Risks, Benefits And Diagnosis

Risks, Benefits And Diagnosis

Risks, Benefits And Diagnosis

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The risk-benefit calculation for any drug assumes a correct diagnosis of the disorder. Many investigators and clinicians feel the current epidemic of child psychiatric disorders is largely due to inappropriate diagnosis. Evaluate the risk and benefits of using psychoactive drugs in children correctly diagnosed with a disorder versus those incorrectly diagnosed with a disorder. Consider the risks and benefits of not treating (drug treatment) a child because he or she is not correctly diagnosed with a disorder.  summarize the natural course of the disorder, the drug action on the neurotransmitter systems in question, and the likelihood of short-term, long-term, and permanent positive and negative effects of drug treatment. Make sure to take into account the ethical dimension of this risk-benefit calculation.  Risks, Benefits And Diagnosis

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TECHNICAL REPORT

Prenatal Substance Abuse: Short- and Long-term Effects on the Exposed Fetus

abstract Prenatal substance abuse continues to be a significant problem in this country and poses important health risks for the developing fetus. The primary care pediatrician’s role in addressing prenatal substance exposure includes prevention, identification of exposure, recognition of medical issues for the exposed newborn infant, protection of the infant, and follow-up of the exposed infant. This report will provide information for the most common drugs involved in prenatal expo- sure: nicotine, alcohol, marijuana, opiates, cocaine, and methamphet- amine. Pediatrics 2013;131:e1009–e1024

Substance abuse has been a worldwide problem at all levels of society since ancient times. Attention has been directed toward the use of legal and illegal substances by pregnant women over the past several decades. Almost all drugs are known to cross the placenta and have some effect on the fetus. The effects on the human fetus of prenatal cigarette use have been identified and studied since the 1960s,1 the effects of alcohol and opiate use have been studied since the 1970s,2–4

and the effects a variety of other illicit drugs have been studied since the 1980s.5–7 This report reviews data regarding the prevalence of exposure and available technologies for identifying exposure as well as current information regarding short- and long-term outcomes of exposed infants, with the aim of facilitating pediatricians in fulfilling their role in the promotion and maintenance of infant and child health.

PREVALENCE

Prevalence estimates for prenatal substance use vary widely and have been difficult to establish. Differences are likely attributable to such things as the use of different sampling methods and drug-detection methods, screening women in different settings, and obtaining data at different points in time. For example, prevalence will vary depending on whether history or testing of biological specimens is used; whether the biological specimen is hair, urine, or meconium; and whether the specimens are merely screened for drugs or screened and confirmed with additional testing. There also will be differences depending on whether the sample being investigated is a community sample or a targeted sample, such as women who are in drug treatment or are incarcerated. Lastly, prevalence must be interpreted in light of the fact

Marylou Behnke, MD, Vincent C. Smith, MD, COMMITTEE ON SUBSTANCE ABUSE, and COMMITTEE ON FETUS AND NEWBORN

KEY WORDS prenatal drug exposure, alcohol, nicotine, marijuana, cocaine, methamphetamine, growth and development

ABBREVIATIONS AAP—American Academy of Pediatrics THC—tetrahydrocannabinol

This document is copyrighted and is property of the American Academy of Pediatrics and its Board of Directors. All authors have filed conflict of interest statements with the American Academy of Pediatrics. Any conflicts have been resolved through a process approved by the Board of Directors. The American Academy of Pediatrics has neither solicited nor accepted any commercial involvement in the development of the content of this publication.

The guidance in this report does not indicate an exclusive course of treatment or serve as a standard of medical care. Variations, taking into account individual circumstances, may be appropriate.

All technical reports from the American Academy of Pediatrics automatically expire 5 years after publication unless reaffirmed, revised, or retired at or before that time.

www.pediatrics.org/cgi/doi/10.1542/peds.2012-3931

doi:10.1542/peds.2012-3931

PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).

Copyright © 2013 by the American Academy of Pediatrics

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that the use of specific drugs waxes and wanes over time nationwide as the popularity of certain substances changes.

Although a variety of prevalence studies have been conducted over the past 2 decades, there is 1 national survey that regularly provides in- formation on trends in substance abuse among pregnant women. The National Survey on Drug Use and Health (formerly called the National Household Survey on Drug Abuse), sponsored by the Substance Abuse and Mental Health Services Adminis- tration (http://www.oas.samhsa.gov/ nhsda.htm), is an annual survey pro- viding national and state level in- formation on the use of alcohol, tobacco, and illicit drugs in a sample of more than 67 000 noninstitu- tionalized people older than 12 years. Data are combined into 2-year epochs and include reported drug use for pregnant women between the ages of 15 and 44 years. Current illegal drug use among pregnant women re- mained relatively stable from 2007– 2008 (5.1%) to 2009–2010 (4.4%). These average prevalence rates are significantly lower than reported current illicit drug use rates for non- pregnant women (10.9%). Importantly, the rate of current drug use among the youngest and possibly the most vulnerable pregnant women was highest (16.2% for 15- to 17-year-olds, compared with 7.4% among 18- to 25- year-olds and 1.9% among 26- to 44- year-olds). Table 1 summarizes these data along with information regarding current alcohol use, binge drinking,

and cigarette use by pregnant and nonpregnant women. An additional important finding from this survey was that the rate of cigarette smoking for those 15 to 17 years of age actually was higher for pregnant women than for nonpregnant women (22.7% vs 13.4%, respectively). This report details many sociodemographic variables re- lated to drug use in the American population, and the reader is referred to the Substance Abuse and Mental Health Services Administration Web site for the full report (http://www.oas. samhsa.gov/nhsda.htm).

IDENTIFICATION OF PRENATAL EXPOSURE

Two basic methods are used to identify drug users: self-report or biological specimens. Although no single ap- proach can accurately determine the presence or amount of drug used during pregnancy, it is more likely that fetal exposure will be identified if a biological specimen is collected along with a structured interview.8

Self-reported history is an inexpensive and practical method for identifying prenatal drug exposure and is the only method available in which information can be obtained regarding the timing of the drug use during pregnancy and the amount used. Unfortunately, self- report suffers from problems with the veracity of the informant and recall accuracy.9,10 Histories obtained by trusted, nonjudgmental individuals or via computerized survey forms; ques- tions referring back to the previous trimester or prepregnancy usage, not current use; and pregnancy calendars used to assist recollection each im- prove the accuracy of the information obtained.11–13

Several biological specimens can be used to screen for drug exposure. Each specimen has its own individual var- iations with regard to the window of detection, the specific drug metabolites

used for identification, methods of adulteration of the sample, and ana- lytical techniques, thus altering the sensitivity and specificity for each drug of interest. The most common analyt- ical method used for screening bi- ological specimens is an immunoassay designed to screen out drug-free samples. Threshold values generally are set high to minimize false-positive test results but may be too high to detect low-dose or remote exposure. Because immunoassay is a relatively nonspecific test, positive results re- quire confirmation by using gas chromatography/mass spectrometry. In addition, confirmation of the presence of a drug is not always associated with drug abuse. Alternative explanations in- clude passive exposure to the drug, in- gestion of other products contaminated with the drug, or use of prescription medications that either contain the drug or are metabolized to the drug.14 Thus, careful patient histories remain essen- tial to the process of identification.

The 3 most commonly used specimens to establish drug exposure during the prenatal and perinatal period are urine, meconium, and hair; however, none is accepted as a “gold standard.” Urine has been the most frequently tested biological specimen because of its ease of collection. Urine testing identifies only recent drug use, be- cause threshold levels of drug metabolites generally can be detected in urine only for several days. A no- table exception to this is marijuana, the metabolites of which can be ex- creted for as long as 10 days in the urine of regular users15 or up to 30 days in chronic, heavy users. Urine is a good medium as well for the de- tection of nicotine, opiate, cocaine, and amphetamine exposure.16,17

Meconium is also easy to collect noninvasively. It is hypothesized that drugs accumulate in meconium through- out pregnancy, and thus, meconium is

TABLE 1 Comparison of Drug Use Among Women 15 to 44 Years of Age by Pregnancy Status: 2009–2010

Pregnant Women, %

Nonpregnant Women, %

Illicit drug use 4.4 10.9 Alcohol use 10.8 54.7 Binge drinking 3.7 24.6 Cigarette use 16.3 26.7

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http://www.oas.samhsa.gov/nhsda.htm

http://www.oas.samhsa.gov/nhsda.htm

http://www.oas.samhsa.gov/nhsda.htm

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thought to reflect exposure during the second and third trimester of preg- nancy when meconium forms. How- ever, use of meconium to determine the timing or extent of exposure during pregnancy is controversial18 because of a lack of studies regarding the effects of the timing and quantity of the post- partum specimen collection as well as the effects of urine or transitional stool contamination of the meconium samples.19 Meconium has been used for the detection of nicotine, alcohol, marijuana, opiate, cocaine, and am- phetamine exposure.16,20

Hair is easy to collect, although some people decline this sampling method because of cosmetic concerns and societal taboos. Drugs become trapped within the hair and, thus, can reflect drug use over a long period of time. Unfortunately, using hair to determine timing and quantity of exposure also is controversial. In addition, envi- ronmental contamination, natural hair colors and textures, cosmetic hair processing, and volume of the hair sample available all affect the rational interpretation of the results.21–24

Hair is useful for the detection of nic- otine, opiate, cocaine, and amphetamine exposure.16,25

Other biological specimens have been studied for use in the detection of in utero drug exposure but are not commonly used in the clinical setting. These include such specimens as cord blood, human milk, amniotic fluid, and umbilical cord tissue.8,19,26 In the case of umbilical cord tissue, drug class- specific immunoassays for amphet- amines, opiates, cocaine, and canna- binoids appear to be as reliable as meconium testing, with the additional benefit of availability of the tissue at the time of birth.27

Beginning in the early 1980s, states began to enact legislation in response to the increasingly popular use of “crack” cocaine in our society. Such

laws required the reporting of women who used drugs during pregnancy to the legal system through states’ child abuse statutes. In 2003, the Keeping Children and Families Safe Act (Public Law 108-36) was passed by Congress, requiring physicians to notify their state child protective services agency of any infant identified as affected by illegal substances at birth or experi- encing drug withdrawal. Currently, issues of whether to use biological specimens to screen for drug abuse; whether to screen the mother, her infant, or both; and which women and infants to screen are issues compli- cated by legal, ethical, social, and scientific concerns. Each of these concerns must be taken into account as obstetricians, neonatologists, and pediatricians work to develop proto- cols for identifying prenatal drug exposure. For example, there is no biological specimen that, when ob- tained randomly, identifies prenatal drug use with 100% accuracy; hence, a negative drug screening result does not ensure that the pregnancy was drug free. Targeted screening of high- risk women is problematic, because it can be biased toward women of racial or ethnic minorities and those who are economically disadvantaged or socially disenfranchised. Universal screening of pregnant women is im- practical and not cost-effective.28–30

Finally, testing of biological specimens when the maternal history is positive for drug use increases medical costs and does not necessarily provide in- formation that guides the medical care of the infant.31

MECHANISMS OF ACTION OF DRUGS ON THE FETUS

Drugs can affect the fetus in multi- ple ways. Early in gestation, during the embryonic stage, drugs can have significant teratogenic effects. How- ever, during the fetal period, after

major structural development is complete, drugs have more subtle effects, including abnormal growth and/or maturation, alterations in neurotransmitters and their recep- tors, and brain organization. These are considered to be the direct effects of drugs. However, drugs also can exert a pharmacologic effect on the mother and, thus, indirectly affect the fetus. For example, nicotine acts on nicotinic cholinergic receptors within the mes- olimbic pathway, and neuropathways activated by alcohol enhance inhibitory γ-aminobutyric acid (GABA) receptors and reduce glutamate receptor activ- ity. Drugs of abuse mimic naturally occurring neurotransmitters, such that marijuana acts as anandamides, opiates act as endorphins, and co- caine and stimulants act within the mesolimbic dopaminergic pathways to increase dopamine and serotonin within the synapses.32 Other indirect effects of drugs of abuse on the fetus include altered delivery of substrate to the fetus for nutritional purposes, either because of placental insuf- ficiency or altered maternal health behaviors attributable to the mother’s addiction. These altered behaviors, which include poor nutrition, decreased access/compliance with health care, increased exposure to violence, and increased risk of mental illness and infection, may place the fetus at risk.33

Nicotine concentrations are higher in the fetal compartment (placenta, am- niotic fluid, fetal serum) compared with maternal serum concentrations.34–36

Nicotine is only 1 of more than 4000 compounds to which the fetus is ex- posed through maternal smoking. Of these, ∼30 compounds have been as- sociated with adverse health out- comes. Although the exact mechanisms by which nicotine produces adverse fetal effects are unknown, it is likely that hypoxia, undernourishment of

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the fetus, and direct vasoconstrictor effects on the placental and umbilical vessels all play a role.37,38 Nicotine also has been shown to have significant deleterious effects on brain devel- opment, including alterations in brain metabolism and neurotransmitter sys- tems and abnormal brain devel- opment.39–43 Additional toxicity from compounds in smoke, such as cyanide and cadmium, contribute to toxicity.44–48

Ethanol easily crosses the placenta into the fetus, with a significant con- centration of the drug identified in the amniotic fluid as well as in maternal and fetal blood.49,50 A variety of mechanisms explaining the effects of alcohol on the fetus have been hy- pothesized. These include direct tera- togenic effects during the embryonic and fetal stage of development as well as toxic effects of alcohol on the pla- centa, altered prostaglandin and pro- tein synthesis, hormonal alterations, nutritional effects, altered neuro- transmitter levels in the brain, altered brain morphology and neuronal de- velopment, and hypoxia (thought to be attributable to decreased placental blood flow and alterations in vascular tone in the umbilical vessels).51–69

Although the main chemical compound in marijuana, δ-9-tetrahydrocannabinol (THC), crosses the placenta rapidly, its major metabolite, 11-nor-9-carboxy- THC, does not.70 Unlike other drugs, the placenta appears to limit fetal ex- posure to marijuana, as fetal THC concentrations have been docu- mented to be lower than maternal concentrations in studies of various animal species.15,70–72 The deleterious effects of marijuana on the fetus are thought to be attributable to complex pharmacologic actions on developing biological systems, altered uterine blood flow, and altered maternal health behaviors.73–75 Similar to other drugs, marijuana has been shown to alter brain neurotransmitters as well

as brain biochemistry, resulting in decreased protein, nucleic acid, and lipid synthesis.74,76–79 Marijuana can remain in the body for up to 30 days, thus prolonging fetal exposure. In addition, smoking marijuana pro- duces as much as 5 times the amount of carbon monoxide as does cigarette smoking, perhaps altering fetal oxy- genation.80

In humans, opiates rapidly cross the placenta, with drug equilibration be- tween the mother and the fetus.81

Opiates have been shown to decrease brain growth and cell development in animals, but studies of their effects on neurotransmitter levels and opi- oid receptors have produced mixed results.82–89

Pharmacologic studies of cocaine in animal models using a variety of species have demonstrated that co- caine easily crosses both the placenta and the blood-brain barrier and can have significant teratogenic effects on the developing fetus, directly and in- directly.90 Cocaine’s teratogenic effects most likely result from interference with the neurotrophic roles of mono- aminergic transmitters during brain development,91–94 which can signifi- cantly affect cortical neuronal devel- opment and may lead to morphologic abnormalities in several brain struc- tures, including the frontal cingulate cortex.94 It also appears that the development of areas of the brain that regulate attention and executive functioning are particularly vulnera- ble to cocaine. Thus, functions such as arousal, attention, and memory may be adversely affected by prenatal co- caine exposure.89,91,95–97 Furthermore, insults to the nervous system dur- ing neurogenesis, before homeostatic regulatory mechanisms are fully developed, differ from those on ma- ture systems. Thus, cocaine exposure occurring during development of the nervous system might be expected to

result in permanent changes in brain structure and function, which can produce altered responsiveness to environmental or pharmacologic chal- lenges later in life.98

Methamphetamine is a member of a group of sympathomimetic drugs that stimulate the central nervous system. It readily passes through the placenta and the blood-brain barrier and can have significant effects on the fetus.99–101 After a single dose of methamphetamine to pregnant mice, levels of substance in the fetal brain were found to be similar to those found in human infants after pre- natal methamphetamine exposure, with accumulation and distribution of the drug most likely dependent on the monoaminergic transport sys- tem. It is possible that the mecha- nism of action of methamphetamine is an interaction with and alteration of these neurotransmitter systems in the developing fetal brain100

as well as alterations in brain morphogenesis.102

MEDICAL ISSUES IN THE NEWBORN PERIOD

Fetal Growth

Fetal tobacco exposure has been a known risk factor for low birth weight and intrauterine growth restriction for more than 50 years,103 with de- creasing birth weight shown to be related to the number of cigarettes smoked.104–107 Importantly, by 24 months of age, most studies no longer dem- onstrate an effect of fetal tobacco ex- posure on somatic growth parameters of prenatally exposed infants.108-114

Growth restriction is 1 of the hall- marks of prenatal alcohol exposure and must be present to establish a di- agnosis of fetal alcohol syndrome.3,115

However, even moderate amounts of alcohol use during pregnancy is asso- ciated with a decrease in size at birth.116–119 In general, marijuana has

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not been associated with fetal growth restriction, particularly after control- ling for other prenatal drug expo- sures.109,120-122 Fetal growth effects are reported in studies of prenatal opiate exposure; however, confounding vari- ables known to be associated with poor growth, such as multiple drug use and low socioeconomic status, were not well controlled in many of the studies.123 Using data from the Mater- nal Lifestyle Study, Bada et al124

reported lower birth weight in opiate- exposed newborn infants born at ≥33 weeks’ gestation, independent of use of other drugs, prenatal care, or other medical risk factors. An in- dependent effect of prenatal cocaine exposure on intrauterine growth has been the most consistent finding across studies of prenatally exposed infants.122,125-130 Early studies on pre- natal methamphetamine exposure131 as well as recent studies132 reveal in- dependent effects of the drug on fetal growth. However, the literature avail- able is limited at this time. Several reviews on the effects of prenatal drug exposure on growth contain additional details.133–135

Congenital Anomalies

Nicotine has been associated with oral facial clefts in exposed newborn infants,136–140 although the data are relatively weak. There is a vast liter- ature on the teratogenic effects of prenatal alcohol exposure after the first description of fetal alcohol syn- drome in 1973.3 The American Acad- emy of Pediatrics (AAP) policy statement “Fetal Alcohol Syndrome and Alcohol-Related Neurodevelopmental Disorders” contains more informa- tion.141 No clear teratogenic effect of marijuana or opiates is documented in exposed newborn infants.142 Origi- nal reports regarding cocaine terato- genicity have not been further documented.133,143 Studies of fetal meth- amphetamine exposure in humans are

limited. However, Little et al131 reported no increase in the frequency of major anomalies in a small sample of exposed infants when compared with non- exposed infants.

Withdrawal

No convincing studies are available that document a neonatal withdrawal syndrome for prenatal nicotine expo- sure. Although several authors de- scribe abnormal newborn behavior of exposed infants immediately after delivery, the findings are more con- sistent with drug toxicity, which steadily improves over time,144,145 as opposed to an abstinence syndrome, in which clinical signs would escalate over time as the drug is metabolized and eliminated from the body. There is 1 report of withdrawal from prenatal alcohol exposure in infants with fetal alcohol syndrome born to mothers who drank heavily during preg- nancy,146 but withdrawal symptoms have not been reported in longitudinal studies available in the extant litera- ture. Neonatal abstinence symptoms have not been observed in marijuana- exposed infants, although abnormal newborn behavior has been reported with some similarities to that associ- ated with narcotic exposure.147 An opiate withdrawal syndrome was first described by Finnegan et al148 in 1975. Neonatal abstinence syndrome includes a combination of physiologic and neurobehavioral signs that in- clude such things as sweating, irrita- bility, increased muscle tone and activity, feeding problems, diarrhea, and seizures. Infants with neonatal abstinence syndrome often require prolonged hospitalization and treat- ment with medication. Methadone ex- posure has been associated with more severe withdrawal than has ex- posure to heroin.149 Early reports re- garding buprenorphine, a more recent alternative to methadone, suggest min- imal to mild withdrawal in exposed

neonates. A large multicenter trial evaluating buprenorphine’s effect on exposed infants documented de- creased morphine dose, hospital length of stay, and length of treat- ment.150–152 There has been no sub- stantiation of early reports regarding cocaine withdrawal.153 Currently, no prospective studies of withdrawal in methamphetamine-exposed infants are available. A retrospective study by Smith et al154 reported with- drawal symptoms in 49% of their sample of 294 methamphetamine- exposed newborn infants. However, only 4% required pharmacologic in- tervention. The AAP clinical report on neonatal drug withdrawal contains in-depth information on neonatal drug withdrawal, including treatment options.155

Neurobehavior

Abnormalities of newborn neuro- behavior, including impaired orienta- tion and autonomic regulation156 and abnormalities of muscle tone,144,147,157

have been identified in a number of prenatal nicotine exposure studies. Poor habituation and low levels of arousal along with motor abnormali- ties have been identified in women who drank alcohol heavily during their pregnancy.80,158 Prenatal mari- juana exposure is associated with in- creased startles and tremors in the newborn.120 Abnormal neurobehavior in opiate-exposed newborn infants is related to neonatal abstinence (see earlier section on Withdrawal). Using the Brazelton Newborn Behavioral As- sessment Scale,159 reported effects of prenatal cocaine exposure on infants have included irritability and lability of state, decreased behavioral and au- tonomic regulation, and poor alertness and orientation.160 Recent data from the Infant Development, Environment, and Lifestyle multicenter study on the effects of prenatal methamphet- amine exposure documented abnormal

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neurobehavioral patterns in exposed newborn infants consisting of poor movement quality, decreased arousal, and increased stress.161