and inexpensively
manufactured in clandestine laboratories. Users describe a sense of euphoria,
increased energy, decreased appetite, and increased concentration. Although
methamphetamine has been abused for decades in the several areas of the
United States, its historically regional distribution appears to have limited
scientific study of its effects on the developing fetus. Antenatal methamphetamine
use has been associated with prematurity, increased risk for abruption,
decreased fetal growth, and intraventricular hemorrhages (1,2), but the
medical literature on neonatal outcomes is relatively sparse compared to
that of cocaine and heroin, and confounding factors are multiple. Additionally,
no long-term developmental studies of fetuses exposed to methamphetamine
have been published.
Because
of the paucity of data, the National Institutes on Drug Abuse called for
increased research in to the effects of methamphetamine abuse on the developing
fetus. Alan Leshner, Ph.D., NIDA's Director from 1994 to 2001, stated that
"We need to get a handle on this fast. Unless we get into this rapidly,
we're going to make the same mistake we made with cocaine."(3) The
mistake Dr. Leshner refers to was the unscientific furor over "crack
babies" of the 1980s; yet already, there are signs that such a furor
over “meth babies” is beginning and, as in the early days of
the crack epidemic, efforts are underway in at least one state (Idaho)
to incarcerate pregnant methamphetamine abusers.
Though long
term methamphetamine studies are lacking, existing human and animal studies
provide ample reason for concern. Animal studies using sheep and rodents
have demonstrated that maternal and neonatal use of methamphetamine during
pregnancy can decrease uterine blood flow, decrease fetal PaO2 (4), cause
poorer maternal post-partum care of rat pups (5), decrease fetal growth
(5), alter learning (6), and increase rates of malformations (7,8). While
several human studies also suggest an association between prenatal methamphetamine
exposure and decreased fetal growth (1, 2, 9, 10), a recent larger study
did not find a significant difference in mean head circumference, length,
or weight. This larger study found that methamphetamine-exposed infants
were significantly more likely to be small for gestational age (defined
as length, head circumference, or weight less than 5%)(11). Interestingly,
this larger study also found that antenatal smoking in combination with
methamphetamine resulted in a significant decrease in birth weight and
head circumference (but not length).
Like cocaine,
methamphetamine has been associated with hemorrhagic and ischemic strokes
in adults. Only one published study, though, examines CNS imaging in neonates
following antenatal use of methamphetamine. Dixon & Bejar found a variety
of hemorrhagic intracranial lesions in a relatively small group (n = 24)
of term infants exposed to antenatal methamphetamine (2). Smith, Chang,
and others examined MRI and MRS results of children exposed prenatally
to methamphetamine and found smaller subcortical volumes and altered creatinine
levels in the striatum as well as decreased performance in a variety of
attentional-based tests (12, 13). Smith also found that withdrawal symptoms
(by "Finnegan" scores) were present in 49% of meth-exposed infants,
but only 4% required treatment, suggesting that the symptoms are not as
pronounced as in narcotic withdrawal (11).
Much about
the antenatal effects of this drug remains to be determined. Large studies
linking methamphetamine to malformations are completely lacking and its
human teratogenic potential at this time cannot be substantiated. While
it is plausible to link maternal methamphetamine to a variety of neonatal
morbidities (supraventricular tachycardia, bowel infarctions, and others),
no published studies have yet supported this link. Additionally, Oro &
Dixon suggest that the withdrawal state characterized by agitation and
poor sleep is actually an intoxication that is followed by true withdrawal,
manifesting as poor feeding requiring gavage and decreased wakefulness
(1).
The studies
discussed herein highlight the truly critical need for controlled long-term
developmental studies of infants exposed antenatally to methamphetamine.
References:
1. |
Oro
AS, Dixon SD. Perinatal
cocaine and methamphetamine exposure: Maternal and neonatal correlates.
J Pediatr. 1987;11(4):571-8. |
2. |
Dixon
SD, Bejar R. Echoencephalographic
findings in neonates associated with maternal cocaine and methamphetamine
use: Incidence and clinical correlates. J Pediatr.1989;115(5): 770-8. |
3. |
Marwick
C. NIDA
seeking data on effect of fetal exposure to methamphetamine. JAMA.
2000; 283(17):2225-6.
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4. |
Stek
AM, Baker RS, Fisher BK, et al. Fetal
responses to maternal and fetal methamphetamine administration in sheep.
Am J Obstet Gynecol. 1995;173(5):1592-8. |
5. |
Slamberova
R, Charousova P, Pometlova M. Methamphetamine
administration during gestation impairs maternal behavior. Dev Psychobiol.
2005; 46(1):57-65. |
6. |
Williams
MT, Moran MS, Vorhees CV. Behavioral
and growth effects induced by low dose methamphetamine administration
during the neonatal period in rats. Int J Devl Neurosci. 2004; 22(5-6):273-83. |
7. |
Yamamoto
Y, Yamamoto K, Fukui Y, Kurishita A. Teratogenic
effects of methamphetamine in mice. Nippon Hoigaku Zasshi. 1992;
46(2):126-31. |
8. |
Acuff-Smith
KD, Schilling MA, Fisher JE, Vorhees CV. Stage-specific
effects of prenatal d-methamphetamine exposure on behavioral and eye
development in rats. Neurotoxicol Teratol. 1996; 18(2):199-215. |
9. |
Little
BB, Snell LM, Gilstrap LC. Methamphetamine
abuse during pregnancy: outcome and fetal effects. Obstet Gynecol.
1988; 72(4):541-4. |
10. |
Comchai
C, Na Manorom N, Watanarungsan, et al. Methamphetamine
abuse during pregnancy and its health impact on neonates born at Siriraj
Hospital, Bangkok, Thailand. Southeast Asian J Trop Med Pub Health.
2004; 35(1):228-231. |
11. |
Smith
L, Yonekura ML, Wallace T, et al. Effects
of prenatal methamphetamine exposure on fetal growth and drug withdrawal
symptoms in infants born at term. J Dev Behav Pediatr. 2003: 24(1):17-23. |
12. |
Chang
L, Smith LM, LoPresti C, et al. Smaller
subcortical volumes and cognitive deficits in children with prenatal
methamphetamine exposure. Psychiatry Res. 2004; 132(2):95-106. |
13. |
Smith
LM, Chang L, Yonekura ML, et al. Brain
proton magnetic resonance spectroscopy in children exposed to methamphetamine
in utero. Neurology. 2001; 57:255-260. |
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ANIMAL
MODELS OF FETAL METHAMPHETAMINE PHYSIOLOGY |
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Stek AM, Baker RS, Fisher BK, et al. Fetal responses to maternal
and fetal methamphetamine administration in sheep. AJOG. 1995;
173(5):1592-1598.
(For non-journal subscribers, an additional fee may apply for full
text articles) |
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Stek et al. at the University of Cincinnati investigated the maternal and
fetal cardiovascular effects of methamphetamine ingestion near term by pregnant
sheep, followed by a dose-response study examining administration of methamphetamine
to the pregnant ewe as well as directly to the fetus. After placing central
lines in both ewe and fetus, the animals recovered for at least 5 days prior
to administration of increasing doses of methamphetamine (0.03, 0.1, 0.3,
and 1.0 mg/kg) to the mother via slow IV bolus. On a different day, the
fetus received increasing doses of methamphetamine based on estimated fetal
weight (0.03, 0.1, 0.3, 1.0, and 3.0 mg/kg). Measured variables included
maternal and fetal blood pressure, left and right uterine arterial blood
flow, umbilical arterial flow, and maternal and fetal blood gas analysis.
Uterine vascular resistance and umbilical vascular resistance were also
calculated.
As expected, maternal administration of methamphetamine caused a statistically
significant dose-related increase in maternal blood pressure that peaked
5 minutes after injection. At the 1 mg/kg dosing level, maternal blood
pressure increased 76% from a baseline of 82 +/- 3 mm Hg to 130 +/- 8 mm Hg.
Uterine vascular resistance increased in all animals after maternal dosing,
to a maximum of 140 +/- 31% over baseline, reaching statistical significance
at the 0.3 and 1 mg/kg doses. The mean uterine blood flow dropped by 19%
(not statistically significant). In response to maternal methamphetamine,
fetal mean arterial pressure demonstrated a progressive dose-related increase
up to 28 +/- 3% over baseline (1 mg/kg dose). In contrast to uterine blood
flow, umbilical blood flow increased by 15 +/- 7% over baseline (p = 0.05).
Fetal blood gas analysis demonstrated a statistically significant progressive
fall in fetal PaO2. At the 1 mg/kg dosing level, fetal PaO2 fell from a
baseline of 21.2 +/-1 mm Hg to 16.3 +/- 2.2 mm Hg (p = 0.01). Fetal pH and
PaCO2 did not change significantly. Administration of methamphetamine directly
to the fetus also produced a large increase (40 +/- 1%) in fetal mean arterial
pressure and a significant drop in pH (from 7.30 at baseline to 7.157 +/-
0.085 (p = 0.05)), but it did not produce a significant change in either
PaO2 or PaCO2.
While the authors caution that significant differences exist in the uteroplacental
unit between sheep and humans, this study provides a basic model for examining
the key fetal physiologic effects of methamphetamine. According to the
authors, the doses used are similar to those typically consumed by humans
(0.2 to 2 mg/kg) and fetal methamphetamine levels were approximately 65%
of maternal levels, indicating substantial placental transfer. Impressive
dose-related changes in multiple variables were evident, including progressive
increases in uterine vascular resistance and fetal and maternal MAP as
well as a progressive fall in fetal PaO2. These findings, particularly
the progressive fetal hypertension and progressive increase in uterine
vascular resistance, provide potential explanations for two reported perinatal
methamphetamine complications: neonatal intracranial hemorrhage (discussed
below) and placental abruption. The authors concluded that the fall in
fetal PaO2 was likely due to compromised uterine blood flow. The study
is also valuable in demonstrating that high doses of methamphetamine (administered
directly to the fetus) can cause a marked acidosis. Although a mild elevation
of fetal PaCO2 was detected following direct administration of methamphetamine
to the fetus, the degree of the acidosis implies compromised metabolism
resulting in lactic acidemia, a finding previously reported (Dickinson
JE, Andres RL, Parisi VM. The ovine fetal sympathoadrenal response to the
maternal administration of methamphetamine. Am J Obstet Gynecol. 1994;
170(5 Pt 1):1452-7). While the study provides attractive basic physiologic
data regarding the transfer of methamphetamine and its effects on the maternal
and fetal circulation, it did not fully model prolonged human methamphetamine
use.
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NEONATAL
INTRACRANIAL HEMORRHAGES |
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Dixon SD and Bejar R. Echoencephalographic findings in neonates
associated with maternal cocaine and methamphetamine use: Incidence
and clinical correlates. J Pediatr. 1989; 115(5):770-778. |
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Cocaine and methamphetamine, substances with strong cardiovascular toxicities,
have been associated with hemorrhagic and ischemic strokes. Suzanne Dixon
and Raul Bejar at UCSD examined cranial ultrasounds of healthy term infants
exposed antenatally to illicit stimulants in comparison to both healthy
term and ill term controls.
Group 1 consisted of clinically healthy "exposed infants" in
the newborn nursery identified by positive urine drug screens. These 82
infants consisted of 37 cocaine-exposed, 27 methamphetamine-exposed, and
18 infants exposed to a stimulant plus a narcotic (heroin and/or methadone).
Group 2 consisted of 87 ill term (> 37 weeks) infants at risk for neurologic
damage due to common neonatal illnesses (asphyxia, meconium aspiration,
severe sepsis (n = 12), etc). Group 3 consisted of 19 randomly selected
healthy term neonates. Infants underwent a cranial ultrasound within 3
days of birth, which was read twice by interpreters blinded to the toxicology
screen results. Additionally, neonatal abstinence scores ("Finnegan"
scores) and growth parameters were recorded.
Although this study examined infants exposed to other drugs (cocaine
and opiates), subgroups were defined a priori. Major differences were present
in group demographics, prenatal care, infant growth parameters, maternal
gravity and parity, and the percentages of infants in each group that were
small for gestational age and subject to intrauterine growth restriction
(see discussion below regarding fetal growth). Overall, 35% of the drug-exposed
infants (Group 1) had abnormal cranial ultrasound results, similar to the
rate of abnormal ultrasound findings in term, ill infants at risk for neurologic
damage (Group 2). Ultrasound findings were classified as white matter cavities,
white matter densities, acute infarctions, intraventricular hemorrhage
(IVH), subarachnoid hemorrhage, subependymal hemorrhage, and ventricular
enlargement. The table below details the findings:
The 19 infants in the healthy control group (Group 3) all had normal
cranial ultrasounds with the exception of a single infant with a subependymal
hemorrhage. For statistical analysis, methamphetamine-exposed infants were
grouped together with cocaine-exposed infants. While the overall incidence
of intracranial ultrasound abnormalities was statistically similar between
drug-exposed and the ill term infants, the exposed infants had significantly
more abnormalities than the healthy control group. The overall incidence
of IVH was 12.1% in drug-exposed infants while only 5.7% in ill term newborns,
and absent in controls (p <0.0001).
This study, the only one of its kind, suggests that apparently healthy
full term infants exposed to stimulants have a relatively high risk for
intracranial abnormalities on neonatal ultrasound. Ultrasound with its
limited window is perhaps not the ideal modality to identify some of the
lesions (acute infarction and subarachnoid hemorrhages) and it is only
fair at identifying white matter lesions (PVL), but it provides a good
assessment of other lesions (IVH, ventricular enlargement, and subependymal
hemorrhage). The numbers of infants in each subgroup are relatively small,
but taken as a whole, the results of this study are thought-provoking,
particularly when seen in conjunction with the animal data documenting
dose-related increases in fetal blood pressure following maternal methamphetamine
ingestion. Although severity was not discussed, the finding of IVH in 4
of 24 apparently healthy term infants exposed to methamphetamine is striking
and suggests that ultrasound and developmental surveillance should be considered
in any exposed infant.
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FETAL
GROWTH, PREMATURITY, AND WITHDRAWAL |
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Oro AS, Dixon SD. Perinatal cocaine and methamphetamine exposure:
Maternal and neonatal correlates. J Pediatr. 1987; 111:571-578. |
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Comchai C, Manorom NN, Watanarungsan P, et al. Methamphetamine
abuse during pregnancy and its health impact on neonates born at Siriraj
Hospital, Bankok, Thailand. Southeast Asian J Trop Med Pub
Health. 2004; 35(1):228-231. |
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Smith L, Yonekura ML, Wallace T, et al. Effects of prenatal
methamphetamine exposure on fetal growth and drug withdrawal symptoms
in infants born at term. Dev Beh Pediatr. 2003; 24(1):17-23.
(For non-journal subscribers, an additional fee may apply for full
text articles) |
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Several studies in diverse populations have examined the effect of methamphetamine
on fetal growth, prematurity, and withdrawal. Oro & Dixon examined
110 infants at UCSD Medical Center with positive maternal or neonatal drug
screens, excluding infants of mothers with histories of methamphetamine
use during pregnancy but negative drug screens, and infants exposed to
phencyclidine or barbiturates. The remaining infants were classified as
exposed to cocaine (13), methamphetamine (28), cocaine plus methamphetamine
(5), narcotics (49), and narcotics plus cocaine or methamphetamine (9).
Controls (45) were randomly identified and matched for ethnicity, maternal
age, and prenatal care. Tracked variables included gestational age (by
Dubowitz), growth parameters and rates of SGA, withdrawal scores and treatment,
and abruption rates. Because the infants exposed to cocaine and methamphetamine
were statistically identical, they were grouped together for comparison
with narcotic-exposed infants and controls.
More recently (2001), Comchai in Bangkok, Thailand examined methamphetamine's
effect on Apgar scores, growth parameters (OFC, length, weight), prematurity,
and withdrawal symptoms. Infants were included in the study group only
if mothers admitted to using methamphetamine and if it was also present
in the infant's urine. The control group consisted of infants born during
the same period whose mothers denied methamphetamine use.
Finally, Smith et al examined fetal growth parameters and withdrawal
symptoms among 134 term singleton infants exposed to methamphetamine at
a large public hospital in Los Angeles County. Although infants exposed
to marijuana and alcohol were included in the study group, infants exposed
to narcotics (4) and cocaine (16) were excluded. The control group consisted
of all live term singleton births with either negative urine drug screens
or no maternal history of drug use. An interesting component of this study
was the examination of nicotine's effect on fetal growth among infants
exposed to methamphetamine.
Oro & Dixon, who grouped cocaine-exposed infants with methamphetamine-exposed
infants into a "stimulant" group, found statistically significant
decreases in birth weight, length, and head circumference relative to controls.
However, the stimulant-exposed group had a higher rate of prematurity (28%)
v controls (9%) and a correspondingly wide range of growth parameters,
suggesting that some of the difference may have been related to premature
birth. Nevertheless, the stimulant-exposed group had higher rates of small-for-gestational-age
infants than controls (8.7% v 2.2%) and microcephaly (17% v 4%). While
Comchai also found a trend toward decreased birthweight and length in methamphetamine-exposed
infants relative to controls, only decreased OFC reached standard statistical
significance. Using multiple regression analysis to control for gestational
age, Comchai found that both birth weight and head circumference were significantly
decreased.
In contrast, Smith's study of 134 term infants exposed to methamphetamine
did not show a statistical decrease in birthweight, length, or OFC compared
to unexposed term infants. When both nicotine and methamphetamine were
used antenatally, however, a significant decrease in birth weight and OFC
was seen relative to infants exposed to methamphetamine alone. Further,
Smith found maternal methamphetamine use in all three trimesters produced
a significant decrease in head circumference and weight relative to use
limited to the first two trimesters. Like Oro & Dixon, Smith found
that the number of small-for-gestational-age infants was statistically
increased among exposed infants. Although all the infants in Smith's study
were considered term, methamphetamine-exposed infants were born earlier
than control infants.
Withdrawal symptoms were examined in two of these studies. Oro &
Dixon found a number of neurobehavioral alterations in cocaine/methamphetamine
exposed infants, including abnormal sleep (81%), tremors (71%), poor feeding
(58%), hypertonia (52%), vomiting (51%), sneezing (45%), high pitched cry
(42%), frantic fist sucking (42%), and others. The mean peak neonatal abstinence
syndrome (NAS) score was elevated among the stimulant-exposed group (5.5
+/-2.2), but much lower than that of the narcotic-exposed group (10.7 +/-
3.7). Peak symptoms were typically noted on day 2 (range 1 to 6). The authors
believed that some of the symptoms could have been due to methamphetamine
intoxication rather than withdrawal, as the drug was recovered from the
urine for up to 7 days and the initial hyperirritable phase was in some
cases followed by extreme drowsiness and need for prolonged gavage feeding
(similar to methamphetamine withdrawal in adults). Similarly, Smith found
that 49% of methamphetamine-exposed infants had withdrawal symptoms (defined
as NAS score >5), but only 4% required treatment.
Multiple factors may contribute to decreased fetal growth, making it
difficult to attribute poor fetal growth solely to maternal methamphetamine
use. Studies are typically complicated by the use of concomitant illicit
substances, poor maternal nutrition, alcohol abuse, difficulty in assigning
accurate gestational age due to lack of prenatal care, and numerous other
problems. Determining duration, timing, and amount of drug abuse is also
very difficult. Some cases of methamphetamine use may have been missed
in these studies because inclusion was determined by maternal report and/or
urine samples without meconium screens. Nevertheless, several results of
these studies deserve emphasis. Both the Oro & Dixon and the Smith
studies demonstrated higher rates of small-for-gestational-age infants
among neonates exposed to antenatal methamphetamine, while Smith also found
that exposure to methamphetamine during all three trimesters was associated
with an increased risk for growth restriction. Cigarette smoking, which
is extremely common among methamphetamine users, appears to contribute
significantly in decreasing fetal growth. Additionally, methamphetamine
use is associated with increased rates for preterm delivery as well as
earlier delivery for infants delivered at term. Finally, antenatal methamphetamine
use is associated with neurobehavioral alterations in the neonatal period
including sleep alteration, irritability, tremors, feeding difficulties,
and others. Possibly, some of these symptoms actually represent intoxication
and may be followed by a prolonged period of drowsiness and poor oral feeding
similar to the depressed withdrawal state noted in adults.
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BRAIN
STRUCTURE AND NEURODEVELOPMENT FOLLOWING ANTENATAL METHAMPHETAMINE EXPOSURE |
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Smith LM, Chang L, Yonekura ML, et al. Brain proton magnetic
resonance spectroscopy in children exposed to methamphetamine in utero.
Neurology. 2001; 57:255-260.
(For non-journal subscribers, an additional fee may apply for full
text articles) |
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Chang L, Smith LM, LoPresti C, et al. Smaller subcortical
volumes and cognitive deficits in children with prenatal methamphetamine
exposure. Psychiatry Research: Neuroimaging. 2004; 132:95-106.
(For non-journal subscribers, an additional fee may apply for full
text articles) |
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Smith & Chang et al have published two controlled studies of brain
magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS)
of children exposed antenatally to methamphetamine for at least 2 of 3
trimesters. Their reports included limited developmental assessments, a
topic receiving very little attention to date. The authors first compared
MRI/MRS and Child Behavioral Checklist (CBCL) results from 12 methamphetamine-exposed
(age 8.1 +/- 0.8 yr) and 14 control children (age 7.3 +/- 1.1 yr). Exclusion
criteria included prematurity, developmental delays, seizures, ADHD, significant
maternal illnesses, other illicit drug exposure in utero, and use of chronic
medications. Levels of creatine, N-acetylaspartate, choline-containing
compounds, and myoinositol were measured in the right frontal white matter
and right striatum (chosen based on previous animal and adult work by the
group). This was followed by a pilot study examining volumes of subcortical
gray matter with MRI and neurocognitive assessments in children (age 6.9
+/- 3.5 yr, range 3 - 16 yr) exposed antenatally to methamphetamine, with
a control group again consisting of children not so exposed. Some of the
children in the study and control groups participated in both studies.
Inclusion and exclusion criteria for the second study were the same as
the first study. Within 1 month of the MRI, 10 exposed and 9 control children
also completed blinded neuropsychological tests of visual motor integration,
motor function, sustained attention, visual attention, memory, and others.
In the first study, MRI scans revealed no detectable gross differences.
The proton NMS revealed significant increases in striatal creatine (+ 10%,
p = 0.02) among exposed children, while levels of N-acetylaspartate, myoinositol,
or choline-containing compounds were unchanged. Frontal white matter levels
of all compounds were unchanged between exposed children and controls.
CBCL revealed that 17% of methamphetamine-exposed children had social problems
or delinquent behavior, with no problems identified in controls (not statistically
significant). The second study, examining subcortical gray matter using
MRI, also found no gross structural abnormalities among the exposed children,
but subcortical gray (putamen, globus pallidus, caudate) and hippocampal
volumes were decreased bilaterally among exposed children. Neuropsychological
testing revealed statistically poorer performance among the exposed children
in visual motor integration, attention and psychomotor speed, and long
term spatial and verbal memory. Though not reaching statistical significance,
a reduction in volume of midbrain and cerebellum among exposed children
was noted as well.
Smith & Chang's studies suggest that intrauterine methamphetamine
exposure is associated with persistent subtle alterations in subcortical
metabolism, structure and function, leading to difficulties with attention,
visual motor skills, and memory. The authors are unable to explain the
etiology of the increased creatine in the brains of children exposed to
methamphetamine, but note that brain creatine levels are also increased
among abstinent adult cocaine users and children exposed antenatally to
cocaine. Increased creatine may be seen following gliosis, a response to
neuronal loss, but the authors note that increased myoinositol should have
been seen if gliosis caused the observed change in creatine. It is also
interesting to note that N-acetylaspartate, which falls with neuronal loss,
remained unchanged between controls and exposed children. This finding
contrasts somewhat with the volumetric analysis performed in their second
study, which revealed decreased size of the putamen, globus pallidus, and
hippocampus, suggesting neuronal loss. Reduction of size of the putamen,
globus pallidus, and hippocampus are an interesting finding in conjunction
with the alterations in visual motor integration, attention, and memory
detected on neuropsychiatric testing.
The authors caution that their study is small and that a larger study
using thinner MRI sections is needed to confirm the reductions in size
of brain structures, particularly the hippocampus.
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SOCIAL
DYSFUNCTION AND PSYCHOLOGICAL DIFFICULTIES AMONG METHAMPHETAMINE USERS:
A SETUP FOR CHILD ABUSE AND NEGLECT |
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Sommers I, Baskin D, Baskin-Sommers A. Methamphetamine use
among adults: Health and social consequences. Addition Behaviors,
Nov 2005. Electronically published ahead of print.
(For non-journal subscribers, an additional fee may apply for full
text articles) |
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Rates of child abuse and neglect among methamphetamine users are unknown,
but social services agencies are taking an increasingly aggressive approach
towards child protection in areas with widespread methamphetamine abuse.
Sommers et al investigated physical, psychological, and behavioral characteristics
of young adult methamphetamine abusers. The study consisted
of interviews with 106 adults, age 18 to 25 years in Los Angeles County,
who had used methamphetamine for at least 3 months. 55 participants were
in a methamphetamine treatment program and 51 users were from the community
at large. Study participants underwent a structured but open-ended interview
about frequency of drug use, lifestyle, health, psychological symptoms,
family background, and involvement in criminal and violent behavior. Participants
were also asked to describe negative psychosocial consequences in relation
to methamphetamine use.
The investigators found that the majority of respondents were addicted
to methamphetamine, with almost 70% using the drug daily. Average duration
of abuse was 3.8 years and almost all users (97%) engaged in methamphetamine
binges typically lasting 2 to 5 days (median 3 days, range 2 to 21 days).
Many users rapidly increased methamphetamine frequency following initial
consumption. Mean weekly cost of methamphetamine was $136 (range $0-800).
Social dysfunction, particularly within the family was common, with 49%
of respondents reporting adverse family problems due to drug use. Psychologically,
respondents experienced a number of adverse effects, including depression
(37%), paranoia (62%), hallucinations (38%), and irritability (79%). Investigators
reported that hallucinations were common (both auditory and command-type),
as was violent behavior, with 35% of respondents having committed violent
acts while under the influence of methamphetamine. Males were more likely
to be violent than females (38% v 30%). Of the violent acts, 61% were in
domestic relationships, 17% drug related, 13% gang related, and 9% random
acts. Respondents described their violent behaviors as being "out
of control," "outburst of rage," and "blowing up."
This study highlights multiple risk factors for abuse and neglect by
caregivers in families affected by methamphetamine abuse. Several factors
are particularly worrisome for an adequate home environment for a neonate.
Binges, in which large amounts of methamphetamine are consumed for a period
of days, were almost universal by users in this study. Given the care needed
by any child, especially a newborn, this common behavior is of obvious
concern. Adverse psychological effects, particularly paranoia, depression,
hallucinations, and feelings of loss of control and rage, appear to be
very common among users and question the suitability of the home environment.
Perhaps most concerning, violent behavior is common with the majority of
violent acts committed within domestic relationships. Given these findings,
active involvement of social work and Child Protective Services are very
important for any neonate with antenatal methamphetamine exposure.
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LAST
MONTH’S Q & A August 2006 - Volume 3 - Issue 12
Last
issue, we reviewed fetal methamphetamine physiology and the effects of
antenatal exposure on neonatal growth, brain structure, and neurodevelopment.
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Commentary
& Reviews:
Declan P. O’Riordan, M.D.
Attending Neonatologist
St. Luke’s Regional Medical Center
Boise, ID |
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The
eNeonatal Review Team asked the August faculty a few questions. |
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How
do you accurately determine whether an infant has been exposed to methamphetamine? |
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While
some mothers readily admit methamphetamine use, most deny any connection
with the drug. Identification of methamphetamine therefore rests upon
laboratory analysis. Methamphetamine has been detected in adult hair,
saliva, maternal and neonatal urine, meconium, and umbilical cord tissue.
Most commonly, hospitals use analysis of maternal and infant urine drug
screens and meconium analysis. Each method has advantages, but no method
completely rules out exposure. Urine and saliva drug screens provide
rapid results, but metabolites are excreted within days of exposure,
minimizing utility if the mother has been hospitalized for several days
prior to delivery or if the mother abstained from use prior to birth.
Meconium may be analyzed as an immunoreactive screen, but positive results
must be confirmed with gas chromatography/mass spectrometry, as immunoreactive
methods have high false positive rates (Moore
C, Lewis D, Leikin J, 1995). Meconium is believed to be a reflection
of mid to late, but not early gestational exposure. More recently, identification
of methamphetamine and other drugs by ELISA and CG/MS in umbilical cord
was reported (Montgomery
D, Plate C, et al, 2006). The authors noted that umbilical cord testing
may be useful in cases of in utero meconium passage or in the preterm
infant with delayed passage of meconium. |
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How
prevalent is maternal use of methamphetamine? |
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Prevalence
of methamphetamine use varies geographically - many areas in the eastern
United States have only limited use, while other areas, particularly
in the west, have high rates - and determining prevalence of maternal
use remains very difficult. A recent prospective study of mothers based
in four areas of high use (Los Angeles, Honolulu, Des Moines, and Tulsa)
found that 84 of 7119 (1.18%) eligible maternal/infant pairs were exposed
to methamphetamine (Smith
LM, LaGasse LL, Derauf C, et al, 2006). This study excluded a number
of potential subjects for a variety of criteria and some exposed infants
may have been missed. Mothers were protected by a National Institute
of Drug Abuse certificate of confidentiality in this study, resulting
in 97.6% of identified mothers actually self-reporting the drug abuse.
Furthermore, gas chromatography-mass spectrometry analysis of meconium
confirmed methamphetamine use in only 21 of these 84 cases (25%), suggesting
that meconium analysis has low sensitivity for detecting maternal use
of methamphetamine during pregnancy. |
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- Identify the neurobehavioral alterations in the newborn produced by antenatal
methamphetamine exposure.
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