Clinical Chemistry 43: 235-242, 1997;
(Clinical Chemistry. 1997;43:235-242.)
© 1997 American Association for Clinical Chemistry, Inc.
Detection of intrauterine illicit drug exposure by newborn drug testing
Tai C. Kwong1,a and
Rita M. Ryan2
Departments of
1
Pathology and Laboratory Medicine and
2
Pediatrics, School of Medicine and Dentistry, University of Rochester, Rochester, NY 14642.
a Author for correspondence. Fax 716-275-9333; e-mail tkwong{at}pathology.rochester.edu
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Abstract
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Identification of intrauterine drug-exposed newborns with toxicological
screening may have benefits including close follow-up of the infant by
both medical and social services. Applying specific written guidelines
to select newborns for drug testing decreases bias and protects the
physicians and hospitals involved. All drugs reported as positive
should be confirmed by an appropriate second test. Urine and meconium
testing are the best current options for identifying drug-exposed
neonates. Urine testing sensitivity is low because of problems
encountered in urine collections and the high thresholds used in
current urine assays. The disadvantage to meconium testing is the
increased labor and time required to work with this material. Testing
of newborn hair is unlikely to be widely used until technically less
demanding assays become available. Testing of amniotic fluid or gastric
lavage is still in the developmental stages. Adopting lower urine assay
thresholds for newborn samples would increase sensitivity and would be
an appropriate modification of current methodologies.
Key Words: indexing terms: meconium • urine testing • hair analysis • gas chromatography–mass spectrometry • drug screening • immunoassays
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Introduction
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Intrauterine drug exposure (IUDE) remains a major health concern
(1)(2).1
Prenatal cocaine use has been associated with placental abruption and
premature labor (3)(4)(5)(6)(7)(8)(9). Intrauterine cocaine exposure has
also been associated with an increased risk of prematurity, small for
gestational age status, microcephaly, congenital anomalies including
cardiac and genitourinary abnormalities, necrotizing enterocolitis, and
central nervous system stroke or hemorrhage
(3)(4)(5)(6)(7)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22). Infants born to mothers using
amphetamines have many of the same problems as cocaine-exposed infants,
including increased rates of maternal abruption, prematurity, and
decreased growth parameters such as low birth weight (2).
In addition to an increased risk of prematurity and being small for
gestational age, striking withdrawal symptoms often requiring treatment
are frequently observed in infants after in utero opioid exposure.
Symptoms include irritability, hypertonia, wakefulness, jitteriness,
diarrhea, increased hiccups, yawning and sneezing, and excessive
sucking and seizures, with onset of withdrawal earlier in
heroin-exposed babies compared with methadone-exposed infants
(23)(24). Some intrauterine cocaine-exposed
infants may manifest symptoms of withdrawal including hypertonicity,
jitteriness, and seizures
(7)(9)(15)(25)(26).
Intrauterine amphetamine-exposed infants may also have similar
postnatal symptoms including hypertonia, tremors, poor feeding, and
abnormal sleep patterns (27). Long-term follow-up of IUDE
infants suggests that in addition to the potential for difficult social
situations, such as increased risk for child abuse and neglect
(28)(29), abnormal neurocognitive and
behavioral development may occur (18)(30)(31)(32)(33)(34),
as well as an increased risk of sudden infant death syndrome
(35)(36)(37)(38).
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guidelines for medically indicated newborn drug testing
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Identification of drug-using mothers before or early in pregnancy
would be ideal, potentially avoiding intrauterine exposure. However,
the physician with primary responsibility for the infant is not in a
position to test mothers, but, rather, can only consider ordering a
newborn drug test after IUDE may have occurred. Possible benefits of
identifying IUDE infants could include programs for improvement of
parenting skills, maternal drug treatment, home assistance, focused
medical observation during the newborn period, restriction of
breast-feeding, and close pediatric follow-up emphasizing developmental
and social issues. In addition, currently unidentified problems caused
by IUDE may be discovered in the future; beyond the immediate newborn
period the opportunity to identify IUDE infants by urine testing is
lost. With adequate testing and successful maternal treatment, there is
also the potential for decreased postnatal infant exposure, which can
have deleterious effects (39)(40)(41) and decreased risk of
IUDE in future pregnancies.
Drug testing is one of the only methods of identification of IUDE.
Maternal history of drug use is often unreliable. If identification of
IUDE infants is worthwhile, it is inadequate to rely on maternal
self-reporting; for example, 24–63% of mothers with positive cocaine
tests deny cocaine use
(4)(21)(42)(43)(44). Even if the
mother does admit to substance abuse, the accuracy of the recall about
frequency of use, purity, and range of drugs used is often poor.
Clinical diagnosis is complicated by the fact that some drug-exposed
infants do not have immediate or specifically recognizable symptoms in
the newborn period. A combination of maternal history, newborn clinical
symptoms, and laboratory toxicological testing of the mother and
newborn serve best to avoid significant underestimation of the
incidence of in utero exposure determined by any one of these
approaches independently. In addition, in many jurisdictions, a
physician caring for a newborn suspected of IUDE is required to
investigate and report the findings to the appropriate authorities. A
positive maternal history of drug use or the demonstration of drug in
maternal urine may not constitute sufficient evidence to indicate a
report to child protective services. Definitive documentation of the
presence of drug in the baby may be required.
Possible maternal and infant risk factors can be culled from the
current literature and then can be developed into specific guidelines
to identify those infants for drug testing; this is more cost-effective
than universal screening, which is currently not recommended
(45). Also, a set of formal guidelines based on maternal
history and newborn clinical findings removes the bias in
physician-ordered drug tests, and fewer IUDE infants are missed.
Guidelines protect the physician who orders the drug screening. When
the ordering physician informs the mother that a drug test has been
ordered for her baby, he or she can inform parents that all infants who
meet these guidelines are screened as a matter of routine, and that
they are not being "singled out" for other reasons. Physicians
should document in the chart the indication for the infant drug test
and that the mother has been informed that an infant sample has been
sent to the laboratory for drug testing. The following guidelines were
developed on the basis of previous studies in the literature:
1) Infants whose mothers have any of the following: (a)
History of drug abuse in present or previous pregnancies;
(b) limited prenatal care (<5 prenatal visits);
(c) history of hepatitis B, AIDS, syphilis, gonorrhea,
prostitution; (d) unexplained placental abruption;
(e) unexplained premature labor.
2) Infants who have any of the following: (a) Unexplained
neurologic complications (e.g., intracranial hemorrhage or infarction,
seizures); (b) evidence of possible drug withdrawal (e.g.,
hypertonia, irritability, seizures, tremulousness, muscle rigidity,
decreased or increased stooling); (c) unexplained
intrauterine growth retardation.
These guidelines were tested prospectively to be 89% sensitive in a
population with mixed socioeconomic status (46) and
confirmed the association of specific maternal characteristics with
maternal cocaine use
(6)(7)(42)(43)(47)(48)(49)(50)(51)(52).
Note that adolescent pregnancy and a maternal history of genital herpes
or Chlamydia infection are not included as risk factors
because they have not been associated with increased maternal drug use
either in our population or in most prior published reports. We include
a full copy of our protocol as an aid to those faced with developing
guidelines at their own institutions (see Appendix).
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laboratory testing of newborns for drugs of abuse
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Testing should aim at accurate and early identification of
drug-exposed newborns. Drug or drug metabolite concentrations in
newborn specimens can be below the detection limits of many of the
clinical laboratory analytical techniques. Thin-layer chromatography
and HPLC methods can detect the relatively high drug concentrations
found in suspected drug overdose patients, but lack the sensitivity
needed for newborn testing. Most testing protocols rely on nonisotopic
immunoassays for the initial testing phase, rather than the more
difficult and costly gas chromatography—mass spectrometry (GC-MS)
procedures. The immunospecificity of immunoassays are generally
directed toward a group of structurally closely related drugs or
metabolites and not a specific drug. Therefore, a positive immunoassay
result must be considered as presumptive for a group of drug compounds
and should be subjected to confirmation testing for definitive
identification.
Confirmation testing, performed on a fresh aliquot, should be an assay
that is based on an analytical principle different from that of the
initial test, and one that is more specific and at least equally
sensitive. Therefore, an initial result by an immunoassay should not be
confirmed by another immunoassay, even if the latter has more selective
immunospecificity or is a product of a different vendor. Confirmation
of a positive result by an amphetamine or methamphetamine-specific
immunoassay is best considered as an intermediary test that will be
followed by a more definitive confirmation test. The laboratory should
be familiar with the specificity of both initial and confirmation
assays, and the drugs or medications that can cause significant
interference, including those that are administered during the birthing
process. If the initial result cannot be confirmed, a negative report
must be issued. If confirmation testing is performed by a reference
laboratory, it is good laboratory quality-assurance practice to save an
aliquot of the specimen for retest if necessary.
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newborn urine testing
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Because the specimen of choice for toxicology analysis in most
clinical laboratories is urine, many laboratories have applied their
urine-based methodologies to testing newborns suspected of IUDE.
Newborn urine is far from ideal for this purpose. The most serious
drawbacks are the difficulty in urine collection and the critical
timing needed for a successful collection (53).
Positioning the collection bag and maintaining it in position to avoid
loss through leakage can be a frustrating exercise, and may require
2–3 attempts before a suitable specimen is obtained. Very often
multiple attempts still result in failure. Skin rashes as a reaction to
the adhesive bag are common and further complicate the collection
process. The urine collected may not be of sufficient quantity to
permit both initial and confirmation testing because of collection
difficulties and also as a result of the lower normal urine volume in
newborns. Timing of specimen collection is critical for testing
newborns. The time a urine specimen is finally collected may be outside
the narrow window of detection. Many negative findings caused by delays
in obtaining a specimen soon after birth can be attributed to late
onset of withdrawal symptoms and belated arrival at the clinical
suspicion of drug exposure as well as difficulties in urine collection
(53). The various problems associated with specimen
collection contribute to the underestimation of IUDE.
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thresholds for urine initial and confirmation tests
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Sensitivity of a urine drug-of-abuse test depends on the threshold
(cutoff) chosen. The convention is to designate a result positive if it
is equal to or greater than the threshold, and negative if it is less.
There are no recommended thresholds for testing of clinical samples,
usually urine, for drugs of abuse. Most clinical laboratories have
adopted for maternal and infant urine testing programs the thresholds
used in workplace drug testing (54). One reason is that
reagent manufacturers have formulated and packaged their kits on the
basis of standard workplace drug testing thresholds. Some of these
thresholds have been shown to be too high for clinical testing, the
consequence of which has been underestimation of drug exposure.
Adopting lower thresholds (e.g., 80 µg/L for benzoylecgonine and 20
µg/L for cannabinoid metabolites) can dramatically improve detection
rates (55)(56). Laboratories planning to use
lower thresholds have to purchase or prepare their own threshold
calibrators and controls, and the stated concentrations of these
materials have to be confirmed. To meet regulatory requirements,
laboratories also must undertake a thorough confirmation of these
"modified" assays in terms of limits of linearity and precision
around the threshold.
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meconium testing
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Meconium has been proposed as an alternative specimen to urine
because of difficulties associated with urine testing. Meconium, the
dark green viscous first stool of a newborn, is a collection of debris
consisting of desquamated cells of the alimentary tract and skin,
lanugo, fatty material from the vernix caseosa, amniotic fluid, and
various intestinal secretions. The disposition of drug in meconium is
not well understood. The proposed mechanism is that the fetus excretes
drug into bile and amniotic fluid. Drug accumulates in meconium either
by direct deposition from bile or through swallowing of amniotic fluid
(47). Meconium appears to form in the second trimester;
because it is not excreted, it contains drugs to which the fetus has
been exposed. Therefore, the presence of drugs in meconium has been
proposed to be indicative of in utero drug exposure in the month or
more before birth, a longer historical measure than is possible by
urinalysis (47). Most reports in the literature describe
the detection of cocaine in meconium, but studies in which meconium was
also analyzed for other drugs of abuse demonstrated that cocaine was
detected at a much higher rate than marijuana, amphetamines, or opiates
(47)(57)(58). Several
studies reported that some infants whose urines were negative for
cocaine had positive meconium, suggesting that meconium testing is more
sensitive than urine testing
(46)(47)(57)(58)(59)(60)(61)(62)(63). However, part of
the improved detection rate relates to the method of analysis—urine by
enzyme immunoassay (EIA) or fluorescence polarization immunoassay
(FPIA) vs meconium by RIA or GC-MS, or the thresholds used (300 vs 80
µg/L for benzoylecgonine) rather than the type of specimen (urine vs
meconium). When more sensitive urine analytical methods and lower
cutoffs were used, infant urine and meconium analyses yielded
equivalent results for identifying newborns who have been exposed to
cocaine in utero (47)(56)(60).
Meconium is easier to collect than urine, and the amount collected is
usually sufficient for complete analysis, including confirmation.
Meconium testing does have some limitations. Meconium is usually passed
by full-term newborns within 24 to 48 h, after which transition
from blackish-green color to yellow color indicates beginning of
passing of neonatal stool (64). Infants with low birth
weight (<1000 g) have been shown to pass their first meconium at a
median age of 3 days (65). Thus, meconium collection can
be missed because of delayed passage and also may not be available soon
after birth for early detection of IUDE. In fact, in a large-scale
study, only 77.6% of 3879 newborns had meconium available for analysis
(58).
In the clinical laboratory, meconium is an unfamiliar matrix, being a
sticky material that is more difficult to work with than urine.
Furthermore, processing of meconium for analysis requires weighing and
extraction steps that are not needed for urine. An accurately weighed
0.1 to 1 g of meconium is generally used, and drug analyte has to
be extracted from meconium into a medium that is compatible with the
initial immunoassays. Extraction has been achieved by acidified water
(47)(58) or saline (59), methanol
(66), or acetonitrile (46). Improved assay
sensitivity can be attained by evaporating the extract solvent either
to dryness or a lower volume. A variety of immunoassays has been used
for the initial testing of meconium extracts: EIA
(63)(67), RIA
(47)(58)(59), FPIA
(46)(60)(61), and
kinetic interaction of microparticles in solution (KIMS)
(61). To improve sensitivity, thresholds for the extract
should be set as low as possible and certainly lower than the workplace
drug-testing thresholds. All urine drugs-of-abuse assays, if they are
used with meconium extracts, must be investigated for possible effect
of matrix on accuracy, precision, and assay linearity.
Confirmation assays for meconium are more difficult than those for
urine. Although HPLC has been used (68), it is GC-MS
methods that have the lower assay detection limits necessary for
identifying newborns with low drug concentration in meconium. Most
published GC-MS procedures involve the extraction of the drug from
meconium by solid-phase extraction columns after meconium has been
dispersed in extraction solvent by rigorous vortex-mixing or
sonication, and particulate materials sedimented by centrifugation
(46)(66)(69)(70).
Recoveries of drugs from meconium can be low (30–50%), which means
that selection of proper internal standards is important. Fortunately,
deuterated internal standards for most of drugs of abuse are now
available.
Some laboratories may find it easier to modify existing urine
methodologies to perform at lower thresholds than to develop and
confirm a new set of more difficult assays for meconium. It is
recommended that laboratories contemplating meconium testing should
consider first lowering the threshold of their urine assays before
embarking on meconium testing because sensitivity of urine testing at
lower urine thresholds has been reported to be comparable with that of
meconium testing.
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hair testing
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Systemic drug exposure leads to incorporation of the drug into
hair. Hair analysis has demonstrated the presence of drugs of abuse in
the hair of drug users (71)(72). Nevertheless,
the proposal to use hair testing in drug screening programs for the
workplace has been controversial. Among the concerns expressed is the
difficulty in identifying the presence of drug in hair caused by
external application, i.e., environmental contamination
(73)(74). Therefore, the presence of cocaine
in hair is not necessarily an indication of drug use. Detection of
benzoylecgonine in hair has been proposed to be a marker of active
cocaine use (75), but unless very careful precautions are
taken to control assay conditions, particularly pH during the
extraction process, artificial production of benzoylecgonine will lead
to a false-positive result (74). Testing of newborn hair
to document IUDE, however, is an appropriate clinical application of
hair testing (76). In testing newborn hair, environmental
contamination is a not an issue if the newborn is tested during the
immediate postdelivery period while still in the hospital and not after
the newborn has been discharged to go home with a mother who is
suspected of drug abuse. Literature reports on newborn hair testing are
mostly related to cocaine exposure, although amphetamines, opiates, and
methadone have been found in adult hair testing (77)(78)(79).
Cocaine crosses the placenta and cocaine and its metabolite have been
found in newborn hair. Hair present at birth grows during the third
trimester; therefore detection of drug in newborn hair reflects
maternal drug use during the last 3 months of pregnancy
(76)(80). The quantity of benzoylecgonine in
newborn hair correlates best with that in the proximal segment of the
mother's hair, which represents maternal hair growth in the 12 weeks
or so before delivery (60). Hair analysis results will be
positive for IUDE newborns whose urines are negative because their
mothers abstained from drug use only for a few days before delivery.
Unlike urine or meconium testing, the timing of hair collection is not
critical. Hair collected even a few weeks after birth offers the
likelihood of detecting gestational drug exposure, assuming
environmental contamination can be ruled out.
Hair analysis is technically much more involved than urine or meconium.
Before extraction, hair samples require decontamination by washings
with a variety of agents including methanol, ethanol, dichloromethane,
acetone, detergent, or warm water (81). Drug is then
extracted from hair by incubation with methanol, ethanol, acid, and
proteinase or pronase. The low drug concentrations in hair are
detectable by RIA only and the amount of neonatal hair needed is 2–5
mg (82). By using GC-MS assays with data acquisition in
selected-ion monitoring mode, as little as 5–10 mg of adult hair is
adequate (74), whereas a sophisticated research protocol
base on tandem mass spectrometry will need only 1 mg of hair
(83). GC-MS procedures requiring 50–100 mg of hair are
more suitable for testing adult hair because most newborns do not have
that much hair, and their mothers probably will object to extensive
shaving of their babies for drug testing.
Because hair analysis is technically demanding, the availability of
newborn hair testing is limited to a few specialized laboratories.
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testing of other fluids
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Analysis of amniotic fluid for detection of IUDE is a largely
unexplored option. Benzoylecgonine concentration in amniotic fluid has
been shown to be higher than that in newborn urine, and more exposed
newborns can be detected compared with urinalysis (84).
Availability of amniotic fluid is an issue with patients who have
premature rupture of membranes or rapidly advancing labor. Whether
amniotic fluid testing has any clinical value as a measure of long-term
exposure has not been studied.
A recent report demonstrated the feasibility of using newborn gastric
amniotic fluid for determining gestational cocaine exposure
(44). In a small sample of 39 newborns, the detection rate
of gastric fluid analysis was essentially that of meconium, and
approximately twice that of urinalysis. It was not mentioned, however,
whether the same or different thresholds had been used for the analysis
of the three specimen types. The advantage of gastric fluid is the
availability of this specimen soon after birth for rapid testing for
drug exposure. The major disadvantages are that not all infants
suspected of IUDE are identified at the time of birth, and that deep
suction of a newborn for gastric secretions is not necessarily a
routine procedure. The usefulness of gastric fluid analysis must await
further studies.
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laboratory report
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The laboratory report should reflect accurately the laboratory
analysis that has been performed, and should contain all the
information necessary for proper interpretation of the analytical
outcome. If the positive result reported is only the initial result
because there is insufficient urine for confirmation, confirmation is
pending, or the laboratory does not perform confirmation testing, the
reason for reporting an unconfirmed positive result should clearly be
stated. Physicians, nurses, and social workers have to know the scope
and limitation of the drug test, and a result reported accurately and
unambiguously is critical in reaching that goal. For example, testing
for opiates for many laboratories is limited to codeine and morphine
only, and a specimen containing opiates other than codeine or morphine
(e.g., dihydrocodone or hydromorphone) should be reported as
negative for codeine and morphine and not as negative for opiates.
Furthermore, if a specimen contains codeine or morphine, the laboratory
report also should state which opiate or opiates have been detected and
confirmed: morphine only, or morphine and codeine. It is not sufficient
to report opiates positive and confirmed because interpretations of the
two results are different, as they suggest different sources for
morphine (85). The same specimen can be either positive or
negative depending on the threshold used. Therefore, the laboratory
report should indicate all threshold concentrations for both initial
and confirmation tests. This is particularly important if
comparison of results from two laboratories is to be meaningful.
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guidelines for chain-of-custody documentation
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The documentation of the presence of an illicit drug in a newborn
can be challenged by the mother or the family. Moreover, in many
jurisdictions, reporting of the finding to state or local authorities
is mandatory and, although infrequent, may result in the mother's
losing custody of her baby. Therefore, depending on the local
environment and needs, testing of newborns for illicit drugs may
require chain-of-custody documentation to prove the integrity of the
test specimen has been maintained and to record all individuals who
have handled the specimen and when. Document by signature all
individuals, starting with the specimen collector, who have handled and
have had custody of the specimen until the specimen is discarded.
Record the time and reason of each transfer (change in custody) of the
specimen. The collector should seal a specimen with tamper-proof tape
and release specimen for transportation to the laboratory in a bag or
package that is sealed also with tamper-proof tape. The chain of
custody of each aliquot from aliquoting to discard should also be
documented. Laboratory areas for specimen processing, analysis, and
storage should be secure and access limited to authorized personnel
only.
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Appendix
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guidelines for medically indicated newborn urine drug
testing
1) Infants whose mothers have any of the following: (a)
History of drug abuse in present or previous pregnancies;
(b) limited prenatal care (<5 prenatal visits);
(c) history of hepatitis B, AIDS, syphilis, gonorrhea,
prostitution; (d) unexplained placental abruption;
(e) unexplained premature labor.
2) Infants who have any of the following: (a) Unexplained
neurologic complications (e.g., intracranial hemorrhage or infarction,
seizures); (b) evidence of possible drug withdrawal (e.g.,
hypertonia, irritability, seizures, tremulousness, muscle rigidity,
decreased or increased stooling); (c) unexplained
intrauterine growth retardation.
If any of these guidelines are met: (a) Nurses will
automatically place a urine collection bag on the infant;
(b) urine screen will not be sent until a
physician writes the order.
If a urine screen is sent, the physician writing the order must:
(a) notify the infant's attending physician (if not the
same) that the screens are being sent; (b) document the
indication for the screen in the infant's hospital chart.
If a urine screen is sent, the physician writing the order or the
infant's attending physician (if not the same) must: (a)
notify the infant's mother and tell her the indication for the screen;
(b) notify the mother's obstetrician that the screen is
being sent; (c) notify social services that the screen is
being sent. If social services had not been previously consulted
because there were no other concerns, social services will simply
review the chart and only talk to the mother after discussion with the
mother's obstetrician or infant's physician.
If the newborn drug screen is positive: (a) the
physician of the newborn is responsible for notifying the mother of the
results of the screen; (b) social services will evaluate the
mother, her resources, home situation, and associated problems, and
will assist the mother with rehabilitation programs, parenting courses,
parent support groups, home health aides, public health nurses, and
medical/mental health referrals as necessary as well as inform Child
Protective Services; (c) HIV and hepatitis B status should
be established in the mother and appropriate care of the infant should
follow; (d) the infant should have close
neurodevelopmental follow-up; (e) performance of a head
ultrasound should be considered; (f)
breast-feeding should not be permitted.
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Summary
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Hospitals involved in drug testing of newborns should have a set
of carefully developed guidelines for selection of infants for testing
and protocols for ordering the test and informing the family.
Laboratory analysis should be performed on the basis of validated
methodologies. It is important that all positive results are confirmed
by a second test before reporting and that clinicians understand the
reported results.
Urine remains the most commonly used specimen for newborn drug testing.
Urine testing has been reported to be less sensitive than meconium
testing, although this may be caused by higher thresholds used in urine
assays. However, urine is definitely more difficult to obtain. Meconium
testing is hampered by the more labor-intensive and time-consuming
preanalytical steps. More extensive testing of newborns by hair
analysis must await the development of technically less demanding
techniques, and testing of amniotic fluid or gastric lavage is still in
the developmental stages. Urine and meconium testing remain the current
options for identifying those newborns exposed to illicit drugs in
utero. Lowering thresholds for urine assays by modifying existing
methodologies would be an appropriate goal for those laboratories
wishing to improve sensitivity.
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Footnotes
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1 Nonstandard abbreviations: IUDE, intrauterine drug
exposure; GC-MS, gas chromatography–mass spectrometry; EIA, enzyme
immunoassay; and FPIA, fluorescence polarization immunoassay. 
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